Abstract
stringlengths 324
3.48k
| processed_image
stringlengths 46
19.6k
|
|---|---|
Gustatory receptors (GRs) are critical for insect chemosensation and are potential targets for controlling pests and disease vectors, making their structural investigation a vital step toward such applications. We present structures of Bombyx mori Gr9 (BmGr9), a fructose-gated cation channel, in agonist-free and fructose-bound states. BmGr9 forms a tetramer similar to distantly related insect odorant receptors (ORs). Upon fructose binding, BmGr9’s channel gate opens through helix S7b movements. In contrast to ORs, BmGr9’s ligand-binding pocket, shaped by a kinked helix S4 and a shorter extracellular S3-S4 loop, is larger and solvent accessible in both agonist-free and fructose-bound states. Also, unlike ORs, fructose binding by BmGr9 involves helix S5 and a pocket lined with aromatic and polar residues. Structure-based sequence alignments reveal distinct patterns of ligand-binding pocket residue conservation in GR subfamilies associated with different ligand classes. These data provide insight into the molecular basis of GR ligand specificity and function.
Keywords: gustation; chemosensation; chemoreceptor; ligand-gated ion channel; taste; seven-transmembrane ion channel; 7TMIC; cryoelectron microscopy | [{'text': 'Bombyx mori Gr9', 'coordinates': [133, 5, 381, 43]}, {'text': 'Ligand-binding pocket', 'coordinates': [599, 2, 916, 43]}, {'text': 'polar', 'coordinates': [582, 437, 667, 480]}, {'text': 'aliphatic', 'coordinates': [690, 434, 819, 482]}, {'text': 'oaromatic', 'coordinates': [827, 439, 975, 475]}, {'text': 'Pore opening', 'coordinates': [133, 509, 325, 549]}, {'text': 'BmGr9 subfamily " fructose', 'coordinates': [633, 529, 829, 582]}, {'text': 'Gr63a subfamily CO_', 'coordinates': [788, 572, 972, 624]}, {'text': 'OR family odorants', 'coordinates': [844, 671, 956, 722]}, {'text': 'GrSa subfamily sugars Insect gustatory receptor superfamily', 'coordinates': [725, 814, 987, 991]}] |
Thalamocortical loops have a central role in cognition and motor control, but precisely how they contribute to these processes is unclear. Recent studies showing evidence of plasticity in thalamocortical synapses indicate a role for the thalamus in shaping cortical dynamics through learning. Since signals undergo a compression from the cortex to the thalamus, we hypothesized that the computational role of the thalamus depends critically on the structure of corticothalamic connectivity. To test this, we identified the optimal corticothalamic structure that promotes biologically plausible learning in thalamocortical synapses. We found that corticothalamic projections specialized to communicate an efference copy of the cortical output benefit motor control, while communicating the modes of highest variance is optimal for working memory tasks. We analyzed neural recordings from mice performing grasping and delayed discrimination tasks and found corticothalamic communication consistent with these predictions. These results suggest that the thalamus orchestrates cortical dynamics in a functionally precise manner through structured connectivity.
Keywords: thalamocortical loop; corticothalamic feedback; thalamus; biologically plausible learning; recurrent neural network; meta-learning; random feedback; motor learning; working memory | [{'text': 'Stimulus', 'coordinates': [404, 2, 526, 34]}, {'text': 'error', 'coordinates': [140, 184, 208, 210]}, {'text': 'Behavior', 'coordinates': [740, 200, 866, 232]}, {'text': 'pre lpost|', 'coordinates': [115, 257, 251, 298]}, {'text': 'Cortex', 'coordinates': [422, 324, 518, 356]}, {'text': 'Local plasticity', 'coordinates': [71, 357, 273, 395]}, {'text': 'Optimized by meta-learning', 'coordinates': [563, 437, 751, 511]}, {'text': 'Thalamus', 'coordinates': [398, 497, 539, 537]}, {'text': 'optimized subspace is task-dependent', 'coordinates': [80, 586, 353, 663]}, {'text': 'neuron 2', 'coordinates': [408, 604, 530, 636]}, {'text': 'behavioral readout', 'coordinates': [538, 633, 687, 696]}, {'text': 'principal component', 'coordinates': [156, 771, 317, 843]}, {'text': 'neuron', 'coordinates': [586, 784, 686, 814]}, {'text': 'neuron 3', 'coordinates': [200, 946, 324, 978]}] |
Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome hyperactivation contributes to many human chronic inflammatory diseases, and understanding how NLRP3 inflammasome is regulated can provide strategies to treat inflammatory diseases. Here, we demonstrate that NLRP3 Cys126 is palmitoylated by zinc finger DHHC-type palmitoyl transferase 7 (ZDHHC7), which is critical for NLRP3-mediated inflammasome activation. Perturbing NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation diminishes NLRP3 activation in macrophages. Furthermore, Cys126 palmitoylation is vital for inflammasome activation in vivo. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on the trans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN, which is indispensable for recruitment and oligomerization of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD). The activation of NLRP3 by ZDHHC7 is different from the termination effect mediated by ZDHHC12, highlighting versatile regulatory roles of S-palmitoylation. Our study identifies an important regulatory mechanism of NLRP3 activation that suggests targeting ZDHHC7 or the NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders.
Keywords: NLRP3; palmitoylation; ZDHHC7; trans-Golgi network localization; inflammasome; endotoxic shock; peritonitis | [{'text': 'Priming', 'coordinates': [34, 43, 157, 92]}, {'text': '126 KKKK PI4P 1', 'coordinates': [761, 85, 867, 187]}, {'text': 'trans-Golgi network localization', 'coordinates': [516, 192, 720, 242]}, {'text': 'Palmitoyl CoA ZDHHC7', 'coordinates': [194, 206, 340, 292]}, {'text': '126 1 KKKK', 'coordinates': [405, 179, 500, 257]}, {'text': '126 1 KKKK', 'coordinates': [73, 219, 167, 297]}, {'text': 'trans-Golgi', 'coordinates': [648, 306, 766, 334]}, {'text': '2-BP', 'coordinates': [200, 346, 256, 370]}, {'text': 'MY-D4', 'coordinates': [270, 344, 342, 370]}, {'text': 'NLRP3', 'coordinates': [70, 382, 152, 410]}, {'text': 'Palmitoylated NLRP3', 'coordinates': [364, 382, 524, 438]}, {'text': 'Palmitoylated NLRP3 localizes on TGN', 'coordinates': [736, 396, 976, 452]}, {'text': 'Activation', 'coordinates': [39, 541, 187, 577]}, {'text': 'Nigericin', 'coordinates': [246, 574, 342, 602]}, {'text': 'ATP', 'coordinates': [356, 574, 402, 598]}, {'text': 'Recruit ASC to form inflammasome', 'coordinates': [700, 564, 924, 621]}, {'text': 'Dispersed TGN NLRP3 transported to MTOC', 'coordinates': [450, 701, 672, 810]}, {'text': 'NLRP3 Aggregation on TGN', 'coordinates': [158, 894, 380, 950]}, {'text': 'Palmitoylation stabilizes NLRP3 on dispersed TGN', 'coordinates': [444, 880, 670, 964]}, {'text': 'Inflammation', 'coordinates': [736, 940, 888, 966]}, {'text': '', 'coordinates': [747, 211, 797, 248]}] |
Nitric oxide (NO) is a gasotransmitter required in a broad range of mechanisms controlling plant development and stress conditions. However, little is known about the specific role of this signaling molecule during lipid storage in the seeds. Here, we show that NO is accumulated in developing embryos and regulates the fatty acid profile through the stabilization of the basic/leucine zipper transcription factor bZIP67. NO and nitro-linolenic acid target and accumulate bZIP67 to induce the downstream expression of FAD3 desaturase, which is misregulated in a non-nitrosylable version of the protein. Moreover, the post-translational modification of bZIP67 is reversible by the trans-denitrosylation activity of peroxiredoxin IIE and defines a feedback mechanism for bZIP67 redox regulation. These findings provide a molecular framework to control the seed fatty acid profile caused by NO, and evidence of the in vivo functionality of nitro-fatty acids during plant developmental signaling.
Keywords: alkenal reductase; bZIP; fatty acid; gasotransmitter; nitric oxide; post-translational modification; redoxin; seed; transcription factor | [{'text': 'NITRATION', 'coordinates': [443, 21, 657, 65]}, {'text': 'ONOO', 'coordinates': [305, 57, 431, 99]}, {'text': 'NOz-Linolenic acid', 'coordinates': [713, 52, 974, 147]}, {'text': 'PRX', 'coordinates': [203, 227, 289, 269]}, {'text': 'PRX', 'coordinates': [445, 227, 531, 271]}, {'text': 'SNO', 'coordinates': [157, 319, 247, 361]}, {'text': 'SH', 'coordinates': [283, 319, 343, 361]}, {'text': 'SH', 'coordinates': [399, 319, 461, 361]}, {'text': 'SH', 'coordinates': [525, 319, 587, 359]}, {'text': 'bZIP67', 'coordinates': [25, 389, 209, 449]}, {'text': 'bZIP67', 'coordinates': [587, 389, 769, 449]}, {'text': 'AER', 'coordinates': [889, 393, 971, 435]}, {'text': 'SH', 'coordinates': [1, 483, 63, 525]}, {'text': 'SH', 'coordinates': [79, 481, 141, 525]}, {'text': 'SH', 'coordinates': [179, 481, 241, 525]}, {'text': 'NO', 'coordinates': [330, 494, 414, 548]}, {'text': 'SNO', 'coordinates': [553, 485, 643, 527]}, {'text': 'SNOSNO', 'coordinates': [659, 485, 835, 527]}, {'text': 'DESTABILIZATION', 'coordinates': [1, 567, 347, 611]}, {'text': 'STABILIZATION', 'coordinates': [536, 570, 832, 612]}, {'text': '258C', 'coordinates': [13, 642, 116, 692]}, {'text': '158€', 'coordinates': [607, 647, 705, 691]}, {'text': 'Linolenic acid (18.3)', 'coordinates': [735, 656, 996, 760]}, {'text': 'Linoleic acid (18.2)', 'coordinates': [742, 864, 983, 966]}, {'text': 'FAD3', 'coordinates': [553, 895, 657, 939]}, {'text': '3', 'coordinates': [262, 720, 250, 927]}, {'text': '3', 'coordinates': [304, 743, 403, 919]}] |
Embryogenesis requires substantial coordination to translate genetic programs to the collective behavior of differentiating cells, but understanding how cellular decisions control tissue morphology remains conceptually and technically challenging. Here, we combine continuous Cas9-based molecular recording with a mouse embryonic stem cell-based model of the embryonic trunk to build single-cell phylogenies that describe the behavior of transient, multipotent neuro-mesodermal progenitors (NMPs) as they commit into neural and somitic cell types. We find that NMPs show subtle transcriptional signatures related to their recent differentiation and contribute to downstream lineages through a surprisingly broad distribution of individual fate outcomes. Although decision-making can be heavily influenced by environmental cues to induce morphological phenotypes, axial progenitors intrinsically mature over developmental time to favor the neural lineage. Using these data, we present an experimental and analytical framework for exploring the non-homeostatic dynamics of transient progenitor populations as they shape complex tissues during critical developmental windows.
Keywords: lineage tracing; single-cell phylogenies; molecular recording; embryonic development; morphogenesis; stem cell embryoids; neuro-mesodermal progenitor dynamics; cell plasticity | [{'text': 'Molecular recording', 'coordinates': [37, 23, 301, 61]}, {'text': 'Lineage Tracing in Trunk-like Structures', 'coordinates': [326, 18, 673, 108]}, {'text': 'Embryoids mESCs', 'coordinates': [759, 23, 905, 116]}, {'text': 'Casg', 'coordinates': [56, 84, 114, 110]}, {'text': 'Lineage barcode', 'coordinates': [81, 135, 252, 164]}, {'text': 'Somitic', 'coordinates': [426, 200, 506, 224]}, {'text': 'Aggregation', 'coordinates': [823, 199, 954, 232]}, {'text': 'NMPs', 'coordinates': [364, 236, 428, 262]}, {'text': 'ECM embedding', 'coordinates': [694, 273, 815, 325]}, {'text': 'mESCs: mouse embryonic stem cells ECM: extracellular matrix neuromesodermal progenitors_', 'coordinates': [779, 349, 985, 393]}, {'text': 'NMPs_ Progenitor fate choice', 'coordinates': [691, 375, 959, 435]}, {'text': 'Cellular phylogenies', 'coordinates': [49, 399, 301, 437]}, {'text': 'State-to-fate analysis NMPs', 'coordinates': [367, 398, 629, 480]}, {'text': 'Self-renewal', 'coordinates': [863, 457, 978, 485]}, {'text': 'Progenitor', 'coordinates': [698, 470, 804, 498]}, {'text': 'Neural bias', 'coordinates': [354, 522, 424, 566]}, {'text': 'Somitic bias', 'coordinates': [566, 520, 644, 566]}, {'text': 'Neural', 'coordinates': [670, 580, 742, 606]}, {'text': 'Bipotent Progeny', 'coordinates': [775, 578, 862, 656]}, {'text': 'Somitic', 'coordinates': [898, 580, 976, 604]}, {'text': 'Genes', 'coordinates': [463, 617, 529, 637]}, {'text': 'Control by signaling', 'coordinates': [132, 670, 378, 708]}, {'text': 'Maturation over time', 'coordinates': [618, 672, 868, 704]}, {'text': 'tWNT !BMP', 'coordinates': [31, 739, 143, 759]}, {'text': 'Multi-generation lineage tracing', 'coordinates': [724, 728, 962, 780]}, {'text': 'Explant', 'coordinates': [510, 744, 590, 772]}, {'text': 'Bipotentiality', 'coordinates': [699, 876, 803, 900]}, {'text': 'Time', 'coordinates': [933, 895, 975, 915]}, {'text': 'Altered morphology', 'coordinates': [25, 923, 223, 959]}, {'text': 'Altered fate choice', 'coordinates': [276, 928, 462, 954]}, {'text': 'Outgrowth', 'coordinates': [524, 938, 632, 966]}, {'text': '"RfiVeural', 'coordinates': [539, 122, 628, 195]}] |
Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.
Keywords: DHX15; G-patch domain; GPATCH8; leukemia; myelodysplastic syndromes; RNA; SF3B1; splicing; SUGP1 | [{'text': 'Synthetic intron reporter unveils major trans factor required for mutant SF3B1 aberrant RNA splicing activity SF3B1-WT mEm erald', 'coordinates': [8, 0, 914, 87]}, {'text': 'GPATCH8', 'coordinates': [813, 59, 875, 75]}, {'text': 'positive enrichment for genePRhoseeoss corrects SF3B1 mutation-dependent mis-splicing', 'coordinates': [590, 81, 712, 169]}, {'text': 'hPGK', 'coordinates': [21, 109, 57, 123]}, {'text': 'mCardinal 97a mEm MAP3K7 erald Intron', 'coordinates': [85, 101, 363, 129]}, {'text': '1 1 Je', 'coordinates': [740, 67, 770, 186]}, {'text': 'SF3B1-mutant', 'coordinates': [359, 159, 439, 173]}, {'text': 'Mem erald', 'coordinates': [455, 153, 547, 165]}, {'text': 'Genes required for wild-type splicing', 'coordinates': [775, 197, 965, 211]}, {'text': 'GPATCH8 deletion corrects mutant SF3B1 splicing_defects by releasing_DHX15 to interact with SUGP1', 'coordinates': [14, 234, 862, 260]}, {'text': 'Mutant SF3B1 GPATCH8 DHX1S', 'coordinates': [207, 283, 398, 378]}, {'text': 'Mutant SF3B1 plus GPATCH8 deletion GPATCHB', 'coordinates': [630, 280, 948, 348]}, {'text': 'DHXIS SUGP1E', 'coordinates': [357, 396, 476, 425]}, {'text': 'Mutant SF3B1', 'coordinates': [709, 405, 767, 443]}, {'text': 'Mutant SF3B1', 'coordinates': [219, 412, 277, 449]}, {'text': 'DHX15 Exon SUGP1', 'coordinates': [806, 415, 893, 517]}, {'text': 'Failure to recognize correct branchpoint', 'coordinates': [18, 511, 115, 586]}, {'text': 'Exon', 'coordinates': [359, 503, 401, 521]}, {'text': 'Correction of SF3B1 mutant mis-splicing', 'coordinates': [523, 507, 617, 583]}, {'text': 'Exon', 'coordinates': [123, 617, 171, 637]}, {'text': 'Exon', 'coordinates': [209, 617, 255, 637]}, {'text': 'Exon', 'coordinates': [705, 615, 753, 635]}, {'text': 'Exon', 'coordinates': [779, 615, 825, 635]}, {'text': 'GPATCH8 deletion restores dysfunctional hematopoiesis in SF3B1-mutant MDS', 'coordinates': [14, 676, 678, 702]}, {'text': 'HSC', 'coordinates': [695, 745, 723, 759]}, {'text': 'HSC', 'coordinates': [253, 753, 283, 765]}, {'text': 'GPATCH8 deletion', 'coordinates': [744, 754, 902, 778]}] |
Although oligodendrocytes (OLs) synthesize laminin-γ1, the most widely used γ subunit, its functional significance in the CNS remains unknown. To answer this important question, we generated a conditional knockout mouse line with laminin-γ1 deficiency in OL lineage cells (γ1-OKO). γ1-OKO mice exhibit weakness/paralysis and die by post-natal day 33. Additionally, they develop blood-brain barrier (BBB) disruption in the cortex and striatum. Subsequent studies reveal decreased major facilitator superfamily domain containing 2a expression and increased endothelial caveolae vesicles, but unaltered tight junction protein expression and tight junction ultrastructure, indicating a transcellular, rather than a paracellular, mechanism of BBB breakdown. Furthermore, significantly reduced OL lineage cells, OL precursor cells (OPCs), proliferating OPCs, and mature OLs are observed in γ1-OKO brains in a region-specific manner. Consistent with this finding, various defects in myelination are detected in γ1-OKO brains at biochemical and ultrastructural levels. Overall, these results highlight important roles of OL-derived laminin-γ1 in BBB maintenance and OL biology (proliferation, differentiation, and myelination).
Keywords: laminin; oligodendrocyte; blood-brain barrier; myelination | [{'text': 'BBB integrity', 'coordinates': [586, 36, 879, 99]}, {'text': 'Oligodendrocyte- derived laminin-V1', 'coordinates': [62, 380, 404, 480]}, {'text': 'Proliferation', 'coordinates': [67, 653, 305, 701]}, {'text': 'Myelination', 'coordinates': [708, 654, 932, 708]}, {'text': 'Differentiation', 'coordinates': [252, 736, 526, 784]}] |
The preoptic area of the hypothalamus (POA) is essential for sleep regulation. However, the cellular makeup of the POA is heterogeneous, and the molecular identities of the sleep-promoting cells remain elusive. To address this question, this study compares mice during recovery sleep following sleep deprivation to mice allowed extended sleep. Single-nucleus RNA sequencing (single-nucleus RNA-seq) identifies one galanin inhibitory neuronal subtype that shows upregulation of rapid and delayed activity-regulated genes during recovery sleep. This cell type expresses higher levels of growth hormone receptor and lower levels of estrogen receptor compared to other galanin subtypes. single-nucleus RNA-seq also reveals cell-type-specific upregulation of purinergic receptor (P2ry14) and serotonin receptor (Htr2a) during recovery sleep in this neuronal subtype, suggesting possible mechanisms for sleep regulation. Studies with RNAscope validate the single-nucleus RNA-seq findings. Thus, the combined use of single-nucleus RNA-seq and activity-regulated genes identifies a neuronal subtype functionally involved in sleep regulation.
Keywords: sleep homeostasis; sleep deprivation; sleep pressure; preoptic area of hypothalamus; single-nucleus RNA sequencing; activity-regulated genes | [{'text': 'RS: recovery sleep High sleep pressure', 'coordinates': [119, 19, 405, 95]}, {'text': 'SD', 'coordinates': [176, 134, 226, 166]}, {'text': '2 200 2', 'coordinates': [30, 144, 103, 284]}, {'text': 'POA', 'coordinates': [818, 206, 884, 238]}, {'text': '3 100', 'coordinates': [30, 284, 103, 363]}, {'text': 'single-nucleus RNA-seq', 'coordinates': [611, 377, 849, 459]}, {'text': 'SS: extended sleep Low sleep pressure', 'coordinates': [123, 401, 403, 475]}, {'text': 'Gal clusters', 'coordinates': [129, 515, 323, 553]}, {'text': 'i14.GallGhr', 'coordinates': [669, 515, 855, 551]}, {'text': '15', 'coordinates': [534, 562, 568, 592]}, {'text': 'rapid-PRG delayed-PRG', 'coordinates': [598, 571, 765, 644]}, {'text': 'Nr4a3', 'coordinates': [864, 590, 926, 616]}, {'text': '10 1 5', 'coordinates': [502, 665, 568, 794]}, {'text': "Nr4a1 Epos Npas4 Hcrtr2 Fosi2 Fosb Pcsk Dusp4 'usp1", 'coordinates': [722, 705, 944, 854]}, {'text': 'log2FC (RS vs: SS)', 'coordinates': [660, 934, 862, 964]}, {'text': 'VLPO', 'coordinates': [194, 946, 279, 982]}] |
Interferon (IFN) contributes to the host’s antiviral response by inducing IFN-stimulated genes (ISGs). However, their functional targets and the mechanism of action remain elusive. Here, we report that one such ISG, TRIM21, interacts with and degrades the TRPV2 channel in myeloid cells, reducing its expression and providing host protection against viral infections. Moreover, viral infection upregulates TRIM21 in paracrine and autocrine manners, downregulating TRPV2 in neighboring cells to prevent viral spread to uninfected cells. Consistently, the Trim21−/− mice are more susceptible to HSV-1 and VSV infection than the Trim21+/+ littermates, in which viral susceptibility is rescued by inhibition or deletion of TRPV2. Mechanistically, TRIM21 catalyzes the K48-linked ubiquitination of TRPV2 at Lys295. TRPV2K295R is resistant to viral-infection-induced TRIM21-dependent ubiquitination and degradation, promoting viral infection more profoundly than wild-type TRPV2 when reconstituted into Lyz2-Cre;Trpv2fl/fl myeloid cells. These findings characterize targeting the TRIM21-TRPV2 axis as a conducive strategy to control viral spread to bystander cells.
Keywords: TRPV2; TRIM21; interferon-stimulated gene; ubiquitination; viral penetration; plasma membrane tension; Ca2+ signal | [{'text': 'JAKI IFNAR TYk2 STAT1 STAT2 Trim21 UAYOA', 'coordinates': [675, 307, 788, 520]}, {'text': 'TRPV2', 'coordinates': [97, 343, 139, 357]}, {'text': 'IFNs', 'coordinates': [413, 349, 443, 361]}, {'text': 'TRPV2', 'coordinates': [929, 411, 971, 425]}, {'text': 'TRIM2I', 'coordinates': [71, 425, 115, 439]}, {'text': 'Ubub', 'coordinates': [153, 443, 187, 463]}, {'text': 'TRIN2I', 'coordinates': [835, 445, 879, 459]}, {'text': 'IFNAR', 'coordinates': [417, 455, 457, 469]}, {'text': 'Ifnap UXO Trim21', 'coordinates': [228, 513, 322, 583]}, {'text': 'HSV-1 VSV TRPV2 IFNs TRIM21 Proteasome degradation', 'coordinates': [449, 555, 581, 705]}, {'text': 'Infected cells', 'coordinates': [179, 699, 257, 713]}, {'text': 'Bystander cells', 'coordinates': [703, 699, 793, 713]}] |
Mouse embryonic stem cells (mESCs) in the primed pluripotency state, which resembles the post-implantation epiblast, can be de-differentiated in culture to a naive state that resembles the pre-implantation inner cell mass. We report that primed-to-naive mESC transition entails a significant slowdown of DNA replication forks and the compensatory activation of dormant origins. Using isolation of proteins on nascent DNA coupled to mass spectrometry, we identify key changes in replisome composition that are responsible for these effects. Naive mESC forks are enriched in MRE11 nuclease and other DNA repair proteins. MRE11 is recruited to newly synthesized DNA in response to transcription-replication conflicts, and its inhibition or genetic downregulation in naive mESCs is sufficient to restore the fork rate of primed cells. Transcriptomic analyses indicate that MRE11 exonuclease activity is required for the complete primed-to-naive mESC transition, demonstrating a direct link between DNA replication dynamics and the mESC de-differentiation process.
Keywords: DNA replication; iPOND; MRE11; primed-to-naive transition; replisome; pluripotency | [{'text': 'PRIMED-TO-NAIVE TRANSITION', 'coordinates': [189, 13, 806, 57]}, {'text': 'naive mESCs', 'coordinates': [57, 97, 197, 185]}, {'text': 'MREI1', 'coordinates': [245, 179, 385, 221]}, {'text': 'SLOW FORKS', 'coordinates': [503, 203, 763, 247]}, {'text': '2i', 'coordinates': [439, 317, 479, 357]}, {'text': 'primed mESCs', 'coordinates': [53, 408, 198, 507]}, {'text': 'Y', 'coordinates': [262, 446, 292, 472]}, {'text': 'FAST FORKS', 'coordinates': [505, 527, 747, 571]}, {'text': '2i + MREITi', 'coordinates': [251, 625, 481, 669]}, {'text': 'sxS', 'coordinates': [262, 776, 348, 802]}, {'text': 'OF', 'coordinates': [387, 775, 483, 815]}, {'text': '4K', 'coordinates': [521, 775, 617, 815]}, {'text': 'NOXX', 'coordinates': [652, 784, 740, 810]}, {'text': 'FAST FORKS', 'coordinates': [505, 859, 747, 903]}, {'text': 'INCOMPLETE PRIMED-TO-NAIVE TRANSITION', 'coordinates': [55, 935, 941, 979]}] |
Proteotoxic stress drives numerous degenerative diseases. Cells initially adapt to misfolded proteins by activating the unfolded protein response (UPR), including endoplasmic-reticulum-associated protein degradation (ERAD). However, persistent stress triggers apoptosis. Enhancing ERAD is a promising therapeutic approach for protein misfolding diseases. The ER-localized Zn2+ transporter ZIP7 is conserved from plants to humans and required for intestinal self-renewal, Notch signaling, cell motility, and survival. However, a unifying mechanism underlying these diverse phenotypes was unknown. In studying Drosophila border cell migration, we discovered that ZIP7-mediated Zn2+ transport enhances the obligatory deubiquitination of proteins by the Rpn11 Zn2+ metalloproteinase in the proteasome lid. In human cells, ZIP7 and Zn2+ are limiting for deubiquitination. In a Drosophila model of neurodegeneration caused by misfolded rhodopsin (Rh1), ZIP7 overexpression degrades misfolded Rh1 and rescues photoreceptor viability and fly vision. Thus, ZIP7-mediated Zn2+ transport is a previously unknown, rate-limiting step for ERAD in vivo with therapeutic potential in protein misfolding diseases.
Keywords: border cell migration; Drosophila; ERAD; ER stress; zinc transport; proteasome; integrated stress response; apoptosis; neurodegeneration; retinitis pigmentosa | [{'text': 'ZIP7 and Zn2t promote ERAD', 'coordinates': [54, 14, 330, 124]}, {'text': 'ZIP7 mitigates ER stress', 'coordinates': [455, 13, 903, 73]}, {'text': 'endoplasmic reticulum (ER)', 'coordinates': [117, 126, 368, 220]}, {'text': 'without ZIP7 TER Stress', 'coordinates': [415, 116, 636, 219]}, {'text': 'with ZIP7 LER Stress', 'coordinates': [710, 116, 910, 224]}, {'text': 'misfolded protein', 'coordinates': [30, 218, 196, 318]}, {'text': 'ZIP7 Zn" luFRn', 'coordinates': [214, 218, 368, 334]}, {'text': "'Zn2t", 'coordinates': [757, 329, 841, 369]}, {'text': 'Ub', 'coordinates': [37, 403, 93, 445]}, {'text': 'cytosol', 'coordinates': [271, 403, 367, 441]}, {'text': 'nucleus', 'coordinates': [437, 409, 561, 447]}, {'text': 'nucleus', 'coordinates': [727, 409, 851, 447]}, {'text': 'proteasome| ZIP7 prevents neurodegeneration', 'coordinates': [157, 439, 981, 529]}, {'text': 'blind fly', 'coordinates': [460, 546, 598, 600]}, {'text': 'vision restored Rh1G69D+ZIP7', 'coordinates': [678, 549, 943, 655]}, {'text': 'Rh1 G69D', 'coordinates': [390, 606, 526, 654]}, {'text': 'Rpn11 Zn2+', 'coordinates': [232, 656, 348, 751]}, {'text': 'ER (endoplasmic reticulum) ERAD (ER-associated degradation)_Ub (ubiquitin)', 'coordinates': [71, 941, 909, 981]}] |
Assembly of TopBP1 biomolecular condensates triggers activation of the ataxia telangiectasia-mutated and Rad3-related (ATR)/Chk1 signaling pathway, which coordinates cell responses to impaired DNA replication. Here, we used optogenetics and reverse genetics to investigate the role of sequence-specific motifs in the formation and functions of TopBP1 condensates. We propose that BACH1/FANCJ is involved in the partitioning of BRCA1 within TopBP1 compartments. We show that Chk1 is activated at the interface of TopBP1 condensates and provide evidence that these structures arise at sites of DNA damage and in primary human fibroblasts. Chk1 phosphorylation depends on the integrity of a conserved arginine motif within TopBP1’s ATR activation domain (AAD). Its mutation uncouples Chk1 activation from TopBP1 condensation, revealing that optogenetically induced Chk1 phosphorylation triggers cell cycle checkpoints and slows down replication forks in the absence of DNA damage. Together with previous work, these data suggest that the intrinsically disordered AAD encodes distinct molecular steps in the ATR/Chk1 pathway.
Keywords: DNA damage response; biomolecular condensates; ATR/Chk1 signaling pathway; DNA replication stress; optogenetics | [{'text': 'Optogenetics (DNA damage-free) DNA damage NN', 'coordinates': [16, 14, 248, 126]}, {'text': 'TopBP1 biomolecular condensates', 'coordinates': [582, 14, 982, 46]}, {'text': 'Clients', 'coordinates': [880, 78, 970, 108]}, {'text': 'N STOP', 'coordinates': [259, 87, 325, 167]}, {'text': 'FANCJ', 'coordinates': [494, 108, 568, 132]}, {'text': 'BRCAT', 'coordinates': [404, 140, 476, 164]}, {'text': 'ATR', 'coordinates': [584, 156, 636, 186]}, {'text': 'Replication stress', 'coordinates': [42, 178, 226, 206]}, {'text': 'TopBPTL', 'coordinates': [510, 214, 598, 246]}, {'text': 'TopBPI 2 1', 'coordinates': [361, 249, 493, 359]}, {'text': 'Chk1', 'coordinates': [911, 267, 987, 303]}, {'text': 'Chk1', 'coordinates': [108, 342, 182, 374]}, {'text': 'ATR', 'coordinates': [508, 346, 574, 378]}, {'text': '1', 'coordinates': [272, 364, 296, 462]}, {'text': '1', 'coordinates': [414, 352, 438, 424]}, {'text': 'Interfacial phosphorylation', 'coordinates': [25, 486, 229, 553]}, {'text': '+ ATR', 'coordinates': [309, 496, 377, 561]}, {'text': 'A A D', 'coordinates': [382, 504, 473, 528]}, {'text': 'pChk1', 'coordinates': [726, 600, 841, 652]}, {'text': 'pChk ', 'coordinates': [116, 652, 234, 709]}, {'text': 'S', 'coordinates': [342, 676, 368, 708]}, {'text': 'Inhibition of replication fork progression AALANNNVK', 'coordinates': [769, 758, 951, 896]}, {'text': 'Cell cycle checkpoints', 'coordinates': [17, 893, 169, 959]}, {'text': 'Go/G1', 'coordinates': [193, 911, 287, 951]}, {'text': 'IK', 'coordinates': [876, 936, 936, 962]}, {'text': 'M', 'coordinates': [382, 950, 420, 982]}] |
Gene repression by the Polycomb pathway is essential for metazoan development. Polycomb domains, characterized by trimethylation of histone H3 lysine 27 (H3K27me3), carry the memory of repression and hence need to be maintained to counter the dilution of parental H3K27me3 with unmodified H3 during replication. Yet, how locus-specific H3K27me3 is maintained through replication is unclear. To understand H3K27me3 recovery post-replication, we first define nucleation sites within each Polycomb domain in mouse embryonic stem cells. To map dynamics of H3K27me3 domains across the cell cycle, we develop CUT&Flow (coupling cleavage under target and tagmentation with flow cytometry). We show that post-replication recovery of Polycomb domains occurs by nucleation and spreading, using the same nucleation sites used during de novo domain formation. By using Polycomb repressive complex 2 (PRC2) subunit-specific inhibitors, we find that PRC2 targets nucleation sites post-replication independent of pre-existing H3K27me3. Thus, competition between H3K27me3 deposition and nucleosome turnover drives both de novo domain formation and maintenance during every cell cycle.
Keywords: PRC2; nucleation; Polycomb; epigenomics; chromatin dynamics | [{'text': 'Polycomb domain maintenance across the cell cycle', 'coordinates': [9, 13, 990, 73]}, {'text': 'Recovery', 'coordinates': [25, 139, 208, 200]}, {'text': 'Dilution', 'coordinates': [801, 145, 949, 189]}, {'text': '2', 'coordinates': [330, 176, 356, 212]}, {'text': '2', 'coordinates': [608, 490, 632, 522]}, {'text': 'Spreading', 'coordinates': [18, 796, 215, 852]}, {'text': 'Nucleation', 'coordinates': [766, 808, 972, 856]}, {'text': 'H3K27me3 , parental and nascent histones and DNA', 'coordinates': [18, 935, 986, 991]}] |
Heterogeneity in gene expression is common among clonal cells in bacteria, although the sources and functions of variation often remain unknown. Here, we track cellular heterogeneity in the bacterium Pseudomonas aeruginosa during colony growth by focusing on siderophore gene expression (pyoverdine versus pyochelin) important for iron nutrition. We find that the spatial position of cells within colonies and non-genetic yet heritable differences between cell lineages are significant sources of cellular heterogeneity, while cell pole age and lifespan have no effect. Regarding functions, our results indicate that cells adjust their siderophore investment strategies along a gradient from the colony center to its edge. Moreover, cell lineages with below-average siderophore investment benefit from lineages with above-average siderophore investment, presumably due to siderophore sharing. Our study highlights that single-cell experiments with dual gene expression reporters can identify sources of gene expression variation of interlinked traits and offer explanations for adaptive benefits in bacteria.
Keywords: single-cell analysis; bacterial gene expression; causes and consequences of cellular heterogeneity; public goods sharing; spatial structure; Pseudomonas aeruginosa | [{'text': '{', 'coordinates': [88, 57, 118, 136]}, {'text': '[', 'coordinates': [85, 134, 123, 289]}, {'text': 'Bacteria on agarose', 'coordinates': [176, 234, 366, 262]}, {'text': 'Imaging every 10 minutes', 'coordinates': [640, 292, 884, 320]}, {'text': 'L', 'coordinates': [90, 372, 122, 480]}, {'text': 'Single cell', 'coordinates': [131, 523, 230, 553]}, {'text': 'L', 'coordinates': [84, 476, 121, 627]}, {'text': 'Small colony', 'coordinates': [322, 579, 447, 610]}, {'text': 'Large colony Sources of heterogeneity spatial position cell polexae genealogy Functions of heterogeneity locally optimal strategy sharing of siderophores', 'coordinates': [615, 628, 890, 952]}, {'text': '85', 'coordinates': [515, 703, 539, 723]}, {'text': '1', 'coordinates': [87, 685, 123, 867]}, {'text': 'J', 'coordinates': [88, 864, 118, 968]}, {'text': 'pad', 'coordinates': [362, 235, 404, 257]}] |
The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.
Keywords: squalene epoxidase; 24(S),25-epoxycholesterol; reactive oxygen species; trained immunity; antitumor immunity | [{'text': 'B-glucan Dectin-1', 'coordinates': [354, 36, 471, 83]}, {'text': 'Cholesterol Metabolism HMG-CoA Squalene Oz+ (NADPH SQLE NADP 2,3- Epoxysqualene Cholesterol ', 'coordinates': [403, 139, 597, 429]}, {'text': 'Glucose Glycolysis Pyruvate', 'coordinates': [125, 219, 246, 325]}, {'text': 'Inhibitors KDIKOI Y193A', 'coordinates': [633, 239, 709, 313]}, {'text': 'HIFIa)', 'coordinates': [283, 263, 333, 281]}, {'text': '24(S),25-EC', 'coordinates': [692, 351, 798, 378]}, {'text': 'TCA Cycle', 'coordinates': [136, 387, 184, 428]}, {'text': 'LXRE 8 EP3OO', 'coordinates': [631, 507, 681, 579]}, {'text': 'Closed', 'coordinates': [173, 515, 229, 535]}, {'text': 'Opened', 'coordinates': [167, 631, 229, 651]}, {'text': 'Ifnb1, Ifng', 'coordinates': [721, 637, 798, 657]}, {'text': 'Trained Macrophages', 'coordinates': [452, 702, 572, 748]}, {'text': 'IFNB IFNY', 'coordinates': [651, 741, 691, 779]}, {'text': 'Antitumor immunity', 'coordinates': [767, 749, 845, 786]}, {'text': 'B-glucan', 'coordinates': [205, 803, 273, 821]}, {'text': 'Trained Monocytes', 'coordinates': [348, 797, 433, 834]}, {'text': 'tumor inoculation', 'coordinates': [523, 843, 605, 873]}, {'text': 'Trained TAMs', 'coordinates': [693, 841, 751, 875]}, {'text': '~TAMs', 'coordinates': [865, 887, 915, 907]}, {'text': 'Promote Inhibit', 'coordinates': [115, 897, 181, 939]}, {'text': 'Terbinafine', 'coordinates': [271, 919, 371, 939]}, {'text': 'Sqle cKo', 'coordinates': [404, 916, 488, 940]}] |
The red sea urchin (Mesocentrotus franciscanus) is one of the Earth’s longest-living animals, reported to live more than 100 years with indeterminate growth, life-long reproduction, and no increase in mortality rate with age. To understand the genetic underpinnings of longevity and negligible aging, we constructed a chromosome-level assembly of the red sea urchin genome and compared it to that of short-lived sea urchin species. Genome-wide syntenic alignments identified chromosome rearrangements that distinguish short- and long-lived species. Expanded gene families in long-lived species play a role in innate immunity, sensory nervous system, and genome stability. An integrated network of genes under positive selection in the red sea urchin was involved in genomic regulation, mRNA fidelity, protein homeostasis, and mitochondrial function. Our results implicated known longevity genes in sea urchin longevity but also revealed distinct molecular signatures that may promote long-term maintenance of tissue homeostasis, disease resistance, and negligible aging.
Keywords: sea urchin; longevity; aging; negligible senescence; comparative genomics; innate immunity; nervous system; genome stability | [{'text': 'Chromosome-level genome assembly', 'coordinates': [506, 38, 928, 70]}, {'text': 'Mesocentrotus franciscanus', 'coordinates': [18, 216, 406, 246]}, {'text': 'COMPARATIVE ANALYSES BETWEEN URCHINS WITH DIFFERENT LIFESPANS', 'coordinates': [512, 286, 886, 334]}, {'text': 'Expanded gene families Contracted gene families', 'coordinates': [37, 311, 199, 361]}, {'text': 'years', 'coordinates': [467, 391, 507, 405]}, {'text': '14 15', 'coordinates': [833, 401, 871, 415]}, {'text': 'years', 'coordinates': [467, 465, 507, 481]}, {'text': 'Chromosomal rearrangements between', 'coordinates': [533, 471, 791, 492]}, {'text': 'and short-lived species', 'coordinates': [829, 473, 981, 489]}, {'text': '>100 years', 'coordinates': [431, 533, 507, 549]}, {'text': '13 14', 'coordinates': [789, 551, 827, 565]}, {'text': '15 16 17 18 19 20 21', 'coordinates': [831, 551, 969, 567]}, {'text': '70 years', 'coordinates': [457, 603, 515, 619]}, {'text': 'Network of genes under positive selection in the long-lived red sea urchin', 'coordinates': [660, 666, 992, 715]}, {'text': 'Expanded gene families in Innate Immunity Sensory Nervous System Genome Stability', 'coordinates': [28, 700, 226, 930]}, {'text': 'lived vs. short-lived species', 'coordinates': [263, 701, 469, 722]}, {'text': 'Genomic regulation', 'coordinates': [570, 747, 641, 785]}, {'text': 'Protein homeostasis', 'coordinates': [749, 777, 835, 813]}, {'text': 'Cellular metabolism', 'coordinates': [523, 875, 603, 913]}, {'text': 'mRNA fidelity', 'coordinates': [805, 877, 851, 915]}, {'text': 'Mitochondrial function', 'coordinates': [673, 889, 767, 925]}, {'text': 'long-', 'coordinates': [791, 470, 827, 492]}, {'text': 'long-|', 'coordinates': [227, 700, 265, 724]}] |
Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.
Keywords: single-cell systems pharmacology; B cell development; acute lymphoblastic leukemia; L-asparaginase; venetoclax; developmental origins; hidden driver; NetBID2; single-cell multiome | [{'text': 'Network Analyses of B Lineage Developmental States', 'coordinates': [198, 26, 804, 59]}, {'text': 'Blood cell scRNA-seq', 'coordinates': [42, 84, 290, 116]}, {'text': 'SJARACNe', 'coordinates': [366, 86, 506, 116]}, {'text': 'NetBID2', 'coordinates': [752, 86, 852, 116]}, {'text': 'B Cell Development and Leukemia Drug Sensitivity', 'coordinates': [215, 458, 790, 494]}, {'text': 'B-ALL', 'coordinates': [336, 524, 412, 552]}, {'text': 'HSC', 'coordinates': [30, 624, 90, 652]}, {'text': 'CLP', 'coordinates': [158, 624, 212, 650]}, {'text': 'Pre-pro-B', 'coordinates': [266, 624, 380, 654]}, {'text': 'Pro-B', 'coordinates': [404, 624, 474, 650]}, {'text': 'Pre-B', 'coordinates': [526, 624, 596, 650]}, {'text': 'Immature-B Mature-B', 'coordinates': [618, 624, 866, 652]}, {'text': 'Plasma', 'coordinates': [892, 623, 982, 654]}, {'text': 'Asparaginase sensitive', 'coordinates': [588, 724, 750, 782]}, {'text': 'Asparaginase', 'coordinates': [806, 723, 964, 753]}, {'text': 'Asparaginase sensitivity', 'coordinates': [66, 752, 226, 815]}, {'text': 'mTOR', 'coordinates': [836, 814, 916, 844]}, {'text': 'Venetoclax sensitive', 'coordinates': [662, 874, 792, 932]}, {'text': 'Venetoclax sensitivity', 'coordinates': [84, 904, 214, 966]}, {'text': 'Venetoclax sensitivity', 'coordinates': [816, 900, 946, 964]}] |
Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.
Keywords: glioma; glioblastoma; tumor-associated macrophages; hypoxia; necrosis; vasculature normalization; single-cell transcriptomics; adrenomedullin; spatial transcriptomics; dabrafenib | [{'text': 'ScRNA-seq hGBM-IDHwt (n=40) hAstro-IDHmut (n=8) hOligo-IDHmut (n-3) mGBM-IDHmut (n=12', 'coordinates': [263, 28, 472, 170]}, {'text': 'Mo-TAM cluster gene signature', 'coordinates': [554, 26, 712, 80]}, {'text': 'Histo-transcriptome assignment', 'coordinates': [786, 26, 974, 80]}, {'text': '2', 'coordinates': [763, 41, 781, 65]}, {'text': 'Spatial Transcriptomics hGBM-IDHwt (n=35)', 'coordinates': [204, 212, 458, 296]}, {'text': 'Human', 'coordinates': [44, 226, 126, 252]}, {'text': 'Hypoxia-TAM characterization Hypoxia-TAM', 'coordinates': [800, 278, 974, 358]}, {'text': 'Clinical implication Hazard Ratio', 'coordinates': [542, 286, 726, 369]}, {'text': 'Monocyte Hypoxia ADM Endothelia', 'coordinates': [758, 334, 970, 494]}, {'text': 'Bulk RNA-seq TCGA_glioma (n=612) IVY_hGBM (n=270)', 'coordinates': [254, 362, 476, 474]}, {'text': 'Adherens Junction', 'coordinates': [759, 467, 833, 501]}, {'text': 'Mouse', 'coordinates': [50, 476, 126, 502]}, {'text': 'Hyperpermeable vessels ADM', 'coordinates': [42, 570, 334, 656]}, {'text': 'Normalized vessels ADM antagolist', 'coordinates': [674, 568, 906, 659]}, {'text': 'Blockade', 'coordinates': [427, 597, 538, 627]}, {'text': 'Hypoxia-TAM', 'coordinates': [91, 943, 238, 976]}, {'text': 'Endothelial cell', 'coordinates': [334, 946, 498, 972]}, {'text': 'OOCO', 'coordinates': [545, 953, 591, 967]}, {'text': 'VE-cadherin', 'coordinates': [602, 946, 738, 972]}, {'text': 'ADM receptor', 'coordinates': [812, 946, 962, 974]}] |
Narratives can synchronize neural and physiological signals between individuals, but the relationship between these signals, and the underlying mechanism, is unclear. We hypothesized a top-down effect of cognition on arousal and predicted that auditory narratives will drive not only brain signals but also peripheral physiological signals. We find that auditory narratives entrained gaze variation, saccade initiation, pupil size, and heart rate. This is consistent with a top-down effect of cognition on autonomic function. We also hypothesized a bottom-up effect, whereby autonomic physiology affects arousal. Controlled breathing affected pupil size, and heart rate was entrained by controlled saccades. Additionally, fluctuations in heart rate preceded fluctuations of pupil size and brain signals. Gaze variation, pupil size, and heart rate were all associated with anterior-central brain signals. Together, these results suggest bidirectional causal effects between peripheral autonomic function and central brain circuits involved in the control of arousal.
Keywords: brain-body interaction; auditory narratives; pupil size; heart rate; gaze position; gaze variation; inter-subject correlation; speech tracking; attention | [{'text': 'Bidirectional Brain-Body interaction', 'coordinates': [154, 0, 854, 50]}, {'text': 'Audio narrative', 'coordinates': [24, 98, 216, 128]}, {'text': 'Brain activity (EEG)', 'coordinates': [575, 95, 739, 160]}, {'text': 'Gaze variation', 'coordinates': [672, 482, 782, 544]}, {'text': 'Pupil size', 'coordinates': [866, 484, 936, 542]}, {'text': 'Heart rate', 'coordinates': [560, 654, 688, 686]}, {'text': 'Breathing volume', 'coordinates': [511, 767, 735, 811]}] |
Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules—which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness—predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.
Keywords: neuronal morphology; dendrite scaling; mitochondrial motility; in vivo imaging | [{'text': 'dendrite scaling = ra + Tzd', 'coordinates': [5, 56, 338, 161]}, {'text': 'Drosophila HS dendrite', 'coordinates': [631, 91, 969, 133]}, {'text': 'parent-daughter', 'coordinates': [39, 336, 272, 376]}, {'text': 'subtree size', 'coordinates': [90, 409, 285, 447]}, {'text': 'sister-sister', 'coordinates': [74, 618, 244, 654]}, {'text': 'linear flux ~ r2', 'coordinates': [371, 635, 589, 673]}, {'text': 'arrest', 'coordinates': [671, 649, 769, 685]}, {'text': '1/rb', 'coordinates': [799, 646, 862, 684]}, {'text': 'mitochondrial transport scaling', 'coordinates': [302, 894, 932, 950]}] |
The gut must perform a dual role of protecting the host against toxins and pathogens while harboring mutualistic microbiota. Previous studies suggested that the NADPH oxidase Duox contributes to intestinal homeostasis in Drosophila by producing reactive oxygen species (ROS) in the gut that stimulate epithelial renewal. We find instead that the ROS generated by Duox in the Malpighian tubules leads to the production of Upd3, which enters the gut and stimulates stem cell proliferation. We describe in Drosophila the existence of a countercurrent flow system, which pushes tubule-derived Upd3 to the anterior part of the gut and stimulates epithelial renewal at a distance. Thus, our paper clarifies the role of Duox in gut homeostasis and describes the existence of retrograde fluid flow in the gut, collectively revealing a fascinating example of inter-organ communication. | [{'text': 'Oral infection', 'coordinates': [188, 74, 312, 98]}, {'text': 'Malpighian tubules Duox', 'coordinates': [603, 98, 776, 151]}, {'text': 'ROS', 'coordinates': [660, 206, 706, 230]}, {'text': 'Midgut Upd3', 'coordinates': [76, 246, 144, 306]}, {'text': 'Transport by Countercurrent flow', 'coordinates': [260, 238, 498, 281]}, {'text': 'Upd3', 'coordinates': [660, 278, 710, 302]}, {'text': 'Jak-STAT Gut homeostasis', 'coordinates': [38, 354, 184, 446]}, {'text': 'Hindgut Upd3 Drip Duox Food bolus flow Peritrophic matrix Countercurrent flow', 'coordinates': [826, 664, 996, 922]}, {'text': 'Midgut', 'coordinates': [366, 700, 434, 726]}, {'text': 'Malpighian tubules', 'coordinates': [362, 890, 536, 916]}] |
Chromatin-associated RNAs (cRNAs) are a poorly characterized fraction of cellular RNAs that co-purify with chromatin. Their full complexity and the mechanisms regulating their packaging and chromatin association remain poorly understood. Here, we address these questions in Drosophila. We find that cRNAs constitute a heterogeneous group of RNA species that is abundant in heterochromatic transcripts. We show that heterochromatic cRNAs interact with the heterogeneous nuclear ribonucleoproteins (hnRNP) hrp36/hrp48 and that depletion of linker histone dH1 impairs this interaction. dH1 depletion induces the accumulation of RNA::DNA hybrids (R-loops) in heterochromatin and, as a consequence, increases retention of heterochromatic cRNAs. These effects correlate with increased RNA polymerase II (RNAPII) occupancy at heterochromatin. Notably, impairing cRNA assembly by depletion of hrp36/hrp48 mimics heterochromatic R-loop accumulation induced by dH1 depletion. We also show that dH1 depletion alters nucleosome organization, increasing accessibility of heterochromatin. Altogether, these perturbations facilitate annealing of cRNAs to the DNA template, enhancing R-loop formation and cRNA retention at heterochromatin.
Keywords: chromosomal RNAs; histone H1; hrp36; hrp48; RNPs; R-loops; chromatin; epigenetics; Drosophila | [{'text': 'Heterochromatin', 'coordinates': [296, 48, 704, 104]}, {'text': 'Linker histone', 'coordinates': [23, 163, 163, 253]}, {'text': 'cRNA', 'coordinates': [291, 159, 397, 201]}, {'text': 'hrp48', 'coordinates': [612, 172, 726, 222]}, {'text': 'hrp36', 'coordinates': [765, 154, 883, 209]}, {'text': 'Decreased linker histone levels', 'coordinates': [134, 528, 873, 590]}, {'text': 'R-loop', 'coordinates': [650, 626, 777, 681]}, {'text': 'Nucleosome destabilization', 'coordinates': [331, 883, 599, 971]}] |
Many studies infer the role of neurons by asking what information can be decoded from their activity or by observing the consequences of perturbing their activity. An alternative approach is to consider information flow between neurons. We applied this approach to the parietal reach region (PRR) and the lateral intraparietal area (LIP) in posterior parietal cortex. Two complementary methods imply that across a range of reaching tasks, information flows primarily from PRR to LIP. This indicates that during a coordinated reach task, LIP has minimal influence on PRR and rules out the idea that LIP forms a general purpose spatial processing hub for action and cognition. Instead, we conclude that PRR and LIP operate in parallel to plan arm and eye movements, respectively, with asymmetric interactions that likely support eye-hand coordination. Similar methods can be applied to other areas to infer their functional relationships based on inferred information flow.
Keywords: eye-hand coordination; functional connectivity; motor planning; parietal cortex | [{'text': 'PRR', 'coordinates': [48, 86, 148, 138]}, {'text': 'Reach plan', 'coordinates': [231, 71, 355, 176]}, {'text': 'Saccade plan', 'coordinates': [611, 77, 779, 184]}, {'text': 'LIP', 'coordinates': [848, 92, 924, 140]}, {'text': 'Sensory information', 'coordinates': [423, 444, 581, 523]}, {'text': 'LFP', 'coordinates': [654, 598, 702, 624]}, {'text': 'PRR', 'coordinates': [50, 634, 150, 684]}, {'text': 'LIP', 'coordinates': [852, 640, 930, 688]}, {'text': 'spikes', 'coordinates': [303, 699, 389, 735]}, {'text': 'spikes', 'coordinates': [634, 700, 718, 732]}, {'text': 'Common input', 'coordinates': [444, 882, 577, 965]}] |
How cancer cells determine their shape in response to three-dimensional (3D) geometric and mechanical cues is unclear. We develop an approach to quantify the 3D cell shape of over 60,000 melanoma cells in collagen hydrogels using high-throughput stage-scanning oblique plane microscopy (ssOPM). We identify stereotypic and environmentally dependent changes in shape and protrusivity depending on whether a cell is proximal to a flat and rigid surface or is embedded in a soft environment. Environmental sensitivity metrics calculated for small molecules and gene knockdowns identify interactions between the environment and cellular factors that are important for morphogenesis. We show that the Rho guanine nucleotide exchange factor (RhoGEF) TIAM2 contributes to shape determination in environmentally independent ways but that non-muscle myosin II, microtubules, and the RhoGEF FARP1 regulate shape in ways dependent on the microenvironment. Thus, changes in cancer cell shape in response to 3D geometric and mechanical cues are modulated in both an environmentally dependent and independent fashion.
Keywords: imaging 3D morphology; oblique plane microscopy; OPM; cell protrusions; FARP1; TIAM2; RhoGEF; melanoma; microenvironment; collagen | [{'text': '1. Stage scanning oblique plane microscopy Collagen hydrogel ,', 'coordinates': [13, 0, 910, 104]}, {'text': 'Light sheet imaging', 'coordinates': [35, 77, 284, 115]}, {'text': 'Lightsheet', 'coordinates': [731, 69, 869, 107]}, {'text': 'Deep', 'coordinates': [853, 107, 930, 148]}, {'text': '60,000+ cells analysed 3D collagen embedded', 'coordinates': [35, 146, 329, 253]}, {'text': 'Shallow Coverslip', 'coordinates': [826, 238, 951, 329]}, {'text': 'siRNAdrug treated', 'coordinates': [34, 280, 279, 323]}, {'text': 'Objective', 'coordinates': [669, 311, 793, 347]}, {'text': '2.', 'coordinates': [13, 373, 49, 411]}, {'text': '3D context dependent control of protrusivity', 'coordinates': [68, 365, 954, 422]}, {'text': '3D Soft Deep', 'coordinates': [45, 431, 171, 514]}, {'text': 'Increased contribution', 'coordinates': [285, 500, 473, 583]}, {'text': 'Reduced contribution', 'coordinates': [755, 495, 941, 579]}, {'text': '8', 'coordinates': [101, 519, 139, 611]}, {'text': 'Non-muscle Myosin-II T ROCK T Microtubules', 'coordinates': [270, 648, 456, 837]}, {'text': '8', 'coordinates': [96, 610, 144, 759]}, {'text': 'FARPI^', 'coordinates': [802, 734, 934, 766]}, {'text': 'TIAM2 Arp2/3', 'coordinates': [546, 754, 647, 833]}, {'text': 'Shallow 3D Flatl Rigid', 'coordinates': [4, 899, 224, 986]}] |
Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2–4 (glutamate receptors 2–4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2–4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
Keywords: hair cell; development; ribbon synapses; afferent fibers; glutamate receptors; hearing loss; NDMA receptors; cochlea; post-synaptic density | [{'text': 'Wild-type_', 'coordinates': [188, 9, 339, 63]}, {'text': 'inner hair cell ribbon synapse', 'coordinates': [353, 16, 801, 57]}, {'text': 'Synaptic Ribbon Synaptic Vesicle', 'coordinates': [765, 91, 924, 174]}, {'text': 'GluR2 GluR3 GluR4 NMDAR PSD95', 'coordinates': [766, 204, 844, 448]}, {'text': 'Bai1 knockout', 'coordinates': [155, 509, 375, 547]}, {'text': 'inner hair cell ribbon synapse', 'coordinates': [391, 509, 839, 551]}, {'text': 'Synaptic Ribbon Synaptic Vesicle', 'coordinates': [766, 588, 924, 668]}, {'text': 'GluR2 GluR3 GluR4 NMDAR PSD95', 'coordinates': [766, 700, 844, 942]}] |
The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child’s health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications—Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.
Keywords: single-cell genomics; host-pathogen interactions; placenta; infections during pregnancy; immunology; macrophages; malaria; Plasmodium; Toxoplasma; Listeria | [{'text': 'Single-cell census', 'coordinates': [672, 26, 913, 66]}, {'text': 'Early placental human explants', 'coordinates': [11, 73, 197, 162]}, {'text': 'Plasmodium falciparum', 'coordinates': [290, 116, 546, 144]}, {'text': 'Placental responses', 'coordinates': [829, 118, 950, 177]}, {'text': 'Toxoplasma gondii', 'coordinates': [343, 191, 553, 224]}, {'text': 'Listeria monocytogenes', 'coordinates': [290, 280, 552, 310]}, {'text': 'Plasmodium adaptations', 'coordinates': [822, 282, 958, 342]}, {'text': 'Extravillous space Inflammation', 'coordinates': [22, 430, 248, 492]}, {'text': 'Inflammation', 'coordinates': [352, 466, 488, 492]}, {'text': 'Inflammation', 'coordinates': [684, 466, 818, 492]}, {'text': 'Plasmodium adaptation', 'coordinates': [482, 508, 612, 564]}, {'text': 'Anti-angiogenic] SFLT1', 'coordinates': [492, 716, 654, 768]}, {'text': 'ILIB Antimicrobial genes', 'coordinates': [176, 792, 318, 890]}, {'text': 'NF-KB Proinflammatory cytokines', 'coordinates': [464, 794, 643, 890]}, {'text': 'Phagocytosis AP-1 ROS Placental core', 'coordinates': [792, 794, 982, 920]}, {'text': 'Hofbauer cells', 'coordinates': [26, 892, 170, 918]}, {'text': 'Pregnancy complications', 'coordinates': [334, 952, 663, 992]}, {'text': 'Placental villus', 'coordinates': [5, 626, 144, 664]}] |
TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design.
Keywords: TRPM7; TRP channel; CCT128930; cancer; drug; inhibitor; cryo-EM; calcium; magnesium; lipids | [{'text': 'Cation channel TRPM7 in closed state', 'coordinates': [44, 14, 460, 44]}, {'text': 'Mg2+ Zn2+ Ca2+', 'coordinates': [654, 14, 826, 44]}, {'text': 'Out', 'coordinates': [932, 72, 972, 96]}, {'text': 'CCT_', 'coordinates': [444, 130, 502, 160]}, {'text': 'In', 'coordinates': [949, 227, 971, 247]}, {'text': 'J', 'coordinates': [168, 566, 196, 702]}, {'text': 'Control 10 pM CCT', 'coordinates': [42, 744, 174, 806]}, {'text': 'NHz', 'coordinates': [739, 755, 791, 791]}, {'text': 'NH', 'coordinates': [938, 832, 980, 858]}, {'text': 'N EN', 'coordinates': [848, 892, 935, 916]}, {'text': '50', 'coordinates': [115, 925, 141, 943]}, {'text': '50', 'coordinates': [355, 925, 383, 943]}, {'text': '100 Voltage (mV)', 'coordinates': [381, 922, 533, 987]}, {'text': 'CCT128930', 'coordinates': [698, 934, 836, 962]}] |
Muscle stem cells (MuSCs) contribute to a robust muscle regeneration process after injury, which is highly orchestrated by the sequential expression of multiple key transcription factors. However, it remains unclear how key transcription factors and cofactors such as the Mediator complex cooperate to regulate myogenesis. Here, we show that the Mediator Med23 is critically important for MuSC-mediated muscle regeneration. Med23 is increasingly expressed in activated/proliferating MuSCs on isolated myofibers or in response to muscle injury. Med23 deficiency reduced MuSC proliferation and enhanced its precocious differentiation, ultimately compromising muscle regeneration. Integrative analysis revealed that Med23 oppositely impacts Ternary complex factor (TCF)-targeted MuSC proliferation genes and myocardin-related transcription factor (MRTF)-targeted myogenic differentiation genes. Consistently, Med23 deficiency decreases the ETS-like transcription factor 1 (Elk1)/serum response factor (SRF) binding at proliferation gene promoters but promotes MRTF-A/SRF binding at myogenic gene promoters. Overall, our study reveals the important transcriptional control mechanism of Med23 in balancing MuSC proliferation and differentiation in muscle regeneration.
Keywords: muscle regeneration; muscle stem cell; Mediator; Med23; Elk1; MRTF-A; proliferation; differentiation | [{'text': 'WT', 'coordinates': [27, 27, 87, 63]}, {'text': 'Med23 KO', 'coordinates': [523, 25, 699, 63]}, {'text': 'Ditt penes', 'coordinates': [387, 241, 442, 257]}, {'text': 'Elkt', 'coordinates': [565, 237, 591, 253]}, {'text': 'peno8 Prolll =', 'coordinates': [647, 256, 711, 285]}, {'text': 'Diff genes', 'coordinates': [870, 314, 945, 350]}, {'text': 'Reduced Proliferation', 'coordinates': [736, 513, 848, 556]}, {'text': 'Precocious Differentiation', 'coordinates': [860, 510, 988, 553]}, {'text': 'Quiescence Activation', 'coordinates': [6, 531, 208, 555]}, {'text': 'Proliferation', 'coordinates': [234, 532, 346, 556]}, {'text': 'Differentiation', 'coordinates': [362, 532, 490, 556]}, {'text': 'Quiescence', 'coordinates': [506, 532, 612, 556]}, {'text': 'Activation', 'coordinates': [625, 531, 717, 555]}, {'text': 'Quiescentmuscle stem cell Activated muscle stem cell', 'coordinates': [82, 806, 387, 898]}, {'text': 'Proliferative myoblast Differentiated myoblast mRNA', 'coordinates': [453, 806, 717, 966]}, {'text': "'Med23", 'coordinates': [722, 806, 792, 832]}, {'text': 'Loss of Med23', 'coordinates': [816, 804, 984, 834]}, {'text': 'Muscle injury', 'coordinates': [816, 874, 968, 904]}, {'text': 'Myofibers and myonuclei', 'coordinates': [132, 932, 412, 965]}, {'text': 'MRTF-A', 'coordinates': [292, 269, 336, 273]}, {'text': '(Med23 Elk1', 'coordinates': [34, 293, 97, 342]}, {'text': 'igenes _ Prolif _', 'coordinates': [136, 293, 237, 314]}, {'text': '(MRTF-A', 'coordinates': [768, 278, 826, 322]}] |
High-penetrance mutations affecting mental health can involve genes ubiquitously expressed in the brain. Whether the specific patterns of dysfunctions result from ubiquitous circuit deficits or might reflect selective vulnerabilities of targetable subnetworks has remained unclear. Here, we determine how loss of ubiquitously expressed fragile X mental retardation protein (FMRP), the cause of fragile X syndrome, affects brain networks in Fmr1y/− mice. We find that in wild-type mice, area-specific knockout of FMRP in the adult mimics behavioral consequences of area-specific silencing. By contrast, the functional axis linking the ventral hippocampus (vH) to the prelimbic cortex (PreL) is selectively affected in constitutive Fmr1y/− mice. A chronic alteration in late-born parvalbumin interneuron networks across the vH-PreL axis rescued by VIP signaling specifically accounts for deficits in vH-PreL theta-band network coherence, ensemble assembly, and learning functions of Fmr1y/− mice. Therefore, vH-PreL axis function exhibits a selective vulnerability to loss of FMRP in the vH or PreL, leading to learning and memory dysfunctions in fragile X mice.
Keywords: autism; monogenic models of autism; mice; repetitive behaviors; insistence on sameness; perirhinal cortex, ASD-like behavior; tail of striatum; context-specific failure to engage; dopamine | [{'text': 'Wild type', 'coordinates': [210, 30, 328, 60]}, {'text': 'Fmriyl-', 'coordinates': [680, 30, 780, 60]}, {'text': 'RSC', 'coordinates': [276, 104, 330, 134]}, {'text': 'RSC', 'coordinates': [758, 102, 812, 132]}, {'text': 'dH', 'coordinates': [188, 142, 224, 172]}, {'text': 'dH', 'coordinates': [670, 140, 706, 168]}, {'text': 'PreL', 'coordinates': [354, 166, 406, 196]}, {'text': 'PreL', 'coordinates': [848, 164, 902, 194]}, {'text': 'vH', 'coordinates': [116, 226, 148, 252]}, {'text': 'vH', 'coordinates': [598, 222, 632, 250]}, {'text': 'BLA', 'coordinates': [296, 262, 344, 292]}, {'text': 'BLA', 'coordinates': [778, 260, 826, 288]}, {'text': 'Dysfunctional', 'coordinates': [118, 382, 272, 414]}, {'text': 'Functional', 'coordinates': [376, 382, 496, 408]}, {'text': 'Absence of FMRP', 'coordinates': [597, 380, 804, 411]}, {'text': 'vH-PreL axis function', 'coordinates': [108, 484, 356, 514]}, {'text': 'vH-PreL axis dysfunction', 'coordinates': [573, 483, 863, 519]}, {'text': 'vH', 'coordinates': [72, 538, 116, 566]}, {'text': 'PreL', 'coordinates': [333, 534, 404, 570]}, {'text': 'vH', 'coordinates': [560, 546, 602, 574]}, {'text': 'PreL', 'coordinates': [822, 546, 890, 576]}, {'text': 'Pyr', 'coordinates': [74, 618, 110, 646]}, {'text': 'VIP', 'coordinates': [354, 630, 394, 658]}, {'text': 'Firing Pyr', 'coordinates': [490, 615, 599, 657]}, {'text': 'VIPt Inhibition - PV Firing Firing', 'coordinates': [842, 638, 980, 820]}, {'text': 'Mm Theta Coherence', 'coordinates': [162, 657, 286, 762]}, {'text': 'Am Theta Coherence', 'coordinates': [656, 663, 782, 770]}, {'text': 'PV', 'coordinates': [358, 710, 390, 736]}, {'text': 'tFiring Inhibition VIP', 'coordinates': [468, 699, 600, 814]}, {'text': 'VIP=', 'coordinates': [74, 780, 112, 804]}, {'text': 'Pyr', 'coordinates': [354, 784, 400, 816]}, {'text': 'Pyr', 'coordinates': [846, 796, 890, 826]}, {'text': 'RE', 'coordinates': [198, 932, 236, 962]}, {'text': 'RE', 'coordinates': [706, 936, 744, 966]}] |
Bone is highly susceptible to cancer metastasis, and both tumor and bone cells enable tumor invasion through a “vicious cycle” of biochemical signaling. Tumor metastasis into bone also alters biophysical cues to both tumor and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuate this cycle has not been studied. Here, we develop highly advanced in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumor-bone cell signaling and mechanobiological cues. In particular, we develop a multicellular healthy and metastatic bone model that can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis, and metastatic activity. Ultimately, we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.
Keywords: bone metastasis; mechanobiology; vicious cycle; osteolysis; osteoclastogenesis; osteoblasts; in vitro models; multicellular models; computational models; tumor growth | [{'text': 'Spheroid size and tumor cell proliferation', 'coordinates': [167, 33, 527, 101]}, {'text': 'Metastatic multicellular mineralized model', 'coordinates': [624, 32, 916, 96]}, {'text': 'Mechanical compression', 'coordinates': [804, 104, 961, 172]}, {'text': 'Growth into spheroids', 'coordinates': [70, 128, 222, 195]}, {'text': 'Growth-induced stress', 'coordinates': [210, 282, 498, 314]}, {'text': 'Co-culture', 'coordinates': [178, 420, 314, 450]}, {'text': 'Tri-culture', 'coordinates': [376, 420, 512, 452]}, {'text': 'PTHrP, IL-6', 'coordinates': [579, 429, 729, 465]}, {'text': 'BSP , DMP1 Osteoblast activity', 'coordinates': [784, 434, 928, 571]}, {'text': 'TNF-a', 'coordinates': [144, 606, 224, 636]}, {'text': 'RANKL_', 'coordinates': [549, 599, 647, 631]}, {'text': 'OPG', 'coordinates': [678, 600, 744, 632]}, {'text': 'M Osteoclast activity', 'coordinates': [584, 765, 724, 849]}, {'text': 'Inhibited proliferation', 'coordinates': [184, 786, 345, 853]}, {'text': 'Proliferation partially rescued', 'coordinates': [350, 784, 506, 878]}, {'text': 'Tumor Cell', 'coordinates': [168, 912, 308, 944]}, {'text': 'Osteoclast Precursors', 'coordinates': [384, 916, 529, 984]}, {'text': 'Osteoblast', 'coordinates': [610, 914, 752, 946]}, {'text': 'Osteocyte', 'coordinates': [828, 909, 963, 949]}] |
A common cause of deafness in humans is dysregulation of the endocochlear potential generated by the stria vascularis (SV). Thus, proper formation of the SV is critical for hearing. Using single-cell transcriptomics and a series of Shh signaling mutants, we discovered that the Shh receptor Patched1 (Ptch1) is essential for marginal cell (MC) differentiation and SV formation. Single-cell RNA sequencing analyses revealed that the cochlear roof epithelium is already specified into discrete domains with distinctive gene expression profiles at embryonic day 14, with Gsc as a marker gene of the MC lineage. Ptch1 deficiency leads to defective specification of MC precursors along the cochlear basal-apical regions. We demonstrated that elevated Gli2 levels impede MC differentiation through sustaining Otx2 expression and maintaining the progenitor state of MC precursors. Our results uncover an early specification of cochlear non-sensory epithelial cells and establish a crucial role of the Ptch1-Gli2 axis in regulating the development of SV.
Keywords: Ptch1; Shh signaling pathway; Gli2; cochlea; marginal cell; stria vascularis | [{'text': 'Differentiation of marginal cells and formation of stria vascularis in the developing cochlea', 'coordinates': [92, 8, 905, 93]}, {'text': 'WT', 'coordinates': [240, 116, 292, 146]}, {'text': 'Ptch1CKo', 'coordinates': [669, 111, 805, 149]}, {'text': '3', 'coordinates': [28, 178, 56, 256]}, {'text': 'Cross section at mid-base cochlea', 'coordinates': [311, 235, 435, 269]}, {'text': 'Cross section at mid-base cochlea', 'coordinates': [539, 239, 663, 273]}, {'text': 'Ptch1', 'coordinates': [316, 340, 412, 376]}, {'text': 'Gsc+ Marginal cell precursors', 'coordinates': [436, 366, 676, 422]}, {'text': '3', 'coordinates': [30, 434, 60, 510]}, {'text': 'Gli2 -', 'coordinates': [335, 465, 451, 501]}, {'text': '000 Gsc+IHmx2+ Differentiating Marginal cells', 'coordinates': [394, 544, 681, 675]}, {'text': 'Cx26+ CD44+ "Kcnq1', 'coordinates': [442, 723, 499, 787]}, {'text': '3', 'coordinates': [28, 726, 58, 804]}, {'text': 'Formation of stria vascularis at mid-base cochlea', 'coordinates': [297, 823, 493, 859]}, {'text': 'Defective formation of stria vascularis at mid-base cochlea', 'coordinates': [521, 823, 737, 857]}, {'text': 'specified Gsct marginal cell precursors in lateral roof epithelium basal-to-apical differentiation of Gsc+/Hmx2+ marginal cells', 'coordinates': [247, 912, 820, 978]}] |
Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
Keywords: oxidative phosphorylation; oxidative stress; ROS; electron transfer chain; intestinal epithelial cells; peptidoglycan; PGN; ATP synthase; energy metabolism; Leigh syndrome; mitochondrial diseases; antibiotic-induced microbiome depletion; intestinal homeostasis | [{'text': 'isolation', 'coordinates': [296, 90, 410, 122]}, {'text': 'Peptidoglycan (PG)', 'coordinates': [669, 105, 859, 175]}, {'text': 'E coli', 'coordinates': [124, 232, 210, 264]}, {'text': 'lysozyme', 'coordinates': [573, 231, 705, 267]}, {'text': 'in vitro', 'coordinates': [366, 336, 460, 366]}, {'text': 'Bind, stabilize & promote ATP synthase', 'coordinates': [63, 351, 364, 424]}, {'text': 'Muropeptides', 'coordinates': [618, 346, 801, 388]}, {'text': 'oral', 'coordinates': [446, 538, 500, 564]}, {'text': 'Disease cells with Mt dysfunction Oxidative respiration Oxidative stress Mt structure Energy metabolism', 'coordinates': [708, 684, 960, 924]}, {'text': 'Human intestinal epithelial cells Oxidative respiration ATP production Oxidative stress', 'coordinates': [56, 710, 309, 912]}, {'text': 'Intestinal cells in antibiotic-treated mice Oxidative stress Energy metabolism Nutrient absorption', 'coordinates': [356, 724, 640, 917]}] |
Current organoid technologies require intensive manual manipulation and lack uniformity in organoid size and cell composition. We present here an automated organoid platform that generates uniform organoid precursors in high-throughput. This is achieved by templating from monodisperse Matrigel droplets and sequentially delivering them into wells using a synchronized microfluidic droplet printer. Each droplet encapsulates a certain number of cells (e.g., 1,500 cells), which statistically represent the heterogeneous cell population in a tumor section. The system produces >400-μm organoids within 1 week with both inter-organoid homogeneity and inter-patient heterogeneity. This enables automated organoid printing to obtain one organoid per well. The organoids recapitulate 97% gene mutations in the parental tumor and reflect the patient-to-patient variation in drug response and sensitivity, from which we obtained more than 80% accuracy among the 21 patients investigated. This organoid platform is anticipated to fulfill the personalized medicine goal of 1-week high-throughput screening for cancer patients.
Keywords: microfluidics; droplet; printing; organoid; tumor | [{'text': 'Drugs', 'coordinates': [145, 109, 244, 153]}, {'text': 'Personalized Medicine', 'coordinates': [468, 148, 665, 222]}, {'text': 'Organoids', 'coordinates': [165, 339, 327, 379]}, {'text': 'Organoid Printing', 'coordinates': [222, 651, 520, 702]}, {'text': 'Tumor', 'coordinates': [698, 748, 798, 780]}, {'text': 'Cells', 'coordinates': [313, 875, 393, 911]}, {'text': 'Matrigel', 'coordinates': [115, 741, 190, 864]}] |
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting millions of elder people due to the degeneration of dopamine neurons in the striatum and substantia nigra. The clinical manifestations of PD include tremor, rigidity, bradykinesia and postural instability. Studying PD is challenging due to two obstacles: 1) disease models such as primary neurons or animal models usually couldn’t recapitulate the disease phenotype, and 2) accessibility of human autopsied brain samples is very limited if not impossible. Induced pluripotent stem cells (iPSCs)-derived neuronal cells from patients emerge as an ideal in vitro model for disease modeling and drug development. Here we describe a cell density-dependent method for preparing functional hiPSC-derived dopamine neurons (iDAs) with ~90% purity (TH-positive cells). iDAs derived from PD patient exhibit the disease-related phenotypes, for example, slowed morphogenesis, reduced dopamine release, impaired mitochondrial function, and α-synuclein accumulation as early as 35 days after induction. Furthermore, we found that the effects of cell density are different between iDA development stages, whereas high cell density increases stress for early neural progenitor cells (NPCs), but are neural-protective for mature iDAs, high density also favors morphogenesis. Hence, using stage and density-dependent strategies we can obtain high quality iDAs, which are critical for disease modeling, drug development and cell replacement therapy.
Keywords: Dopamine neuron; Parkinson’s disease; Cell density; Induced pluripotent stem cells (iPSCs); In vitro differentiation | [{'text': 'A', 'coordinates': [0, 0, 37, 37]}, {'text': 'B', 'coordinates': [988, 2, 1018, 38]}, {'text': 'p.I723V (ATC GTC)', 'coordinates': [1040, 6, 1268, 36]}, {'text': 'Disease-related gene mutation', 'coordinates': [586, 56, 730, 106]}, {'text': 'Reprogramming method Sendai virual Sendai viral Retroviral Episomal', 'coordinates': [778, 56, 928, 318]}, {'text': 'iPS line H1 H2 H3 PD', 'coordinates': [88, 67, 161, 315]}, {'text': 'Age 40 34 newborn', 'coordinates': [199, 68, 277, 257]}, {'text': "Disease Normal Normal Normal Parkinson's disease", 'coordinates': [420, 68, 522, 331]}, {'text': 'male female male male Sex', 'coordinates': [312, 66, 376, 318]}, {'text': '4 T', 'coordinates': [1049, 147, 1105, 165]}, {'text': 'p.M2397T (ATG>ACG)', 'coordinates': [1042, 186, 1304, 218]}, {'text': 'Lrrk2 (p.1723V and p.M2397T)', 'coordinates': [578, 282, 738, 330]}, {'text': 'T A A', 'coordinates': [1057, 323, 1147, 341]}] |
Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies.
Keywords: colorectal cancer; liver metastases; chemotherapy; single-cell analysis; immune microenvironment; organotypic culture; single-cell transcriptome; PD-L1; TIM3; galectin-9 | [{'text': 'Chemotherapy', 'coordinates': [671, 65, 952, 128]}, {'text': '8', 'coordinates': [734, 150, 790, 246]}, {'text': 'Colorectal Liver Metastases', 'coordinates': [25, 263, 542, 315]}, {'text': 'Viability', 'coordinates': [83, 403, 236, 464]}, {'text': 'Single-cell RNAseq', 'coordinates': [739, 387, 936, 493]}, {'text': 'Stem-like', 'coordinates': [181, 593, 359, 637]}, {'text': 'Enterocyte-like', 'coordinates': [612, 580, 890, 632]}, {'text': 'PD-L1', 'coordinates': [34, 783, 139, 824]}, {'text': 'IFN', 'coordinates': [205, 785, 283, 827]}, {'text': 'Gal-9', 'coordinates': [725, 799, 823, 837]}, {'text': 'T cell', 'coordinates': [165, 877, 267, 917]}, {'text': 'anti-Tim3', 'coordinates': [537, 873, 715, 917]}, {'text': 'PD-L1', 'coordinates': [21, 941, 141, 985]}, {'text': 'Galectin', 'coordinates': [801, 929, 958, 979]}] |
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) mediates viral entry into cells and is critical for vaccine development against coronavirus disease 2019 (COVID-19). Structural studies have revealed distinct conformations of S, but real-time information that connects these structures is lacking. Here we apply single-molecule fluorescence (Förster) resonance energy transfer (smFRET) imaging to observe conformational dynamics of S on virus particles. Virus-associated S dynamically samples at least four distinct conformational states. In response to human receptor angiotensin-converting enzyme 2 (hACE2), S opens sequentially into the hACE2-bound S conformation through at least one on-path intermediate. Conformational preferences observed upon exposure to convalescent plasma or antibodies suggest mechanisms of neutralization involving either competition with hACE2 for binding to the receptor-binding domain (RBD) or allosteric interference with conformational changes required for entry. Our findings inform on mechanisms of S recognition and conformations for immunogen design.
Keywords: SARS-CoV-2 spike protein; single-molecule FRET; real-time conformational dynamics; receptor ACE2; antibody neutralization | [{'text': 'SARS-CoV-2', 'coordinates': [31, 44, 282, 88]}, {'text': 'spike', 'coordinates': [512, 46, 622, 96]}, {'text': '4 conformations', 'coordinates': [650, 44, 954, 92]}, {'text': 'spi e', 'coordinates': [358, 141, 499, 214]}, {'text': "Down'", 'coordinates': [669, 155, 794, 203]}, {'text': "'Intermediate'", 'coordinates': [642, 324, 850, 362]}, {'text': 'Up', 'coordinates': [906, 314, 970, 366]}, {'text': 'spike', 'coordinates': [574, 404, 682, 454]}, {'text': 'dynamics', 'coordinates': [705, 401, 894, 456]}, {'text': 'real-time', 'coordinates': [493, 545, 663, 589]}, {'text': '2', 'coordinates': [38, 618, 62, 650]}, {'text': 'activation by ACE2 activated \'Up"', 'coordinates': [20, 658, 382, 760]}, {'text': '3', 'coordinates': [414, 664, 438, 696]}, {'text': 'antagonism by antibodies', 'coordinates': [460, 657, 943, 711]}, {'text': "mimicking 'Up'", 'coordinates': [410, 701, 694, 764]}, {'text': "locking 'Down'", 'coordinates': [716, 707, 992, 760]}] |
Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI.
Keywords: harlequin ichthyosis; epidermal differentiation; skin barrier function; ABCA12; aminosalicylic acid; 5ASA; mesalamine; 4ASA; acitretin | [{'text': 'Aminosalicylic Acid treatment of Harlequin Ichthyosis:', 'coordinates': [124, 4, 885, 124]}, {'text': 'Abca12+lt', 'coordinates': [101, 117, 291, 161]}, {'text': 'Abca12NA', 'coordinates': [351, 113, 544, 163]}, {'text': 'Abca12N4 4ASA', 'coordinates': [751, 113, 942, 201]}, {'text': '+', 'coordinates': [762, 168, 786, 192]}, {'text': '1', 'coordinates': [15, 139, 57, 267]}, {'text': '9', 'coordinates': [15, 267, 57, 383]}, {'text': '1', 'coordinates': [13, 403, 57, 531]}, {'text': '3', 'coordinates': [14, 529, 58, 632]}, {'text': '+I+ NA', 'coordinates': [205, 653, 273, 731]}, {'text': '+/+ 4ASA NA 4ASA', 'coordinates': [287, 649, 471, 731]}, {'text': '40 30 } 20 10', 'coordinates': [87, 677, 193, 906]}, {'text': '+', 'coordinates': [596, 700, 620, 726]}, {'text': '4ASA', 'coordinates': [629, 693, 739, 733]}, {'text': '1', 'coordinates': [41, 671, 83, 825]}, {'text': 'OH', 'coordinates': [874, 750, 924, 780]}, {'text': 'HzN', 'coordinates': [631, 821, 693, 859]}, {'text': 'OH Ieadonocyte', 'coordinates': [734, 822, 975, 947]}, {'text': '1', 'coordinates': [41, 825, 83, 959]}, {'text': 'Time (m) Impufleeereatonc', 'coordinates': [370, 864, 877, 949]}, {'text': '60', 'coordinates': [225, 937, 277, 977]}, {'text': '180', 'coordinates': [317, 935, 393, 979]}, {'text': '360', 'coordinates': [473, 937, 551, 979]}, {'text': 'barrier function', 'coordinates': [619, 935, 905, 979]}] |
Methyl-CpG binding protein 2 (MeCP2) has historically been linked to heterochromatin organization, and in mouse cells it accumulates at pericentric heterochromatin (PCH), closely following major satellite (MajSat) DNA distribution. However, little is known about the specific function of MeCP2 in these regions. We describe the first evidence of a role in neurons for MeCP2 and MajSat forward (MajSat-fw) RNA in reciprocal targeting to PCH through their physical interaction. Moreover, MeCP2 contributes to maintenance of PCH by promoting deposition of H3K9me3 and H4K20me3. We highlight that the MeCP2B isoform is required for correct higher-order PCH organization, and underline involvement of the methyl-binding and transcriptional repression domains. The T158 residue, which is commonly mutated in Rett patients, is directly involved in this process. Our findings support the hypothesis that MeCP2 and the MajSat-fw transcript are mutually dependent for PCH organization, and contribute to clarify MeCP2 function in the regulation of chromatin architecture.
Keywords: chromocenter clustering; major satellite transcripts; MeCP2; pericentric heterochromatin; Rett syndrome | [{'text': 'Pericentric heterochromatin organization in mESC-derived neurons', 'coordinates': [13, 31, 985, 75]}, {'text': 'Mecp2-ly neurons ~', 'coordinates': [38, 86, 321, 187]}, {'text': 'WT neurons upon MajSat-fw RNA KD MoCP2 UCCp2 Mecpe MCp MeCP2 NecP2 Mecp2 MeCP2 KaCp Nacpz Mecp2', 'coordinates': [689, 88, 955, 253]}, {'text': 'ND', 'coordinates': [156, 278, 194, 310]}, {'text': 'WT neurons Mecre Necpz UCCp Mocp2 NaCp2 oCP2 NoCP2 Macpz Macp2 Mecp2 NaCp2 Mac?z_', 'coordinates': [383, 308, 659, 421]}, {'text': 'MexP2', 'coordinates': [219, 361, 263, 375]}, {'text': 'MeCP2B ATRD', 'coordinates': [741, 481, 795, 511]}, {'text': 'MeCP2B', 'coordinates': [211, 487, 265, 501]}, {'text': 'ND Mecpz-ly neurons expressing MeCP2B_ AMBD MCP2B Wcd NaCP28 AC020 Macp8 Hacpz8 A8d Aubd Arad Noy Lkbl Macp28 NeCp2B Rce B OCFZB Rocp2B AHBD HTBD Utrd AMBD Lan MeCP2B AMBD', 'coordinates': [354, 488, 644, 721]}, {'text': 'Mecpzly neurons expressing MeCPZB', 'coordinates': [68, 537, 278, 596]}, {'text': 'Mecp2-ly neurons expressing MeCP2B ATRD', 'coordinates': [679, 537, 970, 592]}, {'text': 'MeCP2B Mocpzb MoCPZB HaCP2B MeCPz8 MoCP2B Vacp28 MeCP28 NOCP2BE MECPzBVccPzB LICP2B', 'coordinates': [29, 641, 319, 691]}, {'text': 'KoCp2B MoCPZB MeCPZB ARD CP2ETRD NaCP2i AIRD lCP2B MOCPZE MoCP28 DRD MaCPze TRD Mocp28 ATRO GRD ARD Aened ARD', 'coordinates': [700, 645, 967, 688]}, {'text': 'ND', 'coordinates': [150, 746, 190, 778]}, {'text': 'ND', 'coordinates': [802, 744, 838, 770]}, {'text': 'ND', 'coordinates': [478, 804, 516, 834]}, {'text': 'H3K9me3;- MajSat-fw RNA; mESC;', 'coordinates': [62, 858, 228, 958]}, {'text': 'H4K2Ome3;', 'coordinates': [211, 854, 336, 884]}, {'text': 'Absence of H3KIme3 or H4K2Ome3;', 'coordinates': [371, 854, 744, 885]}, {'text': 'Not investigated;', 'coordinates': [790, 856, 962, 886]}, {'text': 'MajSat-fw RNA knock-down;', 'coordinates': [288, 894, 576, 920]}, {'text': 'MeCP2 knock-out;', 'coordinates': [636, 894, 824, 920]}, {'text': 'mESC-derived neuron;', 'coordinates': [184, 932, 416, 958]}, {'text': 'chromocenter; ND: Neural differentiation', 'coordinates': [446, 932, 853, 958]}] |
Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.
Keywords: stress; host:commensal immunity; IgA; irritable bowel syndrome | [{'text': 'A', 'coordinates': [219, 87, 237, 113]}, {'text': 'putative model for stress induced anti-bacterial immunity', 'coordinates': [244, 75, 808, 168]}, {'text': "5' 8", 'coordinates': [918, 254, 984, 310]}, {'text': 'GAPs open', 'coordinates': [592, 364, 674, 432]}, {'text': 'Farttication', 'coordinates': [725, 356, 898, 429]}, {'text': 'IL', 'coordinates': [915, 304, 983, 445]}, {'text': 'Dysbiosis', 'coordinates': [322, 464, 474, 513]}, {'text': 'Stress', 'coordinates': [106, 554, 190, 584]}, {'text': 'Increased anti-bacterial IgA', 'coordinates': [587, 546, 754, 647]}, {'text': "9 2 5' 8 [", 'coordinates': [918, 578, 984, 798]}, {'text': 'Diarrhea', 'coordinates': [596, 722, 706, 754]}, {'text': 'Diarrhea-predominant IBS patients', 'coordinates': [14, 804, 291, 877]}] |
Chromosomal translocations are prevalent among soft tissue tumors, including those of the vasculature such as pseudomyogenic hemangioendothelioma (PHE). PHE shows endothelial cell (EC) features and has a tumor-specific t(7;19)(q22;q13) SERPINE1-FOSB translocation, but is difficult to study as no primary tumor cell lines have yet been derived. Here, we engineer the PHE chromosomal translocation into human induced pluripotent stem cells (hiPSCs) using CRISPR/Cas9 and differentiate these into ECs (hiPSC-ECs) to address this. Comparison of parental with PHE hiPSC-ECs shows (1) elevated expression of FOSB, (2) higher proliferation and more tube formation but lower endothelial barrier function, (3) invasive growth and abnormal vessel formation in mice after transplantation, and (4) specific transcriptome alterations reflecting PHE and indicating PI3K-Akt and MAPK signaling pathways as possible therapeutic targets. The modified hiPSC-ECs thus recapitulate functional features of PHE and demonstrate how these translocation models can be used to understand tumorigenic mechanisms and identify therapeutic targets.
Keywords: human induced pluripotent stem cells; hiPSCs; hiPSC-derived ECs; hiPSC-ECs; vascular tumor; tumor model; pseudomyogenic hemangioendothelioma; PHE; chromosomal translocation; gene fusion; CRISPR/Cas9-mediated gene targeting; t(7;19)(q22;q13) SERPINE1-FOSB chromosomal translocation; endothelial cell differentiation | [{'text': 'hiPSC-ECsWT', 'coordinates': [296, 70, 501, 114]}, {'text': 'hiPSC-ECs', 'coordinates': [601, 97, 773, 137]}, {'text': 'PHE model', 'coordinates': [783, 99, 965, 137]}, {'text': 'hiPSCWT', 'coordinates': [10, 226, 147, 268]}, {'text': 'Proliferation, tube formation', 'coordinates': [683, 241, 897, 319]}, {'text': 'FOSB', 'coordinates': [462, 288, 520, 312]}, {'text': 'SERPINET', 'coordinates': [238, 329, 338, 355]}, {'text': '19', 'coordinates': [420, 334, 454, 360]}, {'text': 'Barrier function Invasiveness Formation of abnormal vessels', 'coordinates': [665, 353, 921, 597]}, {'text': 'Functional Assays', 'coordinates': [537, 389, 707, 478]}, {'text': 'SERPINET FOSB', 'coordinates': [262, 622, 362, 672]}, {'text': 'SERPINE-FOSB', 'coordinates': [106, 650, 250, 676]}, {'text': '19', 'coordinates': [444, 644, 478, 670]}, {'text': 'Identification of dysregulated pathways', 'coordinates': [610, 630, 942, 716]}, {'text': 'hiPSC', 'coordinates': [9, 651, 113, 691]}, {'text': 'hiPSC-ECsSERPINEI-FOSB', 'coordinates': [243, 797, 565, 837]}, {'text': '(1) Therapeutic targets; (2) Mechanism of tumorigenesis', 'coordinates': [596, 815, 968, 956]}] |
Cellular identity is ultimately dictated by the interaction of transcription factors with regulatory elements (REs) to control gene expression. Advances in epigenome profiling techniques have significantly increased our understanding of cell-specific utilization of REs. However, it remains difficult to dissect the majority of factors that interact with these REs due to the lack of appropriate techniques. Therefore, we developed TINC: TALE-mediated isolation of nuclear chromatin. Using this new method, we interrogated the protein complex formed at the Nanog promoter in embryonic stem cells (ESCs) and identified many known and previously unknown interactors, including RCOR2. Further interrogation of the role of RCOR2 in ESCs revealed its involvement in the repression of lineage genes and the fine-tuning of pluripotency genes. Consequently, using the Nanog promoter as a paradigm, we demonstrated the power of TINC to provide insight into the molecular makeup of specific transcriptional complexes at individual REs as well as into cellular identity control in general.
Keywords: Epigenetics; Nanog; single-locus pull-down; pluripotency; transcriptional complex; RCOR2; iPSCs; reprogramming; TINC | [{'text': 'OCT4', 'coordinates': [195, 142, 305, 184]}, {'text': 'TALE', 'coordinates': [9, 174, 112, 216]}, {'text': 'SOX2', 'coordinates': [307, 181, 419, 225]}, {'text': 'Nanog', 'coordinates': [648, 153, 804, 216]}, {'text': 'NANOG', 'coordinates': [201, 251, 356, 300]}, {'text': 'Nanog regulatory complex', 'coordinates': [457, 331, 956, 396]}, {'text': 'Stem cell population maintenance Transcription regulation', 'coordinates': [448, 384, 743, 561]}, {'text': 'Chromatin modifications', 'coordinates': [775, 407, 973, 477]}, {'text': 'Cell cycle', 'coordinates': [819, 514, 960, 559]}, {'text': 'TINC-MSIMS', 'coordinates': [59, 549, 309, 593]}, {'text': 'RCORZ in pluripotency', 'coordinates': [498, 573, 922, 630]}, {'text': 'WT ESCs', 'coordinates': [449, 633, 623, 677]}, {'text': 'RCORZ', 'coordinates': [193, 684, 329, 726]}, {'text': 'Pluripotency', 'coordinates': [637, 721, 799, 757]}, {'text': 'OCT4', 'coordinates': [27, 754, 140, 796]}, {'text': 'SOX2', 'coordinates': [160, 779, 272, 823]}, {'text': 'Rcor2 KO ESCs', 'coordinates': [457, 801, 741, 845]}, {'text': 'Differentiation', 'coordinates': [775, 807, 979, 845]}, {'text': 'NANOG', 'coordinates': [11, 883, 167, 925]}, {'text': 'Pluripotency', 'coordinates': [638, 899, 800, 935]}] |
Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67+CD8 and ICOS+CD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.
Keywords: immunotherapy; bispecific; PD-1; CTLA-4; checkpoint; pharmacodynamics; combinatorial | [{'text': 'Combinatorial Checkpoint Blockade', 'coordinates': [212, 42, 776, 90]}, {'text': 'Combination', 'coordinates': [105, 109, 299, 147]}, {'text': 'MGDO19 PD-1 x CTLA-4 Bispecific', 'coordinates': [667, 111, 977, 192]}, {'text': 'PD-1 mAb', 'coordinates': [46, 158, 176, 188]}, {'text': 'CTLA-4 mAb', 'coordinates': [218, 156, 380, 188]}, {'text': 'Tumor', 'coordinates': [452, 370, 544, 402]}, {'text': 'T cells', 'coordinates': [632, 414, 714, 442]}, {'text': 'PD-1+ CTLA-4+', 'coordinates': [772, 442, 868, 496]}, {'text': 'PD-1', 'coordinates': [78, 466, 136, 492]}, {'text': 'CTLA-4+', 'coordinates': [246, 468, 342, 496]}, {'text': 'Healthy tissues', 'coordinates': [395, 545, 607, 583]}, {'text': 'T cells', 'coordinates': [206, 580, 290, 610]}, {'text': 'Blockade', 'coordinates': [128, 740, 256, 772]}, {'text': 'Blockade', 'coordinates': [738, 740, 868, 772]}, {'text': 'Healthy', 'coordinates': [837, 865, 945, 903]}, {'text': 'Tumor', 'coordinates': [50, 904, 142, 936]}, {'text': 'Healthy', 'coordinates': [243, 903, 353, 941]}, {'text': 'Tumor', 'coordinates': [645, 915, 742, 958]}] |
The approval of the first kinase inhibitor, Gleevec, ushered in a paradigm shift for oncological treatment—the use of genomic data for targeted, efficacious therapies. Since then, over 48 additional small-molecule kinase inhibitors have been approved, solidifying the case for kinases as a highly druggable and attractive target class. Despite the role deregulated kinase activity plays in cancer, only 8% of the kinome has been effectively “drugged.” Moreover, 24% of the 634 human kinases are understudied. We have developed a comprehensive scoring system that utilizes differential gene expression, pathological parameters, overall survival, and mutational hotspot analysis to rank and prioritize clinically relevant kinases across 17 solid tumor cancers from The Cancer Genome Atlas. We have developed the clinical kinase index (CKI) app (http://cki.ccs.miami.edu) to facilitate interactive analysis of all kinases in each cancer. Collectively, we report that understudied kinases have potential clinical value as biomarkers or drug targets that warrant further study.
Keywords: target validation; clinical scoring system; data integration; human kinome; cancer drug target; understudied kinase; druggable genome; differential gene expression; TNM score; Kaplan-Meier survival analysis | [{'text': 'Irecount2', 'coordinates': [469, 45, 656, 107]}, {'text': 'PHAROS', 'coordinates': [778, 50, 926, 98]}, {'text': 'Genomic and Clinical Features', 'coordinates': [19, 131, 280, 212]}, {'text': 'cBioPortal FOR CANCER GENOMICS', 'coordinates': [423, 140, 587, 193]}, {'text': 'TCGA CDR', 'coordinates': [652, 130, 790, 160]}, {'text': 'DrugCentral NIH', 'coordinates': [720, 196, 828, 285]}, {'text': 'TCGA', 'coordinates': [398, 232, 532, 280]}, {'text': 'NATIONAL CANCER INSTITUTE CDC Data Portal', 'coordinates': [811, 261, 983, 291]}, {'text': 'Survival', 'coordinates': [568, 342, 676, 372]}, {'text': 'Pathology Q Q 0 Q', 'coordinates': [795, 335, 932, 445]}, {'text': 'MT^ TT^', 'coordinates': [341, 383, 451, 463]}, {'text': 'Data Integration', 'coordinates': [21, 479, 281, 523]}, {'text': 'Expression', 'coordinates': [598, 510, 739, 550]}, {'text': 'Mutations', 'coordinates': [840, 510, 973, 547]}, {'text': 'Tt T^t', 'coordinates': [343, 547, 449, 625]}, {'text': 'Cancer Types', 'coordinates': [568, 682, 741, 721]}, {'text': 'Clinical Kinase Index', 'coordinates': [37, 821, 264, 901]}, {'text': '1', 'coordinates': [380, 774, 404, 924]}] |
Pioneer transcription factors (pTFs) bind to target sites within compact chromatin, initiating chromatin remodeling and controlling the recruitment of downstream factors. The mechanisms by which pTFs overcome the chromatin barrier are not well understood. Here, we reveal, using single-molecule fluorescence, how the yeast transcription factor Rap1 invades and remodels chromatin. Using a reconstituted chromatin system replicating yeast promoter architecture, we demonstrate that Rap1 can bind nucleosomal DNA within a chromatin fiber but with shortened dwell times compared to naked DNA. Moreover, we show that Rap1 binding opens chromatin fiber structure by inhibiting inter-nucleosome contacts. Finally, we reveal that Rap1 collaborates with the chromatin remodeler RSC to displace promoter nucleosomes, paving the way for long-lived bound states on newly exposed DNA. Together, our results provide a mechanistic view of how Rap1 gains access and opens chromatin, thereby establishing an active promoter architecture and controlling gene expression.
Keywords: pioneer transcription factor; Rap1; chromatin structure; chromatin dynamics; single-molecule fluorescence; FRET; RSC; chromatin remodeling | [{'text': 'Rap1', 'coordinates': [475, 9, 586, 65]}, {'text': 'Target search', 'coordinates': [658, 56, 802, 168]}, {'text': 'TF binding', 'coordinates': [12, 113, 205, 169]}, {'text': 'sites', 'coordinates': [13, 171, 101, 213]}, {'text': 'Chromatin invasion & opening', 'coordinates': [661, 270, 884, 447]}, {'text': 'NDR', 'coordinates': [665, 533, 759, 577]}, {'text': 'formation', 'coordinates': [659, 589, 870, 640]}, {'text': 'RSC', 'coordinates': [341, 641, 413, 677]}, {'text': 'Gene', 'coordinates': [662, 798, 778, 848]}, {'text': 'activation', 'coordinates': [659, 858, 867, 908]}, {'text': 'on', 'coordinates': [472, 956, 518, 984]}, {'text': 'off', 'coordinates': [501, 185, 560, 216]}] |
Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.
Keywords: Alzheimer's disease; bile acids; cholesterol metabolism; transcriptomics; metabolomics; genome-scale metabolic models; transcriptional regulatory networks | [{'text': "Altered cholesterol and bile acid metabolism in Alzheimer's disease", 'coordinates': [62, 5, 882, 101]}, {'text': 'Metabolic profile of Bile acids in brain', 'coordinates': [690, 117, 990, 203]}, {'text': 'Cholesterol', 'coordinates': [187, 169, 306, 197]}, {'text': 'Classical pathway CYPZA1 HSD3B7 CYPBB1 CA TCA GCA DCA GDCA | TUDCA', 'coordinates': [117, 192, 278, 516]}, {'text': 'Alternative pathway CYP2ZA1 CYPTB1 HSD3B7 CDCA GCDCA UDCA', 'coordinates': [238, 193, 388, 466]}, {'text': '9 5 9 2', 'coordinates': [620, 190, 682, 342]}, {'text': 'Bile acids in brain tissue', 'coordinates': [680, 338, 982, 370]}, {'text': 'TCDCA LCA TLCA', 'coordinates': [338, 386, 424, 516]}, {'text': 'Brain region-specific metabolic network', 'coordinates': [645, 409, 967, 489]}, {'text': 'TDCA', 'coordinates': [68, 490, 126, 514]}, {'text': 'GUDCA', 'coordinates': [284, 492, 360, 516]}, {'text': 'GLCA', 'coordinates': [436, 490, 496, 516]}, {'text': 'Parahippocampal gyrus', 'coordinates': [297, 554, 552, 637]}, {'text': 'Prefrontal cortex', 'coordinates': [5, 625, 265, 665]}, {'text': 'Brain transcriptional regulatory network', 'coordinates': [634, 668, 950, 758]}, {'text': 'Frontal', 'coordinates': [5, 697, 121, 733]}, {'text': "'Temporal cortex", 'coordinates': [403, 737, 560, 821]}, {'text': 'Inferior frontal gyrus', 'coordinates': [9, 775, 231, 859]}, {'text': 'Cerebellum', 'coordinates': [332, 822, 517, 865]}, {'text': 'Superior temporal gyrus', 'coordinates': [111, 850, 400, 941]}, {'text': 'pole', 'coordinates': [118, 700, 196, 732]}] |
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
Keywords: slow-cycling phenotype; tumor microenvironment; therapy resistance; melanoma; wild-type 53; Wnt5A; aged microenvironment | [{'text': 'DNA Damage, Targeted Therapy, Aging', 'coordinates': [97, 72, 622, 117]}, {'text': 'Wnt5A', 'coordinates': [250, 141, 348, 173]}, {'text': 'Extracellular Space', 'coordinates': [786, 214, 982, 244]}, {'text': '8', 'coordinates': [316, 246, 340, 304]}, {'text': 'Melanoma Cell', 'coordinates': [18, 296, 172, 322]}, {'text': 'Cytoplasm', 'coordinates': [868, 298, 980, 326]}, {'text': 'PKC', 'coordinates': [584, 432, 642, 460]}, {'text': 'p53', 'coordinates': [181, 443, 243, 481]}, {'text': 'iASPP', 'coordinates': [404, 456, 486, 486]}, {'text': 'iASPP', 'coordinates': [740, 466, 822, 496]}, {'text': 'iASPP', 'coordinates': [334, 500, 416, 530]}, {'text': 'MDM2', 'coordinates': [360, 662, 438, 690]}, {'text': 'iASPP', 'coordinates': [614, 692, 698, 722]}, {'text': 'Nucleus', 'coordinates': [846, 798, 930, 822]}, {'text': 'Slow Cycling Phenotype', 'coordinates': [199, 818, 527, 860]}, {'text': 'Apoptosis', 'coordinates': [593, 819, 731, 857]}, {'text': 'Therapy Resistance', 'coordinates': [353, 890, 627, 934]}, {'text': 'p53', 'coordinates': [275, 688, 339, 718]}] |
Accumulation of CD103+CD8+ resident memory T (TRM) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of TRM to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103+CD8+ lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103+CD8+ cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103+CD8+ cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103+CD8+ tumor TRM, but not CD103−CD8+ tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103+CD8+ TRM are associated with better outcomes in anti-PD-(L)1-treated patients.
Keywords: CD8 TRM cells; CTL; Tc17; lung cancer; anti-PD-1 immunotherapy; tumor-infiltrating lymphocytes; ICB response biomarkers; Aiolos, AhR, and T-bet transcription factors; CD103 integrin; TCR repertoire | [{'text': 'anti-PD-(L)1', 'coordinates': [172, 16, 402, 70]}, {'text': 'TRM', 'coordinates': [715, 43, 787, 87]}, {'text': '(CD103-', 'coordinates': [786, 36, 938, 90]}, {'text': 'non-Trm (CD103)', 'coordinates': [462, 110, 786, 164]}, {'text': '3 3', 'coordinates': [494, 228, 520, 296]}, {'text': 'Anti-PD-(L)1 response', 'coordinates': [526, 212, 946, 268]}, {'text': 'Patient survival', 'coordinates': [524, 259, 821, 310]}, {'text': 'IFNY; IL-17', 'coordinates': [157, 365, 327, 405]}, {'text': 'TCR', 'coordinates': [389, 409, 463, 447]}, {'text': 'CD103', 'coordinates': [68, 458, 194, 508]}, {'text': 'CD4ga', 'coordinates': [271, 443, 385, 483]}, {'text': '4-1BB', 'coordinates': [555, 443, 655, 479]}, {'text': 'KLRGT', 'coordinates': [687, 455, 809, 499]}, {'text': 'TCR', 'coordinates': [843, 440, 920, 484]}, {'text': 'CD39', 'coordinates': [471, 475, 565, 517]}, {'text': 'CD69', 'coordinates': [197, 497, 291, 539]}, {'text': 'PD-1 TT', 'coordinates': [13, 527, 105, 665]}, {'text': 'PD-1', 'coordinates': [903, 521, 981, 557]}, {'text': 'Tbet', 'coordinates': [439, 701, 531, 743]}, {'text': 'TRM', 'coordinates': [23, 737, 129, 801]}, {'text': 'non-TRM', 'coordinates': [748, 738, 975, 801]}, {'text': 'pSTAT3', 'coordinates': [303, 773, 453, 834]}, {'text': 'AhR', 'coordinates': [189, 817, 265, 857]}, {'text': 'ZEB1', 'coordinates': [497, 869, 593, 911]}, {'text': 'TCF-1', 'coordinates': [841, 853, 945, 895]}, {'text': 'Aiolos', 'coordinates': [249, 901, 365, 943]}] |
In vitro spermatogenesis has been achieved by culturing mouse embryonic stem cells (ESCs) together with a cell suspension of male juvenile gonad. However, for human fertility treatment or preservation, patient-specific ESCs or juvenile gonad is not available. We therefore aim to achieve in vitro spermatogenesis using male germline stem cells (GSCs) without the use of juvenile gonad. GSCs, when cultured on immortalized Sertoli cells, were able to enter meiosis, reach the meiotic metaphase stages, and sporadically form spermatid-like cells. However, the in vitro-formed pachytene-like spermatocytes did not display full chromosome synapsis and did not form meiotic crossovers. Despite this, the meiotic checkpoints that usually eliminate such cells to prevent genomic instabilities from being transmitted to the offspring were not activated, allowing the cells to proceed to the meiotic metaphase stages. In vitro-generated spermatid-like cells should thus be thoroughly investigated before being considered for clinical use.
Keywords: in vitro spermatogenesis; spermatogonial stem cells; Sertoli cell lines; meiotic checkpoints; meiosis | [{'text': 'Active state of prophase checkpoints', 'coordinates': [411, 81, 597, 123]}, {'text': 'Active state of the spindle assembly checkpoint', 'coordinates': [666, 81, 942, 124]}, {'text': 'On', 'coordinates': [515, 233, 543, 253]}, {'text': 'Meiotic arrest', 'coordinates': [593, 245, 709, 265]}, {'text': 'Pachynema-like Incomplete synapsis No crossover formation', 'coordinates': [316, 309, 516, 380]}, {'text': 'In vivo', 'coordinates': [6, 378, 80, 402]}, {'text': 'Leptonema Zygonema', 'coordinates': [85, 439, 282, 467]}, {'text': 'Off', 'coordinates': [515, 469, 545, 489]}, {'text': 'Off', 'coordinates': [755, 467, 785, 487]}, {'text': 'Pachynema Complete synapsis Crossover formation', 'coordinates': [318, 541, 491, 609]}, {'text': 'Bivalent', 'coordinates': [619, 547, 691, 567]}, {'text': 'Haploid', 'coordinates': [844, 542, 914, 566]}, {'text': 'Off', 'coordinates': [517, 685, 545, 701]}, {'text': 'Off', 'coordinates': [755, 683, 785, 703]}, {'text': 'In vitro', 'coordinates': [6, 694, 84, 718]}, {'text': 'Leptonema Zygonema', 'coordinates': [88, 758, 280, 782]}, {'text': 'Pachynema-like Incomplete synapsis No crossover formation', 'coordinates': [316, 757, 516, 828]}, {'text': 'Univalent', 'coordinates': [617, 759, 702, 785]}, {'text': 'Aneuploid ?', 'coordinates': [823, 755, 926, 783]}, {'text': 'Prophase', 'coordinates': [253, 899, 335, 919]}, {'text': 'Metaphase', 'coordinates': [601, 899, 693, 919]}, {'text': 'After metaphase Il', 'coordinates': [801, 899, 953, 919]}] |
The tetravalent live attenuated dengue vaccine candidate TV003 induces neutralizing antibodies against all four dengue virus serotypes (DENV1–DENV4) and protects against experimental challenge with DENV2 in humans. Here, we track vaccine viremia and B and T cell responses to this vaccination/challenge model to understand how vaccine viremia links adaptive immunity and development of protective antibody responses. TV003 viremia triggers an acute plasmablast response that, in combination with DENV-specific CD4+ T cells, correlates with serum neutralizing antibodies. TV003 vaccinees develop DENV2-reactive memory B cells, including serotype-specific and multivalent specificities in line with the composition of serum antibodies. There is no post-challenge plasmablast response in vaccinees, although stronger and earlier post-TV003 plasmablast responses associate with sterile humoral protection from DENV2 challenge. TV003 vaccine triggers plasmablasts and memory B cells, which, with support from CD4+ T cells, functionally link early vaccine viremia and the serum antibody responses.
Keywords: dengue vaccine; tetravalent live attenuated vaccine; humoral immune response; neutralizing antibodies; memory B cells; CD4 T cells; protective immunity; TV003; serotype-specific antibodies | [{'text': 'Live Attenuated Tetravalent Dengue Vaccine stimulates B and T cell responses in humans', 'coordinates': [14, 9, 984, 42]}, {'text': 'No viremia No Rash Non-sterile protection Dengue 2 antibody boost) Sterile protection I(No DENV2 antibody boost)', 'coordinates': [671, 92, 942, 280]}, {'text': 'months', 'coordinates': [337, 117, 399, 137]}, {'text': 'months', 'coordinates': [681, 117, 747, 137]}, {'text': 'TV003 TV003: Live attenuated tetravalent dengue vaccine', 'coordinates': [9, 135, 168, 293]}, {'text': 'Experimental dengue-2 virus (DENV2) challenge', 'coordinates': [353, 219, 540, 296]}, {'text': "TV003 vaccine response 'DENV1-4 serotypes", 'coordinates': [176, 330, 404, 442]}, {'text': 'Post-challenge response', 'coordinates': [487, 326, 715, 356]}, {'text': 'Relative size of vaccine plasmablast response', 'coordinates': [796, 342, 940, 439]}, {'text': '| { 6', 'coordinates': [60, 345, 108, 558]}, {'text': 'chelengao', 'coordinates': [398, 382, 502, 436]}, {'text': '(vwocination', 'coordinates': [122, 434, 244, 486]}, {'text': 'Non-sterile protection Sterile protection', 'coordinates': [589, 450, 804, 520]}, {'text': 'Time (days) 0', 'coordinates': [4, 567, 132, 597]}, {'text': '14 21 28 56 90', 'coordinates': [152, 568, 363, 592]}, {'text': '180 194 201', 'coordinates': [414, 568, 532, 592]}, {'text': '208 236', 'coordinates': [540, 568, 634, 592]}, {'text': '270 360', 'coordinates': [640, 568, 728, 592]}, {'text': 'No plasmablast boost', 'coordinates': [558, 637, 774, 664]}, {'text': 'TV003 vaccine viremia', 'coordinates': [208, 672, 284, 746]}, {'text': 'Dengue 2+ type-specific Dengue 2+ cross-reactive', 'coordinates': [656, 743, 799, 855]}, {'text': 'IFN-Y', 'coordinates': [338, 782, 394, 808]}, {'text': 'Dengue-specific CD4+ T cells', 'coordinates': [250, 858, 402, 906]}, {'text': 'Plasmablasts', 'coordinates': [98, 878, 224, 902]}, {'text': 'Dengue 2+ Memory B cells', 'coordinates': [497, 877, 758, 905]}] |
Prevotella spp. are a dominant bacterial genus within the human gut. Multiple Prevotella spp. co-exist in some individuals, particularly those consuming plant-based diets. Additionally, Prevotella spp. exhibit variability in the utilization of diverse complex carbohydrates. To investigate the relationship between Prevotella competition and diet, we isolated Prevotella species from the mouse gut, analyzed their genomes and transcriptomes in vivo, and performed competition experiments between species in mice. Diverse dominant Prevotella species compete for similar metabolic niches in vivo, which is linked to the upregulation of specific polysaccharide utilization loci (PULs). Complex plant-derived polysaccharides are required for Prevotella spp. expansion, with arabinoxylans having a prominent impact on species abundance. The most dominant Prevotella species encodes a specific tandem-repeat trsusC/D PUL that enables arabinoxylan utilization and is conserved in human Prevotella copri strains, particularly among those consuming a vegan diet. These findings suggest that efficient (arabino)xylan-utilization is a factor contributing to Prevotella dominance.
Keywords: Prevotella spp.; diet; competition; polysaccharides; gut microbiome; metagenomics; fiber degradation; anaerobic microbiology | [{'text': 'Mouse', 'coordinates': [28, 8, 147, 49]}, {'text': 'Prevotella spp.', 'coordinates': [185, 29, 419, 71]}, {'text': 'MAGs', 'coordinates': [25, 83, 131, 121]}, {'text': 'Isolates', 'coordinates': [151, 85, 281, 121]}, {'text': '3 Species', 'coordinates': [374, 80, 540, 128]}, {'text': '8', 'coordinates': [652, 92, 678, 124]}, {'text': '7', 'coordinates': [652, 126, 678, 266]}, {'text': 'post-colonization', 'coordinates': [736, 275, 936, 307]}, {'text': 'Phylogenomics', 'coordinates': [35, 325, 286, 378]}, {'text': 'Culturomics', 'coordinates': [356, 328, 553, 372]}, {'text': 'In vivo Competitivve fitness', 'coordinates': [647, 333, 955, 406]}, {'text': 'Human', 'coordinates': [27, 429, 153, 467]}, {'text': 'P copri (MAGs)', 'coordinates': [267, 465, 491, 504]}, {'text': '3 dietary habits', 'coordinates': [109, 528, 238, 605]}, {'text': '(Meta)transcriptome', 'coordinates': [628, 536, 956, 584]}, {'text': 'Omnivore', 'coordinates': [297, 595, 459, 637]}, {'text': 'VS', 'coordinates': [558, 672, 602, 702]}, {'text': 'Vegetarian', 'coordinates': [288, 742, 468, 792]}, {'text': 'WAX supplementation', 'coordinates': [614, 764, 974, 820]}, {'text': 'trsusC/D SuSD1 susC2 SUSD2 PUL signature', 'coordinates': [676, 855, 952, 992]}, {'text': 'SusC1', 'coordinates': [660, 916, 730, 940]}, {'text': 'Vegan', 'coordinates': [322, 927, 435, 978]}, {'text': 'Days', 'coordinates': [677, 273, 733, 308]}] |
Mutations in KCNH2 can lead to long QT syndrome type 2. Variable disease manifestation observed with this channelopathy is associated with the location and type of mutation within the protein, complicating efforts to predict patient risk. Here, we demonstrated phenotypic differences in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSC-CMs) genetically edited to harbor mutations either within the pore or tail region of the ion channel. Electrophysiological analysis confirmed that the mutations prolonged repolarization of the hiPSC-CMs, with differences between the mutations evident in monolayer cultures. Blocking the hERG channel revealed that the pore-loop mutation conferred greater susceptibility to arrhythmic events. These findings showed that subtle phenotypic differences related to KCNH2 mutations could be captured by hiPSC-CMs under genetically matched conditions. Moreover, the results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual KCNH2 mutations in humans, which could facilitate patient risk stratification.
Keywords: long QT syndrome 2; disease modeling; induced pluripotent stem cells; isogenic; arrhythmia; risk stratification; genome editing; electrophysiology | [{'text': 'Introduce genetic variants:', 'coordinates': [124, 2, 584, 57]}, {'text': 'ULLLLL', 'coordinates': [338, 198, 466, 226]}, {'text': 'L', 'coordinates': [737, 196, 795, 226]}, {'text': 'KCNHZAS6ITIwt', 'coordinates': [168, 241, 343, 277]}, {'text': 'control hiPSC', 'coordinates': [476, 246, 650, 278]}, {'text': 'KCNH2N9961wt', 'coordinates': [785, 243, 957, 279]}, {'text': 'Differentiate to cardiomyocytes:', 'coordinates': [124, 305, 677, 366]}, {'text': 'hERG', 'coordinates': [76, 500, 148, 530]}, {'text': 'Iaeeee) (9UU', 'coordinates': [198, 515, 356, 590]}, {'text': 'Mheeed (UU', 'coordinates': [502, 515, 658, 590]}, {'text': 'Afipiis) 68620', 'coordinates': [805, 510, 969, 588]}, {'text': 'W', 'coordinates': [166, 564, 212, 588]}, {'text': 'V', 'coordinates': [470, 564, 516, 588]}, {'text': 'W', 'coordinates': [778, 562, 822, 586]}, {'text': 'pore mutation', 'coordinates': [167, 621, 349, 659]}, {'text': 'wildtype', 'coordinates': [511, 621, 621, 659]}, {'text': 'tail mutation', 'coordinates': [788, 622, 950, 652]}, {'text': 'Functionally compare:', 'coordinates': [124, 689, 509, 746]}, {'text': 'H', 'coordinates': [781, 758, 928, 858]}, {'text': 'Action & field potential duration (monolayer): pore > tail >', 'coordinates': [190, 867, 479, 991]}, {'text': 'Compound sensitivity (arrhythmia-like events):', 'coordinates': [643, 866, 949, 943]}, {'text': 'wildtype', 'coordinates': [372, 939, 517, 996]}, {'text': 'pore > tail >', 'coordinates': [624, 951, 807, 991]}, {'text': 'wildtype', 'coordinates': [810, 943, 950, 996]}] |
In mammals, chromatin organization undergoes drastic reorganization during oocyte development. However, the dynamics of three-dimensional chromatin structure in this process is poorly characterized. Using low-input Hi-C (genome-wide chromatin conformation capture), we found that a unique chromatin organization gradually appears during mouse oocyte growth. Oocytes at late stages show self-interacting, cohesin-independent compartmental domains marked by H3K27me3, therefore termed Polycomb-associating domains (PADs). PADs and inter-PAD (iPAD) regions form compartment-like structures with strong inter-domain interactions among nearby PADs. PADs disassemble upon meiotic resumption from diplotene arrest but briefly reappear on the maternal genome after fertilization. Upon maternal depletion of Eed, PADs are largely intact in oocytes, but their reestablishment after fertilization is compromised. By contrast, depletion of Polycomb repressive complex 1 (PRC1) proteins attenuates PADs in oocytes, which is associated with substantial gene de-repression in PADs. These data reveal a critical role of Polycomb in regulating chromatin architecture during mammalian oocyte growth and early development.
Keywords: Oocytes; Embryos; Chromatin architecture; Hi-C; Polycomb; Polycomb-associating domains (PADs) | [{'text': 'Mouse oogenesis', 'coordinates': [364, 15, 632, 63]}, {'text': 'PGC', 'coordinates': [45, 139, 115, 175]}, {'text': 'GO |', 'coordinates': [264, 142, 334, 174]}, {'text': 'GO II', 'coordinates': [394, 142, 468, 174]}, {'text': 'FGO', 'coordinates': [532, 142, 602, 174]}, {'text': 'GVBD', 'coordinates': [706, 142, 796, 174]}, {'text': 'MIl oocyte', 'coordinates': [827, 141, 971, 179]}, {'text': 'Conventional TAD Compartment AIB', 'coordinates': [40, 182, 288, 262]}, {'text': 'PAD', 'coordinates': [508, 264, 572, 296]}, {'text': 'TAD', 'coordinates': [96, 576, 146, 602]}, {'text': 'PAD-PAD interaction', 'coordinates': [224, 598, 346, 654]}, {'text': 'PAD', 'coordinates': [364, 674, 418, 700]}, {'text': 'TAD iPAD', 'coordinates': [432, 674, 492, 736]}, {'text': 'PAD', 'coordinates': [576, 674, 628, 698]}, {'text': 'TAD', 'coordinates': [258, 768, 344, 798]}, {'text': 'H3K27me3 Gene Cohesin Polycomb', 'coordinates': [870, 778, 976, 958]}, {'text': 'PAD', 'coordinates': [292, 930, 358, 960]}] |
Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprising Caenorhabditis elegans and Pseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting an Amycolatopsis methanolica strain 239T chorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC50 value of 1.4 μM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.
Keywords: actinobacteria; genome mining; mutasynthesis; siderophore; Caenorhabditis elegans; Pseudomonas aeruginosa; drug discovery; pathogenesis; NRPS; host-pathogen interaction | [{'text': 'Genome mining', 'coordinates': [169, 27, 381, 65]}, {'text': 'CAya L C-AncLTE', 'coordinates': [395, 73, 515, 89]}, {'text': 'Anti-P aeruginosa agent', 'coordinates': [647, 80, 976, 119]}, {'text': 'C-Asa T-C-AtcT-TE', 'coordinates': [229, 109, 349, 127]}, {'text': 'CAtnTC- AlcTTE CAsT-C At-TTE', 'coordinates': [311, 149, 461, 215]}, {'text': 'HO OH HN- HN', 'coordinates': [721, 161, 825, 269]}, {'text': 'NH HO NH HN', 'coordinates': [809, 227, 925, 355]}, {'text': 'Iron deficient', 'coordinates': [182, 424, 308, 450]}, {'text': 'Fluoroamychelin', 'coordinates': [706, 452, 878, 480]}, {'text': '(3)', 'coordinates': [888, 452, 924, 482]}, {'text': 'Iron supplemented', 'coordinates': [180, 510, 356, 536]}, {'text': 'Natural', 'coordinates': [44, 614, 116, 638]}, {'text': 'Bioassay', 'coordinates': [237, 653, 328, 680]}, {'text': '1 1', 'coordinates': [633, 643, 649, 731]}, {'text': 'Modified', 'coordinates': [46, 708, 130, 732]}, {'text': 'Infection models', 'coordinates': [372, 750, 456, 800]}, {'text': 'IU I50 Hours', 'coordinates': [811, 787, 905, 825]}, {'text': '20', 'coordinates': [951, 787, 977, 801]}, {'text': 'Mutasynthesis and nematode HTS', 'coordinates': [122, 782, 375, 848]}, {'text': 'Mutasynthesis', 'coordinates': [47, 589, 169, 518]}, {'text': '1', 'coordinates': [408, 526, 481, 590]}] |
The histone chaperone FACT and histone H2B ubiquitination (H2Bub) facilitate RNA polymerase II (Pol II) passage through chromatin, yet it is not clear how they cooperate mechanistically. We used genomics, genetic, biochemical, and microscopic approaches to dissect their interplay in Schizosaccharomyces pombe. We show that FACT and H2Bub globally repress antisense transcripts near the 5′ end of genes and inside gene bodies, respectively. The accumulation of these transcripts is accompanied by changes at genic nucleosomes and Pol II redistribution. H2Bub is required for FACT activity in genic regions. In the H2Bub mutant, FACT binding to chromatin is altered and its association with histones is stabilized, which leads to the reduction of genic nucleosomes. Interestingly, FACT depletion globally restores nucleosomes in the H2Bub mutant. Moreover, in the absence of Pob3, the FACT Spt16 subunit controls the 3′ end of genes. Furthermore, FACT maintains nucleosomes in subtelomeric regions, which is crucial for their compaction.
Keywords: FACT; H2B ubiquitination; chromatin structure; histone chaperone; S. pombe | [{'text': 'FACT complex', 'coordinates': [261, 41, 489, 81]}, {'text': 'Pob3 8 8 1 1 8', 'coordinates': [166, 173, 304, 331]}, {'text': 'Pob9 (Spt16', 'coordinates': [399, 175, 591, 235]}, {'text': 'Spt16', 'coordinates': [742, 178, 837, 220]}, {'text': '% 1 2 1', 'coordinates': [652, 200, 770, 321]}, {'text': 'ub', 'coordinates': [234, 438, 268, 462]}, {'text': 'ub', 'coordinates': [386, 438, 422, 462]}, {'text': 'ub', 'coordinates': [546, 438, 582, 462]}, {'text': 'ub', 'coordinates': [684, 438, 720, 462]}, {'text': 'TSS', 'coordinates': [107, 493, 185, 533]}, {'text': 'TTS', 'coordinates': [809, 493, 885, 533]}, {'text': 'Genic nucleosome assembly', 'coordinates': [292, 541, 733, 585]}, {'text': 'H2Bub enhances histone release from FACT', 'coordinates': [210, 640, 412, 726]}, {'text': 'ub', 'coordinates': [442, 642, 478, 666]}, {'text': 'HZBub maintains FACT within genes', 'coordinates': [554, 639, 774, 700]}, {'text': 'Pob3)', 'coordinates': [353, 865, 441, 901]}, {'text': 'ub', 'coordinates': [742, 876, 778, 900]}, {'text': 'Spt16', 'coordinates': [445, 881, 541, 921]}, {'text': 'HZA-HZBub', 'coordinates': [832, 900, 972, 928]}] |
Apicomplexan parasites cause major human disease and food insecurity. They owe their considerable success to highly specialized cell compartments and structures. These adaptations drive their recognition, nondestructive penetration, and elaborate reengineering of the host’s cells to promote their growth, dissemination, and the countering of host defenses. The evolution of unique apicomplexan cellular compartments is concomitant with vast proteomic novelty. Consequently, half of apicomplexan proteins are unique and uncharacterized. Here, we determine the steady-state subcellular location of thousands of proteins simultaneously within the globally prevalent apicomplexan parasite Toxoplasma gondii. This provides unprecedented comprehensive molecular definition of these unicellular eukaryotes and their specialized compartments, and these data reveal the spatial organizations of protein expression and function, adaptation to hosts, and the underlying evolutionary trajectories of these pathogens.
Keywords: apicomplexa; toxoplasma; plasmodium; proteomics; subcellular; organelle; parasitism; invasion; host-pathogen interaction; evolution | [{'text': 'evolution of novelty', 'coordinates': [67, 0, 437, 58]}, {'text': 'global spatial proteome', 'coordinates': [540, 0, 988, 58]}, {'text': 'free-living ancestor', 'coordinates': [60, 50, 197, 129]}, {'text': 'apicomplexan parasite', 'coordinates': [307, 57, 495, 133]}, {'text': 'cellular landscapes of function and evolution', 'coordinates': [593, 502, 941, 577]}, {'text': 'transition to parasitism', 'coordinates': [34, 898, 262, 992]}, {'text': 'adaptation to hosts', 'coordinates': [395, 897, 600, 985]}, {'text': 'bare essential proteomes', 'coordinates': [702, 896, 974, 992]}] |
Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression in vivo and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
Keywords: signal transduction; KRAS; AMG 510; PDAC; acquired resistance; protein translation; cellular toxicity; tumor regression | [{'text': 'Adaptive resistance', 'coordinates': [99, 30, 405, 70]}, {'text': 'Combination drug sensitivity', 'coordinates': [517, 26, 966, 75]}, {'text': 'AMG-51O/Trametinib', 'coordinates': [90, 116, 326, 144]}, {'text': 'AMG-51O/Trametinib', 'coordinates': [581, 116, 817, 144]}, {'text': 'KRASIMEK', 'coordinates': [138, 224, 272, 252]}, {'text': 'KRASIMEK', 'coordinates': [631, 226, 761, 252]}, {'text': 'ERK', 'coordinates': [88, 344, 142, 368]}, {'text': 'mTORC1/2', 'coordinates': [248, 340, 376, 370]}, {'text': 'ERK', 'coordinates': [580, 344, 636, 370]}, {'text': 'mTORC1/2', 'coordinates': [742, 342, 870, 372]}, {'text': 'J', 'coordinates': [944, 314, 968, 398]}, {'text': '{', 'coordinates': [122, 532, 150, 612]}, {'text': '{', 'coordinates': [618, 532, 646, 612]}, {'text': '1', 'coordinates': [121, 609, 150, 678]}, {'text': '1', 'coordinates': [617, 606, 648, 679]}, {'text': 'PDAC tumor growth & metastasis', 'coordinates': [236, 846, 386, 932]}, {'text': 'PDAC tumor growth & metastasis', 'coordinates': [733, 846, 884, 932]}] |
Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8+ T effector cells is critical for obesity-associated breast tumor progression. Ablating T cell Stat3 or treatment with an FAO inhibitor in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8+ T effector cell functions, leading to inhibition of breast tumor development. Moreover, PD-1 ligation in CD8+ T cells activates STAT3 to increase FAO, inhibiting CD8+ T effector cell glycolysis and functions. Finally, leptin enriched in mammary adipocytes and fat tissues downregulates CD8+ T cell effector functions through activating STAT3-FAO and inhibiting glycolysis. We identify a critical role of increased oxidation of fatty acids driven by leptin and PD-1 through STAT3 in inhibiting CD8+ T effector cell glycolysis and in promoting obesity-associated breast tumorigenesis.
Keywords: obesity; FAO; PD-1; leptin; CD8 T cells; tumor; STAT3; IFNγ; PyMT model | [{'text': 'Breast Adipocytes', 'coordinates': [79, 33, 357, 73]}, {'text': 'Tumor CD8+ T cells', 'coordinates': [555, 32, 851, 72]}, {'text': 'Leptin Fatty acids', 'coordinates': [413, 98, 536, 164]}, {'text': 'LEPR', 'coordinates': [622, 118, 686, 142]}, {'text': 'PDI', 'coordinates': [736, 118, 782, 142]}, {'text': 'STAT3 ablation', 'coordinates': [256, 464, 454, 496]}, {'text': 'STAT3', 'coordinates': [582, 456, 666, 486]}, {'text': 'STAT3', 'coordinates': [722, 458, 808, 488]}, {'text': 'STAT3', 'coordinates': [578, 570, 664, 598]}, {'text': 'STAT3', 'coordinates': [722, 570, 808, 598]}, {'text': 'CPTIB', 'coordinates': [649, 615, 743, 643]}, {'text': 'FAO inhibition', 'coordinates': [266, 700, 454, 732]}, {'text': 'Fatty Acid &', 'coordinates': [556, 706, 716, 738]}, {'text': 'Oxidation', 'coordinates': [730, 706, 860, 736]}, {'text': 'Glycolysis, IFNY ', 'coordinates': [601, 797, 815, 833]}, {'text': 'Tumor CD8+ T effector cells', 'coordinates': [531, 890, 886, 922]}] |
Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
Keywords: metabolomics; succinate; SUCNR1; tumor microenvironment; tumor-associated macrophages; cancer metastasis; PI3K-HIF-1α axis | [{'text': 'Cancer cell', 'coordinates': [4, 0, 208, 43]}, {'text': 'E-cadherin N-cadherin Vimentin', 'coordinates': [549, 13, 731, 133]}, {'text': 'Fumarate', 'coordinates': [97, 119, 253, 157]}, {'text': 'SDH', 'coordinates': [83, 169, 165, 205]}, {'text': 'Tumor metastasis', 'coordinates': [686, 155, 898, 247]}, {'text': 'defect Succinate', 'coordinates': [65, 188, 348, 241]}, {'text': 'Ca2+-', 'coordinates': [305, 321, 381, 361]}, {'text': 'HIF-Ia', 'coordinates': [518, 305, 635, 345]}, {'text': 'PI3K', 'coordinates': [415, 372, 502, 415]}, {'text': 'IL-6R', 'coordinates': [853, 391, 947, 427]}, {'text': 'SUCNRI', 'coordinates': [337, 469, 485, 509]}, {'text': 'IL-6', 'coordinates': [811, 537, 879, 575]}, {'text': 'SUCNR1', 'coordinates': [113, 553, 263, 593]}, {'text': 'IHU', 'coordinates': [263, 549, 335, 617]}, {'text': 'PI3K', 'coordinates': [301, 655, 385, 691]}, {'text': 'Fumarate SDH', 'coordinates': [39, 753, 197, 845]}, {'text': 'HIF-Ia', 'coordinates': [322, 744, 439, 784]}, {'text': 'TAM polarization', 'coordinates': [483, 733, 721, 833]}, {'text': 'Succinate', 'coordinates': [131, 825, 291, 863]}, {'text': 'Arg1 , Fizza 1 Mgl1 , Mgl2', 'coordinates': [490, 858, 708, 949]}, {'text': 'Macrophage', 'coordinates': [3, 943, 228, 996]}] |
The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.
Keywords: leptin receptor; pluripotency; embryonic development; diabetes; cancer; neuronal lineage; STAT3; EIF4E | [{'text': 'Ctrl', 'coordinates': [266, 108, 320, 138]}, {'text': 'OB-Rdbldb', 'coordinates': [609, 104, 732, 137]}, {'text': 'iPSCs', 'coordinates': [134, 208, 204, 236]}, {'text': 'RNAseq', 'coordinates': [429, 195, 524, 228]}, {'text': '100', 'coordinates': [187, 325, 223, 345]}, {'text': 'Proteomics', 'coordinates': [414, 321, 546, 347]}, {'text': '100 Metabolic abnormalities, Protein Synthesis, Pluripotency Neuronal development', 'coordinates': [627, 318, 902, 494]}, {'text': 'Normal Metabolic Protein Synthesis_ Pluripotency; Neuronal development', 'coordinates': [193, 348, 394, 487]}, {'text': 'E14.5 MEFs Normal Metabolism and MekIErk pathway', 'coordinates': [75, 494, 262, 674]}, {'text': 'Mitochondrial Proteins Proteomics', 'coordinates': [392, 566, 548, 662]}, {'text': 'Metabolic dysfunction Upregulated MekIErk pathway', 'coordinates': [721, 568, 912, 680]}, {'text': 'Normal Growth And Metabolism', 'coordinates': [200, 804, 380, 858]}, {'text': 'Profound Obesity and Metabolic Derangement', 'coordinates': [518, 818, 782, 874]}, {'text': 'Correction', 'coordinates': [468, 445, 548, 423]}, {'text': 'CRISPRC', 'coordinates': [409, 473, 481, 465]}] |
Plasma dihydroceramides are predictors of type 2 diabetes and related to metabolic dysfunctions, but the underlying mechanisms are not characterized. We compare the relationships between plasma dihydroceramides and biochemical and hepatic parameters in two cohorts of diabetic patients. Hepatic steatosis, steatohepatitis, and fibrosis are assessed by their plasma biomarkers. Plasma lipoprotein sphingolipids are studied in a sub-group of diabetic patients. Liver biopsies from subjects with suspected non-alcoholic fatty liver disease are analyzed for sphingolipid synthesis enzyme expression. Dihydroceramides, contained in triglyceride-rich very-low-density lipoprotein (VLDL), are associated with steatosis and steatohepatitis. Expression of sphingolipid synthesis enzymes is correlated with histological steatosis and inflammation grades. In conclusion, association of plasma dihydroceramides with nonalcoholic fatty liver might explain their predictive character for type 2 diabetes. Our results suggest a relationship between hepatic sphingolipid metabolism and steatohepatitis and an involvement of dihydroceramides in the synthesis/secretion of triglyceride-rich VLDL, a hallmark of NAFLD and type 2 diabetes dyslipidemia.
Keywords: biomarker; diabetes mellitus; dihydroceramide; lipoproteins; liver; NAFLD; sphingolipids; VLDL | [{'text': 'Plasma dihydroceramide (DhCer), a sphingolipid, is described long-term predictor of Type 2 diabetes onset', 'coordinates': [18, 6, 960, 105]}, {'text': 'as a', 'coordinates': [110, 68, 172, 96]}, {'text': 'Two cohorts of Type 2 diabetic patients (n=129 and n= 90)', 'coordinates': [5, 141, 319, 273]}, {'text': '3', 'coordinates': [323, 147, 359, 249]}, {'text': '8', 'coordinates': [645, 145, 687, 250]}, {'text': '2', 'coordinates': [323, 251, 359, 367]}, {'text': '1', 'coordinates': [645, 249, 690, 368]}, {'text': 'Steatosis score', 'coordinates': [375, 369, 611, 407]}, {'text': 'Steatohepatitis score', 'coordinates': [658, 366, 991, 410]}, {'text': 'Type 2 diabetic patients (n-32)', 'coordinates': [0, 436, 246, 530]}, {'text': 'Triglyceride-rich VLDL are enriched in DhCer', 'coordinates': [639, 508, 985, 595]}, {'text': 'NAFLD patients (n-73)', 'coordinates': [8, 718, 253, 807]}, {'text': 'Sphingolipid metabolism enzyme mRNAs', 'coordinates': [498, 716, 887, 808]}, {'text': 'with steatosis and inflammation scores', 'coordinates': [649, 847, 933, 974]}, {'text': 'Liver biopsies', 'coordinates': [208, 921, 426, 971]}] |
Progressive lung fibrosis is a major cause of mortality in systemic sclerosis (SSc) patients, but the underlying mechanisms remain unclear. We demonstrate that immune complexes (ICs) activate human monocytes to promote lung fibroblast migration partly via osteopontin (OPN) secretion, which is amplified by autocrine monocyte colony stimulating factor (MCSF) and interleukin-6 (IL-6) activity. Bulk and single-cell RNA sequencing demonstrate that elevated OPN expression in SSc lung tissue is enriched in macrophages, partially overlapping with CCL18 expression. Serum OPN is elevated in SSc patients with interstitial lung disease (ILD) and prognosticates future lung function deterioration in SSc cohorts. Serum OPN levels decrease following tocilizumab (monoclonal anti-IL-6 receptor) treatment, confirming the connection between IL-6 and OPN in SSc patients. Collectively, these data suggest a plausible link between autoantibodies and lung fibrosis progression, where circulating OPN serves as a systemic proxy for IC-driven profibrotic macrophage activity, highlighting its potential as a promising biomarker in SSc ILD.
Keywords: systemic sclerosis; SSc; fibrosis; osteopontin; SPP1; IL-6; macrophages; immune complex; ILD; biomarker | [{'text': 'Immune', 'coordinates': [12, 56, 222, 110]}, {'text': 'complex', 'coordinates': [0, 115, 233, 191]}, {'text': 'IL6', 'coordinates': [450, 174, 536, 230]}, {'text': 'mono', 'coordinates': [225, 286, 361, 328]}, {'text': 'MCSF', 'coordinates': [484, 300, 647, 362]}, {'text': 'mac.', 'coordinates': [791, 303, 895, 343]}, {'text': 'MCSF', 'coordinates': [21, 311, 183, 371]}, {'text': '~', 'coordinates': [59, 528, 319, 652]}, {'text': 'OPN', 'coordinates': [425, 559, 575, 625]}, {'text': 'Serum level', 'coordinates': [695, 539, 996, 599]}, {'text': 'Invasive myofibroblasts', 'coordinates': [0, 816, 378, 950]}, {'text': '!', 'coordinates': [566, 668, 626, 860]}, {'text': '2', 'coordinates': [567, 867, 627, 983]}] |
In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
Keywords: multi-omics; integrative predictive model; immune checkpoint blockade; melanoma; cancer genomics; T cell repertoire | [{'text': 'Genomic features (tumor)', 'coordinates': [171, 38, 402, 108]}, {'text': 'Transcriptomic features (tumor)', 'coordinates': [528, 37, 833, 107]}, {'text': 'Clonal TMB Mutation signatures HLA variation Aneuploidy 8 po', 'coordinates': [272, 180, 468, 431]}, {'text': 'Expressed TMB PD-L1 expression CTLA-4 expression" 00', 'coordinates': [535, 202, 654, 396]}, {'text': 'Tcell features', 'coordinates': [14, 312, 192, 344]}, {'text': 'B cell features', 'coordinates': [799, 309, 981, 345]}, {'text': 'Tcell density Tcell clonality Tcell dynamism', 'coordinates': [166, 382, 358, 560]}, {'text': 'Tmmunoglobulin rearrangements B cell density Immunglobulin class 008', 'coordinates': [629, 382, 844, 582]}, {'text': 'Multi-modal predictor of response to immunotherapy', 'coordinates': [423, 550, 568, 650]}, {'text': 'Multi-omic analyses of baseline tumors', 'coordinates': [39, 672, 297, 742]}, {'text': 'Computational analyses of on-therapy dynamics', 'coordinates': [653, 673, 965, 750]}, {'text': 'Immune checkpoint blockade for metastatic melanoma', 'coordinates': [289, 789, 673, 860]}, {'text': 'Genomic; trascriptomic, TCR computational deconvolution', 'coordinates': [292, 904, 675, 983]}] |
The proteolytic turnover of mitochondrial proteins is poorly understood. Here, we used a combination of dynamic isotope labeling and mass spectrometry to gain a global overview of mitochondrial protein turnover in yeast cells. Intriguingly, we found an exceptionally high turnover of the NADH dehydrogenase, Nde1. This homolog of the mammalian apoptosis inducing factor, AIF, forms two distinct topomers in mitochondria, one residing in the intermembrane space while the other spans the outer membrane and is exposed to the cytosol. The surface-exposed topomer triggers cell death in response to pro-apoptotic stimuli. The surface-exposed topomer is degraded by the cytosolic proteasome/Cdc48 system and the mitochondrial protease Yme1; however, it is strongly enriched in respiratory-deficient cells. Our data suggest that in addition to their role in electron transfer, mitochondrial NADH dehydrogenases such as Nde1 or AIF integrate signals from energy metabolism and cytosolic proteostasis to eliminate compromised cells from growing populations.
Keywords: apoptosis; apoptosis-inducing factor; mitochondria; NADH:ubiquinone dehydrogenase; protein import; respiration | [{'text': 'Mitochondrial Surface', 'coordinates': [210, 30, 682, 80]}, {'text': 'Healthy Cells', 'coordinates': [115, 321, 403, 381]}, {'text': 'Respiration-Deficient Cells', 'coordinates': [526, 324, 978, 422]}, {'text': 'Proteasome', 'coordinates': [148, 432, 396, 480]}, {'text': 'Cell Death', 'coordinates': [718, 460, 958, 514]}, {'text': 'Cdc48', 'coordinates': [116, 534, 252, 582]}, {'text': 'Nde1', 'coordinates': [870, 610, 982, 658]}, {'text': 'Nde1', 'coordinates': [30, 630, 142, 678]}, {'text': 'Doa1', 'coordinates': [346, 632, 456, 680]}, {'text': 'High Membrane Potential', 'coordinates': [73, 869, 413, 966]}, {'text': 'Low Membrane Potential', 'coordinates': [578, 870, 908, 966]}] |
CD4+ T follicular helper cells (Tfh) are key drivers of antibody development. During Plasmodium falciparum malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental P. falciparum infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental P. falciparum malaria.
Keywords: T follicular helper cells; malaria; antibodies; experimental infection; CHMI; IBSM | [{'text': 'Malaria', 'coordinates': [98, 26, 190, 56]}, {'text': 'Treatment', 'coordinates': [305, 37, 435, 67]}, {'text': '0 Day', 'coordinates': [167, 125, 239, 167]}, {'text': '8 Day', 'coordinates': [335, 127, 405, 165]}, {'text': '14/15 Day', 'coordinates': [571, 127, 698, 165]}, {'text': 'end of study (Day 27-36)', 'coordinates': [833, 129, 987, 197]}, {'text': 'Activation', 'coordinates': [382, 196, 504, 228]}, {'text': 'Activation', 'coordinates': [656, 196, 776, 226]}, {'text': 'CXCRS+ PDI+ CXCR3- CCR6 -', 'coordinates': [360, 306, 452, 410]}, {'text': 'CXCRS+ PDI+ CXCR3+ CCR6-', 'coordinates': [858, 306, 950, 410]}, {'text': 'ICOS CD38', 'coordinates': [116, 508, 178, 558]}, {'text': 'ICOS CD38', 'coordinates': [594, 508, 656, 558]}, {'text': 'Th2-cTfh', 'coordinates': [246, 556, 358, 586]}, {'text': 'Th1-cTfh', 'coordinates': [788, 556, 900, 586]}, {'text': 'association', 'coordinates': [160, 642, 298, 670]}, {'text': 'no association', 'coordinates': [532, 642, 710, 674]}, {'text': 'association', 'coordinates': [850, 642, 990, 674]}, {'text': 'Functional antibody responses (end of study)', 'coordinates': [105, 715, 645, 751]}, {'text': 'Plasma cells', 'coordinates': [780, 716, 934, 744]}, {'text': 'IgG and IgG subclasses', 'coordinates': [60, 906, 214, 960]}, {'text': 'IgM', 'coordinates': [234, 906, 276, 934]}, {'text': 'Complement', 'coordinates': [300, 906, 428, 934]}, {'text': 'Fc', 'coordinates': [454, 906, 484, 930]}, {'text': 'Opsonic receptors phagocytosis', 'coordinates': [422, 906, 656, 960]}] |
Insulin is an essential growth factor for the survival and self-renewal of human embryonic stem cells (hESCs). Although it is best known as the principal hormone promoting glycolysis in somatic cells, insulin's roles in hESC energy metabolism remain unclear. In this report, we demonstrate that insulin is essential to sustain hESC mitochondrial respiration that is rapidly decreased upon insulin removal. Insulin-dependent mitochondrial respiration is stem cell specific, and mainly relies on pyruvate and glutamine, while glucose suppresses excessive oxidative phosphorylation. Pharmacologic and genetic manipulations reveal that continuous insulin signal sustains mitochondrial respiration through PI3K/AKT activation and downstream GSK3 inhibition. We further show that insulin acts through GSK3 inhibition to suppress caspase activation and rescue cell survival. This study uncovers a critical role of the AKT/GSK3 pathway in the regulation of mitochondrial respiration and cell survival, highlighting insulin as an essential factor for accurate assessment of mitochondrial respiration in hESCs.
Keywords: insulin; AKT; GSK3; mitochondrial respiration; caspase; cell survival; human embryonic stem cells | [{'text': 'Insulin', 'coordinates': [198, 26, 358, 76]}, {'text': 'IGF', 'coordinates': [386, 24, 474, 74]}, {'text': 'Insulin', 'coordinates': [411, 193, 537, 235]}, {'text': 'IGF Receptor', 'coordinates': [560, 190, 813, 242]}, {'text': 'Membrane', 'coordinates': [21, 341, 219, 383]}, {'text': 'PI3K', 'coordinates': [306, 374, 418, 422]}, {'text': 'BEZ235', 'coordinates': [513, 381, 645, 417]}, {'text': 'AKT', 'coordinates': [312, 518, 412, 566]}, {'text': 'AKTi VIII', 'coordinates': [513, 525, 661, 561]}, {'text': 'GSK3', 'coordinates': [293, 663, 427, 713]}, {'text': 'CHIR99021', 'coordinates': [511, 677, 695, 713]}, {'text': 'Mitochondrial Respiration', 'coordinates': [20, 836, 332, 953]}, {'text': 'Caspase Activation', 'coordinates': [410, 834, 638, 940]}, {'text': 'Cell Death', 'coordinates': [744, 864, 978, 912]}] |
H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for Escherichia coli MST (eMST) through high-throughput screening of ∼26,000 compounds. The thiazolidinedione-type inhibitors were found to selectively bind to Arg178 and Ser239 residues of eMST but hardly affected human MST. Moreover, the pioglitazone of this class concentration dependently accumulates the 3-mercaptopyruvate substrate and suppresses the H2S and reactive sulfane sulfur products in bacteria. Importantly, pioglitazone could potentiate the level of reactive oxygen species in cellulo and consequently enhance the antimicrobial effects of gentamicin and macrophages in culture. This study has identified the bioactive inhibitor of eMST, paving the way for the pharmacological targeting of eMST to synergistically control the survival of E. coli.
Keywords: 3-mercaptopyruvate sulfurtransferase; hydrogen sulfide; Escherichia coli; pioglitazone; CRISPR-Cas9; ROS; oxidative stress; roGFP2; synergy; antibiotic resistance | [{'text': 'Compound Libraries ~26, 000 compounds)', 'coordinates': [383, 118, 622, 178]}, {'text': 'High-throughput Inhibitor Screening', 'coordinates': [408, 254, 592, 336]}, {'text': 'Bacterial Growth Homeostasis', 'coordinates': [112, 290, 320, 371]}, {'text': 'Bacterial Death Imbalance', 'coordinates': [712, 288, 902, 369]}, {'text': 'ROS', 'coordinates': [39, 381, 119, 417]}, {'text': 'HzS', 'coordinates': [311, 379, 377, 423]}, {'text': '[ ROS', 'coordinates': [615, 385, 721, 428]}, {'text': 'HzS', 'coordinates': [882, 364, 952, 414]}, {'text': 'Induce', 'coordinates': [92, 552, 170, 578]}, {'text': 'Generate', 'coordinates': [336, 552, 442, 578]}, {'text': 'MST', 'coordinates': [304, 598, 356, 624]}, {'text': 'MST', 'coordinates': [900, 596, 950, 622]}, {'text': 'Pioglitazone', 'coordinates': [422, 670, 558, 698]}, {'text': 'Antibiotics Attack', 'coordinates': [52, 749, 173, 814]}, {'text': 'Bacteria Defense', 'coordinates': [287, 748, 382, 814]}, {'text': 'Antibiotics', 'coordinates': [634, 738, 754, 764]}, {'text': 'Bacteria', 'coordinates': [872, 738, 966, 764]}] |
DNA methylation and histone H1 mediate transcriptional silencing of genes and transposable elements, but how they interact is unclear. In plants and animals with mosaic genomic methylation, functionally mysterious methylation is also common within constitutively active housekeeping genes. Here, we show that H1 is enriched in methylated sequences, including genes, of Arabidopsis thaliana, yet this enrichment is independent of DNA methylation. Loss of H1 disperses heterochromatin, globally alters nucleosome organization, and activates H1-bound genes, but only weakly de-represses transposable elements. However, H1 loss strongly activates transposable elements hypomethylated through mutation of DNA methyltransferase MET1. Hypomethylation of genes also activates antisense transcription, which is modestly enhanced by H1 loss. Our results demonstrate that H1 and DNA methylation jointly maintain transcriptional homeostasis by silencing transposable elements and aberrant intragenic transcripts. Such functionality plausibly explains why DNA methylation, a well-known mutagen, has been maintained within coding sequences of crucial plant and animal genes.
Keywords: DNA methylation; gene body methylation; histone H1; transcriptional silencing; antisense transcription | [{'text': 'Histone HI increases nucleosome spacing', 'coordinates': [318, 6, 708, 34]}, {'text': 'Nucleosome spacing', 'coordinates': [63, 49, 191, 65]}, {'text': 'Nucleosome spacing', 'coordinates': [797, 49, 923, 65]}, {'text': 'Long linker DNA', 'coordinates': [521, 55, 621, 73]}, {'text': 'Short linker DNA', 'coordinates': [209, 71, 311, 87]}, {'text': 'H1 condenses heterochromatin', 'coordinates': [368, 204, 656, 230]}, {'text': 'dispersed chromocenters', 'coordinates': [153, 277, 305, 293]}, {'text': 'condensed chromocenters', 'coordinates': [721, 281, 881, 297]}, {'text': 'Arabidopsis nucleus', 'coordinates': [363, 375, 485, 391]}, {'text': 'H1 suppresses gene expression', 'coordinates': [366, 404, 660, 433]}, {'text': 'GQJ', 'coordinates': [106, 446, 347, 571]}, {'text': 'DNA methylation and H1 jointly silence transposons', 'coordinates': [276, 602, 750, 633]}, {'text': 'DNA methylation DNA methylation and H1 suppresses intragenic antisense transcripts', 'coordinates': [200, 751, 826, 833]}, {'text': 'DNA methylation', 'coordinates': [489, 955, 591, 971]}] |
Neural crest cells are an embryonic multipotent stem cell population. Recent studies in model organisms have suggested that neural crest cells are specified earlier than previously thought, at blastula stages. However, the molecular dynamics of early neural crest specification, and functional changes from pluripotent precursors to early specified NC, remain to be elucidated. In this report, we utilized a robust human model of cranial neural crest formation to address the distinct molecular character of the earliest stages of neural crest specification and assess the functional differences from its embryonic stem cell precursor. Our human neural crest model reveals a rapid change in the epigenetic state of neural crest and pluripotency genes, accompanied by changes in gene expression upon Wnt-based induction from embryonic stem cells. These changes in gene expression are directly regulated by the transcriptional activity of β-catenin. Furthermore, prospective cranial neural crest cells are characterized by restricted stem cell potential compared to embryonic stem cells. Our results suggest that human neural crest induced by Wnt/β-catenin signaling from human embryonic stem cells rapidly acquire a prospective neural crest cell state defined by a unique molecular signature and endowed with limited potential compared to pluripotent stem cells.
Keywords: Neural crest; Stem cells; Embryonic stem cells; Specification; Neural plate border; Cell fate; Cranial neural crest; Pluripotency | [{'text': 'A', 'coordinates': [0, 0, 28, 30]}, {'text': 'ES', 'coordinates': [1651, 91, 1701, 127]}, {'text': 'NC-6h NC-12h', 'coordinates': [1650, 163, 1771, 267]}, {'text': 'NC-18h', 'coordinates': [1651, 305, 1771, 341]}, {'text': 'NC-D1 NC-D2 NC-D3 NC-D4 NC-D5', 'coordinates': [1650, 375, 1759, 685]}, {'text': 'B', 'coordinates': [0, 836, 30, 870]}, {'text': 'OCT4', 'coordinates': [126, 840, 204, 872]}, {'text': 'SOX2', 'coordinates': [334, 840, 414, 870]}, {'text': 'NANOG', 'coordinates': [520, 840, 624, 870]}, {'text': 'KLF4', 'coordinates': [724, 840, 798, 870]}, {'text': 'TFCPZL1', 'coordinates': [876, 840, 998, 870]}, {'text': 'LIN28', 'coordinates': [1080, 837, 1165, 873]}, {'text': 'MYC', 'coordinates': [1282, 840, 1346, 870]}, {'text': 'FOXD3', 'coordinates': [1446, 840, 1544, 870]}, {'text': 'PAX2', 'coordinates': [1664, 840, 1738, 870]}, {'text': '2.5- 2.0 1.5 1.0 0.5', 'coordinates': [268, 883, 300, 1033]}, {'text': '1.5- 8 0.5- 2 0.0-', 'coordinates': [35, 903, 103, 1067]}, {'text': '1.5- 1.0- 0.5- 0.0', 'coordinates': [465, 905, 497, 1067]}, {'text': '2.01 1.54 1.0 0.5', 'coordinates': [652, 903, 689, 1031]}, {'text': '1.51 1.0 0.54 0.01', 'coordinates': [841, 903, 879, 1067]}, {'text': '2.01 1.51 1.0 0.54 0.0-', 'coordinates': [1027, 903, 1063, 1067]}, {'text': '8007 600 400 200', 'coordinates': [1577, 897, 1621, 1032]}, {'text': '1.0 0.51 0.0-', 'coordinates': [1215, 951, 1249, 1067]}, {'text': 'PAX3', 'coordinates': [126, 1166, 200, 1194]}, {'text': 'PAX7', 'coordinates': [336, 1164, 408, 1194]}, {'text': 'SOX5', 'coordinates': [520, 1164, 600, 1194]}, {'text': 'SOX9', 'coordinates': [714, 1164, 792, 1194]}, {'text': 'SOX1O', 'coordinates': [888, 1163, 984, 1193]}, {'text': 'ETS1', 'coordinates': [1064, 1164, 1136, 1194]}, {'text': 'SNAI2', 'coordinates': [1262, 1164, 1348, 1194]}, {'text': 'AP2', 'coordinates': [1460, 1166, 1518, 1194]}, {'text': 'TWIST1', 'coordinates': [1640, 1164, 1742, 1194]}, {'text': '15000 8 10000- 5000 2', 'coordinates': [12, 1222, 104, 1370]}, {'text': '50007 4000 3000- 2000- 1000-', 'coordinates': [258, 1222, 312, 1362]}, {'text': '80', 'coordinates': [469, 1227, 493, 1243]}, {'text': '15- 10', 'coordinates': [659, 1225, 687, 1293]}, {'text': '30 20 10', 'coordinates': [846, 1222, 872, 1341]}, {'text': '1507 100 50', 'coordinates': [1196, 1222, 1240, 1341]}, {'text': '100007 8000 6000- 4000 2000', 'coordinates': [1374, 1222, 1436, 1361]}, {'text': '40 20', 'coordinates': [467, 1297, 494, 1356]}, {'text': '6?', 'coordinates': [1720, 1390, 1748, 1418]}, {'text': 'DLX5', 'coordinates': [128, 1480, 204, 1510]}, {'text': 'SP5', 'coordinates': [338, 1480, 396, 1510]}, {'text': 'GBX2', 'coordinates': [524, 1478, 604, 1510]}, {'text': 'ZIC1', 'coordinates': [716, 1480, 780, 1510]}, {'text': 'ZIC3', 'coordinates': [892, 1478, 958, 1510]}, {'text': 'ID2 10', 'coordinates': [1031, 1480, 1116, 1551]}, {'text': 'MSXI', 'coordinates': [1252, 1480, 1330, 1510]}, {'text': 'MSX2', 'coordinates': [1464, 1478, 1542, 1510]}, {'text': 'NRZF1', 'coordinates': [1654, 1478, 1740, 1510]}, {'text': '10 8', 'coordinates': [46, 1531, 101, 1635]}, {'text': '1500- 1000- 500-', 'coordinates': [258, 1537, 307, 1651]}, {'text': '50 40 30', 'coordinates': [467, 1531, 493, 1609]}, {'text': '1507 100 50', 'coordinates': [657, 1531, 699, 1649]}, {'text': '2001 1504 100 50', 'coordinates': [1196, 1530, 1240, 1661]}, {'text': '3001 200| 100', 'coordinates': [1392, 1531, 1435, 1649]}, {'text': '40007 3000- 2000- 1000-', 'coordinates': [1580, 1525, 1633, 1656]}, {'text': '2', 'coordinates': [50, 1634, 74, 1690]}, {'text': 'FOXD3 ETS1 OCTA TFCPZL1', 'coordinates': [3, 747, 303, 724]}, {'text': 'NANOG', 'coordinates': [259, 772, 371, 722]}, {'text': 'Zic3 KLFA LIN28 SOX2 CMYC MYB MSX2 SOX5 sOX9 MSX1 SNAI2', 'coordinates': [344, 739, 1072, 723]}, {'text': 'ID2 SOX1O DLX5 ZIC1 AP2 PAX3 PAX7 GBX2 SP5', 'coordinates': [1059, 728, 1640, 723]}] |
Mode of delivery strongly influences the early infant gut microbiome. Children born by cesarean section (C-section) lack Bacteroides species until 6–18 months of age. One hypothesis is that these differences stem from lack of exposure to the maternal vaginal microbiome. Here, we re-evaluate this hypothesis by comparing the microbial profiles of 75 infants born vaginally or by planned versus emergent C-section. Multiple children born by C-section have a high abundance of Bacteroides in their first few days of life, but at 2 weeks, both C-section groups lack Bacteroides (primarily according to 16S sequencing), despite their difference in exposure to the birth canal. Finally, a comparison of microbial strain profiles between infants and maternal vaginal or rectal samples finds evidence for mother-to-child transmission of rectal rather than vaginal strains. These results suggest differences in colonization stability as an important factor in infant gut microbiome composition rather than birth canal exposure.
Keywords: infant gut microbiota, caesarean delivery, Bacteroides, delivery mode, transmission of maternal strains | [{'text': 'Week 1', 'coordinates': [533, 35, 597, 55]}, {'text': 'Number of families by delivery mode: Vaginal 40 C-section = 35', 'coordinates': [38, 46, 240, 156]}, {'text': 'Delivery', 'coordinates': [247, 91, 324, 118]}, {'text': 'D2', 'coordinates': [503, 97, 531, 117]}, {'text': 'D3', 'coordinates': [619, 99, 645, 117]}, {'text': 'Week 2', 'coordinates': [844, 94, 916, 118]}, {'text': 'D-', 'coordinates': [133, 227, 155, 245]}, {'text': 'rectal sample vaginal sample', 'coordinates': [208, 224, 358, 276]}, {'text': 'Week 1 (@hospital) Multiple stool samples', 'coordinates': [468, 221, 680, 274]}, {'text': 'Week 2 (@home) stool sample', 'coordinates': [796, 221, 966, 279]}, {'text': 'Persistent', 'coordinates': [658, 374, 806, 406]}, {'text': '1', 'coordinates': [12, 388, 44, 562]}, {'text': 'Vaginal', 'coordinates': [79, 447, 191, 487]}, {'text': 'Early-only', 'coordinates': [660, 555, 809, 599]}, {'text': ']', 'coordinates': [11, 561, 47, 737]}, {'text': 'C-section', 'coordinates': [75, 623, 217, 659]}, {'text': 'Infant bacterial strains match maternal rectal rather than vaginal strains', 'coordinates': [185, 769, 817, 845]}] |
R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In response to aberrant R loop accumulation, the ataxia telangiectasia and Rad3-related (ATR)-Chk1 pathway is activated by R loop-induced reversed replication forks. In contrast to the activation of ATR by replication inhibitors, R loop-induced ATR activation requires the MUS81 endonuclease. ATR protects the genome from R loops by suppressing transcription-replication collisions, promoting replication fork recovery, and enforcing a G2/M cell-cycle arrest. Furthermore, ATR prevents excessive cleavage of reversed forks by MUS81, revealing a MUS81-triggered and ATR-mediated feedback loop that fine-tunes MUS81 activity at replication forks. These results suggest that ATR is a key sensor and suppressor of R loop-induced genomic instability, uncovering a signaling circuitry that safeguards the genome against R loops.
Keywords: R loop; ATR; Chk1; checkpoint; MUS81; Fork reversal; Genomic Instability | [{'text': 'ATR', 'coordinates': [530, 260, 588, 288]}, {'text': 'Mitotic entry', 'coordinates': [862, 291, 954, 360]}, {'text': 'MUS81', 'coordinates': [258, 398, 352, 428]}, {'text': 'Further collisions', 'coordinates': [818, 462, 946, 522]}, {'text': 'RNAPII', 'coordinates': [287, 575, 383, 603]}, {'text': 'Fork recovery', 'coordinates': [675, 570, 792, 632]}, {'text': 'R loop', 'coordinates': [126, 617, 213, 649]}, {'text': 'MUS81', 'coordinates': [560, 608, 654, 638]}, {'text': 'Replication fork', 'coordinates': [348, 672, 496, 732]}] |
The acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Here, we report that either pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram, or maprotiline or genetic downregulation of the enzyme prevents infection of cultured cells or freshy isolated human nasal epithelial cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or vesicular stomatitis virus (VSV) pseudoviral particles (pp-VSV) presenting SARS-CoV-2 spike protein (pp-VSV-SARS-CoV-2 spike), a bona fide system mimicking SARS-CoV-2 infection. Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treating volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike. The data justify clinical studies investigating whether amitriptyline, a safe drug used clinically for almost 60 years, or other antidepressants that functionally block acid sphingomyelinase prevent SARS-CoV-2 infection.
Keywords: SARS-CoV-2; acid sphingomyelinase; ceramide; antidepressants; amitriptyline; infection; human nasal epithelial cells; fluoxetine; escitalopram | [{'text': 'Acid sphingomyelinase inhibition', 'coordinates': [24, 32, 245, 122]}, {'text': 'Acid sphingomyelinase inhibition', 'coordinates': [516, 32, 734, 122]}, {'text': 'No inhibition', 'coordinates': [304, 62, 458, 92]}, {'text': 'No inhibition', 'coordinates': [796, 60, 948, 90]}, {'text': 'pp-VSV-SARS-CoV-2 spike', 'coordinates': [733, 142, 992, 172]}, {'text': 'Spike protein', 'coordinates': [560, 178, 686, 208]}, {'text': 'per Os', 'coordinates': [126, 202, 200, 230]}, {'text': 'Amitriptyline', 'coordinates': [20, 262, 158, 294]}, {'text': 'Amitriptyline', 'coordinates': [506, 288, 644, 320]}, {'text': 'Isolated nasal epithelial cells', 'coordinates': [8, 362, 167, 425]}, {'text': 'Angiotensin Converting Enzyme 2', 'coordinates': [766, 358, 878, 439]}, {'text': 'Acid sphingomyelinase', 'coordinates': [654, 454, 842, 508]}, {'text': 'Sphingomyelin Cell membrane', 'coordinates': [503, 499, 671, 590]}, {'text': 'Ceramide', 'coordinates': [856, 506, 966, 534]}, {'text': 'Infection with pp-VSV-SARS CoV-2 spike', 'coordinates': [8, 541, 175, 634]}, {'text': 'Reduced infection', 'coordinates': [28, 876, 242, 908]}, {'text': 'Infection', 'coordinates': [324, 878, 432, 908]}, {'text': 'Reduced infection', 'coordinates': [516, 876, 730, 908]}, {'text': 'Infection', 'coordinates': [818, 878, 926, 908]}] |
Hydroxychloroquine is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, hydroxychloroquine inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that hydroxychloroquine inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.
Keywords: COVID-19; SARS-CoV-2; hydroxychloroquine; trained immunity; interferon; chloroquine; innate immune memory; lipidome; monocytes | [{'text': 'Trained monocytes', 'coordinates': [789, 30, 968, 123]}, {'text': 'Primary stimulation', 'coordinates': [305, 58, 449, 128]}, {'text': 'Secondary stimulation', 'coordinates': [566, 59, 711, 128]}, {'text': '1 5 1', 'coordinates': [27, 68, 104, 212]}, {'text': 'Human monocytes', 'coordinates': [167, 204, 280, 260]}, {'text': '00', 'coordinates': [23, 201, 103, 340]}, {'text': 'Training blocked', 'coordinates': [803, 351, 952, 435]}, {'text': 'Hydroxy chloroquine', 'coordinates': [228, 433, 529, 546]}, {'text': 'IFN stimulated gene expression:', 'coordinates': [583, 493, 973, 532]}, {'text': 'C. albicans', 'coordinates': [38, 550, 166, 576]}, {'text': 'XAXIXK', 'coordinates': [632, 570, 952, 646]}, {'text': 'Histone modification:', 'coordinates': [584, 674, 838, 704]}, {'text': 'JRTR', 'coordinates': [603, 729, 763, 807]}, {'text': 'Lipid composition:', 'coordinates': [583, 846, 805, 887]}, {'text': 'HO', 'coordinates': [625, 967, 647, 979]}] |
Lymphocytes in barrier tissues play critical roles in host defense and homeostasis. These cells take up residence in tissues during defined developmental windows, when they may demonstrate distinct phenotypes and functions. Here, we utilized mass and flow cytometry to elucidate early features of human skin immunity. Although most conventional αβ T (Tconv) cells in fetal skin have a naive, proliferative phenotype, a subset of CD4+ Tconv and CD8+ cells demonstrate memory-like features and a propensity for interferon (IFN)γ production. Skin regulatory T cells dynamically accumulate over the second trimester in temporal and regional association with hair follicle development. These fetal skin regulatory T cells (Tregs) demonstrate an effector memory phenotype while differing from their adult counterparts in expression of key effector molecules. Thus, we identify features of prenatal skin lymphocytes that may have key implications for understanding antigen and allergen encounters in utero and in infancy.
Keywords: lymphocytes; human skin; fetal; skin development; hair follicle development; Tregs; memory T cells | [{'text': 'CD8+RA+', 'coordinates': [182, 312, 296, 344]}, {'text': 'Memory Tregs', 'coordinates': [365, 365, 478, 437]}, {'text': 'CD8+ROt', 'coordinates': [792, 368, 908, 398]}, {'text': 'CDA+ RA', 'coordinates': [88, 482, 194, 512]}, {'text': 'CDA+ ROt', 'coordinates': [566, 478, 684, 508]}, {'text': 'IL-22', 'coordinates': [750, 492, 810, 520]}, {'text': 'IL-17', 'coordinates': [522, 558, 580, 582]}, {'text': 'Human Skin Lymphocytes', 'coordinates': [308, 724, 712, 772]}, {'text': 'CDASRA Ki-67 CD27 CD31', 'coordinates': [96, 770, 216, 909]}, {'text': 'Adult', 'coordinates': [655, 773, 761, 817]}, {'text': 'Cell # CDASRO CD25 Cytokines', 'coordinates': [784, 770, 929, 914]}, {'text': 'Development', 'coordinates': [246, 850, 498, 902]}, {'text': 'IFNg', 'coordinates': [666, 409, 720, 447]}, {'text': 'IFNg', 'coordinates': [369, 532, 423, 569]}] |
Constant neuroregeneration in adult olfactory epithelium maintains olfactory function by basal stem cell proliferation and differentiation to replace lost olfactory sensory neurons (OSNs). Understanding the mechanisms regulating this process could reveal potential therapeutic targets for stimulating adult olfactory neurogenesis under pathological conditions and aging. Ciliary neurotrophic factor (CNTF) in astrocytes promotes forebrain neurogenesis but its function in the olfactory system is unknown. Here, we show in mouse olfactory epithelium that CNTF is expressed in horizontal basal cells, olfactory ensheathing cells (OECs) and a small subpopulation of OSNs. CNTF receptor alpha was expressed in Mash1-positive globose basal cells (GBCs) and OECs. Thus, CNTF may affect GBCs in a paracrine manner. CNTF−/− mice did not display altered GBC proliferation or olfactory function, suggesting that CNTF is not involved in basal olfactory renewal or that they developed compensatory mechanisms. Therefore, we tested the effect of increased CNTF in wild type mice. Intranasal instillation of a focal adhesion kinase (FAK) inhibitor, FAK14, upregulated CNTF expression. FAK14 also promoted GBC proliferation, neuronal differentiation and basal stem cell self-renewal but had no effective in CNTF−/− mice, suggesting that FAK inhibition promotes olfactory neuroregeneration through CNTF, making them potential targets to treat sensorineural anosmia due to OSN loss.
Keywords: Olfactory stem cell; Basal cell proliferation; Neuronal differentiation; Olfactory function; Neuroregeneration | [{'text': 'A', 'coordinates': [0, 9, 39, 53]}, {'text': 'B-gallDAPI', 'coordinates': [65, 7, 235, 49]}, {'text': 'OMPIDAPI', 'coordinates': [433, 9, 601, 45]}, {'text': 'B-gallOMFI431"', 'coordinates': [748, 8, 1007, 50]}, {'text': '50 um', 'coordinates': [12, 298, 98, 328]}, {'text': 'B', 'coordinates': [8, 386, 40, 422]}, {'text': 'B-galIDAPI', 'coordinates': [82, 378, 253, 423]}, {'text': 'BLBP IDAPI', 'coordinates': [433, 380, 615, 420]}, {'text': 'B-gall BLBP', 'coordinates': [779, 381, 959, 425]}, {'text': '50 um', 'coordinates': [249, 681, 337, 719]}, {'text': 'C', 'coordinates': [3, 757, 41, 801]}, {'text': 'B-gallDAPL', 'coordinates': [54, 757, 229, 802]}, {'text': 'p7 IDAPI', 'coordinates': [386, 752, 541, 802]}, {'text': 'B-gallp75', 'coordinates': [718, 759, 867, 800]}, {'text': 'D', 'coordinates': [1066, 762, 1096, 796]}, {'text': 'B-gall975', 'coordinates': [1150, 758, 1299, 799]}, {'text': '50 um', 'coordinates': [241, 1041, 329, 1079]}, {'text': 'E', 'coordinates': [3, 1117, 39, 1155]}, {'text': 'CNTFIDAPI', 'coordinates': [92, 1112, 272, 1148]}, {'text': 'p7EIDAPI', 'coordinates': [453, 1113, 603, 1153]}, {'text': 'CNTFI 75', 'coordinates': [790, 1110, 947, 1154]}, {'text': 'CNTFI675', 'coordinates': [1156, 1110, 1315, 1154]}, {'text': '20 um', 'coordinates': [232, 1394, 318, 1424]}, {'text': 'G', 'coordinates': [3, 1469, 43, 1511]}, {'text': 'B-gallDAPI', 'coordinates': [94, 1471, 267, 1513]}, {'text': 'GFAI IDAPI', 'coordinates': [427, 1469, 609, 1507]}, {'text': 'B-gall FAT IDAPI', 'coordinates': [754, 1469, 1021, 1512]}, {'text': 'H', 'coordinates': [1066, 1472, 1096, 1510]}, {'text': 'B-gall GFAFIDAPI', 'coordinates': [1114, 1469, 1381, 1514]}, {'text': '50 um', 'coordinates': [28, 1768, 115, 1800]}] |
While obesity and associated metabolic complications are linked to inflammation of white adipose tissue (WAT), the causal factors remain unclear. We hypothesized that the local metabolic environment could be an important determinant. To this end, we compared metabolites released from WAT of 81 obese and non-obese women. This identified glutamine to be downregulated in obesity and inversely associated with a pernicious WAT phenotype. Glutamine administration in vitro and in vivo attenuated both pro-inflammatory gene and protein levels in adipocytes and WAT and macrophage infiltration in WAT. Metabolomic and bioenergetic analyses in human adipocytes suggested that glutamine attenuated glycolysis and reduced uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) levels. UDP-GlcNAc is the substrate for the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) mediated by the enzyme O-GlcNAc transferase. Functional studies in human adipocytes established a mechanistic link between reduced glutamine, O-GlcNAcylation of nuclear proteins, and a pro-inflammatory transcriptional response. Altogether, glutamine metabolism is linked to WAT inflammation in obesity.
Keywords: adipocyte; leukocyte; macrophage; inflammation; obesity; epigenetics; metabolomics; adipokine | [{'text': 'LEAN', 'coordinates': [150, 16, 292, 66]}, {'text': 'OBESE', 'coordinates': [644, 14, 840, 68]}, {'text': 'Glutamine', 'coordinates': [62, 142, 204, 174]}, {'text': 'Inflammation', 'coordinates': [760, 186, 938, 218]}, {'text': 'CDA+ T cell M1 ATM', 'coordinates': [914, 256, 994, 376]}, {'text': 'High glutamine', 'coordinates': [185, 305, 393, 345]}, {'text': 'Low glutamine', 'coordinates': [573, 299, 773, 343]}, {'text': 'M2 ATM', 'coordinates': [4, 334, 52, 382]}, {'text': 'Glycolysis', 'coordinates': [415, 341, 559, 379]}, {'text': 'Adipocyte', 'coordinates': [193, 427, 286, 455]}, {'text': 'Treg cell', 'coordinates': [82, 454, 152, 480]}, {'text': 'CD8+ T cell', 'coordinates': [810, 450, 866, 498]}, {'text': 'UDP-GIcNAc', 'coordinates': [388, 500, 568, 532]}, {'text': 'Chromatin O-GIcNAcylation', 'coordinates': [360, 608, 610, 634]}, {'text': '(Proteins', 'coordinates': [363, 651, 433, 671]}, {'text': 'Proteins', 'coordinates': [521, 651, 589, 671]}, {'text': 'Pro-inflammatory genes] Nucleus', 'coordinates': [368, 682, 590, 738]}, {'text': 'O-GIcNAc modification', 'coordinates': [60, 744, 268, 768]}] |
In animal models, time-restricted feeding (TRF) can prevent and reverse aspects of metabolic diseases. Time-restricted eating (TRE) in human pilot studies reduces the risks of metabolic diseases in otherwise healthy individuals. However, patients with diagnosed metabolic syndrome often undergo pharmacotherapy, and it has never been tested whether TRE can act synergistically with pharmacotherapy in animal models or humans. In a single-arm, paired-sample trial, 19 participants with metabolic syndrome and a baseline mean daily eating window of ≥14 h, the majority of whom were on a statin and/or antihypertensive therapy, underwent 10 h of TRE (all dietary intake within a consistent self-selected 10 h window) for 12 weeks. We found this TRE intervention improves cardiometabolic health for patients with metabolic syndrome receiving standard medical care including high rates of statin and anti-hypertensive use. TRE is a potentially powerful lifestyle intervention that can be added to standard medical practice to treat metabolic syndrome.
Video Abstract | [{'text': 'BASELINE', 'coordinates': [388, 44, 630, 96]}, {'text': '6am', 'coordinates': [170, 180, 226, 208]}, {'text': 'Metabolic Syndrome Waist Circumference Blood Pressure Blood Glucose Triglycerides HDL Cholesterol', 'coordinates': [370, 189, 712, 406]}, {'text': '>14 hours eating $ <10 hours fasting On Medication', 'coordinates': [89, 245, 333, 360]}, {'text': '6pm', 'coordinates': [169, 421, 229, 457]}, {'text': '10-HR TIME-RESTRICTED EATING (TRE)', 'coordinates': [76, 546, 929, 606]}, {'text': '6am', 'coordinates': [168, 678, 224, 706]}, {'text': 'Y0 W 3 ]', 'coordinates': [269, 695, 333, 907]}, {'text': 'Body Weight Waist Circumference Blood Pressure LDL Cholesterol Non-HDL Cholesterol Hemoglobin A1C Restful Sleep', 'coordinates': [419, 698, 701, 946]}, {'text': '~10 hours eating ~14 hours fasting On Medication', 'coordinates': [85, 753, 299, 860]}, {'text': '6pm', 'coordinates': [168, 918, 224, 950]}, {'text': '1', 'coordinates': [317, 302, 329, 379]}, {'text': 'Random', 'coordinates': [240, 429, 334, 394]}, {'text': 'Time', 'coordinates': [239, 915, 306, 913]}] |
In 2014, an outbreak of avian A/H10N7 influenza virus occurred among seals along North-European coastal waters, significantly impacting seal populations. Here, we examine the cross-species transmission and mammalian adaptation of this influenza A virus, revealing changes in the hemagglutinin surface protein that increase stability and receptor binding. The seal A/H10N7 virus was aerosol or respiratory droplet transmissible between ferrets. Compared with avian H10 hemagglutinin, seal H10 hemagglutinin showed stronger binding to the human-type sialic acid receptor, with preferential binding to α2,6-linked sialic acids on long extended branches. In X-ray structures, changes in the 220-loop of the receptor-binding pocket caused similar interactions with human receptor as seen for pandemic strains. Two substitutions made seal H10 hemagglutinin more stable than avian H10 hemagglutinin and similar to human hemagglutinin. Consequently, identification of avian-origin influenza viruses across mammals appears critical to detect influenza A viruses posing a major threat to humans and other mammals.
Keywords: influenza; A/H10N7; transmission; aerosol; respiratory droplet; hemagglutinin; receptor-binding; stability; glycan microarrays | [{'text': 'N-Europe AHIONZ outbreak', 'coordinates': [28, 29, 187, 153]}, {'text': '1/8', 'coordinates': [741, 57, 795, 93]}, {'text': 'LAvian]', 'coordinates': [394, 117, 514, 159]}, {'text': 'Early', 'coordinates': [391, 231, 481, 275]}, {'text': 'Avian A/HION7', 'coordinates': [645, 275, 885, 313]}, {'text': '1/4', 'coordinates': [741, 373, 793, 409]}, {'text': 'Late', 'coordinates': [115, 391, 191, 427]}, {'text': 'Side view', 'coordinates': [41, 499, 199, 541]}, {'text': 'view', 'coordinates': [381, 503, 461, 541]}, {'text': 'Seal AHION7 , Early', 'coordinates': [602, 587, 929, 636]}, {'text': 'Ile244 Leu226', 'coordinates': [193, 671, 319, 758]}, {'text': 'Asp74 (HA2)', 'coordinates': [481, 667, 585, 749]}, {'text': '6/8', 'coordinates': [737, 689, 795, 725]}, {'text': 'HA 2,6-SA binding HA stability', 'coordinates': [250, 784, 545, 875]}, {'text': 'HIONZ HA trimer', 'coordinates': [125, 919, 397, 957]}, {'text': 'Seal AHION7, Late', 'coordinates': [609, 905, 921, 945]}, {'text': 'Top', 'coordinates': [315, 499, 377, 545]}] |
Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.
Keywords: Castleman disease; orphan disease; patient-powered; direct-to-patient; natural history registry | [{'text': 'Physician-directed', 'coordinates': [284, 0, 634, 46]}, {'text': 'Patient-powered Gopn', 'coordinates': [668, 0, 980, 74]}, {'text': 'Two-arm enrollment', 'coordinates': [17, 39, 226, 134]}, {'text': 'Data collection', 'coordinates': [21, 225, 298, 269]}, {'text': 'Data curation', 'coordinates': [21, 391, 275, 435]}, {'text': 'Data utilization', 'coordinates': [21, 559, 296, 603]}, {'text': 'Biobank', 'coordinates': [695, 605, 853, 647]}, {'text': 'High-impact discoveries', 'coordinates': [19, 697, 251, 793]}, {'text': 'ACCELERATE', 'coordinates': [536, 750, 735, 795]}, {'text': 'Results', 'coordinates': [21, 865, 167, 909]}, {'text': 'dissemination', 'coordinates': [19, 915, 280, 959]}, {'text': 'N', 'coordinates': [666, 950, 690, 974]}] |
Phagocytosis is a key function in various cells throughout the body. A deficiency in photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) causes vision loss in inherited retinal diseases and possibly age-related macular degeneration. To date, there are no effective therapies available aiming at recovering the lost phagocytosis function. Here, we developed a high-throughput screening assay based on RPE derived from human embryonic stem cells (hRPE) to reveal enhancers of POS phagocytosis. One of the hits, ramoplanin (RM), reproducibly enhanced POS phagocytosis and ensheathment in hRPE, and enhanced the expression of proteins known to regulate membrane dynamics and ensheathment in other cell systems. Additionally, RM rescued POS internalization defect in Mer receptor tyrosine kinase (MERTK) mutant hRPE, derived from retinitis pigmentosa patient induced pluripotent stem cells. Our platform, including a primary phenotypic screening phagocytosis assay together with orthogonal assays, establishes a basis for RPE-based therapy discovery aiming at a broad patient spectrum.
Keywords: RPE; POS; phagocytosis; Ramoplanin; MERTK; RP38 | [{'text': 'Human pluripotent derived RPE- based screening and validation platform', 'coordinates': [120, 0, 876, 30]}, {'text': 'Human PSC RPE inTranswell', 'coordinates': [80, 63, 222, 107]}, {'text': 'Hits Confirmation Dose Response', 'coordinates': [434, 91, 586, 139]}, {'text': 'Miniaturization', 'coordinates': [221, 109, 349, 129]}, {'text': 'HTS 1600 FDA approved compounds Inducers of POS phagocytosis', 'coordinates': [260, 175, 532, 240]}, {'text': 'Ramoplanin', 'coordinates': [624, 186, 730, 210]}, {'text': 'Pyrithione Zinc', 'coordinates': [764, 184, 896, 208]}, {'text': 'RP patient iPSC', 'coordinates': [438, 288, 574, 314]}, {'text': 'Disease RPE MERTK deficiency Rescue internalization defect', 'coordinates': [381, 389, 630, 459]}, {'text': 'Phagocytosis Biology Bound POS Internalized POS Degraded POS', 'coordinates': [141, 489, 389, 648]}, {'text': 'RPE health VEGF secretion', 'coordinates': [701, 491, 859, 553]}, {'text': 'Polarized', 'coordinates': [641, 517, 723, 537]}, {'text': 'Hit Validation', 'coordinates': [422, 610, 580, 634]}, {'text': 'VEGF Transepithelial resistance Electron microscopy', 'coordinates': [639, 621, 860, 686]}, {'text': 'MOA NGS: ERMN, S1PRST', 'coordinates': [422, 741, 600, 802]}] |
End of preview. Expand
in Dataset Viewer.
No dataset card yet
New: Create and edit this dataset card directly on the website!
Contribute a Dataset Card- Downloads last month
- 5