bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra-Host Mutation Rate of Acute SARS-CoV-2 Infection During the Initial Pandemic Wave
Authors: El-Haddad Kim , Adhikari Thamali M , Jin Tu Zheng , Cheng Yu-Wei , Leng Xiaoyi , Zhang Xiangyi , Rhoads Daniel , Ko Jennifer S. , Worley Sarah , Li Jing , Rubin Brian P. , Esper Frank P. 
Published: March 2023

AbstractBackgroundOur understanding of SARS-CoV-2 evolution and mutation rate is limited. The rate of SARS-CoV-2 evolution is minimized through a proofreading function encoded byNSP-14and may be affected by patient comorbidity. Current understanding of SARS-CoV-2 mutational rate is through population based analysis while intra-host mutation rate remains poorly studied.MethodsViral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥0.25, ≥0.5 and ≥0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity.ResultsForty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI:90.8-96.4], 40.7 (95%CI:38.9-42.6) and 34.7 (95%CI:33.0-36.4) substitutions/genome/year at AF ≥0.25, ≥0.5, ≥0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF>0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies.DiscussionIntra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.
A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19
Authors: Van Damme Karel F.A. , Hoste Levi , Declercq Jozefien , Leeuw Elisabeth De , Maes Bastiaan , Martens Liesbet , Colman Roos , Browaeys Robin , Bosteels Cédric , Verwaerde Stijn , Vermeulen Nicky , Lameire Sahine , Debeuf Nincy , Deckers Julie , Stordeur Patrick , Guilliams Martin , Schetters Sjoerd T.T. , Haerynck Filomeen , Tavernier Simon J. , Lambrecht Bart N. 
Published: March 2023

AbstractTo improve COVID-19 therapy, it is essential to understand the mechanisms driving critical illness. The complement system is an essential part of innate host defense that can also contribute to injury. All complement pathways have been implicated in COVID-19 pathogenesis, however the upstream drivers and downstream consequences on tissue injury remain ill-defined. Here, we demonstrate that complement activation is mediated by the alternative pathway and we provide a comprehensive atlas of the alterations in complement around the time of respiratory deterioration. Proteome and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal and myeloid cells in the production of complement, in addition to liver-derived factors. Upstream, IL-6 drives complement responses, linking complement dysregulation to approved COVID-19 therapies. In an exploratory proteomic study, C5 inhibition improves epithelial damage and markers of disease severity. Collectively, these results identify complement dysregulation as a key druggable feature of COVID-19.
A phenotypically robust model of Spinal and Bulbar Muscular Atrophy inDrosophila
Authors: Richardson Kristin , Sengupta Medha , Sujkowski Alyson , Libohova Kozeta , Harris Autumn C. , Wessells Robert , Merry Diane E. , Todi Sokol V. 
Published: March 2023

AbstractSpinal and bulbar muscular atrophy (SBMA) is an X-linked disorder that affects males who inherit theandrogen receptor(AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen-dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA inDrosophila melanogaster. We generated transgenic flies that express the full-length, human AR with a wild-type or pathogenic polyQ repeat. Each transgene is inserted into the same “safe harbor” site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild-type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ-expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool towards future investigations of this incurable disease.
Left or right: Handedness in free-ranging Hanuman langurs (Semnopithecus entellus) residing in an urban ecosystem
Authors: Dutta Akash , Dasgupta Dishari , Banerjee Arnab , Hasnain Sk Anzar , Sen Debadrita , Kuleri Milan Sahadevan , Bhattacharjee Pritha , Paul Manabi 
Published: March 2023

AbstractExamining manual lateralization (handedness) in nonhuman primates might be an interesting approach to gaining insight into the evolution of asymmetry in humans. Moreover, handedness could also reflect the effect of environmental alterations on the free-ranging animals who are forced to live with anthropogenic interferences. Despite addressing the handedness among monkeys and apes, only a few studies have focused on these free-ranging urban-adapted nonhuman primates, which could challenge our perception of habitat loss and deforestation. Here, we conducted 193 field-based experimental trials with two experimental tasks, one unimanual (simple reaching) and one bimanual (tube task) to explore manual lateralization in a highly human-provisioned group of free-ranging Hanuman langur (Semnopithecus entellus). Experimental outcomes revealed an asymmetrical hand-use distribution, with a bias toward the left hand. As bimanual tasks evoked a higher degree of lateralization, these tasks seem to be more suited to study manual laterality, and our results also highlight the significance of experimental tasks in establishing hand preference in langurs. Furthermore, this study also reveals that such lateralization developed with age as adults distinctly displayed their preference toward left-hand usage in contrast to juveniles and subadults who used both hands comparably. Mostly considered to be arboreal, the langurs of our study group spend a considerable amount of time with humans on the ground, thereby portraying a terrestrial tendency. Postural Origin Theory states that terrestrial animals tend to use their right hand and arboreal their left. Therefore, here the presence of group-level left-hand biasness in the adult langurs of Dakshineswar creates a dilemma in the Postural Origin Theory.
Frequent transitions in mating-type locus chromosomal organization inMalasseziaand early steps in sexual reproduction
Authors: Coelho Marco A. , Ianiri Giuseppe , David-Palma Márcia , Theelen Bart , Goyal Rohit , Narayanan Aswathy , Lorch Jeffrey M. , Sanyal Kaustuv , Boekhout Teun , Heitman Joseph 
Published: March 2023

AbstractFungi in the basidiomycete genusMalasseziaare the most prevalent eukaryotic microbes resident on the skin of human and other warm-blooded animals and have been implicated in skin diseases and systemic disorders. Analysis ofMalasseziagenomes revealed that key adaptations to the skin microenvironment have a direct genomic basis, and the identification of mating/meiotic genes suggests a capacity to reproduce sexually, even though no sexual cycle has yet been observed. In contrast to other bipolar or tetrapolar basidiomycetes that have either two linked mating-type-determining (MAT) loci or twoMATloci on separate chromosomes, inMalasseziaspecies studied thus far the twoMATloci are arranged in a pseudobipolar configuration (linked on the same chromosome but capable of recombining). By incorporating newly generated chromosome-level genome assemblies, and an improvedMalasseziaphylogeny, we infer that the pseudobipolar arrangement was the ancestral state of this group and revealed six independent transitions to tetrapolarity, seemingly driven by centromere fission or translocations in centromere- flanking regions. Additionally, in an approach to uncover a sexual cycle,Malassezia furfurstrains were engineered to express differentMATalleles in the same cell. The resulting strains produce hyphae reminiscent of early steps in sexual development and display upregulation of genes associated with sexual development as well as others encoding lipases and a protease potentially relevant for pathogenesis of the fungus. Our study reveals a previously unseen genomic relocation of mating-type loci in fungi and provides insight towards the discovery of a sexual cycle inMalassezia, with possible implications for pathogenicity.Significance StatementMalassezia, the dominant fungal group of the mammalian skin microbiome, is associated with numerous skin disorders. Sexual development and yeast-to-hyphae transitions, governed by genes at two mating-type (MAT) loci, are thought to be important for fungal pathogenicity. However,Malasseziasexual reproduction has never been observed. Here, we used chromosome-level assemblies and comparative genomics to uncover unforeseen transitions inMATloci organization withinMalassezia, possibly related with fragility of centromeric-associated regions. Additionally, by expressing differentMATalleles in the same cell, we show thatMalasseziacan undergo hyphal development and this phenotype is associated with increased expression of key mating genes along with other genes known to be virulence factors, providing a possible connection between hyphal development, sexual reproduction, and pathogenicity.
Cultivation of SAR202 Bacteria from the Ocean
Authors: Lim Yeonjung , Seo Ji-Hui , Giovannoni Stephen J. , Kang Ilnam , Cho Jang-Cheon 
Published: March 2023

AbstractHere we report the first successful cultivation of SAR202 bacteria, a superorder in the phylumChloroflexota, which have long been at the top of “most wanted” lists of uncultivated microbial life. It has been proposed that ancient expansions of catabolic enzyme paralogs in SAR202 broadened the spectrum of organic compounds they could oxidize, leading to transformations of the Earth’s carbon cycle. We cultured the cells from surface seawater using dilution-to-extinction culturing. Their growth was very slow (0.18-0.24 day-1) and was inhibited by exposure to light. The genomes, of ca. 3.08 Mbp, encoded archaella, archaeal motility structures, and multiple sets of paralogs, including 80 genes in enolase superfamily and 44 genes in NAD(P)-dependent dehydrogenase family. We propose that these paralogs participate in multiple parallel pathways of non-phosphorylative sugar and sugar acid catabolism, and demonstrate that, as predicted by this scheme, the sugars ʟ-fucose and ʟ-rhamnose and their lactone and acid forms are utilized by these cells.
Stratified assessment for geriatric mental health using probabilistic graphical model: a cross-sectional observational study in India
Authors: Jha Indra Prakash , Mishra Shreya , Pandey Neetesh , Kumar Vibhor 
Published: March 2023

AbstractBackgroundThe mental health among seniors presents a diverse set of challenges that can be attributed to a number of different causes, including social factors, economic factors, and psychological factors. Researchers are attempting to understand its complexity; however, there is a limited amount of systematic robust analysis that has been conducted. It is, therefore, critical to identify and quantify the driver characteristics or factors that are related to mental health and conduct age-specific stratified analysis in order to guide and provide tailor-made policy-level interventions.MethodsWe used “Longitudinal Ageing Study in India (LASI) wave-1 survey” data of 72250 (47% male and 53% female) carried out in April 2017 to December 2018 spanning over 35 states and union territories with socioeconomic, behavioural, psychological, and health-related indicators. We utilised a probabilistic graphical model named Bayesian Network to identify key factors of mental health variables.ResultsAgeism, social discrimination (the inferred conditional probability difference is ∼30% with 95% CI: ∼5%) and Food insecurity (>19% with a 95% CI of >3%) were found to negatively impact mental health in older adults, while connectedness with family and friends (9.34% with 95% CI: 1.41%) positively affected mental health. The sense of general dissatisfaction or discontentment with one’s own life (17% with 95% of CI: ∼2.8%) is one of the factors that plays a significant role in mental health among elderly people. Additionally, multimorbidities of mental health problems in older adults, which were found to be arthritis, sleep disorders, and stroke. The incidence of multimorbidity due to mental issues were shown to be higher in older adults than younger adults, with sleep disorders being associated with mental health in older age groups. By incorporating age based stratification analysis, we also identified the specific age group when older people from India are most vulnerable to mental health issues.ConclusionThe prevalence of mental illness in senior citizens in India needs to be reduced, and one way to do this is through the development of targeted policies to combat food insecurity and social discrimination, as well as to improve communication of older people with their loved ones. In addition to this, the issue of arthritis must be tackled in a more in-depth manner given the result that it also has a severe impact on the mental health among elderly.
Evaluation of antiviral drugs against newly emerged SARS-CoV-2 Omicron subvariants
Authors: Cho Junhyung , Shin Younmin , Yang Jeong-Sun , Kim Jun Won , Kim Kyung-Chang , Lee Joo-Yeon 
Published: March 2023

AbstractThe ongoing emergence of SARS-CoV-2 Omicron subvariants and their rapid worldwide spread pose a threat to public health. From November 2022 to February 2023, newly emerged Omicron subvariants, including BQ.1.1, BF.7, BA.5.2, XBB.1, XBB.1.5, and BN.1.9, became prevalent global strains (>5% global prevalence). These Omicron subvariants are resistant to several therapeutic antibodies. Thus, the antiviral activities of current drugs such as remdesivir, molnupiravir, and nirmatrelvir, which target highly conserved regions of SARS-CoV-2, against newly emerged Omicron subvariants need to be evaluated. We assessed the antiviral efficacy of the drugs using half maximal inhibitory concentration (IC50) against human isolated 23 Omicron subvariants and four former SARS-CoV-2 variants of concern (VOC) and compared them with the antiviral efficacy of these drugs against the SARS-CoV-2 reference strain (hCoV/Korea/KCDC03/2020). Maximal IC50fold changes of remdesivir, molnupiravir, and nirmatrelvir were 1.9- (BA.2.75.2), 1.2-(B.1.627.2), and 1.4-fold (BA.2.3), respectively, compared to median IC50values of the reference strain. Moreover, median IC50-fold changes of remdesivir, molnupiravir, and nirmatrelvir against the Omicron variants were 0.96, 0.4, and 0.62, similar to 1.02, 0.88, and 0.67, respectively, of median IC50-fold changes for previous VOC. Although K90R and P132H in Nsp 5, and P323L, A529V, G671S, V405F, and ins823D in Nsp 12 mutations were identified, these amino acid substitutions did not affect drug antiviral activity. Altogether, these results indicated that the current antivirals retain antiviral efficacy against newly emerged Omicron subvariants, and provide comprehensive information on the antiviral efficacy of these drugs.
Demixing model: A normative explanation for inter-item biases in memory and perception
Authors: Chetverikov Andrey 
Published: March 2023

AbstractMany studies in perception and in the working memory literature demonstrate that human observers systematically deviate from the truth when estimating the features of one item in the presence of another. Such inter-item or contextual biases are well established but lack a coherent explanation at the computational level. Here, I propose a novel normative model showing that such biases exist for any observer striving for optimality when trying to infer the features of multiple similar objects from a mixture of sensory observations. The ‘demixing’ model predicts that bias strength and direction would vary as a function of the amount of sensory noise and the similarity between items. Crucially, these biases exist not because of the prior knowledge in any form, but simply because the biased solutions to this inference problem are more probable than unbiased ones, counter to the common intuition. The model makes novel predictions about the effect of discriminability along the dimension used to select the item to report (e.g., spatial location) and the relative amount of sensory noise. Although the model is consistent with previously reported data from human observers, more carefully controlled studies are needed for a stringent test of its predictions. The strongest point of the ‘demixing’ model, however, is that it shows that interitem biases are inevitable when observers lack perfect knowledge of which stimuli caused which sensory observations, which is, arguably, always the case.
SLAPSHOT reveals rapid dynamics of extracellularly exposed proteome in response to calcium-activated plasma membrane phospholipid scrambling
Authors: Tuomivaara Sami T. , Teo Chin Fen , Jan Yuh Nung , Jan Lily Y. , Wiita Arun P. 
Published: March 2023

AbstractTo facilitate our understanding of the often rapid and nuanced dynamics of extracellularly exposed proteomes during signaling events, it is important to devise robust workflows affording fast time resolution without biases and confounding factors. Here, we presentSurface-exposed proteinLabeling usingPeroxidaSe,H2O2, andTyramide-derivative (SLAPSHOT), to label extracellularly exposed proteins in a rapid, sensitive, and specific manner, while preserving cellular integrity. This experimentally simple and flexible method utilizes recombinant soluble APEX2 peroxidase that is applied to cells, thus circumventing biological perturbations, tedious engineering of tools and cells, and labeling biases. APEX2 neither requires metal cations for activity nor contains disulfide bonds, conferring versatility for a wide spectrum of experimental setups. We applied SLAPSHOT followed by quantitative mass spectrometry-based proteomics analysis to examine the immediate and extensive cell surface expansion and ensuing restorative membrane shedding upon the activation of Scott syndrome-linked TMEM16F, a ubiquitously expressed calcium-dependent phospholipid scramblase and ion channel. Time-course data ranging from one to thirty minutes of calcium stimulation using wild-type and TMEM16F deficient cells revealed intricate co-regulation of known protein families, including those in the integrin and ICAM families. Crucially, we identified proteins that are known to reside in intracellular organelles, including ER, as occupants of the freshly deposited membrane, and mitovesicles as an abundant component and contributor to the extracellularly exposed proteome. Our study not only provides the first accounts of the immediate consequences of calcium signaling on the extracellularly exposed proteome, but also presents a blueprint for the application of SLAPSHOT as a general approach for monitoring extracellularly exposed protein dynamics.HighlightsAn enzyme-driven method to tag extracellularly exposed proteins in an unbiased manner with a superior combination of temporal resolution, spatial specificity, and sensitivityA general approach applicable to primary and scarce cells without involving cellular engineeringShort time scale proteome dynamics of Jurkat cells with and without TMEM16F revealed by SLAPSHOT coupled with quantitative mass spectrometry provide insights into phospholipid scrambling-mediated plasma membrane remodeling
FIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination
Authors: Ito Masaru , Furukohri Asako , Matsuzaki Kenichiro , Fujita Yurika , Toyoda Atsushi , Shinohara Akira 
Published: March 2023

AbstractThe formation of RAD51/DMC1 filaments on single-stranded (ss)DNAs essential for homology search and strand exchange in DNA double-strand break (DSB) repair is tightly regulated. FIGNL1 AAA+++ ATPase controls RAD51-mediated recombination in human cells. However, its role in gametogenesis remains unsolved. Here, we characterized a germ-line-specific conditional knockout (cKO) mouse ofFIGNL1.Fignl1cKO male mice showed defective chromosome synapsis and impaired meiotic DSB repair with the accumulation of RAD51/DMC1 on meiotic chromosomes, supporting a positive role of FIGNL1 in homologous recombination at a post-assembly stage of RAD51/DMC1 filaments.Fignl1cKO spermatocytes also accumulate RAD51/DMC1 on chromosomes in pre-meiotic S-phase. These RAD51/DMC1 assemblies are independent of meiotic DSB formation. We also showed that purified FIGNL1 dismantles RAD51 filament on double-stranded (ds)DNA as well as ssDNA. These results suggest an additional role of FIGNL1 in limiting the non-productive assembly of RAD51/DMC1 on native dsDNAs during pre-meiotic S-phase and meiotic prophase I.
Cooperative Motility, Force Generation and Mechanosensing in a Foraging Non-Photosynthetic Diatom
Authors: Zheng Peng , Kumadaki Kayo , Quek Christopher , Lim Zeng Hao , Ashenafi Yonatan , Yip Zhi Ting , Newby Jay , Alverson Andrew J. , Jie Yan , Jedd Gregory 
Published: March 2023

SUMMARYDiatoms are ancestrally photosynthetic microalgae. However, some underwent a major evolutionary transition, losing photosynthesis to become obligate heterotrophs. The molecular and physiological basis for this transition is unclear. Here, we isolate and characterize new strains of non-photosynthetic diatoms from the coastal waters of Singapore. These diatoms occupy diverse ecological niches and display glucose-mediated catabolite repression, a classical feature of bacterial and fungal heterotrophs. Live-cell imaging reveals deposition of secreted extracellular polymeric substance (EPS). Diatoms moving on pre-existing EPS trails (runners) move faster than those laying new trails (blazers). This leads to cell-to-cell coupling where runners can push blazers to make them move faster. Calibrated micropipettes measure substantial single cell pushing forces, which are consistent with high-order myosin motor cooperativity. Collisions that impede forward motion induce reversal, revealing navigation-related force sensing. Together, these data identify aspects of metabolism and motility that are likely to promote and underpin diatom heterotrophy.