bluuebunny/crossref_metadata_2025_split huggingface dataset:
Forecasting admissions in psychiatric hospitals before and during Covid-19
Authors: Wolff Jan , Klimke Ansgar , Marschollek Michael , Kacprowski Tim 
Published: July 2021

AbstractIntroductionThe COVID-19 pandemic has strong effects on most health care systems and individual services providers. Forecasting of admissions can help for the efficient organisation of hospital care. We aimed to forecast the number of admissions to psychiatric hospitals before and during the COVID-19 pandemic and we compared the performance of machine learning models and time series models. This would eventually allow to support timely resource allocation for optimal treatment of patients.MethodsWe used admission data from 9 psychiatric hospitals in Germany between 2017 and 2020. We compared machine learning models with time series models in weekly, monthly and yearly forecasting before and during the COVID-19 pandemic. Our models were trained and validated with data from the first two years and tested in prospectively sliding time-windows in the last two years.ResultsA total of 90,686 admissions were analysed. The models explained up to 90% of variance in hospital admissions in 2019 and 75% in 2020 with the effects of the COVID-19 pandemic. The best models substantially outperformed a one-step seasonal naïve forecast (seasonal mean absolute scaled error (sMASE) 2019: 0.59, 2020: 0.76). The best model in 2019 was a machine learning model (elastic net, mean absolute error (MAE): 7.25). The best model in 2020 was a time series model (exponential smoothing state space model with Box-Cox transformation, ARMA errors and trend and seasonal components, MAE: 10.44), which adjusted more quickly to the shock effects of the COVID-19 pandemic. Models forecasting admissions one week in advance did not perform better than monthly and yearly models in 2019 but they did in 2020. The most important features for the machine learning models were calendrical variables.ConclusionModel performance did not vary much between different modelling approaches before the COVID-19 pandemic and established forecasts were substantially better than one-step seasonal naïve forecasts. However, weekly time series models adjusted quicker to the COVID-19 related shock effects. In practice, different forecast horizons could be used simultaneously to allow both early planning and quick adjustments to external effects.
Reduced asymmetry of the hand knob area and decreased sensorimotor u-fiber connectivity in middle-aged adults with autism
Authors: Hau Janice , Baker Ashley , Chaaban Chantal , Kohli Jiwandeep S. , Keehn R. Joanne Jao , Linke Annika C. , Mash Lisa E. , Wilkinson Molly , Kinnear Mikaela K. , Müller Ralph-Axel , Carper Ruth A. 
Published: July 2021

AbstractIndividuals with autism spectrum disorder (ASD) frequently present with impairments in motor skills (e.g., limb coordination, handwriting and balance), which are observed across the lifespan but remain largely untreated. Many adults with ASD may thus experience adverse motor outcomes in aging, when physical decline naturally occurs. The ‘hand knob’ of the sensorimotor cortex is an area that is critical for motor control of the fingers and hands. However, this region has received little attention in ASD research, especially in adults after midlife. The hand knob area of the precentral (PrChand) and postcentral (PoChand) gyri was semi-manually delineated in 49 right-handed adults (25 ASD, 24 typical comparison [TC] participants, aged 41-70 years). Using multimodal (T1-weighted, diffusion-weighted, and resting-state functional) MRI, we examined the morphology, ipsilateral connectivity and laterality of these regions. Correlations between hand knob measures with motor skills and autism symptoms, and between structural and functional connectivity measures were also investigated. The right PrChand volume was greater, and typical leftward laterality of PrChand and PoChand volume was lower in the ASD than the TC group. Furthermore, we observed increased mean diffusivity of the right PoC-PrChand u-fibers in the ASD group. In the ASD group, right PoC-PrChand u-fiber volume was negatively associated with current autism severity, and positively associated with right PoC-PrChand functional connectivity (FC). Correlations of hand knob measures were observed with manual dexterity and coordination skills but did not survive multiple comparisons correction. Our findings suggest decreased morphological laterality and u-fiber connectivity of the sensorimotor network involved in hand function in middle-aged adults with ASD. The altered morphology may relate to atypical functional asymmetries found in ASD earlier in life, but additionally, could reflect an overreliance on right hemisphere motor circuits over time. The right PoC-PrChand u-fibers may underlie compensatory self-regulation of unwanted core motor behaviors seen in ASD.
Multi-Omic Analyses Characterize the Ceramide/Sphingomyelin Pathway as a Therapeutic Target in Alzheimer’s Disease
Authors: Baloni Priyanka , Arnold Matthias , Moreno Herman , Nho Kwangsik , Buitrago Luna , Huynh Kevin , Brauner Barbara , Louie Gregory , Kueider-Paisley Alexandra , Suhre Karsten , Saykin Andrew J. , Ekroos Kim , Meikle Peter J. , Hood Leroy , Price Nathan D. ,   The Alzheimer’s disease Metabolomics Consortium, Doraiswamy P. Murali , Funk Cory C. , Kastenmüller Gabi , Baillie Rebecca , Han Xianlin , Kaddurah-Daouk Rima 
Published: July 2021

AbstractDysregulation of sphingomyelin (SM) and ceramide metabolism have been implicated in Alzheimer’s Disease (AD). Genome-wide and transcriptome wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with AD. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. Evaluation of peripheral lipidomic profiles is useful in providing perspective on metabolic dysregulation in preclinical and clinical AD states. In this study, we focused on the sphingolipid pathway and carried out multi-omic analyses to identify central and peripheral metabolic changes in AD patients and correlate them to imaging features and cognitive performance in amyloidogenic mouse models. Our multi-omic approach was based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on 1708 context-specific metabolic networks to identify differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in SM pathway with AD pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in AD; (e) metabolite genome-wide association studies (mGWAS) to define receptors within pathway as potential drug target. Our findings from complementary approaches suggested that depletion of S1P compensated for AD cellular pathology, likely by upregulating the SM pathway, suggesting that modulation of S1P signaling may have protective effects in AD. We tested this hypothesis in APP/PS1 mice and showed that prolonged exposure to fingolimod, an S1P signaling modulator approved for treatment of multiple sclerosis, alleviated the cognitive impairment in mice. Our multi-omic approach identified potential targets in the SM pathway and suggested modulators of S1P metabolism as possible candidates for AD treatment.
The Tabula Sapiens: a multiple organ single cell transcriptomic atlas of humans
Authors:   The Tabula Sapiens Consortium, Quake Stephen R 
Published: July 2021

AbstractMolecular characterization of cell types using single cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues and tissue specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, the tissue specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type specific RNA splicing was discovered and analyzed across tissues within an individual.
An improved auxin-inducible degron system for fission yeast
Authors: Zhang Xiao-Ran , Zhao Lei , Suo Fang , Gao Yadong , Wu Qingcui , Qi Xiangbing , Du Li-Lin 
Published: July 2021

ABSTRACTConditional degron technologies, which allow a protein of interest to be degraded in an inducible manner, are important tools for biological research, and are especially useful for creating conditional loss-of-function mutants of essential genes. The auxin-inducible degron (AID) technology, which utilizes plant auxin signaling components to control protein degradation in non-plant species, is a widely used small-molecular-controlled degradation method in yeasts and animals. However, the currently available AID systems still have room for further optimization. Here, we have improved the AID system for the fission yeast Schizosaccharomyces pombe by optimizing all three components: the AID degron, the small-molecule inducer, and the inducer-responsive F-box protein. We chose a 36-amino-acid sequence of the Arabidopsis IAA17 protein as the degron and employed three tandem copies of it to enhance efficiency. To minimize undesirable side effects of the inducer, we adopted a bulky analog of auxin, 5-adamantyl-IAA, and paired it with the F-box protein OsTIR1 that harbors a mutation (F74A) at the auxin-binding pocket. 5-adamantyl-IAA, when utilized with OsTIR1-F74A, is effective at concentrations thousands of times lower than auxin used in combination with wild-type OsTIR1. We tested our improved AID system on 10 essential genes and achieved inducible lethality for all of them, including ones that could not be effectively inactivated using a previously published AID system. Our improved AID system should facilitate the construction of conditional loss-of-function mutants in fission yeast.
Regulation of a bacterial histidine kinase by a phase separating scaffolding protein
Authors: Zhang Chao , Zhao Wei , Duvall Samuel W. , Kowallis Kimberly A. , Childers W. Seth 
Published: July 2021

AbstractScaffolding proteins customize the response of signaling networks to support cell development and behaviors. We investigated how the bacterial scaffolding protein PodJ regulates the histidine kinase PleC involved in the asymmetric cell division of Caulobacter crescentus. We reconstituted the PleC-PodJ signaling complex through both heterologous expression in E. coli and in vitro studies. In vitro PodJ phase separates as a biomolecular condensate that recruits and inhibits PleC kinase activity. By constructing an in vivo PleC-CcaS chimeric histidine kinase reporter assay, we have demonstrated how PodJ leverages its intrinsically disordered region (IDR) to bind and regulate PleC-CcaS signaling. Moreover, we observed that full-length PodJL regulates PleC-CcaS signaling, while a truncated PodJs could not regulate signaling activity. These results support a model where PodJ biomolecular condensate formation regulates the localization and activity of the cell fate determining kinase PleC.
Deficient thalamo-cortical networks dynamics and sleep homeostatic processes in a redox dysregulation model relevant to schizophrenia
Authors: Czekus C , Steullet P , Rusterholz T , Bozic I , Bandarabadi M , Do KQ , Herrera C Gutierrez 
Published: July 2021

AbstractA growing body of evidence implicates thalamo-cortical oscillations with the neuropathophysiology of schizophrenia (SZ) in both mice and humans. Yet, the precise mechanisms underlying sleep perturbations in SZ remain unclear. Here, we characterised the dynamics of thalamo-cortical networks across sleep-wake states in a mouse model carrying a mutation in the enzyme glutathione synthetase gene (Gclm-/-) associated with SZ in humans. We hypothesised that deficits in parvalbumin immunoreactive cells in the thalamic reticular nucleus (TRN) and the anterior cingulate cortex (ACC) - caused by oxidative stress - impact thalamocortical dynamics, thus affecting non-rapid eye movement (NREM) sleep and sleep homeostasis. Using polysomnographic recordings in mice, we showed that KO mice exhibited a fragmented sleep architecture, similar to SZ patients and altered sleep homeostasis responses revealed by an increase in NREM latency and slow wave activities during the recovery period (SR). Although NREM sleep spindle rate during spontaneous sleep was similar in Gclm-/- and Gcml +/+, KO mice lacked a proper homeostatic response during SR. Interestingly, using multisite electrophysiological recordings in freely-moving mice, we found that high order thalamic network dynamics showed increased synchronisation, that was exacerbated during the sleep recovery period subsequent to SD, possibly due to lower bursting activity in TRN-antero dorsal thalamus circuit in KO compared to WT littermates. Collectively, these findings provide a mechanism for SZ associated deficits of thalamo-cortical neuron dynamics and perturbations of sleep architecture.
GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing
Authors: Valls-Margarit Jordi , Galván-Femenía Iván , Matías-Sánchez Daniel , Blay Natalia , Puiggròs Montserrat , Carreras Anna , Salvoro Cecilia , Cortés Beatriz , Amela Ramon , Farre Xavier , Lerga-Jaso Jon , Puig Marta , Sánchez-Herrero Jose Francisco , Moreno Victor , Perucho Manuel , Sumoy Lauro , Armengol Lluís , Delaneau Olivier , Cáceres Mario , de Cid Rafael , Torrents David 
Published: July 2021

ABSTRACTThe combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression models, we present a catalogue of 35,431,441 variants, including 89,178 SVs (≥50bp), 30,325,064 SNVs and 5,017,199 indels, across 785 Illumina high coverage (30X) whole-genomes from the Iberian GCAT Cohort, containing 3.52M SNVs, 606,336 indels and 6,393 SVs in median per individual. The haplotype panel is able to impute up to 14,360,728 SNVs/indels and 23,179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.
Two circadian oscillators in one cyanobacterium
Authors: Köbler Christin , Schmelling Nicolas M. , Pawlowski Alice , Spät Philipp , Scheurer Nina M. , Sebastian Kim , Berwanger Lutz C. , Maček Boris , Wiegard Anika , Axmann Ilka M. , Wilde Annegret 
Published: July 2021

AbstractOrganisms from all kingdoms of life have evolved diverse mechanisms to address the predictable environmental changes resulting from the Earth’s rotation. The circadian clock of cyanobacteria is a particularly simple and elegant example of a biological timing mechanism for predicting daily changes in the light environment. The three proteins KaiA, KaiB, and KaiC constitute the central timing mechanism that drives circadian oscillations in the cyanobacteriumSynechococcus elongatusPCC 7942. In addition to the standard oscillator,Synechocystissp. PCC 6803, another model organism for cyanobacterial research, harbors several divergent clock homologs. Here, we describe a potential new chimeric KaiA homolog that we named KaiA3. At the N-terminus, KaiA3 is similar to the NarL-type response regulator receiver domain. However, its similarity to canonical NarL transcription factors drastically decreases in the C-terminal domain, which resembles the circadian clock protein, KaiA. In line with this, we detected KaiA3-mediated stimulation of KaiC3 phosphorylation. Phosphorylation of KaiC3 was rhythmic over 48 h in vitro in the presence of KaiA3 and KaiB3 as well as inSynechocystiscells under free-running conditions after light/dark entrainment. This results in the presence of two different oscillators in a single-celled prokaryotic organism. Deletion of thekaiA3gene leads to KaiC3 dephosphorylation and results in growth defects during mixotrophic growth and in the dark. In summary, we suggest that KaiA3 is a nonstandard KaiA homolog, thereby extending the KaiB3-KaiC3 system in Cyanobacteria and potentially other prokaryotes.
Growth and immunolocalisation of the brown alga Ectocarpus in a microfluidic environment
Authors: Charrier Bénédicte , Boscq Samuel , Nelson Bradley J. , Läubli Nino F. 
Published: July 2021

AbstractPDMS chips have proven to be suitable environments for the growth of several filamentous organisms. However, depending on the specimen, the pattern of growth and cell differentiation has been rarely investigated. We monitored the developmental pattern of the brown alga Ectocarpus inside a PDMS lab-on-chip. Two main methods of inoculation of the lab-on-chip were tested, i.e. by injection of spores or by insertion of sporophyte filaments into the chamber. Growth rate, growth trajectory, cell differentiation, and branching were the main development steps that were monitored for 20 days inside 25 μm or 40 μm parallel channels under standard light and temperature conditions. They were shown to be similar to those observed in non-constrained in-vitro conditions. Labelling of Ectocarpus cell wall polysaccharides – both with calcofluor for cellulose, and by immunolocalisation for alginates with monoclonal antibodies–showed expected patterns when compared to open space growth using either epifluorescence or confocal microscopy. Overall this article describes the experimental conditions for observing and studying the basic unaltered processes of brown algal growth using microfluidic technology, which provides the basis for future biochemical and biological research.
Plant-associated Pseudomonas aeruginosa harbor multiple virulence traits essential for mammalian infection
Authors: Ambreetha Sakthivel , Marimuthu Ponnusamy , Mathee Kalai , Balachandar Dananjeyan 
Published: July 2021

SummaryPseudomonas aeruginosa is a leading opportunistic pathogen capable of causing fatal infections in immunocompromised individuals and patients with degenerative lung diseases. Agricultural soil and plants are the vast reservoirs of this dreaded pathogen. However, there have been limited attempts to analyze the pathogenicity of P. aeruginosa strains associated with edible vegetable plants. This study aims to elucidate the virulence attributes of P. aeruginosa strains isolated from the rhizosphere and endophytic niches of cucumber, tomato, eggplant, and chili collected from agricultural fields. Virulence of the agricultural strains was compared to three previously characterized clinical isolates. Our results showed that 50% of the plant-associated strains formed significant levels of biofilm and exhibited swarming motility. Nearly 80% of these strains produced considerable levels of rhamnolipid and exhibited at least one type of lytic activity (hemolysis, proteolysis, and lipolysis). Their virulence was also assessed based on their ability to suppress the growth of plant pathogens (Xanthomonas oryzae, Pythium aphanidermatum, Rhizoctonia solani, and Fusarium oxysporum) and kill a select nematode (Caenorhabditis elegans). The plant-associated strains showed significantly higher virulence against the bacterial phytopathogen whereas the clinical strains had significantly higher antagonism against the fungal pathogens. In C. elegans slow-killing assay, the clinical strains caused 50-100% death while a maximum of 40% mortality was induced by the agricultural strains. This study demonstrates that some of the P. aeruginosa strains associated with edible plants harbor multiple virulence traits. Upon infection of humans or animals, these strains may evolve to be more pathogenic and pose a significant health hazard.
Immunogenic SARS-CoV2 Epitopes Defined by Mass Spectrometry
Authors: Pan Ke , Chiu Yulun , Huang Eric , Chen Michelle , Wang Junmei , Lai Ivy , Singh Shailbala , Shaw Rebecca , MacCoss Michael , Yee Cassian 
Published: July 2021

AbstractSARS-CoV-2 infections elicit both humoral and cellular immune responses. For the prevention and treatment of COVID19, the disease caused by SARS-CoV-2, T cell responses are important in mediating recovery and immune-protection. The identification of immunogenic epitopes that can elicit a meaningful T cell response can be elusive. Traditionally, this has been achieved using sophisticatedin silicomethods to predict putative epitopes; however, our previous studies find that ‘immunodominant’ SARS-CoV-2 peptides defined by suchin silicomethods often fail to elicit T cell responses recognizing SARS-CoV-2. We postulated that immunogenic epitopes for SARS-CoV-2 are best defined by directly analyzing peptides eluted from the peptide-MHC complex and then validating immunogenicity empirically by determining if such peptides can elicit T cells recognizing SARS-CoV-2 antigen-expressing cells. Using a tandem mass spectrometry approach, we identified epitopes of SARS-CoV-2 derived not only from structural but also non-structural genes in regions highly conserved among SARS-CoV-2 strains including recently recognized variants. We report here, for the first time, several novel SARS-CoV-2 epitopes from membrane glycol-protein (MGP) and non-structure protein-13 (NSP13) defined by mass-spectrometric analysis of MHC-eluted peptides, provide empiric evidence for their immunogenicity to induce T cell response.Significance StatementCurrent state of the art uses putative epitope peptides based onin silicoprediction algorithms to evaluate the T cell response among COVID-19 patients. However, none of these peptides have been tested for immunogenicity, i.e. the ability to elicit a T cell response capable of recognizing endogenously presented peptide. In this study, we used MHC immune-precipitation, acid elution and tandem mass spectrometry to define the SARS-CoV-2 immunopeptidome for membrane glycol-protein and the non-structural protein. Furthermore, taking advantage of a highly robust endogenous T cell (ETC) workflow, we verify the immunogenicity of these MS-defined peptides by in vitro generation of MGP and NSP13 peptide-specific T cells and confirm T cell recognition of MGP or NSP13 endogenously expressing cell lines.