bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct Plasma Protein Profiles Distinguish Faster from Slower Disease Progression in HIV-1 and HIV-2 infections
Authors: Johansson Emil , Nazziwa Jamirah , Freyhult Eva , Hong Mun-Gwan , Neptin Malin , Karlson Sara , Rezeli Melinda , da Silva Zacarias J. , Biague Antonio J. , Lindman Jacob , Palm Angelica , Medstrand Patrik , Månsson Fredrik , Norrgren Hans , Jansson Marianne , Esbjörnsson Joakim ,   the SWEGUB CORE group
Published: July 2024

ABSTRACTThe asymptomatic disease stage in HIV-2 infection is approximately twice as long compared to in HIV-1 infection, still the majority of HIV-2 infected individuals progress to AIDS in the absence of antiretroviral treatment. In this study, we applied data-independent acquisition mass spectrometry analysis of blood plasma samples collected from HIV negative, and HIV-1 or HIV-2 infected individuals in Guinea-Bissau with an estimated date of HIV infection, to explore associations between plasma proteome alterations and HIV disease progression. In total, 609 proteins were quantified and mapped towards publicly available data on tissue-enhanced genes, to provide insight on the tissue-specific origin of the detected proteins. Here we identified ten proteins that could differentiate between faster and slower HIV disease progression. The analysis also suggested a larger leakage of proteins from the sigmoid colon in HIV-1 compared to HIV-2 infection. Moreover, the levels of sigmoid colon and spleen tissue proteins were associated with disease progression among all HIV infected individuals. In conclusion, these results encourage further research on the role of both target and bystander cells in HIV disease progression.
Sex differences in circulating metabolites across glycemic status and risk of coronary heart disease
Authors: Yoshida Yilin , Li Danting , Li Xiang , Fonseca Vivian A. , Qi Lu , Mauvais-Jarvis Franck 
Published: July 2024

AbstractBackgroundWomen with type 2 diabetes (T2D) have a 50% excess risk of coronary heart disease (CHD) than men with T2D. We compared circulating metabolites and their associations with CHD in men and women across glycemic status.MethodsWe used metabolomic data (lipoproteins, fatty acids, amino acids, glycolysis, ketones, inflammation, and fluid balance) for 87,326 CHD-free UK Biobank participants. We used linear regressions to examine the association of sex and metabolites (log) in newly diagnosed T2D (diagnosis<2 yrs from baseline), prediabetes (A1c 5.7-6.5%), and euglycemia, accounting for age, race, Deprivation Index, income, smoking, alcohol drinking, obesity, physical activity, medications for hypertension, hyperlipidemia, and diabetes. We used Cox models to evaluate the association of metabolites and CHD risk by sex, adjusting the same covariates and menopausal status (women). All analyses were FDR-adjusted.FindingsWe included 1250 individuals with new T2D, 12,706 with prediabetes, and 83,315 with euglycemia. In adjusted linear regressions, women showed a progressive increase in atherogenic lipid and lipoprotein markers and inflammatory marker, glycoprotein acetyls, compared to men as their glycemic status advanced. However, women had lower levels of albumin during this transition. Menopausal status did not alter these sex differences. In a 10-year follow-up, an SD higher total TG, TG in VLDL, LDL, and HDL, saturated fatty acids (SFA) were positively associated with a higher risk of CHD in women with T2D but not in men (p-interactions 0.03-0.15).InterpretationWith advancing glycemic status, women exhibited higher levels of atherogenic lipids and lipoproteins, as well as inflammatory markers, but lower circulating albumin. Women with T2D appear to be at a higher risk of CHD associated with TG, VLDL-TG, LDL-TG, and HDL-TG, and SFA than men with T2D.
Towards Treatment Effect Interpretability: A Bayesian Re-analysis of 194,129 Patient Outcomes Across 230 Oncology Trials
Authors: Sherry Alexander D. , Msaouel Pavlos , Kupferman Gabrielle S. , Lin Timothy A. , Jaoude Joseph Abi , Kouzy Ramez , El-Alam Molly B. , Patel Roshal , Koong Alex , Lin Christine , Passy Adina H. , Miller Avital M. , Beck Esther J. , Fuller C. David , Meirson Tomer , McCaw Zachary R. , Ludmir Ethan B. 
Published: July 2024

ABSTRACTMost oncology trials define superiority of an experimental therapy compared to a control therapy according to frequentist significance thresholds, which are widely misinterpreted. Posterior probability distributions computed by Bayesian inference may be more intuitive measures of uncertainty, particularly for measures of clinical benefit such as the minimum clinically important difference (MCID). Here, we manually reconstructed 194,129 individual patient-level outcomes across 230 phase III, superiority-design, oncology trials. Posteriors were calculated by Markov Chain Monte Carlo sampling using standard priors. All trials interpreted as positive had probabilities > 90% for marginal benefits (HR < 1). However, 38% of positive trials had ≤ 90% probabilities of achieving the MCID (HR < 0.8), even under an enthusiastic prior. A subgroup analysis of 82 trials that led to regulatory approval showed 30% had ≤ 90% probability for meeting the MCID under an enthusiastic prior. Conversely, 24% of negative trials had > 90% probability of achieving marginal benefits, even under a skeptical prior, including 12 trials with a primary endpoint of overall survival. Lastly, a phase III oncology-specific prior from a previous work, which uses published summary statistics rather than reconstructed data to compute posteriors, validated the individual patient-level data findings. Taken together, these results suggest that Bayesian models add considerable unique interpretative value to phase III oncology trials and provide a robust solution for overcoming the discrepancies between refuting the null hypothesis and obtaining a MCID.SIGNIFICANCE STATEMENTThe statistical analyses of oncology trials are usually performed by calculatingPvalues, although these are poorly understood. UsingPvalue cutoffs, such asP< 0.05, may lead to some treatments being accepted which have little benefit, and other therapies being rejected which have considerable benefit. A more intuitive and direct probability— that an experimental treatment is better than a standard treatment—can be calculated by Bayesian statistics. Here we used software to obtain the outcomes of 194,129 patients enrolled across 230 trials and then calculated probabilities of benefit. Interpretations based onPvalues disagreed with the probabilities of benefit in one-third of trials. This study suggests that probabilities of benefit would considerably enhance the interpretation of oncology trials.
Flexible Control of Motor Units: Is the Multidimensionality of Motor Unit Manifolds a Sufficient Condition?
Authors: Dernoncourt François , Avrillon Simon , Logtens Tijn , Cattagni Thomas , Farina Dario , Hug François 
Published: July 2024

AbstractUnderstanding flexibility in the neural control of movement requires identifying the distribution of common inputs to the motor units. In this study, we identified large samples of motor units from two lower limb muscles: the vastus lateralis (VL; up to 60 motor units/participant) and the gastrocnemius medialis (GM; up to 67 motor units/participant). First, we applied a linear dimensionality reduction method to assess the dimensionality of the manifolds underlying the motor unit activity. We subsequently investigated the flexibility in motor unit control under two conditions: sinusoidal contractions with torque feedback, and online control with visual feedback on motor unit firing rates. Overall, we found that the activity of GM motor units was effectively captured by a single latent factor defining a unidimensional manifold, whereas the VL motor units were better represented by three latent factors defining a multidimensional manifold. Despite this difference in dimensionality, the recruitment of motor units in the two muscles exhibited similarly low levels of flexibility. Using a spiking network model, we tested the hypothesis that dimensionality derived from factorization does not solely represent descending cortical commands but is also influenced by spinal circuitry. We demonstrated that a heterogeneous distribution of inputs to motor units, or specific configurations of recurrent inhibitory circuits, could produce a multidimensional manifold. This study clarifies an important debated issue, demonstrating that while motor unit firings of a non-compartmentalised muscle can lie in a multidimensional manifold, the central nervous system may still have limited capacity for flexible control of these units.Key pointsTo generate movement, the central nervous system distributes both excitatory and inhibitory inputs to the motor units.The level of flexibility in the neural control of these motor units remains a topic of debate with significant implications for identifying the smallest unit of movement control.By combining experimental data and in silico models, we demonstrated that the activity of a large sample of motor units from a single muscle can be represented by a multidimensional linear manifold; however, these units show very limited flexibility in their recruitment.The dimensionality of the linear manifold may not directly reflect the dimensionality of descending inputs but could instead relate to the organisation of local spinal circuits.
Chimerism and altruism
Authors: Hitchcock Thomas J. , Patten Manus M. 
Published: July 2024

AbstractChimerism spans the tree of life, from mammals and corals to plants and fungi. In such organisms, individuals contain within them cells and genomes from another once distinct member of the population. This chimeric genetic composition may subsequently alter patterns of relatedness not only between those individuals, but also within them. Consequently, we may expect unique patterns of social behaviour in such species. To explore the social evolutionary consequences of chimerism, here we develop a kin-selection model of a structured population. First, we show how somatic and germline chimerism influence patterns of relatedness and play an important role in modulating social behaviour. Specifically, we find that increased heterogeneity of the soma relative to the germline boosts the opportunity for altruism between individuals. We then explore how differences in chimerism levels within the body may generate within-organism differences in the valuation of social partners and thus foment internal conflicts between tissues and organs. Finally, we show how differences in the development of male and female germlines in chimeras provides a novel source of relatedness asymmetry between maternal-origin and paternal-origin genes. Overall, we find that chimerism introduces additional opportunities for internal conflicts over the development of behavioural phenotypes, most of which have been unexplored by empiricists.
Evolutionary Origins of Self-sustained Kai Protein Circadian Oscillators
Authors: Mukaiyama Atsushi , Furuike Yoshihiko , Ito-Miwa Kumiko , Onoue Yasuhiro , Horiuchi Kota , Yamashita Eiki , Akiyama Shuji 
Published: July 2024

AbstractLight–dark cycles affect photosynthetic efficiency in autotrophic cyanobacteria; therefore, determining whether ancient cyanobacteria possessed a self-sustained circadian clock when oxygenic photosynthetic systems were established is an important issue in chronobiology. Here we examined the oscillation of the clock protein KaiC in modern cyanobacteria, as well as the function and structure of ancestral Kai proteins, to determine the evolutionary origin of the self-sustained Kai-protein oscillators. The results show that the oldest double-domain KaiC in ancestral bacteria lacked the factors functionally and structurally essential for rhythmicity. The ancestral Kai proteins had acquired these factors through molecular evolution that occurred around Global Oxidation and Snowball Earth events, and were eventually inherited as a self-sustained circadian oscillator by the most recent common ancestor of cyanobacteria capable of oxygenic photosynthesis. This autonomous Kai protein oscillator was further inherited by most freshwater and marine cyanobacteria present today as an autotrophic basis for time-optimal acquisition and consumption of energy from oxygenic photosynthesis.
Novel Approach for Refractive Index Matching in Calcified Tissues
Authors: Laudier Damien , Mora-Antionette Macy , Garcia-Ortiz Andi , Lewis Karl J. 
Published: July 2024

AbstractTissue-clearing techniques have become indispensable in biomedical research, especially for three-dimensional (3D) imaging. These techniques enable the visualization of complex biological structures by rendering tissues transparent while preserving their structural integrity. Calcified tissues, such as bone and cartilage, pose a unique challenge in imaging studies due to their inherent opacity and rigidity. In this work, we introduce a novel modification to the BABB clearing protocol aimed at enhancing the clearing efficacy specifically for calcified tissues. Through this work, we provide an enhanced tissue-clearing method that addresses the specific challenges associated with calcified tissues. This advancement has the potential to facilitate more precise and comprehensive studies in fields such as developmental biology, orthopedics, and regenerative medicine.
Molecular and Mechanical Signatures Contributing to Epidermal Differentiation and Barrier Formation
Authors: Prado-Mantilla Alexandra , Ning Wenxiu , Lechler Terry 
Published: July 2024

AbstractFormation of the skin barrier requires rapid proliferation coupled with differentiation and stratification of the embryonic epidermis. Basal progenitors give rise to progeny throughout development – first to intermediate cells, a transient proliferative suprabasal cell population, and later to spinous cells. Neither the function nor the differentiation trajectory of intermediate cells has been documented. We generated transcriptomes of intermediate and spinous cells and identified specific markers that distinguish these two populations. Further, we found that intermediate cells express a subset of genes in common with granular cells of the epidermis – the terminal living cell type that helps establish the barrier. Lineage tracing revealed that most intermediate cells directly transition to granular cells without expressing markers specific to spinous cells, thus revealing a distinct lineage pathway leading to granular fate. In addition to their transcriptional similarities, intermediate and granular cells both had hallmarks of increased actomyosin contractility. We found that rather than simply lying downstream of cell fate pathways, contractility was sufficient to suppress spinous fate and promote granular gene expression. Together, these data establish the molecular and mechanical characteristics of the developing epidermis that allow this tissue to rapidly develop barrier activity.
scRNA-seq identifies unique macrophage population in murine model of ozone induced asthma exacerbation
Authors: Ray Jess L. , Walum Joshua , Jelic Daria , Barnes Ryelie , Bentley Ian D. , Britt Rodney D. , Englert Joshua A. , Ballinger Megan N. 
Published: July 2024

AbstractOzone (O3) inhalation triggers asthmatic airway hyperresponsiveness (AHR), but the mechanisms by which this occurs are unknown. Previously, we developed a murine model of dust mite, ragweed, andaspergillus(DRA)-induced allergic lung inflammation followed by O3exposure for mechanistic investigation. The present study used single cell RNA-sequencing for unbiased profiling of immune cells within the lungs of mice exposed to DRA, O3, or DRA+O3, to identify the components of the immune cell niche that contribute to AHR. Alveolar macrophages (AMs) had the greatest number of differentially expressed genes following DRA+O3, most of which were unique to the 2-hit exposure. Following DRA+O3, AMs activated transcriptional pathways related to cholesterol biosynthesis, degradation of the extracellular matrix, endosomal TLR processing, and various cytokine signals. We also identified AM and monocyte subset populations that were unique to the DRA+O3group. These unique AMs activated gene pathways related to inflammation, sphingolipid metabolism, and bronchial constriction. The unique monocyte population had a gene signature that suggested phospholipase activation and increased degradation of the extracellular matrix. Flow cytometry analysis of BAL immune cells showed recruited monocyte-derived AMs after DRA and DRA+O3, but not after O3exposure alone. O3alone increased BAL neutrophils but this response was attenuated in DRA+O3mice. DRA-induced changes in the airspace immune cell profile were reflected in elevated BAL cytokine/chemokine levels following DRA+O3compared to O3alone. The present work highlights the role of monocytes and AMs in the response to O3and suggests that the presence of distinct subpopulations following allergic inflammation may contribute to O3-induced AHR.
Site-specific metabolic labeling reveals proteome-wide phospho-dynamics
Authors: Alevra Mihai , Correa Marrero Miguel , Kluever Verena , Mandad Sunit , Hemandhar-Kumar Nisha , Pan Kuan-Ting , van Gerwen Julian , Glowacki Selda Kabatas , Wildhagen Hanna , Ischebeck Till , Liu Yansheng , Rizzoli Silvio O. , Urlaub Henning , Beltrao Pedro , Fornasiero Eugenio F. 
Published: July 2024

AbstractProtein phosphorylation is a critical post-translational modification that orchestrates cellular signaling. Here, we introduce PulsPhos, a method combining metabolic labeling with phosphoproteomics, spectral analysis and modeling, to quantify site-specific phosphorylation lifetimes in living cells. Phosphosite lifetimes vary over multiple orders of magnitude and are influenced by factors such as amino acid composition and subcellular localization. PulsPhos was readily applied to pharmacological perturbations revealing fundamental mechanisms governing protein phosphorylation dynamics.
Evidence for biomolecular condensates of MatP in spatiotemporal regulation of the bacterial cell division cycle
Authors: Barros-Medina Inés , Robles-Ramos Miguel Ángel , Sobrinos-Sanguino Marta , Luque-Ortega Juan Román , Alfonso Carlos , Margolin William , Rivas Germán , Monterroso Begoña , Zorrilla Silvia 
Published: July 2024

ABSTRACTAn increasing number of proteins involved in bacterial cell cycle events have been recently shown to undergo phase separation. The resulting biomolecular condensates play an important role in cell cycle protein function and may be involved in development of persister cells tolerant to antibiotics. Here we report that theE. colichromosomal Ter macrodomain organizer MatP, a division site selection protein implicated in the coordination of chromosome segregation with cell division, forms biomolecular condensates in cytomimetic systems. These condensates are favored by crowding and preferentially localize at the membrane of microfluidics droplets, a behavior probably mediated by MatP-lipid binding. Condensates are negatively regulated and partially dislodged from the membrane by DNA sequences recognized by MatP (matS), which partition into them. Unexpectedly, MatP condensation is enhanced by FtsZ, a core component of the division machinery previously described to undergo phase separation. Our biophysical analyses uncover a direct interaction between the two proteins, disrupted bymatSsequences. This binding might have implications for FtsZ ring positioning at mid-cell by the Ter linkage, which comprises MatP and two other proteins that bridge the canonical MatP/FtsZ interaction. FtsZ/MatP condensates interconvert with bundles in response to GTP addition, providing additional levels of regulation. Consistent with discrete foci reported in cells, MatP biomolecular condensates may facilitate MatP’s role in chromosome organization and spatiotemporal regulation of cytokinesis and DNA segregation. Moreover, sequestration of MatP in these membraneless compartments, with or without FtsZ, could promote cell entry into dormant states that are able to survive antibiotic treatments.
Resolving artefacts in voltage-clamp experiments with computational modelling: an application to fast sodium current recordings
Authors: Lei Chon Lok , Clark Alexander P. , Clerx Michael , Wei Siyu , Bloothooft Meye , de Boer Teun P. , Christini David J. , Krogh-Madsen Trine , Mirams Gary R. 
Published: July 2024

AbstractCellular electrophysiology is the foundation of many fields, from basic science in neurology, cardiology, oncology to safety critical applications for drug safety testing, clinical phenotyping, etc. Patch-clamp voltage clamp is the gold standard technique for studying cellular electrophysiology. Yet, the quality of these experiments is not always transparent, which may lead to erroneous conclusions for studies and applications. Here, we have developed a new computational approach that allows us to explain and predict the experimental artefacts in voltage-clamp experiments. The computational model captures the experimental procedure and its inadequacies, including: voltage offset, series resistance, membrane capacitance and (imperfect) amplifier compensations, such as series resistance compensation and supercharging. The computational model was validated through a series of electrical model cell experiments. Using this computational approach, the artefacts in voltage-clamp experiments of cardiac fast sodium current, one of the most challenging currents to voltage clamp, were able to be resolved and explained through coupling the observed current and the simulated membrane voltage, including some typically observed shifts and delays in the recorded currents. We further demonstrated that the typical way of averaging data for current-voltage relationships would lead to biases in the peak current and shifts in the peak voltage, and such biases can be in the same order of magnitude as those differences reported for disease-causing mutations. Therefore, the presented new computational pipeline will provide a new standard of assessing the voltage-clamp experiments and interpreting the experimental data, which may be able to rectify and provide a better understanding of ion channel mutations and other related applications.
The dynamic crosstalk between cytoskeletal filaments regulates the cytoplasmic mechanics across the apicobasal axis
Authors: Ray Dipanjan , Sinha Deepak Kumar 
Published: July 2024

AbstractThe cytoplasm exhibits viscoelastic properties, displaying both solid and liquid-like behavior, and can actively regulate its mechanical attributes. The cytoskeleton is a major regulator among the numerous factors influencing cytoplasmic mechanics. We explore the interdependence of various cytoskeletal filaments and the impact of their density on cytoplasmic viscoelasticity. The heterogeneous distribution of these filaments give rise to polarised mechanical properties of the cytoplasm along the apicobasal axis. Actin filament (F-actin) disassembly softens the basal cytoplasm while stiffening the mid-cytoplasm due to increased vimentin filament assembly. Disruption of microtubules (MT) or depletion of vimentin softens both the basal and mid-cytoplasm. Cyto D treatment results in localised increase of vimentin assembly in the mid cytoplasm which is dependent on the cytolinker plectin. Nocodazole treatment has a negligible effect on F-actin distribution but significantly alters vimentin’s spatial arrangement. We demonstrate that Cyto D treatment upregulates vimentin expression via ROS-mediated activation of NF-κΒ. This manuscript investigates how different cytoskeletal filaments influence the rheological characteristics of various cytoplasmic regions.