bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerated growth increases the somatic epimutation rate in trees
Authors: Zhou M , Schmied G , Bradatsch M , Resente G , Hazarika R , Kakoulidou I , Costa M , Serra M , Uhl E , Schmitz RJ , Hilmers T , Toraño Caicoya A , Crivellaro A , Pretzsch H , Johannes F
Published: May 2024

Trees are critical components of ecosystems and of major economic importance. Due to their extraordinary longevity and well-defined modular architecture they have also emerged as model systems to study the long-term accumulation of somatic mutations in plants. Coupled with retrospective life-history and environmental data, trees can offer unique insights into mutational processes that would be difficult to obtain with prospective studies. In addition to genetic mutations, somatic epimutations in the form of stochastic gains and losses of DNA cytosine methylation have been shown to accumulate rapidly during ontogeny. One hypothesis is that somatic epimutations originate from DNA methylation maintenance errors during mitotic cell divisions, which would predict that their rate of accumulation scales with growth rate, rather than with age.

Here we test this hypothesis in European beech. We analyzed one of the oldest continuously measured experimental plots in the world. The plot contains an even-aged beech stand that was established in 1822 and monitored for growth at regular intervals until the present. Starting ∼150 years ago, alternative thinning strategies were applied to subplots of this experiment, resulting in differential stem growth rates among trees. We show that accelerated growth significantly increased the per-year somatic epimutation rate at CG dinucleotides, and that this effect is accompanied by differences in cell division rates. Hence, faster growth elevates the chances for methylation maintenance errors during DNA replication per unit time. As somatic CG epimutations can be stably inherited to subsequent generations in plants, our insights have direct ecological and evolutionary implications.
Epigenenomic and transcriptomic characterization ofNPM1-mutated CN-AML subtypes
Authors: N’Guyen Lia , Tellez-Quijorna Clara , Vernerey Julien , Garciaz Sylvain , Carbuccia Nadine , Guille Arnaud , Burny Claire , Poplineau Mathilde , Murati Anne , Hospital Marie-Anne , Vey Norbert , Birnbaum Daniel , Duprez Estelle
Published: May 2024

Cytogenetic normal AML withNPM1mutations forms a distinct AML entity, associated with an intermediate prognosis and a heterogeneous response to treatment. We previously described an epigenetic biomarker, defined by the level of H3K27me3 on 70kb of theHIST1cluster in patient blast DNA. This epigenetic mark separates cytogenetically normalNPM1mutAML into two groups of patients differing in their survival rate following chemotherapy. To better characterize the influence of the biomarker on disease progression, we performed transcriptomic and histone mark profiling on patient blasts according to the level of H3K27me3HIST1. Our integrated analysis revealed that the two groups of patients display differences in terms of transcriptomic, chromatin landscape and cell surface markers, which could explain the clinical difference. Our profiling revealed novel targets and therefore constitutes an (epi)transcriptomic resource forNPM1AML. It also highlights the power of epigenetic profiling to dissect the heterogeneity of a single AML genetic entity.
BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer
Authors: Sriramulu Sushmitha , Thoidingjam Shivani , Chen Wei-Min , Hassan Oudai , Siddiqui Farzan , Brown Stephen L , Movsas Benjamin , Green Michael D , Davis Anthony J , Speers Corey , Walker Eleanor , Nyati Shyam
Published: May 2024

Background

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment.

Methods

Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays.

Results

BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho– and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade.

Conclusions

BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.
Inconspicuous breeding coloration to conceal eggs during mouthbrooding in male cardinalfish
Authors: Ishihara Hikaru , Kanda Shinji
Published: May 2024

The body coloration of animals has various functions, such as camouflage coloration for hiding their existence from other organisms and conspicuous coloration for appealing to their potential mates. Since the breeding colorations of males are widely considered to attract females, most previous studies on breeding coloration have mostly focused on conspicuous breeding coloration, which may have prevented the discovery of possible functions other than appealing. Here, based on a speculation that such breeding coloration might occur in species with weak sexual selection in males, we focused on Apogoninae whose sex role is considered to be reversed due to their characteristic parental behavior, paternal mouthbrooding. Through detailed morphological observations, we found that males exhibit non-conspicuous white structures, consisting of iridophores, in the lower jaw during the breeding season. Artificial implantation of eggs inside the mouth in both sexes showed that the white structure in the lower jaws, which specifically exists in males, drastically reduces the visibility of eggs during mouthbrooding. This suggested that this coloration may serve to conceal the conspicuous coloration of eggs during mouthbrooding. In addition,in vivoandin vitrohormone treatment experiments revealed that iridophore development in the lower jaw is induced by androgen through the Alkal-Ltk pathway. These results suggest that androgen-dependent breeding colorations in males, which have been considered to attract females, may serve the opposite function in these species, “inconspicuous coloration”, to increase the fitness of their specialized behavior, mouthbrooding.
AAV-mediated genome editing is influenced by the formation of R-loops
Authors: Puzzo Francesco , Crossley Magdalena P. , Goswami Aranyak , Zhang Feijie , Pekrun Katja , Garzon Jada L. , Cimprich Karlene A. , Kay Mark A.
Published: May 2024

Recombinant adeno-associated viral vectors (rAAV) hold an intrinsic ability to stimulate homologous recombination (AAV-HR) and are the most used in clinical settings forin vivogene therapy. However, rAAVs also integrate throughout the genome. Here, we describe DNA-RNA immunoprecipitation sequencing (DRIP-seq) in murine HEPA1-6 hepatoma cells and whole murine liver to establish the similarities and differences in genomic R-loop formation in a transformed cell line and intact tissue. We show enhanced AAV-HR in mice upon genetic and pharmacological upregulation of R-loops. Selecting the highly expressedAlbumingene as a model locus for genome editing in bothin vitroandin vivoexperiments showed that the R-loop prone, 3’ end ofAlbuminwas efficiently edited by AAV-HR, whereas the upstream R-loop- deficient region did not result in detectable vector integration. In addition, we found a positive correlation between previously reported off-target rAAV integration sites and R-loop enriched genomic regions. Thus, we conclude that high levels of R-loops, present in highly transcribed genes, promote rAAV vector genome integration. These findings may shed light on potential mechanisms for improving the safety and efficacy of genome editing by modulating R-loops and may enhance our ability to predict regions most susceptible to off-target insertional mutagenesis by rAAV vectors.
5-Deazaflavin (TND1128) and its hybrid analogs are cytoprotective against hydrogen peroxide (H2O2)-induced oxidative stress
Authors: Kubota Kaori , Katsurabayashi Shutaro , Watanabe Takuya , Iwasaki Katsunori , Nagamatsu Tomohisa , Akaike Norio
Published: May 2024

Increased production of reactive oxygen species (ROS) and oxidative stress are implicated in mitochondrial dysfunction, contributing to the pathogenesis of many neurodegenerative diseases. Research is ongoing into a new treatment approach for neurodegeneration, focusing on reactivating dysfunctional mitochondria. Some 5-deazaflavins, such as 10-ethyl-3-methylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione (TND1128), and four analogs of 5-deazaflavin, including β-nicotinamide mononucleotide (β-NMN), demonstrate efficient self-redox abilities similar to β-NMN, making them potential activators of mitochondrial energy synthesis. This study examines whether TND1128 and its analogs have protective effects against cellular impairment induced by oxidative stress. These compounds exhibit proliferative potential against normal cells. Moreover, TND1128 and its analogs significantly improved cell viability against hydrogen peroxide (H2O2)-induced oxidative stress injury. Our study confirms the cytoprotective effect of these 5-deazaflavins through mitochondrial activation. We anticipate TND1128 and its analogs will serve as mitochondria-stimulating drugs capable of rescuing deteriorating neurons in aging or diseases.
Antagonistic histone post-translational modifications improve the fidelity of epigenetic inheritance - a Bayesian perspective
Authors: Prabhu B. N. Balakrishna , Pillai Sibi Raj B. , Ramakrishnan Nithya
Published: May 2024

Histone Post-Translational Modifications (PTMs) are important epigenetic marks regulating gene expression. The specific pattern of histone PTMs across the gene is critical for turning on/off the expression of the corresponding gene. During DNA replication in mitotic cells, the histone PTMs are dislodged from the mother chromatid, ahead of the replication fork, and distributed uniformly at random among the daughter chromatids. Building on our previous work which modelled the inheritance of a single PTM, the current work considers the effect of an additional antagonistic PTM. We model the joint PTM sequence as a Hidden Markov Model (HMM) and the DNA replication fork as a noisy communication channel. The optimal Bayesian sequence estimator is employed at the daughter chromatids to reconstruct the mother. A high-fidelity reconstruction, aided by the enzyme machinery, is shown to be possible in the presence of epigenetic memory. The structural properties derived for the optimal estimator are then verified through simulations, which show the improvement in fidelity of inheritance in the presence of antagonism. This is further validated through recent experimental data.
WITHDRAWN: Mechanistic modeling of Mycobacterium tuberculosis β-carbonic anhydrase inhibitors using integrated systems biology and the QSAR approach
Authors: Bhowmik Ratul , Manaithiya Ajay , Parkkinen Jenny , Kumar Sunil , Mathew Bijo , Parikka Mataleena , Carta Fabrizio , Supuran Claudiu T. , Parkkila Seppo , Aspatwar Ashok
Published: May 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Mitochondrial network branching enables rapid protein spread with slower mitochondrial dynamics
Authors: Chuphal Prabha , Brown Aidan I.
Published: May 2024

Mitochondrial network structure is controlled by the dynamical processes of fusion and fission, which merge and split mitochondrial tubes into structures including branches and loops. To investigate the impact of mitochondrial network dynamics and structure on the spread of proteins and other molecules through mitochondrial networks, we used stochastic simulations of two distinct quantitative models that each included mitochondrial fusion and fission, and particle diffusion via the network. Better-connected mitochondrial networks and networks with faster dynamics exhibit more rapid particle spread on the network, with little further improvement once a network has become well-connected. As fragmented networks gradually become better-connected, particle spread either steadily improves until the networks become well-connected for slow-diffusing particles or plateaus for fast-diffusing particles. We compared model mitochondrial networks with both end-to-end and end-to-side fusion, which form branches, to non-branching model networks that lack end-to-side fusion. To achieve the optimum (most rapid) spread that occurs on well-connected branching networks, non-branching networks require much faster fusion and fission dynamics. Thus the process of end-to-side fusion, which creates branches in mitochondrial networks, enables rapid spread of particles on the network with relatively slow fusion and fission dynamics. This modeling of protein spread on mitochondrial networks builds towards mechanistic understanding of how mitochondrial structure and dynamics regulate mitochondrial function.
Ancient secretory pathways contributed to the evolutionary origin of an ecologically impactful bioluminescence system
Authors: Mesrop Lisa Y. , Minsky Geetanjali , Drummond Michael S. , Goodheart Jessica A. , Proulx Stephen R. , Oakley Todd H.
Published: May 2024

Evolutionary innovations in chemical secretion – such as the production of secondary metabolites, pheromones, and toxins – profoundly impact ecological interactions across a broad diversity of life. These secretory innovations may involve a “legacy-plus-innovation” mode of evolution, whereby new biochemical pathways are integrated with conserved secretory processes to create novel products. Among secretory innovations, bioluminescence is important because it evolved convergently many times to influence predator-prey interactions, while often producing courtship signals linked to increased rates of speciation. However, whether or not deeply conserved secretory genes are used in secretory bioluminescence remains unexplored. Here, we show that in the ostracodVargula tsujii, the evolutionary novel c-luciferase gene is co-expressed with many conserved genes, including those related to toxin production and high-output protein secretion. Our results demonstrate that the legacy-plus-innovation mode of secretory evolution, previously applied to sensory modalities of olfaction, gustation, and nociception, also encompasses light-producing signals generated by bioluminescent secretions. This extension broadens the paradigm of secretory diversification to include not only chemical signals but also bioluminescent light as an important medium of ecological interaction and evolutionary innovation.

Significance Statement

Animals produce an enormous diversity of secreted chemical products, like toxins and pheromones, with wide-ranging impacts on ecological interactions. Although a deeply conserved toolkit of secretory genes may often underlie chemical interactions mediated through smell, taste, and sensing pain, whether or not this evolutionary mode generalizes to sensing light is unknown. Here we show that a bioluminescence secretion system, which creates light for anti-predator and courtship interactions, also uses genes of a deeply conserved secretory toolkit. Therefore, secretory innovations may act through all sensory modalities by integrating conserved genes with novel biosynthesis pathways, to serve as crucibles of evolutionary and ecological diversity.
Screening for Right Ventricular Dysfunction in the Emergency Department Using a Smartphone ECG Analysis Application: An External Validation Study with Acute Pulmonary Embolism Patients
Authors: Choi Yoo Jin , Park Min Ji , Cho Youngjin , Kim Joonghee , Lee Eunkyoung , Son Dahyeon , Kim Seo-Yoon , Soh Moon Seung
Published: May 2024

Background

Acute pulmonary embolism (PE) is a critical condition where timely and accurate assessment of right ventricular (RV) dysfunction is important for patient management. Given the limited availability of echocardiography in emergency departments (EDs), an artificial intelligence (AI) application that can identify RV dysfunction from electrocardiograms (ECG) could improve the treatment of acute PE.

Methods

This retrospective study analyzed adult acute PE patients in an ED from January 2021 to December 2023. We evaluated a smartphone application which analyzes printed ECG to generate digital biomarkers for various conditions including RV dysfunction (QCG-RVDys). The biomarker’s performance was compared with that of cardiologists and emergency physicians.

Results

Among 116 included patients, 35 (30.2%) were diagnosed with RV dysfunction. The QCG-RVDys score demonstrated significant effectiveness in identifying RV dysfunction, with a receiver operating characteristic - area under the curve(AUC) of 0.895 (95% CI, 0.829-0.960), surpassing traditional biomarkers such as Troponin I (AUC: 0.692, 95% CI: 0.536-0.847) and ProBNP (AUC: 0.655, 95% CI: 0.532-0.778). Binarized based on the Youden Index, QCG-RVDys achieved an AUC of 0.845 (95% CI: 0.778-0.911), with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 91.2% (95% CI: 82.4-100%), 77.8% (95% CI: 69.1-86.4%), 63.3% (95% CI: 54.4-73.9%), and 95.5% (95% CI: 90.8-100%), respectively, significantly outperforming all the expert clinicians with their AUCs ranging from 0.628 to 0.683.

Conclusion

The application demonstrates promise in rapidly assessing RV dysfunction in acute PE patients. Its high NPV could streamline patient management, potentially reducing the reliance on echocardiography in emergency settings.
A cross-tissue, age-specific flow cytometry reference for immune cells in the airways and blood of children
Authors: Shanthikumar Shivanthan , Gubbels Liam , Davies Karen , Walker Hannah , Wong Anson Tsz Chun , Maksimovic Jovana , Oshlack Alicia , Saffery Richard , Levi Eric , Ranganathan Sarath C. , Neeland Melanie R.
Published: May 2024

Respiratory diseases are a common cause of morbidity and hospitalisation for children. Despite this, treatment options are limited and are often ineffective. The development of curative or disease-modifying treatments for children relies on a better understanding of underlying immunity in the early airway. To establish a flow cytometry reference for immune cells in the paediatric airway, we analysed 178 samples from 66 children aged between 1-15 years. This included five tissues of the upper (nasal brushings, palatine tonsils, adenotonsil) and lower (bronchial brushings, bronchoalveolar lavage (BAL)) airway, as well as whole blood for paired analysis of local and systemic immune response. Nasal, bronchial, and alveolar samples were analysed using a 17-plex antibody panel that captures cells of immune and epithelial lineage, while tonsil, adenoid, and blood samples were analysed using a 31-plex antibody panel that extensively phenotypes mononuclear immune cells. All protocols, panels, and data are openly available, to facilitate implementation in paediatric clinical laboratories. We provide age-specific cell reference data for infancy (0-2 years), preschool (3-5 years), childhood (6-10 years) and adolescence (11-15 years) for 37 cell populations. We show tissue-specific maturation of the airway immune system across childhood, further highlighting the importance of developing age-specific references of the paediatric airway. Intra-individual, cross-tissue analysis of paired samples revealed marked correlation in immune cell proportions between paired nasal-bronchial samples, paired tonsil-adenoid samples, and paired adenoid-blood samples, which may have implications for clinical testing. Our study advances knowledge of airway immunity from infancy through to adolescence and provides an openly available control dataset to aid in interpretation of clinical findings in samples obtained from children with respiratory diseases.
Association between lockdown and changes in subspecies diversity with a focus onHaemophilus influenzaeandStaphylococcus aureus
Authors: Hmidi Slim , Cassir Nadim , Colson Philippe , Ruimy Raymond , Chaudet Hervé
Published: May 2024

Background

The social distancing measures implemented to curb SARS-CoV-2 transmission provided a unique opportunity to study the association between reduced human interaction and epidemiological changes related to human bacterial pathogens. While studies have indicated a decrease in respiratory infections during lockdowns, further description is needed regarding the changes in the incidence of bacterial populations. This study investigates the changes in strain richness of community infections with two bacterial species,Haemophilus influenzaeandStaphylococcus aureusduring the waning related to France’s social distancing measures, especially lockdown.

Methods

MALDI-TOF MS spectra analyses of routine clinical bacterial identifications were used as proxies for genomic analyses. Spectra from lockdown and reference periods were compared using unsupervised classification methods. A total of 251 main spectrum profiles ofH. influenzae, 2079 main spectrum profiles ofS. aureusfor respiratory tract and blood samples, and 414 main spectrum profiles for skin samples ofS. aureuswere examined. Data were analyzed using hierarchical clustering, binary discriminant analysis, and statistical tests for significance.

Results

The strain mix of both bacteria during the lockdown was deeply altered, but with different further evolutions.H. influenzaeexhibited a shift in spectra composition, with a subsequent return towards pre-lockdown diversity observed in 2021. In contrast,S. aureusexhibited a persistent change in spectra composition, with a gradual return to pre-lockdown patterns one year later.

Conclusions

Hindering inter-human transmission, as was done during the lockdown measures, was associated with significant alterations in bacterial species compositions, with differential impacts observed forH. influenzaeandS. aureus.This study provides data on the putative relationship between genetic diversity and transmission dynamics during a public health crisis. Describing the dynamics of bacterial populations during lockdowns could contribute providing information for the implementation of future strategies for infectious disease control and surveillance.
Comparative effectiveness of the monovalent XBB.1.5-containing covid-19 mRNA vaccine across three Nordic countries
Authors: Andersson Niklas Worm , Thiesson Emilia Myrup , Pihlström Nicklas , Perälä Jori , Faksová Kristýna , Gram Mie Agermose , Poukka Eero , Leino Tuija , Ljung Rickard , Hviid Anders
Published: May 2024

Objective

To estimate the effectiveness of vaccination with a monovalent XBB.1.5-containing covid-19 mRNA vaccine against severe covid-19 across three Nordic countries.

Design

Nationwide cohort studies, using target trial emulation.

Setting

Denmark, Finland, and Sweden, from 1 October 2023 to 29 February 2024.

Participants

Individuals aged ≥65 years who had previously received at least four covid-19 vaccine doses.Main outcome measures:Cumulative incidences of covid-19 hospital admission and death for 12 weeks after immunisation (defined as 1 week after vaccination) among recipients of an XBB.1.5-containing covid-19 mRNA vaccine and matched non-recipients. Cumulative incidences were used to calculate comparative vaccine effectiveness (1-risk ratio) and risk differences.

Results

During autumn and winter 2023-2024, a total of 1,867,448 1:1 matched pairs of XBB-containing covid-19 mRNA vaccine recipients and non-recipients were included (mean age 75.4 years, standard deviation 7.4 years). The comparative vaccine effectiveness was 60.6% (95% confidence interval, 46.1% to 75.1%) against covid-19 hospital admission (930v2,551 events) and 77.9% (69.2% to 86.7%) against covid-19 related death (301v1,326 events) at 12 weeks of follow-up. This corresponded to 191.1 (95% confidence interval, 50.2 to 332.1) covid-19 hospital admissions and 109.2 (100.2 to 118.1) deaths prevented per 100,000 individuals vaccinated with an XBB.1.5-containing vaccine. The comparative vaccine effectiveness was similar across sex, age (65-74/≥75 years), number of previous covid-19 vaccine doses received, and seasonal influenza vaccination co-administration subgroups and periods of either omicron XBB- or BA.2.86-sublineage dominance. While the protection was highest during the first weeks after vaccination, it was well-preserved at end of week 12 of follow-up.

Conclusion

Among adults aged ≥65 years, vaccination with a monovalent XBB.1.5-containing covid-19 mRNA vaccine reduced the rates of covid-19 related hospital admission and death during autumn and winter 2023-2024 across three Nordic countries.
Clinical Characteristics and Patterns of Valve Lesions in Rheumatic Heart Disease Among Children at Hiwot Fana Comprehensive Specialized Hospital: A Comparative Study of Newly Diagnosed and Known Cases
Authors: Libe Temesgen Teferi , Kelil Yunus Edris , Tegene Samrawit Abebaw , Abdi Faisal , Mesfin Kibrom Hailemariam
Published: May 2024

Background

Rheumatic heart disease remains a significant health burden in resource-limited settings. This study investigates the clinical characteristics and valve lesion patterns of RHD in children from Eastern Ethiopia, comparing newly diagnosed and known RHD patients.

Objective

This study aims to characterize the clinical features and valve lesion patterns in children with Rheumatic heart disease and provide a comparative analysis between newly diagnosed and known cases.

Methods

A hospital-based cross-sectional study was conducted at Hiwot Fana Comprehensive Specialized Hospital from January 1 to December 31, 2021. A total of 39 children with RHD were included, with data collected from medical records, clinical assessments, and echocardiographic evaluations. Descriptive statistics and chi-square tests were used for analysis.

Results

Among the 39 children studied, 25 were newly diagnosed and 14 were known RHD cases. The majority were female (71.8%). The median age was 10 years. Shortness of breath (53.9%) and cough (38.5%) were the most common presenting complaints. Only 14.3% of known RHD patients were adherent to secondary prophylaxis. Severe acute malnutrition and severe anemia were the most common comorbidities. Class IV heart failure was present in 89.7% of the patients. Echocardiographic findings revealed that all patients had mitral valve involvement, with mitral regurgitation (94.9%) being the most frequent.

Conclusion

The study highlights significant clinical characteristics and valve lesion patterns among children with Rheumatic heart disease at Hiwot Fana Comprehensive Specialized Hospital, emphasizing the need for early diagnosis, improved adherence to prophylaxis, and targeted interventions to manage comorbidities and advanced heart failure.
Effects of Age and Sex on Systemic Inflammation and Cardiometabolic Function in Individuals with Type 2 Diabetes
Authors: Dushay Jody , Rickers Eva S. , Wang Enya , Gilman Jessica , Zhang Ying , Blankstein Ron , Gervino Ernest V. , Jerosch-Herold Michael , Veves Aristidis
Published: May 2024

Objective

Systemic inflammation, aging, and type 2 diabetes (T2DM) all contribute to the development of cardiovascular dysfunction and impaired aerobic exercise capacity but their interplay remains unclear. This study evaluates the impact of age, sex, and inflammation on coronary and peripheral vascular function and exercise capacity in elderly individuals with and without type 2 diabetes (T2DM).

Research Design and Methods

Elderly individuals (age ≥65 years) underwent biochemical and tissue inflammatory phenotyping, cardiopulmonary exercise testing (CPET), cardiovascular magnetic resonance (CMR) imaging, and vascular reactivity testing. Correlation and regression analyses determined the effects of systemic inflammation, older age, and sex on cardiovascular health, stratified by T2DM status.

Results

For the 133 recruited individuals (44% female; median age 71, IQR=7 years, 41% with T2DM) the presence of T2DM did not have an effect on most blood serum inflammatory markers and skin biopsies. Hyperemic myocardial blood flow (hMBF), flow-mediated, and flow-independent nitroglycerin induced brachial artery dilation were significantly impaired in males, but not females with T2DM. Peak VO2 was lower with T2DM (p=0.022), mostly because of the effect of T2DM in females. Females showed more adverse myocardial remodeling assessed by extracellular volume (p=0.008), independent of T2DM status.

Conclusions

Our findings suggest that the pathophysiological manifestations of T2DM on vascular function and aerobic exercise capacity are distinct in elderly males and females and this may reflect underlying differences in vascular and myocardial aging in the presence of T2DM.
HIV-Associated Heart Failure: Phenotypes and Clinical Outcomes in a Safety-Net Setting
Authors: Durstenfeld Matthew S. , Thakkar Anjali , Jeon Diane , Short Robert , Ma Yifei , Tseng Zian H. , Hsue Priscilla Y.
Published: May 2024

Background

Human immunodeficiency virus (HIV) is associated with increased risk of heart failure (HF) but data regarding phenotypes of heart failure and outcomes after HF diagnosis, especially within the safety-net which is where half of people with HIV in the United States receive care, are less clear.

Methods

Using an electronic health record cohort of all individuals with HF within a municipal safety-net system from 2001-2019 linked to the National Death Index Plus, we compared HF phenotypes, all-cause mortality, HF hospitalization, and cause of death for individuals with and without HIV.

Results

Among people with HF (n=14,829), 697 individuals had HIV (4.7%). Persons with HIV (PWH) were diagnosed with HF ten years younger on average. A higher proportion of PWH had a reduced ejection fraction at diagnosis (37.9% vs 32.7%). Adjusted for age, sex, and risk factors, coronary artery disease on angiography was similar by HIV status. HIV was associated with 55% higher risk of all-cause mortality (HR 1.55; 95% CI 1.37-1.76; P<0.001) and lower odds of HF hospitalization (OR 0.51; 95% CI 0.39-0.66; P<0.001). Among PWH with HF, cause of death was less often attributed to cardiovascular disease (22.5% vs 54.6% uninfected; P<0.001) and more to substance use (17.9% vs 9.3%; P<0.001), consistent with autopsy findings in a subset (n=81).

Conclusions

Among people with HF who receive care within a municipal safety-net system, HIV infection is associated with higher mortality, despite lower odds of HF hospitalization, attributable to non-cardiovascular causes including substance-related and HIV-related mortality.

Clinical Perspectives

People with HIV develop heart failure 10 years earlier than people without HIV, with a higher proportion with HFrEF at diagnosis.

HIV is associated with higher mortality among people with heart failure, primarily due to non-cardiovascular causes including HIV/AIDS and substance use.

Research Perspectives

The reasons for higher mortality in PWH with HF are not yet fully understood; higher levels of myocardial fibrosis may predispose people with substance use and advanced HIV disease to increased risk of mortality.
H2consumption by various acetogenic bacteria follows first-order kinetics up to H2saturation
Authors: Muñoz-Duarte Laura , Chakraborty Susmit , Grøn Louise Vinther , Bambace Maria Florencia , Catalano Jacopo , Philips Jo
Published: May 2024

Acetogenic bacteria play an important role in various biotechnological processes, because of their chemolithoautotrophic metabolism converting carbon dioxide with molecular hydrogen (H2) as electron donor into acetate. As the main factor limiting acetogenesis is often H2, insights into the H2consumption kinetics of acetogens is required to assess their potential in biotechnological processes. In this study, initial H2consumption rates at a range of different initial H2concentrations were measured for three different acetogens. Interestingly, for all three strains, H2consumption was found to follow first-order kinetics, i.e. the H2consumption rate increased linearly with the dissolved H2concentration, up to almost saturated H2levels (600 µM). This is in contrast with Monod kinetics and low half-saturation concentrations, which have commonly been assumed for acetogens. The obtained biomass specific first-order rate coefficients (k1X) were further validated by comparison with values obtained by fitting first-order kinetics on previous time-course experimental results. The latter method was also used to determine thek1Xvalue of five additional acetogens strains. Biomass specific first-order rate coefficients were found to vary up to six-fold, with the highestk1XforAcetobacterium wieringaeand the lowest forSporomusa sphaeroides. Overall, our results demonstrate the importance of the dissolved H2concentration to understand the rate of acetogenesis in biotechnological systems.
varVAMP: automated pan-specific primer design for tiled full genome sequencing and qPCR of highly diverse viral pathogens
Authors: Fuchs Jonas , Kleine Johanna , Schemmerer Mathias , Kreibich Julian , Maier Wolfgang , Battur Namuun , Krannich Thomas , Sedaghatjoo Somayyeh , Jaki Lena , Maks Anastasija , Boehm Christina , Wilhelm Carina , Schulze Jessica , Mache Christin , Berger Elischa , Panajotov Jessica , Eidenschink Lisa , Grüning Björn , Bauswein Markus , Böttcher Sindy , Johne Reimar , Wenzel Jürgen , Hölzer Martin , Panning Marcus
Published: May 2024

Time- and cost-saving surveillance of viral pathogens is achieved by tiled sequencing in which a viral genome is amplified in overlapping PCR amplicons and qPCR. However, designing pan-specific primers for viral pathogens that have high genomic variability represents a major challenge. Here, we present a bioinformatics command-line tool, called varVAMP (variablevirusamplicons). It relies on multiple sequence alignments of highly variable virus sequences and enables automatic pan-specific primer design for qPCR or tiled amplicon whole genome sequencing.

The varVAMP software guarantees pan-specificity by two means: it designs primers in regions with minimal variability and introduces degenerate nucleotides into primer sequences to compensate for common sequence variations. We demonstrate varVAMP’s utility by designing and evaluating novel pan-specific primer schemes suitable for sequencing the genomes of SARS-CoV-2, Hepatitis E virus, rat Hepatitis E virus, Hepatitis A virus, Borna-disease-virus-1, and Poliovirus. Moreover, we established highly sensitive and specific Poliovirus qPCR assays that could potentially simplify current Poliovirus surveillance. Importantly, wet-lab and bioinformatic techniques established for SARS-CoV-2 tiled amplicon sequencing were readily transferable to these new primer schemes and will allow sequencing laboratories to extend their established methodology to other human pathogens.
Mismatch between pollen and pistil size causes asymmetric mechanical reproductive isolation acrossPhloxspecies
Authors: Feller Anna F. , Burgin Grace , Lewis Nia , Prabhu Rohan , Hopkins Robin
Published: May 2024

In flowering plants, pollen-pistil interactions can serve as an important barrier to reproduction between species. As the last barrier to reproduction before fertilization, interactions between these reproductive organs are both complex and important for determining a suitable mate. Here, we test whether differences in style length generate a post-mating prezygotic mechanical barrier between five species of perennialPhloxwildflowers with geographically overlapping distributions. We perform controlled pairwise reciprocal crosses between three species with long styles and two species with short styles to assess crossing success (seed set). We find that heterospecific seed set is broadly reduced compared to conspecific cross success and reveal a striking asymmetry in heterospecific crosses between species with different style lengths. To determine the mechanism underlying this asymmetric reproductive isolating barrier we assess pollen tube growthin vitroandin vivo. We demonstrate that pollen tubes of short-styled species do not grow long enough to reach the ovaries of long-styled species. We find that short-styled species also have smaller pollen and that both within and between species pollen diameter is highly correlated with pollen tube length. Our results support the hypothesis that the small pollen of short-styled species lacks resources to grow pollen tubes long enough to access the ovaries of the long-styled species, resulting in an asymmetrical, mechanical barrier to reproduction. Such mechanisms, combined with additional pollen-pistil incompatibilities, may be particularly important for closely related species in geographic proximity that share pollinators.
In vitroassays for clinical isolates of sequence type 131Escherichia colido not recapitulatein vivoinfectivity using a murine model of urinary tract infection
Authors: Rudick Courtney P. , Cox Rachel S. , Bourret Travis J. , Hanson Nancy D.
Published: May 2024

Sequence Type 131 isolates are a major cause of cystitis and pyelonephritis. Many studies rely solely onin vitroassays to screen for bacterial virulence factors associated with the pathogenicity of clinical isolates ofE. coli. Few studies have comparedin vitrofindings toin vivoinfectivity of clinical isolates. The purpose of this study was to evaluate the correlation betweenin vitroassays with the ability to cause cystitis and pyelonephritis in a murine model of urinary tract infection.In vitroassays were conducted according to published protocols and included: motility assays, biofilm formation, epithelial cell adhesion and invasion, and curli production. Twenty-one UPEC isolates ofE. coliST131 and non-ST131 were used for bothin vivoandin vitrostudies. Six mice per isolate were inoculated via urethral catheterization. CFUs were determined from bladder and kidneys.In vitroandin vivocorrelations were evaluated by multiple linear regression analysis. Pairwise linear regressions showed trendlines with weak positive correlations for motility, adhesion, and invasion and weak negative correlations for hemagglutination, biofilm and curli production. The ability ofE. coliST131 and non-ST131 clinical isolates to cause cystitis and pyelonephritis varies among strains. The R2Pearson Correlation value was less than ±0.5 for any pair, indicating little to no statistical association betweenin vitroandin vivofindings. These data showin vitrodata are not predictive of the ability of ST131E. colito infect and/or cause disease in a mouse model.

Author summary

Urinary tract infections affect 150 million people annually andE. coliST131 have become the pandemic strain responsible for a majority of UTI, cystitis, and pyelonephritis cases. How ST131E. colihave become such prolific strain still remains to be elucidated. When evaluating bacterial pathogenicity, it is customary practice to usein vitroassays to predict isolate virulence and mechanisms of fitness, due to the lower cost, and relative ease of experimentation compared to more costly and complicatedin vivomodels. It is also common to use model organisms like pathogenicE. coliCFT073 or non-pathogenic lab strains such as BW25113 as representatives for the entire species. However, our research has shown that not only are model organisms substantially different from clinical isolates of ST131E. coli, butin vitroassays are poor predictors of clinical isolates’ ability to cause infection in a murine model of UTI. As such, research into the mechanisms of fitness for ST131 infectivity need to veer away from studying only model organisms and focus on utilizing pathogenic clinical isolates in conditions that more closely recapitulate urinary tract environmental niches.
Enhanced binding of guanylated poly(A) RNA by the LaM domain of LARP1
Authors: Kozlov Guennadi , Jiang Jianning , Rutherford Tyler , Noronha Anne M. , Wilds Christopher J. , Gehring Kalle
Published: May 2024

La-related proteins (LARPs) are a family of RNA-binding proteins that share a conserved La motif (LaM) domain. LARP1 plays a role in regulating ribosomal protein synthesis and stabilizing mRNAs and has a unique structure without an RNA binding RRM domain adjoining the LaM domain. In this study, we investigated the physical basis for LARP1 specificity for poly(A) sequences and observed an unexpected bias for sequences with single guanines. Multiple guanine substitutions did not increase the affinity, demonstrating preferential recognition of singly guanylated sequences. We also observed that the cyclic di- nucleotides in the cCAS/STING pathway, cyclic-di-GMP and 3’,3’-cGAMP, bound with sub-micromolar affinity. Isothermal titration measurements were complemented by high-resolution crystal structures of the LARP1 LaM with six different RNA ligands, including two stereoisomers of a phosphorothioate linkage. The selectivity for singly substituted poly(A) sequences suggests LARP1 may play a role in the stabilizing effect of poly(A) tail guanylation.
Laser NIR irradiation enhances antimicrobial photodynamic inactivation of biofilms ofStaphylococcus aureus
Authors: Mamone Leandro , Tomás Roberto , Di Venosa Gabriela , Gándara Lautaro , Durantini Edgardo , Buzzola Fernanda , Casas Adriana
Published: May 2024

Photodynamic inactivation (PDI) utilizes a photosensitizer (PS) activated by visible light to generate reactive oxygen species (ROS), to kill bacteria. PDI is effective against planktonic microorganisms, but biofilms are less sensitive due to limited PS and oxygen penetration. Near-infrared treatment (NIRT), involve the use of near-infrared light to kill bacteria either via thermal effects or ROS production.

Our objective was to enhanceS. aureusbiofilm’s sensitivity to PDI by pre-treating with NIR irradiation before visible light exposure.

In anin vitrobiofilm model, laser NIRT (980 nm) followed by exposure to PDI, showed a synergistic effect on bacterial viability loss (4-log CFU vs 1-log loss with individual treatments). Interestingly, pre-heating liquid medium had no significant impact on PDI efficacy, suggesting that both thermal and non-thermal effects of NIR may be involved.

NIRT increased PS uptake, induced clefts in the biofilm matrix, and released bacterial cells from the biofilm. NIRT induced a transient increase in the temperature to 46°C ofin vitrocultures, however under the same conditions, when mice were irradiated, skin temperature rose to 37°.

Our findings suggest that NIR irradiation serves as a complementary treatment to PDI, allowing reducing PS concentration, and highlighting its potential as an effective and resource-efficient antibacterial approach.
The roles of TGFβ and serotonin signaling in regulating proliferation of oocyte precursors and germline aging
Authors: Aprison Erin Z. , Dzitoyeva Svetlana , Ruvinsky Ilya
Published: May 2024

Abstract

The decline of oocyte quality in aging but otherwise relatively healthy individuals compels a search for underlying mechanisms. Building upon a finding that exposure to male pheromone ascr#10 improves oocyte quality inC. elegans, we uncovered a regulatory cascade that promotes proliferation of oocyte precursors in adults and regulates oocyte quality. We found that the male pheromone promotes proliferation of oocyte precursors by upregulating LAG-2, a ligand of the Notch-like pathway in the germline stem cell niche. LAG-2 is upregulated by a TGFβ-like ligand DAF-7 revealing similarity of regulatory mechanisms that promote germline proliferation in adults and larvae. A serotonin circuit that also regulates food search and consumption upregulates DAF-7 specifically in adults. The serotonin/DAF-7 signaling promotes germline expansion to compensate for oocyte expenditure which is increased by the male pheromone. Finally, we show that the earliest events in reproductive aging may be due to declining expression of LAG-2 and DAF-7. Our findings highlight neuronal signals that promote germline proliferation in response to the environment and argue that deteriorating oocyte quality may be due to reduced neuronal expression of key germline regulators.
An unbiased method to partition diverse neuronal responses into functional ensembles reveals interpretable population dynamics during innate social behavior
Authors: Lin Alexander , Akafia Cyril , Dal Monte Olga , Fan Siqi , Fagan Nicholas , Putnam Philip , Tye Kay M. , Chang Steve , Ba Demba , Allsop AZA Stephen
Published: May 2024

In neuroscience, understanding how single-neuron firing contributes to distributed neural ensembles is crucial. Traditional methods of analysis have been limited to descriptions of whole population activity, or, when analyzing individual neurons, criteria for response categorization varied significantly across experiments. Current methods lack scalability for large datasets, fail to capture temporal changes and rely on parametric assumptions. There’s a need for a robust, scalable, and non-parametric functional clustering approach to capture interpretable dynamics. To address this challenge, we developed a model-based, statistical framework for unsupervised clustering of multiple time series datasets that exhibit nonlinear dynamics into ana-priori-unknown number of parameterized ensembles called Functional Encoding Units (FEUs). FEU outperforms existing techniques in accuracy and benchmark scores. Here, we apply this FEU formalism to single-unit recordings collected during social behaviors in rodents and primates and demonstrate its hypothesis-generating and testing capacities. This novel pipeline serves as an analytic bridge, translating neural ensemble codes across model systems.
Neural correlates of rapid familiarization to novel taste
Authors: Svedberg Daniel A. , Katz Donald B.
Published: May 2024

The gustatory cortex (GC) plays a pivotal role in taste perception, with neural ensemble responses reflecting taste quality and influencing behavior. Recent work, however, has shown that GC taste responses change across sessions of novel taste exposure in taste-naïve rats. Here, we use single-trial analyses to explore changes in the cortical taste-code on the scale of individual trials. Contrary to the traditional view of taste perception as innate, our findings suggest rapid, experience-dependent changes in GC responses during initial taste exposure trials. Specifically, we find that early responses to novel taste are less “stereotyped” and encode taste identity less reliably compared to later responses. These changes underscore the dynamic nature of sensory processing and provides novel insights into the real-time dynamics of sensory processing across novel-taste familiarization.