bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Analysis of Within-Host Dynamics of Acute Infection and Viral Rebound Dynamics in Postnatally SHIV-Infected ART-Treated Infant Rhesus Macaques
Authors: Mainou Ellie , Berendam Stella J , Obregon-Perko Veronica , Uffman Emilie A , Phan Caroline T , Shaw George M , Bar Katharine J , Kumar Mithra R , Fray Emily J , Siliciano Janet M , Siliciano Robert F , Silvestri Guido , Permar Sallie R , Fouda Genevieve G , McCarthy Janice , Chahroudi Ann , Chan Cliburn , Conway Jessica M 
Published: May 2024

AbstractViral dynamics of acute HIV infection and HIV rebound following suspension of antiretroviral therapy may be qualitatively similar but must differ given, for one, development of adaptive immune responses. Understanding the differences of acute HIV infection and viral rebound dynamics in pediatric populations may provide insights into the mechanisms of viral control with potential implications for vaccine design and the development of effective targeted therapeutics for infants and children. Mathematical models have been a crucial tool to elucidate the complex processes driving viral infections within the host. Traditionally, acute HIV infection has been modeled with a standard model of viral dynamics initially developed to explore viral decay during treatment, while viral rebound has necessitated extensions of that standard model to incorporate explicit immune responses. Previous efforts to fit these models to viral load data have underscored differences between the two infection stages, such as increased viral clearance rate and increased death rate of infected cells during rebound. However, these findings have been predicated on viral load measurements from disparate adult individuals. In this study, we aim to bridge this gap, in infants, by comparing the dynamics of acute infection and viral rebound within the same individuals by leveraging an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Ten infant Rhesus macaques (RMs) orally challenged with SHIV.C.CH505 375H dCT and given ART at 8 weeks post-infection. These infants were then monitored for up to 60 months post-infection with serial viral load and immune measurements. We use the HIV standard viral dynamics model fitted to viral load measurements in a nonlinear mixed effects framework. We find that the primary difference between acute infection and rebound is the increased death rate of infected cells during rebound. We use these findings to generate hypotheses on the effects of adaptive immune responses. We leverage these findings to formulate hypotheses to elucidate the observed results and provide arguments to support the notion that delayed viral rebound is characterized by a stronger CD8+ T cell response.
Different orthology inference algorithms generate similar predicted orthogroups among Brassicaceae species
Authors: Liao Irene T. , Sears Karen E. , Hileman Lena C. , Nikolov Lachezar A. 
Published: May 2024

ABSTRACTPremise – Orthology inference is crucial for comparative genomics, and multiple algorithms have been developed to identify putative orthologs for downstream analyses. Despite the abundance of proposed solutions, including publicly available benchmarks, it is difficult to assess which tool to best use for plant species, which commonly have complex genomic histories.Methods – We explored the performance of four orthology inference algorithms – OrthoFinder, SonicParanoid, Broccoli, and OrthNet – on eight Brassicaceae genomes in two groups: one group comprising only diploids and another set comprising the diploids, two mesopolyploids, and one recent hexaploid genome.Results – Orthogroup compositions reflect the species’ ploidy and genomic histories. Additionally, the diploid set had a higher proportion of identical orthogroups. While the diploid+higher ploidy set had a lower proportion of orthogroups with identical compositions, the average degree of similarity between the orthogroups was not different from the diploid set.Discussion – Three algorithms – OrthoFinder, SonicParanoid, and Broccoli – are helpful for initial orthology predictions. Results from OrthNet were generally an outlier but could provide detailed information about gene colinearity. With our Brassicaceae dataset, slight discrepancies were found across the orthology inference algorithms, necessitating additional analyses, such as tree inference to fine-tune results.
Parkinson’s disease-associated alterations in DNA methylation and hydroxymethylation in human brain
Authors: Choza Juliana I. , Virani Mahek , Kuhn Nathan C. , Adams Marie , Kochmanski Joseph , Bernstein Alison I. 
Published: May 2024

AbstractEpigenetic mechanisms are mediators of interactions between aging, genetics, and environmental factors in sporadic Parkinson’s disease (PD). Multiple studies have explored the DNA modifications in PD, but few focus on 5-hydroxymethylcytosine (5-hmC), which is important in the central nervous system and sensitive to environmental exposures. To date, studies have not differentiated between 5-methylcytosine (5-mC) and 5-hmC or have analyzed them separately. In this study, we modeled paired 5-mC and 5-hmC data simultaneously. We identified 108 cytosines with significant PD-associated shifts between these marks in an enriched neuronal population from PD postmortem parietal cortex, within 83 genes and 34 enhancers associated with 67 genes. These data potentially link epigenetic regulation of genes related to LRRK2 and endolysosomal sort (RAB32andAGAP1), and genes involved in neuroinflammation, the inflammasome, and neurodevelopment with early changes in PD and suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes not captured by standard methods.
The effect of dipeptide repeat proteins on FUS/TDP43-RNA condensation in C9orf72 ALS/FTD
Authors: Driver Mark D. , Postema Jasper , Onck Patrick R. 
Published: May 2024

SUMMARYCondensation of RNA binding proteins (RBPs) with RNA is essential for cellular function. The most common familial cause of the diseases ALS and FTD are C9orf72 repeat expansion disorders that produce dipeptide repeat proteins (DPRs). We explore the hypothesis that DPRs disrupt the native condensation behaviour of RBPs and RNA through molecular interactions resulting in toxicity. FUS and TDP43 are two RBPs known to be affected in ALS/FTD. We use our previously developed 1-bead-per-amino acid and a newly developed 3-bead-per-nucleic acid molecular dynamics model to explore ternary phase diagrams of FUS/TDP43-RNA-DPR systems. We show that the most toxic arginine containing DPRs (R-DPRs), can disrupt the RBP condensates through cation-πinteractions, and can strongly sequester RNA through electrostatic interactions. The native droplet morphologies are already modified at small additions of R-DPRs leading to non-native FUS/TDP43-encapsulated condensates with a marbled RNA/DPR core.
Enhanced thermal stability enables human mismatch-specific Thymine-DNA glycosylase to catalyse futile DNA repair
Authors: Manapkyzy Diana , Joldybayeva Botagoz , Ishchenko Alexander A. , Matkarimov Bakhyt T. , Zharkov Dmitry O. , Taipakova Sabira , Saparbaev Murat K. 
Published: May 2024

AbstractHuman thymine-DNA glycosylase (TDG) excises T mispaired with G in a CpG context to initiate the base excision repair (BER) pathway. TDG is also involved in epigenetic regulation of gene expression by participating in active DNA demethylation. Here we demonstrate that under extended incubation time the full-length TDG (TDGFL), but not its truncated catalytic domain TDG (TDGcat) or methyl-binding protein 4 (MBD4) DNA glycosylase, exhibits a significant excision activity towards T and C in regular non-damaged DNA duplex in TpG/CpA and CpG/CpG contexts. Time course of the cleavage product generation under single-turnover conditions shows that the maximal rate of base excision (kobs) of TDGFL-catalysed excision of T in the T•A base pair (0.0014 – 0.0069 min-1) is 85 - 330-fold lower than that of T in T•G mismatch (0.47 – 0.61 min-1). Unexpectedly, TDGFL, but not TDGcat, exhibits prolonged enzyme stability under 37°C when incubated in the presence of equimolar concentration of non-specific DNA duplex, suggesting that the disordered N- and C-terminal domains of TDG can interact with DNA and stabilize the overall conformation of the protein. Noteworthy, TDGFLis able to excise 5-hydroxymethylcytosine (5hmC), but not 5-methylcytosine residues, from duplex DNA with the efficiency that could be physiologically relevant in post-mitotic cells. Our findings demonstrate that, under the experimental conditions used, TDG catalyses sequence context-dependent removal of T, C and 5hmC residues in regular DNA duplexes. We propose thatin vivothis futile DNA repair may lead to formation of persistent single-strand breaks in non-methylated regions of chromosomal DNA.
Haspin kinase binds to a nucleosomal DNA supergroove
Authors: Hicks Chad W. , Gliech Colin R. , Zhang Xiangbin , Rahman Sanim , Vasquez Stacy , Holland Andrew J. , Wolberger Cynthia 
Published: May 2024

AbstractPhosphorylation of histone H3 threonine 3 (H3T3) by Haspin recruits the chromosomal passenger complex to the inner centromere and ensures proper cell cycle progression through mitosis. The mechanism by which Haspin binds to nucleosomes to phosphorylate H3T3 is not known. We report here cryo-EM structures of the Haspin kinase domain bound to a nucleosome. In contrast with previous structures of histone-modifying enzymes, Haspin solely contacts the nucleosomal DNA, inserting into a supergroove formed by apposing major grooves of two DNA gyres. This unique binding mode provides a plausible mechanism by which Haspin can bind to nucleosomes in a condensed chromatin environment to phosphorylate H3T3. We identify key basic residues in the Haspin kinase domain that are essential for phosphorylation of nucleosomal histone H3 and binding to mitotic chromatin. Our structure is the first of a kinase domain bound to a nucleosome and is the first example of a histone-modifying enzyme that binds to nucleosomes solely through DNA contacts.
Linear models replicate the energy landscape and dynamics of resting-state brain activity
Authors: Hosaka Yuki , Hieda Takemi , Hayashi Kenji , Jimura Koji , Matsui Teppei 
Published: May 2024

AbstractThe spatiotemporal dynamics of resting-state brain activity can be characterized by switching between multiple brain states, and numerous techniques have been developed to extract such dynamic features from resting-state functional magnetic resonance imaging (fMRI) data. However, many of these techniques are based on momentary temporal correlation and co-activation patterns and merely reflect stationary, linear features of the data, suggesting that the non-stationary dynamic features extracted by these techniques may be misinterpreted. To examine whether such misinterpretations occur when using techniques that are not based on momentary temporal correlation or co-activation patterns, we addressed Energy Landscape Analysis (ELA), a statistical physics-inspired method that was designed to extract multiple brain states and dynamics of resting-state fMRI data. We found that the ELA-derived features were almost identical for real data and surrogate data suggesting that the features derived from ELA were accounted for by stationary and linear properties of the real data rather than non-stationary or non-linear properties. To confirm that surrogate data were distinct from the real data, we replicated a previous finding that some topological properties of resting-state fMRI data differed between the real and surrogate data. Overall, the present finding that the energy landscape and activity dynamics of resting-state fMRI data were well captured by stationary and linear surrogate data supports the notion that linear models sufficiently describe the dynamics of resting-state brain activity.
Quantification supports amyloid-PET visual assessment of challenging cases: results from the AMYPAD-DPMS study
Authors: Collij Lyduine E. , Bischof Gérard N. , Altomare Daniele , Bader Ilse , Battle Mark , Vállez García David , Lopes Alves Isadora , Wolz Robin , Gismondi Rossella , Stephens Andrew , Walker Zuzana , Scheltens Philip , Nordberg Agneta , Gispert Juan Domingo , Drzezga Alexander , Perissinotti Andrés , Morbelli Silvia , Buckley Christopher , Garibotto Valentina , Frisoni Giovanni B. , Farrar Gill , Barkhof Frederik 
Published: May 2024

ABSTRACTSeveral studies have demonstrated the high agreement between routine clinical visual assessment and quantification, suggesting that quantification approaches could support the assessment of less experienced readers and/or in challenging cases. However, all studies to date have implemented a retrospective case collection and challenging cases were generally underrepresented.MethodsIn this prospective study, we included all participants (N=741) from the AMYPAD Diagnostic and Patient Management Study (DPMS) with available baseline amyloid-PET quantification. Quantification was done with the PET-only AmyPype pipeline, providing global Centiloid (CL) and regional z-scores. Visual assessment was performed by local readers for the entire cohort. From the total cohort, we selected a subsample of 85 cases 1) for which the amyloid status based on the local reader’s visual assessment and CL classification (cut-off=21) was discordant and/or 2) that were assessed with a low confidence (i.e. ≤3 on a 5-point scale) by the local reader. In addition, concordant negative (N=8) and positive (N=8) scans across tracers were selected. In this sample, (N=101 cases: ([18F]flutemetamol,N=48; [18F]florbetaben,N=53) the visual assessments and corresponding confidence by 5 certified independent central readers were captured before and after disclosure of the quantification results.ResultsFor the AMYPAD-DPMS whole cohort, the overall assessment of local readers highly agreed with CL status (κ=0.85, 92.3% agreement). This was consistently observed within disease stages (SCD+: κ=0.82/92.3%; MCI: κ=0.80/89.8%; dementia: κ=0.87/94.6%). Across all central reader assessments in the challenging subsample, global CL and regional z-scores quantification were considered supportive of visual read in 70.3% and 49.3% of assessments, respectively. After disclosure of quantitative results, we observed an improvement in concordance between the 5 readers (κbaseline=0.65/65.3%; κpost-disclosure=0.74/73.3%) and a significant increase in reader confidence (Mbaseline=4.0 vs.Mpost-disclosure=4.34,W=101056,p<0.001).ConclusionIn this prospective study enriched for challenging amyloid-PET cases, we demonstrate the value of quantification to support visual assessment. After disclosure, both inter-reader agreement and confidence showed a significant improvement. These results are important considering the arrival of anti-amyloid therapies, which utilized the Centiloid metric for trial inclusion and target-engagement. Moreover, quantification could support determining Aβ status with high certainty, an important factor for treatment initiation.
Calmodulin variants in schizophrenia patients display gain-of-function or loss-of-function effects
Authors: Jensen Helene Halkjær , Brohus Malene , Hussey John W. , Busuioc Ana-Octavia , Iversen Emil Drivsholm , Darki Faezeh , Nikolova Gabriela Dobromirova , Baisgaard Amalie Elton , Rohde Palle Duun , Holm Ida Elisabeth Gad , McQuillin Andrew , Moos Torben , Dick Ivy E. , Overgaard Michael Toft , Nyegaard Mette 
Published: May 2024

AbstractCalmodulin acts as a vital calcium sensor in cells, crucial for relaying calcium signals to different protein partners. While rare missense variants in calmodulin are linked to cardiac arrhythmia, particularly long QT syndrome (LQTS), their role in schizophrenia remains unexplored. We investigated missense variants in the calmodulin-encoding genesCALM1-3in a large-scale sequencing effort involving 24,248 schizophrenia patients and 97,322 controls. Seven carriers were found among cases and twenty among controls. Notably, all schizophrenia variants affected the C-terminal lobe of the protein, compared to only five in controls, linking calmodulin C-lobe missense variants and schizophrenia risk (odds ratio 5.62,P=0.043). Functional analyses revealed two classes of calmodulin variants in schizophrenia: 1) loss-of-function variants that reduce calcium affinity and impair the interaction with voltage-gated calcium channel 1.2 (CaV1.2), akin to LQTS variants but with smaller effect size, and 2) gain-of-function variants that unexpectedly enhance calcium affinity with no impact on CaV1.2 gating. This study for the first time statistically and functionally links calmodulin missense variants to a neurological disorder, expanding the phenotypic spectrum of calmodulinopathies to include schizophrenia.SignificanceNeurons use calmodulin to monitor calcium signals and modulate hundreds of target proteins, thereby regulating key processes such as neuronal firing and memory and learning. Here, we link genetic variants in calmodulin to schizophrenia risk. Moreover, these genetic variants have divergent consequences for calmodulin protein function. Our results expand the current understanding of calmodulin variants, which are primarily reported in cardiac arrhythmia patients, and generally have a strong loss-of-function effect on the protein. We here provide the first identification and characterization of calmodulin variants in non-cardiac patients. This broadens our view of the physiological and functional consequences of human calmodulin variants and presents novel mechanistic entries to understanding the molecular mechanisms of schizophrenia.
The selective pressure induced by malaria vaccines onPlasmodium falciparum
Authors: Masserey Thiery , Lee Tamsin , Cavelan Aurélien , Neafsey Daniel E. , Malinga Josephine , Penny Melissa A 
Published: May 2024

AbstractAntigens ofPlasmodium falciparumtargeted by most current and future vaccines are generally not conserved. There are limited studies estimating the risk of parasite selection with vaccines. We adapted an individual-based model of malaria to assess which conditions favour genotypes having some degree of vaccine resistance and estimate the impact of resistance spread on vaccine effectiveness. Even parasite genotypes with low degrees of vaccine resistance are likely to spread relatively quickly if vaccines are implemented in children and even faster in a broader population. However, only highly resistant genotypes could strongly reduce vaccine effectiveness. These results highlight that it is essential to understand the degree to which genotypes exhibit reduced sensitivity to vaccines and monitor genotype frequency and vaccine effectiveness along with vaccine deployment. If some genotypes exhibit reduced efficacy to vaccines, our results further suggest that polyvalent or combination vaccines should be considered to limit resistance spread.
Approximating R1 and R2: a quantitative approach to clinical weighted MRI
Authors: Moskovich Shachar , Shtangel Oshrat , Mezer Aviv A. 
Published: May 2024

AbstractWeighted MRI images are widely used in clinical as well as open-source neuroimaging databases. Weighted images such as T1-weighted, T2-weighted, and proton density-weighted (T1w, T2w, and PDw, respectively) are used for evaluating the brain’s macrostructure; however, their values cannot be used for microstructural analysis, since they lack physical meaning. Quantitative MRI (qMRI) relaxation rate parameters (e.g., R1 and R2), and related relaxivity coefficients, do contain microstructural physical meaning.Nevertheless, qMRI is rarely done in large-scale clinical databases.Currently, the weighted images ratio T1w/T2w is used as a quantifier to approximate the brain’s microstructure. In this paper, we propose three additional quantifiers that approximate quantitative maps, which can help bring quantitative MRI to the clinic for easy use.Following the signal equations and using simple mathematical operations, we combine the T1w, T2w, and PDw images to estimate the R1 and R2.We find that two of these quantifiers (T1w/PDw and T1w/ln(T2w)) can serve as a semi-quantitative proxy for R1, and that (ln(T2w/PDw)) can approximate R2.We find that this approach also can be applied to T2w scans taken from widely available DTI datasets. We tested these quantifiers on bothin vitrophantom andin vivohuman datasets. We found that the quantifiers accurately represent the quantitative parameters across datasets. Finally, we tested the quantifiers within a clinical context, and found that they retain tissue information across datasets. Our work provides a simple pipeline to enhance the usability and quantitative accuracy of MRI weighted images.
Geospatial patterns and predictors of neonatal mortality among HIV infected and non-infected mothers of rural Zambia: A comparative analysis of the 2018 Zambia Demographic and Health Survey
Authors: Shumba Samson , Tembo Deborah , Simwaka Miyanda , Musonda Nedah Chikonde , Nkwemu Chipo , Mayimbo Sebean 
Published: May 2024

AbstractNeonatal mortality is the death of a live-born infant within the first 28 completed days of life. Neonatal mortality remains a major public health concern in most African countries, with the Sub-Saharan region being the highest contributor at 27 deaths per 1000 live births, accounting for 43% of the total number of deaths. Zambia still fares poorly in terms of neonatal mortality, ranking 162 out of 195 countries globally. The study aimed to investigate the spatial patterns and predictors of neonatal mortality in rural Zambia. This study utilized the national-level data from the Zambia Demographic and Health Survey (ZDHS) program, utilizing the survey dataset from 2018. Statistical analyses were conducted using the Rao – Scott Chi-square test to assess associations between dependent and independent variables. Additionally, a multilevel mixed effect logistic regression model was used to examine predictors of neonatal mortality. Geospatial patterns of neonatal mortality across Zambia’s ten provinces were investigated using Quantum Geographical Information System (QGIS) version 3.34.1 to generate a univariate choropleth map. Data analysis was performed using Stata version 14.2. The study findings indicate a higher mortality rate among HIV-infected mothers aged 45 to 49 (100%) compared to 95.21% among non-HIV-infected mothers. Neonatal mortality was notably elevated among neonates born to mothers with no education (40.78%) and those with HIV infection (54.56%). Employment status also influenced mortality rates, with employed non-HIV-infected mothers showing 36.35% mortality compared to 49.39% among unemployed HIV-infected mothers. Higher birth weights, particularly 4000 grams or higher, were associated with increased mortality for both HIV-infected (81.15%) and non-infected (21.00%) mothers. Multilevel logistic regression identified predictors of mortality, including maternal age (40 to 44 years), neonate’s sex (female), and maternal HIV status. Geospatial analysis revealed Eastern and North-Western provinces as hotspots for neonatal mortality among HIV-infected mothers, while Muchinga was a hotspot for non-HIV-infected mothers. This study examined neonatal mortality among HIV-infected and non-infected mothers in rural Zambia, uncovering predictors such as maternal age, neonate sex, birthweight, maternal HIV status, and community desired number of children. Regional variations in mortality underscore the necessity for targeted interventions. Strengthening healthcare infrastructure, community outreach, healthcare worker training, maternal education, and addressing regional differences are crucial for improving maternal and child health and meeting Sustainable Development Goals targets.