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JACC. Advances Sep 2023Genetic factors are not included in prediction models for coronary heart disease (CHD).
BACKGROUND
Genetic factors are not included in prediction models for coronary heart disease (CHD).
OBJECTIVES
The authors assessed the predictive utility of a polygenic risk score (PRS) for CHD (defined as myocardial infarction, coronary revascularization, or cardiovascular death) and whether the risks due to monogenic familial hypercholesterolemia (FH) and family history (FamHx) are independent of and additive to the PRS.
METHODS
In UK-biobank participants, PRS was calculated using metaGRS, and 10-year risk for incident CHD was estimated using the pooled cohort equations (PCE). The area under the curve (AUC) of the receiver operator curve and net reclassification improvement (NRI) were assessed. FH was defined as the presence of a pathogenic or likely pathogenic variant in , , or . FamHx was defined as a diagnosis of CHD in first-degree relatives. Independent and additive effects of PRS, FH, and FamHx were evaluated in stratified analyses.
RESULTS
In 323,373 participants with genotype data, the addition of PRS to PCE increased the AUC from 0.759 (95% CI: 0.755-0.763) to 0.773 (95% CI: 0.769-0.777). The AUC and NRI for PRS were higher before the age of 55 years. Of 199,997 participants with exome sequence data, 10,000 had a PRS ≥95th percentile (PRS), 673 had FH, and 46,163 had FamHx. The CHD risk associated with PRS was independent of FH and FamHx. The risks associated with combinations of PRS, FH, and FamHx were additive and comprehensive estimates could be obtained by multiplying the risk from each genetic factor.
CONCLUSIONS
Incorporating PRS into the PCE improves risk prediction for CHD, especially at younger ages. The associations of PRS, FH, and FamHx with CHD were independent and additive.
PubMed: 38939477
DOI: 10.1016/j.jacadv.2023.100567 -
Case Reports in Pediatrics 2024In infants and children, bacterial meningitis caused by anaerobic bacteria is rare. However, a serious infection with the anaerobe can occur in previously healthy...
In infants and children, bacterial meningitis caused by anaerobic bacteria is rare. However, a serious infection with the anaerobe can occur in previously healthy children with a peak incidence in preschool children and in adolescents. As the clinical presentation can be very similar to meningitis caused by aerobic bacteria, one should consider as the causative agent when preceded by or associated with otitis media with purulent otorrhea or mastoiditis, in combination with minimal or no improvement on empiric antibiotic treatment. As this pathogen can be difficult to culture, anaerobic cultures should be obtained. Prompt treatment with a third-generation cephalosporin and metronidazole should be initiated once suspected or confirmed. Surgical source control is often necessary, but even with adequate and prompt treatment, the morbidity and mortality in children with a meningitis remains high. In this report, we describe a case of meningitis in a previously healthy child and review the available literature.
PubMed: 38939326
DOI: 10.1155/2024/6365796 -
Frontiers in Microbiology 2024Sodium pheophorbide a (SPA) is a natural plant-derived photosensitizer, with high photoactivated antifungal activity against some phytopathogenic fungi. However, its...
INTRODUCTION
Sodium pheophorbide a (SPA) is a natural plant-derived photosensitizer, with high photoactivated antifungal activity against some phytopathogenic fungi. However, its fungicidal effect on , a novel pathogen that causes leaf spot blight, is unclear.
METHODS
In the present study, we explored its inhibitory effects on spore germination and mycelial growth of . Then we determined its effects on the cell membrane, mycelial morphology, redox homeostasis, and cell death through bioassay. Finally, RNA-seq was used further to elucidate its mode of action at the transcriptional level.
RESULTS
We found that SPA effectively inhibited the growth of , with half-maximal effective concentrations to inhibit mycelial growth and spore germination of 1.059 and 2.287 mg/mL, respectively. After 1.0 mg/mL SPA treatment, the conductivity and malondialdehyde content of were significantly increased. Scanning electron microscopy and transmission electron microscopy indicated that SPA significantly affected the morphology and ultrastructure of hyphae, revealing that SPA can destroy the mycelial morphology and cell structure, especially the cell membrane of . Furthermore, transcriptome analysis revealed that SPA significantly suppressed the expression of genes involved in morphology, cell membrane permeability, and oxidative stress. Then, we also found that SPA significantly promoted the accumulation of reactive oxygen species (ROS) in of , while it decreased the content of reduced glutathione, inhibited the enzyme activities of superoxide dismutase and catalase, and exacerbated DNA damage. Annexin V-FITC/PI staining also confirmed that 1.0 mg/mL SPA could significantly induce apoptosis and necrosis.
DISCUSSION
Generally, SPA can induce ROS-mediated oxidative stress and cell death, thus destroying the cell membrane and hyphal morphology, and ultimately inhibiting mycelial growth, which indicates that SPA has multiple modes of action, providing a scientific basis for the use of SPA as an alternative plant-derived photoactivated fungicide against leaf spot blight.
PubMed: 38939192
DOI: 10.3389/fmicb.2024.1403478 -
Frontiers in Microbiology 2024The expansion of betel palm cultivation is driven by rising demand for betel nut, yet this growth is accompanied by challenges such as decreased agricultural...
The expansion of betel palm cultivation is driven by rising demand for betel nut, yet this growth is accompanied by challenges such as decreased agricultural biodiversity and the spread of infectious pathogens. Among these, Yellow Leaf Disease (YLD) emerges as a prominent threat to betel palm plantation. (APV1) has been identified as a primary causative agent of YLD, precipitating leaf yellowing, stunted growth, and diminished yield. However, the precise mechanisms underlying APV1-induced damage remain elusive. Our study elucidates that APV1 infiltrates chloroplasts, instigating severe damage and consequential reductions in chlorophyll a/b and carotene levels, alongside notable declines in photosynthetic efficiency. Moreover, APV1 infection exerts broad regulatory effects on gene expression, particularly suppressing key genes implicated in chloroplast function and photosynthesis. These disruptions correlate with growth retardation, yield diminishment, and compromised nut quality. Intriguingly, the paradoxical destruction of the host's photosynthetic machinery by APV1 prompts inquiry into its evolutionary rationale, given the virus's dependence on host resources for replication and proliferation. Our findings reveal that APV1-induced leaf yellowing acts as a beacon for transmission vectors, hinting at a nuanced "host-pathogen-vector co-evolutionary" dynamic.
PubMed: 38939190
DOI: 10.3389/fmicb.2024.1424489 -
Frontiers in Microbiology 2024Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout... (Review)
Review
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout and human suffering. The unique structure of SARS-CoV-2 and its underlying pathogenic mechanism were responsible for the global pandemic. In addition to the direct damage caused by the virus, SARS-CoV-2 triggers an abnormal immune response leading to a cytokine storm, culminating in acute respiratory distress syndrome and other fatal diseases that pose a significant challenge to clinicians. Therefore, potential treatments should focus not only on eliminating the virus but also on alleviating or controlling acute immune/inflammatory responses. Current management strategies for COVID-19 include preventative measures and supportive care, while the role of the host immune/inflammatory response in disease progression has largely been overlooked. Understanding the interaction between SARS-CoV-2 and its receptors, as well as the underlying pathogenesis, has proven to be helpful for disease prevention, early recognition of disease progression, vaccine development, and interventions aimed at reducing immunopathology have been shown to reduce adverse clinical outcomes and improve prognosis. Moreover, several key mutations in the SARS-CoV-2 genome sequence result in an enhanced binding affinity to the host cell receptor, or produce immune escape, leading to either increased virus transmissibility or virulence of variants that carry these mutations. This review characterizes the structural features of SARS-CoV-2, its variants, and their interaction with the immune system, emphasizing the role of dysfunctional immune responses and cytokine storm in disease progression. Additionally, potential therapeutic options are reviewed, providing critical insights into disease management, exploring effective approaches to deal with the public health crises caused by SARS-CoV-2.
PubMed: 38939189
DOI: 10.3389/fmicb.2024.1334152 -
Frontiers in Microbiology 2024This review aims to comprehensively chronicle the biosynthesis, classification, properties, and applications of bacteriocins produced by genus strains, particularly... (Review)
Review
This review aims to comprehensively chronicle the biosynthesis, classification, properties, and applications of bacteriocins produced by genus strains, particularly emphasizing their potential benefits in food preservation, human health, and animal productivity. Lactic Acid Bacteria (LAB) are a class of microorganisms well-known for their beneficial role in food fermentation, probiotics, and human health. A notable property of LAB is that they can synthesize antimicrobial peptides known as bacteriocins that exhibit antimicrobial action against both closely related and other bacteria as well. Bacteriocins produced by spp. are known to exhibit antimicrobial activity against several pathogenic bacteria including food spoilage species, making them highly invaluable for potential application in food preservation and food safety. Importantly, they provide significant health benefits to humans, including combating infections, reducing inflammation, and modulating the gut microbiota. In addition to their applications in food fermentation and probiotics, bacteriocins show promising prospects in poultry production, processing, and improving animal productivity. Future research should explore the utilization of bacteriocins in innovative food safety measures and medical applications, emphasizing their potential to combat antibiotic-resistant pathogens, enhance gut microbiota composition and function, and synergize with existing antimicrobial therapies.
PubMed: 38939182
DOI: 10.3389/fmicb.2024.1406904 -
Chemical Science Jun 2024Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There...
Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant ; however, understanding of the structure-activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in . This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.
PubMed: 38939155
DOI: 10.1039/d4sc00995a -
Research (Washington, D.C.) 2024Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse...
Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota-gut-brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2-TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2-PPARγ-TPH2 axis. In summary, brain SCFAs can activate ACSS2-PPARγ-TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.
PubMed: 38939042
DOI: 10.34133/research.0400 -
Frontiers in Veterinary Science 2024Elasmobranchs are common, iconic species in public aquaria; their wild counterparts are key members of marine ecosystems. Post-mortem examination is a critical tool for...
Elasmobranchs are common, iconic species in public aquaria; their wild counterparts are key members of marine ecosystems. Post-mortem examination is a critical tool for disease monitoring of wild elasmobranchs and for management of those under human care. Careful necropsy of the head, with a focus on clinically relevant anatomy, can ensure that proper samples are collected, increasing the chance of presumptive diagnoses prior to slower diagnostic workup. Immediate feedback from a thorough head necropsy allows for faster management decisions, often identifying pathogens, routes of pathogen entry, and pathogenesis, which are current shortcomings in published literature. This article proposes a protocol for necropsy of the elasmobranch chondrocranium, emphasizing unique anatomy and careful dissection, evaluation, and sampling of the endolymphatic pores and ducts, inner ears, brain, and olfactory system as part of a complete, whole-body necropsy. Extensive use of cytology and microbiology, along with thorough sample collection for histology and molecular biology, has proven effective in identifying a wide range of pathogens and assisting with characterization of pathogenesis. The cause of mortality is often identified from a head necropsy alone, but does not replace a thorough whole-body dissection. This protocol for necropsy and ancillary diagnostic sample collection and evaluation was developed and implemented in the necropsy of 189 wild and aquarium-housed elasmobranchs across 18 species over 13 years (2011-2023) in California. Using this chondrocranial approach, meningoencephalitis was determined to be the primary cause of mortality in 70% (118/168) of stranded wild and aquarium-housed elasmobranchs. Etiology was largely bacterial or protozoal. bacterial meningoencephalitis occurred in salmon sharks (), shortfin mako sharks (), common thresher sharks (), and one Pacific electric ray (). was the most common cause of protozoal meningoencephalitis and found almost exclusively in leopard sharks () and bat rays () that stranded in San Francisco Bay. Bacterial pathogens were found to use an endolymphatic route of entry, while protozoa entered via the nares and olfactory lamellae. Trauma was the second most common cause of mortality and responsible for 14% (24/168) of wild shark strandings and deaths of aquarium-housed animals.
PubMed: 38938914
DOI: 10.3389/fvets.2024.1410332 -
Frontiers in Cellular and Infection... 2024and belong to the Bacteroidota phylum. Both species inhabit the oral cavity and can be associated with periodontal diseases. To survive, they must uptake heme from the...
INTRODUCTION
and belong to the Bacteroidota phylum. Both species inhabit the oral cavity and can be associated with periodontal diseases. To survive, they must uptake heme from the host as an iron and protoporphyrin IX source. Among the best-characterized heme acquisition systems identified in members of the Bacteroidota phylum is the Hmu system, with a leading role played by the hemophore-like HmuY (HmuY) protein.
METHODS
Theoretical analysis of selected HmuY proteins and spectrophotometric methods were employed to determine the heme-binding mode of the HmuY homolog (HmuY) and its ability to sequester heme. Growth phenotype and gene expression analysis of were employed to reveal the importance of the HmuY and Hmu system for this bacterium.
RESULTS
Unlike in , where HmuY uses two histidines for heme-iron coordination, other known HmuY homologs use two methionines in this process. HmuY is the first characterized representative of the HmuY family that binds heme using a histidine-methionine pair. It allows HmuY to sequester heme directly from serum albumin and HmuY, the HmuY homolog which uses two methionines for heme-iron coordination. In contrast to HmuY, which sequesters heme directly from methemoglobin, HmuY may bind heme only after the proteolytic digestion of hemoglobin.
CONCLUSIONS
We hypothesize that differences in components of the Hmu system and structure-based properties of HmuY proteins may evolved allowing different adaptations of species to the changing host environment. This may add to the superior virulence potential of over other members of the Bacteroidota phylum.
Topics: Heme; Porphyromonas gingivalis; Tannerella forsythia; Bacterial Proteins; Porphyromonas endodontalis; Humans; Gene Expression Regulation, Bacterial; Protein Binding; Iron
PubMed: 38938884
DOI: 10.3389/fcimb.2024.1421018