bluuebunny/crossref_metadata_2025 huggingface dataset:
Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models
Authors: Sedki Mai , Kwong Allison , Bhargava Meera , Ahmed Aijaz , Daugherty Tami , Kwo Paul , Dronamraju Deepti , Kumari Radhika , Kim W. Ray , Esquivel Carlos , Melcher Marc , Bonham C. Andrew , Gallo Amy , Nelson Ashly , Norwood Amanda , Hussain Filza , Goel Aparna
Published: October 2023

Background.

The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse.

Methods.

A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared.

Results.

Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%).

Conclusions.

AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.
A Pilot Randomized Controlled Trial of De Novo Belatacept-based Immunosuppression After Lung Transplantation
Authors: Huang Howard J. , Schechtman Kenneth , Askar Medhat , Bernadt Cory , Mitter Brigitte , Dore Peter , Goodarzi Ahmad , Yau Simon , Youssef J. Georges , Witt Chad A. , Byers Derek E. , Vazquez-Guillamet Rodrigo , Halverson Laura , Nava Ruben , Puri Varun , Kreisel Daniel , Gelman Andrew E. , Hachem Ramsey R.
Published: October 2023

Background.

Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. The development of donor-specific antibodies (DSA) is a recognized risk factor for CLAD. Based on experience in kidney transplantation, we hypothesized that belatacept, a selective T-cell costimulatory blocker, would reduce the incidence of DSA after lung transplantation, which may ameliorate the risk of CLAD.

Methods.

We conducted a pilot randomized controlled trial (RCT) at 2 sites to assess the feasibility and inform the design of a large-scale RCT. All participants were treated with rabbit antithymocyte globulin for induction immunosuppression. Participants in the control arm were treated with tacrolimus, mycophenolate mofetil, and prednisone, and participants in the belatacept arm were treated with tacrolimus, belatacept, and prednisone through day 89 after transplant then converted to belatacept, mycophenolate mofetil, and prednisone for the remainder of year 1.

Results.

After randomizing 27 participants, 3 in the belatacept arm died compared with none in the control arm. As a result, we stopped enrollment and treatment with belatacept, and all participants were treated with standard-of-care immunosuppression. Overall, 6 participants in the belatacept arm died compared with none in the control arm (log rank P = 0.008). We did not observe any differences in the incidence of DSA, acute cellular rejection, antibody-mediated rejection, CLAD, or infections between the 2 groups.

Conclusions.

We conclude that the investigational regimen used in this pilot RCT is associated with increased mortality after lung transplantation.
Staphylococcus Great Britain and Ireland 2023 (StaphGBI 2023) Conference Report
Authors: O'Gara James P. , Zeden Merve Suzan
Published: October 2023

Established in 1999, StaphGBI brings together the Staphylococcus research community in the UK and Ireland. The first meetings in this series were hosted by Prof Simon Foster at University of Sheffield in 1997 and 1999, followed by University of Leicester (2001), University of Liverpool (2006), University of Leeds (2008), University of Edinburgh (2011), Trinity College Dublin (2013), University of Reading (2015), Swansea University (2017), University of Warwick (2019) and University of Sheffield (2021). The 2023 conference, hosted by University of Galway for the first time on June 22nd and 23rd, was co-chaired by Dr Merve S. Zeden and Prof James P. O’Gara supported by a local organising committee of Chloe Hobbs-Tobin, Dr Rakesh Roy, Órla Burke and Aaron Nolan. Anchored by a keynote lecture from a leading expert, all other StaphGBI conference oral and post presentations are delivered by early career researchers. StaphGBI 2023 in Galway attracted approximately 100 delegates including 72 MRes/PhD students and postdoctoral fellows, 22 principal investigators and 4 exhibitors.
Rosace: a robust deep mutational scanning analysis framework employing position and mean-variance shrinkage
Authors: Rao Jingyou , Xin Ruiqi , Macdonald Christian , Howard Matthew , Estevam Gabriella O. , Yee Sook Wah , Wang Mingsen , Fraser James S. , Coyote-Maestas Willow , Pimentel Harold
Published: October 2023

Deep mutational scanning (DMS) enables functional insight into protein mutations with multiplexed measurements of thousands of genetic variants in a protein simultaneously. The small sample size of DMS renders classical statistical methods ineffective, for example, p-values cannot be correctly calibrated when treating variants independently. We proposeRosace, a Bayesian framework for analyzing growth-based deep mutational scanning data.Rosaceleverages amino acid position information to increase power and control the false discovery rate by sharing information across parameters via shrinkage. To benchmarkRosaceagainst existing methods, we developedRosette, a simulation framework that simulates the distributional properties of DMS. Further, we show thatRosaceis robust to the violation of model assumptions and is more powerful than existing tools underRosettesimulation and real data.
A female heterogametic ZW sex-determination system in Acariformes
Authors: Wulsch Svenja , Öztoprak Hüsna , Guiglielmoni Nadège , Jeffries Daniel L. , Bast Jens
Published: October 2023

Sexual reproduction, while often associated with separate sexes, is an ancient and widespread feature of multicellular eukaryotes. While a diversity of sex-determination mechanisms exist, for many organisms, which of these mechanisms is used remains unknown. Exploring sex-determination mechanisms in Acariformes, among the oldest chelicerate clades, is intriguing due to its potential to unveil conserved sex-determination systems. This insight can have implications for understanding sex chromosome evolution and its broader impact on higher taxa.To identify the mechanism of sex determination in Acari, i.e., oribatid mites, we generated a high-quality chromosome-level genome assembly ofHermannia gibba(Koch, 1839) by combining PacBio HiFi and Hi-C sequencing. Coverage and allele-frequency analyses on pools of male and female individuals suggest a female-heterogametic ZW sex-determination system with little degeneration of the W chromosome. To date, this represents the only documented case of a ZW system in Acariformes. Further comparative studies in H.gibbawill reveal how old the ZW system is and whether it exhibits conservation or polymorphism.
A novel Bayesian model for assessing intratumor heterogeneity of tumor infiltrating leukocytes with multi-region gene expression sequencing
Authors: Yang Peng , Hubert Shawna M. , Futreal P. Andrew , Song Xingzhi , Zhang Jianhua , Lee J. Jack , Wistuba Ignacio , Yuan Ying , Zhang Jianjun , Li Ziyi
Published: October 2023

Intratumor heterogeneity (ITH) of tumor-infiltrated leukocytes (TILs) is an important phenomenon of cancer biology with potentially profound clinical impacts. Multiregion gene expression sequencing data provide a promising opportunity that allows for explorations of TILs and their intratumor heterogeneity for each subject. Although several existing methods are available to infer the proportions of TILs, considerable methodological gaps exist for evaluating intratumor heterogeneity of TILs with multi-region gene expression data. Here, we develop ICeITH,immunecellestimation revealsintratumorheterogeneity, a Bayesian hierarchical model that borrows cell type profiles as prior knowledge to decompose mixed bulk data while accounting for the within-subject correlations among tumor samples. ICeITH quantifies intratumor heterogeneity by the variability of targeted cellular compositions. Through extensive simulation studies, we demonstrate that ICeITH is more accurate in measuring relative cellular abundance and evaluating intratumor heterogeneity compared with existing methods. We also assess the ability of ICeITH to stratify patients by their intratumor heterogeneity score and associate the estimations with the survival outcomes. Finally, we apply ICeITH to two multi-region gene expression datasets from lung cancer studies to classify patients into different risk groups according to the ITH estimations of targeted TILs that shape either pro- or anti-tumor processes. In conclusion, ICeITH is a useful tool to evaluate intratumor heterogeneity of TILs from multi-region gene expression data.
Bioactive coatings on 3D printed scaffolds for bone regeneration: Use of Laponite™ to deliver BMP-2 for bone tissue engineering – progression throughin vitro, chorioallantoic membrane assay and murine subcutaneous model validation
Authors: Marshall Karen. M. , Wojciechowski Jonathan P. , Echalier Cécile , Callens Sebastien J. P. , Yang Tao , Øvrebø Øystein , Jayawarna Vineetha , Kanczler Janos M. , Stevens Molly M. , Dawson Jonathan I. , Oreffo Richard O.C.
Published: October 2023

Fracture non-union occurs as a consequence of various factors, leading to the development of potentially substantial bone defects. Biomaterial-based approaches for bone regeneration aim to explore alternative strategies to repair non-healing fractures and critical-sized bone defects. Thus, rigorous assessment of the ability to translate biomaterials towards clinical use is vital. Growth factors induce an effect on cells to change their phenotype, behaviour and initiate signalling pathways, leading to an effect on matrix deposition and tissue formation. Bone morphogenetic protein-2 (BMP-2) is a potent osteogenic growth factor, with a rapid clearance timein vivonecessitating clinical use of high doses, with potential deleterious side-effects. This work explored the potential for Laponite™ nanoclay coating of poly(caprolactone) trimethacrylate (PCL-TMA900) scaffolds to bind BMP-2 for enhanced osteoinduction.In vitroexperiments confirmed the cytocompatibility of the PCL-TMA900 scaffolds and effective osteogenic differentiation of C2C12 myoblast cells in response to the Laponite/BMP-2 coating. The chorioallantoic membrane (CAM) assay verified PCL-TMA900 scaffold material biocompatibility and ability to support angiogenesis. A murine subcutaneous implantation model assessed heterotopic bone formation in response to the Laponite/BMP-2 coating, when used immediately post-coating and after 24 hours of room temperature storage, to evaluate a delayed use manner. The Laponite/BMP-2 coated PCL-TMA900 scaffolds implanted showed consistent, significant bone formation over the study period compared to the uncoated PCL-TMA 900 scaffold and BMP-2 only coated control scaffoldsin vivo, indicating the ability of Laponite to bind the BMP-2 to the PCL-TMA900 scaffold. Bone formed peripherally around the Laponite/BMP-2 coated scaffold, with no aberrant bone formation observed. The Laponite/BMP-2 coating was found to retain its bioactivity after storage for 24 hours prior to usein vivo, however this was not to the same volume or reliability of bone formation as when used immediately post-coating. To take these studies forward, the Laponite/BMP-2 coating warrants examination in a critical-sized bone defect model to assess efficacy in an osseous site.
Multimodal fusion of brain signals for robust prediction of psychosis transition
Authors: Reinen Jenna M. , Polosecki Pablo , Castro Eduardo , Corcoran Cheryl M. , Cecchi Guillermo , Colibazzi Tiziano
Published: October 2023

Psychosis symptoms are often evident before diagnosis, suggesting the underlying biology of high-risk status may predict later disease outcomes. However, a single predictor remains unknown, indicating a need for algorithms that integrate complex information. Here, to identify risk and psychosis conversion, we implemented multiple kernel learning (MKL), a multimodal machine learning approach allowing patterns from each modality to inform each other. Baseline multimodal scans (n=74, 11 converters) included structural, resting-state functional imaging, and diffusion-weighted data. Multimodal MKL outperformed unimodal models (AUC=0.73 vs. 0.66 in predicting conversion). Moreover, patterns learned by MKL were robust to training set variations, suggesting it can identify cross-modality redundancies and synergies to stabilize the predictive pattern. We identified many predictors consistent with the literature, including frontal cortices, cingulate, thalamus, and striatum. This highlights the advantage of methods that leverage the complex pathophysiology of psychosis.
Decomposing the effects of α-tACS on brain oscillations and aperiodic 1/f activity
Authors: Kasten Florian H. , Lattmann René , Strüber Daniel , Herrmann Christoph S.
Published: October 2023

Background

Aftereffects of transcranial alternating current stimulation (tACS) are usually analyzed with a focus on the individual frequency band, thereby neglecting broadband spectral components. Recently, it was shown that the broadband spectrum, which exhibits a 1/f-like characteristic, is functionally relevant.

Objective/Hypothesis

The goal of this study was a spectral parameterization of brain activity into oscillatory alpha activity and aperiodic 1/f components before and after tACS and sham stimulation. It was expected that the broadband spectrum will not be differentially influenced by 20-min of tACS at individual α-frequency (IAF) in comparison to sham. Additionally, it was expected that the tACS aftereffect on the α-band can still be observed, even when controlling for 1/f activity differences.

Methods

We performed a re-analysis of a recently published resting-state tACS-magnetoencephalography (MEG) data set. Parameterization of the frequency spectrum was computed with the fitting-oscillations-and-one-over-F (FOOOF) algorithm. The intercept as well as the slope parameter of the aperiodic 1/f fit was extracted. Data was analyzed in sensor space with a focus on magnetometers. Comparison of changes in α-band power and 1/f activity was performed with non-parametric cluster-based random permutation tests.

Results

The tACS aftereffect survived the 1/f-correction. The previously observed natural rise in alpha oscillations over time independent of experimental conditions could not be replicated. However, differences in aperiodic parameters over time were observed. Especially, the intercept parameter increased from pre to post stimulation to a similar degree in both conditions.

Conclusion

It is imperative to correct for the aperiodic 1/f spectral component when analyzing aftereffects of brain stimulation on brain oscillations.
PCMD: A Multilevel Comparison Database of Intra- and Cross-species Metabolic Profiling in 530 Plant Species
Authors: Hu Yue , Ruan Yao , Zhao Xin-Le , Jiang Feng , Zhu Qiang , Zhang Qing-Ye , Yang Qing-Yong
Published: October 2023

Comparative metabolomics plays a crucial role in understanding gene function, exploring metabolite evolution, and improving crop genetic breeding. However, a systematic platform for comparing intra- and cross-species metabolites is currently lacking. In this study, we present the plant comparative metabolome database (PCMD;http://yanglab.hzau.edu.cn/PCMD), a comprehensive multi-level comparison database encompassing intra- and cross-species metabolic profiling in 530 plants. Remarkably, PCMD offers a multi-level platform for comparative metabolite analysis, allowing for the examination of metabolite characteristics across species at various levels including species, metabolites, pathways, and biological taxonomy. In addition, PCMD standardizes metabolite numbering, establishing a uniform system based on existing metabolite-related databases. The database also provides a range of user-friendly online tools, such as Species-comparison, Metabolites-enrichment, and ID conversion, enabling users to perform comparisons and enrichment analyses of metabolites across different species. PCMD stands out as the most comprehensive and species-rich comparative plant metabolomics database currently available, as demonstrated by two case studies that highlight its ability to supplement phylogenetic similarity mining among species through phylogenetic trees and offer new insights into the diversity and species-specificity of metabolites.
ZNF865 Regulates Senescence and Cell Cycle for Applications to Cell Engineering and Gene Therapy
Authors: Levis Hunter , Lewis Christian , Stockham Elise , Weston Jacob , Lawal Ameerah , Lawrence Brandon , Gullbrand Sarah E. , Bowles Robby D.
Published: October 2023

Zinc finger (ZNF) proteins represent the largest group of regulatory proteins within eukaryotic genomes. However, despite their broad regulatory function, the majority of ZNF protein function remains unknown. Recently, we discovered ZNF865, which has no in-depth publications and has not been functionally characterized. Utilizing CRISPR-guided gene modulation, we show that ZNF865 regulates key cellular and molecular processes associated with healthy cell function by primarily regulating cellular senescence, cell cycle progression, and protein processing. As a result, regulating this gene acts as a primary titratable regulator of cell activity, and we demonstrate the potential of targeted ZNF865 regulation as a tool to control senescence and protein production in multiple clinically relevant cell types for cell engineering/tissue engineering/gene therapy applications. We demonstrate its ability to rescue human senescent cell populations, boost T-cell activity, and dramatically deposit more cartilaginous tissue in a whole organ tissue-engineered intervertebral disc. Overall, we present novel biology and regulatory mechanisms of senescence and cell cycle that were previously unknown and display the power of CRISPR-cell engineering to enhance cell engineering strategies treating disease.
X-chromosome inactivation in human iPSCs provides insight into escape-regulated gene expression
Authors: Topa Hande , Benoit-Pilven Clara , Tukiainen Taru , Pietiläinen Olli
Published: October 2023

Epigenetic variation in the X chromosome inactivation (XCI) of human induced pluripotent stem cells (hiPSCs) can impact their ability to accurately model biological sex biases. However, the gene-wise landscape of escape from XCI remains unresolved in female hiPSCs. To characterize the patterns of escape from inactivation, we performed a systematic survey of allele specific expression (ASE) in 165 female hiPSC lines. The analysis revealed that the escape from XCI was non-random and affected primarily genes that escape also in human tissues. However, individual genes and cell lines varied in the frequency and degree of escape. The escape increased gradually after modest decrease ofXISTin cultures, whose loss is commonly used to mark lines with eroded XCI. We identified three clusters of female lines at different stages of XCI. The increased degree of escape from XCI amplified female-biased expression and reduced male-female differences in genes with male-biased expression in the X chromosome. In autosomes, the increased escape modified genuine sex differences in a dose-dependent way suggesting that escape from XCI directly regulated autosomal gene expression. The variation in escape was sufficient to compensate for a dominant loss of function effect in several disease genes. The study presents a comprehensive view of escape from XCI in hiPSCs and emphasizes the need to monitor the XCI status at gene level for disease modeling. It further suggests that the uncommon and variable escape in hiPSCs can provide insight into X chromosome’s role in regulating gene expression and sex differences in humans.
Assessing the impact of 20th century internal migrations on the genetic structure of Estonia
Authors: Kuznetsov Ivan A. ,   Estonian Biobank Research Team, Metspalu Mait , Vainik Uku , Pagani Luca , Montinaro Francesco , Pankratov Vasili
Published: October 2023

Spatial genetic structure observed in many human populations is in large part attributed to past demographic events and isolation by distance. However, how intensifying migration affects this structure remains understudied. Here we harness a sample of more than 180 thousand individuals to explore the genetic correlates and consequences of contemporary migrations in Estonia. While we show that migration smoothens the genome-wide genetic structure, it intensifies inter-regional differences in polygenic scores (PGS) for certain traits, derived both from population as well as within-sibship studies. The strongest effect is observed for educational attainment which is consistent with previous observations in the UK and suggests this to be a general pattern. We explore those regional differences in PGS in terms of the driving forces behind them and from a temporal perspective, and suggest urbanisation as a major driver for this pattern in Estonia from at least the first half of the 20th century.
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

Introduction

In 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.

Methods

We 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.

Results

Regression 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.

Conclusion

Studies 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

We 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

Single-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

Feeding 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

Stratification 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

Point 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

Action 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

Hepatitis 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

Background and objective

Diagnosis 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.

Methods

Patients 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.

Results

One 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).

Conclusion

P. jiroveciiPCR on NPS was highly specific but poorly sensitive. Proper specimen collection is essential to ensure adequate quality and prevent misclassification.

Summary at a Glance

Using 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

Background

Antibiotic 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.

Results

of 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.

Conclusions

ABR 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

Alzheimer’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.
Effect of Behaviourally Informed Text Messages to Promote Retention in HIV Care: A Randomized Trial in Ekurhuleni District, South Africa
Authors: Govathson Caroline , Pascoe Sophie , Chetty-Makkan Candice , Schmucker Laura , Mistri Preethi , Thirumurthy Harsha , Mabuto Tonderai
Published: October 2023

Introduction

Sustained engagement in care among people living with HIV is vital for realising the individual and public health benefits of antiretroviral therapy (ART). We examined whether mobile phone-based text messages that leveraged behavioural science principles promoted timely clinic attendance among ART recipients.

Methods

We conducted a randomized controlled trial in three primary health clinics in Gauteng Province, South Africa between July 2021 and December 2021. ART recipients with an upcoming clinic appointment were randomised to standard of care appointment reminders or three enhanced reminders that leveraged behavioural science principles of loss aversion, social norms, and altruism. The primary outcome was a timely clinic visit, on or before the scheduled appointment day. Poisson regression with clinic fixed effects and controls for age, sex, and ART duration was used to examine the effect of the enhanced reminders on the primary outcome.

Results

Among 1539 participants, 690 (44.8%) were male and median time on ART was 11 months (IQR, 3.7-51.9). The primary outcome of timely clinic visit was 50.3% in the standard of care arm, and similar in the loss aversion arm (53.5%; adjusted risk ratio, ARR 1.1; 95% CI: 0.9-1.2), social norms arm (48.0%; ARR 1.1; 95% CI: 0.8-1.1), and altruism arm (50.9% ARR 1.0; 95% CI: 0.9-1.5). In subgroup analyses, messages framed with loss aversion increased the timely clinic visits among participants with ART duration <90 days (ARR=1.37; 95% CI: 1.08-1.74).

Conclusions

The use of behavioural science principles to frame reminder messages did not increase timely clinic visits among HIV care recipients. Among those who recently initiated ART, however, loss aversion framing increased timely clinic visits. Future research should explore alternative behavioural science principles to revise health communication with HIV care recipients.

Clinical Trials Number

NCT05010291