bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whi5 hypo- and hyper-phosphorylation dynamics control cell cycle entry and progression
Authors: Xiao Jordan , Turner Jonathan J. , Kõivomägi Mardo , Skotheim Jan M. 
Published: November 2023

SummaryProgression through the cell cycle depends on the phosphorylation of key substrates by cyclin-dependent kinases. In budding yeast, these substrates include the transcriptional inhibitor Whi5 that regulates the G1/S transition. In early G1 phase, Whi5 is hypo-phosphorylated and inhibits the SBF complex that promotes transcription of the cyclinsCLN1andCLN2. In late-G1, Whi5 is rapidly hyper-phosphorylated by Cln1,2 in complex with the cyclin-dependent kinase Cdk1. This hyper-phosphorylation inactivates Whi5 and excludes it from the nucleus. Here, we set out to determine the molecular mechanisms responsible for Whi5’s multi-site phosphorylation and how they regulate the cell cycle. To do this, we first identified the 19 Whi5 sites that are appreciably phosphorylated and then determined which of these sites are responsible for G1 hypo-phosphorylation. Mutation of 7 sites removed G1 hypo-phosphorylation, increased cell size, and delayed the G1/S transition. Moreover, the rapidity of Whi5 hyper-phosphorylation in late G1 depends on ‘priming’ sites that dock the Cks1 subunit of Cln1,2-Cdk1 complexes. Hyper-phosphorylation is crucial for Whi5 nuclear export, normal cell size, full expression of SBF target genes, and timely progression through both the G1/S transition and S/G2/M phases. Thus, our work shows how Whi5 phosphorylation regulates the G1/S transition and how it is required for timely progression through S/G2/M phases and not only G1 as previously thought.
The role of alternative polyadenylation in Epithelial-mesenchymal transition of non-small cell lung cancer
Authors: Wu Sijia , Qin Xinyu , Huang Liyu 
Published: November 2023

AbstractThe metastatic non-small cell lung cancer (NSCLC) is one of the cancers with high incidence, poor survival, and limited treatment. Epithelial-mesenchymal transition (EMT) is the first step by which an early tumor converts to an invasive one. Studying the underlying mechanisms of EMT can help the understanding of cancer metastasis and improve the treatment. In this study, 1,013 NSCLC patients and 123 NSCLC cell lines are deeply analyzed for the potential roles of alternative polyadenylation (APA) in the EMT process. A trend of shorter 3’-UTRs is discovered in the mesenchymal samples. The identification of EMT-related APA events highlights the proximal poly(A) selection ofCARM1. It is a pathological biomarker of mesenchymal tumor and cancer metastasis through losing miRNA binding to upregulate the EMT inducer ofCARM1and releasing miRNAs to downregulate the EMT inhibitor ofRBM47. The crucial role of this APA event in EMT also guides its effect on drug responses. The patients with shorter 3’-UTR ofCARM1are more benefit from chemotherapy drugs, especially cisplatin. A stratification of NSCLC patients based on this APA event is useful for chemotherapy design in future clinics.
An end-to-end approach for protein folding by integrating Cryo-EM maps and sequence evolution
Authors: Li Pan , Guo Liangyue , Liu Haibin , Liu Binghua , Meng Fanhao , Ni Xiaodan , Guo Allen Chunlong 
Published: November 2023

AbstractProtein structure modeling is an important but challenging task. Recent breakthroughs in Cryo-EM technology have led to rapid accumulation of Cryo-EM density maps, which facilitate scientists to determine protein structures but it remains time-consuming. Fortunately, artificial intelligence has great potential in automating this process. In this study, we present SMARTFold, a deep learning protein structure prediction model combining sequence alignment features and Cryo-EM density map features. First, using density map, we sample representative points along the predicted high confidence areas of protein backbone. Then we extract geometric features of these points and integrate these features with sequence alignment features in our proposed protein folding model. Extensive experiments confirm that our model performs best on both single-chain and multi-chain benchmark dataset compared with state-of-the-art methods, which makes it a reliable tool for protein atomic structure determination from Cryo-EM maps.
MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C)
Authors: Iqbal Khizer , Sinha Saptarshi , David Paula , De Marco Gabriele , Taheri Sahar , McLaren Ella , Maisuria Sheetal , Arumugakani Gururaj , Ash Zoe , Buckley Catrin , Coles Lauren , Hettiarachchi Chamila , Smithson Gayle , Slade Maria , Shah Rahul , Marzo-Ortega Helena , Keen Mansoor , Lawson Catherine , Mclorinan Joanna , Nizam Sharmin , Reddy Hanu , Sharif Omer , Sultan Shabina , Tran Gui , Wood Mark , Wood Samuel , Ghosh Pradipta , McGonagle Dennis 
Published: November 2023

AbstractBackgroundAnti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus.MethodsThis is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak.ResultsSixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strongIFIH1(gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, andIFIH1strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. TheIFIH1rs1990760TT variant blunted such response.ConclusionsA distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.
Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy
Authors: Belle Kinsley , Kreymerman Alexander , Vadgama Nirmal , Ji Marco H. , Randhawa Sandeep , Caicedo Juan , Wong Megan , Muscat Stephanie P. , Gifford Casey A. , Lee Richard T. , Nasir Jamal , Young Jill L. , Enns Gregory , Karakikes Ioannis , Mercola Mark , Wood Edward H. 
Published: November 2023

ABSTRACTPatients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease.
Low density neutrophils and neutrophil extracellular traps (NETs) are new inflammatory players in heart failure
Authors: Dumont Benjamin L. , Neagoe Paul-Eduard , Charles Elcha , Villeneuve Louis , Ninni Sandro , Tardif Jean-Claude , Räkel Agnès , White Michel , Sirois Martin G. 
Published: November 2023

AbstractBackgroundHeart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) is characterized by low-grade chronic inflammation. Circulating neutrophils regroup two subtypes termed high- and low-density neutrophils (HDNs and LDNs). LDNs represent less than 2% of total neutrophil under physiological conditions, but their count increase in multiple pathologies, releasing more inflammatory cytokines and neutrophil extracellular traps (NETs).ObjectivesAssess the differential count and role of HDNs, LDNs and NETs-related activities in HF patients.MethodsHDNs and LDNs were isolated from human blood by density gradient and purified by FACS and their counts obtained by flow cytometry. NETs formation (NETosis) was quantified by confocal microscopy. Circulating inflammatory and NETosis biomarkers were measured by ELISA. Neutrophil adhesion onto human extracellular matrix (hECM) was assessed by optical microscopy.ResultsA total of 140 individuals were enrolled, including 33 healthy volunteers (HV), 41 HFrEF (19 stable patients and 22 presenting acute decompensated HF; ADHF) and 66 HFpEF patients (36 stable patients and 30 presenting HF decompensation). HDNs and LDNs counts were significantly increased up to 39% and 2740% respectively in HF patients compared to HV. In HF patients, the correlations between LDNs counts and circulating inflammatory (CRP, IL-6 and -8), Troponin T, NT-proBNP and NETosis components were all significant. In vitro, LDNs expressed more H3Cit and NETs and were more pro-adhesive, with ADHFpEF patients presenting the highest pro-inflammatory profile.ConclusionsHFpEF patients present higher levels of circulating LDNs and NETs related activities, which are the highest in the context of acute HF decompensation.Clinical PerspectiveIn comparison to HFrEF, HFpEF patients have higher levels of circulation LDNs and NETs-associated inflammatory cytokines, peaking in acute decompensated clinical condition.Furthermore, LDNs are producing more NETs and are more adhesive than HDNs, which can contribute to pro-thrombogenesis status described in HF patientsMeasurement of circulating NETs-associated biomarkers could become a novel tool to assess the the risk of acute thrombogenesis in hospitalized ADHFpEF patients.These measurements could lead to future clinical treatments using NETosis inhibitors alone or combined with NETs degradation enzymes (e.g. DNase I).At this time, additional preclinical studies are required to determine specific cell surface markers that could distinguish LDNs from HDNs in whole blood.Once available, circulating LDNs levels would be routinely measured and integrated in the complete blood count analysis to better assess patients’ inflammatory status.
link-ancestors: Fast simulation of local ancestry with tree sequence software
Authors: Tsambos Georgia , Kelleher Jerome , Ralph Peter , Leslie Stephen , Vukcevic Damjan 
Published: November 2023

AbstractSummaryIt is challenging to simulate realistic tracts of genetic ancestry on a scale suitable for simulation based inference. We present an algorithm that enables this information to be extracted efficiently from tree sequences produced by simulations run with msprime and SLiM.Availability and ImplementationA C-based implementation of the link-ancestors algorithm is in tskit (https://tskit.dev/tskit/docs/stable/). We also provide a user-friendly wrapper for link-ancestors in tspop, a Python-based utility package.Contactgtsambos@uw.edu.Supplementary informationTechnical details of link-ancestors are in the Supplementary Information. Documentation for the tspop package is athttp://tspop.readthedocs.io/.
Interleukin-10-producing monocytes contribute to sex differences in pain resolution in mice and humans
Authors: Sim Jaewon , O’Guin Elizabeth , Monahan Karli , Sugimoto Chiho , McLean Samuel A. , Albertorio-Sáez Liz , Zhao Ying , Laumet Sophie , Dagenais Andrew , Bernard Matthew P. , Folger Joseph K. , Robison Alfred J. , Linnstaedt Sarah D. , Laumet Geoffroy 
Published: November 2023

AbstractPain is closely associated with the immune system, which exhibits sexual dimorphism. For these reasons, neuro-immune interactions are suggested to drive sex differences in pain pathophysiology. However, our understanding of peripheral neuro-immune interactions on sex differences in pain resolution remains limited. Here, we have shown, in both a mouse model of inflammatory pain and in humans following traumatic pain, that males had higher levels of interleukin (IL)-10 than females, which were correlated with faster pain resolution. Following injury, we identified monocytes (CD11b+ Ly6C+ Ly6G-F4/80mid) as the primary source of IL-10, with IL-10-producing monocytes being more abundant in males than females. In a mouse model, neutralizing IL-10 signaling through antibodies, genetically ablating IL-10R1 in sensory neurons, or depleting monocytes with clodronate all impaired the resolution of pain hypersensitivity in both sexes. Furthermore, manipulating androgen levels in mice reversed the sexual dimorphism of pain resolution and the levels of IL-10-producing monocytes. These results highlight a novel role for androgen-driven peripheral IL-10-producing monocytes in the sexual dimorphism of pain resolution. These findings add to the growing concept that immune cells play a critical role in resolving pain and preventing the transition into chronic pain.Graphical abstract
ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation
Authors: Coleman Olivia I. , Sorbie Adam , Bierwith Sandra , Kövilein Janine , von Stern Miriam , Köhler Nikolai , Wirbel Jakob , Schmidt Christina , Kacprowski Tim , Dunkel Andreas , Pauling Josh K. , Plagge Johannes , Mediel-Cuadra Diego , Wagner Sophia , Peng Tingying , Metzler Thomas , Schafmayer Clemens , Hinz Sebastian , Röder Christian , Röcken Christoph , Stecher Bärbel , Rosenstiel Philip , Steiger Katja , Jesinghaus Moritz , Liebisch Gerhard , Ecker Josef , Zeller Georg , Janssen Klaus-Peter , Haller Dirk 
Published: November 2023

AbstractThe induction of endoplasmic reticulum unfolded protein responses (UPRER) contributes to cancer development and progression. We recently linked microbiota-related triggers to the tumor-promoting role of signal transducer activating transcription factor 6 (ATF6) in the colon. Here we substantiate the clinical relevance of ATF6 and related bacterial genera in colorectal cancer patient cohorts. Spatial and longitudinal bacterial profiling in ATF6 transgenic mice (nATF6IEC) identified tumor-initiating and tumor-progressing shifts in the mucosa-associated microbiota. Transcriptional analysis in intestinal epithelial cells (IEC) of germ-free and specific pathogen-free nATF6IECmice defined bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics, isotope-labeling in intestinal organoids and FASN inhibition confirmed ATF6-mediated involvement of long-chain fatty acids in tumorigenesis. Multi-omics data integration identified a bacteria-lipid network characterized by fatty acid efflux, catabolism and detoxification. We postulate chronic ATF6 signaling to drive a clinically relevant pathologic response altering lipid metabolism to select for a tumor-promoting microbiota.Graphical AbstractChronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiotanATF6 expression is induced in intestinal epithelial cells in transgenic mice (nATF6IEC)Biallelic nATF6IECgerm-free mice (grey circle) and floxed or monoallelic specific pathogen-free mice (black circle) remain in a state of homeostasis (yellow circle), while biallelic specific pathogen-free mice (black circle) develop spontaneous colon tumorigenesis (red circle)Mechanistically, biallelic nATF6IECmice in the presence of an intestinal microbiota alter colonic lipid metabolism, including the upregulation of FasnThe microbial lipid-response to the altered lipid milieu results in dysbiosis and the subsequent formation of colon adenomasInhibition of FASN in biallelic nATF6IECmice prevents colon tumor formation (yellow arrow)Created withBioRender.comnATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.
Pangenomic exploration ofTheobroma cacao: New Insights into Gene Content Diversity and Selection During Domestication
Authors: Argout Xavier , Droc Gaetan , Fouet Olivier , Rouard Mathieu , Labadie Karine , Rhoné Bénédicte , Rey Loor Gaston , Lanaud Claire 
Published: November 2023

AbstractThe Cacao tree (Theobroma cacao L.)is a major cash crop and an important source of income for millions of farmers across Africa, Asia and Latin America. However, cacao farmers and producing countries are facing multiple challenges including pest and disease management, sustainable production under threat of climate changes and diversification of cocoa flavor profiles. Addressing these challenging requires a deeper understanding of the existing genetic diversity of the species. Yet, very little is known about the intraspecific gene content variation.In this study, we used the genome of 216 accessions ofT. cacao(including 185 newly re-sequenced) covering a broad genetic diversity of the species to construct the first pan-genome of the cacao tree. As a result, we predicted a total of 30,489 pan-genes, enriching the reference Criollo genome with 1,407 new genes.Our analysis revealed that only a small fraction of these genes (9.2%) is dispensable, being absent in some individuals. However, these genes could represent a valuable resource for breeding efforts aimed at improving disease resistance in the species.We used this new pangenome resource to gain insights into how diversification and domestication processes have influenced genomic variability within the species. Notably, we observed a significant loss of genes within the domesticated Criollo genetic group. Furthermore, we found evidences suggesting that domestication processes have had an impact on the vigor and disease tolerance of Criollo accessions. In summary, our research has contributed to a better understanding of the cacao tree’s genome diversity. These findings offer new avenues for biological discovery and breeding, ultimately addressing the challenges faced by cacao farmers and producing countries.
Time-dependent Interaction Modification Generated from Plant-soil Feedback
Authors: Zou Heng-Xing , Yan Xinyi , Rudolf Volker H.W. 
Published: November 2023

AbstractPairwise interactions between species can be modified by other community members, leading to emergent dynamics contingent on community composition. Despite the prevalence of such higher-order interactions, little is known about how they are linked to the timing and order of species’ arrival. We generate population dynamics from a mechanistic plant-soil feedback model, then apply a general theoretical framework to show that the modification of a pairwise interaction by a third plant depends on its germination phenology. These time-dependent interaction modifications emerge from concurrent changes in plant and microbe populations and are strengthened by higher overlap between plants’ associated microbiomes. The interaction between this overlap and the specificity of microbiomes further determines plant coexistence. Our framework is widely applicable to mechanisms in other systems from which similar time-dependent interaction modifications can emerge, highlighting the need to integrate temporal shifts of species interactions to predict the emergent dynamics of natural communities.
Design rules for efficient endosomal escape
Authors: Zoltek Madeline , Vázquez Angel , Zhang Xizi , Dadina Neville , Lesiak Lauren , Schepartz Alanna 
Published: November 2023

AbstractThe inefficient translocation of proteins across biological membranes limits their application as therapeutic compounds and research tools. In most cases, translocation involves two steps: uptake into the endocytic pathway and endosomal escape. Certain charged or amphiphilic molecules promote protein uptake but few enable efficient endosomal escape. One exception is ZF5.3, a mini-protein that exploits natural endosomal maturation machinery to translocate across endosomal membranes. Although certain ZF5.3-protein conjugates are delivered efficiently into the cytosol or nucleus, overall delivery efficiency varies widely with no obvious design rules. Here we evaluate the role of protein size and thermal stability in the ability to efficiently escape endosomes when attached to ZF5.3. Using fluorescence correlation spectroscopy, a singlemolecule technique that provides a precise measure of intra-cytosolic protein concentration, we demonstrate that delivery efficiency depends on both size and the ease with which a protein unfolds. Regardless of size and pI, low-Tm cargos of ZF5.3 (including intrinsically disordered domains) bias its endosomal escape route toward a high-efficiency pathway that requires the homotypic fusion and protein sorting (HOPS) complex. Small protein domains are delivered with moderate efficiency through the same HOPS portal even if the Tm is high. These findings imply a novel protein- and/or lipid-dependent pathway out of endosomes that is exploited by ZF5.3 and provide clear guidance for the selection or design of optimally deliverable therapeutic cargo.Significance StatementThe results described in this paper provide new insights into how protein delivery works and how it can be best utilized in the future. Although intracellular protein delivery has been studied for decades, this paper describes the first interrogation of why certain protein cargos are privileged for efficient endosomal escape. These results represent a fundamental advance in the long-awaited goal of efficient protein delivery and provide design rules to overcome one of the most significant challenges for the future of biotechnology.