bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells
Authors: Rao Priyanka Gadam , Lambert Gregory S. , Upadhyay Chitra 
Published: January 2023

AbstractThe envelope glycoproteins (Env) on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAb) and the focus of vaccines. However, many cross-reactive conserved epitopes are often occluded on virus particles, contributing to the evasion of humoral immunity. This study aimed to identify the Env epitopes that are exposed/occluded on HIV-1 particles and to investigate the mechanisms contributing to their masking. Using a flow cytometry-based assay, three HIV-1 isolates, and a panel of antibodies, we show that only select epitopes including V2i, gp120-g41 interface, and gp41-MPER are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are masked. These epitopes become accessible after allosteric conformational changes are induced by pre-binding of select Abs, prompting us to test if similar conformational changes are required for these Abs to exhibit their neutralization capability. We tested HIV-1 neutralization where virus-mAb mix was pre-incubated/not pre-incubated for one hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. We further show that lectin-glycan interactions can also expose these epitopes. However, this effect is dependent on the lectin specificity. Given that, bNAbs are the ideal for providing sterilizing immunity and are the goal of current HIV-1 vaccine efforts, these data offer insight on how HIV-1 may occlude these vulnerable epitopes from the host immune response. In addition, the findings can guide the formulation of effective antibody combinations for therapeutic use.ImportanceThe human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein mediates viral entry, and is the sole target of neutralizing antibodies. Our data suggest that antibody epitopes including V2q (e.g., PG9, PGT145), CD4bs (e.g., VRC01, 3BNC117) and V3 (2219, 2557) are masked on HIV-1 particles. The PG9 and 2219 epitopes became accessible for binding after conformational unmasking was induced by pre-binding of select mAbs. Attempts to understand the masking mechanism led to the revelation that interaction between virus and host cells is needed to sensitize the virions for neutralization by broadly neutralizing antibodies (bNAbs). These data provide insight on how bNAbs may gain access to these occluded epitopes to exert their neutralization effects and block HIV-1 infection. These findings have important implications for the way we evaluate the neutralizing efficacy of antibodies and can potentially guide vaccine design.
Intergenerational scaling law determines the precision kinematics of stochastic individual-cell-size homeostasis
Authors: Joshi Kunaal , Biswas Rudro R. , Iyer-Biswas Srividya 
Published: January 2023

AbstractIndividual bacterial cells grow and divide stochastically. Yet they maintain their characteristic sizes across generations within a tightly controlled range. What rules ensure intergenerational stochastic homeostasis of individual cell sizes? Valuable clues have emerged from high-precision longterm tracking of individual statistically-identicalCaulobacter crescentuscells as reported in [1]: Intergenerational cell size homeostasis is an inherently stochastic phenomenon, follows Markovian or memory-free dynamics, and cells obey an intergenerational scaling law, which governs the stochastic map characterizing generational sequences of characteristic cell sizes. These observed emergent simplicities serve as essential building blocks of the first-principles-based theoretical framework we develop here. Our exact analytic fitting-parameter-free results for the predicted intergenerational stochastic map governing the precision kinematics of cell size homeostasis are remarkably well borne out by experimental data, including extant published data on other microorganisms,Escherichia coliandBacillus subtilis. Furthermore, our framework naturally yields the general exact and analytic condition, necessary and sufficient, which ensures that stochastic homeostasis can be achieved and maintained. Significantly, this condition is more stringent than the known heuristic result for the popular quasi-deterministic adder-sizer-timer frameworks. In turn the fully stochastic treat-ment we present here extends and updates extant frameworks, and challenges the notion that the mythical “average cell” can serve as a reasonable proxy for the inherently stochastic behaviors of actual individual cells.
ERK1/2-dependent TSPO overactivation associates with the loss of mitophagy and mitochondrial respiration in ALS
Authors: Magrì Andrea , Rita Lipari Cristiana Lucia , Risiglione Pierpaolo , Zimbone Stefania , Guarino Francesca , Caccamo Antonella , Messina Angela 
Published: January 2023

AbstractMitochondrial dysfunction and the loss of mitophagy, aimed at recycling irreversibly damaged organelles, contribute to the onset of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting spinal cord motor neurons. In this work, we showed that the reduction of mitochondrial respiration, exactly oxygen flows linked to ATP production and maximal capacity, correlates with the appearance of the most common ALS motor symptoms in a transgenic mice model expressing SOD1 G93A mutant. This is the result of the equal inhibition in the respiration linked to complex I and II of the electron transport chain, but not their protein levels. Since the overall mitochondrial mass was unvaried, we investigated the expression of the Translocator Protein (TSPO), a small mitochondrial protein whose overexpression was recently linked to the loss of mitophagy in a model of Parkinson’s disease. Here we clearly showed that levels of TSPO are significantly increased in ALS mice. Mechanistically, this increase is linked to the overactivation of ERK1/2 pathway and correlates with a decrease in the expression of the mitophagy-related marker, Atg12, indicating the occurrence of impairments in the activation of mitophagy. Overall, our work sets out TSPO as a key regulator of mitochondrial homeostasis in ALS.
Glycoprotein-glycoprotein receptor binding detection using bioluminescence resonance energy transfer (BRET)
Authors: Adamczuk Kamila , Rivero-Müller Adolfo 
Published: January 2023

AbstractThe glycoprotein receptors, members of the large G protein-coupled receptors (GPCRs) family, are characterized by a large extracellular domains responsible of binding their glycoprotein hormones. Hormone-receptor interactions are traditionally analyzed by ligand-binding assays most often using radiolabeling but also by thermal shift assays. However, the use of radioisotopes requires appropriate laboratory conditions, and moreover, for this purpose, purified cell membranes are most often used instead of living cells. This in turn poses another challenge due to the altered stability of membrane proteins in detergents used for purification. Here, we overcome such limitations by applying bioluminescence resonance energy transfer (BRET) in living cells to determine hormone-receptor interactions between aGaussialuciferase (Gluc) luteinizing hormone/chorionic gonadotropin receptor (LHCGR) fusion and its ligands (yoked human chorionic gonadotropin (yhCG) or luteinizing hormone (LH)) fused to the enhanced green fluorescent protein (eGFP). We first show that the Gluc-LHCGR is expressed on the plasma membrane and is fully functional, as well as the chimeric eGFP-hormones that are properly secreted and able to bind and activate the WT LHCGR. Finally, we applied the method to determine the interactions between clinically relevant mutations in the hormone as well as the receptor and show that this assay is fast and effective, plus safer and cost efficient alternative to radioligand-based assays, to screen for mutations in either the receptor or ligand. It enables kinetic measurements in living cells, detection of biosynthesis of the receptor (membrane expression) and it is compatible with downstream cellular assays - including firefly luciferase-based readouts.
Inconsistent estimates of hybridization frequency in newts revealed by SNPs and microsatellites
Authors: Miralles Aurélien , Secondi Jean , Pabijan Maciej , Babik Wiesław , Lemaire Christophe , Crochet Pierre-André 
Published: January 2023

AbstractHybridization between the European smooth and palmate newts has recurrently been mentioned in the literature. The only two studies that attempted to quantify the frequency of hybridization and gene admixture between these two species came to strikingly opposite conclusions. According to Arntzen et al (1998, 42 allozymes), hybrids are rare in nature and introgression negligible, while according to Johanet et al (2011, 6 microsatellites), introgressive hybridization is significant and widespread across the shared distribution range. To clarify this question, we implemented high-throughput SNP genotyping with diagnostic biallelic SNPs on 965 specimens sampled across Europe. Our results are in line with Arntzen et al, since only two F1 hybrids were identified in two distinct French localities, and no further hybrid generations or backcrosses. Moreover, reanalysis of 78 of the samples previously studied by Johanet et al. (2011) using our SNPs panel could not reproduce their results, suggesting that microsatellite-based inference overestimated the hybridization frequency between these two species. Since we did not detect methodological issues with the analyses of Johanet et al., our results suggest that SNP approaches outperform microsatellite-based assessments of hybridization frequency, and that conclusions previously published on this topic with a small number of microsatellite loci should be taken with caution, and ideally be repeated with an increased genomic coverage.
Evolutionarily diverse origins of honey bee deformed wing viruses
Authors: Hasegawa Nonno , Techer Maeva A. , Adjlane Noureddine , al-Hissnawi Muntasser Sabah , Antúnez Karina , Beaurepaire Alexis , Christmon Krisztina , Delatte Helene , Dukku Usman H. , Eliash Nurit , El-Niweiri Mogbel A. A. , Esnault Olivier , Evans Jay D. , Haddad Nizar J. , Locke Barbara , Muñoz Irene , Noël Grégoire , Panziera Delphine , Roberts John M. K. , De la Rúa Pilar , Shebl Mohamed A. , Stanimirovic Zoran , Rasmussen David A. , Mikheyev Alexander S. 
Published: January 2023

AbstractNovel transmission routes can allow infectious diseases to spread, often with devastating consequences. Ectoparasitic varroa mites vector a diversity of RNA viruses and, having switched hosts from the eastern to western honey bees (Apis ceranatoApis mellifera). They provide an opportunity to explore how novel transmission routes shape disease epidemiology. As the principal driver of the spread of Deformed Wing Viruses (mainly DWV-A and DWV-B), varroa infestation has also driven global honey bee health declines. The more virulent DWV-B strain has been replacing the original DWV-A strain in many regions over the past two decades. Yet, how these viruses originated and spread remains poorly understood. Here we use a phylogeographic analysis based on whole genome data to reconstruct the origins and demography of DWV spread. We found that, rather than reemerging in western honey bees after varroa switched hosts, as suggested by previous work, DWV-A most likely originated in Asia and spread in the mid-20thcentury. It also showed a massive population size expansion following the varroa host switch. By contrast, DWV-B was most likely acquired more recently from a source outside Asia, and appears absent from eastern honey bees, the original varroa host. These results highlight the dynamic nature of viral adaptation, whereby a vector’s host switch can give rise to competing and increasingly virulent disease pandemics. The evolutionary novelty and rapid global spread of these host-virus interactions, together with observed spillover into other species, illustrate how increasing globalisation poses urgent threats to biodiversity and food security.
Evidence for cryptic gene flow in parthenogenetic stick insects of the genusTimema
Authors: Freitas Susana , Parker Darren J. , Labédan Marjorie , Dumas Zoé , Schwander Tanja 
Published: January 2023

ABSTRACTObligately parthenogenetic species are expected to be short lived since the lack of sex and recombination should translate into a slower adaptation rate and increased accumulation of deleterious alleles. Some, however, are thought to have been reproducing without males for millions of years. It is not clear how these old parthenogens can escape the predicted long-term costs of parthenogenesis, but an obvious explanation is cryptic sex.In this study we screen for signatures of cryptic sex in eight populations of four parthenogenetic species ofTimemastick insects, some estimated to be older than 1M yrs. Low genotype diversity, homozygosity of individuals and high linkage disequilibrium (LD) unaffected by marker distances support exclusively parthenogenetic reproduction in six populations. However, in two populations (namely, of the speciesTimema douglasiandT. monikensis) we find strong evidence for cryptic sex, most likely mediated by rare males. These populations had comparatively high genotype diversities, lower LD, and a clear LD decay with genetic distance. Rare sex in species that are otherwise largely parthenogenetic could help explain the unusual success of parthenogenesis in theTimemagenus and raises the question whether episodes of rare sex are in fact the simplest explanation for the persistence of many old parthenogens in nature.
Hippocampal subfield volumes contribute to working memory interference control in aging: Evidence from longitudinal associations over 5 years
Authors: Andersson P , Samrani G , Andersson M , Persson J 
Published: January 2023

ABSTRACTIn memory, familiar but no longer relevant information may disrupt encoding and retrieval of to-be-learned information. While it has been demonstrated that the ability to resolve proactive interference (PI) in working memory (WM) is reduced in aging, the neuroanatomical components of this decline have yet to be determined. Hippocampal (HC) involvement in age- related decline in control of PI is currently not known. In particular, the association between HC subfield volumes and control of PI in WM has not been examined previously. Here we investigate the associations between mean level and 5-year trajectories of gray matter subfield volumes and PI in WM across the adult life span (N = 157). Longitudinal analyses over 5- years across all participants revealed that reduced volume in the subiculum was related to impaired control of PI. Age-stratified analyses showed that this association was most pronounced in older adults. Furthermore, we found that in older adults the effect of age on PI was mediated by GM volume in the HC. The current results show that HC volume is associated with the ability to control PI in WM, and that these associations are modulated by age.
Implications of gene tree heterogeneity on downstream phylogenetic analyses: A case study employing the Fair Proportion index
Authors: Wicke Kristina , Haque Md Rejuan , Kubatko Laura 
Published: January 2023

AbstractMany questions in evolutionary biology require the specification of a phylogeny for downstream phylogenetic analyses. However, with the increasingly widespread availability of genomic data, phylogenetic studies are often confronted with conflicting signal in the form of genomic heterogeneity and incongruence between gene trees and the species tree. This raises the question of determining what data and phylogeny should be used in downstream analyses, and to what extent the choice of phylogeny (e.g., gene trees versus species trees) impacts the analyses and their outcomes.In this paper, we study this question in the realm of phylogenetic diversity indices, which provide ways to prioritize species for conservation based on their relative evolutionary isolation on a phylogeny, and are thus one example of downstream phylogenetic analyses. We use the Fair Proportion (FP) index, also known as the evolutionary distinctiveness score, and explore the variability in species rankings based on gene trees as compared to the species tree for several empirical data sets. Our results indicate that prioritization rankings among species vary greatly depending on the underlying phylogeny, suggesting that the choice of phylogeny is a major influence in assessing phylogenetic diversity in a conservation setting.While we use phylogenetic diversity conservation as an example, we suspect that other types of downstream phylogenetic analyses such as ancestral state reconstruction are similarly affected by genomic heterogeneity and incongruence. Our aim is thus to raise awareness of this issue and inspire new research on which evolutionary information (species trees, gene trees, or a combination of both) should form the basis for analyses in these settings.
Dynamics of blood cells during a routine laboratory examination
Authors: Taye Mesfin Asfaw 
Published: January 2023

AbstractCentrifugation is a commonly performed laboratory procedure that helps to separate blood cells such as red blood cellsRBCs, white bood cellsWBCs, and platelets from plasma or serum. Although centrifugation is a routine procedure in most medical laboratories, factors that affect the efficacy of the centrifugation process have never been studied analytically. In this paper, we examine the effect of centrifugation time on the efficacy of the centrifugation process by studying the dynamics of blood cells via the well-known Langevin equation or equivalently, by solving the Fokker-Plank equation. Our result depicts that the speed of the centrifuge is one of the determinant factors concerning the efficacy of the centrifugation process. As angular speed increases, centrifugal force increases and as a result, the particles are forced to separate from plasma or serum. The room temperature also considerably affects the dynamics of the sample during centrifugation. Most importantly, the generation of heat during centrifugation increases the temperature within a centrifuge, and as a result, not only the stability of the sample but also the mobility of analyse is affected. We show that as the temperature within the centrifuge intensifies, the velocity of the cells as well as the displacement of the cells in the fluid increases. We then study the dynamics of the whole blood during capillary action where in this case the blood flows upward in a narrow space without the assistance of external forces. Previous investigations show that the height that the fluid rises increases as surface tension steps up. The viscosity of the fluid also affects the capillary action but to date, the dependence of the height on viscosity has never been explored due to the lack of a mathematical correlation between the viscosity of blood and surface tension [1]. In this work, we first examine the correlation between surface tension and viscous friction via data fitting. Our result exhibits that the viscosity of the blood increases linearly as surface tension increases. The mathematical relation between the height and viscous friction is derived. It is shown that the height of the blood that rises in the capillary increases as the viscous friction intensifies. As the temperature of the room steps up, the height also decreases. The dependence of erythrocytes sedimentation rate on surface tension is also studied. The results obtained in this work show that the erythrocyte sedimentation rate ESR increases as surface tension steps down.PACS numbersValid PACS appear here
Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity
Authors: Stöber Maja C , González Rocío Chamorro , Brückner Lotte , Conrad Thomas , Wittstruck Nadine , Szymansky Annabell , Eggert Angelika , Schulte Johannes H , Koche Richard P , Henssen Anton G , Schwarz Roland F , Haase Kerstin 
Published: January 2023

AbstractNeuroblastoma is characterised by extensive inter- and intra-tumour genetic heterogeneity and varying clinical outcomes. One possible driver for this heterogeneity are extrachromosomal DNAs (ecDNA), which segregate independently to the daughter cells during cell division and can lead to rapid amplification of oncogenes. While ecDNA-mediated oncogene amplification has been shown to be associated with poor prognosis in many cancer entities, the effects of ecDNA copy number heterogeneity on intermediate phenotypes are still poorly understood.Here, we leverage DNA and RNA sequencing data from the same single cells in cell lines and neuroblastoma patients to investigate these effects. We utilise ecDNA amplicon structures to determine precise ecDNA copy numbers and reveal extensive intercellular ecDNA copy number heterogeneity. We further provide direct evidence for the effects of this heterogeneity on gene expression of cargo genes, includingMYCNand its downstream targets, and the overall transcriptional state of neuroblastoma cells.These results highlight the potential for rapid adaptability of cellular states within a tumour cell population mediated by ecDNA copy number, emphasising the need for ecDNA-specific treatment strategies to tackle tumour formation and adaptation.
Adult-specific Reelin expression alters striatal neuronal organization. Implications for neuropsychiatric disorders
Authors: Pardo Mònica , Gregorio Sara , Montalban Enrica , Pujadas Lluís , Elias-Tersa Alba , Masachs Núria , Vílchez-Acosta Alba , Parent Annabelle , Auladell Carme , Girault Jean-Antoine , Vila Miquel , Nairn Angus C , Manso Yasmina , Soriano Eduardo 
Published: January 2023

AbstractIn addition to neuronal migration, brain development and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder and autistic spectrum disorder. Moreover, heterozygousreelermice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brain’s striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by μ-opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal Parvalbumin- and Cholinergic-interneurons, and to a slight increase in the tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.