bluuebunny/crossref_metadata_2025_split huggingface dataset:
Female-specific factors are associated with cognition in the UK Biobank cohort
Authors: Lindseth Linn R.S. , de Lange Ann-Marie G. , van der Meer Dennis , Agartz Ingrid , Westlye Lars T. , Tamnes Christian K. , Barth Claudia 
Published: June 2022

AbstractBackgroundRelative to males, females are at a higher risk of developing age-related neurocognitive disorders including Alzheimer’s disease. Emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence female’s cognition later in life. Yet, female’s health has historically been understudied, and little is known about the relationship between female-specific factors and cognition.MethodsUsing multiple linear regression, we investigated the associations between reproductive history, exogenous hormone use, apolipoprotein (APOE) ε4 genotype and cognition in 221,124 middle-to older-aged (mean age 56.2 ± 8.0 years) females from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function.ResultsA longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen’s d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition.ConclusionOur findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). Future research is needed to investigate the effects of sex hormone exposure and cognition to develop a better understanding of female’s brain health.
Points-Based Models for Predicting Severe Disease related to Covid-19 with the SARS-CoV-2 Omicron Variant
Authors: Ben Shlomo Yatir , Waxman Jacob G. , Shaham Galit , Netzer Doron , Reis Ben , Balicer Ran , Dagan Noa 
Published: June 2022

AbstractIntroductionThroughout the SARS-CoV-2 pandemic, resources for various aspects of patient care have been limited, necessitating risk-stratification. The need for good risk-stratification tools has been enhanced by the availability of new Covid-19 therapeutics that are effective at preventing severe disease among high-risk patients if given promptly following SARS-CoV-2 infection. We describe the development of two points-based models for predicting the risk of deterioration to severe disease from an Omicron-variant SARS-CoV-2 infection.MethodsWe developed two logistic regression-based models for predicting the risk of severe Covid-19 within a 21-days follow-up period among Clalit Health Services members aged 18 and older, with confirmed SARS-CoV-2 infection from December 25, 2021 to March 16, 2022. In the first model, aimed for the use of healthcare providers, the model coefficients were linearly transformed into integer risk points. In the second model, a simplified version designed for self-assessment by the general public, the risk points were further scaled down to smaller numbers with less variability across risk factors.Results613,513 individuals met the inclusion criteria, of which 1,763 (0.287%) developed the outcome. The AUROC estimates for both models were 0.95, although the ‘full’ model demonstrated more granular risk-stratification capabilities (77 vs. 27 potential thresholds on the test set). Both models proved effective in identifying small subsets of the population enriched with individuals who ended up deteriorating. For example, prioritizing the top 1%, 5% or 10% individuals in the population for interventions with the full model results in coverage of 36%, 68% or 83% (respectively) of the individuals that actually end up deteriorating. Risk point count increased with age, number of chronic conditions and previous hospitalizations, and decreased with recent vaccination and infection.DiscussionThe models presented, one more expressive and one more accessible, are transparent and explainable models applicable to the general population that can be used in the prioritization of Covid-19-related resources, including therapeutics.
Causal effects from tobacco smoking on obesity-related traits: a Mendelian randomization study
Authors: Park Sehoon , Kim Seong Geun , Lee Soojin , Kim Yaerim , Cho Semin , Kim Kwangsoo , Kim Yong Chul , Han Seung Seok , Lee Hajeong , Lee Jung Pyo , Joo Kwon Wook , Lim Chun Soo , Kim Yon Su , Kim Dong Ki 
Published: June 2022

AbstractBackgroundThere is a notion that tobacco smoking would have weight control effect based on the appetite suppressive effect of nicotine. However, a causal effect from being an ever smoker on obesity-related traits in the general population has yet been determined.MethodsThis Mendelian randomization (MR) analysis instrumented 378 genetic variants associated with being an ever smoker which mostly initiated in adolescents or young adulthood, identified from a genome-wide association study (GWAS) meta-analysis of 1.2 million individuals. The outcome data for body mass index, waist circumference, hip circumference, and waist-to-hip ratio was collected in 337,318 white British ancestry UK Biobank participants with 40-69 ages. Replication analysis was performed for GWAS meta-analysis for body mass index including the GERA/GIANT data including 364,487 mostly European samples. Summary-level MR by inverse variance weighted method and pleiotropy-robust MR methods, including median-based and MR–Egger regression, was performed.ResultsSummary-level MR analysis indicated that genetically predicted being an ever smoker is causally linked to higher body mass index [+0.28 (0.18, 0.38) kg/m2], waist circumference [+0.88 (0.66, 1.10) cm], hip circumference [+0.40 (0.23, 0.57) cm], and waist-to-hip ratio [+0.006 (0.005, 0.007)]. The results were consistently supported by pleiotropy-robust MR analysis. In the replication analysis, genetically predicted being an ever smoker was again significantly associated with higher body mass index [+0.03 (0.01, 0.05) kg/m2].ConclusionInitiation of tobacco use may consequently lead to worse obesity-related traits of the general population in middle-to-old ages.
Teenage pregnancy and timing of first marriage in Cameroon - What has changed over the last three decades, and what are the implications?
Authors: Fotso Jean Christophe , Cleland John G , Muki Berienis , Olaïtan Elihou Adje , Mayack Josiane Ngo 
Published: June 2022

AbstractBackgroundThe consequences of teenage childbearing on the health of mothers and children, and on girls’ schooling have been documented in many studies. The objectives of this study are to: 1) examine trends and differentials in teenage motherhood in Cameroon, with a distinction between premarital and marital teenage pregnancy; and 2) investigate trends and differentials in the length of time to marriage following a premarital teenage pregnancy.MethodsWe use data from five demographic and health surveys (DHS) conducted in Cameroon between 1991 and 2018. Teenage pregnancy, defined as first pregnancy occurring before the age of 20 years, is recode as a trichotomous variable (0 = No teenage pregnancy; 1 = marital teenage pregnancy; 2 = premarital teenage pregnancy). Time from first premarital teenage pregnancy to first marriage is analyzed as a continuous variable.ResultsThe percentage of women who experienced a marital teenage pregnancy declined from 39.6% to 26.4% between 1991 and 2018. After an initial drop between 1991 and 2004, premarital teenage pregnancy stabilized at about 25%. Women with intermediate levels of schooling were more likely to experience a premarital pregnancy than those with no schooling or higher secondary/tertiary education. The median length of time to first marriage following a premarital teenage pregnancy rose from 16 months in 1991 to 45 months in 2018. Further analysis suggests that marriage may be a more severe barrier to continued schooling than motherhood and that the desire to continue schooling is an important reason for postponing marriage for women who have given birth.Conclusion and recommendationsBesides strengthening interventions to curb adolescent pregnancy, efforts should be made to support families, communities and schools to help adolescent mothers return to school, prevent future unintended pregnancies, and delay further family formation. Accessibility to youth-friendly FP/RH services should be addressed.
Accounting for small variations in the tracrRNA sequence improves sgRNA activity predictions for CRISPR screening
Authors: DeWeirdt Peter C , McGee Abby V , Zheng Fengyi , Nwolah Ifunanya , Hegde Mudra , Doench John G 
Published: June 2022

ABSTRACTCRISPR technology is a powerful tool for studying genome function. To aid in picking sgRNAs that have maximal efficacy against a target of interest from many possible options, several groups have developed models that predict sgRNA on-target activity. Although multiple tracrRNA variants are commonly used for screening, no existing models account for this feature when nominating sgRNAs. Here we develop an on-target model, Rule Set 3, that makes optimal predictions for multiple tracrRNA variants. We validate Rule Set 3 on a new dataset of sgRNAs tiling essential and non-essential genes, demonstrating substantial improvement over prior prediction models. By analyzing the differences in sgRNA activity between tracrRNA variants, we show that Pol III transcription termination is a strong determinant of sgRNA activity. We expect these results to improve the performance of CRISPR screening and inform future research on tracrRNA engineering and sgRNA modeling.
Protein k-mers enable assembly-free microbial metapangenomics
Authors: Reiter Taylor E. , Pierce-Ward N. Tessa , Irber Luiz , Botvinnik Olga Borisovna , Brown C. Titus 
Published: June 2022

AbstractAn estimated 2 billion species of microbes exist on Earth with orders of magnitude more strains. Microbial pangenomes are created by aggregating all genomes of a single clade and reflect the metabolic diversity of groups of organisms. As de novo metagenome analysis techniques have matured and reference genome databases have expanded, metapangenome analysis has risen in popularity as a tool to organize the functional potential of organisms in relation to the environment from which those organisms were sampled. However, the reliance on assembly and binning or on reference databases often leaves substantial portions of metagenomes unanalyzed, thereby underestimating the functional potential of a community. To address this challenge, we present a method for metapangenomics that relies on amino acid k-mers (kaa-mers) and metagenome assembly graph queries. To enable this method, we first show that kaa-mers estimate pangenome characteristics and that open reading frames can be accurately predicted from short shotgun sequencing reads using the previously developed tool orpheum. These techniques enable pangenomics to be performed directly on short sequencing reads. To enable metapangenome analysis, we combine these approaches with compact de Bruijn assembly graph queries to directly generate sets of sequencing reads for a specific species from a metagenome. When applied to stool metagenomes from an individual receiving antibiotics over time, we show that these approaches identify strain fluctuations that coincide with antibiotic exposure.
Activity-driven extracellular volume expansion drives vertebrate axis elongation
Authors: Michaut Arthur , Mongera Alessandro , Gupta Anupam , Serra Mattia , Rigoni Pietro , Lee Jong Gwan , Duarte Felipe , Hall Adam R. , Mahadevan L. , Guevorkian Karine , Pourquié Olivier 
Published: June 2022

AbstractThe vertebrate bauplan is primarily established via the formation of embryonic tissues in a head-to-tail progression. The biomechanics of this elongation, which requires the presomitic mesoderm (PSM), remains poorly understood. Here, we find that avian PSM explants can elongate autonomously when physically confined in vitro, producing a pushing force that can largely account for the posterior elongation of the embryo. Tissue elongation results from volumetric expansion that is driven by cellular activity and accompanied by inhomogeneous increase of the extracellular fraction along the AP axis. We show that FGF signaling promotes glycolysis-dependent production of Hyaluronic Acid (HA), which is required for expansion of the posterior PSM. Our findings link body axis elongation to tissue expansion through the metabolic control of extracellular matrix production downstream of FGF signaling.One-Sentence SummaryActive tissue expansion propels body elongation independent of cell proliferation-driven growth
Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2
Authors: Gahbauer Stefan , Correy Galen J. , Schuller Marion , Ferla Matteo P. , Doruk Yagmur Umay , Rachman Moira , Wu Taiasean , Diolaiti Morgan , Wang Siyi , Neitz R. Jeffrey , Fearon Daren , Radchenko Dmytro , Moroz Yurii , Irwin John J. , Renslo Adam R. , Taylor Jenny C. , Gestwicki Jason E. , von Delft Frank , Ashworth Alan , Ahel Ivan , Shoichet Brian K. , Fraser James S. 
Published: June 2022

AbstractThe nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 152 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated protein dynamics within the active site, and key inhibitor motifs that will template future drug development against Mac1.Significance StatementSARS-CoV-2 encodes a viral macrodomain protein (Mac1) that hydrolyzes ribo-adenylate marks on viral proteins, disrupting the innate immune response to the virus. Catalytic mutations in the enzyme make the related SARS-1 virus less pathogenic and non-lethal in animals, suggesting that Mac1 will be a good antiviral target. However, no potent inhibitors of this protein class have been described, and pharmacologically the enzyme remains an orphan. Here, we computationally designed potent inhibitors of Mac1, determining 150 inhibitor-enzyme structures to ultra-high resolution by crystallography. In silico fragment linking and molecular docking of > 450 million virtual compounds led to inhibitors with submicromolar activity. These molecules may template future drug discovery efforts against this crucial but understudied viral target.
Hepatocytes deficient in nuclear envelope protein lamina-associated polypeptide 1 are an ideal mammalian system to study intranuclear lipid droplets
Authors: Östlund Cecilia , Hernandez-Ono Antonio , Turk Samantha J. , Dauer William T. , Ginsberg Henry N. , Worman Howard J. , Shin Ji-Yeon 
Published: June 2022

ABSTRACTLipid droplets (LDs) are generally considered to be synthesized in the ER and utilized in the cytoplasm. However, LDs have been observed inside nuclei in some cells, although recent research on nuclear LDs has focused on cultured cell lines. To better understand nuclear LDs that occur in vivo, here we examined LDs in primary hepatocytes from mice following depletion of the nuclear envelope protein lamina-associated polypeptide 1 (LAP1). Microscopic image analysis showed that LAP1-depleted hepatocytes contain frequent nuclear LDs, which differ from cytoplasmic LDs in their associated proteins. We found type 1 nucleoplasmic reticula, which are invaginations of the inner nuclear membrane, are often associated with nuclear LDs in these hepatocytes. Furthermore, in vivo depletion of the nuclear envelope proteins lamin A and C from mouse hepatocytes led to severely abnormal nuclear morphology, but significantly fewer nuclear LDs than were observed upon depletion of LAP1. In addition, we show both high fat diet feeding and fasting of mice increased cytoplasmic lipids in LAP1-depleted hepatocytes, but reduced nuclear LDs, demonstrating a relationship of LD formation with nutritional state. Finally, depletion of microsomal triglyceride transfer protein did not change the frequency of nuclear LDs in LAP1-depleted hepatocytes, suggesting that it is not necessary for the biogenesis of nuclear LDs in these cells. Together, these data show that LAP1-depleted hepatocytes represent an ideal mammalian system to investigate the biogenesis of nuclear LDs and their partitioning between the nucleus and cytoplasm in response to changes in nutritional state and cellular metabolism in vivo.
The COVID-19 pandemic sparked off a large-scale outbreak of carbapenem-resistantAcinetobacter baumanniifrom the endemic strains of an Italian hospital
Authors: Petazzoni Greta , Bellinzona Greta , Merla Cristina , Corbella Marta , Samuelsen Ørjan , Corander Jukka , Sassera Davide , Gaiarsa Stefano , Cambieri Patrizia 
Published: June 2022

AbstractAcinetobacter baumanniiis a nosocomial pathogen that poses a serious threat due to the rise of incidence of multidrug resistant (MDR) strains. During the COVID-19 pandemic, MDRA.baumanniiclones have caused several outbreaks worldwide. Here we describe a detailed investigation of an MDRA. baumanniioutbreak that occurred at Fondazione IRCCS Policlinico San Matteo (Pavia, Italy). A total of 96A. baumanniistrains, isolated between January and July 2020 from 41 inpatients (both SARS-CoV-2 positive and negative) in different wards, were characterized by phenotypic and genomic analyses combining Illumina and Nanopore sequencing. Antibiotic susceptibility testing revealed that all isolates were resistant to carbapenems and the sequence analysis attributed this to the carbapenemase geneblaOXA-23. Screening of virulence factors unveiled that all strains carried determinants for biofilm formation, while plasmid analysis revealed the presence of two plasmids, one of which was a ⍰100kbp long and encoded a phage sequence.A core genome-based phylogeny was inferred to integrate outbreak strain genomes with background genomes from public databases and from the local surveillance program. All strains belonged to the globally disseminated ST2 clone and were mainly divided into two clades. Isolates from the outbreak clustered with surveillance isolates from 2019, suggesting that the outbreak was caused by two strains that were already circulating in the hospital before the start of the pandemic. The intensive spread ofA. baumanniiin the hospital was enhanced by the extreme emergency situation of the first COVID-19 pandemic wave that resulted in minor attention to infection prevention and control practices.ImportanceThe COVID-19 pandemic, especially during the first wave, posed a great challenge to the hospital management and generally promoted nosocomial pathogen dissemination. Multidrug resistant (MDR)A. baumanniican easily spread and persist for a long time on surfaces, causing outbreaks in healthcare settings. Infection prevention and control practices, epidemiological surveillance and microbiological screening are fundamental in order to control such outbreaks.Here, we sequenced the genomes of 96 isolates from an outbreak of MDRA. baumanniistrains using both short- and long-read technology in order to reconstruct the outbreak events in fine detail. The sequence data demonstrated that two endemic clones of MDRA. baumanniiwere the source of this large hospital outbreak during the first COVID-19 pandemic wave, confirming the effect of COVID-19 emergency disrupting the protection provided by the use of the standard prevention procedures.
The ribosome inhibitor chloramphenicol induces motility deficits in human spermatozoa: a proteomic approach identifies potentially involved proteins
Authors: Bisconti Marie , Leroy Baptiste , Gallagher Meurig , Senet Coralie , Martinet Baptiste , Arcolia Vanessa , Wattiez Ruddy , Kirkman-Brown Jackson , Simon Jean-François , Hennebert Elise 
Published: June 2022

AbstractMature spermatozoa are almost completely devoid of cytoplasm; as such it has long been believed that they do not contain ribosomes and are therefore not capable of synthesising proteins. However, since the 1950s, various studies have shown translational activity within spermatozoa, particularly during their in vitro capacitation. Most of them demonstrated that mitochondrial (and not cytoplasmic) ribosomes would be involved in the translation of mitochondrial and nuclear-encoded cytoplasmic mRNAs. However, some evidence suggests that cytoplasmic ribosomes could also be active. Here, we investigate the presence and activity of the two types of ribosomes in mature human spermatozoa. By targeting ribosomal RNAs and proteins, we show that both types of ribosomes are localized in the midpiece as well as in the neck and the base of the head of the spermatozoa. We assessed the impact of cycloheximide (CHX) and chloramphenicol (CP), inhibitors of cytoplasmic and mitochondrial ribosomes, respectively, on different sperm parameters. Neither CHX, nor CP impacted sperm vitality, mitochondrial activity (measured through the ATP content), or capacitation (measured through the content in phosphotyrosines). However, increasing CP concentrations induced a decrease in total and progressive motilities as well as on some kinematic parameters while no effect was observed with CHX. A quantitative proteomic analysis was performed by mass spectrometry in SWATH mode to compare the proteomes of spermatozoa capacitated in the absence or presence of the two ribosome inhibitors. Among the ∼ 700 proteins identified in the different tested conditions, 3, 3 and 25 proteins presented a modified abundance in the presence of 1 and 2 mg/ml of CHX, and 1 mg/ml of CP, respectively. The observed abundance variations of some CP-down regulated proteins were validated using Multiple-Reaction Monitoring (MRM). Taken together, our results show that the sperm motility deficits induced in the presence of CP could be linked to the observed decrease of the abundance of several proteins, at least FUNDC2 and QRICH2.