bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mineralocorticoid receptor antagonists in cardiovascular translational biology
Authors: Chilton Robert J. , Silva-Cardoso José 
Published: August 2023

This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid receptor antagonism. The data discussed suggest that MRAs can play an important role in decreasing the impact of inflammation and fibrosis on cardiorenal outcomes. Evidence derived from major randomized clinical trials demonstrates that steroidal MRAs reduce mortality in patients with heart failure and reduced ejection fraction. Initial positive findings observed in patients with chronic kidney disease and type 2 diabetes (T2D) indicate the possible mechanisms of action of nonsteroidal MRAs, and the clinical benefits for patients with cardiorenal disease and T2D. This article supports the application of basic science concepts to expand our understanding of the molecular mechanisms of action involved in pathophysiology. This approach encourages the development of treatment options before diseases clinically manifest.
Video Abstract: http://links.lww.com/CAEN/A42
Long-read sequencing resolves a complex structural variant inPRKNParkinson’s disease
Authors: Daida Kensuke , Funayama Manabu , Billingsley Kimberley J , Malik Laksh , Miano-Burkhardt Abigail , Leonard Hampton L. , Makarious Mary B. , Iwaki Hirotaka , Ding Jinhui , Gibbs J. Raphael , Ishiguro Mayu , Yoshino Hiroyo , Ogaki Kotaro , Oyama Genko , Nishioka Kenya , Nonaka Risa , Akamatsu Wado , Blauwendraat Cornelis , Hattori Nobutaka 
Published: August 2023

AbstractBackgroundPRKNmutations are the most common cause of young onset and autosomal recessive Parkinson’s disease (PD).PRKNis located in FRA6E which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions ofPRKNare seldom reported, suggesting that there are potentially unrevealed complex pathogenicPRKNstructural variants.ObjectivesTo identify complex structural variants inPRKNusing long-read sequencing.MethodsWe investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read. We assessed the presence and frequency of complex inversions overlappingPRKNusing whole-genome sequencing data of AMP-PD and UK-Biobank datasets.ResultsMultiple ligation probe amplification identified a heterozygous exon 3 deletion inPRKNand long-read sequencing identified a large novel inversion spanning over 7Mb, including a large part of the coding DNA sequence ofPRKN. We could diagnose the affected subjects as compound heterozygous carriers ofPRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4,941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affectPRKNisoforms.ConclusionsThis is the first report describing a large 7Mb inversion involving breakpoints outside ofPRKN. This study highlights the importance of using long-read whole genome sequencing for structural variant analysis in unresolved young-onset PD cases.
Changes in an Enzyme Ensemble During Catalysis Observed by High Resolution XFEL Crystallography
Authors: Smith Nathan , Dasgupta Medhanjali , Wych David C. , Dolamore Cole , Sierra Raymond G. , Lisova Stella , Marchany-Rivera Darya , Cohen Aina E. , Boutet Sébastien , Hunter Mark S. , Kupitz Christopher , Poitevin Frédéric , Moss Frank R. , Brewster Aaron S. , Sauter Nicholas K. , Young Iris D. , Wolff Alexander M. , Tiwari Virendra K. , Kumar Nivesh , Berkowitz David B. , Hadt Ryan G. , Thompson Michael C. , Follmer Alec H. , Wall Michael E. , Wilson Mark A. 
Published: August 2023

AbstractEnzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) to observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme that enhances sampling of important minor conformations. The active site exists in a mixture of conformations and formation of the thioimidate catalytic intermediate selects for catalytically competent substates. A prior proposal for active site cysteine charge-coupled conformational changes in ICH is validated by determining structures of the enzyme over a range of pH values. A combination of large molecular dynamics simulations of the enzyme in crystallo and time-resolved electron density maps shows that ionization of the general acid Asp17 during catalysis causes additional conformational changes that propagate across the dimer interface, connecting the two active sites. These ionization-linked changes in the ICH conformational ensemble permit water to enter the active site in a location that is poised for intermediate hydrolysis. ICH exhibits a tight coupling between ionization of active site residues and catalysis-activated protein motions, exemplifying a mechanism of electrostatic control of enzyme dynamics.
Predicting risk of Alzheimer’s disease using polygenic risk scores developed for Parkinson’s disease
Authors: Graham Britney E. , Williams Scott M. , Moore Jason H. 
Published: August 2023

AbstractBackground and ObjectivesThe two most common neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD), both related to age and affect millions of people across the world, especially as life expectancy increases in certain countries. Here, we explore the potential predictiveness of the genetic risk of AD and PD separately and then the extent of the underlying shared genetics of AD and PD.MethodsThe population genetic risk estimates for AD and PD were derived using a previously developed population specific polygenic risk score (psPRS) and regression-based SNP filtering method. To test the overlap between AD and PD, we ran a regression of the AD psPRSs versus the population PD prevalences for both the filtered and unfiltered AD PRS and vice versa. We then assessed gene-gene interaction and pathway involvement using the Alzheimer’s KnowledgeBase (AlzKB) and STRINGdb, respectively.ResultsThe unfiltered PD psPRS was moderately predictive, while the AD psPRS was not. After filtering, both the AD and PD, psPRSs improved to strongly predictive, explained most of the genetic variation. The ability of the unfiltered AD psPRS to predict PD, and vice versa, is poor. However, the filtered AD, and PD, psPRS were highly predictive.DiscussionOur results suggest that there is a correlation between AD, and PD, specific allele frequency and prevalence, as well as an overlap of AD and PD generally. However, the AD psPRS is a better predictor of PD, than the PD psPRS is of AD. Our results call for further research into the general overlap of Alzheimer’s disease and Parkinson’s disease, despite the previous lack of evidence.
Unraveling COVID-19: Descriptive Analytics in a Middle-Income Country, Paving the Path Forward
Authors: Bansilan Norvin P. , Rabajante Jomar F. 
Published: August 2023

AbstractThe outbreak of COVID-19 unleashed an unprecedented global pandemic, leaving a profound impact on lives and economies worldwide. Recognizing its severity, the World Health Organization swiftly declared it a public health emergency of international concern. Tragically, the Philippines reported the first death case outside China, leading to a surge in cases following the first instance of local transmission. In response to this crisis, collaborative efforts have been underway to control the disease and minimize its health and socio-economic impacts. The COVID-19 epidemic curve holds vital insights into the history of exposure, transmission, testing, tracing, social distancing measures, community lockdowns, quarantine, isolation, and treatment, offering a comprehensive perspective on the nation’s response. One approach to gaining crucial insights is through meticulous analysis of available datasets, empowering us to inform future strategies and responses effectively. This paper aims to provide descriptive data analytics of the COVID-19 pandemic in the Philippines, summarizing the country’s fight by visualizing epidemiological and mobility datasets, revisiting scientific papers and news articles, and creating a timeline of the key issues faced during the pandemic. By leveraging these multifaceted analyses, policymakers and health authorities can make informed decisions to enhance preparedness, expand inter-agency cooperation, and combat future public health crises effectively. This study seeks to serve as a valuable resource, guiding nations worldwide in comprehending and responding to the challenges posed by COVID-19 and beyond.
Chromosome 20p11.2 deletions cause congenital hyperinsulinism via the likely disruption ofFOXA2
Authors: Laver Thomas W , Wakeling Matthew N , Caswell Richard C , Bunce Benjamin , Yau Daphne , Houghton Jayne AL , Hopkins Jasmin J. , Weedon Michael N , Saraff Vrinda , Kershaw Melanie , Honey Engela M , Murphy Nuala , Giri Dinesh , Nath Stuart , Saredo Ana Tangari , Banerjee Indraneel , Hussain Khalid , Owens Nick DL , Flanagan Sarah E 
Published: August 2023

AbstractPersistent congenital hyperinsulinism (HI) is a rare genetically heterogeneous condition characterised by dysregulated insulin secretion leading to life-threatening hypoglycaemia. For up to 50% of affected individuals screening of the known HI genes does not identify a disease-causing variant. Large deletions have previously been used to identify novel regulatory regions causing HI. Here, we used genome sequencing to search for novel large (>1Mb) deletions in 180 probands with HI of unknown cause and replicated our findings in a large cohort of 883 genetically unsolved individuals with HI using off-target copy number variant calling from targeted gene panels. We identified overlapping heterozygous deletions in five individuals (range 3-8 Mb) spanning chromosome 20p11.2. The pancreatic beta-cell transcription factor gene,FOXA2, a known cause of HI was deleted in two of the five individuals. In the remaining three, we found a minimal deleted region of 2.4 Mb adjacent toFOXA2that encompasses multiple non-coding regulatory elements that are in conformational contact withFOXA2. Our data suggests that the deletions in these three patients may cause disease through the dysregulation ofFOXA2expression. These findings provide new insights into the regulation ofFOXA2in the beta-cell and confirm an aetiological role for chromosome 20p deletions in syndromic HI.
Trending Drugs Combination to Target Leukemia associated Proteins/Genes: using Graph Neural Networks under the RAIN Protocol
Authors: Boush Mahnaz , Kiaei Ali A. , Mahboubi Hossein 
Published: August 2023

ABSTRACTBackgroundLeukemia, a cancer impacting blood-forming tissues such as bone marrow and the lymphatic system, presents in various forms, affecting children and adults differently. The therapeutic approach is complex and depends on the specific leukemia type. Effective management is crucial as it disrupts normal blood cell production, increasing infection susceptibility. Treatments like chemotherapy can further weaken immunity. Thus, a patient’s healthcare plan should focus on comfort, reducing chemotherapy side effects, protecting veins, addressing complications, and offering educational and emotional support.MethodThis article reviews studies on the combined use of drugs for treating leukemia. Employing a mix of medicines might decrease the chances of tumor resistance. Starting multiple drugs concurrently allows for immediate application during disease onset, avoiding delays. Initial chemotherapy uses a drug combination to eliminate maximum leukemia cells and restore normal blood counts. Afterwards, intensification chemotherapy targets any residual, undetectable leukemia cells in the blood or bone marrow. To recommend a drug combination to treat/manage Leukemia, under first step of RAIN protocol, we have searched articles including related trend drugs using Natural Language Processing. In the second step, we have employed Graph Neural Network to pass information between these trending drugs and genes that act as potential targets for Leukemia.ResultAs a result, the Graph Neural network recommends combining Tretinoin, Asparaginase, and Cytarabine. The network meta-analysis confirmed the effectiveness of these drugs on associated genes.ConclusionThe p-value between leukemia and the scenario that includes combinations of the mentioned drugs is almost zero, indicating an improvement in leukemia treatment. Reviews of clinical trials on these medications support this claim.HighlightsCombined drugs that make p-value between Leukemia and target proteins/genes close to 1Using Graph Neural network to recommend drug combinationA Network meta-analysis to measure the comparative efficacyConsidered drug interactions
Kinesiophobia and physical activity: A systematic review and meta-analysis
Authors: Goubran Miriam , Farajzadeh Ata , Lahart Ian M. , Bilodeau Martin , Boisgontier Matthieu P. 
Published: August 2023

ABSTRACTObjectivePhysical activity contributes to the primary, secondary, and tertiary prevention of multiple diseases. However, in some patients, an excessive, irrational, and debilitating fear of movement (i.e., kinesiophobia) is thought to induce avoidance behaviors, contributing to decreased engagement in physical activity. The aim of this study was to examine whether kinesiophobia is negatively associated with physical activity in several health conditions and what factors may influence this relationship.MethodsFive databases were searched for studies including both a measure of kinesiophobia and physical activity. Two reviewers screened articles for inclusion, assessed risk of bias, and extracted data from each study. Pearson product-moment correlations were pooled from eligible studies using the generic inverse pooling and random effects method to examine the relationship between kinesiophobia and physical activity.ResultsSeventy-four studies were included in the systematic review and 63 studies (83 estimates, 12,278 participants) in the main meta-analysis. Results showed a small-to-moderate negative correlation between kinesiophobia and physical activity (r = −0.19; 95% confidence interval: −0.26 to −0.13; I2= 85.5%; p < 0.0001). Funnel plot analysis showed evidence of publication bias, but p-curve analysis suggested that our results could not be caused by selective reporting. A subgroup meta-analysis showed that the correlation was statistically significant in patients with cardiac, rheumatologic, neurologic, or pulmonary conditions, but not in patients with chronic or acute pain.ConclusionOur results suggest that higher levels of kinesiophobia are associated with lower levels of physical activity in several health conditions that are not necessarily painful.ImpactKinesiophobia should be dissociated from pain and considered in relation to specific health conditions when implementing exercise therapy. Kinesiophobia may have prognostic implications in patients for whom physical activity contributes to prevent recurrence or worsening of their condition.
Antimicrobial activity of NK cells toTrypanosoma cruziinfected human primary Keratinocytes
Authors: Kroh Keshia , Barton Jessica , Fehling Helena , Lotter Hanna , Volkmer Beate , Greinert Rüdiger , Mhamdi-Ghodbani Mouna , Vanegas Andrea , Jacobs Thomas , Gálvez Rosa Isela 
Published: August 2023

AbstractInfection with the protozoan parasiteTrypanosoma cruziis causative for Chagas disease, which is a highly neglected tropical disease prevalent in Latin America. Humans are primary infected through vectorial transmission by blood-sucking triatomine bugs. The parasite enters the human host through mucous membranes or small skin lesions. Since keratinocytes are the predominant cell type in the epidermis, they play a critical role in detecting disruptions in homeostasis and aiding in pathogen elimination by the immune system in the human skin as alternative antigen-presenting cells. Interestingly, keratinocytes also act as a reservoir forT. cruzi, as the skin has been identified as a major site of persistent infection in mice with chronic Chagas disease. Moreover, there are reports of the emergence ofT. cruziamastigote nests in the skin of immunocompromised individuals who are experiencing reactivation of Chagas disease. This observation implies that the skin may serve as a site for persistent parasite presence during chronic human infection too and underscores the significance of investigating the interactions betweenT. cruziand skin cells. Consequently, the primary objective of this study was to establish and characterize the infection kinetics in human primary epidermal keratinocytes (hPEK). Our investigation focused on surface molecules that either facilitated or hindered the activation of natural killer (NK) cells, which play a crucial role in controlling the infection. To simulate thein vivosituation in humans, an autologous co-culture model was developed to examine the interactions betweenT. cruziinfected keratinocytes and NK cells. We evaluated the degranulation, cytokine production, and cytotoxicity of NK cells in response to the infected keratinocytes. We observed a strong activation of NK cells by infected keratinocytes, despite minimal alterations in the expression of activating or inhibitory ligands on NK cell receptors. However, stimulation with recombinant interferon-gamma (IFN-γ), a cytokine known to be present in significant quantities during chronicT. cruziinfections in the host, resulted in a substantial upregulation of these ligands on primary keratinocytes. Overall, our findings suggest the crucial role of NK cells in controlling acuteT. cruziinfection in the upper layer of the skin and shed light on keratinocytes as potential initial targets of infection.
Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress
Authors: Al-Onaizi Mohammed , Braysh Kawthar , Alkefeef Selma , Altarrah Dana , Dannoon Shorouk , Alasousi Dalal , Adel Hawraa , Al-Ajmi Mariam , Kandari Anwar , Najem Rawan , Nizam Rasheeba , Williams Michayla R , John Sumi , Thanaraj Thangavel Alphonse , Ahmad Rasheed , Al-Hussaini Heba , Al-Mulla Fahd , Alzaid Fawaz 
Published: August 2023

AbstractType 2 diabetes (T2D) and its comorbidities are a major public health concern. In addition to peripheral tissues, T2D also impacts the central nervous system leading to neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we used a novel proprietary high-fat diet, in which glucose intolerance precedes weight gain, to decipher the metabolic determinants of neurocognitive affects. We show that this model exhibits anxiety-like behaviors, without eliciting depression nor recognition memory deficits. Long-term feeding leads to weight gain, brain glucose hypometabolism and impaired recognition memory alongside the early onset anxiety-like behavior. Using an established genetic model of T2D (db/db) and of diet-induced obesity we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. Our findings indicate that glucose intolerance alone can elicit anxiety-like behaviors. Through this study we also provide a novel nutritional model to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.
LPATH: A semi-automated Python tool for clustering molecular pathways
Authors: Bogetti Anthony T. , Leung Jeremy M. G. , Chong Lillian T. 
Published: August 2023

AbstractThe pathways by which a molecular process transitions to a target state are highly sought-after as direct views of a transition mechanism. While great strides have been made in the physics-based simulation of such pathways, the analysis of these pathways can be a major challenge due to their diversity and variable lengths. Here we present the LPATH Python tool, which implements a semi-automated method for linguistics-assisted clustering of pathways into distinct classes (or routes). This method involves three steps: 1) discretizing the configurational space into key states, 2) extracting a text-string sequence of key visited states for each pathway, and 3) pairwise matching of pathways based on a text-string similarity score. To circumvent the prohibitive memory requirements of the first step, we have implemented a general two-stage method for clustering conformational states that exploits machine learning. LPATH is primarily designed for use with the WESTPA software for weighted ensemble simulations; however, the tool can also be applied to conventional simulations. As demonstrated for the C7eqto C7axconformational transition of alanine dipeptide, LPATH provides physically reasonable classes of pathways and corresponding probabilities.TOC Graphic
Effectiveness and residual activity of four common insecticides used in the Mississippi Delta to control tarnished plant bugs in cotton
Authors: Portilla Maribel , Little Nathan S. , Allen Clint , Zhu Yu Cheng 
Published: August 2023

AbstractThe tarnished plant bug, (TPB)Lygus lineolarisPalisot de Beauvois (Hemiptera: Miridae) is a key pest of cotton in the midsouth region and some areas of the eastern United States. Its control methods have been solely based on chemical insecticides which has contributed to insecticidal resistance and shortened residual periods for control of this insect pest. This study was conducted over a two-year period and examined the efficacy and residual effect of four commercial insecticides including lambda-cyhalothrin (pyrethroid), acephate (organophosphate), imidacloprid (neonicotinoid), and sulfoxaflor (sulfoxamine). The effectiveness and residual effects of these insecticides were determined by application on cotton field plots on four different dates during each season using three different concentrations (high: highest labeled commercial dose (CD), medium: 1/10 of the CD, low: 1/100 of the CD) on field cotton plots. Four groups of cotton leaves were randomly pulled from each treated plot and control 0-, 2-, 4-, 7-, and 9-days post treatment (DPT) and exposed to a lab colony of TPB adults. One extra leaf sample/ plot/ spray /DPT interval (0-2-4-7-9-11) during 2016 was randomly collected from the high concentration plots and sent to Mississippi State Chemical Laboratory for residual analysis. Mortality of TPB adults was greatest for those placed on leaves sprayed with the organophosphate insecticide with mortalities (%) of 81.7±23.4 and 63.3±28.8 (SE) 1-day after exposure (DAE) on leaves 0-DPT with the high concentration for 2016 and 2017, respectively, reaching 94.5±9.5 and 95.4±7.6 6-DAE each year. Mortality to all insecticides continued until 9 and 4-DPT for high and medium concentrations, respectively. However, organophosphate (39.4±28.6) and pyrethroid (24.4±9.9) exhibited higher mortality than sulfoxamine (10.6±6.6) and the neonicotinoid (4.0±1.5) 7-DAE on 9-DPT leaves with the high concentration. Based on our results using the current assay procedure, TPB adults were significantly more susceptible to contact than systemic insecticides and due to its residual effect, organophosphate could kill over 80% of the TPB population 7-DPT.