bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of the stress peptides PACAP and CRF on sleep architecture in mice
Authors: Foilb Allison R. , Taylor-Yeremeeva Elisa M. , Fritsch Emma L. , Ravichandran Caitlin , Lezak Kimberly R. , Missig Galen , McCullough Kenneth M. , Carlezon William A. 
Published: March 2023

ABSTRACTStress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics, and provide new insights into the mechanisms by which stress disrupts sleep.
HCC-1 accelerates atherosclerosis by inducing endothelial cells and macrophages pyroptosis and serves as an early diagnostic biomarker
Authors: Bu Fan , Wang Junhui , Zhang Qi , Lin Xiaomin , Zhang Ruyi , Bai Huanlan , Chen Juanjiang , Hua Yuneng , Wang Haifang , Huang Mei , Huang Yiyi , Hu Xiumei , Zheng Lei , Wang Qian 
Published: March 2023

BACKGROUNDHCC-1 (Hemofiltrate CC chemokine-1), a CC-type chemokine, exerts function to change intracellular calcium concentration, induce leukocyte and manipulate enzyme release especially in monocytes. It has been reported that HCC-1 could predict the persistent acute kidney injury (AKI) or suppress hepatocellular carcinoma (HCC) by modulating cell cycle and promoting apoptosis, but the effect of HCC-1 on atherosclerosis is poorly understood. Here, we aimed to clarify the function and mechanism of HCC-1 in atherosclerosis and whether it could serve as a novel biomarker for the diagnosis of atherosclerosis.METHODSHCC-1 expression in serum, atherosclerotic plaques and normal arterial tissue from patients with atherosclerosis and control group was assessed by enzyme-linked immunosorbent assay, immunohistochemistry and con-focal microscope. The atherosclerotic model of HCC-1 overexpressing mice and control mice were generated by infection of AAV9-HCC-1 on an ApoE−/−background. Cell adhesion, polarization and pyroptosis were evaluated in vitro. The relationship between HCC-1 concentration in serum and atherosclerosis was analyzed in patients with atherosclerosis.RESULTSHCC-1 expression increased in patients with atherosclerosis both in serum and atherosclerotic plaque. HCC-1 overexpression mice had an enhancement in macrophage accumulation in plaque, higher levels of inflammatory factors, increased pyroptotic rate in ECs and Macrophages in plaque and decreased atherosclerotic plaque stability. In vitro, HCC-1 promoted monocytes to adhere to endothelial cells and M1 polarization, induced inflammation and pyroptosis both in ECs and Macrophages.CONCLUSIONSHCC-1 expression markedly increased in patients with atherosclerosis and HCC-1 overexpression accelerated atherosclerotic burden via an enhancement in monocytes recruitment, M1 polarization and pyroptosis both in ECs and Macrophages. Our findings suggested that HCC-1 may serve as an early biomarker for the diagnosis of atherosclerosis, with the capacity to reflect the degree of stenosis.GRAPHIC ABSTRACTA graphic abstract is available for this article.
Enterococcus faecalisOG1RF Evolution at Low pH Selects Fusidate-sensitive Mutants in Elongation Factor G and at High pH Selects Defects in Phosphate Transport
Authors: Fitzgerald Bailey A. , Wadud Ayman , Slimak Zachary , Slonczewski Joan L. 
Published: March 2023

ABSTRACTEnterococcusbacteria inhabit human and soil environments that show a wide range of pH. Strains include commensals as well as antibiotic-resistant pathogens. We investigated adaptation to pH stress inE. faecalisOG1RF by conducting experimental evolution in acid (pH 4.8), neutral pH (pH 7.0), and base (pH 9.0). Serial planktonic culture was performed for 500 generations, and in high-pH biofilm culture for four serial bead transfers. Nearly all mutations led to nonsynonomous codons, indicating adaptive selection. All acid-adapted clones from planktonic culture showed a mutation infusA(encoding elongation factor G). The acid-adaptedfusAmutants had a tradeoff of decreased resistance to fusidic acid (fusidate). All base-adapted clones from planktonic cultures, and some from biofilm-adapted cultures, showed mutations affecting the Pst phosphate ABC transporter (pstA, pstB, pstB2, pstC) andpyrR(pyrimidine biosynthesis regulator/uracil phosphoribosyltransferase). Biofilm culture produced small-size colonies on brain-heart infusion agar; these variants each contained a single mutation inpstB2,pstC, orpyrR. ThepstandpyrRmutants outgrew the ancestral strain at pH 9.2, with a tradeoff of lower growth at pH 4.8. Additional genes that had a mutation in multiple clones evolved at high pH (but not at low pH) includeoppBCDF(oligopeptide ABC transporter),ccpA(catabolite control protein A), andftsZ(septation protein). Overall, experimental evolution ofE. faecalisshowed strong pH dependence, favoring fusidate-sensitive elongation factor G modification at low pH and loss of phosphate transport genes at high pH.IMPORTANCEE. faecalisbacteria are found in dental biofilms where they experience low pH as a result of fermentative metabolism. Thus the effect of pH on antibiotic resistance has clinical importance. In endodontal infections, enterococci can resist calcium hydroxide therapy that generates extreme high pH. In other environments such as soil and plant rhizosphere, enterococci experience acidification associated with climate change. Thus the pH modulation of natural selection in enterococci is important for human health as well as for understanding soil environments.
The alternative sigma factor SigN ofBacillus subtilisis intrinsically toxic
Authors: Burton Aisha T. , Kálalová Debora , Snider Elizabeth V. , Burrage Andrew M. , Krásný Libor , Kearns Daniel B. 
Published: March 2023

ABSTRACTSigma factors bind and direct the RNA polymerase core to specific promoter sequences and alternative sigma factors direct transcription of different regulons of genes. Here, we study the pBS32 plasmid-encoded sigma factor SigN ofBacillus subtilisto determine how it contributes to DNA damage-induced cell death. We find that SigN causes cell death when expressed at high level and does so in the absence of its regulon suggesting it is intrinsically toxic. One way toxicity was relieved was by curing the pBS32 plasmid, which eliminated a positive feedback loop that lead to SigN hyper-accumulation. Another way toxicity was relieved was through mutating the chromosomally-encoded transcriptional repressor protein AbrB and derepressing a potent antisense transcript that antagonized SigN expression. We note that SigN exhibits a relatively high affinity for the RNA polymerase core, efficiently competing with the vegetative sigma factor SigA, suggesting that toxicity was due to the competitive inhibition of one or more essential transcripts. WhyB. subtilisencodes a potentially toxic sigma factor is unclear but SigN may be related to phage-like genes also encoded on pBS32.SIGNIFICANCEAlternative sigma factors activate entire regulons of genes to improve viability in response to environmental stimuli. The pBS32 plasmid-encoded SigN ofBacillus subtilisis activated by the DNA damage response and leads to cellular demise. Here we find that SigN impairs viability by hyper-accumulating and outcompeting the vegetative sigma factor for the RNA polymerase core. WhyB. subtilisretains a plasmid with a deleterious alternative sigma factor is unknown.
Analysis of the risk and pre-emptive control of viral outbreaks accounting for within-host dynamics: SARS-CoV-2 antigen testing as a case study
Authors: Hart William S , Park Hyeongki , Jeong Yong Dam , Kim Kwang Su , Yoshimura Raiki , Thompson Robin N , Iwami Shingo 
Published: March 2023

AbstractIn the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multi-scale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multi-scale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.
Heart failure, female sex and atrial fibrillation are the main drivers of human atrial cardiomyopathy: results from the CATCH ME consortium
Authors: Winters J. , Isaacs A. , Zeemering S. , Kawczynski M. , Maesen B. , Maessen J. , Bidar E. , Boukens B. , Hermans B. , van Hunnik A , Casadei B. , Fabritz L. , Chua W. , Sommerfeld L.C. , Guasch E. , Mont L. , Batlle M. , Hatem S. , Kirchhof P. , Wakili R. , Sinner M.F. , Kääb S. , Stoll M. , Goette A. , Verheule S. , Schotten U. 
Published: March 2023

AbstractBackgroundAtrial cardiomyopathy (AtCM) is emerging as an independent prognostic factor in cardiovascular disease. Fibrotic remodeling, cardiomyocyte hypertrophy, and capillary density are histological hallmarks of atCM. However, the contribution of various etiological factors and atrial fibrillation (AF) to the development of differential atCM phenotypes has not been robustly quantified. We aimed to evaluate the association between histological features of atCM and the clinical phenotype.MethodsWe examined left (LA, n=95) and right (RA, n=76) atrial appendages sampled from a European cohort of patients undergoing cardiac surgery. Quantification of histological atCM features was performed using the JavaCyte algorithm, following staining with agglutinin (WGA), CD31 and vimentin. The contributions of AF, heart failure (HF), sex and age to histological characteristics were determined in a multivariate model. K-means clustering of 6 histological features was performed to identify different types of atCM.ResultsIn both LA and RA, persistent AF was associated with increased endomysial fibrosis (LA:+1.07±0.41µm,p=0.01; RA:+0.89±0.43µm,p=0.032), whereas total extracellular matrix (ECM) content was unchanged in AF. Men had larger cardiomyocytes (LA:+1.87±0.72μm,p=0.012), while women had a higher degree of endomysial fibrosis (LA:+0.99±0.51µm,p=0.048). Heart failure patients showed more endomysial fibrosis (LA:+1.79±0.41µm,p<0.001) and ECM content (LA:+2.93±1.15%, p=0.014), and a higher capillary density (LA:+0.14±0.06,p=0.032) and size (LA:+0.48±0.23µm,p=0.041; RA:+0.31±0.16µm,p=0.047). Clustering of samples based on structural features identified 2 distinct atCM phenotypes; one characterized by enhanced endomysial fibrosis (LA:+3.35µm,p<0.001; RA:+1.88μm,p<0.001), ECM content (LA:+5.68%,p<0.001; RA:+7.78%,p<0.001), and a higher fibroblast density (LA:+4.79%,p<0,001) and one characterized by cardiomyocyte hypertrophy (LA:+1.20µm,p=0.009; RA:+2.95µm, p<0.001). Patients with fibrotic atCM were more often female (LA:OR=1.31,p=0.003; RA:OR=1.55,p=0.003), had more often persistent AF (LA:OR=1.23,p=0.031) or heart failure (LA:OR=1.62,p<0.001) whereas hypertrophic features were more common in men (LA:OR=1.31,p=0.031; RA:OR= 1.55,p=0.003).ConclusionsAtCM phenotypes vary with patient characteristics. Fibrotic atCM is associated with female sex, persistent AF and heart failure, while hypertrophic features are more common in men.
Long-term Exposure to Ambient PM2.5and Hospitalizations for Myocardial Infarction among U.S. Residents: A Difference-in-Differences Analysis
Authors: Wang Yichen , Qiu Xinye , Wei Yaguang , Schwartz Joel D. 
Published: March 2023

AbstractBackgroundAir pollution has been recognized as an untraditional risk factor for myocardial infarction (MI). However, the MI risk attributable to long-term exposure to fine particulate matter (PM2.5) is unclear, especially in younger populations, and few studies represented the general population.MethodsWe applied the difference-in-differences approach to estimate the relationship between annual PM2.5exposure and hospitalizations for MI among U.S. residents and further identified potential susceptible subpopulations. All hospital admissions for MI in ten U.S. states over the period 2002-2016 were obtained from the Healthcare Cost and Utilization Project State Inpatient Database.ResultsIn total, 1,914,684 MI hospital admissions from 8,106 ZIP codes in ten states from 2002 to 2016 were included in this study. We observed a 1.35% (95% CI: 1.11-1.59%) increase in MI hospitalization rate for 1 μg/m3increase in annual PM2.5exposure. The estimate was robust to adjustment for surface pressure, relative humidity and co-pollutants. In the population with exposure at or below 12 μg/m3, there was a larger increment of 2.17% (95% CI: 1.79-2.56%) in hospitalization rate associated with 1 μg/m3increase in PM2.5. Young people (0-34 years) and elderly people (≥75 years) were the two most susceptible age groups. Residents living in more densely populated or poorer areas and individuals with comorbidities were observed to be at a greater risk.ConclusionsThis study indicates long-term residential exposure to PM2.5could lead to increased risk of MI among U.S. general population. The association persists below current standards.Clinical PerspectiveWhat is new?Long-term exposure to PM2.5increased the risk of myocardial infarction in the general U.S. population.Young individuals aged 0-34 years had the highest relative risk from long-term exposure to PM2.5, and elderly people aged ≥75 years were the second most susceptible to the effects.Individuals with iron deficiency anemia, psychosis, and renal failure were more susceptible to the long-term effects of PM2.5on MI.What are the clinical implications?Long-term PM2.5exposure is one of the important modifiable environmental risk factors for myocardial infarction, therefore, air pollution control and behavioral interventions should be taken to prevent the occurrence of myocardial infarction.
Solid Tumor Treatment via Augmentation of Bioactive C6 Ceramide Levels with Thermally Ablative Focused Ultrasound
Authors: Thim E. Andrew , Fox Todd , Deering Tye , Vass Luke R. , Sheybani Natasha D. , Kester Mark , Price Richard J. 
Published: March 2023

AbstractSparse scan partial thermal ablation (TA) with focused ultrasound (FUS) may be deployed to treat solid tumors and increase delivery of systemically administered therapeutics. Further, C6-ceramide-loaded nanoliposomes (CNLs), which rely upon the enhanced permeation and retention (EPR) effect for delivery, have shown promise for treating solid tumors and are being tested in clinical trials. Here, our objective was to determine whether CNLs synergize with TA in the control of 4T1 breast tumors. CNL-monotherapy of 4T1 tumors yielded significant intratumoral bioactive C6 accumulation by the EPR effect, but tumor growth was not controlled. TA increased bioactive C6 accumulation by ∼12.5-fold over the EPR effect. In addition, TA+CNL caused shifts in long-chain to very-long-chain ceramide ratios (i.e., C16/24 and C18/C24) that could potentially contribute to tumor control. Nonetheless, these changes in intratumoral ceramide levels were still insufficient to confer tumor growth control beyond that achieved when combining with TA with control “ghost” nanoliposomes (GNL). While this lack of synergy could be due to increased “pro-tumor” sphingosine-1-phosphate (S1P) levels, this is unlikely because S1P levels exhibited only a moderate and statistically insignificant increase with TA+CNL. In vitro studies showed that 4T1 cells are highly resistant to C6, offering the most likely explanation for the inability of TA to synergize with CNL. Thus, while our results show that sparse scan TA is a powerful approach for markedly enhancing CNL delivery and generating “anti-tumor” shifts in long-chain to very-long-chain ceramide ratios, resistance of the tumor to C6 can still be a rate-limiting factor for some solid tumor types.
Presynaptic and Postsynaptic Determinants of the Functional Connectivity Between the Claustrum and Anterior Cingulate Cortex
Authors: de la Torre-Martínez Roberto , Chia Zach , Tokarska Anna , Frost-Nylén Johanna , Augustine George J , Silberberg Gilad 
Published: March 2023

AbstractThe claustrum (CLA) is a brain nucleus located between the insula and lateral striatum, implicated in a wide range of behaviors. Underpinning the different behavioral phenotypes is the connectivity between the claustrum and various cortical regions, including the anterior cingulate cortex (ACC). CLA projection neurons are glutamatergic neurons, however, the impact of CLA on its cortical targets has been shown in some studies to be inhibitory. Such inhibition is likely to arise from claustral activation of cortical interneurons, however, the intricate synaptic connectivity between different CLA and cortical cell types is not known. Here, we combinein vivoandex vivoelectrophysiology and optogenetics to reveal the functional organization of the CLA-ACC pathway according to the identity of its pre- and postsynaptic populations. Optogenetic stimulation of CLA neurons in awake mice resulted in multiphasic excitatory and inhibitory responses in ACC cells, which depended on the layer, cell type, and stimulated CLA population. Usingex vivopaired recordings in ACC, monosynaptic responses were recorded in pyramidal cells and different types of interneurons following photostimulation of CLA-ACC synaptic terminals. CLA axons formed monosynaptic connections in all ACC cortical layers, but the probability and strength of synaptic responses depended on the type of CLA projection, target layer in ACC, and the type of postsynaptic neuron. This intricate organization of the CLA-ACC pathway may explain the complex impact of CLA on ACC and other cortical regions, thus resolving some of the discrepancies in the field and shedding light on the functional role CLA plays in cortical function.
Ex vivoprimary liver sections recapitulate disease phenotype and therapeutic rescue for liver monogenic diseases
Authors: Perocheau Dany , Gurung Sonam , Touramanidou Loukia , Duff Claire , Sharma Garima , Sebire Neil , Finn Patrick F. , Cavedon Alex , Siddiqui Summar , Rice Lisa , Martini Paolo G.V. , Frassetto Andrea , Baruteau Julien 
Published: March 2023

AbstractIn academic research and the pharmaceutical industry,in vitrosingle cell line cultures andin vivoanimal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have limitations, with incomplete reproduction of pathophysiological characteristics and absence of 3-dimensional architecture with cell lines or the use of live animals brings ethical considerations, limiting the experimental scale and design. The use of precision-cut tissue slices can bridge the gap between these mainstream models as this technique combines the advantages of studying all cell sub-types whilst preserving the tissue-matrix architecture, thereby closely mimicking a mini-organ. Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers. We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively. Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases.
Visualization of translation reorganization upon persistent collision stress in mammalian cells
Authors: Fedry Juliette , Silva Joana , Vanevic Mihajlo , Fronik Stanley , Mechulam Yves , Schmitt Emmanuelle , Georges Amédée des , Faller William , Förster Friedrich 
Published: March 2023

AbstractAberrantly slow mRNA translation leads to ribosome stalling and subsequent collision with the trailing neighbor. Ribosome collisions have recently been shown to act as stress sensors in the cell, with the ability to trigger stress responses balancing survival and apoptotic cell-fate decisions depending on the stress level. However, we lack a molecular understanding of the reorganization of translation processes over time in mammalian cells exposed to an unresolved collision stress. Here we visualize the effect of a persistent collision stress on translation usingin situcryo electron tomography. We observe that low dose anisomycin collision stress leads to the stabilization of Z-site bound tRNA on elongating 80S ribosomes, as well as to the accumulation of an off-pathway 80S complex possibly resulting from collision splitting events. We visualize collided disomesin situ, occurring on compressed polysomes and revealing a stabilized geometry involving the Z-tRNA and L1 stalk on the stalled ribosome, and eEF2 bound to its collided rotated-2 neighbor. In addition, non-functional post-splitting 60S complexes accumulate in the stressed cells, indicating a limiting Ribosome associated Quality Control clearing rate. Finally, we observe the apparition of tRNA-bound aberrant 40S complexes shifting with the stress timepoint, suggesting a succession of different initiation inhibition mechanisms over time. Altogether, our work visualizes the changes of translation complexes under persistent collision stress in mammalian cells, indicating how perturbations in initiation, elongation and quality control processes contribute to an overall reduced protein synthesis.SummaryUsingin situcryo electron tomography we visualized the reorganization of mammalian translation processes during a persistent collision stress.