bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust Determinants of Neurocognitive Development in Children: Evidence from the Pune Maternal Nutrition Study (PMNS)
Authors: Yajnik Chittaranjan S. , Tan Chih Ming , Bhate Vidya , Bandyopadhyay Souvik , Sankar Ashwini , Behere Rishikesh V. 
Published: February 2022

AbstractNeurocognitive development is a dynamic process over the life course and is influenced by intrauterine factors as well as later life environment. Using data from the Pune Maternal Nutrition Study (PMNS) from 1994 to 2008, we investigate the association of in-utero, birth, and childhood conditions with offspring neurocognitive development in 686 participants of the cohort, at age 12 years. The life course exposure variables in the analysis include maternal pre-pregnancy size and nutrition during pregnancy, offspring birth measurements, nutrition and physical growth at age 12 years along with parental education and socio-economic status. We used the novel Bayesian Model Averaging (BMA) approach; which has been shown to have better predictive performance over traditional tests of associations. Our study employs 8 standard neurocognitive tests that measure intelligence, working memory, visuo-conceptual and verbal learning, and decision-making/attention at 12 years of age. We control for nutritional-metabolic information based on blood measurements from the pregnant mothers and the children at 12 years of age. Our findings highlight the critical role of parental education and socioeconomic background in determining child neurocognitive performance. Maternal characteristics (pre-pregnancy BMI, fasting insulin during pregnancy) and child height at 12 years were also robust predictors on the BMA. A range of early factors – such as maternal folate and ferritin concentrations during pregnancy, and child’s head circumference at birth – remained important determinants of some dimensions of child’s neurocognitive development, but their associations were not robust once we account for model uncertainty. Our results suggest that intrauterine influences on long term neurocognitive outcomes may be potentially reversible by post birth remediation. In addition to the current nutritional interventions, public health policy should also consider social interventions in children born into families with low socio-economic status to improve human capital.
Deep tissue infection by an invasive human fungal pathogen requires novel lipid-based suppression of the IL-17 response
Authors: Basso P. , Dang E.V. , Urisman A. , Cowen L.E. , Madhani H. D. , Noble S. M. 
Published: February 2022

AbstractCandida albicans is the most common cause of human fungal infection, but the mechanisms of invasive pathogenesis remain poorly defined. Here we identify an unexpected mechanism: lipid-mediated immunosuppression. Through forward genetics, we found that C. albicans secretes a lipase, Lip2, that is critical for invasive disease. Murine infection with C. albicans strains that lack Lip2 display an exaggerated host IL-17 response that leads to fungal clearance from solid organs and host survival. IL-17 signaling is required for Lip2 action. The lipase activity of Lip2 inhibits IL-17 production indirectly through suppression of IL-23 production by tissue resident dendritic cells. We conclude that C. albicans suppresses antifungal IL-17 defense in solid organs by altering the tissue lipid milieu.
De novo mass spectrometry peptide sequencing with a transformer model
Authors: Yilmaz Melih , Fondrie William E. , Bittremieux Wout , Oh Sewoong , Noble William Stafford 
Published: February 2022

AbstractTandem mass spectrometry is the only high-throughput method for analyzing the protein content of complex biological samples and is thus the primary technology driving the growth of the field of proteomics. A key outstanding challenge in this field involves identifying the sequence of amino acids—the peptide—responsible for generating each observed spectrum, without making use of prior knowledge in the form of a peptide sequence database. Although various machine learning methods have been developed to address this de novo sequencing problem, challenges that arise when modeling tandem mass spectra have led to complex models that combine multiple neural networks and post-processing steps. We propose a simple yet powerful method for de novo peptide sequencing, Casanovo, that uses a transformer framework to map directly from a sequence of observed peaks (a mass spectrum) to a sequence of amino acids (a peptide). Our experiments show that Casanovo achieves state-of-the-art performance on a benchmark dataset using a standard cross-species evaluation framework which involves testing with spectra with never-before-seen peptide labels. Casanovo not only achieves superior performance but does so at a fraction of the model complexity and inference time required by other methods.
Proteomics profiling reveals regulation of immune response to Salmonella Typhimurium infection in mice
Authors: Huang He , Even Zachary , Erickson Alyssa , Li Ling , Golovko Mikhail , Golovko Svetlana , Mathur Ramkumar , Wang Xusheng 
Published: February 2022

AbstractRegulation of the immune response to Salmonella typhimurium (S. Typhimurium) infection is a complex process, influenced by genetic and environmental factors. Different inbred mouse strains show distinct levels of resistance to S. Typhimurium infection, ranging from susceptible (e.g., C57BL/6J) to resistant (e.g., DBA/2J) strains. However, the underlying molecular mechanisms contributing to the host response remain elusive. In this study, we present a comprehensive proteomics profiling of the spleen tissue from C57BL/6J and DBA/2J strains with different doses of S. Typhimurium infection by tandem tag mass coupled with two-dimensional liquid chromatography-tandem mass spectrometry. We identified and quantified 3,986 proteins, resulting in 475 differentially expressed proteins between C57BL/6J and DBA/2J strains. Functional enrichment analysis revealed that the mechanisms of innate immune responses to S. Typhimurium infection are associated with several signaling pathways, including the interferon signaling pathway. Our proteomic data also discovered a plausible gene in a genomic region that control different levels of resistance to S. Typhimurium infection. We further revealed the roles of macrophage cells and pro-inflammatory cytokines in the mechanisms under the natural resistance to S. Typhimurium. In summary, our results provide new insights into the genetic regulation of the immune response to S. Typhimurium infection in mice.Author SummarySalmonella infection (salmonellosis) is a common zoonotic disease that mainly propagates through contaminated food and drink. Various mouse strains display prominent disparities in responses to Salmonella invasion. Elucidating the heterogeneous immune reactions between different mouse strains can shed light on the fundamental molecular mechanisms of the innate immune system. Here, we employed a combination of proteomics and systems biology approaches to provide an unprecedented panorama of the inextricably interlaced immune signaling pathways in response to Salmonella infection in mice. Our results revealed the dynamics of cell signaling molecules elicited by inflammation and established new connections among them. We also identified a new candidate gene involved in the combat with pathogens. Our proteomic data and results contribute to understanding the intricate interactions of immune responses to Salmonella infection from molecular to systemic levels.
MCMBP promotes the assembly of the MCM2-7 hetero-hexamer to ensure robust DNA replication in human cells
Authors: Saito Yuichiro , Santosa Venny , Ishiguro Kei-ichiro , Kanemaki Masato T. 
Published: February 2022

AbstractThe MCM2-7 hetero-hexamer is the replicative DNA helicase that plays a central role in eukaryotic DNA replication. In proliferating cells, the expression level of the MCM2-7 hexamer is kept high, which safeguards the integrity of the genome. However, how the MCM2-7 hexamer is assembled in living cells remains unknown. Here, we revealed that the MCM-binding protein (MCMBP) plays a critical role in the assembly of this hexamer in human cells. MCMBP associates with MCM3 which is essential for maintaining the level of the MCM2-7 hexamer. Acute depletion of MCMBP demonstrated that it contributes to MCM2-7 assembly using nascent MCM3. Cells depleted of MCMBP gradually ceased to proliferate because of reduced replication licensing. Under this condition, p53-positive cells exhibited arrest in the G1 phase, whereas p53-null cells entered the S phase and lost their viability because of the accumulation of DNA damage, suggesting that MCMBP is a potential target for killing p53-deficient cancers.
Relative enrichment – a density-based colocalization measure for single-molecule localization microscopy
Authors: Ejdrup Aske L. , Lycas Matthew D. , Lorenzen Niels , Konomi Ainoa , Herborg Freja , Madsen Kenneth L. , Gether Ulrik 
Published: February 2022

AbstractDual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization of different molecular species in a cell. However, the informational richness of the data is not fully exploited by current analysis tools that often reduce colocalization to a single value. Here, we describe a new tool specifically designed for determination of co-localization in both 2D and 3D from SMLM data. The approach uses a novel function that describes the relative enrichment of one molecular species on the density distribution of a reference species. The function reframes the question of colocalization by providing a density-context relevant to multiple biological questions. Moreover, the function visualize enrichment (i.e. colocalization) directly in the images for easy interpretation. We demonstrate the approach’s functionality on both simulated data and cultured neurons, and compare it to current alternative measures. The method is available in a Python function for easy and parameter-free implementation.
Multi-excitation Raman Spectroscopy Complements Whole Genome Sequencing for Rapid Detection of Bacterial Infection and Resistance in WHO Priority Pathogens
Authors: Lister Adam , Avershina Ekaterina , Ali Jawad , Devitt George , Hanrahan Niall , Highmore Callum , Webb Jeremy , Muller Fredrik , Mahajan Sumeet , Ahmad Rafi 
Published: February 2022

AbstractCurrent methods for diagnosing acute and complex infections mostly rely on culture-based methods and, for biofilms, fluorescencein-situhybridization. These techniques are labor-intensive and can take 2-4 days to return a test result, especially considering an extra culturing step required for the antibiotic susceptibility testing (AST). This places a significant burden on healthcare providers, delaying treatment and leading to adverse patient outcomes. Here, we report the complementary use of our newly developed multi-excitation Raman spectroscopy (ME-RS) method with whole-genome sequencing (WGS). Four WHO priority pathogens are AST phenotyped and their antimicrobial resistance (AMR) profile determined by WGS. On application of ME-RS method we find high correlation with the WGS characterization. Highly accurate classification based on the species (98.93%), wild-type/non-wild type (99.45%), and presence or absence of thick peptidoglycan layers in cell walls (100%), as well as at the individual strain level (99.29%). These results clearly demonstrate the potential of ME-RS as a rapid and first-stage tool for species, resistance and strain-level classification which can be followed up by WGS for confirmation. Such a workflow can facilitate efficient antimicrobial stewardship to handle and prevent the spread of AMR.
Spike Protein-independent Attenuation of SARS-CoV-2 Omicron Variant in Laboratory Mice
Authors: Liu Shufeng , Selvaraj Prabhuanand , Sangare Kotou , Luan Binquan , Wang Tony T. 
Published: February 2022

SummaryDespite being more transmissible, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant was found to cause milder diseases in laboratory animals, often accompanied by a lower viral load compared to previous variants of concern. This study revealed the structural basis for a robust interaction between the receptor binding domain of the Omicron spike protein and mouse ACE2. Pseudovirus bearing the Omicron spike protein efficiently utilized mouse ACE2 for entry. By comparing viral load and disease severity among laboratory mice infected by a natural Omicron variant or recombinant ancestral viruses bearing either the entire Omicron Spike or only the N501Y/Q493R mutations in its spike, we found that mutations outside the spike protein in the Omicron variant may be responsible for the observed lower viral load. Together, our results indicated that a post-entry block to the Omicron variant exists in laboratory mice.
The influence of biological and statistical properties of CpGs on epigenetic predictions of eighteen traits
Authors: Hillary Robert F. , McCartney Daniel L. , McRae Allan F. , Campbell Archie , Walker Rosie M. , Hayward Caroline , Horvath Steve , Porteous David J. , Evans Kathryn L. , Marioni Riccardo E. 
Published: February 2022

AbstractBackgroundCpG methylation levels can help to explain inter-individual differences in phenotypic traits. Few studies have explored whether identifying CpG subsets based on biological and statistical properties can maximise predictions while minimising array content.MethodsVariance component analyses and penalised regression (epigenetic predictors) were used to test the influence of (i) the number of CpGs considered, (ii) mean CpG methylation variability and (iii) methylation QTL status on the variance captured in eighteen traits by blood DNA methylation. Training and test sets comprised ≤4,450 and ≤2,578 unrelated individuals from Generation Scotland, respectively.ResultsAs the number of CpG sites under consideration decreased, so too did the estimates from the variance components and prediction analyses. Methylation QTL status and mean CpG variability did not influence variance components. However, relative effect sizes were 15% larger for epigenetic predictors based on CpGs with methylation QTLs compared to sites without methylation QTLs. Relative effect sizes were 45% larger for predictors based on CpGs with mean beta-values between 10%-90% compared to those using hypo- or hypermethylated CpGs (beta-value ≤10% or ≥90%).ConclusionArrays with fewer CpGs could reduce costs, leading to increased sample sizes for analyses. Our results show that reducing array content can restrict prediction metrics and careful attention must be given to the biological and distribution properties of CpGs in array content selection.
Astrocytes regulate inhibition in Fragile X Syndrome
Authors: Rais Maham , Kulinich Anna O. , Wagner Victoria , Woodard Walker , Shuai Xinghao S. , Sutley Samantha N. , Kokash Jamiela , Piepponen Timo P. , Castren Maija , Razak Khaleel A. , Ethell Iryna M. 
Published: February 2022

AbstractFragile X syndrome (FXS) is a leading genetic cause of autism-like symptoms associated with sensory hypersensitivity and cortical hyperexcitability. Recent observations in humans and Fmr1 knockout (KO) animal models of FXS suggest abnormal GABAergic signaling. As most studies focused on neuron-centered mechanisms, astrocytes’ contribution to defective inhibition is largely unknown. Here we show abnormally increased GABA levels in human FXS astrocytes derived from patient-specific induced pluripotent stem cells (iPSCs) and mouse astrocytes following astrocyte-specific Fmr1 KO during the postnatal period, affecting synaptic GABAA receptor levels and parvalbumin (PV) cell development. Developmental deletion of Fmr1 from astrocytes altered communication between excitatory neurons and PV cells, impairing cortical sound-evoked gamma synchronization, while enhancing baseline and on-going sound-evoked EEG power, and lead to increased locomotor activity and altered social behaviors in adult mice. These results demonstrate a profound role of astrocytic FMRP in the development of inhibitory circuits and shaping normal inhibitory responses.
Differentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids
Authors: Lindoso Rafael Soares , Yousef Yengej Fjodor A , Voellmy Franziska , Altelaar Maarten , Juncosa Estela Mancheño , Tsikari Theano , Ammerlaan Carola M.E. , Van Balkom Bas W.M. , Rookmaaker Maarten B , Verhaar Marianne C , Masereeuw Rosalinde 
Published: February 2022

ABSTRACTAdvanced kidney in vitro models such as organoids or tubuloids still lack the intrinsic expression of various transport proteins needed for active secretory function. Extracellular vesicles (EVs), cell-derived structures that constitute the organ’s microenvironment, are known to regulate various cellular processes, including kidney development and regeneration across the nephron. In this study, we propose a new application of renal tubular epithelial cell EVs as modulators for tubuloid functional maturation by increasing the levels of various differentiation markers such as organic anion transport 1 (OAT1), a protein involved in endogenous waste excretion. First, we show that EVs from engineered proximal tubule cells increased the expression of several transcription factors and epithelial transporters in tubuloids that resulted in improved cellular transport capacity. Next, a more in-depth proteomic data analysis demonstrated that EVs can trigger various biological pathways, including mesenchymal-to-epithelial transition, which is crucial in the tubular epithelial maturation process. Moreover, we demonstrated that EV-treated tubuloid-derived cells in a 3D tubular conformation as part of a bioartificial kidney can generate a tight polarized epithelial monolayer with formation of dense cilia structures. In conclusion, EVs from renal tubular epithelial cells can phenotypically improve tubuloid maturation, thereby enhancing their potential as preclinical models and functional units in regenerative therapies.
Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit
Authors: Nguyen Eileen , Smith Kelly M. , Cramer Nathan , Holland Ruby A. , Bleimeister Isabel H. , Flores-Felix Krystal , Silberberg Hanna , Keller Asaf , Le Pichon Claire E. , Ross Sarah E. 
Published: February 2022

AbstractIn perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit nociception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the RVM has never been achieved. We now expose a cellular circuit that inhibits nociception and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and nociception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVMKOR neurons inhibit nociception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal gray (PAG) that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and nociception.
Technical efficiency in the Ghanaian banking sector: does boardroom gender diversity matter?
Authors: Boadi Isaac , Dziwornu Raymond , Osarfo Daniel 
Published: February 2022

PurposeThe marginalization of women on boards is a heavily discussed topic across the world, especially in Ghana. Apart from estimating the link between boardroom gender diversity and technical efficiency of banks, this study aims to test the presence of upper echelons theory in the Ghanaian banking sector.Design/methodology/approachThe study examines data from 2000 to 2019 annual reports of 23 banks in Ghana. The stochastic frontier analysis is used to estimate the impact of boardroom gender diversity on technical efficiency of banks in Ghana.FindingsThis study finds that greater boardroom gender diversity generates technical efficiencies for banks. The results remain unchanged after accounting for bank types (listed and non-listed). Thus, all banks benefit in terms of technical efficiency from more boardroom gender diversity. The upper echelons theory is validated in the Ghanaian banking context. Overall, the study supports pro-gender diversity on boards.Practical implicationsThe results have implications at corporate, social and national levels. It supports the need for policies that improve greater boardroom gender diversity.Originality/valueThis study adds to a growing number of non-developed countries by investigating the link between the boardroom gender diversity and technical efficiency of banks in Ghana, a country which historically has had minimal female participation in the workforce. New insight is, therefore, offered into this relationship by using data which examines the technical efficiency of banks periods before and after the Women in Finance Charter in 2016.
Organizational climate and organizational politics: understanding the role of employees using parallel mediation
Authors: Tripathi Swati , Tripathi Divya 
Published: February 2022

PurposeThe purpose of this paper is to inspect the influence of organizational climate on the social desirability of political behaviour of employees. It also examines perception of politics and perceived behavioural choice as the underlying mechanisms that mediate the relationship between organizational climate and social desirability of political tactics. Finally, the paper studies the influence of desirability of politics on frequency of use of political tactics.Design/methodology/approachThe study uses data (n = 234) collected from a large public sector organization in India. The inter-relationships are tested empirically using structural equation modelling.FindingsThe findings suggest that organizational climate significantly influences the social desirability of political tactics such that positive climate leads to lower social desirability of political tactics. Also, perception of politics and perceived behavioural choice mediate the relationship between organizational climate and desirability of political tactics. Finally, the social desirability of political tactics positively and significantly influences frequency of political tactics used.Research limitations/implicationsBecause of the nature of the study, generalization must be made with caution since it has been conducted in an Indian public sector organization, and errors due to measurement method could be present. The study provides a better understanding of the relationship between organizational climate and political behaviour and clarifies the mediating role of perception of politics and behavioural choices. It also elucidates the need for organizations to accept the active role of employees in determining the nature of workplace politics.Originality/valueThe study establishes political perceptions and perceived behavioural choice as important mediators between climate and political behaviour, fostering in-depth research into the environmental aspects of public sector organizations. It also establishes employees as autonomous members of the organization who make political choices by taking into account their organizational contexts, a concept much newer to highly formalized and codified public sector organizations.