bluuebunny/crossref_metadata_2025 huggingface dataset:
All Staphylococcus aureus bacteraemia strains have the potential to cause infective endocarditis: results of GWAS and experimental animal studies
Authors: Bastien Sylvère , Meyers Severien , Salgado-Pabón Wilmara , Giulieri Stefano , Rasigade Jean-Phillipe , Liesenborghs Laurens , Kinney Kyle J. , Couzon Florence , Martins-Simoes Patricia , Le Moing Vincent , Duval Xavier , Holmes Natasha E , Bruun Niels Eske , Skov Robert , Howden Benjamin P , Fowler Vance G. , Verhamme Peter , Andersen Paal Skytt , Bouchiat Coralie , Moreau Karen , Vandenesch François
Published: May 2022

Abstract and Keywords

Aims

Infective endocarditis (IE) complicates 10-20% of Staphylococcus aureus bacteraemia (SAB). We aimed to determine whether IE strains of S. aureus are genotypically different or behave differently in experimental endocarditis models as compared to non-IE SAB strains.

Methods and Results

We conducted a genome wide association study (GWAS) of 924 S. aureus genomes from IE (274) and non-IE (650) SAB patients, and tested a subset of strains in two experimental animal models of IE, one studying the early step of bacterial adhesion to inflamed mice valves, the second evaluating the local and systemic developmental process of IE on mechanically damaged rabbit valves. The genetic profile of S. aureus IE and non-IE SAB strains did not differ when considering single nucleotide polymorphisms, coding sequences and k-mers analyses in GWASs. In the inflammation-induced IE model in mice no difference was observed between IE and non-IE SAB strains both in adhesion to the cardiac valves and in the propensity to cause IE; in the mechanical IE-induced rabbit model, there was no difference between IE and non-IE SAB strains regarding vegetation size and CFU.

Conclusion

S. aureus isolates from SAB patients with and without IE were indistinguishable, by GWAS and by two in vivo models of IE. Thus, S. aureus strain variation is not the primary determinant of IE. Pending the possible identification of host factors predisposing to IE, all strains of S. aureus must be considered in patients as capable of causing this common, lethal infection once they have accessed the bloodstream.

Translational Perspective

Staphylococcus aureus endocarditis (IE) is a deadly complication of S. aureus bacteraemia (SAB). Beyond well-identified host related IE risk factors, whether bacterial features may influence the occurrence of IE in the course of bacteraemia remain elusive. We analysed the genomes of 924 S. aureus strains from IE and non-IE SAB and compared some in two in vivo IE models. We demonstrated that the propensity of S. aureus to cause IE in the course of bacteraemia does not depend on the intrinsic genetic or virulence factors of S. aureus. These findings are of importance for the management of S. aureus bacteraemia.
SARS-CoV-2 ORF1abA1061S potentiate autoreactive T cell responses via epitope mimicry: an explanation to hepatitis of unknown cause
Authors: Wang Yu , Liu Yuexing
Published: May 2022

The World Health Organization have recently announced outbreak news of acute, severe hepatitis of unknown cause in children under a Covid-19 pandemic. Whether it is associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still under debating. Here, we performed genomic sequence alignment analysis of the genome of SARS-Cov-2 (Wuhan-hu-1) to the human genome reference. Sequence analysis revealed that the SARS-CoV-2 ORF1ab1056-1173 presented high identities with the human protein PAPR1453-176(3Q6Z_A). After searching the fully sequenced SARS-CoV-2 genomes deposited in GISAID (https://www.gisaid.org/), we detected 170 SARS-CoV-2 variants with mutation in ORF1ab1061, where alanine (A) was substituted by serine (S). This alteration made a 7-amino acid peptide (VVVNASN) in ORF1ab1056-1062 identical to its counterpart in PARP1453-59(3Q6Z_A). HLA prediction suggested that the peptides with high identities in PARP14 and ORF1ab could be presented by a same globally prevalent HLA-A*11:01 molecule. And in consistent with the first reported case of hepatitis of unknown, SARS-CoV-2 ORF1abVVVNASN variants were mostly identified as Delta lineages in UK by the late 2021, with an overall frequency of 0.00161%. Thus, our preliminary results raised a possibility that infection by SARS-CoV-2 ORF1abVVVNASN variant might elicit an autoimmune T cell response via epitope mimicry and is associated with the outbreak of unknown hepatitis. We anticipated that these findings will alert the human societies to pay more attention to rare mutations beyond the spike proteins.
Retina Gap Junction Networks Facilitate Blind Denoising in the Visual Hierarchy
Authors: Yue Yang , Lun Kehuan , He Liuyuan , He Gan , Zhang Shenjian , Ma Lei , Liu Jian.K. , Tian Yonghong , Du Kai , Huang Tiejun
Published: May 2022

Gap junctions in the retina are electrical synapses, which strength is regulated byambient light conditions. Such tunable synapses are crucial for the denoising function of the early visual system. However, it is unclear that how the plastic gap junction network processes unknown noise, specifically how this process works synergistically with the brain’s higher visual centers. Inspired by the electrically coupled photoreceptors, we develop a computational model of the gap junction filter (G-filter). We show that G-filter is an effective blind denoiser that converts different noise distributions into a similar form. Next, since deep convolutional neural networks (DCNNs) functionally reflect some intrinsic features of the visual cortex, we combine G-filter with DCNNs as retina and ventral visual pathways to investigate the relationship between retinal denoising processing and the brain’s high-level functions. In the image denoising and reconstruction task, G-filter dramatically improve the classic deep denoising convolutional neural network (DnCNN)’s ability to process blind noise. Further, we find that the gap junction strength of the G-filter modulates the receptive field of DnCNN’s output neurons by the Integrated Gradients method. At last, in the image classification task, G-filter strengthens the defense of state-of-the-arts DCNNs (ResNet50, VGG19 and InceptionV3) against blind noise attacks, far exceeding human performance when noise is large. Our results indicate G-filter significantly enhance DCNNs’ ability on various blind denoising tasks, implying an essential role for retina gap junction networks in high-level visual processing.
Network Topology Metrics Explaining Enrichment of Hybrid Epithelial Mesenchymal Phenotypes in Metastasis
Authors: Rashid Mubasher , Hari Kishore , Thampi John , Santhosh Nived Krishnan , Jolly Mohit Kumar
Published: May 2022

Epithelial to mesenchymal transition (EMT) and its reverse mesenchymal to epithelial transition (MET) are hallmarks of metastasis. Cancer cells use this reversible cellular programming to switch among Epithelial (E), Mesenchymal (M), and hybrid Epithelial/Mesenchymal (hybrid E/M) state(s) and seed tumors at distant sites. Hybrid E/M cells are often more aggressive and metastatic than the “pure” E and M cells. Thus, identifying mechanisms to inhibit hybrid E/M cells can be promising in curtailing metastasis. While multiple gene regulatory networks (GRNs) based mathematical models for EMT/MET have been developed recently, identifying topological signatures enriching for hybrid E/M phenotypes remains to be done. Here, we investigate the dynamics of 13 different GRNs and identify which network topologies can enrich for hybrid E/M phenotype(s) across GRNs. We found that increasing negative feedback loops enhances the “hybridness” of these networks, but increasing the number of positive feedback loops or their specific combinations can decrease the frequency of hybrid E/M phenotype. Thus, our analysis identifies network topology based signatures that can give rise to, as well as prevent, the emergence of hybrid E/M phenotype in GRNs underlying EMP. Our results can have implications in terms of targeting specific interactions in GRNs as a potent way to restrict switching to the hybrid E/M phenotype(s) to curtail metastasis.
The Clinical Response of Upadacitinib and Risankizumab is Associated with Reduced Inflammatory Bowel Disease Anti-TNFα Inadequate Response Mechanisms
Authors: Wang Jing , Macoritto Michael , Guay Heath , Davis Justin W. , Levesque Marc C. , Cao Xiaohong
Published: May 2022

Background and Aims

JAK1 inhibitor upadacitinib and IL23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are anti-TNFα inadequate responders (TNF-IR). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.

Methods

Eight tissue transcriptomic datasets from IBD patients treated with anti-TNFα therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms. RNAseq colon tissue data from clinical studies of TNF-IR Crohn’s disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab.

Results

We found seven TNF-IR up-regulated modules (M1-M7) related to innate/adaptive immune responses, interferon signaling and tissue remodeling, and five TNF-IR down-regulated modules (M8-M12) primarily related to metabolism. TNF-IR up-regulated cell types were inflammatory fibroblasts, post-capillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells while subtypes of immature enterocytes, WNT5B+ cells and myofibroblasts were TNF-IR down-regulated cell types. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR up-regulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, four of the six TNF-IR up-regulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab.

Conclusions

Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR up-regulated mechanisms, which may account for their clinical response among TNF-IR IBD patients.
Chromosome-level Reference Genome Provides Insights into Divergence and Stress Adaptation of the African Oil Palm
Authors: Wang Le , Lee May , Wan Zi Yi , Bai Bin , Ye Baoqing , Alfiko Yuzer , Ramadsyah Ramadsyah , Purwantomo Sigit , Song Zhuojun , Suwanto Antonius , Yue Gen Hua
Published: May 2022

The palm family (Arecaceae), consisting of ∼ 2600 species, is the third most economically important family of plants. The African oil palm (Elaeis guineensis) is one of the most important palms. However, the genome sequences of palms available are still limited and fragmented. Here, we report a high-quality chromosome-level reference genome of an oil palm Dura. The genome of 1.7 Gb was assembled by integrating long reads with ∼ 150 × genome coverage. The assembled genome covered 94.5% of the estimated genome size, within which 91.6% were assigned into 16 pseudochromosomes and 73.7% were repetitive sequences. Relying on the conserved synteny with oil palm, the existing draft genome sequences of both date palm and coconut were further assembled into chromosomal level. Transposon burst, particularly long terminal repeat retrotransposons (LTRs) retrotransposons, following the last whole-genome duplication (WGD), likely explains genome size variation across palms. Convergent evolution of fruit colors tends to eliminate the roles of the virescens gene in controlling accumulation of anthocyanins in exocarp of ripe fruit of palms. Recent duplications of high tandemly repeated pathogenesis-related proteins (PRs) from the same tandem arrays played an important role in defense responses to Ganoderma. Whole genome re-sequencing of both ancestral African and introduced oil palms in Southeast Asia revealed that genes under putative selection were notably associated with stress responses, suggesting adaptation to stresses in the new habitat. The genomic resources and insights gained in this study could be exploited for accelerating genetic improvement and understanding the evolution of palms.
Evolution and Diversification Dynamics of Butterflies
Authors: Kawahara Akito Y. , Storer Caroline , Carvalho Ana Paula S. , Plotkin David M. , Condamine Fabien , Braga Mariana P. , Ellis Emily A. , St Laurent Ryan A. , Li Xuankun , Barve Vijay , Cai Liming , Earl Chandra , Frandsen Paul B. , Owens Hannah L. , Valencia-Montoya Wendy A. , Aduse-Poku Kwaku , Toussaint Emmanuel F. A. , Dexter Kelly M. , Doleck Tenzing , Markee Amanda , Messcher Rebeccah , Nguyen Y-Lan , Badon Jade Aster T. , Benítez Hugo A. , Braby Michael F. , Buenavente Perry A. C. , Chan Wei-Ping , Collins Steve C. , Childers Richard A. Rabideau , Dankowicz Even , Eastwood Rod , Fric Zdenek F. , Gott Riley J. , Hall Jason P. W. , Hallwachs Winnie , Hardy Nate B. , Sipe Rachel L. Hawkins , Heath Alan , Hinolan Jomar D. , Homziak Nicholas T. , Hsu Yu-Feng , Inayoshi Yutaka , Itliong Micael G.A. , Janzen Daniel H. , Kitching Ian J. , Kunte Krushnamegh , Lamas Gerardo , Landis Michael J. , Larsen Elise A. , Larsen Torben B. , Leong Jing V. , Lukhtanov Vladimir , Maier Crystal A. , Martinez Jose I. , Martins Dino J. , Maruyama Kiyoshi , Maunsell Sarah C. , Mega Nicolás Oliveira , Monastyrskii Alexander , Morais Ana B. B. , Müller Chris J. , Naive Mark Arcebal K. , Nielsen Gregory , Padrón Pablo Sebastián , Peggie Djunijanti , Romanowski Helena Piccoli , Sáfián Szabolcs , Saito Motoki , Schröder Stefan , Shirey Vaughn , Soltis Doug , Soltis Pamela , Sourakov Andrei , Talavera Gerard , Vila Roger , Vlasanek Petr , Wang Houshuai , Warren Andrew D. , Willmott Keith R. , Yago Masaya , Jetz Walter , Jarzyna Marta A. , Breinholt Jesse W. , Espeland Marianne , Ries Leslie , Guralnick Robert P. , Pierce Naomi E. , Lohman David J.
Published: May 2022

Butterflies are a diverse and charismatic insect group that are thought to have diversified via coevolution with plants and in response to dispersals following key geological events. These hypotheses have been poorly tested at the macroevolutionary scale because a comprehensive phylogenetic framework and datasets on global distributions and larval hosts of butterflies are lacking. We sequenced 391 genes from nearly 2,000 butterfly species to construct a new, phylogenomic tree of butterflies representing 92% of all genera and aggregated global distribution records and larval host datasets. We found that butterflies likely originated in what is now the Americas, ∼100 Ma, shortly before the Cretaceous Thermal Maximum, then crossed Beringia and diversified in the Paleotropics. The ancestor of modern butterflies likely fed on Fabaceae, and most extant families were present before the K/Pg extinction. The majority of butterfly dispersals occurred from the tropics (especially the Neotropics) to temperate zones, largely supporting a “cradle” pattern of diversification. Surprisingly, host breadth changes and shifts to novel host plants had only modest impacts.
Global and tissue-specific aging effects on murine proteomes
Authors: Keele Gregory R. , Zhang Ji-Gang , Szpyt John , Korstanje Ron , Gygi Steven P. , Churchill Gary A. , Schweppe Devin K.
Published: May 2022

Maintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional changes with age. To define the effects of age directly at the protein level, we performed discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes at adult and late midlife ages (8 and 18 months). Consistent with previous studies, age-related changes in protein abundance often have no corresponding transcriptional change. Aging resulted in increases in immune protein abundance across all tissues, consistent with a global pattern of immune infiltration with age. Our protein-centric data revealed tissue-specific aging changes with potential functional consequences, including altered endoplasmic reticulum and protein trafficking in the spleen. We further observed changes in the stoichiometry of protein complexes with important roles in protein homeostasis such as the CCT/TriC complex and large ribosomal subunit. These data provide a foundation for understanding how proteins contribute to systemic aging across tissues.
USP11 promotes endothelial apoptosis-resistance in pulmonary hypertension by deubiquitinating HINT3
Authors: Jang Andrew J. , Tseng Victor , Kim Jae Sun , Stearman Robert S. , Zhao Yutong , Zhao Jing , Choi Jiwoong , Lister John , Passineau Michael J. , Lam Wilbur A. , Park Changwon , Benza Raymond J. , Kang Bum-Yong
Published: May 2022

Introduction

Pulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. Evolving evidence indicates that the ubiquitin-specific proteases (USPs), play an important role in the pathogenesis of PAH by deubiquitinating key proteins involved in cell proliferation, migration, and apoptosis. Our genome-wide association study (GWAS) analysis-paired with transcriptomic profiling indicated that deubiquitinase USP11 and histidine triad nucleotide binding protein 3 (HINT3) are positively correlated and that their expression increased in lungs of PAH patients compared to control (fail donor) group, and inversely correlated with survival. However, mechanisms and function of the USP11/HNT3 axis have not been explored in PAH. Therefore, we aimed to investigate that HINT3 stabilized by USP11 activation links to endothelial apoptosis-resistance in PAH.

Methods and Results

Expression of USP11 and HINT3 was increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice using qRT-PCR and Western blot analyses. USP11 and HINT3 interacted physically as shown by co-immunoprecipitation (co-IP) assay in human pulmonary artery endothelial cells (HPAECs). HINT3 levels were decreased upon transfection of HA-tagged Ubi plasmid into HPAECs. Pretreatment with the potent proteasome inhibitor MG132 prolonged the half-life of HINT3 protein, indicating that HINT3 is degraded by polyubiquitination. HINT3 was stabilized and destabilized by forced overexpression or siRNA knockdown of USP11 respectively. Similarly, treatment with mitoxantrone, a USP11 antagonist, reduced HPAEC HINT3 expression. HINT3 interacted with the antiapoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, knockdown of HINT3 function led to depletion of BCL2.

Conclusions

The HINT3-USP11 axis contributes to apoptosis-resistance in pulmonary artery endothelial cells, as is potentially a novel and attractive therapeutic target for ubiquitination modulators.
Selenocysteine metabolism is a targetable vulnerability inMYCN-amplified cancers
Authors: Alborzinia Hamed , Chen Zhiyi , Yildiz Umut , Freitas Florencio Porto , Vogel Felix C.E. , Varga Julianna , Batani Jasmin , Bartenhagen Christoph , Schmitz Werner , Büchel Gabriele , Michalke Bernhard , Zheng Jashuo , Meierjohann Svenja , Girardi Enrico , Espinet Elisa , Florez Andres , dos Santos Ancely Ferreira , Aroua Nesrine , Schlicker Lisa , Xavier da Silva Thamara N. , Przybylla Adriana , Zeisberger Petra , Superti-Furga Giulio , Eilers Martin , Conrad Marcus , Fischer Matthias , Schulze Almut , Trumpp Andreas , Friedmann Angeli José Pedro
Published: May 2022

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma.

Statement of significance

Given the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.
Machine Learning Reveals The Effect of Maternal Age on The Mouse Pre-Implantation Embryo Developmental Timing
Authors: Daniel Nati , Wasserman Tanya , Adler Zohar , Czyzewski Tomer , Savir Yonatan
Published: May 2022

In recent years, many women have delayed childbearing, thus increasing the necessity for assisted reproductive technology (ART) for older women1–3. Despite advances in ART4, its success rate in advanced-age women is still very low3,4. As time-lapse imaging became available, morphological features of the developing pre-implantation embryo, in-vitro, are heavily used to assess its potency5–9. Timing of embryo cleavage is also an important factor that correlates with blastocyst formation and pregnancy rates8,10–14. Yet, our understanding of the interplay between embryos’ morphology, viability, and maternal age is limited, as manual approaches to infer embryo morphokinetics are time-consuming, subjective, and prone to errors. Machine learning15–18 was recently harnessed to predict embryo developmental potential19,20, however, with limited success.

Here, we develop an artificial intelligence (AI) platform that infers the embryos’ developmental stage and captures tens of morphological properties and developmental dynamics. We show that developmental timing is the most informative and predictive morphokinetic property, particularly for embryos from maternally aged females. Analyzing the timing distributions reveals that viable embryos are confined into an age-independent temporal corridor while non-viable embryos deviate from it towards slower transition times. Yet, the deviation of non-viable embryos from the temporal corridor is age-dependent. Furthermore, there is a significant correlation between consecutive developmental stages transition times that diminishes in maternally old embryos. Overall, our results suggest that maternally old embryos’ most apparent morphokinetic property is the loss of temporal regulation. Our results and platform pave the way for a more accurate, maternally-age-dependent, assisted reproductive technology.
Menin-MLL Inhibitor MI-503 Blocks Menin Nuclear Export and Suppresses Hypergastrinemia
Authors: Merchant Juanita L. , Wang Zhen , Sundaresan Sinju
Published: May 2022

Menin is the protein product of the Multiple Endocrine Neoplasia 1 (MEN1) gene locus at 11q13 and is a known tumor suppressor of neuroendocrine neoplasms (NENs). Gastrin-expressing NENs (gastrinomas) comprise the most frequent and malignant of the MEN1-dependent endocrine tumors. When gastrinomas are part of the MEN1 syndrome, they exhibit a greater propensity to develop within the submucosal Brunner’s glands of the duodenum. Therefore, models to analyze the biology of these intestinal gastrin-expressing NENs should consider their submucosal location.

Aim

The goal of this study was to determine whether the Menin-MLL inhibitor MI-503 suppressed hypergastrinemia.

Methods

A murine model of hypergastrinemia generated by omeprazole treatment of mice carrying a conditional deletion of Men1 bred onto a somatostatin null genetic background (OMS) was treated intraperitoneally with MI-503 for 1 month. Primary enteric glial cells were prepared from these OMS mice and were treated with increasing doses of MI-503. Similarly human AGS and mouse STC-1 gastrin producing cell lines were treated with EGF without or with MI-503.

>Results

We found that the treatment reduced serum and gastro-duodenal tissue expression of gastrin. Ex vivo MI-503 treatment of glial fibrillary acidic protein (GFAP)+ enteric cells isolated from the OMS mice or gastrin-expressing cell lines revealed that MI-503 blocked the nuclear export of Menin and suppressed gastrin gene expression. RNA-Seq analysis of gastrin-treated GFAP+ enteric cells revealed that they express EGF receptor ligands and that EGF treatment of GFAP+ cells also induced Menin translocation and concurrent induction of gastrin gene expression.

Conclusion

We concluded that MI-503 inhibits gastrin gene expression by blocking Menin translocation.
A structural basis for prion strain diversity
Authors: Manka Szymon W. , Wenborn Adam , Betts Jemma , Joiner Susan , Saibil Helen R. , Collinge John , Wadsworth Jonathan D.F.
Published: May 2022

Recent cryo-EM studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML prion strains revealed a comparable, parallel in-register intermolecular β-sheet (PIRIBS) amyloid architecture. Rungs of the fibrils are composed of individual prion protein (PrP) monomers that fold to create distinct N- and C-terminal lobes. However, disparity in the hamster/mouse PrP sequence precludes understanding how divergent prion strains emerge from an identical PrP substrate. Here, we determined the near-atomic resolution cryo-EM structure of infectious,ex vivomouse prion fibrils from the ME7 prion strain and have compared this with the RML fibril structure. This structural comparison of two biologically distinct mouse-adapted prion strains suggests defined folding sub-domains of PrP rungs and the way in which they are interrelated, providing the first structural definition of intra-species prion strain-specific conformations.
Dendritic cell Piezo1 integrating mechanical stiffness and inflammatory signals directs the differentiation of TH1 and Treg cells in cancer
Authors: Wang Yuexin , Yang Hui , Jia Anna , Wang Yufei , Yang Qiuli , Dong Yingjie , Bi Yujing , Liu Guangwei
Published: May 2022

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the mechanical sensor Piezo1 expressed by DCs integrates innate inflammatory stimuli and stiffness signals and directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.
Rabphilin 3A binds the N-peptide of SNAP-25 to promote SNARE complex assembly in exocytosis
Authors: Li Tianzhi , Cheng Qiqi , Wang Shen , Ma Cong
Published: May 2022

Exocytosis of secretory vesicles requires the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and small GTPase Rabs. As a Rab3/Rab27 effector protein on secretory vesicles, Rabphilin 3A was implicated to interact with SNAP-25 to regulate vesicle exocytosis in neurons and neuroendocrine cells, yet the underlying mechanism remains unclear. In this study, we have characterized the physiologically relevant binding sites between Rabphilin 3A and SNAP-25. We found that an intramolecular interplay between the N-terminal Rab-binding domain and C-terminal C2AB domain enables Rabphilin 3A to strongly bind the SNAP-25 N-peptide region via its C2B bottom α-helix. Disruption of this interaction significantly impaired docking and fusion of vesicles with the plasma membrane in PC12 cells. In addition, we found that this interaction allows Rabphilin 3A to accelerate SNARE complex assembly. Furthermore, we revealed that this interaction accelerates SNARE complex assembly via inducing a conformational switch from random coils to α-helical structure in the SNAP-25 SNARE motif. Altogether, our data suggest that promotion of SNARE complex assembly by binding of the C2B bottom α-helix of Rabphilin 3A to the N-peptide of SNAP-25 underlies a pre-fusion function of Rabphilin 3A in vesicle exocytosis.
Kynurenic acid, a key L-tryptophan-derived metabolite, protects the heart from an ischemic damage
Authors: Bigelman Einat , Pasmanik-Chor Metsada , Dassa Bareket , Itkin Maxim , Malitsky Sergey , Dorot Orly , Pichinuk Edward , Levin-Zaidman Smadar , Dezorella Nili , Gross Atan , Abashidze Anastasia , Kleinberg Yuval , Keren Gad , Entin-Meer Michal
Published: May 2022

Background

Renal injury induces major changes in plasma and cardiac metabolites. We sought to identify a key metabolite that may affect cardiac mitochondria following an acute kidney injury (AKI) that may be harnessed to protect the heart following an acute ischemic event.

Methods and Results

Metabolomics profiling of cardiac lysates and plasma samples derived from rats that underwent AKI 1 or 7 days earlier by 5/6 nephrectomy versus sham-operated controls was performed. We detected only 26 differential metabolites in both heart and plasma samples at the two selected time points, relative to sham. Out of which, kynurenic acid (kynurenate, KYNA) seemed most relevant. Interestingly, KYNA given at 10 mM concentration significantly rescued the viability of H9C2 cardiac myoblast cells grown under anoxic conditions and largely improved their mitochondrial structure and function as determined by flow cytometry and cell staining with MitoTracker dyes. Moreover, KYNA diluted in the drinking water of animals induced with an acute myocardial infarction, highly enhanced their cardiac recovery according to echocardiography and histopathology.

Conclusion and translational aspect

KYNA may represent a key metabolite absorbed by the heart following AKI. This metabolite can enhance cardiac cell viability following an ischemic event in a mechanism that is mediated, at least in part, by the protection of the cardiac mitochondria. A short-term administration of KYNA may be highly beneficial in the treatment of the acute phase of kidney disease in order to attenuate progression to CRS and in ischemic cardiac conditions to reduce ischemic myocardial damage.

Highlights

The levels of the L-Tryptophan-derived metabolite, Kynurenic acid (KYNA), are significantly elevated in the heart and the plasma of animals induced with an acute kidney disease.

KYNA rescues the viability of cardiac cells from an ischemic damage both in vitro and in vivo.

KYNA can protect the structure & function of cardiac mitochondria in H9C2 cardiomyoblast cells upon exposure to anoxia.

Graphical abstract
PRR14 organizes H3K9me3-modifed heterochromatin at the nuclear lamina
Authors: Kiseleva Anna A. , Cheng Yu-Chia , Smith Cheryl L. , Katz Richard A. , Poleshko Andrey
Published: May 2022

The eukaryotic genome is organized in three dimensions within the nucleus. Transcriptionally active chromatin is spatially separated from silent heterochromatin, a large fraction of which is located at the nuclear periphery. However, the mechanisms by which chromatin is localized at the nuclear periphery remain poorly understood. Here we demonstrate that Proline Rich 14 (PRR14) protein specifically organizes H3K9me3-modified heterochromatin at the nuclear lamina. We show that PRR14 dynamically associates with both the nuclear lamina and heterochromatin, and is able to reorganize heterochromatin in the nucleus of interphase cells independent of mitosis. We demonstrate that PRR14 can bind all isoforms of heterochromatin protein 1 (HP1). We characterize two functional HP1-binding sites within PRR14 that contribute to its association with heterochromatin. Results of fluorescent recovery after photobleaching (FRAP) and super-resolution imaging indicate that PPR14 forms an anchoring surface for heterochromatin at the nuclear lamina where it interacts dynamically with HP1-associated, H3K9me3-modified chromatin. Our study reveals the mechanism through which PRR14 tethers heterochromatin to the nuclear lamina and we propose a model of dynamic heterochromatin organization at the nuclear periphery.
Maintaining a stable head direction representation in naturalistic visual environments
Authors: Haberkern Hannah , Chitnis Shivam S , Hubbard Philip M , Goulet Tobias , Hermundstad Ann M , Jayaraman Vivek
Published: May 2022

Many animals rely on a representation of head direction for flexible, goal-directed navigation. In insects, a compass-like head direction representation is maintained in a conserved brain region called the central complex. This head direction representation is updated by self-motion information and by tethering to sensory cues in the surroundings through a plasticity mechanism. However, under natural settings, some of these sensory cues may temporarily disappear—for example, when clouds hide the sun—and prominent landmarks at different distances from the insect may move across the animal’s field of view during translation, creating potential conflicts for a neural compass. We used two-photon calcium imaging in head-fixed Drosophila behaving in virtual reality to monitor the fly’s compass during navigation in immersive naturalistic environments with approachable local landmarks. We found that the fly’s compass remains stable even in these settings by tethering to available global cues, likely preserving the animal’s ability to perform compass-driven behaviors such as maintaining a constant heading.
Semi-supervised deep learning with graph neural network for cross-species regulatory sequence prediction
Authors: Mourad Raphaël
Published: May 2022

Genome-wide association studies have systematically identified thousands of single nucleotide polymorphisms (SNPs) associated with complex genetic diseases. However, the majority of those SNPs were found in non-coding genomic regions, preventing the understanding of the underlying causal mechanism. Predicting molecular processes based on the DNA sequence represents a promising approach to understand the role of those non-coding SNPs. Over the past years, deep learning was successfully applied to regulatory sequence prediction. Such method required DNA sequences associated with functional data for training. However, the human genome has a finite size which strongly limits the amount of DNA sequence with functional data available for training. Conversely, the amount of mammalian DNA sequences is exponentially increasing due to ongoing large sequencing projects, but without functional data in most cases. Here, we propose a semi-supervised learning approach based on graph neural network which allows to borrow information from homologous mammal sequences during training. Our approach can be plugged into any existing deep learning model and showed improvements in many different situations, including classification and regression, and for different types of functional data.
Ultra-small bispecific fusion protein augments tumor penetration and treatment efficacy for pancreatic cancer
Authors: Wang Qian , Wang Jingyun , Yan Hao , Li Zheng , Wang Kun , Kang Feiyu , Tian Jie , Zhao Xinming
Published: May 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Due to drugs’ low intrinsic anticancer activity and the unique physiological barrier of PDAC tumors, the once highly anticipated antibody-based pathway-targeted therapies have not achieved promising improvement in outcomes. Here, an ultra-small-sized bispecific fusion protein, termed Bi-fp50, that could largely enrich deep tumor tissue and effectively inhibit PDAC tumor growth was reported. The bispecific Bi-fp50 protein was constructed by a typical synthetic biology method that could efficiently target EGFR and VEGF of PDAC cells simultaneously in vitro and in vivo. For Bxpc3 and Aspc1 PDAC cells, the Bi-fp50 achieved a significant and synergistic therapeutic effect. Owing to the small size of only 50 kDa and the function of reducing the interstitial fluid pressure by vascular normalization, the Bi-fp50 showed enhanced penetration, considerable accumulation, and uniform distribution in tumor and subsequently led to effective inhibition of the growth of Bxpc3 cells-induced PDAC tumor in vivo. Furthermore, no noticeable side effect of Bi-fp50 was found in vitro and in vivo. This work demonstrates that the synthetic Bi-fp50 fusion protein could be used as a new effective pathway-specific targeted therapy for PDACs.
PPARγ/ETV2 Axis Regulates Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension
Authors: Lee Dong Hun , Kim Minseong , Chang Sarah S. , Jang Andrew J. , Kim Juyoung , Ma Jing , Passineau Michael J. , Benza Raymond L. , Karmouty-Quintana Harry , Lam Wilbur A. , Sutliff Roy L. , Hart C. Michael , Park Changwon , Kang Bum-Yong
Published: May 2022

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH). Also, the molecular mechanisms regulating EndoMT in PH remain to be defined. In this study, we first showed that reduced expression of the transcription factors ETV2 (ETS variant 2) and PPARγ (Peroxisome Proliferator-Activated Receptor gamma) along with reduced endothelial markers and increased EndoMT markers were consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension (IPAH) patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced EndoMT cells. Base on this observation, we aimed to investigate the function of ETV2 and PPARγ in EndoMT. We have explored the function of ETV2 and PPARγ and its mechanism in PH using in Etv2+/- mice or PPARγ KO mice. Etv2+/- mice spontaneously developed PH and right ventricular hypertrophy, associated with increased EndoMT markers and decreased EC markers. PPARγ transcriptionally activated the ETV2 promoter. Endothelial PPARγ expression in mice is positively correlated with ETV2 expression, but inversely with EndoMT markers.

Overexpression of ETV2 in hypoxia-exposed rat pulmonary artery led to vascular relaxation. We conclude that PPARγ-ETV2 signaling can function as a novel pathway in PH pathogenesis by attenuating EndoMT.
Endothelial neuropilin-1 and neuropilin-2 are essential for tumour angiogenesis
Authors: Benwell CJ , Johnson RT , Taylor JAGE , Price CA , Robinson SD
Published: May 2022

Neuropilin (NRP) expression is highly correlated with poor outcome in multiple cancer subtypes. As known co-receptors for vascular endothelial growth factor receptors (VEGFRs), core drivers of angiogenesis, past investigations have alluded to their functional roles in facilitating tumorigenesis by promoting invasive vessel growth. Despite this, it remains unclear as to whether NRP1 and NRP2 act in a synergistic manner to enhance pathological angiogenesis. Here we demonstrate, using NRP1ECKO, NRP2ECKO and NRP1/NRP2ECKO mouse models, that maximum inhibition of primary tumour development and angiogenesis is only achieved when both endothelial NRP1 and NRP2 are targeted simultaneously. Metastasis and secondary site angiogenesis were also significantly inhibited in NRP1/NRP2ECKO animals. Mechanistic studies revealed that co-depleting NRP1 and NRP2 in mouse-microvascular endothelial cells (ECs) stimulates rapid shuttling of VEGFR-2 to Rab7+ endosomes for proteosomal degradation. Our results highlight the importance of targeting both NRP1 and NRP2 to modulate tumour angiogenesis.
Nitrogenase resurrection and the evolution of a singular enzymatic mechanism
Authors: Garcia Amanda K. , Harris Derek F. , Rivier Alex J. , Carruthers Brooke M. , Pinochet-Barros Azul , Seefeldt Lance C. , Kaçar Betül
Published: May 2022

The planetary biosphere is powered by a suite of key metabolic innovations that emerged early in the history of life. However, it is unknown whether life has always followed the same set of strategies for performing these critical tasks. Today, microbes access atmospheric sources of bioessential nitrogen through the activities of just one family of enzymes, nitrogenases. Here, we show that the only dinitrogen reduction mechanism known to date is an ancient feature conserved from nitrogenase ancestors. We designed a paleomolecular engineering approach wherein ancestral nitrogenase genes were phylogenetically reconstructed and inserted into the genome of the diazotrophic bacterial model,Azotobacter vinelandii, enabling an integrated assessment of bothin vivofunctionality and purified nitrogenase biochemistry. Nitrogenase ancestors are active and robust to variable incorporation of one or more ancestral protein subunits. Further, we find that all ancestors exhibit the reversible enzymatic mechanism for dinitrogen reduction, specifically evidenced by hydrogen inhibition, that is also exhibited by extantA. vinelandiinitrogenase isozymes. Our results suggest that life may have been constrained in its sampling of protein sequence space to catalyze one of the most energetically challenging biochemical reactions in nature. The experimental framework established here is essential for probing how nitrogenase functionality has been shaped within a dynamic, cellular context to sustain a globally consequential metabolism.

IMPACT STATEMENT

The enzymatic mechanism for dinitrogen reduction is an ancient feature of nitrogenases that persisted over hundreds of millions of years.
Short-term monocular deprivation boosts neural responsiveness to audio-visual events for the undeprived eye
Authors: Federici A. , Bernardi G. , Senna I. , Fantoni M. , Ernst M.O. , Ricciardi E. , Bottari D.
Published: May 2022

A brief period of monocular deprivation (MD) induces short-term plasticity of the adult visual system. Whether MD elicits changes beyond visual processing is yet unclear. Here, we assessed the specific impact of MD on multisensory processes. Neural oscillations associated with visual and audio-visual processing were measured for both the deprived and the undeprived eye. Results revealed that MD changed neural activities associated with unimodal and multisensory processes in an eye-specific manner. Selectively for the deprived eye, alpha activity was reduced within the first 150 ms of visual processing. Conversely, gamma activity was enhanced in response to audio-visual events only for the undeprived eye within 100-300 ms after stimulus onset. The analysis of gamma responses to unimodal auditory events revealed that MD elicited a crossmodal upweighting for the undeprived eye. Distributed source modeling suggested that the right parietal cortex played a major role in all neural effects induced by MD. Finally, visual and audio-visual processing alterations emerged selectively for the induced (but not the evoked) component of the neural oscillations, indicating a major role of feedback connectivity. These findings support a model in which MD increases excitability to visual events for the deprived eye and to audio-visual and auditory events for the undeprived eye. On the one hand, these results reveal the causal impact of MD on both unisensory and multisensory processes but with distinct frequency-specific profiles. On the other hand, they highlight the feedback nature of short-term neural plasticity. Overall this study shed light on the high flexibility and interdependence of unimodal and multisensory functions.

Highlights

- We unveiled the impact of temporary MD on visual and audio-visual processing

- MD enhanced visual excitability for the deprived eye

- MD boosted neural responses to audio-visual events for the undeprived eye

- Analyses of auditory processing revealed crossmodal effects following MD

- Short-term MD primarily affects induced, non-phase-locked, oscillatory activity
scMoMaT: Mosaic integration of single cell multi-omics data using matrix tri-factorization
Authors: Zhang Ziqi , Sun Haoran , Mariappan Ragunathan , Chen Xi , Chen Xinyu , Jain Mika S , Efremova Mirjana , Teichmann Sarah A , Rajan Vaibhav , Zhang Xiuwei
Published: May 2022

Single cell data integration methods aim to integrate cells across data batches and modalities, and obtain a comprehensive view of the cells. Single cell data integration tasks can be categorized into horizontal, vertical, diagonal, and mosaic integration, where mosaic integration is the most general and challenging case with few methods developed. We propose scMoMaT, a method that is able to integrate single cell multi-omics data under the mosaic integration scenario using matrix tri-factorization. During integration, scMoMaT is also able to uncover the cluster specific bio-markers across modalities. These multi-modal bio-markers are used to interpret and annotate the clusters to cell types. Moreover, scMoMaT can integrate cell batches with unequal cell type compositions. Applying scMoMaT to multiple real and simulated datasets demonstrated these features of scMoMaT and showed that scMoMaT has superior performance compared to existing methods. We also show that integrated cell embedding combined with learned bio-markers leads to cell type annotations of higher quality or resolution compared to their original annotations.
RNA sequence to structure analysis from comprehensive pairwise mutagenesis of multiple self-cleaving ribozymes
Authors: Roberts Jessica M. , Beck James D. , Pollock Tanner B. , Bendixsen Devin P. , Hayden Eric J.
Published: May 2022

Self-cleaving ribozymes are RNA molecules that catalyze the cleavage of their own phosphodiester backbones. These ribozymes are found in all domains of life and are also a tool for biotechnical and synthetic biology applications. Self-cleaving ribozymes are also an important model of sequence to function relationships for RNA because their small size simplifies synthesis of genetic variants and self-cleaving activity is an accessible readout of the functional consequence of the mutation. Here we used a high-throughput experimental approach to determine the relative activity for every possible single and double mutant of five self-cleaving ribozymes. From this data, we comprehensively identified non-additive effects between pairs of mutations (epistasis) for all five ribozymes. We analyzed how changes in activity and trends in epistasis map to the ribozyme structures. The variety of structures studied provided opportunities to observe several examples of common structural elements, and the data was collected under identical experimental conditions to enable direct comparison. Heat-map based visualization of the data revealed patterns indicating structural features of the ribozymes including paired regions, unpaired loops, non-canonical structures and tertiary structural contacts. The data also revealed signatures of functionally critical nucleotides involved in catalysis. The results demonstrate that the data sets provide structural information similar to chemical or enzymatic probing experiments, but with additional quantitative functional information. The large-scale data sets can be used for models predicting structure and function and for efforts to engineer self-cleaving ribozymes.