bluuebunny/crossref_metadata_2025_split huggingface dataset:
SpeciateIT and vSpeciateDB: Novel, fast and accurate per sequence 16S rRNA gene taxonomic classification of vaginal microbiota
Authors: Holm Johanna B. , Gajer Pawel , Ravel Jacques 
Published: April 2024

AbstractClustering of sequences into operational taxonomic units (OTUs) and denoising methods are a mainstream stopgap to taxonomically classifying large numbers of 16S rRNA gene sequences. We developed speciateIT, a novel taxonomic classification tool which rapidly and accurately classifies individual amplicon sequences (https://github.com/Ravel-Laboratory/speciateIT). Environment-specific reference databases generally yield optimal taxonomic assignment. To this end, we also present vSpeciateDB, a custom reference database for the taxonomic classification of 16S rRNA gene amplicon sequences from vaginal microbiota. We show that speciateIT requires minimal computational resources relative to other algorithms and, when combined with vSpeciateDB, affords accurate species level classification in an environment-specific manner.ImportanceHerein, two resources with new and practical importance are described. The novel classification algorithm, speciateIT, is based on 7thorder Markov chain models and allows for fast and accurate per-sequence taxonomic assignments (as little as 10 min for 107sequences). vSpeciateDB, a meticulously tailored reference database, stands as a vital and pragmatic contribution. Its significance lies in the superiority of this environment-specific database to provide more species-resolution over its universal counterparts.
Spatial Transcriptomics in Bone Mechanomics: Exploring the Mechanoregulation of Fracture Healing in the Era of Spatial Omics
Authors: Mathavan Neashan , Singh Amit , Correia Marques Francisco , Günther Denise , Kuhn Gisela , Wehrle Esther , Müller Ralph 
Published: April 2024

AbstractIn recent decades, the field of bone mechanobiology has sought experimental techniques to unravel the molecular mechanisms governing the phenomenon of mechanically-regulated fracture healing. Each cell within a fracture site resides within different local micro-environments characterized by different levels of mechanical strain - thus, preserving the spatial location of each cell is critical in relating cellular responses to mechanical stimuli. Our spatial transcriptomics based “mechanomics” platform facilitates spatially-resolved analysis of the molecular profiles of cells with respect to their localin vivomechanical environment by integrating time-lapsedin vivomicro-computed tomography, spatial transcriptomics, and micro-finite element analysis. We investigate the transcriptomic responses of cells as a function of the local strain magnitude by identifying the differential expression of genes in regions of high and low strain within a fracture site. Our platform thus has the potential to address fundamental open questions within the field and to discover mechano-responsive targets to enhance fracture healing.
Massive outsourcing of energetically costly amino acids at the origin of animals
Authors: Kasalo Niko , Domazet-Lošo Mirjana , Domazet-Lošo Tomislav 
Published: April 2024

AbstractAnimals are generally capable of synthesizing eleven amino acids, while the remaining nine, often referred to as essential, must be acquired through diet. This characteristic profoundly impacts animals by defining their ecological lifestyles and evolutionary trajectory. Recent phylogenomic studies reveal that this phenotype results from gene losses that occurred at the root of the animal tree. However, it remains unclear which selective forces, if any, directed this far-reaching metabolic simplification event. Here, we show that essential amino acids are energetically far more expensive to synthesize than non-essential ones, particularly under high respiratory conditions—a hallmark of animal lifestyle. By applying permutation tests, we found that these difference in energy costs, counteracted by pleiotropy, created a selective pressure which led to the outsourcing of essential amino acids. Remarkably, we also found that extant animals use expensive amino acids more frequently compared to their closest unicellular relatives. This shows that animals significantly removed constraints on the usage of essential amino acids under high respiratory conditions by externalizing their production. Together, this implies that stabilizing selection underpinned by energy management drove this metabolic outsourcing in nutrient rich environments, thereby allowing animal genes to evolve more freely through protein sequence space. In this context, we propose that the origin of animals is tightly linked to energy-related adaptations rather than to unpredictable stochastic events, as recently suggested.
The F-box protein FBXL-5 governs vitellogenesis and lipid homeostasis inC. elegans
Authors: Breen Peter C. , Kanakanui Kendall G. , Newman Martin A. , Dowen Robert H. 
Published: April 2024

ABSTRACTThe molecular mechanisms that govern the metabolic commitment to reproduction, which often occurs at the expense of somatic reserves, remain poorly understood. We identified theC. elegansF-box protein FBXL-5 as a negative regulator of maternal provisioning of vitellogenin lipoproteins, which mediate the transfer of intestinal lipids to the germline. Mutations infbxl-5partially suppress the vitellogenesis defects observed in the heterochronic mutantslin-4andlin-29,both of which ectopically expressfbxl-5at the adult developmental stage. FBXL-5 functions in the intestine to negatively regulate expression of the vitellogenin genes; and consistently, intestine-specific over-expression of FBXL-5 is sufficient to inhibit vitellogenesis, restrict lipid accumulation, and shorten lifespan. Our epistasis analyses suggest thatfbxl-5functions in concert withcul-6, a cullin gene, and the Skp1-related geneskr-3to regulate vitellogenesis. Additionally,fbxl-5acts genetically upstream ofrict-1, which encodes the core mTORC2 protein Rictor, to govern vitellogenesis. Together, our results reveal an unexpected role for a SCF ubiquitin-ligase complex in controlling intestinal lipid homeostasis by engaging mTORC2 signaling.
Local cryptic diversity in salinity adaptation mechanisms in a wild outcrossingBrassica
Authors: Busoms Silvia , da Silva Ana C. , Escolà Glòria , Abdilzadeh Raziyeh , Curran Emma , Bollmann-Giolai Anita , Bray Sian , Wilson Michael , Poschenrieder Charlotte , Yant Levi 
Published: April 2024

AbstractIt is generally assumed that populations of the same species should evolve shared mechanisms of adaptation to common stressors due to evolutionary constraint. Here, we describe a novel system of within-species local adaptation to coastal habitats,Brassica fruticulosa,and detail surprising mechanistic variability in adaptive responses to extreme salinity. These radically different adaptive responses in neighbouring populations are evidenced by transcriptomes, diverse physiological outputs, and completely distinct genomic selective landscapes. In response to high salinity Northern Catalonian populations restrict root-to-shoot Na+transport, favouring K+uptake. Contrastingly, Central Catalonian populations accumulate Na+in leaves and compensate for the osmotic imbalance with compatible solutes such as proline and elevated Ca2+. Despite contrasting responses, both metapopulations were salinity tolerant relative to all inland accessions. To characterise the genomic basis of these two divergent adaptive strategies in an otherwise non-saline-tolerant endemic, we generate a long-read-based genome and population sequencing of 18 populations (9 inland, 9 coastal) across theB. fruticulosaspecies range. Results of genomic and transcriptomic approaches confirm the physiological observations of completely distinct underlying mechanisms of adaptation to extreme salinity and reveal potential genetic targets of these two recently evolved salinity adaptations. We therefore provide a new model of within-species salinity adaptation and reveal cryptic variation in neighbouring plant populations in the mechanisms of adaptation to an important natural stressor highly relevant to agriculture.SignificanceIt’s usually expected that closely related populations of a given species should adapt to the same environmental stressor in the same way due to genetic or physiological constraints. However, this is not commonly tested due to practical constraints. Here we show that, even at the level of neighbouring populations, contrasting adaptive mechanisms control adaptive responses to extreme coastal salinity in a new plant model,Brassica fruticulosa, a close wild relative of many crops of worldwide importance. This indicates multiple options for engineering an agriculturally crucial adaptation: soil salinization. These results will be of great interest to not only those studying fundamental mechanisms of adaptation, but also resilience improvement in Brassica species.
Coupling the role of lipids to the conformational dynamics of the ABC transporter P-gp
Authors: Vecchis Dario De , Schäfer Lars V. 
Published: April 2024

AbstractThe ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) is a multidrug efflux pump that is overexpressed in a variety of cancers and associated with the drug resistance phenomenon. P-gp structures were previously determined in detergent and in nanodiscs, in which different transmembrane helix conformations were found, “straight” and “kinked”, respectively, indicating a possible role of the lipid environment on the P-gp structural ensemble. Here, we investigate the dynamic conformational ensembles and protein-lipid interactions of the two human P-gp inward-open conformers (straight and kinked) employing all-atom molecular dynamics simulations in asymmetric multicomponent lipid bilayers that mimic the highly specialized hepatocyte membrane in which P-gp is expressed. The two conformers are found to differ in terms of the accessibility of the substrate cavity. The MD simulations show how cholesterol and different lipid species wedge, snorkel, and partially enter within the cavity of the straight P-gp conformer solved in detergent. However, the access to the cavity of kinked P-gp conformer solved in nanodiscs is restricted. Furthermore, the volume and dynamic fluctuations of the substrate cavity largely differ between the two P-gp structures, and are modulated by the presence (or absence) of cholesterol in the membrane and/or of ATP. From the mechanistic perspective, our findings indicate that the straight conformer likely precedes the kinked conformer in the functional working cycle of P-pg, with the latter conformation representing a post substrate-bound state. The inaccessibility of the main transmembrane cavity in the kinked conformer might be crucial in preventing substrate disengagement and transport withdrawal. Remarkably, in our unbiased MD simulations, one transmembrane portal helix (TM10) of the straight conformer underwent a spontaneous conformational transition to a kinked conformation, underlining the relevance of both conformations in a native phospholipid environment and revealing structural descriptors defining the transition between two P-gp conformers.
ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus
Authors: Mitias Samira , Schaffer Nicholas , Nair Saaya , Hook Chelsea , Lindberg Iris 
Published: April 2024

AbstractThe accumulation of β-amyloid in Alzheimer’s disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha synuclein and β-amyloid fibrillationin vitro, and is upregulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer’s progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using Western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control (and/or reduced degradation). ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Interestingly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer’s disease progression.
Chronic intermittent fasting impairs β-cell maturation and function in adolescent mice
Authors: Matta Leonardo , Weber Peter , Erener Suheda , Walth-Hummel Alina , Hass Daniela , Bühler Lea K. , Klepac Katarina , Szendroedi Julia , Guerra Joel , Rohm Maria , Sterr Michael , Lickert Heiko , Bartelt Alexander , Herzig Stephan 
Published: April 2024

SummaryIntermittent fasting (IF) is a nutritional lifestyle intervention with broad metabolic benefits, but whether the impact of IF depends on the individual’s age is unclear. Here, we investigated the effects of IF on systemic metabolism and pancreatic islet function in old, middle-aged, and young mice. Short-term IF improved glucose homeostasis across all age groups, without altering islet function and morphology. In contrast, while chronic IF was beneficial for adult mice, it resulted in impaired β-cell function in the young. Using scRNAseq, we delineated that the β-cell maturation and function score were reduced in young mice. In human islets, a similar pattern was observed in Type 1 (T1D), but not in Type 2 diabetes (T2D), suggesting that the impact of chronic IF in adolescence is linked to the development of β-cell dysfunction. Our study suggests considering the duration of IF in younger people, as it may enhance rather than reduce diabetes outcomes.Graphical abstractLong-term IF impairs β-cell function in adolescent mice.IF-induced impaired β-cell function is associated with impaired proliferative capacity and lower levels of mature cells.IF-induced impaired β-cell function is associated with a transcriptional change highly conserved in type 1-, but not type 2 diabetes.
Nrf2 regulates the activation-driven expansion of CD4+T-cells by differentially modulating glucose and glutamine metabolism
Authors: Tripathi Aprajita , Dasgupta Debolina , Pant Anil , Bugbee Ashlyn , Yellapu Nanda Kumar , Choi Ben H. Y. , Giri Shailendra , Pyaram Kalyani 
Published: April 2024

SUMMARYUpon antigenic stimulation, CD4+T-cells undergo clonal expansion, elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T-cells remains unexplored. Here, we elucidate the role of Nrf2 beyond the traditional antioxidation, in modulating activation-driven expansion of CD4+T-cells by influencing their nutrient metabolism. T-cell-specific activation of Nrf2 enhances early activation and IL-2 secretion, upregulates TCR-signaling, and increases activation-driven proliferation of CD4+T-cells. Mechanistically, high Nrf2 inhibits glucose metabolism through glycolysis but promotes glutamine metabolism via glutaminolysis to support increased T-cell proliferation. Further, Nrf2 expression is temporally regulated in activated CD4+T-cells with elevated expression during the early activation, but decreased expression thereafter. Overall, our findings uncover a novel role of Nrf2 as a metabolic modulator of CD4+T-cells, thus providing a framework for improving Nrf2-targeting therapies and T-cell immunotherapies.
Control over a mixture of policies determines change of mind topology during continuous choice
Authors: Fine Justin M. , Yoo Seng-Bum Michael , Hayden Benjamin Y. 
Published: April 2024

ABSTRACTBehavior is naturally organized into categorically distinct states with corresponding patterns of neural activity; how does the brain control those states? We propose that states are regulated by specific neural processes that implement meta-control that can blend simpler control processes. To test this hypothesis, we recorded from neurons in the dorsal anterior cingulate cortex (dACC) and dorsal premotor cortex (PMd) while macaques performed a continuous pursuit task with two moving prey that followed evasive strategies. We used a novel control theoretic approach to infer subjects’ moment-to-moment latent control variables, which in turn dictated their blend of distinct identifiable control processes. We identified low-dimensional subspaces in neuronal responses that reflected the current strategy, the value of the pursued target, and the relative value of the two targets. The top two principal components of activity tracked changes of mind in abstract and change-type-specific formats, respectively. These results indicate that control of behavioral state reflects the interaction of brain processes found in dorsal prefrontal regions that implement a mixture over low-level control policies.
Colonial Architecture Modulates the Speed and Efficiency of Multi-Jet Swimming in Salp Colonies
Authors: Damian-Serrano Alejandro , Walton Kai A. , Bishop-Perdue Anneliese , Bagoye Sophie , Du Clos Kevin T. , Gemmell Bradford J. , Colin Sean P. , Costello John H. , Sutherland Kelly R. 
Published: April 2024

AbstractSalps are marine pelagic tunicates with a complex life cycle including a solitary and colonial stage. Salp colonies are composed of asexually budded individuals that coordinate their swimming by multi-jet propulsion. Colonies develop into species-specific architectures with distinct zooid orientations. We hypothesize that colonial architecture drives differences in swimming performance between salps due to differences in how frontal drag scales with the number of propeller zooids in the colony. Moreover, we hypothesize that faster-swimming taxa are more energetically efficient in their locomotion since less energy would be devoted to overcoming drag forces. We (1) compare swimming speed across salp species and architectures, (2) evaluate how swimming speed scales with the number of zooids in the colony in architectures with constant and scaling frontal cross-sectional area, and (3) compare the metabolic cost of transport across different species and how it scales with swimming speed. To measure their swimming speeds, we recorded swimming salp colonies using in situ videography while SCUBA diving in the open ocean. To estimate the cost of transport, we measured the respiration rates of swimming and anesthetized salps collected in situ using jars equipped with non-invasive oxygen sensors. We found that linear colonies generally swim faster and with a lower cost of transport due to their differential advantage in frontal drag scaling with an increasing number of zooids. These findings underscore the importance of considering propeller arrangement to optimize speed and energy efficiency in bioinspired underwater vehicle design, leveraging lessons learned from the diverse natural laboratory provided by salp diversity.Summary StatementLinear arrangements in multi-jet propelled marine colonial invertebrates are faster and more energetically efficient than less streamlined architectures, offering insights for bioinspired underwater vehicle design.
Image-based Strain Analysis Reveals Intracellular Strain Controlled by Nucleo-Cytoskeletal Coupling
Authors: Chen Jerry C.C. , Sloan Iris , Bermudez Alexandra , Choi David , Tsai Ming-Heng , Jin Lihua , Hu Jimmy K. , Lin Neil Y.C. 
Published: April 2024

ABSTRACTCells can sense and transduce mechanical forces, such as stretching, and convert these signals into diverse cell biological events. While much effort has been devoted to identifying the downstream biochemical and cellular responses, it is equally crucial to pinpoint the mechanical stimuli within a cell driving these responses. Specifically, much remains unknown about how intracellular strains are distributed and controlled during mechanical deformation. In this study, we developed a microscopy-based intracellular strain measurement technique. Utilizing the intrapopulation mechanical heterogeneity of epithelial monolayers, we observed an inverse relationship between cytoplasmic and nuclear strains. We found that this anti-correlation is abolished by the inhibition of Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, suggesting that nucleo-cytoskeletal coupling controls intracellular strain distribution. We discovered a direct connection between cytoplasmic strain and stretch-induced nucleus size changes, implying that molecular events arising from cytoplasmic deformation may drive nuclear remodeling during stretching. By conducting multivariable analyses, we found that the intracellular strain can be inferred from cell morphology. Overall, our experimental platform and findings provide a foundation for unraveling the relationship between mechanotransduction pathways and upstream intracellular strain.SIGNIFICANCEMechanical stimuli exert influence on epithelial cells, not only orchestrating embryogenesis and regeneration, but also regulating cancer progression and inflammatory conditions. Despite efforts to identify mechanically activated molecular events, understanding how deformation is distributed within cells to induce subcellular responses remains limited. Specifically, the control of subcellular strain distribution during mechanical stretch is unclear. In this study, we developed a microscopy-based method to measure subcellular strain and observed an inverse relationship between cytoplasmic and nuclear strains. Disrupting nucleo-cytoplasmic coupling abolished this relationship, suggesting its role in controlling strain distribution. Additionally, we found that cytoplasmic strain correlates with nucleus size changes during stretching, indicating cytoplasmic events influence nucleus remodeling.