bluuebunny/crossref_metadata_2025 huggingface dataset:
Seroepidemiology of human leptospirosis in the Dominican Republic: a multistage cluster survey, 2021
Authors: Nilles Eric J. , Paulino Cecilia Then , Galloway Renee , Aubin Michael de St. , Mayfield Helen J. , Restrepo Angela Cadavid , Dumas Devan , Garnier Salome , Etienne Marie Caroline , Duke William , Peña Farah , Iihoshi Naomi , Abdalla Gabriela , Lopez Beatriz , de la Cruz Lucia , Henríquez Bernarda , Durski Kara , Baldwin Margaret , Loevinsohn Gideon , Rees Eleanor M. , Martin Beatris , Sartorius Benn , Skewes-Ramm Ronald , Gutiérrez Emily Zielinski , Kucharski Adam , Lau Colleen L.
Published: August 2024

Little is known about the epidemiology of leptospirosis in the Dominican Republic, the second most populous country in the Caribbean. We report on findings from a multi-stage household survey across two regions in the country that reveals a previously under-estimated burden of humanLeptospirainfection. Our findings, based on the reference-standard microscopic agglutination test, indicate a complex picture of serogroup diversity, spatial heterogeneity in infection and risk, and a marked discrepancy between reported cases and serologically estimated infections. Given an overall seroprevalence of 11.3% (95% CI: 10.8-13.0%) and a lower estimated force of infection (0.30% per year [0.27% - 0.35%]) the number of infections may exceed national reported case data by 145-fold or more. Icterohaemorrhagiae, associated with severe Weil’s disease, was the most commonly identified serogroup with a serogroup-specific prevalence of 4.4%. Consistent with other settings, risk factors including age, male sex, and rat exposure were associated with higher seroprevalence. Our study highlights the need for targeted public health interventions informed by serogroup-specific dynamics, detailed spatial analyses, knowledge of local animal reservoirs, and strengthened laboratory surveillance to effectively control this pathogen.
Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease
Authors: Foguet Carles , Jiang Xilin , Ritchie Scott C. , Persyn Elodie , Xu Yu , Ben-Eghan Chief , Di Angelantonio Emanuele , Danesh John , Butterworth Adam S. , Lambert Samuel A. , Inouye Michael
Published: August 2024

Genome-wide association studies have identified thousands of variants associated with disease risk but the mechanism by which such variants contribute to disease remains largely unknown. Indeed, a major challenge is that variants do not act in isolation but rather in the framework of highly complex biological networks, such as the human metabolic network, which can amplify or buffer the effect of specific risk alleles on disease susceptibility. In our previous work, we established that metabolic models can be leveraged to simulate the emerging metabolic effects of genetically driven variation in transcript levels and estimate personalized metabolic reaction fluxes. Here we use genetically predicted reaction fluxes to perform a systematic search for metabolic fluxes acting as buffers or amplifiers of coronary artery disease (CAD) risk alleles. Our analysis identifies 30 risk locus - reaction flux pairs with significant interaction on CAD susceptibility involving 18 individual reaction fluxes and 8 independent risk loci. Notably, many of these reactions are linked to processes with putative roles in the disease such as the metabolism of inflammatory mediators and fatty acids. In summary, this work establishes proof of concept that biochemical reaction fluxes can have non-additive effects with risk alleles and provides novel insights into the interplay between metabolism and genetic variation on disease susceptibility.
Thomasclavelia ramosais a Signature of Gut Dysbiosis associated with Alcohol-Related Hepatocellular Carcinoma: A First Microbial Culturomics Study
Authors: Wasfy Reham Magdy , Abdoulaye Anissa , Borentain Patrick , Mbaye Babacar , Alou Maryam Tidjani , Caputo Aurelia , Andrieu Claudia , Mottola Giovanna , Levasseur Anthony , Million Matthieu , Gerolami Rene
Published: August 2024

Background

Gut microbiota alteration is implicated in the pathogenesis of alcoholic liver disease (ALD) and HCC. No study has characterized the dysbiosis associated with ALD by microbial culturomics, an approach that certifies viability and allows the characterization of pathobiont strain candidates.

Methods

A case-control study was conducted on patients with ALD without HCC (ALD-NoHCC) (n=16), ALD with HCC (ALD-HCC) (n=19), and controls (n=24). 16S rRNA amplicon sequencing and microbial culturomics were used as complementary methods for gut microbiome profiling.

Results

By microbial culturomics,Thomasclavelia ramosawas the most enriched and detected in all ALD samples (100%), while it was cultivated in only a small proportion of controls (20%, p < 0.001). By 16S rRNA amplicon sequencing and 3-groups linear discriminant analysis,T. ramosawas increased explicitly in the ALD-HCC group (LDA-score > 5, p < 0.05).

Conclusions

T. ramosa,identified by culturomics and 16 rRNA sequencing, is associated with ALD and ALD-HCC. Alongside the recently reported in vitro genotoxicity of this species in colorectal cancer, this species has been identified as a candidate oncobiont in ALD-HCC.

Highlights

The gut microbiota signature of ALD and ALD-HCC was explored by microbial culturomics and 16S amplicon sequencing

By culturomics,T. ramosawas the most enriched and cultured from all included ALD patients, but in only 20% of controls (p < 0.05).

T. ramosawas significantly associated with alcohol-related HCC by 16S sequencing.

T. ramosais identified as a putative oncobiont associated with ALD-HCC, thus opening new avenues for diagnosis and treatment.

Graphical abstract
Pulmonary FABP4 is an inverse biomarker of pneumonia in critically ill children and adults
Authors: Lydon Emily C , Phan Hoang Van , Mick Eran , Spottiswoode Natasha , Calfee Carolyn , Mourani Peter M , Langelier Charles
Published: August 2024

Lower respiratory tract infection (LRTI) is a leading cause of mortality, yet accurate diagnosis remains challenging. We studied two prospective observational cohorts of critically ill patients with acute respiratory failure (pediatric, N=261; adult N=202) and analyzed RNA sequencing data from tracheal aspirate collected following intubation. Patients with LRTI or non-infectious acute respiratory failure were adjudicated by a multi-physician team. We found that FABP4 expression was significantly downregulated in children with confirmed LRTI compared to those with non-infectious respiratory failure, and when incorporated into a diagnostic classifier, achieved an area under the receiver operating characteristic curve (AUC) of 0.90. When tested in the adult cohort, and AUC of 0.85 was attained. These findings suggest that pulmonary FABP4 could serve as a valuable biomarker for the early diagnosis of LRTI in critically ill patients across the age spectrum, offering a potential tool for improving clinical outcomes and reducing unnecessary antibiotic use.
Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer’s disease
Authors: Birkenbihl Colin , Cuppels Madison , Boyle Rory T. , Klinger Hannah M. , Langford Oliver , Coughlan Gillian T. , Properzi Michael J. , Chhatwal Jasmeer , Price Julie C. , Schultz Aaron P. , Rentz Dorene M. , Amariglio Rebecca E. , Johnson Keith A. , Gottesman Rebecca F. , Mukherjee Shubhabrata , Maruff Paul , Lim Yen Ying , Masters Colin L. , Beiser Alexa , Resnick Susan M. , Hughes Timothy M. , Burnham Samantha , Tunali Ilke , Landau Susan , Cohen Ann D. , Johnson Sterling C. , Betthauser Tobey J. , Seshadri Sudha , Lockhart Samuel N. , O’Bryant Sid E. , Vemuri Prashanthi , Sperling Reisa A. , Hohman Timothy J. , Donohue Michael C. , Buckley Rachel F.
Published: August 2024

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer’s disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model’s residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach’s limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.
Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding
Authors: Amemiya Yuna , Ioi Yuichiro , Maki Masatoshi , Shibata Hideki , Takahara Terunao
Published: August 2024

The 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

Identification 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 summary

Lung 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

When 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.

HIGHLIGHTS

Plasticity and learning rate should reflect novelty and familiarity, i.e. uncertainty

Change of context and task requirements increase uncertainty

Familiarization with context and task reduces uncertainty

For context, this pattern is matched by dynamics of IEG+ ensembles in CA1

Task demands have modulating influence on CA1 IEG+ ensembles

GRAPHICAL 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

Harnessing 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

APOBEC3 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

Bacteriophage (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

Parkinson’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

The 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

Patients 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 Statement

Patients 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

Planktonic 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

The 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

Most 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

Fructose 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.
Interdependent regulation of alternative splicing by SR and hnRNP proteins
Authors: Holmes Megan E. , Hertel Klemens J.
Published: August 2024

Alternative pre-mRNA splicing is a combinatorial process involving SR and hnRNP splicing factors. These proteins can silence or enhance splicing based on their expression levels and binding positions. To better understand their combinatorial and interdependent regulation, computational analyses were performed using HepG2 and K562 cell knockdown and binding datasets from the ENCODE Project. Analyses of diMerential splicing for 6 SR proteins and 13 hnRNP knockdowns revealed statistically significant exon overlap among most RBP combinations, albeit at diMerent levels. Neither SR proteins nor hnRNPs showed strong preferences for collaborating with specific RBP classes in mediating exon inclusion. While SRSF1, hnRNPK, and hnRNPC stand out as major influencers of alternative splicing, they do so predominantly independent of other RBPs. Meanwhile, minor influencers of alternative splicing such as hnRNPAB and hnRNPA0 predominantly regulate exon inclusion in concert with other RBPs, indicating that inclusion can be mediated by both single and multiple RBPs. Interestingly, the higher the number of RBPs that regulate the inclusion of an exon, the more variable exon inclusion preferences become. Interdependently regulated exons are more modular and have diMerent physical characteristics such as reduced exon length compared to their independent counterparts. A comparison of RBP interdependence between HepG2 and K562 cells provides the framework that explains cell-type-specific alternative splicing. Our study highlights the importance of the interdependent regulation of alternative exons and identifies characteristics of interdependently regulated exons that diMer from independently regulated exons.
Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing
Authors: Shvedova Maria , Thanapaul Rex Jeya Rajkumar Samdavid , Ha Joy , Dhillon Jannat , Shin Grace H , Crouch Jack , Gower Adam C , Gritli Sami , Roh Daniel S
Published: August 2024

Senescent cells (SnC) accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating SnC skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescent markers p16 and p21, accompanied by reductions in SA-β-gal and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.
Functional Regrowth of Norepinephrine Axons in the Adult Mouse Brain Following Injury
Authors: Cooke Patrick , Linden David J.
Published: August 2024

It is widely believed that axons in the central nervous system of adult mammals do not regrow following injury. This failure is thought, at least in part, to underlie the limited recovery of function following injury to the brain or spinal cord. Some studies of fixed tissue have suggested that, counter to dogma, norepinephrine (NE) axons regrow following brain injury. Here, we have used in vivo two-photon microscopy in layer 1 of the primary somatosensory cortex in transgenic mice harboring a fluorophore selectively expressed in NE neurons. This protocol allowed us to explore the dynamic nature of NE axons following injury with the selective NE axon toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). Following DSP4 treatment, NE axons were massively depleted and then slowly and partially recovered their density over a period of weeks. This regrowth was dominated by new axons entering the imaged volume. There was almost no contribution from local sprouting from spared NE axons. Regrown axons did not appear to use either the paths of previously lesioned NE axons nor NE axons that were spared and survived DSP4 treatment as a guide. To measure NE release, GCaMP8s was selectively expressed in neocortical astrocytes and startle-evoked, NE receptor-mediated Ca2+transients were measured. These Ca2+transients were abolished soon after DSP4 lesion but returned to pre-lesion values after 3-5 weeks, roughly coincident with NE axon regrowth, suggesting that the regrown NE axons are competent to release NE in response to a physiological stimulus in the awake mouse.

Significance Statement

It is widely believed that axons in the central nervous system (CNS) of adult mammals are incapable of regrowth following injury. Counter to this notion, we describe the structural and functional regrowth of norepinephrine axons following brain injury in the adult mouse. These results extend previous studies describing the regenerative capacity of serotonin axons in the CNS by demonstrating axon regrowth of another neuronal subtype and the capacity of these regrown axons to respond normally to an external physiological stimulus. Taken together, these findings suggest that monoaminergic neurons share a common program for axon regrowth. Elucidation of this molecular and genetic program could inform therapies to promote axon regrowth and functional recovery following injury to the CNS.
High-throughput affinity measurements of direct interactions between activation domains and co-activators
Authors: DelRosso Nicole , Suzuki Peter H. , Griffith Daniel , Lotthammer Jeffrey M. , Novak Borna , Kocalar Selin , Sheth Maya U. , Holehouse Alex S. , Bintu Lacramioara , Fordyce Polly
Published: August 2024

Sequence-specific activation by transcription factors is essential for gene regulation1,2. Key to this are activation domains, which often fall within disordered regions of transcription factors3,4and recruit co-activators to initiate transcription5. These interactions are difficult to characterize via most experimental techniques because they are typically weak and transient6,7. Consequently, we know very little about whether these interactions are promiscuous or specific, the mechanisms of binding, and how these interactions tune the strength of gene activation. To address these questions, we developed a microfluidic platform for expression and purification of hundreds of activation domains in parallel followed by direct measurement of co-activator binding affinities (STAMMPPING, for Simultaneous Trapping of Affinity Measurements via a Microfluidic Protein-Protein INteraction Generator). By applying STAMMPPING to quantify direct interactions between eight co-activators and 204 human activation domains (>1,500Kds), we provide the first quantitative map of these interactions and reveal 334 novel binding pairs. We find that the metazoan-specific co-activator P300 directly binds >100 activation domains, potentially explaining its widespread recruitment across the genome to influence transcriptional activation. Despite sharing similar molecular properties (e.g.enrichment of negative and hydrophobic residues), activation domains utilize distinct biophysical properties to recruit certain co-activator domains. Co-activator domain affinity and occupancy are well-predicted by analytical models that account for multivalency, andin vitroaffinities quantitatively predict activation in cells with an ultrasensitive response. Not only do our results demonstrate the ability to measure affinities between even weak protein-protein interactions in high throughput, but they also provide a necessary resource of over 1,500 activation domain/co-activator affinities which lays the foundation for understanding the molecular basis of transcriptional activation.
DIAMOND2GO: A rapid Gene Ontology assignment and enrichment tool for functional genomics
Authors: Golden Christopher , Studholme David J. , Farrer Rhys A.
Published: August 2024

DIAMOND2GO (D2GO) is a new toolset to rapidly assign Gene Ontology (GO) terms to genes or proteins based on sequence similarity searches. D2GO uses DIAMOND for alignment, which is 100 - 20,000 X faster than BLAST. D2GO leverages GO- terms already assigned to sequences in the NCBI non-redundant database to achieve rapid GO-term assignment on large sets of query sequences. In one test, 98% of the 130,184 predicted human proteins and splice variants were assigned GO-terms (>2 million in total) in < 13 minutes on a laptop computer. D2GO also features the ability to perform enrichment analysis between subsets of data, thereby allowing rapid assignment and detection of over-represented GO-terms in novel sets of sequences. D2GO is freely available under the MIT licence fromhttps://github.com/rhysf/DIAMOND2GO
A criterion characterizing accumulated neurotoxicity of Aβ oligomers in Alzheimer’s disease
Authors: Kuznetsov Andrey V.
Published: August 2024

The paper develops a criterion to quantify the accumulated neurotoxicity of Aβ oligomers in Alzheimer’s disease (AD). Accumulated neurotoxicity is determined by integrating the concentration of Aβ oligomers within the control volume over time. In the scenario of a low rate of free Aβ oligomer deposition into senile plaques and dysfunctional degradation machinery, resulting in an infinitely long half-life of Aβ monomers and aggregates, the obtained analytical solution reveals a quadratic relationship between accumulated neurotoxicity and time. This suggests that initially, neurotoxicity increases slowly but accelerates as time progresses. This could help to understand the prolonged delay in the onset of AD symptoms. Furthermore, as the model indicates that accumulated neurotoxicity increases with the duration of the aggregation process, it implies that if the protein degradation system is compromised, the onset of AD becomes unavoidable. Eventually, neuronal death is only a question of time. The only way to prevent this outcome is to ensure that the degradation machinery for Aβ peptides and their aggregates remains functional. A threshold value of accumulated neurotoxicity is suggested. The developed theory suggests that if this value is exceeded, nearby neurons will die. The progression of accumulated neurotoxicity over time is analyzed. An S-shaped growth pattern as the half-deposition time of Aβ aggregates into senile plaques increases is revealed. Additionally, the sensitivity of accumulated neurotoxicity to different parameter values is examined.
Temperature fluctuations influence predictions of landscape-scale patterns of spruce budworm defoliation
Authors: Black Emily N. , Pureswaran Deepa S. , Marshall Katie E.
Published: August 2024

The geographic range of insects is heavily influenced by their tolerance for stressful abiotic conditions, including temperature. While many studies on insect thermal tolerance consider temperature exposure, the frequency of temperature exposures is emerging as an important and generally overlooked driver of insect fitness. The (eastern) spruce budworm (Choristoneura fumiferana) is a lepidopteran defoliating pest of coniferous forests across Canada whose outbreaks lead to large-scale tree mortality. Studies have shown the frequency of temperature fluctuations affects spruce budworm overwintering survival rates in the laboratory; however, the influence of temperature fluctuations on spruce budworm defoliation at the landscape level has not been investigated. We used a species distribution model approach to evaluate the influence of temperature fluctuations on the distribution and severity of spruce budworm defoliation. We combined publicly available maps of spruce budworm outbreaks between 2006-2016 in Quebec with climate, temperature fluctuation, and forest composition predictors to train a species distribution model. Our model evaluated how predictors influence spruce budworm defoliation, and compared these results to a model trained without temperature fluctuations. Additionally, we predicted future spruce budworm defoliation under 2041-2070 climate change conditions using the models trained with and without temperature fluctuation predictors and compared the results to determine the effect of temperature fluctuations on future defoliation predictions. We found that model performance improved with the inclusion of temperature fluctuation predictors, and these predictors ranked highly, relative to predictors in other categories. The model trained with temperature fluctuation predictors also predicted vastly different defoliation distribution and severity across Quebec and Ontario than the model trained without them under climate change conditions. These results reveal the previously overlooked importance of temperature fluctuations on landscape-scale spruce budworm defoliation and support their inclusion in insect species distribution models.
Quantum phase transitions and cat states in cavity-coupled quantum dots
Authors: Kozin Valerii K. , Miserev Dmitry , Loss Daniel , Klinovaja Jelena
Published: August 2024

We study double quantum dots coupled to a quasistatic cavity mode with high mode-volume compression allowing for strong light-matter coupling. Besides the cavity-mediated interaction, electrons in different double quantum dots interact with each other via dipole-dipole (Coulomb) interaction. There is a first-order cavity-induced ferroelectric quantum phase transition when the attractive dipolar interaction is smaller than the critical value defined by the energy splitting in DQDs and a smooth transition, otherwise. We show that, in the smooth transition region, both the ground and the first excited states of an array of double quantum dots are cat states. Such states are actively discussed as high-fidelity qubits for quantum computing, and thus our proposal provides a platform for semiconductor implementation of such qubits. We also calculate gauge-invariant observables such as the net dipole moment, the optical conductivity, and the absorption spectrum beyond the semiclassical approximation. The results are robust against cavity losses and variations of system parameters.

Published by the American Physical Society
2024