bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and adapt to glucose depletion
Authors: Niphadkar Shreyas , Karinje Lavanya , Laxman Sunil 
Published: July 2023

AbstractTo sustain growth in changing nutrient conditions, cells reorganize outputs of metabolic networks and appropriately reallocate resources. Signaling by reversible protein phosphorylation can control such metabolic adaptations. In contrast to kinases, the functions of phosphatases that enable metabolic adaptation as glucose depletes are poorly studied. Using aSaccharomyces cerevisiaedeletion screen, we identified the requirement of PP2A-like phosphatase Ppg1 for appropriate carbon allocations towards gluconeogenic outputs – trehalose, glycogen, UDP-glucose, UDP-GlcNAc – specifically after glucose depletion. This homeostatic Ppg1 function is mediated via regulation of the assembly of the Far complex - a multi-subunit complex that tethers to the ER and mitochondrial outer membranes as localized signaling hubs. We show that the Far complex assembly is Ppg1 catalytic activity-dependent. The assembled Far complex is required to maintain gluconeogenic outputs after glucose depletion. Glucose in turn regulates Far complex abundance. This Ppg1-mediated Far complex assembly, and dependent control of gluconeogenic outputs enhances adaptive growth under glucose depletion. Our study illustrates how protein dephosphorylation is required for the assembly of a multi-protein scaffold present in localized cytosolic pools, to thereby enable cells metabolically adapt to nutrient fluctuations.
LRP1 mediates leptin transport by coupling with the short-form leptin receptor in the choroid plexus
Authors: Uner Aaron Aykut , Yang Won-Mo , Kang Min-Cheol , Rodrigues Kellen Cristina da Cruz , Aydogan Ahmet , Seo Ji A , Mendes Natalia F. , Kim Min-Seon , Timzoura Fatima Ezzahra , Holtzman Michael J. , Lehtinen Maria , Prevot Vincent , Kim Young-Bum 
Published: July 2023

AbstractAdipocyte-derived leptin enters the brain to exert its anorexigenic action, yet its transport mechanism is poorly understood. Here we report that LRP1 (low-density lipoprotein receptor-related protein-1) mediates the transport of leptin across the blood-CSF barrier inFoxj1expressing cells highly enriched at the choroid plexus (ChP), coupled with the short-form leptin receptor, and LRP1 deletion from ependymocytes and ChP cells leads to leptin resistance and hyperphagia, causing obesity. Thus, LRP1 in epithelial cells is a principal regulator of leptin transport in the brain.
Putting cognitive tasks on trial: A measure of reliability convergence
Authors: Kadlec Jan , Walsh Catherine , Sadé Uri , Amir Ariel , Rissman Jesse , Ramot Michal 
Published: July 2023

AbstractThe surge in interest in individual differences has coincided with the latest replication crisis centered around brain-wide association studies of brain-behavior correlations. Yet the reliability of the measures we use in cognitive neuroscience, a crucial component of this brain-behavior relationship, is often assumed but not directly tested. Here, we evaluate the reliability of different cognitive tasks on a large dataset of over 250 participants, who each completed a multi-day task battery. We show how reliability improves as a function of number of trials, and describe the convergence of the reliability curves for the different tasks, allowing us to score tasks according to their suitability for studies of individual differences. To improve the accessibility of these findings, we designed a simple web-based tool that implements this function to calculate the convergence factor and predict the expected reliability for any given number of trials and participants, even based on limited pilot data.
Competition for light can drive adverse species-composition shifts in the Amazon Forest under elevated CO2
Authors: Joshi Jaideep , Hofhansl Florian , Singh Shipra , Stocker Benjamin D. , Brännström Åke , Franklin Oskar , Blanco Carolina C. , Aleixo Izabela F. , Lapola David , Prentice Iain Colin , Dieckmann Ulf 
Published: July 2023

AbstractThe resilience of biodiverse forests to climate change depends on an interplay of adaptive processes operating at multiple temporal and organizational scales. These include short-term acclimation of physiological processes like photosynthesis and respiration, mid-term changes in forest structure due to competition, and long-term changes in community composition arising from competitive exclusion and genetic trait evolution. To investigate the roles of diversity and adaptation for forest resilience, we present Plant-FATE, a parsimonious eco-evolutionary vegetation model. Tested with data from a hyperdiverse Amazonian terra-firme forest, our model accurately predicts multiple emergent ecosystem properties characterizing forest structure and function. Under elevated CO2conditions, we predict an increase in productivity, leaf area, and aboveground biomass, with the magnitude of this increase declining in nutrient-deprived soils if trees allocate more carbon to the rhizosphere to overcome nutrient limitation. Furthermore, increased aboveground productivity leads to greater competition for light and drives a shift in community composition towards fast-growing but short-lived species characterized by lower wood densities. Such a transition reduces the carbon residence time of woody biomass, dampening carbon-sink strength and potentially rendering the Amazon Forest more vulnerable to future climatic extreme events.
Covalent macrocyclic proteasome inhibitors mitigate resistance inPlasmodium falciparum
Authors: Bennett John M. , Ward Kurt E. , Muir Ryan , Kabeche Stephanie , Yoo Euna , Yeo Tomas , Lam Grace , Zhang Hao , Almaliti Jehad , Berger Gabriel , Faucher Franco F. , Lin Gang , Gerwick William H. , Yeh Ellen , Fidock David A. , Bogyo Matthew 
Published: July 2023

ABSTRACTThePlasmodiumproteasome is a promising antimalarial drug target due to its essential role in all parasite lifecycle stages. Furthermore, proteasome inhibitors have synergistic effects when combined with current first-line artemisinins. Linear peptides that covalently inhibit the proteasome are effective at killing parasites and have a low propensity for inducing resistance. However, these scaffolds generally suffer from poor pharmacokinetics and bioavailability. Here we describe the development of covalent, irreversible macrocyclic inhibitors of theP. falciparumproteasome. We identified compounds with excellent potency and low cytotoxicity, however, the first generation suffered from poor microsomal stability. Further optimization of an existing macrocyclic scaffold resulted in an irreversible covalent inhibitor carrying a vinyl sulfone electrophile that retained high potency, low cytotoxicity, and had acceptable metabolic stability. Importantly, unlike the parent reversible inhibitor that selected for multiple mutations in the proteasome, with one resulting in a 5,000-fold loss of potency, the irreversible analog only showed a 5-fold loss in potency for any single point mutation. Furthermore, an epoxyketone analog of the same scaffold retained potency against a panel of known proteasome mutants. These results confirm that macrocycles are optimal scaffolds to target the malarial proteasome and that the use of a covalent electrophile can greatly reduce the ability of the parasite to generate drug resistance mutations.
Divergent Molecular Phenotypes in Point Mutations at the Same Residue in Beta-Myosin Heavy Chain Lead to Distinct Cardiomyopathies
Authors: Lehman Sarah J. , Meller Artur , Solieva Shahlo O. , Lotthammer Jeffrey M. , Greenberg Lina , Langer Stephen J. , Greenberg Michael J. , Tardiff Jil C. , Bowman Gregory R. , Leinwand Leslie 
Published: July 2023

AbstractIn genetic cardiomyopathies, a frequently described phenomenon is how similar mutations in one protein can lead to discrete clinical phenotypes. One example is illustrated by two mutations in beta myosin heavy chain (β-MHC) that are linked to hypertrophic cardiomyopathy (HCM) (Ile467Val, I467V) and left ventricular non-compaction (LVNC) (Ile467Thr, I467T). To investigate how these missense mutations lead to independent diseases, we studied the molecular effects of each mutation using recombinant human β-MHC Subfragment 1 (S1) inin vitroassays. Both HCM-I467V and LVNC-I467T S1 mutations exhibited similar mechanochemical function, including unchanged ATPase and enhanced actin velocity but had opposing effects on the super-relaxed (SRX) state of myosin. HCM-I467V S1 showed a small reduction in the SRX state, shifting myosin to a more actin-available state that may lead to the “gain-of-function” phenotype commonly described in HCM. In contrast, LVNC-I467T significantly increased the population of myosin in the ultra-slow SRX state. Interestingly, molecular dynamics simulations reveal that I467T allosterically disrupts interactions between ADP and the nucleotide-binding pocket, which may result in an increased ADP release rate. This predicted change in ADP release rate may define the enhanced actin velocity measured in LVNC-I467T, but also describe the uncoupled mechanochemical function for this mutation where the enhanced ADP release rate may be sufficient to offset the increased SRX population of myosin. These contrasting molecular effects may lead to contractile dysregulation that initiates LVNC-associated signaling pathways that progress the phenotype. Together, analysis of these mutations provides evidence that phenotypic complexity originates at the molecular level and is critical to understanding disease progression and developing therapies.
InterpretingCis-Regulatory Interactions from Large-Scale Deep Neural Networks for Genomics
Authors: Toneyan Shushan , Koo Peter K 
Published: July 2023

ABSTRACTThe rise of large-scale, sequence-based deep neural networks (DNNs) for predicting gene expression has introduced challenges in their evaluation and interpretation. Current evaluations align DNN predictions with experimental perturbation assays, which provides insights into the generalization capabilities within the studied loci but offers a limited perspective of what drives their predictions. Moreover, existing model explainability tools focus mainly on motif analysis, which becomes complex when interpreting longer sequences. Here we introduce CREME, anin silicoperturbation toolkit that interrogates large-scale DNNs to uncover rules of gene regulation that it learns. Using CREME, we investigate Enformer, a prominent DNN in gene expression prediction, revealingcis-regulatory elements (CREs) that directly enhance or silence target genes. We explore the intricate complexity of higher-order CRE interactions, the relationship between CRE distance from transcription start sites on gene expression, as well as the biochemical features of enhancers and silencers learned by Enformer. Moreover, we demonstrate the flexibility of CREME to efficiently uncover a higher-resolution view of functional sequence elements within CREs. This work demonstrates how CREME can be employed to translate the powerful predictions of large-scale DNNs to study open questions in gene regulation.
Correlated evolution of conspicuous coloration and burrowing in crayfish
Authors: Graham Zackary A. , Padilla Perez Dylan J. 
Published: July 2023

AbstractConspicuous colors have fascinated biologists for centuries, leading to much research on the evolution and functional significance of color traits. However, some authors have critiqued the adaptationist dogma amongst color researchers. When investigating a color trait, researchers often exclusively consider the alternative hypotheses—they assume color is adaptive. The null hypothesis of animal color—that coloration is non-adaptive or evolutionary neutral, is rarely considered. Here, we use phylogenetic comparative methods to investigate color evolution throughout freshwater crayfishes. Within the taxa we analyzed, conspicuous colors have evolved independently over 50 times. The intuitive, but not evolutionary-justified assumption when presented these results is to assume that these colors are an adaptation. But contrary to this intuition, our work might support the hypothesis that coloration in crayfish is neutral; because we show that conspicuous colors are evolutionary correlated to a semi-terrestrial burrowing lifestyle. Conspicuous coloration being common in semi-terrestrial burrowers is paradoxical, because these species are nocturnal, and rarely leave their burrows. Overall, our work brings into question to traditional view of animal coloration as a perfectly adapted phenotype.
Modeling the Neurocognitive Dynamics of Language across the Lifespan
Authors: Guichet C. , Banjac S. , Achard S. , Mermillod M. , Baciu M. 
Published: July 2023

AbstractHealthy aging is associated with a heterogeneous decline across cognitive functions, typically observed between language comprehension and language production (LP). Examining resting-state fMRI and neuropsychological data from 628 healthy adults (age 18-88) from the CamCAN cohort, we performed state-of-the-art graph theoretical analysis to uncover the neural mechanisms underlying this variability. At the cognitive level, our findings suggest that LP is not an isolated function but is modulated throughout the lifespan by the extent of inter-cognitive synergy between semantic and domain-general processes. At the cerebral level, we show that DMN (Default Mode Network) suppression coupled with FPN (Fronto-Parietal Network) integration is the way for the brain to compensate for the effects of dedifferentiation at a minimal cost, efficiently mitigating the age-related decline in LP. Relatedly, reduced DMN suppression in midlife could compromise the ability to manage the cost of FPN integration. This may prompt older adults to adopt a more cost-efficient compensatory strategy that maintains global homeostasis at the expense of LP performances. Taken together, we propose that midlife represents a critical neurocognitive juncture that signifies the onset of LP decline, as older adults gradually lose control over semantic representations. We summarize our findings in a novel SENECA model (Synergistic, Economical, Nonlinear, Emergent, Cognitive Aging), integrating connectomic and cognitive dimensions within a complex system perspective.HighlightsLexical production (LP) relies on the interplay between domain-general and semantic processes throughout life.DMN (Default Mode Network) suppression cooperates with FPN (Fronto-Parietal Network) integration to maintain LP performance at a minimal cost.Midlife marks a neurocognitive shift, with reduced DMN suppression prompting a more cost-efficient compensatory strategy that prioritizes homeostasis over LP performance.
A short-lived peptide signal regulates cell-to-cell communication inListeria monocytogenes
Authors: Bejder Benjamin S. , Monda Fabrizio , Gless Bengt H. , Bojer Martin S. , Ingmer Hanne , Olsen Christian A. 
Published: July 2023

AbstractQuorum sensing (QS) is a mechanism that regulates group behavior in bacteria, and in Gram-positive bacteria, the communication molecules are often cyclic peptides, called autoinducing peptides (AIPs). We recently showed that pentameric thiolactone-containing AIPs fromListeria monocytogenes, and from other species, spontaneously undergo rapid rearrangement to homodetic cyclopeptides, which hampers our ability to study the activity of these short-lived compounds. Here, we developed chemically modified analogues that closely mimic the native AIPs while remaining structurally intact, by introducing N-methylation or thioester-to-thioether substitutions. The stablilized AIP analogues exhibit strong QS agonism inL. monocytogenesand allow structure–activity relationships to be studied. Our data provide evidence that loudly suggest that the most potent AIP is in fact the very short-lived thiolactone-containing pentamer. Further, we find that the QS system inL. monocytogenesis more promiscuous with respect to the structural diversity allowed for agonistic AIPs than reported for the more extensively studied QS systems inStaphylococcus aureusandStaphylococcus epidermidis. The developed compounds will be important for uncovering the biology ofL. monocytogenes, and the design principles should be broadly applicable to the study of AIPs in other species.
Structure-based engineering of Tor complexes uncovers different roles of two types of yeast TORC1s
Authors: Kamada Yoshiaki , Umeda Chiharu , Mukai Yukio , Ohtsuka Hokuto , Otsubo Yoko , Yamashita Akira , Kosugi Takahiro 
Published: July 2023

AbstractCertain proteins assemble into diverse complex states, each having a distinctive and unique function in the cell. The target of rapamycin complex 1 (TORC1) plays a central role in signaling pathways for cells to respond to their environment, such as nutritional status. TORC1 is widely recognised for its association with various diseases. The budding yeastSaccharomyces cerevisiaehas two types of TORC1s comprising different constituent proteins, Tor1- and Tor2-containing TORC1s but are considered to have the same function. Here, we rationally redesigned the complex states by structure-based engineering and constructed a Tor2 mutant to form TORC2 but not TORC1. Functional analysis of the mutant revealed that the two types of TORC1s induced different phenotypes-rapamycin, caffeine and pH dependences of cell growth and replicative and chronological lifespans. These findings are expected to provide further insights into various fields such as molecular evolution and lifespan.
Charting the brain networks of impulsivity: Meta-analytic synthesis, functional connectivity modelling and neurotransmitter associations
Authors: Gell Martin , Langner Robert , Küppers Vincent , Cieslik Edna C. , Satterthwaite Theodore D. , Eickhoff Simon B. , Müller Veronika I. 
Published: July 2023

AbstractImpulsivity is a multidimensional construct that plays a crucial role in human behaviour and is believed to be a transdiagnostic marker of several psychiatric disorders. However, given its multifaceted nature, comprehensive investigations of its neural correlates are challenging. In this study, we used a multi-modal approach to investigate the functional network organisation of two domains in which impulsivity manifests: decision-making and action control. Within domain ALE meta-analyses identified two distinct functional systems: one located in the default-mode network, associated with value-based judgments and goal-directed decision-making, and the other distributed across higher-order networks associated with cognitive control. These systems were organised into four specialised communities of default-mode, cingulo-insular, frontoparietal, and temporal regions. Integration within those communities was associated with serotonin receptor density. These findings reinforce insights from previous behavioural research and provide substantial evidence for the multidimensional nature of impulsivity on the neural level.
AMPK activation induces RALDHhightolerogenic dendritic cells through rewiring of glucose and lipid metabolism
Authors: Brombacher E. C. , Patente T. A. , van der Ham A. J. , Moll T. J. A. , Otto F. , Verheijen F. W. M. , Zaal E. A. , de Ru A.H. , Tjokrodirijo R. T. N. , Berkers C. R. , van Veelen P. A. , Guigas B. , Everts B. 
Published: July 2023

AbstractIt is well known that dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. The AMP-activated kinase (AMPK) is a central nutrient and energy sensor whose activation promotes catabolism while inhibiting ATP-consuming anabolic pathways. Yet the contribution of AMPK activation to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a number of distinct metabolic changes, in particular increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest that AMPK may serve as new target to direct DC-driven immune responses in therapeutic settings.
Molecular Dynamics Simulations on Quercetin-3-(6-Malonylglucoside) FromMorus AlbaShows Optimal Inhibition of Bcl-2 with Favorable Anti-Tumor Activities
Authors: Omirin Emmanuel Sunday , Omotuyi Olaposi Idowu , Afokhume Oluwaseun Grace , Okoh Ehisdiame Favour , Boboye Samuel Oluwaseun , Ibitoye Babatunde Oluwaseun , Adelegan Olabode Oluwagbemiga , Olugbogi Ezekiel Abiola , Aderiye Michael Aladejare , Agosile Oluwafemi Ojo 
Published: July 2023

AbstractThe target of most cancer chemotherapeutic agents is to drive cancer cells toward death. A fine balance between anti-apoptotic and pro-apoptotic proteins is needed to maintain cellular homeostasis. Any shift favoring the pro-apoptotic ones is needed to drive cellular death in cancer chemotherapy. However, anti-apoptotic proteins such as Bcl-2 and Bcl-xL bind with pro-apoptotic proteins to hinder apoptosis mechanisms. Overexpression of these anti-apoptotic proteins lead to several cancers by preventing apoptosis. In this study, molecular docking, ADMET predictions, and molecular dynamics simulations were performed for the identification of potent inhibitors of anti-apoptotic Bcl-2 with compounds ofMorus alba.Our study discovered that Quercetin-3-(6-Malonylglucoside) and Epigallocatechin gallate recorded excellent binding affinity with Bcl-2. Therefore, we conclude that compounds ofMorus albashould be subjected to further experimental studies (in vitroandin vivo)in order to confirm the findings that they could be used as better options in cancer chemotherapy.
Acquisition of non-olfactory encoding improves odour discrimination in olfactory cortex
Authors: Federman Noel , Romano Sebastián A. , Amigo-Duran Macarena , Salomon Lucca , Marin-Burgin Antonia 
Published: July 2023

AbstractPrimary sensory cortices, initially considered elementary encoders of physicochemical attributes of environmental stimuli, are now known to be modulated by other aspects of experience, such as attentional state and internal expectations1–3, movement-related signals4–7and spatial information2, 8, 9. However, the specific role of these signals in cortical sensory processing is not fully understood10. Here we reveal multiple and diverse non-olfactory responses in the primary olfactory (piriform) cortex (PCx), which dynamically enhance PCx odour discrimination according to behavioural demands. We designed a behavioural task using a virtual reality environment and performed recordings in PCx neurons. In this task, mice were trained to associate specific odours with visual contexts in order to receive a reward. We found that learning shifts PCx activity from encoding solely odour identity to a more complex regime. In this regime, positional, contextual, and associative responses emerge on odour-responsive neurons that thus become mixed-selective. Contextual information is sustained in PCx activity of expert animals, specifically when visual context identity is needed to solve the task. After learning, odours are better decoded from PCx activity when mice are engaged in the task and when odours are presented within a rewarded context. This enhancement of PCx olfactory processing is reliant on the acquired mixed-selectivity. Thus, the integration of extra-sensory inputs within primary sensory cortices can encode the behavioural relevance of encountered stimuli while improving sensory processing.