bluuebunny/crossref_metadata_2025_split huggingface dataset:
SomaScan Bioinformatics: Normalization, Quality Control, and Assessment of Pre-Analytical Variation
Authors: Candia Julián 
Published: February 2024

ABSTRACTSomaScan is an aptamer-based proteomics assay designed for the simultaneous measurement of thousands of human proteins with a broad range of endogenous concentrations. In its most current version released on November 1, 2023, the 11K SomaScan assay v5.0 is capable of measuring 10,776 human proteins covering major biological processes and disease areas, including cardiology, inflammation, neurology, and oncology. Here, I review bioinformatic approaches to perform normalization, quality control, and variability assessments.
Developmental pathways underlying sexual differentiation in a U/V sex chromosome system
Authors: Liesner Daniel , Cossard Guillaume , Zheng Min , Godfroy Olivier , Barrera-Redondo Josué , Haas Fabian B. , Coelho Susana M. 
Published: February 2024

SummaryIn many multicellular organisms, sexual development is not determined by XX/XY or ZW/ZZ systems but by U/V sex chromosomes. In U/V systems, sex determination occurs in the haploid phase, with U chromosomes in females and V chromosomes in males. Here, we explore several male, female and partially sex-reversed male lines of giant kelp to decipher how U/V sex chromosomes and autosomes initiate male versus female development. We identify a key set of genes on the sex chromosomes involved in triggering sexual development, and characterise autosomal effector genes underlying sexual differentiation. We show that male, but not female, development involves large-scale transcriptome reorganisation with pervasive enrichment in regulatory genes, faster evolutionary rates, and high species specificity of male-biased genes. Our observations imply that a female-like phenotype is the “ground state”, which is complemented by the presence of a U-chromosome, but overridden by a dominant male developmental program in the presence of a V-chromosome.
Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis
Authors: Lee-Ødegård Sindre , Hjorth Marit , Olsen Thomas , Moen Gunn-Helen , Daubney Emily , Evans David M , Hevener Andrea , Lusis Aldons Jake , Zhou Mingqi , Seldin Marcus Michael , Allayee Hooman , Hilser James R. , Viken Jonas Krag , Gulseth Hanne L. , Norheim Frode , Drevon Christian A. , Birkeland Kåre I. 
Published: February 2024

AbstractBackgroundPhysical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking.MethodsWe analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using 2-sample Mendelian randomization and mice models.ResultsFollowing 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7% and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2-hour glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female,Cd300lgknockout mice.ConclusionOur study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes.
Predator cues and environmental enrichment during development drive intraspecific variation in the behaviour and life history of juvenile lobsters
Authors: Polverino Giovanni , Latini Lorenzo , Nascetti Giuseppe , Grignani Giacomo , Bello Eleonora , Gili Claudia , Carere Claudio , Canestrelli Daniele 
Published: February 2024

ABSTRACTIntraspecific variation in ecologically relevant traits is critical for animal populations to survive in our rapidly changing world. This is especially true for species that suffer from intense harvesting regimes, whereby populations density is often low. Standard hatchery procedures can assist some management and conservation programs by producing large numbers of juveniles to be released into the wild. Yet we know surprisingly little on the impact that such standard, minimalistic settings have on the development of intraspecific variation in important phenotypes of the individuals, including among-individual variation in behavioural (individuality) and life-history traits, and in the plasticity of those traits in response to varying environmental conditions. Here, we fill this gap by testing whether early-life exposure to different environmental conditions alters the development of individuality and plasticity in ecologically relevant behaviours and life-history traits of the European lobster (Homarus gammarus)—one the most harvested species in the Mediterranean, which has been subjected to conservation programs for decades. By accessing one of the largest lobsters hatcheries in Italy, we used the progeny of wild-caught females and manipulated—in a full factorial design—the environmental complexity of the individual enclosures (i.e. presence/absence of substrate and/or shelter) and the level of exposure to cues from their natural predators. We repeatedly quantified behaviours (i.e. activity, refuge use, and aggressiveness) and life-history traits (i.e. carapace length and intermoult period) of the individuals throughout their early development, capturing both mean and individual-level variation across treatments. Our results offer solid evidence that effects of standard hatchery settings extend far beyond mean changes in the behaviour and life history of the animals, compromising the development of individual plasticity in those traits that are essentials for populations to survive in the wild—likely reducing the effectiveness of conservation programs.
Causal mediation analysis for time-varying heritable risk factors with Mendelian Randomization
Authors: Wu Zixuan , Lewis Ethan , Zhao Qingyuan , Wang Jingshu 
Published: February 2024

AbstractUnderstanding the causal pathogenic mechanisms of diseases is crucial in clinical research. When randomized controlled experiments are not available, Mendelian Randomization (MR) offers an alternative, leveraging genetic mutations as a natural “experiment” to mitigate environmental confoundings. However, most MR analyses treat the risk factors as static variables, potentially oversimplifying dynamic risk factor effects. The framework of life-course MR has been introduced to address this issue. However, current methods face challenges especially when the age-specific GWAS datasets have limited cohort sizes and there are substantial correlations between time points for a single trait. This study proposes a novel approach, estimating a unified system of structural equations for a sequence of temporally ordered heritable traits, requiring only GWAS summary statistics. The method facilitates statistical inference on direct, indirect, and path-wise causal effects and demonstrates superior efficiency and reliability, particularly with noisy GWAS data. By incorporating a spike-and-slab prior for genetic effects, the approach can address extreme polygenicity and weak instrument bias. Through this methodology, we uncovered a protective effect of BMI on breast cancer during a confined period of childhood development. We also analyzed how BMI, systolic blood pressure (SBP), and low-density cholesterol levels influence stroke risk across childhood and adulthood, and identified the intriguing relationships between these risk factors.
Impaired ovarian development in a zebrafishfmr1knockout model
Authors: Rani Rita , Sri N Sushma , Medishetti Raghavender , Chatti Kiranam , Sevilimedu Aarti 
Published: February 2024

AbstractFragile X syndrome (FXS) is an inherited neurodevelopmental disorder and the leading genetic cause of autism spectrum disorders. FXS is caused by loss of function mutations in Fragile X mental retardation protein (FMRP), an RNA binding protein that is known to regulate translation of its target mRNAs, predominantly in the brain and gonads. The molecular mechanisms connecting FMRP function to neurodevelopmental phenotypes are well understood. However, neither the full extent of reproductive phenotypes, nor the underlying molecular mechanisms have been as yet determined. Here, we developed newfmr1knockout zebrafish lines and show that they mimic key aspects of FXS neuronal phenotypes across both larval and adult stages. Results from thefmr1knockout females also showed that altered gene expression in the brain, via the neuroendocrine pathway contribute to distinct abnormal phenotypes during ovarian development and oocyte maturation. We identified at least three mechanisms underpinning these defects, including altered neuroendocrine signaling in sexually mature females resulting in accelerated ovarian development, altered expression of germ cell and meiosis promoting genes at various stages during oocyte maturation, and finally a strong mitochondrial impairment in late stage oocytes from knockout females. Our findings have implications beyond FXS in the study of reproductive function and female infertility. Dissection of the translation control pathways during ovarian development using models like the knockout lines reported here may reveal novel approaches and targets for fertility treatments.Abstract FigureGraphical Abstract
Tropical and montaneA.ceranashow distinct dance-distance calibration curves
Authors: Bharath Kumar A. K , George Ebi Antony , Brockmann Axel 
Published: February 2024

AbstractSocial bees have evolved sophisticated communication systems to recruit nestmates to newly found food sources. As foraging ranges can vary from a few hundred meters to several kilometers depending on the environment or season, populations living in different climate zones likely show specific adaptations in their recruitment communication. Accordingly, studies in the western honey bee,Apis mellifera, demonstrated that temperate populations exhibit shallower dance-calibration curves compared to tropical populations. Here we report the first comparison of calibration curves for three IndianA. ceranalineages: the tropicalA. indica, and the two montane Himalayan populationsA. c. cerana(Himachal Pradesh) andA. c. kashmirensis(Jammu and Kashmir). We found that the colonies of the two montaneA. ceranapopulations show dance-distance calibration curves with significantly shallower slopes than the tropicalA. indica. Next, we transferredA. c. ceranacolonies to Bangalore (∼ 2600 km away) to obtain calibration curves in the same location asA. indica. The common garden experiment confirmed this difference in slopes, implying that the lineages exhibit genetically fixed differences in dance-distance coding. However, the slopes of the calibration curves of the transferredA. c. ceranacolonies were also significantly higher than those tested in Himachal Pradesh indicating an important effect of the environment. The differences in dance-distance coding between temperate and tropicalA. ceranalineages resemble those described forA. melliferasuggesting that populations of both species independently evolved similar adaptations.
Serotonin deficiency from constitutive SKN-1 activation drives pathogen apathy
Authors: Nair Tripti , Weathers Brandy A. , Stuhr Nicole L. , Nhan James D. , Curran Sean P. 
Published: February 2024

ABSTRACTWhen an organism encounters a pathogen, the host innate immune system activates to defend against pathogen colonization and toxic xenobiotics produced.C. elegansemploy multiple defense systems to ensure survival when exposed toPseudomonas aeruginosaincluding activation of the cytoprotective transcription factor SKN-1/NRF2. Although wildtypeC. elegansquickly learn to avoid pathogens, here we describe a peculiar apathy-like behavior towards PA14 in animals with constitutive activation of SKN-1, whereby animals choose not to leave and continue to feed on the pathogen even when a non-pathogenic and healthspan-promoting food option is available. Although lacking the urgency to escape the infectious environment, animals with constitutive SKN-1 activity are not oblivious to the presence of the pathogen and display the typical pathogen-induced intestinal distension and eventual demise. SKN-1 activation, specifically in neurons and intestinal tissues, orchestrates a unique transcriptional program which leads to defects in serotonin signaling that is required from both neurons and non-neuronal tissues. Serotonin depletion from SKN-1 activation limits pathogen defense capacity, drives the pathogen-associated apathy behaviors and induces a synthetic sensitivity to selective serotonin reuptake inhibitors. Taken together, our work reveals new insights into how animals perceive environmental pathogens and subsequently alter behavior and cellular programs to promote survival.KEY POINTSIdentify an apathy-like behavioral response for pathogens resulting from the constitutive activation of the cytoprotective transcription factor SKN-1.Uncover the obligate role for serotonin synthesis in both neuronal and non-neuronal cells for the apathy-like state and ability of serotonin treatment to restore normal behaviors.Characterize the timing and tissue specificity of SKN-1 nuclear localization in neurons and intestinal cells in response to pathogen exposure.Define the unique and context-specific transcriptional signatures of animals with constitutive SKN-1 activation when exposed to pathogenic environments.Reveal necessity for both neuronal and non-neuronal serotonin signaling in host survival from pathogen infection.
Substrate recognition principles for the PP2A-B55 protein phosphatase
Authors: Kruse Thomas , Garvanska Dimitriya H. , Varga Julia , Garland William , McEwan Brennan , Hein Jamin B. , Weisser Melanie Bianca , Puy Iker Benavides , Chan Camilla Bachman , Parrila Paula Sotelo , Mendez Blanca Lopez , Arulanandam Jeyaprakash , Schueler-Furman Ora , Jensen Torben Heick , Kettenbach Arminja , Nilsson Jakob 
Published: February 2024

AbstractThe PP2A-B55 phosphatase regulates a plethora of signaling pathways throughout eukaryotes. How PP2A-B55 selects its substrates presents a severe knowledge gap. By integrating AlphaFold modelling with comprehensive high resolution mutational scanning, we show that α-helices in substrates bind B55 through an evolutionary conserved mechanism. Despite a large diversity in sequence and composition, these α-helices share key amino acid determinants that engage discrete hydrophobic and electrostatic patches. Using deep learning protein design, we generate a specific and potent competitive peptide inhibitor of PP2A-B55 substrate interactions. With this inhibitor, we uncover that PP2A-B55 regulates the nuclear exosome targeting complex by binding to an α-helical recruitment module in RBM7. Collectively, our findings provide a framework for the understanding and interrogation of PP2A-B55 in health and disease.One sentence summaryα-helices in PP2A-B55 substrates bind a conserved pocket on B55 through a common mechanism that is conserved in eukaryotes.
Pushing the limits: expanding the temperature tolerance of a coral photosymbiont through differing selection regimes
Authors: Scharfenstein Hugo J. , Peplow Lesa M. , Alvarez-Roa Carlos , Nitschke Matthew R. , Chan Wing Yan , Buerger Patrick , van Oppen Madeleine JH 
Published: February 2024

AbstractCoral thermal bleaching resilience can be improved by enhancing photosymbiont thermal tolerance via experimental evolution. While successful for some strains, selection under stable temperatures was ineffective at increasing the thermal threshold of an already thermo-tolerant photosymbiont (Durusdinium trenchii). Corals from environments with fluctuating temperatures tend to have comparatively high heat tolerance. Therefore, we investigated whether exposure to temperature oscillations can raise the upper thermal limit ofD. trenchii. We exposed aD. trenchiistrain to stable and fluctuating temperatures profiles, which varied in oscillation frequency. After 2.1 years (54-73 generations), we characterised the adaptive responses under the various experimental evolution treatments by constructing thermal performance curves of growth from 21 to 31°C for the heat-evolved and wild-types lineages. Additionally, oxidative stress, photophysiology, photosynthesis and respiration rates were assessed under increasing temperatures. Of the fluctuating temperature profiles investigated, selection under the most frequent oscillations (diurnal) induced the greatest widening ofD. trenchii’s thermal niche. Continuous selection under elevated temperatures induced the only increase in thermal optimum and a degree of generalism. Our findings demonstrate how differing levels of thermal homogeneity during selection drive unique adaptative responses to heat in a coral photosymbiont.
Sarbecovirus RBD indels and specific residues dictating ACE2 multi-species adaptiveness
Authors: Si Junyu , Chen Yuanmei , Gu Mengxue , Sun Yehui , Huang Meiling , Shi Lulu , Yu Xiao , Yang Xiao , Xiong Qing , Ma Chenbao , Liu Peng , Shi Zheng-Li , Yan Huan 
Published: February 2024

SummarySarbecoviruses exhibit varying abilities in using angiotensin-converting enzyme 2 (ACE2) receptor1–3. However, a comprehensive understanding of their multi-species ACE2 adaptiveness and the underlying mechanism remains elusive, particularly for many sarbecoviruses with various receptor binding motif (RBM) insertions/deletions (indels)4–11. Here, we analyzed RBM sequences from 268 sarbecoviruses categorized into four RBM indel types. We extensively examined the capability of 14 representative sarbecoviruses and their derivatives in using ACE2 orthologues from 51 bats and five non-bat mammals. We revealed that most sarbecoviruses with longer RBMs (type-I), present broad ACE2 tropism, whereas viruses with single deletions in Region 1 (type-II) or Region 2 (type-III) generally exhibit narrow ACE2 tropism, typically favoring their hosts’ ACE2. Sarbecoviruses with double region deletions (type-IV) exhibit a complete loss of ACE2 usage. Subsequent investigations unveiled that both loop deletions and critical RBM residues significantly impact multi-species ACE2 tropism in different ways. Additionally, fine mapping based on type-IV sarbecoviruses elucidated the role of several clade-specific residues, both within and outside the RBM, in restricting ACE2 usage. Lastly, we hypothesized the evolution of sarbecovirus RBM indels and illustrated how loop length, disulfide, and adaptive mutations shape their multi-species ACE2 adaptiveness. This study provides profound insights into the mechanisms governing ACE2 usage and spillover risks of sarbecoviruses.
Electrophysiological Effects Of Kappa-Opioid Analgesic, RU-1205, Using Machine Learning Methods
Authors: Kalitin Konstantin Y. , Mukha Olga Y. , Spasov Alexander A. 
Published: February 2024

This study focuses on RU-1205, a new kappa-opioid agonist exhibiting analgesic effect without causing dysphoric or aversive reactions. It is assumed that the absence of dysphoric or aversive effects can be attributed to functional selectivity or it might be due to an additional mechanism of action that involves blocking the p38 mitogen-activated protein kinase (MAPK).The aimof this study was the experimental identification of the mechanisms of action of RU-1205 associated with inhibition of MAPK p38 and functional selectivity at kappa-opioid receptors.Materials and methodsRats weighing 260-280 g were implanted with chronic cortical and deep electrodes. LFP activity was recorded after intracerebroventricular administration of well-studied reference substances: the selective kappa-opioid agonist U-50488 at a dose of 100 μg; the MAPK p38 blocker SB203580 at a dose of 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning techniques were employed to reduce dimensionality and extract connectivity features using the principal component analysis method. Finally, signal classification was conducted using models based on Gaussian processes.By applying the patch-clamp technique in the whole-cell configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. The neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001–10 μM) and RU-1205 (10 μM); and (3) combinations of U-50488 (0.01–10 μM) and RU-1205 (100 μM).ResultsThe developed models were able to classify the compound RU-1205 as a «non-inhibitor» of MAPK p38 with a probability of 0.89. The results obtained were confirmed in patch clamp experiments on acute brain slices, where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons in the basolateral amygdala (p <0.05) and RU-1205 interacts with U-50488, suppressing its effect on the spike activity of neurons.ConclusionsThe findings suggest that compound RU-1205 displays properties consistent with a functional kappa opioid receptor agonist and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of neuronal mechanisms of drug action and underscores the potential for further research in this area.