bluuebunny/crossref_metadata_2025_split huggingface dataset:
Habitat structural complexity increases age-class coexistence and population growth rate through relaxed cannibalism in medaka fish
Authors: Edeline Eric , Bennevault Yoann , Rozen-Rechels David 
Published: July 2023

ABSTRACTStructurally-complex habitats harbour more taxonomically-diverse and more productive communities, a phenomenon generally ascribed to habitat complexity relaxing the strength of inter-specific predation and competition. Here, we challenge this classical, community-centred view by showing that positive complexity-diversity and complexity-productivity relationships may also emerge from between-age-class,intra-specific interactions at a single-population level. In the laboratory, we show that medaka fish (Oryzias latipes) are strongly cannibalistic in complexity-free habitats, and that cannibalism may occur over a wide range of victim/cannibal body size ratios. In replicated outdoor pond populations, we manipulated habitat structural complexity using floating artificial structures, which selectively hampered movements of large-bodied medaka. Habitat structural complexity relaxed the strength of cannibalism, resulting in (1) increased survival of age-0+ individuals, (2) elevated age-class diversity through more balanced age-class proportions, (3) a 80 % increase in population growth rate, (4) dampened negative density-dependence in the effects of age-1+ medaka on the recruitment of age-0+ medaka, resulting in elevated habitat carrying capacity. The resultant higher population density in complex habitats was associated with increased competition for food among both age-0+ and age-1+ individuals. Our results highlight that positive complexity-diversity and complexity-productivity relationships may be considered as a generally-emergent property of size-structured populations and communities in which a larger body size brings a predation or interference advantage. Hence, enhancement of habitat structural complexity may be seen as a pivotal management strategy not only in favour of taxonomic diversity, but also to increase the productivity of exploited populations and to improve the conservation status of endangered species.
RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses
Authors: Rahjouei Ali , Kabrani Eleni , Berruezo-Llacuna Maria , Altwasser Robert , Delgado-Benito Veronica , Pavri Rushad , Virgilio Michela Di 
Published: July 2023

AbstractThe establishment of protective immune responses relies on the ability of terminally differentiated B cells to secrete a broad variety of antigen-specific antibodies with different effector functions. RIF1 is a multifunctional protein that promotes antibody isotype diversificationviaits DNA end protection activity during class switch recombination (CSR). In this study, we showed that RIF1 ablation resulted in increased plasmablast (PB) formationex vivoand enhanced terminal differentiation into plasma cells (PCs) upon immunization. Mechanistically, this phenotype is independent from RIF1’s role in DNA repair and CSR, and reflects its ability to modulate the transcriptional status of a subset of BLIMP1 target genes. Therefore, in addition to promoting antibody isotype diversification, RIF1 fine-tunes the kinetics of late B cell differentiation, thus providing an additional layer of control in the establishment of humoral immunity.
A Refined Phylochronology of the Second Plague Pandemic in Western Eurasia
Authors: Keller Marcel , Guellil Meriam , Slavin Philip , Saag Lehti , Irdt Kadri , Niinemäe Helja , Solnik Anu , Malve Martin , Valk Heiki , Kriiska Aivar , Cessford Craig , Inskip Sarah A. , Robb John E. , Cooper Christine , von Planta Conradin , Seifert Mathias , Reitmaier Thomas , Baetsen Willem A. , Walker Don , Lösch Sandra , Szidat Sönke , Metspalu Mait , Kivisild Toomas , Tambets Kristiina , Scheib Christiana L. 
Published: July 2023

AbstractAlthough dozens of ancientYersinia pestisgenomes and a vast corpus of documentary data are available, the origin and spread of consecutive outbreaks of the Second Plague Pandemic in Europe (14th–18th c.) are still poorly understood. For the majority of ancient genomes, only radiocarbon dates spanning several decades are available, hampering an association with historically recorded plague outbreaks. Here, we present new genomic evidence of the Second Pandemic from 11 sites in England, Estonia, the Netherlands, Russia, and Switzerland yielding 11Y. pestisgenomes with >4-fold mean coverage dating to between 1349 and 1710. In addition, we present a novel approach for integrating the chronological information retrieved from phylogenetic analysis with their respective radiocarbon dates, based on a novel methodology offering more precise dating intervals. Together with a fine-grained analysis of documentarily recorded plague outbreaks, this allows us to tentatively associate all availableY. pestisgenomes of the Second Pandemic with historically documented plague outbreaks. Through these combined multidisciplinary analytical efforts, our newly sequenced genomes can be attributed to the Black Death in Cambridge (England), thepestis tertiaorpestis quartain the late 14th century (Estonia), previously unknown branches emerging in the 15th century (Estonia, the Netherlands and England), and a widespread pandemic in Eastern Europe around 1500 (western Russia), which all seem to have originated from one or multiple reservoirs located in Central Europe. While the latter continued to harbour a majorY. pestislineage at least until the 1630s, represented by new genomes of the Thirty Years’ War plague (Switzerland), another lineage consecutively spread into Europe between the 17th and 18th century from the Ottoman Empire, as evidenced by a genome associated with the Great Northern War plague (Estonia). By combining phylogenetic analysis with a systematic historical reconstruction based on textual sources and an innovative phylogenetically informed radiocarbon modelling (PhIRM), we offer a new groundbreaking interdisciplinary approach that solves several fundamental methodological challenges associated with phylogenetic and spatio-temporal reconstruction of historical pandemics.
Conjugation ofcis-OPDA with amino acids is a conserved pathway affectingcis-OPDA homeostasis upon stress responses
Authors: Brunoni Federica , Široká Jitka , Mik Václav , Pospíšil Tomáš , Kralová Michaela , Ament Anita , Pernisová Markéta , Karady Michal , Htitich Mohamed , Ueda Minoru , Floková Kristýna , Wasternack Claus , Strnad Miroslav , Novák Ondřej 
Published: July 2023

AbstractJasmonates (JAs) are a family of oxylipin phytohormones regulating plant development and growth and mediating ‘defenseversusgrowth’ responses. The upstream JA biosynthetic precursorcis-(+)-12-oxo-phytodienoic acid (cis-OPDA) has been reported to act independently of the COI1-mediated JA signaling in several stress-induced and developmental processes. However, its means of perception and metabolism are only partially understood. Furthermore,cis-OPDA, but not JA, occurs in non-vascular plant species, such as bryophytes, exhibiting specific functions in defense and development. A few years ago, a low abundant isoleucine analog of the biologically active JA-Ile, OPDA-Ile, was detected in wounded leaves of flowering plants, opening up to the possibility that conjugation ofcis-OPDA to amino acids might be a relevant mechanism forcis-OPDA regulation. Here, we extended the analysis of amino acid conjugates ofcis-OPDA and identified naturally occurring OPDA-Val, OPDA-Phe, OPDA-Ala, OPDA-Glu, and OPDA-Asp in response to biotic and abiotic stress in Arabidopsis. The newly identified OPDA-amino acid conjugates showcis-OPDA-related plant responses in a JAR1-dependent manner. We also discovered that the synthesis and hydrolysis ofcis-OPDA amino acid conjugates are regulated by members of the amidosynthetase GH3 and the amidohydrolase ILR1/ILL families. Finally, we found that thecis-OPDA conjugative pathway already functions in non-vascular plants and gymnosperms. Thus, one level of regulation by which plants modulatecis-OPDA homeostasis is the synthesis and hydrolysis of OPDA-amino acid conjugates, which temporarily storecis-OPDA in stress responses.
Microfluidic organotypic device to test intestinal mucosal barrier permeability ex vivo
Authors: Cherwin Amanda E , Templeton Hayley N , Ehrlich Alexis T , Patlin Brielle H , Henry Charles S , Tobet Stuart A 
Published: July 2023

AbstractTo protect the body from external pathogens, the intestines have sophisticated epithelial and mucosal barriers. Disruptions to barrier integrity are associated with a variety of disorders such as irritable bowel disease, Crohn’s Disease, and celiac disease. One critical component of all barriers are collagens in the extracellular matrix. While the importance of the intestinal barrier is established, current models lack the ability to represent the complex biology that occurs at these barriers. For the current study a microfluidic device model was modified to determine the effectiveness of collagen breakdown to cause barrier disruption. Bacterial collagenase was added for 48 h to the luminal channel of a dual flow microfluidic device to examine changes in intestinal barrier integrity. Tissues exhibited dose-dependent alterations in immunoreactive collagen-1 and claudin-1, and coincident disruption of the epithelial monolayer barrier as indicated by goblet cell morphologies. This ex vivo model system offers promise for further studies exploring factors that affect gut barrier integrity and potential downstream consequences that cannot be studied in current models.
Metformin acts directly in the brain to slow features of neurodegeneration
Authors: Harding Edward C. , Chen Hsiao-Jou Cortina , Shepilov Dmytro , Welzer Marc , Macarelli Viviana , Schwiening Alix , Rowley Christine , Aggarwal Sanya , Swinden Dean , Kronenberg-Versteeg Deborah , Merkle Florian T. 
Published: July 2023

ABSTRACTDementia is a largely untreatable syndrome that is epidemiologically associated with metabolic diseases such as type 2 diabetes (T2D) and obesity. Drugs used to treat T2D such as metformin are inexpensive, safely given to millions of people, and have also been reported to slow neurodegeneration. We hypothesised that the neuroprotective benefits of metformin might extend to metabolically healthy individuals and tested this hypothesis in a mouse prion model that recapitulates key features of human neurodegenerative disease, including synaptic loss and motor impairment. These features and the time course of this model (24 weeks) allows the effects of metabolic risk factors and metformin to be tested and potentially generalised to other forms of neurodegenerative disease. Mice fed a high fat diet (HFD) developed high adiposity with impaired glucose and insulin homeostasis, similar to the effects of chronic obesity seen in humans whereas mice on matched control diet (CD) remain metabolically healthy. Chronic treatment with metformin in HFD-fed mice significantly increased survival and health span relative to vehicle-treated mice. Mice fed a HFD also had a modestly extended health span relative to mice fed CD, as measured by development of motor signs of prion disease. Metformin also significantly extended health span in metabolically healthy CD-fed mice. Using targeted mass spectrometry, we found that metformin reached deep brain structures at functional concentrations, driving a reduction in pPERK and changing the activity of microgliain vivo. Metformin was able to alter ER stress pathways at the same concentrations in healthy animals and using human iPSC-derived microglia and mouse organotypic slices we show that the action of metformin at these concentrations does not require a systemic mechanism, necessary for the treatment of diabetes, and is likely a result of direct secondary pharmacology in the brain. Together, these data broadly support the premise of repurposing metformin for neuroprotection, even in metabolically healthy individuals.
Determinants of Astrocytic Pathology in Stem Cell Models of Primary Tauopathies
Authors: Fiock Kimberly L. , Hook Jordan , Hefti Marco M. 
Published: July 2023

ABSTRACTAstrocytic tau aggregates are seen in several primary and secondary tauopathies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and chronic traumatic encephalopathy (CTE). In all cases, astrocytic tau consists exclusively of the longer (4R) tau isoform, even when adjacent neuronal aggregates consist of a mixture of 3- and 4R tau, as in CTE. The reasons for this and the mechanisms by which astrocytic tau aggregates form remain unclear. We used a combination of RNAin situhybridization and immunofluorescence in post-mortem human brain tissue, as well as tau uptake studies in human stem cell-derived astrocytes, to determine the origins of astrocytic tau in 4R tauopathies. We found that astrocytes across tauopathies do not upregulate tau mRNA expression between diseases or between tau-positive and -negative astrocytes within PSP. We then found that stem cell-derived astrocytes preferentially take up long isoform (4R) labeled recombinant tau and that this uptake is impaired by induction of reactivity with inflammatory stimuli or nutritional stress. Astrocytes exposed to either 3R or 4R tau also showed downregulation of genes related to astrocyte differentiation. Our findings suggest that astrocytes preferentially take up neuronal 4R tau from the extracellular space, which potentially explains why astrocytic tau aggregates contain only 4R tau, and that tau uptake is impaired by decreased nutrient availability or neuroinflammation, both of which are common in the aging brain.
BRAIDing receptors for cell-specific targeting
Authors: Chen Hui , Lee Sung-Jin , Li Ryan , Sura Asmiti , Suen Nicholas , Dilip Archana , Pomogov Yan , Vuppalapaty Meghah , Suen Timothy T. , Lu Chenggang , Post Yorick , Li Yang 
Published: July 2023

AbstractSystemic toxicity is a major challenge in the development of therapeutics. Consequently, cell-type-specific targeting is needed to improve on-target efficacy while reducing off-target toxicity. Here, we describe a cell-targeting system we have termed BRAID (BRidgedActivation byIntra/intermolecularDivision) whereby an active molecule is divided into two inactive or less active parts that are subsequently brought together via a so-called ‘bridging receptor’ on the target cell. This concept was validated using the WNT/β-catenin signaling system, demonstrating that a multivalent WNT agonist molecule divided into two inactive components assembled from different epitopes via the hepatocyte receptor βKlotho induces signaling specifically on hepatocytes. These data provide proof-of-concept for this cell-specific targeting strategy and in principle, this may also allow activation of multiple signaling pathways where desirable. This approach has broad application potential for other receptor systems.
Antimicrobial activity of iron-depriving pyoverdines against human opportunistic pathogens
Authors: Vollenweider Vera , Rehm Karoline , Chepkirui Clara , Pérez-Berlanga Manuela , Polymenidou Magdalini , Piel Jörn , Bigler Laurent , Kümmerli Rolf 
Published: July 2023

AbstractThe global rise of antibiotic resistance calls for new drugs against bacterial pathogens. A common approach is to search for natural compounds deployed by microbes to inhibit competitors. Here we show that the iron chelating pyoverdines, siderophores produced by environmentalPseudomonasspp., have strong antibacterial properties by inducing iron starvation and growth arrest in pathogens. A screen of 320 naturalPseudomonasisolates used against 12 human pathogens uncovered several pyoverdines with particularly high antibacterial properties and distinct chemical characteristics. The most potent pyoverdine effectively reduced growth of the pathogensAcinetobacter baumannii,Klebsiella pneumoniaeandStaphylococcus aureusin a concentration- and iron-dependent manner. Pyoverdine increased survival of infectedGalleria mellonellahost larvae, and showed low toxicity for the host, mammalian cell lines, and erythrocytes. Furthermore, experimental evolution combined with whole-genome sequencing revealed reduced potentials for resistance evolution compared to an antibiotic. Thus, pyoverdines from environmental strains have the potential to become a new class of sustainable antibacterials against specific human pathogens.
The miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Authors: Kretov Dmitry A. , Folkes Leighton , Mora-Martin Alexandra , Syedah Noreen , Walawalkar Isha A. , Vanyustel Kim , Moxon Simon , Murphy George J. , Cifuentes Daniel 
Published: July 2023

SUMMARYDifferentiation of stem and progenitor cells is a highly regulated process that involves the coordinated action of multiple layers of regulation. Here we show how the post-transcriptional regulatory layer instructs the level of chromatin regulation via miR-144 and its targets to orchestrate chromatin condensation during erythropoiesis. The loss of miR-144 leads to impaired chromatin condensation during erythrocyte maturation. Among the several targets of miR-144 that influence chromatin organization, the miR-144-dependent regulation of Hmgn2 is conserved from fish to humans. Our genetic probing of the miR-144/Hmgn2 regulatory axis established that intact miR-144 target sites in the Hmgn2 3’UTR are necessary for the proper maturation of erythrocytes in both zebrafish and human iPSC-derived erythroid cells while loss of Hmgn2 rescues in part the miR-144 null phenotype. Altogether, our results uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
Analysis of small EV proteomes reveals unique functional protein networks regulated by VAP-A
Authors: Barman Bahnisikha , Ramirez Marisol , Dawson T. Renee , Liu Qi , Weaver Alissa M 
Published: July 2023

AbstractExtracellular vesicles (EVs) influence cell phenotypes and functions via protein, nucleic acid and lipid cargoes. EVs are heterogeneous, due to diverse biogenesis mechanisms that remain poorly understood. Our previous study revealed that the endoplasmic rectiulum (ER) membrane contact site (MCS) linker protein VAP-A drives biogenesis of a subset of RNA-enriched EVs. Here, we examine the protein content of VAP-A-regulated EVs. Using label-free proteomics, we identified down- and up-regulated proteins in sEVs purified from VAP-A knockdown (KD) colon cancer cells. Gene set enrichment analysis (GSEA) of the data revealed protein classes that are differentially sorted to SEVs dependent on VAP-A. STRING protein-protein interaction network analysis of the RNA-binding protein (RBP) gene set identified several RNA functional machineries that are downregulated in VAP-A KD EVs, including ribosome, spliceosome, mRNA surveillance, and RNA transport proteins. We also observed downregulation of other functionally interacting protein networks, including cadherin-binding, unfolded protein binding, and ATP-dependent proteins.Significance of the studyLittle is known about biogenesis mechanisms that underlie EV heterogeneity. This study explores the protein repertoire of a specific subset of EVs that we recently identified to be generated at ER MCS and that are highly enriched in RNAs. We find that proteins from several classes of RNA machineries, including spliceosomes, are downregulated in EVs purified from cells knocked down for the ER MCS linker protein VAP-A. These data suggest that dynamic regulation of these protein machineries at ER MCS are involved in the sorting of RNA-RBP complexes into EVs.
Estimating error rates for single molecule protein sequencing experiments
Authors: Smith Matthew Beauregard , VanderVelden Kent , Blom Thomas , Stout Heather D. , Mapes James H. , Folsom Tucker M. , Martin Christopher , Bardo Angela M. , Marcotte Edward M. 
Published: July 2023

AbstractThe practical application of new single molecule protein sequencing (SMPS) technologies requires accurate estimates of their associated sequencing error rates. Here, we describe the development and application of two distinct parameter estimation methods for analyzing SMPS reads produced by fluorosequencing. A Hidden Markov Model (HMM) based approach, extendswhatprot, where we previously used HMMs for SMPS peptide-read matching. This extension offers a principled approach for estimating key parameters for fluorosequencing experiments, including missed amino acid cleavages, dye loss, and peptide detachment. Specifically, we adapted the Baum-Welch algorithm, a standard technique to estimate transition probabilities for an HMM using expectation maximization, but modified here to estimate a small number of parameter values directly rather than estimating every transition probability independently, which should help prevent overfitting. We demonstrate a high degree of accuracy on simulated data, but on experimental datasets, we observed that the model needed to be augmented with an additional error type, N-terminal blocking. This, in combination with data pre-processing, results in reasonable parameterizations of experimental datasets that agree with controlled experimental perturbations. A second independent implementation using a hybrid of DIRECT and Powell’s method to reduce the root mean squared error (RMSE) between simulations and the real dataset was also developed. We compare these methods on both simulated and real data, finding that our Baum-Welch based approach outperforms DIRECT and Powell’s method by most, but not all, criteria. Although some discrepancies between the results exist, we also find that both approaches provide similar error rate estimates from experimental single molecule fluorosequencing datasets.
Distinct haplogroups with star-like diversification in the APOBEC3 regulatory region indicate ancient viral pandemics before and during the Out-of-Africa migration of modern humans
Authors: Fujito Naoko T , Sundaramoorthy Revathi Devi , Satta Yoko , Inoue Ituro 
Published: July 2023

AbstractAPOBEC3s are powerful human anti-viral proteins that inhibit viral replication and proliferation by inducing mutations in viral genomes. We found that in the regulatory region of the APOBEC3 cluster on human chromosome 22, there exist three distinct haplogroups that began to have diverged nearly 1 million years ago and have since been maintained in both African and non-African populations today. Despite the long persistence time of the haplogroups, one of which is shared by archaic hominins, we also found that the nucleotide diversity within each haplogroup is extremely low. With a simulation-based method, the observed low diversity within haplogroups and large divergence between haplogroups suggested that these haplogroups have been maintained by special forms of positive Darwinian selection. Repeated occurrence of such selection entails the enhanced substitution rate in this regulatory region in both the human and chimpanzee lineages. The causal events of such positive selection, which are most likely viral epidemics, are shown to have occurred at least three times in the modern human population: one before the Out-of-Africa migration and another two in the common ancestors of non-Africans.