bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mathematical model of the Alzheimer’s Disease biomarker cascade demonstrates statistical pitfalls in identifying neurobiological surrogates of cognitive reserve
Authors: Fischer Florian U. , Gerber Susanne , Tüscher Oliver ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

AbstractIntroductionIn order to investigate neurobiological surrogates of cognitive reserve, statistical interaction analyses have been put forward and used by several studies. However, as these neurobiological surrogates are potentially affected by neurodegeneration as part of the amyloid cascade, which is characterized by chronological time-moderated associations between biomarkers, cross sectional sampling in combination with the disregard of time as a confounder could introduce interaction effects that may be misinterpretabed as cognitive reserve in statistical analyses.MethodsWe modeled the amyloid cascade with a minimal set of three biomarkers amyloid load, corticospinal fluid tau, hippocampal volume and cognitive outcome using a differential equation system, whose parameters were estimated from empirical data from the ADNI. Interaction effects between pathology markers amyloid and tau with hippocampal volume as potential marker of cognitive reserve were estimated on two simulated data samples. Both samples were calculated from varying amyloid, tau and hippocampal volume for the initial configuration of individual trajectories. For Sample 1, data points were sampled at a fixed time after baseline. For Sample 2, data points were sampled at random time points.ResultsRegression analyses on Sample 1 yielded estimates for interaction effects of 0. For Sample 2, estimates were -.1692 and -.0807 for amyloid and tau with hippocampal volume, respectively. The interaction effect estimates for Sample 2 decreased several orders of magnitude when taking into account the timepoint of sampling.ConclusionStudies aiming to investigate neurobiological surrogates of cognitive reserve that are affected by Alzheimer’s Disease-related neurodegenerative processes need to consider inter-individually varying sampling time points in the data to avoid misinterpreting interaction effects.
Differential response ofSenna occidentalisL. to arsenic and cadmium contaminated soil
Authors: Lai Zoe , Datir Sagar , Weber Jacqueline , Belford Ebenezer , Regan Sharon 
Published: October 2023

AbstractWe investigated the phytoremediation potential ofSenna occidentalisL., a pantropical plant that has been associated with tolerance to heavy metal-contaminated soils around mining sites. Seedlings ofS. occidentaliswere exposed to cadmium chloride (CdCl2) and sodium arsenate (Na3AsO4) at concentrations of 200, 300, and 400 mg L-1under greenhouse conditions. Heavy metal tolerance was assessed by comparing biomass and stress indicators such as chlorophyll, proline, and hydrogen peroxide content. Arsenic treatment had more toxic effects than cadmium onSennaphysiology. Regardless of concentration of arsenic applied, the biomass decreased by 50% as compared to control and cadmium-treated plants. Chlorophyll content decreased with exposure to both heavy metals. Higher concentration of Cd and As (400 mg L-1) resulted in 50% reduction in chlorophyll content. Proline and hydrogen peroxide levels were higher in arsenic-treated plants compared to controls and cadmium-treated plants, indicating an enhanced stress response when exposed to arsenic. When heavy metal content was measured, there was a significant accumulation of arsenic in the leaves, stems, and roots, indicating that arsenic in these tissues was responsible for the profound changes in biomass, proline, and hydrogen peroxide content. In contrast, although significant, there was less cadmium uptake bySennaand tolerance can be seen, which was reflected by normal biomass, proline, and hydrogen peroxide levels. High translocation of metals from soil into roots and low translocation from root to shoot tissues suggests the potential forS. occidentalisto be used for phytostabilization of arsenic- and cadmium-contaminated soils.
Longitudinal single-cell data informs deterministic modelling of inflammatory bowel disease
Authors: Kilian Christoph , Ulrich Hanna , Zouboulis Viktor , Sprezyna Paulina , Schreiber Jasmin , Landsberger Tomer , Büttner Maren , Biton Moshe , Villablanca Eduardo J. , Huber Samuel , Adlung Lorenz 
Published: October 2023

ABSTRACTSingle-cell mRNA sequencing (scRNA-seq) allows deep molecular and cellular profiling of immunological processes. Longitudinal scRNA-seq datasets can be used for deterministic ordinary differential equation (ODE)-based modelling to mechanistically describe immune dynamics. Here, we derived longitudinal changes in the abundance of six colonic cell types during inflammatory bowel disease (IBD) from scRNA-seq data of a mouse model of colitis using ODE-based models. We then predicted the immune dynamics of a different mouse colitis protocol and confirmed these scRNA-seq-based predictions with our previously published single-cell-based flow cytometry data. We further hypothesised that the estimated model parameters reflect biological processes. We validated this prediction of cellular turnover rates with KI-67 staining and with gene expression information from the scRNA-seq data not used for model fitting. Finally, we tested the translational relevance of the model simulations by predicting genes indicative of treatment response in human IBD patients. The predictive power of IBD deterministic modelling from scRNA-seq data highlights its potential to advance our understanding of immune dynamics in health and disease.
Productive foraging sites enhance maternal health and impact offspring fitness in a capital breeding species
Authors: Fouda Leila , Negus Stuart R. B. , Lockley Emma C. , Fairweather Kirsten , Lopes Artur , Lopes Anice , Correia Sandra M. , Taxonera Albert , Schofield Gail , Eizaguirre Christophe 
Published: October 2023

AbstractFeeding ecology is an essential component of an organism’s life, but foraging comes with risks and energetic costs. Species in which populations exhibit more than one feeding strategy, such as sea turtles, are good systems for investigating how feeding ecology impacts life-history traits, reproduction and carried over effects across generations. Here, we investigated how the feeding ecology of loggerhead sea turtles (Caretta caretta) nesting at the Cabo Verde archipelago correlates with reproductive outputs and offspring fitness. We determined the feeding ecology of female turtles before and during the breeding season from stable isotope analysis of carbon and nitrogen, and correlated isotopic ratio with female and hatchling fitness traits. We found that female turtles feeding at higher trophic positions produced larger clutches. We also found that females with less depleted δ13C values, typical of productive foraging areas, had greater fat reserves, were less likely to be infected by leech parasites, and produced heavier offspring. The offspring of infected mothers with less depleted δ13C values performed best in crawling and self-righting trials than those of non-infected mothers with less depleted δ13C values. Overall, our study shows adult female loggerheads that exploit productive areas build capital reserves that impact their reproductive success and offspring fitness. Together, we uphold the suggestion that not all foraging habitats are equal, and can alter the fitness of populations.
The GIAB genomic stratifications resource for human reference genomes
Authors: Dwarshuis Nathan , Kalra Divya , McDaniel Jennifer , Sanio Philippe , Jerez Pilar Alvarez , Jadhav Bharati , Huang Wenyu (Eddy) , Mondal Rajarshi , Busby Ben , Olson Nathan D. , Sedlazeck Fritz J , Wagner Justin , Majidian Sina , Zook Justin M. 
Published: October 2023

AbstractStratification of the genome into different genomic contexts is useful when developing bioinformatics software like variant callers, to assess performance in difficult regions in the human genome. Here we describe a set of genomic stratifications for the human reference genomes GRCh37, GRCh38, and T2T-CHM13v2.0. Generating stratifications for the new complete CHM13 reference genome is critical to understanding improvements in variant caller performance when using this new complete reference. The GIAB stratifications can be used when benchmarking variant calls to analyze difficult regions of the human genome in a standardized way. Here we present stratifications in the CHM13 genome in comparison to GRCh37 and GRCh38, highlighting expansions in hard-to-map and GC-rich stratifications which provide useful insight for accuracy of variants in these newly-added regions. To evaluate the reliability and utility of the new stratifications, we used the stratifications of the three references to assess accuracy of variant calls in diverse, challenging genomic regions. The means to generate these stratifications are available as a snakemake pipeline athttps://github.com/ndwarshuis/giab-stratifications.
G51D mutation of the endogenous ratSncagene disrupts synaptic localisation of α-synuclein priming for Lewy-like pathology
Authors: West Stephen , Natalwala Ammar , Dolt Karamjit Singh , Lamont Douglas J. , McMillan Melanie , Luk Kelvin , Mashimo Tomoji , Kunath Tilo 
Published: October 2023

AbstractPoint mutations in theSNCAgene, encoding α-synuclein (αSyn), are a known cause of familial Parkinson’s disease. The G51D mutation causes early onset neurodegeneration with complex pathology. We used CRISPR/Cas9 in rats to introduce the G51D mutation into the endogenousSncagene. Co-localisation immunostaining studies with synaptic proteins showed that αSynG51Dprotein is no longer efficiently localised to synapses. Furthermore, biochemical isolation of synaptosomes from rat cortex demonstrated a significant depletion of αSyn inSncaG51D/+andSncaG51D/G51Drats. Unbiased proteomic investigation of the cortex identified significant synaptic dysregulation inSncaG51D/G51Danimals. Finally, we compared the propensity for Lewy-like pathology ofSnca+/+andSncaG51D/G51Drats by stereotaxically delivering αSyn pre-formed fibrils (PFFs) into the pre-frontal cortex. At an early time-point, 6 weeks post-injection, we observed discrete Lewy-like structures positive for phosphoserine-129-αSyn (pS129-αSyn) only inSncaG51D/G51Dbrains. At 26 weeks post-injection of PFFsSncaG51D/G51Dbrains exhibited intense, discrete pS129-αSyn-positive structures, whileSnca+/+brains exhibited diffuse pS129-αSyn immunostaining. Quantification of discrete pS129-αSyn-positive structures revealed the striatum ofSncaG51D/G51Drats had significantly more Lewy-like pathology thanSnca+/+rats. In summary, this novelSncaG51Drat model exhibits molecular characteristics of early synaptic dysfunction and is primed for αSyn pathology.
Molecular definition of distinct active zone protein machineries for Ca2+channel clustering and synaptic vesicle priming
Authors: Emperador-Melero Javier , Andersen Jonathan W. , Metzbower Sarah R. , Levy Aaron D. , Dharmasri Poorna A. , de Nola Giovanni , Blanpied Thomas A. , Kaeser Pascal S. 
Published: October 2023

SummaryAction potentials trigger neurotransmitter release with minimal delay. Active zones mediate this temporal precision by co-organizing primed vesicles with CaV2 Ca2+channels. The presumed model is that scaffolding proteins directly tether primed vesicles to CaV2s. We find that CaV2 clustering and vesicle priming are executed by separate machineries. At hippocampal synapses, CaV2 nanoclusters are positioned at variable distances from those of the priming protein Munc13. The active zone organizer RIM anchors both proteins, but distinct interaction motifs independently execute these functions. In heterologous cells, Liprin-α and RIM from co- assemblies that are separate from CaV2-organizing complexes upon co-transfection. At synapses, Liprin-α1-4 knockout impairs vesicle priming, but not CaV2 clustering. The cell adhesion protein PTPσ recruits Liprin-α, RIM and Munc13 into priming complexes without co- clustering of CaV2s. We conclude that active zones consist of distinct complexes to organize CaV2s and vesicle priming, and Liprin-α and PTPσ specifically support priming site assembly.
Annual risk of hepatitis E virus infection and seroreversion: insights from a serological cohort in Sitakunda, Bangladesh
Authors: Dighe Amy , Khan Ashraful Islam , Bhuiyan Taufiqur Rahman , Islam Md Taufiqul , Khan Zahid Hasan , Khan Ishtiakul Islam , Hulse Juan Dent , Ahmed Shakeel , Rashid Mamunur , Hossain Md Zakir , Rashid Rumana , Hegde Sonia , Gurley Emily S , Qadri Firdausi , Azman Andrew S 
Published: October 2023

AbstractHepatitis E virus (HEV) is a major cause of acute jaundice in South Asia. Gaps in our understanding of transmission are driven by non-specific symptoms and scarcity of diagnostics, impeding rational control strategies. In this context, serological data can provide important proxy measures of infection. We enrolled a population-representative serological cohort of 2337 individuals in Sitakunda, Bangladesh. We estimated the annual risks of HEV infection and seroreversion both using serostatus changes between paired serum samples collected 9 months apart, and by fitting catalytic models to the age-stratified cross-sectional seroprevalence. At baseline, 15% (95CI: 14-17%) of people were seropositive, with seroprevalence highest in the relatively urban south. During the study, 27 individuals seroreverted (annual seroreversion risk: 15%, 95CI: 10-21%), and 38 seroconverted (annual infection risk: 3%, 95CI: 2-5%). Relying on cross-sectional seroprevalence data alone, and ignoring seroreversion, underestimated the annual infection risk fivefold (0.6%, 95CrI: 0.5-0.6%). When we accounted for the observed seroreversion in a reversible catalytic model, infection risk was more consistent with measured seroincidence. Our results quantify HEV infection risk in Sitakunda and highlight the importance of accounting for seroreversion when estimating infection incidence from cross-sectional seroprevalence data.
Comparison of nasopharyngeal swab vs. lower respiratory tract specimen PCR for the diagnosis ofPneumocystis jiroveciipneumonia
Authors: Chew Rusheng , Tozer Sarah , Ulett Kimberly , Paterson David L. , Whiley David , Sloots Theo , Fielding David , Zappala Christopher , Bashirzadeh Farzad , Hundloe Justin , Bletchley Cheryl , Woods Marion L. 
Published: October 2023

AbstractBackground and objectiveDiagnosis ofP. jiroveciipneumonia (PJP) is by PCR on lower respiratory tract specimens, the collection of which is not always well-tolerated and requires trained staff and costly equipment not usually available in low-resource settings. We aimed to evaluateP. jiroveciiPCR performed on nasopharyngeal swabs (NPS) as a diagnostic test for PJP, as well as the impact of specimen quality on test performance.MethodsPatients with clinically-suspected PJP in public hospitals in Queensland, Australia, who had quantitativeP. jiroveciiPCR performed on lower respiratory tract specimens from 1 January 2015 to 31 December 2016, and also had NPS collected by healthcare staff within seven days of lower respiratory tract specimen collection were included in this retrospective cohort study. QuantitativeP. jiroveciiPCR was performed, and sensitivity, specificity, and positive and negative predictive values were calculated. Specimen quality was assessed by quantifying endogenous retrovirus 3 (ERV3) loads, with higher values indicating better specimen quality.ResultsOne hundred and eleven patients were included. The sensitivity of NPSP. jiroveciiPCR was 0.66 and specificity was 1.0. The positive predictive value was 1.0 and the negative predictive value was 0.63. Median ERV3 loads in lower respiratory tract specimens and NPS were not significantly different in true positive vs. true negative patients, but was significantly higher in true positives vs. false negatives (7.55×102vs. 3.67×102;P=0.05).ConclusionP. jiroveciiPCR on NPS was highly specific but poorly sensitive. Proper specimen collection is essential to ensure adequate quality and prevent misclassification.Summary at a GlanceUsing nasopharyngeal swabs instead of lower respiratory tract specimens for PCR to diagnoseP. jiroveciipneumonia (PJP) may be better tolerated and improve diagnostic accessibility. In this two-year retrospective cohort study of patients with clinically-suspected PJP from Queensland, Australia,P. jiroveciiPCR on NPS had high specificity but low sensitivity.
The epidemiology of antibiotic-resistant clinical pathogens in Uganda
Authors: Namusoosa Ritah , Mugerwa Ibrahimm , Kasozi Keneth Iceland , Muruta Allan , Najjuka Grace , Atuhaire Winifred D. , Nabadda Susan , Mwebesa Henry , Charlse Olaro , Ssewanyana Isaac , Ssemaganda Aloysious , Muwonge Adrian 
Published: October 2023

ABSTRACTBackgroundAntibiotic resistance (ABR) is silent global pandemic. Our current global control strategies are informed by evidence primarily from surveillance strategies. Here, we use a national surveillance dataset to demonstrate how such evidence can be systematically generated, in so doing we characterize ABR profiles of priority clinical pathogens and identify potential drivers in addition to inferences on antibiotic usage in Uganda.Resultsof the 12,262 samples cultured between 2019-2021, 9,033 with complete metadata were analyzed, Female patients accounted for 57.8% of the patients who were between 1 to 104 years. The isolated bacteria (69%) were clustered into twelve clinical pathogens and eight syndromes. This includedEscherichia coli26%(n=1620),Klebsiella spp.11% (n=685),Acinetobacter spp. 4%(n=250),Citrobacter spp. 4% (n=250),Pseudomonas spp. 3% (n=187), andEnterobacter spp. 2% (n=124), as well asSalmonella spp. 1% (n=62). Among gram-positive bacteria,Staphylococcus aureus10% (n=623),Enterococcus spp. 8% (n=498), andStreptococcus spp. 2% (n=124) were predominant.Acinetobacter baumanniiwas predominantly multi drug resistant (MDR) and mostly recovered from septic wound infection (SWI).Pseudomonas aeruginosa,Escherichia coli,Klebsiella pneumoniae, andStaphylococcus aureuswere also linked to ABR SWIs & urinary tract infections (UTIs). Male patients were more likely to carry ABR pathogens OR=1.14, 95% CI [1.12-1.42], p<0.001), within specific age groups (51-60, OR=1.16, 95% CI [0.88-1.28], p=0.001). Seasonality also influences ABR associated to clinical syndromes, for example, the second quarter, OR=2.1, 95% CI [1.9-2.6], p<0.001), is associated with resistance to narrow spectrum antibiotics OR=1,64, 95% CI [1.39-1.94], p<0.001) targeting respiratory tract infections (RTIs). ABR associated bloodstream infections (BSIs) were significantly more common than UTIs and RTIs.ConclusionsABR across clinical pathogens was increasing at a rate of 2.8% per year, with an upsurge in 2021. SWIs account for the disproportionately high prevalence of ABR and MDR mostly caused byAcinetobacter spp. Staphylococcus aureusincluding MRSA is main driver of BSIs. Male patients are far more likely to carry ABR in their adult life. Encouragingly, carbapenem resistance remains relatively low in-line with the predicted antibiotic use. Such evidence is critical for effective implementation and evaluation AMR National action plans, therefore national public health institutes (NPHIs) ought to invest in building capacity for surveillance and data analysis to support informed decision-making.
Proteomic Network Analysis of Alzheimer’s Disease Cerebrospinal Fluid Reveals Alterations Associated withAPOEε4 Genotype and Atomoxetine Treatment
Authors: Dammer Eric B. , Shantaraman Anantharaman , Ping Lingyan , Duong Duc M. , Gerasimov Ekaterina S. , Ravindran Suda Parimala , Gudmundsdottir Valborg , Frick Elisabet A. , Gomez Gabriela T. , Walker Keenan A. , Emilsson Valur , Jennings Lori L. , Gudnason Vilmundur , Western Daniel , Cruchaga Carlos , Lah James J. , Wingo Thomas S. , Wingo Aliza P. , Seyfried Nicholas T. , Levey Allan I. , Johnson Erik C.B. 
Published: October 2023

AbstractAlzheimer’s disease (AD) is currently defined at the research level by the aggregation of amyloid-β (Aβ) and tau proteins in brain. While biofluid biomarkers are available to measure Aβ and tau pathology, few biomarkers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here we describe the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aβ and tau pathology in 300 individuals as assessed by two different proteomic technologies—tandem mass tag (TMT) mass spectrometry and SomaScan. Harmonization and integration of both data types allowed for generation of a robust protein co-expression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 (APOEε4) AD risk genotype mapped to oxidant detoxification, mitogen associated protein kinase (MAPK) signaling, neddylation, and mitochondrial biology, and overlapped with a previously described lipoprotein module in serum. Neddylation and oxidant detoxification/MAPK signaling modules had a negative association withAPOEε4 whereas the mitochondrion module had a positive association withAPOEε4. The directions of association were consistent between CSF and blood in two independent longitudinal cohorts, and altered levels of all three modules in blood were associated with dementia over 20 years prior to diagnosis. Dual-proteomic platform analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module—the network module most strongly correlated to cognitive function—were reduced by ATX treatment. Individuals who had more severe glycolytic changes at baseline responded better to ATX. Clustering of individuals based on their CSF proteomic network profiles revealed ten groups that did not cleanly stratify by Aβ and tau status, underscoring the heterogeneity of pathological changes not fully reflected by Aβ and tau. AD biofluid proteomics holds promise for the development of biomarkers that reflect diverse pathologies for use in clinical trials and precision medicine.