bluuebunny/crossref_metadata_2025_split huggingface dataset:
Divergence of the Individual repeats in the leucine-rich repeat domains of human Toll-like receptors explain their diversity and functional adaptations
Authors: Takkouche Abraham , Ichii Keita , Qui Xinru , Jaroszewski Lukasz , Godzik Adam 
Published: October 2024

AbstractThe receptor domains of Toll-like receptors (TLRs) are characterized by a solenoid-like structure composed of tandem repeats of α/β units known as Leucine Rich Repeats (LRRs). LRR proteins form large paralogous families, with nearly 400 in the human genome alone, all sharing similar semi-regular solenoid-like structures. Despite this structural similarity, they exhibit remarkable diversity in binding specificity. For TLR receptors, this includes a range of pathogen-associated molecular patterns (PAMPs), while other LRR proteins bind an extensive array of ligands, including proteins, DNA, RNA, and small molecules. The LRR domains contain repeats that have similar, yet not identical, 3D structures and patterns of conserved residues. Through in-depth analysis of sequence and structural conservation in individual repeats of human TLRs, we demonstrate that even subtle variations between these repeats alter the local solenoid structure, leading to significant functional changes. Variations in repeat length and defining patterns result in local changes in curvature and the emergence of structural features such as loops, cavities, or specific interaction interfaces. Understanding how divergence in LRR repeats influences their functional roles can provide deeper insights into their binding mechanisms, including interactions with unknown ligands, both in humans and across the diverse phylogenetic spectrum of animals that rely on their TLR repertoires for immune activation.
Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax
Authors: Jones Dallas , Woods Elena , Li Zhenhua , Schaller Kristin L. , Hoffmeyer Eric , Kooiman Ben , Fernandez Joseph , Wharton Tegan , Tufa Dejene , Hall Spencer C. , Trahan George , Maloney Kelly W. , Pacenta Holly , Sullivan Kelly , Espinosa Joaquin , Roede James R. , Marentette John , Stevens Brett , Inguva Anagha , Stephenson Daniel , Reisz Julie A. , D’Alessandro Angelo , Jordan Craig T. , Yang Jun J. , Verneris Michael R. 
Published: October 2024

AbstractChildren with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) are at increased risk for treatment-related mortality and relapse, highlighting the need for new therapies. Leukemia cell lines (CLs) have been fundamental to understanding therapeutic responses to pharmacological agents. We generated three DS B-ALL CLs characterized with diverse genomic alterations, includingIGH::CRLF2rearrangement (BCR::ABL1 like), mutations inFLT3andTP53, and a novelERG::CEBPDrearrangement. DS CLs had diminished proliferation, metabolism, and mitochondrial function when compared to non-DS (NDS) CLs and interestingly, these findings were similar to NDS Philadelphia chromosome-like (Ph-like) B-ALL CLs. Based on similar mitochondrial defects and prior preclinical data using Venetoclax for Ph-like B-ALL, we hypothesized that Venetoclax would be effective in DS. Intriguingly, Venetoclax was more effective in DS when compared to both NDS and Ph-like CLs. Efficacy was observed in DS patient derived xenografts (PDXs) and diagnostic/relapsed patient samples treated with Venetoclax, which synergized with Trametinib and Vincristine. Mass spectrometry-based multiomics analyses in DS and NDS B-ALL patient samples revealed an enriched metabolite profile in DS, particularly in the hubs of glucose metabolism and polyunsaturated phosphatidylcholines and phosphatidylinositols. Transcriptome analyses in DS B-ALL patients (n=249) supported enhanced glucose and fatty acid metabolism. Glucose regulated B-ALL viability throughde novoserine biosynthesis. Targeting serine synergized with Venetoclax in DS B-ALL CLs. In summary, we have generated novel tools for studying DS B-ALL and identify altered metabolism in DS that responds to Venetoclax.
Quantitative 2D J-resolved metabolite-cycled semiLASER spectroscopy of metabolites and macromolecules in the human brain at 9.4 T
Authors: Murali-Manohar Saipavitra , Borbath Tamas , Wright Andrew Martin , Avdievich Nikolai I. , Henning Anke 
Published: October 2024

AbstractPurposeWhile two-dimensional (2D) in vivo spectroscopy yields rich information and has been successfully used in clinical trials, it requires a localization scheme that minimizes the impact of chemical shift displacement on J-coupling evolution, a robust frequency drift correction and dedicated processing and quantification methods. Considering these needs this study demonstrates a novel data acquisition and an analysis pipeline to quantify 16 metabolites in mmol/kg in the human brain using a 2D J-resolved metabolite-cycled (MC) semiLASER localization sequence at 9.4 T in the human brain.MethodsMetabolite spectra were acquired in vivo using the newly developed J-resolved MC semiLASER localization sequence with maximum echo sampling (MES) at 9.4 T. In order to account for the underlying macromolecular (MM) spectra in the acquired metabolite spectra, J-resolved MM spectra were acquired using a double inversion recovery (DIR) J-resolved MC semiLASER. Spectral fitting was performed with ProFit 2.0 using a simulated basis set from VesPA tailored to 2D J-resolved semiLASER with MES. Finally, metabolite concentrations were calculated using internal water referencing.ResultsTissue concentrations for 16 metabolites in mmol/kg are reported after correcting for number of protons, tissue content, and relaxation effects of both water and metabolites at 9.4T. Quantification results of spectra considering 8 and 2 averages per TE did not show any significant differences.Conclusion2D spectra of metabolites acquired at 9.4T and 2D MMs acquired at any field strength are presented for the first time. Basis set simulation and quantification of metabolites for metabolite spectra acquired using maximum-echo-sampled 2D J-resolved semiLASER was performed for the first time. The sensitivity in the detection of J-coupled metabolites such as glutamine, glucose or lactate. At ultra-high field, the acquisition duration of 2D MRS can be also substantially reduced since only a very low number of averages per TE are needed.
Biologically grounded brain-on-chip model identifies selective topographic reorganization within hyperexcitable neural networks
Authors: Poinsot Maxime , Dos Santos Marine , Marthy Baptiste , Borges-Correia Ana , Gascon-Gonzalo Eduardo , Charlot Benoit , Cazorla Maxime 
Published: October 2024

ABSTRACTConnectomics has revolutionized our understanding of brain function by emphasizing the importance of neural networks and their topographical organization. Corticostriatal circuits, which play a critical role in cognition and emotion, follow a precise topographic architecture essential for integrating and processing cortical information within the basal ganglia. Disruptions to this connectivity are often implicated in neurodevelopmental and psychiatric disorders such as obsessive compulsive disorders, schizophrenia, epilepsy, and autism spectrum disorders. However, studying network disruptionsin vivopresents significant challenges due to their intricate architecture and early developmental onset. To address this, we employed a brain-on-chip microfluidic platform to recreate a biologically relevant model of topographically organized corticostriatal networks. By mimicking the directional control of neuronal projections using Tesla valve-inspired microchannels, we demonstrate that genetic perturbations affecting neuronal excitability during development lead to selective alterations of local versus long-range network topology, resulting in the formation of new convergent nodes. This model offers critical insights into how early perturbations contribute to circuit-specific pathologies, providing a valuable tool for understanding neurodevelopmental disorders and advancing therapeutic strategies.
Hierarchical Patterns of Soil Biodiversity in the Atacama Desert: Insights Across Biological Scales
Authors: Villegas Laura , Pettrich Laura , Acevedo-Trejos Esteban , Suwanngam Arunee , Wassey Nadim , Allende Miguel L , Stoll Alexandra , Holovachov Oleksandr , Waldvogel Ann-Marie , Schiffer Philipp H. 
Published: October 2024

ABSTRACTSpecies diversity and distribution, in relation to how they interact with their environment is a major focus of ecological research. Particularly for soil ecosystems, information about geographical patterns of biota is scarce despite the pivotal role of soils as ecosystem service providers. The Atacama is the driest non-polar desert on earth: water is scarce, high salinity patches are frequent and water bodies have high concentrations of metals. It is believed that only specialized taxa can survive in this Desert. Accordingly, only some microbial life-forms and few plants, and vertebrates are present. Above ground invertebrates have been reported in the desert but its soils have not been comprehensively analyzed. By studying different areas in the Atacama, we aim to better understand resilience of soil organisms in times of global aridification. Nematodes are one of the most important groups of soil organisms in abundance and biodiversity. Here, we investigated diversity of soil nematodes at the genetic, taxonomic, community and life-cycle levels. We find distinct patterns and assemblages along the different habitats in the desert: dune systems, high altitude mountains, saline lakes, river valleys and fog oases. We also find that distribution of asexual taxa appears to be in the marginal ranges of high altitudes, and that the distribution of genera richness in the Atacama follows a latitudinal diversity gradient, as well as an increase with increasing precipitation. Our work shows that even under extreme environmental conditions stable, healthy soil communities can persist, but we see indicatives of poor soil food webs.
Mapping the attractor landscape of Boolean networks
Authors: Trinh Van-Giang , Park Kyu Hyong , Pastva Samuel , Rozum Jordan C 
Published: October 2024

AbstractBoolean networks are popular dynamical models of cellular processes in systems biology. Their attractors model phenotypes that arise from the interplay of key regulatory subcircuits. A succession diagram describes this interplay in a discrete analog of Waddington’s epigenetic attractor landscape that allows for fast identification of attractors and attractor control strategies. We present a new approach to succession diagram construction for asynchronously updated Boolean networks, implemented in the biologist’s Boolean attractor landscape mapper,biobalm, a Python 3 library. We compare the performance ofbiobalmto similar tools and find a substantial performance increase in succession diagram construction, attractor identification, and attractor control. To illustrate the utility ofbiobalm, we perform the most comprehensive comparative analysis to date of the succession diagram structure in experimentally-validated Boolean network models of cell processes and random ensembles. We find that random models (including critical Kauffman networks) have relatively small succession diagrams, indicating simple decision structures. In contrast, non-random models from the literature are enriched in extremely large succession diagrams, indicating an abundance of decision points in their dynamics and suggesting the presence of complex Waddington landscapes in nature.
rDNA copy number variation in yeast alters response to environmental conditions
Authors: Thornton Kevin , Kwan Elizabeth X. , Bubb Kerry , Paleologu Luana , Raghuraman M. K. , Brewer Bonita J. , Cuperus Josh T. , Queitsch Christine 
Published: October 2024

ABSTRACTRibosomal DNA (rDNA) in eukaryotes is maintained in hundreds of copies with rDNA copy number varying greatly among individuals within a species. In the budding yeastSaccharomyces cerevisiae, the rDNA copy number across wild isolates ranges from 90 to 300 copies. Previous studies showed that 35 rDNA copies are sufficient for ribosome biogenesis in this yeast and enable wild-type-like growth in standard laboratory growth conditions. We addressed two major questions concerning rDNA copy number variation in this yeast: (1) What are the fitness consequences of rDNA copy number variation outside and within the natural range in standard laboratory growth conditions? (2) Do these fitness effects change in different growth conditions? We used growth competitions to compare the fitness effects of rDNA copy number variation in otherwise isogenic strains whose rDNA copy number ranged from 35 to 200. In standard growth conditions, we found that fitness gradually increases from 35 rDNA copies until reaching a plateau that spans from 98 to 160 rDNA copies, well within the natural range. However, rDNA copy number-dependent fitness differed across environments. Compared to standard growth conditions, strains with higher rDNA copy numbers showed improved fitness when grown at increased temperature or in glycerol media. Moreover, the gradual fitness increase with increasing rDNA copy number in standard growth conditions gave way to a markedly lower fitness of strains with copy numbers below the natural range in these two stress conditions. These results suggest that selective pressures drive rDNA copy number in this yeast to at least ~100 copies and that a higher number of copies buffers against environmental stress. The similarity of theS. cerevisiaerDNA copy number range to the ranges reported inC. elegans, D. melanogaster, and humans points to conserved selective pressures maintaining the range of natural rDNA copy number in these highly diverse species.
Sociality shapes mitochondrial adaptations supporting hypoxia tolerance
Authors: Rossi Alice , Ruwolt Max , Kakouri Paraskevi , Kosten Tetiana , Kunz Severine , Puchkov Dmytro , Reznick Jane , Purfürst Bettina , Omerbašić Damir , Aranda Daniel Méndez , Carai Giorgia , Mastrobuoni Guido , Hart Daniel W. , Carraro Michela , Tommasin Ludovica , Bennett Nigel C. , Bégay Valérie , Faelber Katja , Daumke Oliver , Bernardi Paolo , Park Thomas J. , Kempa Stefan , Liu Fan , Lewin Gary R. 
Published: October 2024

AbstractOxygen deprivation or hypoxia is poorly dealt with by most terrestrial species and often leads to permanent tissue damage and death. One prominent exception is the naked mole-rat (Heterocephalus glaber) which is remarkably adapted to withstand prolonged periods (∼18 mins) of severe hypoxia, a trait likely driven by its crowded underground lifestyle. Other African mole-rat species are less social or entirely solitary like the Cape mole-rat (Georychus capensis). Here, we asked whether cellular and molecular adaptations to hypoxia map to social traits. We discovered that at the cellular level naked mole-rat fibroblasts survive >30 hours in 1% oxygen, while fibroblasts from terrestrial or non-social mole-rat species (human, mouse and Cape mole-rat) die rapidly under hypoxic conditions. We further show that naked mole-rat mitochondria have evolved morphological, functional and proteomic adaptations crucial for hypoxia resistance, remaining unaffected after long periods of severe hypoxia. We identify the mitochondrial protein Optic Atrophy 1 (OPA1) as a key player in naked mole-rat hypoxia resilience. Naked mole-rat mitochondria not only express more protective forms of OPA1, but also harbor a structurally unique isoform that likely protects cells from hypoxic damage. We show that evolutionary changes including the functionalization of a uniqueOpa1exon support mitochondrial mediated cellular protection. Indeed, knockdown of OPA1 in naked mole-rat cells is sufficient to render them equally susceptible to hypoxia as human cells or cells from non-social African species. Our study demonstrates how molecular evolution drives unique adaptations that enable cells to achieve unprecedented resistance to hypoxic damage. We also show that molecular changes at the level of mitochondria are crucial in conferring hypoxia resistance. Our results thus chart a novel molecular path to understand how robust cellular hypoxia resistance can be achieved. Such knowledge may eventually inspire novel strategies to circumvent the consequences of hypoxic-damage in humans.
Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression
Authors: Martin Cole , Sullivan William B. , Brinkman Jacqueline , Scoville Deena , Yashinskie Jossie J , Tian Sha , Mezzadra Riccardo E. , Ho Yu-Jui , Koche Richard P. , Baslan Timour , Raab Jesse , Corcoran David , Finley Lydia W.S. , Lowe Scott W. , Morris John P. 
Published: October 2024

ABSTRACTp53 prevents tumor initiation and progression via transcriptional regulation of target gene networks. Here, we find that cancer-associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes the outgrowth of cancer cells with transcriptionally active, wild-type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (αKG)-dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression, resulting in disabled upregulation of targets that execute tumor suppression. Specifically, mutant IDH disrupts the expression of pro-apoptotic p53 targets that enable p53-dependent tumor regressions, including the death ligand receptor Fas. Pharmacological inhibition of mutant IDH in TP53 wild-type cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy-induced apoptosis. Therefore, we implicate the disruption of p53 target gene regulation as a reversible, oncogenic feature of cancer-associated IDH mutations.SIGNIFICANCEWe find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.
Age dependency of neurometabolite T1relaxation times
Authors: Murali-Manohar Saipavitra , Zöllner Helge J. , Hupfeld Kathleen E. , Song Yulu , Carter Emily E. , Yedavalli Vivek , Hui Steve C. N. , Simicic Dunja , Gudmundson Aaron T. , Simegn Gizeaddis Lamesgin , Davies-Jenkins Christopher W. , Oeltzschner Georg , Porges Eric C. , Edden Richard A. E. 
Published: October 2024

AbstractPurposeTo measure T1relaxation times of metabolites at 3T in a healthy aging population and investigate age dependence.MethodsA cohort of 101 healthy adults were recruited with approximately 10 male and 10 female participants in each ‘decade’ band: 18-29, 30-39, 40-49, 50-59, and 60+ years old. Inversion-recovery PRESS data (TE/TR: 30/2000 ms) were acquired at 8 inversion times (TIs) (300, 400, 511, 637, 780, 947, 1148 and 1400 ms) from voxels in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). Modeling of TI-series spectra was performed in Osprey 2.5.0. Quantified metabolite amplitudes for total N-acetylaspartate (tNAA2.0), total creatine at 3.0 ppm (tCr3.0) and 3.9 ppm (tCr3.9), total choline (tCho), myo-inositol (mI), and the sum of glutamine and glutamate (Glx) were modeled to calculate T1relaxation times of metabolites.ResultsT1relaxation times of tNAA2.0in CSO and tNAA2.0, tCr3.0, mI and Glx in PCC decreased with age. These correlations remained significant when controlling for cortical atrophy. T1relaxation times were significantly different between PCC and CSO for all metabolites except tCr3.0. We also propose linear models for predicting metabolite T1s at 3T to be used in future aging studies.ConclusionMetabolite T1relaxation times change significantly with age, an effect that will be important to consider for accurate quantitative MRS, particularly in studies of aging.
A sustainable and bee-pollinated coffee to start your day
Authors: Alves Denise Araujo , Ramos Jenifer Dias , dos Santos Charles Fernando , Moure-Oliveira Diego , Almeida-Dias Joyce Mayra Volpini , Santos Gustavo Souza , Kaminski Thamires Sá de Oliveira , Cione Ana Paola , Quenzer Fernando Celso Longhim , Campbell Alistair John , Berretta Andresa Aparecida , Sousa Guilherme Jorge Gomes e , Pereira Andrigo Monroe , Thompson Helen , Vasconcelos Natalia Bottan de Toledo , Cruz Rafael , de Queiroz Ana Carolina Martins , Bento José Maurício Simões , Menezes Cristiano 
Published: October 2024

AbstractThe integration of managed pollinators into agricultural systems represents a practical strategy for boosting crop production, optimising sustainable farming practices, and improving rural livelihoods. However, the use of managed bees to supplement the contribution of wild pollinators still faces challenges, such as over-reliance on pesticides in intensively managed agroecosystems. Here, we placed managed bee colonies on conventional farms to assess their impact on arabica coffee yield, quality and market value, while also to evaluate colony health in coffee fields treated with field rates of thiamethoxam-based products. We show that supplementing farms with managed bees increased farmer income by enhancing coffee yield and beverage quality, which is rewarded by specialty coffee markets. Moreover, our field-based study reveals that, even when exposed to field-realistic levels of the neonicotinoid thiamethoxam, managed bee colonies exhibited no significant adverse effects on their health within coffee fields. Our results underline that pollination is a key input on intensively managed coffee farms, and that agricultural production and environmental conservation interact synergically to maximize profitability, which is fundamental to encourage farmers to be good stewards of their croplands by adopting nature-positive practices.
Multiplexed functional analysis of TAP2 variants in regulating MHC-I cell surface abundance reveals overexpression of PLK1 downregulates antigen presentation
Authors: Nagy Gregory , Presley Rebecca , Jeon Hyeongseon , Moreira Lynn , Dhar Shruti , Tull Olivia , Soysal Burak , Yadati Anika S. , Cook Kayleigh D. , Schnell Laura E. , Gupta Arkobrato , Banerjee Tapahsama , Chung Dongjun , Tsichlis Philip N. , Parvin Jeffrey D. 
Published: October 2024

ABSTRACTThe abundance of MHC-I on the cell surface depends on its association with antigenic peptides transported to the endoplasmic reticulum by the Transporter Associated with Antigen Processing (TAP), a peptide channel composed of TAP1 and TAP2. We functionally screened over 1400 TAP2 variants for effects on MHC-I cell surface abundance. Amino-acid substitutions of loss of function (LOF) variants clustered in the NTP-binding domain and along the TAP1-TAP2 binding interface, suggesting that these variants interfered with TAP conformational changes associated with peptide transport. Some LOF variants carried potential phosphomimetic substitutions; one such substitution at Ser251 was embedded in a sequence context consistent with the phosphorylation motif of PLK kinases. Inhibition of PLK kinases increased MHC-I surface expression, while overexpression of PLK1 in cells decreased MHC-I in wild type TAP2, but not in TAP2-S251A-expressing cells. Importantly, site-specific phosphorylation of TAP2 in human tumor samples correlated with alterations of gene expression in the cell cycle and antigen presentation pathways, consistent with the notion that phosphorylation downregulates antigenic peptide transport in human tumors. These data strongly support the hypothesis that in cancer cells, TAP2 phosphorylation by PLK1, and perhaps other kinases, can downregulate the antigen presentation process.