bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with vaccine coverage improvements in Senegal between 2005-2019: A quantitative retrospective analysis
Authors: Smalley Hannah K , Castillo-Zunino Francisco , Keskinocak Pinar , Nazzal Dima , Sakas Zoe , Sarr Moussa , Freeman Matthew C. 
Published: March 2023

ABSTRACTObjectiveSenegal has demonstrated catalytic improvements in national coverage rates for early childhood vaccination, despite lower development assistance for childhood vaccines in Senegal compared to other low and lower-middle income countries. Understanding factors associated with historical changes in childhood vaccine coverage in Senegal, as well as heterogeneities across its 14 regions, can highlight effective practices that might be adapted to improve vaccine coverage elsewhere.DesignChildhood vaccination coverage rates, demographic information, and health system characteristics were identified from Senegal’s Demographic and Health Surveys (DHS) and Senegal national reports for years 2005 to 2019. Multivariate logistic and linear regression analyses were performed to determine statistical associations of demographic and health system characteristics with respect to childhood vaccination coverage rates.SettingThe 14 administrative regions of Senegal were chosen for analysis.ParticipantsDHS women’s survey respondents with living children aged 12-23 months for survey years 2005-2019.Outcome MeasuresImmunization with the third dose of the diphtheria-tetanus-pertussis vaccine (DTP3), widely used as a proxy for estimating immunization coverage levels and the retention of children in the vaccine program.ResultsFactors associated with childhood vaccination coverage include urban residence (β=0·61, p=0·0157), female literacy (β=1·11, p=0·0007), skilled prenatal care (β=1·80, p<0·0001), and self-reported ease of access to care when sick, considering travel distance to a healthcare facility (β=-0·70, p=0·0009) and concerns over traveling alone (β=-1·08, p<0·0001). Higher coverage with less variability over time was reported in urban areas near the capital and the coast (p=0·076), with increased coverage in recent years in more rural and landlocked areas.ConclusionsChildhood vaccination was more likely among children whose mothers had higher literacy, received skilled prenatal care, and had perceived ease of access to care when sick. Overall, vaccination coverage is high in Senegal and disparities in coverage between regions have decreased significantly in recent years.
Machine learning based time series forecasting of chemical levels from the East Palestine, Ohio train derailment site
Authors: Ramachandra Vikas , Sethi Mohit 
Published: March 2023

AbstractThe paper presents a time series analysis of the air, water and soil data from the East Palestine, Ohio, train derailment site. The goal of the analysis is to investigate the temporal pattern of chemical pollutant levels in air, water and soil and to build machine learning and statistical models for forecasting various chemical concentrations over time.
Implementation and prospective real-time evaluation of a generalized system for in-clinic deployment and validation of machine learning models in radiology
Authors: Hawkins James R , Olson Marram P. , Harouni Ahmed , Qin Ming Melvin , Hess Christopher P , Majumdar Sharmila , Crane Jason C 
Published: March 2023

AbstractThe medical imaging community has embraced Machine Learning (ML) as evidenced by the rapid increase in the number of ML models being developed, but validating and deploying these models in the clinic remains a challenge. The engineering involved in integrating and assessing the efficacy of ML models within the clinical workflow is complex. This paper presents a general-purpose, end-to-end, clinically integrated ML model deployment and validation system implemented at UCSF. Engineering and usability challenges and results from 3 use cases are presented.A generalized validation system based on free, open-source software was implemented, connecting clinical imaging modalities, the Picture Archiving and Communication System (PACS), and an ML inference server. ML pipelines were implemented in NVIDIA’s Clara Deploy framework with results and clinician feedback stored in a customized XNAT instance, linked within PACS. Prospective clinical validation studies of 3 ML models were conducted, with data routed from multiple clinical imaging modalities and PACS. Completed validation studies provided expert clinical feedback on model performance and usability, plus system reliability and performance metrics.Clinical validation of ML models entails assessing model performance, impact on clinical infrastructure, robustness, and usability. Study results must be easily accessible to participating clinicians but remain outside the clinical record. Building a system that generalizes and scales across multiple ML models takes the concerted effort of software engineers, clinicians, data scientists, and system administrators, and benefits from the use of modular open-source software. The present work provides a template for institutions looking to translate and clinically validate ML models in the clinic, together with required resources and expected challenges.Author summaryAcademic medical centers gather and store vast quantities of digital data, and with the increase in accessibility of Machine Learning (ML) techniques, there has been an explosion of ML model development in the medical imaging community. Most of this work remains in research, though, and connecting ML models to the clinic for testing on live patient data and integration into the clinical workflow remains a challenge and impedes clinical impact. We present a general-purpose system, implemented and deployed at UCSF, for in-clinic validation of ML models and their incorporation into patient care. This work, based on free and open-source software packages, can serve as a template for other institutions looking to solve ML’s “last mile” problem and move their models out of research and into the clinic.
Replisome loading reduces chromatin motion independent of DNA synthesis
Authors: Pabba Maruthi K. , Ritter Christian , Chagin Vadim O. , Meyer Janis , Celikay Kerem , Stear Jeffrey H. , Loerke Dinah , Kolobynina Ksenia , Prorok Paulina , Schmid Alice Kristin , Leonhardt Heinrich , Rohr Karl , Cardoso M. Cristina 
Published: March 2023

SUMMARYChromatin has been shown to undergo diffusional motion, which is affected during gene transcription by RNA polymerase activity. However, the relationship between chromatin mobility and other genomic processes remains unclear. Hence, we set out to label the DNA directly in a sequence unbiased manner and followed labeled chromatin dynamics in interphase human cells expressing GFP-tagged PCNA, a cell cycle marker and core component of the DNA replication machinery. We detected decreased chromatin mobility during the S-phase compared to G1 and G2 phases in tumor as well as normal diploid cells using automated particle tracking. To gain insight into the dynamical organization of the genome during DNA replication, we determined labeled chromatin domain sizes and analyzed their motion in replicating cells. By correlating chromatin mobility proximal to the active sites of DNA synthesis, we showed that chromatin motion was locally constrained at the sites of DNA replication. Furthermore, inhibiting DNA synthesis led to increased loading of DNA polymerases. This was accompanied by accumulation of the single-stranded DNA binding protein on the chromatin and activation of DNA helicases further restricting local chromatin motion. We, therefore, propose that it is the loading of replisomes but not their catalytic activity that reduces the dynamics of replicating chromatin segments in the S-phase as well as their accessibility and probability of interactions with other genomic regions.Highlights-Direct and sequence unbiased labeling of DNA genome-wide-DNA labeled chromatin is more mobile in G1/G2 relative to the S-phase-Restriction of chromatin motion occurs proximal to sites of DNA replication-Loading of replisomes, even in the absence of processive DNA synthesis, restricts chromatin motion
Global identification of direct SWI/SNF targets reveals compensation by EP400
Authors: Martin Benjamin J.E. , Ablondi Eileen F. , Goglia Christine , Adelman Karen 
Published: March 2023

SummaryMammalian SWI/SNF chromatin remodeling complexes move and evict nucleosomes at gene promoters and enhancers to modulate DNA access. Although SWI/SNF subunits are commonly mutated in disease, therapeutic options are limited by our inability to predict SWI/SNF gene targets and conflicting studies on functional significance. Here, we leverage a fast-acting inhibitor of SWI/SNF remodeling to elucidate direct targets and effects of SWI/SNF. Blocking SWI/SNF activity causes a rapid and global loss of chromatin accessibility and transcription. Whereas repression persists at most enhancers, we uncover a compensatory role for the EP400/TIP60 remodeler, which reestablishes accessibility at most promoters during prolonged loss of SWI/SNF. Indeed, we observe synthetic lethality between EP400 and SWI/SNF in lung cancer cell lines and human cancer patient data. Our data define a set of molecular genomic features that accurately predict gene sensitivity to SWI/SNF inhibition in diverse cancer cell lines, thereby improving the therapeutic potential of SWI/SNF inhibitors.Highlights-Genes repressed by long-term SWI/SNF loss do not accurately reflect direct targets-Promoters that fail to reestablish activity are those lacking a compensatory remodeler-Accessibility and activity recovery requires EP400, synthetically lethal with SWI/SNF-SWI/SNF dependence in cancer cells can be predicted from the promoter chromatin state
Structurally divergent and recurrently mutated regions of primate genomes
Authors: Mao Yafei , Harvey William T. , Porubsky David , Munson Katherine M. , Hoekzema Kendra , Lewis Alexandra P. , Audano Peter A. , Rozanski Allison , Yang Xiangyu , Zhang Shilong , Gordon David S. , Wei Xiaoxi , Logsdon Glennis A. , Haukness Marina , Dishuck Philip C. , Jeong Hyeonsoo , del Rosario Ricardo , Bauer Vanessa L. , Fattor Will T. , Wilkerson Gregory K. , Lu Qing , Paten Benedict , Feng Guoping , Sawyer Sara L. , Warren Wesley C. , Carbone Lucia , Eichler Evan E. 
Published: March 2023

ABSTRACTTo better understand the pattern of primate genome structural variation, we sequenced and assembled using multiple long-read sequencing technologies the genomes of eight nonhuman primate species, including New World monkeys (owl monkey and marmoset), Old World monkey (macaque), Asian apes (orangutan and gibbon), and African ape lineages (gorilla, bonobo, and chimpanzee). Compared to the human genome, we identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. Across 50 million years of primate evolution, we estimate that 819.47 Mbp or ~27% of the genome has been affected by SVs based on analysis of these primate lineages. We identify 1,607 structurally divergent regions (SDRs) wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (CARDs,ABCD7,OLAH) and new lineage-specific genes are generated (e.g.,CKAP2,NEK5) and have become targets of rapid chromosomal diversification and positive selection (e.g.,RGPDs). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species for the first time.
Prediction of protein assemblies by structure sampling followed by interface-focused scoring
Authors: Olechnovič Kliment , Valančauskas Lukas , Dapkūnas Justas , Venclovas Česlovas 
Published: March 2023

AbstractProteins often function as part of permanent or transient multimeric complexes, and understanding function of these assemblies requires knowledge of their three-dimensional structures. While the ability of AlphaFold to predict structures of individual proteins with unprecedented accuracy has revolutionized structural biology, modeling structures of protein assemblies remains challenging. To address this challenge, we developed a protocol for predicting structures of protein complexes involving model sampling followed by scoring focused on the subunit-subunit interaction interface. In this protocol, we diversified AlphaFold models by varying construction and pairing of multiple sequence alignments as well as increasing the number of recycles. In cases when AlphaFold failed to assemble a full protein complex or produced unreliable results, additional diverse models were constructed by docking of monomers or subcomplexes. All the models were then scored using a newly developed method, VoroIF-jury, which relies only on structural information. Notably, VoroIF-jury is independent of AlphaFold self-assessment scores and therefore can be used to rank models originating from different structure prediction methods. We tested our protocol in CASP15 and obtained top results, significantly outperforming the standard AlphaFold-Multimer pipeline. Analysis of our results showed that the accuracy of our assembly models was capped mainly by structure sampling rather than model scoring. This observation suggests that better sampling, especially for the antibody-antigen complexes, may lead to further improvement. Our protocol is expected to be useful for modeling and/or scoring protein assemblies.
Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function
Authors: Dacheux Denis , Martinez Guillaume , Broster Reix Christine E. , Beurois Julie , Lorès Patrick , Tounkara Magamba , Dupuy Jean-William , Robinson Derrick R. , Loeuillet Corinne , Lambert Emeline , Wehbe Zeina , Amiri-Yekta Amir , Daneshipour Abbas , Hosseini Seyedeh-Hanieh , Zouari Raoudha , Ben Mustapha Sélima Fourati , Halouani Lazhar , Jiang Xiaohui , Shen Ying , Liu Chunyu , Thierry-Mieg Nicolas , Septier Amandine , Bidart Marie , Satre Véronique , Cazin Caroline , Kherraf Zine-Eddine , Arnoult Christophe , Ray Pierre F. , Touré Aminata , Bonhivers Mélanie , Coutton Charles 
Published: March 2023

ABSTRACTMale infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygousZMYND12variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66 and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using theTrypanosoma bruceimodel. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygousZMYND12variants. Co-immunoprecipitation and ultrastructure expansion microscopy inT. bruceirevealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples fromTrypanosomaandTtc29KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.
Discovery of long non-coding RNAs in the liver fluke,Fasciola hepatica
Authors: McVeigh Paul , McCammick Erin , Robb Emily , Brophy Peter , Morphew Russell M , Marks Nikki J , Maule Aaron G 
Published: March 2023

ABSTRACTLong non-coding (lnc)RNAs are a class of eukaryotic RNA that do not code for protein and are linked with transcriptional regulation, amongst a myriad of other functions. Using a customin silicopipeline we have identified 6,436 putative lncRNA transcripts in the liver fluke parasite,Fasciola hepatica; none of which are conserved with those previously described fromSchistosoma mansoni. F. hepaticalncRNAs were distinct fromF. hepaticamRNAs in transcript length, coding probability, exon/intron composition, expression patterns, and genome distribution. RNA-Seq and digital droplet PCR measurements demonstrated developmentally regulated expression of lncRNAs between intra-mammalian life stages; a similar proportion of lncRNAs (14.2 %) and mRNAs (12.8 %) were differentially expressed (p<0.001), supporting a functional role for lncRNAs inF. hepaticalife stages. While most lncRNAs (81%) were intergenic, we identified some that overlapped protein coding loci in antisense (13%) or intronic (6%) configurations. We found no unequivocal evidence for correlated developmental expression within positionally correlated lncRNA:mRNA pairs, but global co-expression analysis identified five lncRNA that were inversely co-regulated with 89 mRNAs, including a large number of functionally essential proteases. The presence of micro (mi)RNA binding sites in 3135 lncRNAs indicates the potential for miRNA-based post-transcriptional regulation of lncRNA, and/or their function as competing endogenous (ce)RNAs. This first description of lncRNAs inF. hepaticaprovides an avenue to future functional and comparative genomics studies that will provide a new perspective on a poorly understood aspect of parasite biology.
Inference and reconstruction of the heimdallarchaeial ancestry of eukaryotes
Authors: Eme Laura , Tamarit Daniel , Caceres Eva F. , Stairs Courtney W. , Anda Valerie De , Schön Max E. , Seitz Kiley W. , Dombrowski Nina , Lewis William H. , Homa Felix , Saw Jimmy H. , Lombard Jonathan , Nunoura Takuro , Li Wen-Jun , Hua Zheng-Shuang , Chen Lin-Xing , Banfield Jillian F. , John Emily St , Reysenbach Anna-Louise , Stott Matthew B. , Schramm Andreas , Kjeldsen Kasper U. , Teske Andreas P. , Baker Brett J. , Ettema Thijs J. G. 
Published: March 2023

AbstractIn the ongoing debates about eukaryogenesis, the series of evolutionary events leading to the emergence of the eukaryotic cell from prokaryotic ancestors, members of the Asgard archaea play a key role as the closest archaeal relatives of eukaryotes. However, the nature and phylogenetic identity of the last common ancestor of Asgard archaea and eukaryotes remain unresolved. Here, we analyze distinct phylogenetic marker datasets of an expanded genomic sampling of Asgard archaea and evaluate competing evolutionary scenarios using state-of-the-art phylogenomic approaches. We find that eukaryotes are placed, with high confidence, as a well-nested clade within Asgard archaea, as a sister lineage to Hodarchaeales, a newly proposed order within Heimdallarchaeia. Using sophisticated gene tree/species tree reconciliation approaches, we show that, in analogy to the evolution of eukaryotic genomes, genome evolution in Asgard archaea involved significantly more gene duplication and fewer gene loss events compared to other archaea. Finally, we infer that the last common ancestor of Asgard archaea likely was a thermophilic chemolithotroph, and that the lineage from which eukaryotes evolved adapted to mesophilic conditions and acquired the genetic potential to support a heterotrophic lifestyle. Our work provides key insights into the prokaryote-to-eukaryote transition and the platform for the emergence of cellular complexity in eukaryotic cells.
CaudalFgfr1disruption produces localised spinal mis-patterning and a terminal myelocystocele-like phenotype in mice
Authors: Maniou Eirini , Farah Faduma , Crane-Smith Zoe , Krstevski Andrea , Stathopoulou Athanasia , Greene Nicholas D.E. , Copp Andrew J. , Galea Gabriel L. 
Published: March 2023

AbstractClosed spinal dysraphisms are poorly understood neurodevelopmental malformations commonly classed as neural tube defects. Several, including terminal myelocystocele, selectively affect the distal lumbosacral spine. We previously identified a neural tube closure-initiating point, Closure 5, involved in forming the distal spine of mice. Here we document equivalent morphology of the caudal-most end of the closing posterior neuropore (PNP) in mice and humans, suggesting Closure 5 is conserved in humans. It forms in a region of active fibroblast growth factor (FGF) signalling and pharmacological blockade of FGF receptors (Fgfr) impairs Closure 5 formation in cultured mouse embryos. Conditional genetic deletion ofFgfr1in caudal embryonic tissues withCdx2Cresimilarly impairs Closure 5 formation and leads to morphologically abnormal PNPs, which nonetheless achieve delayed closure although delayed. After PNP closure, a localised region of the distal neural tube ofFgfr1-disrupted embryos re-opens into a trumpet-like flared central canal between the presumptive hindlimbs, progressing to form a distal fluid-filled sac overlying ventrally flattened spinal cord. This phenotype resembles terminal myelocystocele. Histological analysis of spinal progenitor domains reveals regional and progressive loss of ventral spinal cord progenitor domains preceding cystic dilation of the central canal. Initially, the Shh and FoxA2-positive ventral domains are lost, resulting in Olig2-labelling of the ventral-most neural tube. The Olig2-domain is also subsequently lost, eventually producing a neural tube entirely positive for the dorsal marker Pax3. Thus, a terminal myelocystocele-like phenotype can arise after completion of neural tube closure due to localised spinal mis-patterning caused by disruption of Fgfr1 signalling.
The role of glutathione in periplasmic redox homeostasis and oxidative protein folding inEscherichia coli
Authors: Knoke Lisa R. , Zimmermann Jannik , Lupilov Natalie , Schneider Jannis F. , Celebi Beyzanur , Morgan Bruce , Leichert Lars I. 
Published: March 2023

AbstractThe thiol redox balance in the periplasm ofE. colidepends on the DsbA/B pair for oxidative power and the DsbC/D system as its complement for isomerization of non-native disulfides. While the standard redox potentials of those systems are known, thein vivoredox potential imposed onto protein thiol disulfide pairs in the periplasm remains unknown. Here, we used genetically encoded redox probes (roGFP2 and roGFP-iL), targeted to the periplasm, to directly probe the thiol redox homeostasis in this compartment. These probes contain two cysteine residues, that are virtually completely reduced in the cytoplasm, but once exported into the periplasm, can form a disulfide bond, a process that can be monitored by fluorescence spectroscopy. Even in the absence of DsbA, roGFP2, exported to the periplasm, was fully oxidized, suggesting the presence of an alternative system for the introduction of disulfide bonds into exported proteins. However, the absence of DsbA shifted the periplasmic thiol-redox potential from -228 mV to a more reducing -243 mV and the capacity to re-oxidize periplasmic roGFP2 after a reductive pulse was significantly decreased. Re-oxidation in a DsbA strain could be fully restored by exogenous oxidized glutathione (GSSG), while reduced GSH accelerated re-oxidation of roGFP2 in the WT. In line, a strain devoid of endogenous glutathione showed a more reducing periplasm, and was significantly worse in oxidatively folding PhoA, a native periplasmic protein and substrate of the oxidative folding machinery. PhoA oxidative folding could be enhanced by the addition of exogenous GSSG in the WT and fully restored in a ΔdsbAmutant. Taken together this suggests the presence of an auxiliary, glutathione-dependent thiol-oxidation system in the bacterial periplasm.