bluuebunny/crossref_metadata_2025_split huggingface dataset:
VAPA mediates lipid exchange betweenLeishmania amazonensisand host macrophages
Authors: Gdovinova Ilona , Descoteaux Albert 
Published: October 2024

ABSTRACTLeishmaniais a vacuolar pathogen that replicates within parasitophorous vacuoles inside host phagocytes. To promote its replication,Leishmaniarelies on a panoply of strategies to acquire macromolecules such as lipids from host macrophages. In this study, we have evaluated the role of VAPA, an endoplasmic reticulum-resident membrane protein involved in inter-organellar lipid transport, in macrophages infected withL. amazonensis. Following infection of bone marrow-derived macrophages with metacyclicL. amazonensispromastigotes, we observed that VAPA gradually associates with communal parasitophorous vacuoles. Knockdown of VAPA prevented the replication ofL. amazonensis, which was accompanied by an impaired parasitophorous vacuole expansion. Using fluorescent ceramide, we established that VAPA is required for the transport of sphingolipids to the parasitophorous vacuoles and for its acquisition byL. amazonensisamastigotes. Proximity-ligation and immunoprecipitation assays revealed thatL. amazonensishijacks VAPA by disrupting its interactions with the lipid transfer proteins CERT and ORP1L. Finally, we found that VAPA is essential for the transfer of theLeishmaniavirulence glycolipid lipophosphoglycan from the parasitophorous vacuoles to the host cell endoplasmic reticulum. We propose that VAPA contributes to the ability ofL. amazonensisto colonize macrophages by mediating bi-directional transfer of lipids essential for parasite replication and virulence between the parasitophorous vacuoles and the host cell endoplasmic reticulum.AUTHOR SUMMARYThe protozoan parasiteLeishmania amazonensisreplicates in macrophages, within communal parasitophorous vacuoles. To satisfy its various auxotrophies, this parasite must obtain macronutrients and metabolites from its host cell, including lipids. To salvage host sphingolipids, we obtained evidence thatL. amazonensisexploits a macrophage nonvesicular lipid transport mechanism that requires the endoplasmic reticulum membrane protein VAPA. Moreover, we found that VAPA is also required for the transfer of theLeishmaniavirulence glycolipid lipophosphoglycan from the parasitophorous vacuole to the macrophage endoplasmic reticulum. The fact that VAPA is essential forL. amazonensisto colonize macrophages is consistent with the central role that VAPA plays in mediating bi-directional transfer of lipids and illustrates the importance of the host cell endoplasmic reticulum in this host-parasite interaction.
De novo design of ATPase based on the blueprint optimized for harboring the P-loop motif
Authors: Kosugi Takahiro , Tanabe Mikio , Koga Nobuyasu 
Published: October 2024

AbstractDe novo design of proteins has seen remarkable recent progress and has provided understanding of folding and functional expression. However, rationally creating enzymes with high activity comparable to most naturally occurring enzymes remains challenging. Here, we attempted to design an ATPase de novo, through the exploration of an optimal backbone blueprint to incorporate a conserved phosphate binding motif, the P-loop, into designed structures. The designed protein, based on the identified blueprint, was found to be a monomer with high thermal stability, and exhibited the ATPase ability. The crystal structure was closely matched to the design model, both at the overall structure level and within the P-loop motif. Interestingly, AlphaFold was not able to predict the designed structure accurately, indicating the difficulties of predicting folded structures for novel protein sequences. Remarkably, the designed protein exhibited ATPase ability even at temperatures around 100 °C, with significantly increased activity. However, the ATPase activity was still not comparable to those of naturally occurring enzymes. This suggests that the P-loop motif alone is insufficient to achieve the high ATPase activity seen in naturally occurring enzymes, indicating that other structural components are necessary to reach such activity levels.
3D mechanical confinement directs muscle stem cell fate and function
Authors: Park GaYoung , Grey Josh A. , Mourkioti Foteini , Han Woojin M. 
Published: October 2024

ABSTRACTMuscle stem cells (MuSCs) play a crucial role in skeletal muscle regeneration, residing in a niche that undergoes dimensional and mechanical changes throughout the regeneration process. This study investigates how three-dimensional (3D) confinement and stiffness encountered by MuSCs during the later stages of regeneration regulate their function, including stemness, activation, proliferation, and differentiation. We engineered an asymmetric 3D hydrogel bilayer platform with tunable physical constraints to mimic the regenerating MuSC niche. Our results demonstrate that increased 3D confinement maintainsPax7expression, reduces MuSC activation and proliferation, inhibits differentiation, and is associated with smaller nuclear size and decreased H4K16ac levels, suggesting that mechanical confinement modulates both nuclear architecture and epigenetic regulation. MuSCs in unconfined two-dimensional (2D) environments exhibited larger nuclei and higher H4K16ac expression compared to those in more confined 3D conditions, leading to progressive activation, expansion, and myogenic commitment. This study highlights the importance of 3D mechanical cues in MuSC fate regulation, with 3D confinement acting as a mechanical brake on myogenic commitment, offering novel insights into the mechano-epigenetic mechanisms that govern MuSC behavior during muscle regeneration.
Population history of Swedish cattle breeds: estimates and model checking
Authors: Adepoju Dolapo , Ohlsson J Ingemar , Klingström Tomas , Rius-Vilarrasa Elisenda , Johansson Anna M , Johnsson Martin 
Published: October 2024

AbstractIn this work, we use linkage disequilibrium-based methods to estimate recent population history from genotype data in Swedish cattle breeds, as well as international Holstein and Jersey cattle data for comparison. Our results suggest that these breeds have been effectively large up until recently, when they declined around the onset of systematic breeding. The inferred trajectories were qualitatively similar, with a large historical population and one decline. We used population genetic simulation to check the inferences. When comparing simulations from the inferred population histories to real data, the proportion low-frequency variants in real data was different than was implied by the inferred population histories, and there was somewhat higher genomic inbreeding in real data than implied by the inferred histories. The inferred population histories imply that much of the variation we see today is transient, and it will be lost as the populations settle into a new equilibrium, even if efforts to maintain effective population size at current levels are successful.
APC coordinates GSK3 phosphorylation of SETD8 to suppress colorectal cancer
Authors: Cramer Zvi , Monaghan Keara , Petroni Ricardo , Wang Xin , Adams-Tzivelekidis Stephanie , Durning Kayla , Kim Melissa S. , Tian Yuhua , Johnson Nicolette M. , Leu Nicolae A. , Sidoli Simone , Li Ning O. , Andres Blanco M. , Lengner Christopher J. 
Published: October 2024

AbstractColorectal cancer (CRC) is the second-leading cause of cancer-related deaths with increasing incidence globally. Mutations in the tumor suppressor APC initiate CRC at least in part by preventing the GSK3 kinase from phosphorylating β-CATENIN, leading to its constitutive stabilization and transactivation of mitogenic target genes. While the importance of β-CATENIN phosphorylation by GSK3 is well-established, APC regulation of GSK3 activity upon other targets with potential oncogenic relevance are not understood. Here, we identify the H4K20 methyltransferase SETD8 as target of APC-coordinated GSK3 phosphorylation in the intestinal epithelium. We found that phosphorylation by GSK3 restrains the oncogenic activity of SETD8, with loss of phosphorylation sensitizing mice to oncogenic insults. Mechanistically, phosphorylation alters the role of SETD8 in transcriptional regulation, most notably by preventing it from activating oncogenic YAP signaling and a fetal-like transcriptional program. These results underscore the importance of SETD8 in CRC and represent a novel β-CATENIN -independent oncogenic consequence of APC loss.SignificanceGSK3 is thought to restrain colorectal cancer primarily by phosphorylation of β-CATENIN. We show that GSK3 also phosphorylates SETD8, preventing SETD8 activation of oncogenic programs including YAP-driven fetal-like gene expression.
Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome
Authors: Islam Md Rezaul , Jackson Brennan , Naomi Maeesha Tasnim , Schatz Brooke , Tan Noah , Murdock Mitchell , Park Dong Shin , Amorim Daniela Rodrigues , Jiang Fred , Sebastian Pineda S. , Adaikkan Chinnakkaruppan , Fernandez Vanesa , Geigenmuller Ute , Firenze Rosalind Mott , Kellis Manolis , Boyden Edward S. , Tsai Li-Huei 
Published: October 2024

SummaryDown syndrome (DS) has been linked with deficits in hippocampal dependent cognitive tasks and adult neurogenesis, yet treatment options are still very limited. We and others previously showed that a non-invasive multisensory gamma stimulation using light and sound at 40 Hz ameliorated Alzheimer’s disease pathology and symptoms in mouse models. In this study, we tested the effects of 40 Hz multisensory stimulation in the Ts65Dn mice, a mouse model of DS. For three weeks, mice were exposed daily to one hour of stimulation or one hour of ambient light and sound. Mice receiving the stimulation showed improved object recognition and spatial working memory. Using single nuclei RNA-seq and experimental validations in mouse hippocampal samples, we identified underlying expression changes in gene regulatory networks and demonstrated increased adult neurogenesis and reorganization of synapses as potential mechanisms for these improved cognitive phenotypes. Together, our data reveal a novel effect of multisensory gamma stimulation on adult neurogenesis and beneficial effects of 40 Hz treatment on cognitive function in DS model mice.Significance StatementWe present strong evidence, using a well-characterized mouse model, that the cognitive and neurogenesis deficits in Down syndrome can be improved through non-invasive multi-sensory gamma stimulation. Employing a systems biology approach, we provide extensive hippocampal single-cell resolution gene expression signatures and changes in gene regulatory networks in response to sensory gamma stimulation.
Mosaic Regulation of Stress Pathways Underlies Senescent Cell Heterogeneity
Authors: Avelar Roberto A. , Duffield Thomas , Lagger Cyril , Krstevska Nikita , Breuer Marian , de Magalhães João Pedro 
Published: October 2024

AbstractCellular senescence (CS) and quiescence (CQ) are stress responses characterised by persistent and reversible cell cycle arrest, respectively. These phenotypes are heterogeneous, dependent on the cell type arrested and the insult inciting arrest. Because a universal biomarker for CS has yet to be identified, combinations of senescence-associated biomarkers linked to various biological stress responses including lysosomal activity (β-galactosidase staining), inflammation (senescence-associated secretory phenotypes, SASPs), and apoptosis (senescent cell anti-apoptotic pathways) are used to identify senescent cells.Using in vitro human bulk RNA-seq datasets, we find that senescent states enrich for various stress responses in a cell-type, temporal, and insult-dependent manner. We further demonstrate that various gene signatures used to identify senescent cells in the literature also enrich for stress responses, and are inadequate for universally and exclusively identifying senescent samples.Genes regulating stress responses – including transcription factors and genes controlling chromatin accessibility – are contextually differentially expressed, along with key enzymes involved in metabolism across arrest phenotypes. Additionally, significant numbers of SASP proteins can be predicted from senescent cell transcriptomes and also heterogeneously enrich for various stress responses in a context-dependent manner.We propose that ‘senescence’ cannot be meaningfully defined due to the lack of underlying preserved biology across senescent states, and CS is instead a mosaic of stress-induced phenotypes regulated by various factors, including metabolism, TFs, and chromatin accessibility. We introduce the concept of Stress Response Modules, clusters of genes modulating stress responses, and present a new model of CS and CQ induction conceptualised as the differential activation of these clusters.
An electrophysiological study about the pharmacological manipulation of the immediate consequences of a spinal trauma reveals a crucial role for TRPV4 antagonism
Authors: Mohammadshirazi Atiyeh , Taccola Giuliano 
Published: October 2024

AbstractA physical trauma to the spinal cord produces an immediate massive depolarizing injury potential accompanied both by a transient episode of spinal hypoxia, and an extensive cell loss at the level of injury, which interrupts conduction of longitudinal input along white matter tracts. Afterwards, the transient hypotonia and areflexia characterize the following spinal shock phase. The relationship between the extent of injury potentials and spinal cord injury (SCI) progression, as well as the potential pharmacological modulation of the immediate consequences of a trauma, have not yet been explored. To limit the peak of injury potentials and speed up recovery of reflex motor responses, we serially applied selective neurochemicals in the exact moment of an experimental physical trauma delivered through a calibrated device impacting the mid-thoracic cord of an entire CNS preparation of neonatal rats. Continuous lumbar root recordings monitored baseline DC-levels and reflex responses elicited by trains of electric pulses applied to sacrocaudal afferents. In uninjured preparations, each agent showed distinct effects on baseline polarization, modulation of synaptic responses, and appearance of bursting activity. Interestingly, neurochemicals acting on glutamatergic-, adenosinergic-, glycinergic- or GABAergic receptors, did not affect the monitored outcome when each parameter was normalized against pre-injury values. Conversely, the selective TRPV4 antagonist, RN1734, unlike the TRPA1 antagonist, AP18, reduced peak of injury potentials and speeded up full recovery of reflex responses within 1 min from trauma. Similarly, blockage of gap junctions quickly, yet partially, restored motor reflexes, while antagonism of GABAAreceptors restored full reflexes, though slightly later. The current study indicates that both mechanosensitive TRPV4 receptors and GABAergic transmission reduce the immediate pathological consequences of a trauma when applied at the moment of impact, envisaging a clinical translation for preventing accidental spinal lesions during the most delicate spinal surgeries.
ENDOTHELIAL PROX1 INDUCES BLOOD-BRAIN BARRIER DISRUPTION IN THE CENTRAL NERVOUS SYSTEM
Authors: González-Hernández Sara , Sato Ryo , Sato Yuya , Liu Chang , Li Wenling , Liu Chengyu , Jackson Sadhana , Kubota Yoshiaki , Mukouyama Yoh-suke 
Published: October 2024

ABSTRACTThe central nervous system (CNS) parenchyma has conventionally been believed to lack lymphatic vasculature, likely due to a non-permissive microenvironment that hinders the formation and growth of lymphatic endothelial cells (LECs). Recent findings of ectopic expression of LEC markers including Prospero Homeobox 1 (PROX1), a master regulator of lymphatic differentiation, and the vascular permeability marker Plasmalemma Vesicle Associated Protein (PLVAP), in certain glioblastoma and brain arteriovenous malformations (AVMs), has prompted investigation into their roles in cerebrovascular malformations, tumor environments, and blood-brain barrier (BBB) abnormalities. To explore the relationship between ectopic LEC properties and BBB disruption, we utilized endothelial cell-specificProx1overexpression mutants. When induced during embryonic stages of BBB formation, endothelialProx1expression induces hybrid blood-lymphatic phenotypes in the developing CNS vasculature. This effect is not observed whenProx1is overexpressed during postnatal BBB maturation. EctopicProx1expression leads to significant vascular malformations and enhanced vascular leakage, resulting in BBB disruption when induced during both embryonic and postnatal stages. Mechanistically, PROX1 downregulates critical BBB-associated genes, includingß-cateninandClaudin-5, which are essential for BBB development and maintenance. These findings suggest that PROX1 compromises BBB integrity by negatively regulating BBB-associated gene expression and Wnt/ß-catenin signaling.
A feedforward loop between STAT1 and YAP1 stimulates lipid biosynthesis, accelerates tumor growth, and promotes chemotherapy resistance in mutant KRAS colorectal cancer
Authors: Wang Shuo , Diao Shiqi , Kim Hyungdong , Zou Jia Yi , Li Ke Ke , Koromilas Antonis E. 
Published: October 2024

ABSTRACTIn tumorous conditions, the transcription factor STAT1, traditionally recognized for its anti-tumor role in immunology, exhibits pro-survival characteristics, though the underlying mechanisms remain unclear. Investigating STAT1’s function in isogenic colorectal tumor cells with wild-type or mutant KRAS, we found that STAT1 specifically promotes the survival and proliferation of cells with mutant KRAS. Through gene expression profiling, we discovered a previously unknown role of STAT1 in upregulating sterol and lipid biosynthetic genes specifically in mutant KRAS cells. This effect is driven by STAT1’s phosphorylation at serine 727 and its cooperation with STAT3 and STAT5 for the transcriptional upregulation of sterol regulatory element-binding proteins (SREBP) 1 and 2, which boostde novosterol and lipid biosynthesis. In mutant KRAS cells, STAT1 amplifies the mevalonate pathway, maintaining its serine 727 phosphorylation through RHO GTPase signaling and establishing a positive feedback loop through the transcription factors YAP1 and TEAD4, further driving lipid biosynthesis and tumor growth. Through xenograft tumor assays in mice, we discovered that the STAT1-YAP1 axis plays a role in mutant KRAS tumor cells’ resistance to mevalonate pathway inhibitors, which can be overcome by pharmacologically targeting the YAP1-TEAD interaction. Additionally, the STAT1-YAP1 arm is essential for the intrinsic resistance to EGFR-targeting therapy in the mutant KRAS colon cancer cells. These findings indicate that the STAT1-YAP1 pathway plays a significant role in therapy resistance and presents a potential therapeutic target in mutant KRAS colorectal cancer.
Disruptive effect of rainfalls on the diurnal periodicity of airborne wheat rust spore under field conditions
Authors: Suffert Frederic 
Published: October 2024

AbstractStripe rust and leaf rust, caused byPuccinia striiformisf. sp.tritici(Pst) andPuccinia triticina(Pt), respectively, are major threats to wheat production. Forecasting epidemics requires a deeper understanding of the mechanisms driving spore dispersal. Many studies have either employed field data for purely correlative approaches without incorporating established knowledge on physical mechanisms or, conversely, relied on specific physical approaches in controlled environments focusing on only a few mechanisms or factors. Little emphasis has been placed on holistic field-based studies, where wind and rain play crucial roles. This study fills that gap by attempting to unravel the processes by which rainfall affects airborne spore concentrations over a wheat canopy during active rust epidemics. Over more than two months, bi-hourly spore counts from Burkard traps were integrated with detailed meteorological data, revealing both seasonal and diurnal trends. Diurnal peaks in airborne spore concentrations, typically driven by cyclic changes in wind and humidity, were dramatically altered by rain. Rain events either amplified spore concentrations by up to 25-fold through ‘rain-puff’ and/or depletes them via ‘wash-out’ and ‘wash-off’. Rains events from the dataset were classified into categories with distinct impacts: ‘precursor’ rains often trigger spore release, while ‘follower’ (and prolonged rains) reduce airborne spore concentrations. Moreover, differences in the dispersal dynamics ofPstandPtwere observed, and some were linked to how humidity and wind influence spore clustering. These results provide valuable insights for a more integrated understanding of the effect of rain and in order to enhance forecasting models.
Quantifying transcriptome turnover on phylogenies by modeling gene expression as a binary trait
Authors: Thompson Ammon , May Michael R. , Hopkins Ben , Riedl Nerisa , Barmina Olga , Liebeskind Benjamin J. , Zhao Li , Begun David , Kopp Artyom 
Published: October 2024

AbstractChanges in gene expression are a key driver of phenotypic evolution, leading to a persistent interest in the evolution of transcriptomes. Traditionally, gene expression is modeled as a continuous trait, leaving qualitative transitions largely unexplored. In this paper, we detail the development of new Bayesian inference techniques to study the evolutionary turnover of organ-specific transcriptomes, which we define as instances where orthologous genes gain or lose expression in a particular organ. To test these techniques, we analyze the transcriptomes of two male reproductive organs, testes and accessory glands, across 11 species of the Drosophila melanogaster species group. We first discretize gene expression states by estimating the probability that each gene is expressed in each organ and species. We then define a phylogenetic model of correlated transcriptome evolution in two or more organs and fit it to the expression state data. Inferences under this model show that many genes have gained and lost expression in each organ, and that the two organs experienced accelerated transcriptome turnover on different branches of the Drosophila phylogeny.
CMTM4 is an adhesion modulator that regulates skeletal patterning and primary mesenchyme cell migration in sea urchin embryos
Authors: Descoteaux Abigail E. , Radulovic Marko , Alburi Dona , Bradham Cynthia A. 
Published: October 2024

AbstractMARVEL proteins, including those of the CMTM gene family, are multi-pass transmembrane proteins that play important roles in vesicular trafficking and cell migration; however, little is understood about their role in development, and their role in skeletal patterning is unexplored. CMTM4 is the only CMTM family member found in the developmental transcriptome of the sea urchinLytechinus variegatus. Here, we validate that LvCMTM4 is a transmembrane protein and show that perturbation of CMTM4 expression via zygotic morpholino or mRNA injection perturbs skeletal patterning, resulting in loss of secondary skeletal elements and rotational defects. We also demonstrate that normal levels of CMTM4 are required for normal PMC migration and filopodial organization, and that these effects are not due to gross mis-specification of the ectoderm. Finally, we show that CMTM4 is sufficient to mediate PMC cell-cell adhesion. Taken together, these data suggest that CMTM4 controls PMC migration and biomineralization via adhesive regulation during sea urchin skeletogenesis. This is the first discovery of a functionally required adhesive gene in this skeletal patterning system.Graphical Abstract