bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding
Authors: Amemiya Yuna , Ioi Yuichiro , Maki Masatoshi , Shibata Hideki , Takahara Terunao 
Published: August 2024

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) functions as a master regulator of cell growth and proliferation. We previously demonstrated that intracellular calcium ion (Ca2+) concentration modulates the mTORC1 pathway via binding of the Ca2+sensor protein calmodulin (CaM) to tuberous sclerosis complex 2 (TSC2), a critical negative regulator of mTORC1. However, the precise molecular mechanism by which Ca2+/CaM modulates mTORC1 activity remains unclear. Here, we performed a binding assay based on nano-luciferase reconstitution, a method for detecting weak interactions between TSC2 and its target, Ras homolog enriched in brain (Rheb), an activator of mTORC1. CaM inhibited the binding of TSC2 to Rheb in a Ca2+-dependent manner. Live-cell imaging analysis indicated increased interaction between the CaM-binding region of TSC2 and CaM in response to elevated intracellular Ca2+levels. Furthermore, treatment with carbachol, an acetylcholine analog, elevated intracellular Ca2+levels, and activated mTORC1. Notably, carbachol-induced activation of mTORC1 was inhibited by CaM inhibitors, corroborating the role of Ca2+/CaM in promoting the mTORC1 pathway. Consistent with the effect of Ca2+/CaM on the TSC2-Rheb interaction, increased intracellular Ca2+concentration promoted the dissociation of TSC2 from lysosomes without affecting Akt-dependent phosphorylation of TSC2, suggesting that the regulatory mechanism of TSC2 by Ca2+/CaM is distinct from the previously established action mechanism of TSC2. Collectively, our findings offer mechanistic insights into TSC2–Rheb regulation mediated by Ca2+/CaM, which links Ca2+signaling to mTORC1 activation.
Lung basement membranes are compositionally and structurally altered following resolution of acute inflammation
Authors: Brand Oliver , Kirkham Sara , Jagger Christopher , Ozols Matiss , Lennon Rachel , Hussell Tracy , Eckersley Alexander 
Published: August 2024

AbstractIdentification of pathways preventing recovery from acute respiratory viral infection is under-studied but essential for long-term health. Using unbiased proteomics, we reveal an unexpected persistent reduction in lung basement membrane proteins in mice recovered from influenza infection. Basement membrane provides a critical scaffold for heterogeneous cell types and the proteins they secrete/express at the endothelial and epithelial barrier. Further peptide location fingerprinting analysis shows inherent structure-associated changes within core collagen IV and laminin components, particularly within matrikine-producing regions of collagen IV. Our results imply lingering damage to the basement membrane network despite full recovery from viral infection. Surprisingly, these structure-associated changes in laminin and collagen IV components are also observed in non-infected aged mice indicating that inflammation-driven basement membrane degeneration may contribute to tissue ageing. Interestingly, macrophages in regions deficient in basement membrane express collagen IV and laminin chains. Repair of the basement membrane should therefore be targeted to improve overall lung health.Non-technical summaryLung virus infection is a constant global threat, despite developments in vaccination and anti-viral treatments. We have a deep understanding of this inflammatory condition, but less is known about the drivers of persistent problems, including fatigue and breathlessness as illustrated by “long COVID”. Here, we reveal a novel finding that a critical structure in the lung (the basement membrane) remains damaged even after the virus and symptoms have cleared. This structure supports a variety of cells that and forms a barrier that lines the airspaces. It also regulates fluid and cell movement into these airspaces. Remarkably, we show that similar persistent changes after virus infection are also evident in aged lungs, which implies that lung complications with age may be due to repeated inflammation. By deciphering the processes causing persistent basement membrane changes, we provide an entirely novel area to target with new medicines to treat complications arising from viral infection.
CA1 ensemble plasticity is coupled to context change and modulated by task familiarity
Authors: Krajcovic Branislav , Cernotova Daniela , Stuchlik Ales , Kubik Stepan , Svoboda Jan 
Published: August 2024

ABSTRACTWhen should plasticity mechanisms get recruited (stability-plasticity dilemma)? Environments change over time, re/entering a given context increases uncertainty and predicts the need for updating. Hippocampus (HPC) is key to tracking context change but also navigation in relation to moving targets. CA1 ensembles expressing immediate-early genes (IEGs) are contextually specific, while the amount of IEG expression correlates with HPC-dependent task demands. However, task effects on the IEG-expressing ensemblesper seremain unclear. In three experiments, we tested the effect of context change and HPC task demands on CA1 IEG+ ensembles in rats. Experiment 1 showed that the IEG+ (Arc,Homer1aRNA) ensemble size drops to baseline level during uninterrupted 30 min exploration, reflecting familiarization and decreasing uncertainty, unless context change is present; the ensemble sizes reflect both context identity and context change. Experiment 2 showed no evidence of task-specificity of IEG+ ensembles during highly HPC-dependent mobile robot avoidance nor HPC-independent stationary robot avoidance. Experiment 3 replicated the findings of Experiment 2 for c-Fos protein. Nonetheless, the data suggest that ensembles shrink with task mastery/familiarity and grow with novelty presented by acquisition of behavioral extinction. Overall, our results shed light on the temporal dynamics, and the context and task control of CA1 IEG+ ensembles. The present results and the relevant literature suggest that context change resets the ensemble of IEG-expressing CA1 neurons and novelty delays the time-dependent ensemble shrinking.HIGHLIGHTSPlasticity and learning rate should reflect novelty and familiarity, i.e. uncertaintyChange of context and task requirements increase uncertaintyFamiliarization with context and task reduces uncertaintyFor context, this pattern is matched by dynamics of IEG+ ensembles in CA1Task demands have modulating influence on CA1 IEG+ ensemblesGRAPHICAL ABSTRACT
Genetic bioaugmentation-mediated bioremediation of terephthalate in soil microcosms using an engineered environmental plasmid
Authors: Marquiegui Alvaro Alejandro , Kottara Anastasia , Chacón Micaela , Cliffe Lisa , Brockhurst Michael , Dixon Neil 
Published: August 2024

AbstractHarnessing in situ microbial communities to clean-up polluted natural environments is a potentially efficient means of bioremediation, but often the necessary genes to breakdown pollutants are missing. Genetic bioaugmentation, whereby the required genes are delivered to resident bacteria via horizonal gene transfer, offers a promising solution to this problem. Here we engineered a conjugative plasmid previously isolated from soil, pQBR57, to carry a synthetic set of genes allowing bacteria to consume terephthalate, a chemical component of plastics commonly released during their manufacture and breakdown. Our engineered plasmid caused a low fitness cost and was stably maintained in terephthalate contaminated soil by the bacteriumP. putida.Plasmid carriers efficiently bioremediated contaminated soil, achieving complete breakdown of 3.2 mg/g of terephthalate within 8 days. The engineered plasmid horizontally transferred the synthetic operon toP. fluorescens in situ, and the resulting transconjugants degraded 10 mM terephthalate during a 180-hour incubation. Our findings show that environmental plasmids carrying synthetic catabolic operons can be useful tools forin situengineering of microbial communities to perform clean-up even of complex environments like soil.
DHX15 inhibits mouse APOBEC3 deamination
Authors: Zhao Wenming , Ross Susan R. 
Published: August 2024

AbstractAPOBEC3 family proteins are critical host factors that counteract and prevent the replication of retroviruses and other viruses through cytidine deamination. Human APOBEC3 proteins inactivate HIV-1 through the introduction of lethal mutations to viral genomes. In contrast, mouse APOBEC3 does not induce DNA hypermutation of murine retroviruses, although it retains functional cytidine deaminase activity. Why mouse APOBEC3 does not effectively deaminate murine retroviruses is still unknown. In this study, we found that the dead box helicase DHX15 interacts with mouse APOBEC3 and inhibits its deamination activity. DHX15 was packaged into murine leukemia virus (MLV) virions independent of its binding with APOBEC3. Moreover, DHX15 knockdown inhibited MLV replication and resulted in more G-to-A mutations in proviral DNA. Finally, DHX15 knockdown induced DNA damage in murine cells, suggesting that it plays a role in preserving genome integrity in cells expressing mouse APOBEC3 protein.
Bacteriophage infection drives loss of β-lactam resistance in methicillin-resistantStaphylococcus aureus
Authors: Tran My , Hernandez Viera Angel J. , Tran Patricia Q. , Mo Charlie Y. 
Published: August 2024

AbstractBacteriophage (phage) therapy has been proposed as a means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical use. Here we report the discovery of staphylococcal phages that cause different strains of methicillin-resistantStaphylococcus aureus(MRSA) to become sensitized to β-lactams, a class of antibiotics against which MRSA is typically highly resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Phage-treated MRSA further exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.
Peripheral Blood Immune Cells from Individuals with Parkinson’s Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal Anti-Inflammatory Drugs
Authors: Bolen MacKenzie L. , Gomes Beatriz Nuñes , Gill Blake , Menees Kelly B. , Staley Hannah , Jernigan Janna , Tansey Malú Gámez 
Published: August 2024

ABSTRACTParkinson’s Disease (PD) is a multisystem disorder in which dysregulated neuroimmune crosstalk and inflammatory relay via the gut-blood-brain axis have been implicated in PD pathogenesis. Although alterations in circulating inflammatory cytokines and reactive oxygen species (ROS) have been associated with PD, no biomarkers have been identified that predict clinical progression or disease outcome. Gastrointestinal (GI) dysfunction, which involves perturbation of the underlying immune system, is an early and often-overlooked symptom that affects up to 80% of individuals living with PD. Interestingly, 50-70% of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia — which drives toxic accumulation of iron in the gut. Ferroptotic (or iron loaded) cells have small and dysmorphic mitochondria—suggesting that mitochondrial dysfunction is a consequence of iron accumulation. In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction. Peripheral blood mononuclear cells (PBMCs) recapitulate certain PD-associated neuropathological and inflammatory signatures and can act as communicating messengers in the gut-brain axis. Additionally, this communication can be modulated by several environmental factors; specifically, our data further support existing literature demonstrating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in modulating immune transcriptional states in inflamed individuals. A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD. To that end, we isolated PBMCs and simultaneously evaluated their directed transcriptome and bioenergetic status, to investigate if iron dysregulation and mitochondrial sensitization are linked in individuals living with PD or IBD because of chronic underlying remittent immune activation. We have identified shared features of peripheral inflammation and immunometabolism in individuals living with IBD or PD that may contribute to the epidemiological association reported between IBD and risk for PD.
Trust or doubt? Neural resonance based on facial expressions in a deception game reflected by frontal EEG activities
Authors: He Dongcheng 
Published: August 2024

AbstractThe frontal cortex plays a critical role in the deception. While previous neuroimaging studies have examined the functions of various subregions within the frontal cortex, particularly in relation to truth inhibition and lie production, there is a limited understanding of frontal activities during deception in the context of social interaction. To bridge this gap, we investigated an EEG dataset collected during a deception game involving two participants (one player and one observer) who engaged in social interaction. In the game, the player was instructed or chose spontaneously whether to lie or tell the truth, while the observer decided whether to doubt or trust the player based on the player’s facial expressions. Our analyses on the behavioral and EEG data revealed two major findings: (1) The observers’ responses were directly impacted by the players’ facial expressions. Without being informed about the trial conditions, the observer was more likely to doubt the player in instructed conditions compared to the spontaneous ones, a tendency that was evident in both the behavioral data and the observer’s vlPFC activities. (2) Despite a performance at the chance level, the observer’s responses seemed to depend on the player’s neural activities. As evidence, both the observer’s vlPFC and the player’s dmPFC-vlPFC activities reflected the observer’s responses (trust versus doubt). According to these results and previous research, we propose a neural resonance model driven by facial expressions from the player’s emotional regulation system (dmPFC-vlPFC) to the observer’s emotion perception system (vlPFC) during the deception game.
Renal proximal tubules are sensitive to metabolic acidosis
Authors: Hennings J. Christopher , Murthy Keerthana S. , Picard Nicolas , Cabrita Inês , Böhm David , Krause Maria E. , Shah Vandit , Baraka-Vidot Jennifer , Khundadze Mukhran , Stauber Tobias , Böckenhauer Detlef , Jentsch Thomas J. , Bachmann Sebastian , Schermer Bernhard , Eladari Dominique , Chambrey Régine , Hübner Christian A. 
Published: August 2024

AbstractPatients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular-weight proteins, also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported onAtp6v0a4knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that Rab7, a key regulator of endo-lysosomal trafficking and lysosomal biogenesis, is strongly diminished in proximal tubules ofAtp6v0a4KO mice, while the number of abnormal Ist1-labelled Lamp1-positive vesicles is increased. This is accompanied by the accumulation of autophagosomes, autolysosomes and autophagic substrates. Importantly, correction of metabolic acidosis with bicarbonate therapy resolves proximal tubule dysfunction and trafficking defects inAtp6v0a4KO mice. Acid-challenged wildtype mice also show trafficking defects with Rab7-downregulation and an increase in Ist1-labeled Lamp1-positive vesicles and develop proximal tubule damage in the long-term. Similar acidosis-induced alterations also occur in human kidney organoids. Altogether, our data provide insights, why patients suffering from severe dRTA may develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.Translational StatementPatients with renal acidosis caused by impaired proton secretion in the collecting duct (distal renal tubular acidosis - dRTA) sometimes show unexplained symptoms of proximal tubule dysfunction such as proteinuria and phosphaturia. Here, we show that proximal tubules are particularly sensitive to acidosis as evidenced by impaired trafficking, lysosomal damage and accumulation of autophagic substrates. We also show that early treatment of dRTA by alkali supplementation can prevent proximal tubule dysfunction. Because metabolic acidosis represents a well-known risk factor for the progression of chronic kidney disease (CKD), our findings highlight the potential clinical importance of early alkali supplementation to delay disease progression.
Impactful feeding ecology of a predatory guild of oceanic jellies
Authors: Irvine Thomas , Costello John H. , Gemmell Brad J. , Sutherland Kelly R. , Colin Sean P. 
Published: August 2024

AbstractPlanktonic organisms are integral members of open ocean ecosystems and are critical drivers of material cycles in the world’s oceans. Ctenophores may be numerically dominant predators in these oceanic ecosystems but have been ignored due to the difficulty in both sampling and handling their extremely delicate, gelatinous bodies. To better understand their trophic impact, we combined SCUBA with novel imaging techniques to non-invasively document prey ingestion patterns of four widespread oceanic ctenophore species. We found that these ctenophores ingested 32 prey per hour and the most voracious species ingested nearly 50 prey per hour. Further, the size and number of prey ingested increased with ctenophore size. At these rates, lobate and cestid ctenophores consume prey at similar rates to their highly impactful coastal relative,Mnemiopsis leidyiand are likely the most impactful planktonic predator in the open oceans. Further, we showed that although major dietary components overlapped, different oceanic ctenophore species appear to specialize on different members of the plankton. Since these oceanic ctenophore species frequently co-occur, they comprise a powerful guild of influential planktonic predators with synergistic impacts. These results indicate that epipelagic ctenophores have much greater trophic effects on material cycles over broad areas of the open ocean than previously considered. Models of oceanic carbon cycling will benefit by more fully incorporating the impacts of oceanic ctenophores on their planktonic prey.
Recent Bovine HPAI H5N1 Isolate Is Highly Virulent For Mice, Rapidly Causing Acute Pulmonary And Neurologic Disease
Authors: Tipih Thomas , Mariappan Vignesh , Yinda Kwe C , Meade-White Kimberly , Lewis Matthew , Okumura Atsushi , McCarthy Natalie , Clancy Chad , de Wit Emmie , Munster Vincent J , Feldmann Heinz , Rosenke Kyle 
Published: August 2024

AbstractThe highly pathogenic avian influenza (HPAI) A(H5N1) clade 2.3.4.4b viruses, responsible for the current outbreak in dairy cows in the United States, pose a significant animal and public health threat. In this study, we compared disease progression and pathology of three recent clade 2.3.4.4b isolates derived from a cow, mountain lion, and mink to a human HPAI A(H5N1) isolate from Vietnam in mice. Inoculation of C57BL/6J and BALB/c mice with all four HPAI A(H5N1) isolates resulted in comparable levels of virus replication in the lung inducing severe respiratory disease. C57BL/6J mice infected with the bovine isolate also developed high virus titers in the brain, resulting in a significant pro-inflammatory cytokine response and neurologic disease. Our findings suggest the recent bovine isolate possesses enhanced respiratory and neuroinvasive/neurovirulent properties causing fatal respiratory and neurologic disease in C57BL/6J mice.
RNA promotes mitochondrial import of F1-ATP synthase subunit alpha (ATP5A1)
Authors: Chatterjee Aindrila , Noble Michelle , Sekaran Thileepan , Ravi Venkatraman , Ferring–Appel Dunja , Schwarzl Thomas , Rampelt Heike , Hentze Matthias W. 
Published: August 2024

AbstractMost mitochondrial proteins are encoded by the nuclear genome, translated as precursor proteins in the cytosol and matured during directed import into the mitochondria1. For many mitochondrial proteins this process is carefully regulated to meet demand and to avoid mitochondrial stress2,3,4. Recently, mitochondrial F1-ATP synthase subunits have been found to interact with RNA across various eukaryotes. This includes genome wide RNA-interactome studies from yeast5–7, fruit flies8,9, plants10–12, mice13–17and humans18–24. To shed light on this unexpected observation, we determined the interacting cellular RNAs of ATP5A1 and the subcellular sites of interaction. Using RNA binding-deficient mutants of ATP5A1 and functional assays, we show that specific cytosolic RNAs bind ATP5A1 precursor proteins at the outer surface of mitochondria and promote their mitochondrial import both in vitro and in cellulo. These findings add an unexpected twist to understanding mitochondrial protein import and expand the growing list of riboregulated cellular processes.
Abnormal activation of the mineralocorticoid receptor in the aldosterone-sensitive distal nephron contributes to fructose-induced salt-sensitive hypertension
Authors: Zhang Ronghao , Shi Shujie , Jadhav Darshan Aatmaram , Kim Najeong , Brostek Autumn , Forester Beau R. , Shukla Rashi , Qu Christina , Kramer Benjamin , Garvin Jeffrey L. , Kleyman Thomas R. , Gonzalez-Vicente Agustin 
Published: August 2024

AbstractFructose high-salt (FHS) diets increase blood pressure (BP) in an angiotensin II (Ang II)-dependent manner. Ang II stimulates aldosterone release, which, by acting on the mineralocorticoid receptor (MR), regulates Na+reabsorption by the aldosterone-sensitive distal nephron (ASDN). The MR can be transactivated by glucocorticoids, including those locally produced by 11β-HSD1. The epithelial sodium channel (ENaC) is a key transporter regulated by MRs. We hypothesized that fructose-induced salt-sensitive hypertension depends in part on abnormal activation of MRs in the ASDN with consequent increases in ENaC expression. We found that aldosterone-upregulated genes in mice ASDN, significantly overlapped with 74 genes upregulated by FHS in the rat kidney cortex (13/74; p≤1x10-8), and that these 74 genes are prominently expressed in rat ASDN cells. Additionally, the average z-score expression of mice-aldosterone-upregulated genes is highly correlated with FHS compared to glucose high-salt (GHS) in the rat kidney cortex (Pearson correlation; r=0.66; p≤0.005). There were no significant differences in plasma aldosterone concentrations between the FHS and GHS. However, 11β-HSD1 transcripts were upregulated by FHS (log2FC=0.26, p≤0.02). FHS increased BP by 23±6 mmHg compared to GHS, and blocking MRs with eplerenone prevented this increase. Additionally, inhibiting ENaC with amiloride significantly reduced BP in FHS from 148±6 to 134±5 mmHg (p≤0.019). Compared to GHS, FHS increased total and cleaved αENaC protein by 89±14 % (p≤0.03) and 47±16 % (p≤0.01) respectively. FHS did not change β- or γ-subunit expression. These results suggest that fructose-induced salt-sensitive hypertension depends, in part, on abnormal Na+retention by ENaC, resulting from the activation of MRs by glucocorticoids.