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François' langur is an Endangered colobine inhabiting limestone habitats in southern China and northern Vietnam. Its global population has been estimated to be just more than 2000 mature individuals. Populations in Vietnam are highly fragmented with reportedly fewer than 200 adults in total and 50 in a single location. Although the François' langur in Vietnam is highly imperiled as remnant populations persist in only three to four sites, little research has been carried out to provide a reliable estimate of its remaining population. In this study, we conducted field surveys in Lam Binh District, Tuyen Quang Province, northeastern Vietnam. In total, we recorded at least 16 groups of François' langurs, with 156 individuals, raising the total number of individuals by approximately 10% compared to a previous study. The group structure, group size, activity budget, and density of the Lam Binh population resemble those reported in François' langurs in China and other limestone langur species. The results show that the behavior ecology of limestone langurs significantly differs from that of forest langurs probably because they occupy separate habitats with distinctly different environmental variables. During our surveys, we detected a number of direct threats to this population, namely illegal logging, hunting, firewood collecting, hydropower development, grazing, and mining. It is recommended that the protection forest be elevated to the nature reserve status to better protect the most important population of the François' langur in Vietnam. [ABSTRACT FROM AUTHOR]

The majority of people who contract COVID-19 experience a short period of symptomatic infection. However, symptoms persist for months or years following initial exposure to the virus in some cases. This has been described as long COVID. Little is known about the lived experience of this condition, as it has only recently emerged. This study aimed to explore the experiences of mental health, quality of life, and coping among people living with long COVID. A sample of 47 adults with lived experience participated in web-based focus groups. Separate focus groups were held for 24 individuals with pre-existing mental health conditions and 23 individuals without pre-existing mental health conditions. Data were analyzed using a codebook thematic analysis approach. Five themes were identified as integral to the long COVID experience: The Emotional Landscape of Long COVID, New Limits to Daily Functioning, Grief and Loss of Former Identity, Long COVID-related Stigmatization, and Learning to Cope with Persisting Symptoms. These findings illustrate the immense impact of long COVID on mental health and quality of life. Minimal differences were found between those with and those without pre-existing mental health conditions, as both groups were substantially impacted by the condition. Attention to the perspectives of people with lived experience of long COVID is necessary to inform future directions for research and clinical practice. [ABSTRACT FROM AUTHOR]

Background: A constellation of often disabling long-term physical symptoms enduring after an acute SARS-COV-2 infection is commonly referred to as Long COVID. Since Long COVID is a new clinical entity, research is required to clarify treatment needs and experiences of individuals affected. This qualitative descriptive study aimed to provide insight into Long COVID treatment and service experiences and preferences of individuals experiencing Long COVID and the intersections with mental health. Methods: The study was conducted out of a tertiary care mental health hospital, with online recruitment from the community across Canada. A total of 47 individuals (average age = 44.9) participated in one of 11 focus groups between June and December 2022. Five focus groups were conducted with participants who had pre-existing mental health concerns prior to contracting SARS-CoV-2, and six were with people with Long COVID but without pre-existing mental health concerns. A semi-structured interview guide asked about service experiences and service preferences, including mental health and well-being services. Discussions were recorded, transcribed, and analyzed using codebook thematic analysis. Results: When accessing services for Long COVID, patients experienced: (1) systemic barriers to accessing care, and (2) challenges navigating the unknowns of Long COVID, leading to (3) negative impacts on patient emotional well-being and recovery. Participants called for improvements in Long COVID care, with a focus on: (1) developing Long COVID-specific knowledge and services, (2) enhancing support for financial well-being, daily living, and building a Long COVID community, and (3) improving awareness and the public representation of Long COVID. Conclusions: Substantial treatment barriers generate considerable burden for individuals living with Long COVID. There is a pressing need to improve treatment, social supports, and the social representation of Long COVID to create integrated, accessible, responsive, and ongoing support systems. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate genetic structures and expression of blaOXA-58 gene in five Acinetobacter baumannii clinical isolates recovered from two hospitals in southern Vietnam during 2012-2014. A. baumannii isolates were identified by automated microbiology systems and confirmed by PCR. All isolates were characterized as multidrug resistant by antimicrobial testing using the disk diffusion method. Four imipenem susceptible and one nonsusceptible isolates (MIC > 32 μ g ·ml-1) were identified by E-test. PCR amplification of blaOXA-58 gene upstream and downstream sequences revealed the presence of ISAba3 at both locations in one multidrug-resistant isolate. Semiquantitation of blaOXA-51 and blaOXA-58 gene expression was performed by the 2-ΔΔCt method. The blaOXA-51 gene expression of five isolates showed little difference, but the isolate bearing ISAba3-blaOXA-58-ISAba3 exhibited significantly higher blaOXA-58 mRNA level. Higher β-lactamases activity in periplasmic than cytoplasmic fraction was found in most isolates. The isolate overexpressing blaOXA-58 gene possessed very high periplasmic enzyme activity. In conclusion, the A. baumannii isolate bearing ISAba3-blaOXA-58 gene exhibited high resistance to imipenem, corresponding to an overexpression of blaOXA-58 gene and very high periplasmic β-lactamase activity. [ABSTRACT FROM AUTHOR]

Rice production helps feed at least half of the world's population but generates approximately one billion tonnes of straw residue per annum. On-site open burning of rice straw after harvesting is common in recent times because there has been less demand for rice straw to use as fuel and fodder. Due to health and climate change concerns, open burning, which results in biomass losses, smog and emissions of green house gases, e.g., CO2, has been widely criticized and banned in many countries. Little is known about the positive benefits of straw burning, such as field care (eradication of biotic diseases) or nutrient cycling. Herein, we propose a new viewpoint in which the burning of rice straw followed by cycling of the burned materials, including silica material (so-called phytolith), into soil is demonstrated as a CO2-sequestration strategy via buffering the soil CO2 flux and coupling CO2 with the silicon cycle. [ABSTRACT FROM AUTHOR]

Recent smooth muscle cell (SMC) lineage-tracing studies have revealed that SMCs undergo remarkable changes in phenotype during development of atherosclerosis. Of major interest, we demonstrated that Kruppel-like factor 4 (KLF4) in SMCs is detrimental for overall lesion pathogenesis, in that SMC-specific conditional knockout of the KLF4 gene (Klf4) resulted in smaller, more-stable lesions that exhibited marked reductions in the numbers of SMC-derived macrophage- and mesenchymal stem cell-like cells. However, since the clinical consequences of atherosclerosis typically occur well after our reproductive years, we sought to identify beneficial KLF4-dependent SMC functions that were likely to be evolutionarily conserved. We tested the hypothesis that KLF4-dependent SMC transitions play an important role in the tissue injury-repair process. Using SMC-specific lineage-tracing mice positive and negative for simultaneous SMC-specific conditional knockout of Klf4, we demonstrate that SMCs in the remodeling heart after ischemia-reperfusion injury (IRI) express KLF4 and transition to a KLF4-dependent macrophage-like state and a KLF4-independent myofibroblast-like state. Moreover, heart failure after IRI was exacerbated in SMC Klf4 knockout mice. Surprisingly, we observed a significant cardiac dilation in SMC Klf4 knockout mice before IRI as well as a reduction in peripheral resistance. KLF4 chromatin immunoprecipitation- sequencing analysis on mesenteric vascular beds identified potential baseline SMC KLF4 target genes in numerous pathways, including PDGF and FGF. Moreover, microvascular tissue beds in SMC Klf4 knockout mice had gaps in lineage-traced SMC coverage along the resistance arteries and exhibited increased permeability. Together, these results provide novel evidence that Klf4 has a critical maintenance role within microvascular SMCs: it is required for normal SMC function and coverage of resistance arteries. [ABSTRACT FROM AUTHOR]

Synthetic hexaploid wheat is an effective genetic resource for transferring agronomically important genes from Aegilops tauschii to common wheat. Wide variation in grain size and shape, one of the main targets for wheat breeding, has been observed among Ae. tauschii accessions. To identify the quantitative trait loci (QTLs) responsible for grain size and shape variation in the wheat D genome under a hexaploid genetic background, six parameters related to grain size and shape were measured using SmartGrain digital image software and QTL analysis was conducted using four F2 mapping populations of wheat synthetic hexaploids. In total, 18 QTLs for the six parameters were found on five of the seven D-genome chromosomes. The identified QTLs significantly contributed to the variation in grain size and shape among the synthetic wheat lines, implying that the D-genome QTLs might be at least partly functional in hexaploid wheat. Thus, synthetic wheat lines with diverse D genomes from Ae. tauschii are useful resources for the identification of agronomically important loci that function in hexaploid wheat. [ABSTRACT FROM AUTHOR]

Wheat landraces carry abundant genetic variation in heading and flowering times. Here, we studied flowering-related traits of two Nepalese varieties, KU-4770 and KU-180 and a Japanese wheat cultivar, Shiroganekomugi (SGK). These three wheat varieties showed similar flowering time in a common garden experiment. In total, five significant quantitative trait loci (QTLs) for three examined traits, the heading, flowering and maturation times, were detected using an F2 population of SGK/KU-4770. The QTLs were found at the Ppd-1 loci on chromosomes 2B and 2D and the 2B QTL was also confirmed in another F2 population of SGK/KU-180. The Ppd-D1 allele from SGK and the Ppd-B1 alleles from the two Nepalese varieties might be causal for early-flowering phenotype. The SGK Ppd-D1 allele contained a 2-kb deletion in the 5′ upstream region, indicating a photoperiod-insensitive Ppd-D1a allele. Real-time PCR analysis estimating the Ppd-B1 copy number revealed that the two Nepalese varieties included two intact Ppd-B1 copies, putatively resulting in photoperiod insensitivity and an early-flowering phenotype. The two photoperiod-insensitive Ppd-1 homoeoalleles could independently contribute to segregation of early-flowering individuals in the two F2 populations. Therefore, wheat landraces are genetic resources for discovery of alleles useful for improving wheat heading or flowering times. [ABSTRACT FROM AUTHOR]

Background Highly trained vascular sonographers make up a significant cost of abdominal aortic aneurysm (AAA) ultrasound screening. However, they are over-trained for this very limited task. Others have reported that health workers (e.g. emergency room staff and nurses) with far less training may be able to perform these scans. The national AAA screening programme in the UK uses staff with limited training. Whether individuals without a health professional qualification could be trained to perform the scan accurately to improve cost-effectiveness is not known. We aimed to investigate whether a short, well-supervised course in ultrasonography could train novices to detect AAA for screening purposes. Methods Three novices were trained by an experienced sonographer for 15 days to perform abdominal aortic ultrasound examinations and detect AAA using a portable ultrasound system. The examination included four anterior-posterior aortic measurements: a maximal diameter in the coronal plane and three diameters of the suprarenal, mid and distal infrarenal aorta in the transverse plane. The novices independently scanned 215 subjects following training; experienced sonographers repeated the measurements on the same subject in the same session. Using Bland-Altman plots and CUSUM analysis, the novices' and experienced sonographers' accuracy and efficiency measurements were compared. Factors influencing performance were recorded. Results The novices measured the maximal coronal aortic diameter accurately, to within 0.46-0.52 cm of the true diameter; 85-97% of their coronal measurements were within 0.5 cm of the assessors; kappa statistic and Bland-Altman plots show a high agreement with the assessor's measurements. However, the novices' measurements of the three diameters in the transverse plane were outside clinically acceptable limits. Assuming a referral policy for a second scan for scans recorded as 'difficult', only one novice missed a 3.13 cm aneurysm. A CUSUM quality improvement analysis demonstrated substantial improvements in the scanning efficiency of the novices with continued scanning experience. Conclusion This study showed that novices could be trained to screen for AAA over 15 days. However, the need for continuing quality improvement is critical, especially in more technically demanding cases. Measuring the maximal infrarenal diameter instead of specific segmental diameters may be more appropriate for AAA screening using novices. [ABSTRACT FROM AUTHOR]

Degenerative retinopathies, including age-related macular degeneration, diabetic retinopathy, and hereditary retinal disorders-major causes of world blindness-are potentially treatable by using low-molecular weight neuroprotective, antiapoptotic, or antineovascular drugs. These agents are, however, not in current systemic use owing to, among other factors, their inability to passively diffuse across the microvasculature of the retina because of the presence of the inner blood-retina barrier (1BRB). Moreover, preclinical assessment of the efficacies of new formulations in the treatment of such conditions is similarly compromised. We describe here an experimental process for RNAi-mediated, size-selective, transient, and reversible modulation of the iBRB in mice to molecules up to 800 Da by suppression of transcripts encoding claudin-5, a protein component of the tight junctions of the inner retinal vasculature. MRI produced no evidence indicative of brain or retinal edema, and the process resulted in minimal disturbance of global transcriptional patterns analyzed in neuronal tissue. We show that visual function can be improved in lMPDH1-/- mice, a model of autosomal recessive retinitis pigmentosa, and that the rate of photoreceptor cell death can be reduced in a model of light-induced retinal degeneration by systemic drug delivery after reversible barrier opening. These findings provide a platform for high-throughput drug screening in models of retinal degeneration, and they ultimately could result in the development of a novel "humanized" approach to therapy for conditions with little or no current forms of treatment. [ABSTRACT FROM AUTHOR]

Flavonoids and stilbenoids, crucial secondary metabolites abundant in plants and fungi, display diverse biological and pharmaceutical activities, including potent antioxidant, anti-inflammatory, and antimicrobial effects. However, conventional production methods, such as chemical synthesis and plant extraction, face challenges in sustainability and yield. Hence, there is a notable shift towards biological production using microorganisms like Escherichia coli and yeast. Yet, the drawbacks of using E. coli and yeast as hosts for these compounds persist. For instance, yeast's complex glycosylation profile can lead to intricate protein production scenarios, including hyperglycosylation issues. Consequently, Corynebacterium glutamicum emerges as a promising alternative, given its adaptability and recent advances in metabolic engineering. Although extensively used in biotechnological applications, the potential production of flavonoid and stilbenoid in engineered C. glutamicum remains largely untapped compared to E. coli. This review explores the potential of metabolic engineering in C. glutamicum for biosynthesis, highlighting its versatility as a cell factory and assessing optimization strategies for these pathways. Additionally, various metabolic engineering methods, including genomic editing and biosensors, and cofactor regeneration are evaluated, with a focus on C. glutamicum. Through comprehensive discussion, the review offers insights into future perspectives in production, aiding researchers and industry professionals in the field. [ABSTRACT FROM AUTHOR]

The zebrafish (Danio rerio) has become a widely used vertebrate model for bacterial, fungal, viral, and protozoan infections. Due to its genetic tractability, large clutch sizes, ease of manipulation, and optical transparency during early life stages, it is a particularly useful model to address questions about the cellular microbiology of host–microbe interactions. Although its use as a model for systemic infections, as well as infections localised to the hindbrain and swimbladder having been thoroughly reviewed, studies focusing on host–microbe interactions in the zebrafish gastrointestinal tract have been neglected. Here, we summarise recent findings regarding the developmental and immune biology of the gastrointestinal tract, drawing parallels to mammalian systems. We discuss the use of adult and larval zebrafish as models for gastrointestinal infections, and more generally, for studies of host–microbe interactions in the gut. [ABSTRACT FROM AUTHOR]

Background: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Streptococcus pneumoniae and Staphylococcus aureus are major bacterial causes of lower respiratory tract infections (LRTIs) globally, leading to substantial morbidity and mortality. The rapid increase of antimicrobial resistance (AMR) in these pathogens poses significant challenges for their effective antibiotic therapy. In low-resourced settings, patients with LRTIs are prescribed antibiotics empirically while awaiting several days for culture results. Rapid pathogen and AMR gene detection could prompt optimal antibiotic use and improve outcomes. Methods: Here, we developed multiplex quantitative real-time PCR using EvaGreen dye and melting curve analysis to rapidly identify six major pathogens and fourteen AMR genes directly from respiratory samples. The reproducibility, linearity, limit of detection (LOD) of real-time PCR assays for pathogen detection were evaluated using DNA control mixes and spiked tracheal aspirate. The performance of RT-PCR assays was subsequently compared with the gold standard, conventional culture on 50 tracheal aspirate and sputum specimens of ICU patients. Results: The sensitivity of RT-PCR assays was 100% for K. pneumoniae, A. baumannii, P. aeruginosa, E. coli and 63.6% for S. aureus and the specificity ranged from 87.5% to 97.6%. The kappa correlation values of all pathogens between the two methods varied from 0.63 to 0.95. The limit of detection of target bacteria was 1600 CFU/ml. The quantitative results from the PCR assays demonstrated 100% concordance with quantitative culture of tracheal aspirates. Compared to culture, PCR assays exhibited higher sensitivity in detecting mixed infections and S. pneumoniae. There was a high level of concordance between the detection of AMR gene and AMR phenotype in single infections. Conclusions: Our multiplex quantitative RT-PCR assays are fast and simple, but sensitive and specific in detecting six bacterial pathogens of LRTIs and their antimicrobial resistance genes and should be further evaluated for clinical utility. [ABSTRACT FROM AUTHOR]

Adenosine receptors are a family of GPCRs containing four subtypes (A1 , A2A , A2B and A3 receptors), all of which bind the ubiquitous nucleoside adenosine. These receptors play an important role in physiology and pathophysiology and therefore represent attractive drug targets for a range of conditions. The theoretical framework surrounding drug action at adenosine receptors now extends beyond the notion of prototypical agonism and antagonism to encompass more complex pharmacological concepts. New paradigms include allostery, in which ligands bind a topographically distinct receptor site from that of the endogenous agonist, homomeric or heteromeric interactions across receptor oligomers and biased agonism, that is, ligand-dependent differential intracellular signalling. This review provides a concise overview of allostery, oligomerization and biased agonism at adenosine receptors and outlines how these paradigms may enhance future drug discovery endeavours focussed on the development of novel therapeutic agents acting at adenosine receptors.Linked Articles: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. [ABSTRACT FROM AUTHOR]

Abstract: We test people's ability to optimize performance across two concurrent tasks. Participants performed a number entry task while controlling a randomly moving cursor with a joystick. Participants received explicit feedback on their performance on these tasks in the form of a single combined score. This payoff function was varied between conditions to change the value of one task relative to the other. We found that participants adapted their strategy for interleaving the two tasks, by varying how long they spent on one task before switching to the other, in order to achieve the near maximum payoff available in each condition. In a second experiment, we show that this behavior is learned quickly (within 2–3 min over several discrete trials) and remained stable for as long as the payoff function did not change. The results of this work show that people are adaptive and flexible in how they prioritize and allocate attention in a dual‐task setting. However, it also demonstrates some of the limits regarding people's ability to optimize payoff functions. [ABSTRACT FROM AUTHOR]

Sexually transmitted diseases are major causes of infertility, ectopic pregnancy, and premature birth. Here, we developed a new multiplex real-time polymerase chain reaction (PCR) assay for the simultaneous detection of nine major sexually transmitted infections (STIs) found in Vietnamese women, including Chlamydia trachomatis, Neisseria gonorrhoeae, Gardnerella vaginalis, Trichomonas vaginalis, Candida albicans, Mycoplasma hominis, Mycoplasma genitalium, and human alphaherpesviruses 1 and 2. A panel containing three tubes × three pathogens/tube was predesigned based on double-quenched TaqMan probes to increase detection sensitivity. There was no cross-reactivity among the nine STIs and other non-targeted microorganisms. Depending on each pathogen, the agreement with commercial kits, sensitivity, specificity, repeatability and reproducibility coefficient of variation (CV), and limit of detection of the developed real-time PCR assay were 99.0%–100%, 92.9%–100%, 100%, <3%, and 8–58 copies/reaction, respectively. One assay cost only 2.34 USD. Application of the assay for the detection of the nine STIs in 535 vaginal swab samples collected from women in Vietnam yielded 532 positive cases (99.44%). Among the positive samples, 37.76% had one pathogen, with G. vaginalis (33.83%) as the most prevalent; 46.36% had two pathogens, with G. vaginalis + C. albicans as the most prevalent combination (38.13%); and 11.78%, 2.99%, and 0.56% had three, four, and five pathogens, respectively. In conclusion, the developed assay represents a sensitive and cost-effective molecular diagnostic tool for the detection of major STIs in Vietnam and is a model for the development of panel detections of common STIs in other countries. [ABSTRACT FROM AUTHOR]

Histone methylation plays an important role in regulating gene expression. One such methylation occurs at Lys 79 of histone H3 (H3K79) and is catalyzed by the yeast DOT1 (disruptor of telomeric silencing) and its mammalian homolog, DOT1L. Previous studies have demonstrated that germline disruption of Dot1L in mice resulted in embryonic lethality. Here we report that cardiac-specific knockout of Dot1L results in increased mortality rate with chamber dilation, increased cardiomyocyte cell death, systolic dysfunction, and conduction abnormalities. These phenotypes mimic those exhibited in patients with dilated cardiomyopathy (DCM). Mechanistic studies reveal that DOT1L performs its function in cardiomyocytes through regulating Dystrophin (Dmd) transcription and, consequently, stability of the Dystrophin--"glycoprotein complex important for cardiomyocyte viability. Importantly, expression of a miniDmd can largely rescue the DCM phenotypes, indicating that Dmd is a major target mediating DOT1L function in cardiomyocytes. Interestingly, analysis of available gene expression data sets indicates that DOT1L is down-regulated in idiopathic DCM patient samples compared with normal controls. Therefore, our study not only establishes a critical role for DOT1L-mediated H3K79 methylation in cardiomyocyte function, but also reveals the mechanism underlying the role of DOT1L in DCM. In addition, our study may open new avenues for the diagnosis and treatment of human heart disease. [ABSTRACT FROM AUTHOR]

A crystalline copper-based metal-organic framework Cu-MOF-74 was synthesized, and was characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR), atomic absorption spectrophotometry (AAS), and nitrogen physisorption measurements. The Cu-MOF-74 exhibited high catalytic activity in the synthesis of indolizines through aldehyde–amine–alkyne three-component coupling transformation and higher than those of other Cu-MOFs such as Cu 2 (BDC) 2 (DABCO), Cu 3 (BTC) 2 , Cu(BDC), Cu 2 (NDC) 2 (DABCO), and Cu 4 I 4 (DABCO) 2 . The reactions could only proceed to produce indolizines in the presence of the solid Cu-MOF catalyst, and contribution from active copper species leached from the solid Cu-MOF-74, if any, was negligible. The Cu-MOF catalyst be recovered and reused several times for the synthesis of indolizines without a significant degradation in catalytic activity. To the best of our knowledge, the synthesis of indolizines using a recyclable heterogeneous catalyst was not previously mentioned in the literature. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and related dementias (AD/ADRD) are a public health challenge for Vietnam because of its rapidly aging population. However, very few community-based programs exist to support people living with AD/ADRD and their family caregivers. Resources for Enhancing Alzheimer's Caregiver Health in Vietnam (REACH VN) is a culturally adapted family caregiver intervention shown in a pilot study to be feasible and promising in terms of preliminary efficacy. We describe the protocol for a larger cluster randomized controlled trial (RCT) to test the efficacy of REACH VN among family caregivers of people living with dementia in a semi-rural area outside of Hanoi, Vietnam.Methods: Thirty-two clusters with approximately 350 caregivers will be randomized to either REACH VN intervention or enhanced usual care. REACH VN is a multicomponent intervention delivered in-home or by phone over the course of 2 to 3 months. To be eligible, family caregivers need to be ≥18 years old, be the person who provides the most day-to-day care for people living with dementia, and have a score ≥ 6 on the Zarit Burden Interview-4. The primary outcomes are caregiver burden (Zarit Burden Interview-12) and psychological distress (Patient Health Questionnaire-4). Secondary outcomes include caregiver somatic symptoms (Patient Health Questionnaire-15) and perceived stress (Perceived Stress Scale-10). These outcomes will be assessed at baseline, 3 months, and 6 months. Exploratory analyses to examine potential mediators of primary outcomes are also planned.Discussion: To our knowledge, this is the first large-scale study to test the efficacy of a community-based family dementia caregiver intervention in Vietnam. Results from this study will help inform efforts to widely deliver the REACH VN intervention or similar community-based family dementia caregiver support programs in Vietnam and other low- and middle-income countries (LMIC).Trial Registration: ClinicalTrials.gov NCT04542317 . Registered on 9 September 2020. [ABSTRACT FROM AUTHOR]

The role of calcium in blood pressure has been widely studied among hypertensive patients; however, no study has explored the role of calcium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum calcium levels between hypertensive crises patients and a 1:1 random matched controls (age‐, sex‐, race‐, diabetes, and body mass index matched). This study is a single‐center, retrospective, chart review, case‐control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented calcium level. The control group patients were required to be 18 years of age or older, have a documented calcium level, and have no diagnosis of hypertensive crises. The primary outcome of the study was to compare the mean serum calcium in patients with hypertensive crises vs patients without hypertensive crises. Five hundred and sixty‐six patients were included in the study: 283 patients in both the case group and control group. The primary outcome results showed that serum calcium concentration was not significantly different between the case group (8.99 ± 0.78 mg/dL) and control group (8.96 ± 0.75 mg/dL) (P =.606). This study found no significant difference in serum calcium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of calcium on blood pressure in hypertensive crises. [ABSTRACT FROM AUTHOR]

This study was conducted to evaluate the routine medical check-up and self-treatment behaviors of people living in a remote and mountainous setting in Northern Vietnam and identify their associations. A cross-sectional study was conducted on 175 people in August 2018 in Cao Son commune, Da Bac district, Hoa Binh. Information regarding routine medical check-ups and self-treatment behaviors was collected by using a structured questionnaire. Multivariate logistic regression was used to examine the associations. Results show that 24% of the mountainous people had routine medical check-ups in the last 12 months. The rate of self-treatment in the past three months was 33.7%. The number of chronic diseases (OR = 1.5 , 95% CI = 1.0 ‐ 2.3), health information sources from radio/television (OR = 3.3 , 95% CI = 1.2 ‐ 9.5), or social media (OR = 24.8 , 95% CI = 1.2 ‐ 512.4) was related to routine medical check-up. People who did not have routine medical check-up were more likely to have self-treatment practice (OR = 6.3 , 95% CI = 1.9 ‐ 21.1) than those who had a regular health check. Promoting health education and communication through mass media to raise people's awareness about regular health check-ups is a promising way to improve people's self-treatment status. [ABSTRACT FROM AUTHOR]

Background: Rupture and erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a limited understanding of the identity, origin, and function of many cells that make up late-stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability.Methods: We conducted a comprehensive single-cell RNA sequencing of advanced human carotid endarterectomy samples and compared these with single-cell RNA sequencing from murine microdissected advanced atherosclerotic lesions with smooth muscle cell (SMC) and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. We further used chromatin immunoprecipitation sequencing (ChIP-seq), bulk RNA sequencing, and an innovative dual lineage tracing mouse to understand the mechanism by which SMC phenotypic transitions affect lesion pathogenesis.Results: We provide evidence that SMC-specific Klf4- versus Oct4-knockout showed virtually opposite genomic signatures, and their putative target genes play an important role regulating SMC phenotypic changes. Single-cell RNA sequencing revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and endothelial cell-derived cells including 7 distinct clusters, most negative for traditional markers. In particular, SMC contributed to a Myh11-, Lgals3+ population with a chondrocyte-like gene signature that was markedly reduced with SMC-Klf4 knockout. We observed that SMCs that activate Lgals3 compose up to two thirds of all SMC in lesions. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene-positive, extracellular matrix-remodeling, "pioneer" cell phenotype that is the first to invest within lesions and subsequently gives rise to at least 3 other SMC phenotypes within advanced lesions, including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization.Conclusions: Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3+ osteogenic cells likely to be detrimental for late-stage atherosclerosis plaque pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is a severe condition in premature infants that compromises lung function and necessitates oxygen support. Despite major improvements in perinatal care minimizing the devastating effects, BPD remains the most frequent complication of extreme preterm birth. Our study reports the safety of the allogeneic administration of umbilical cord-derived mesenchymal stem/stromal cells (allo-UC-MSCs) and the progression of lung development in four infants with established BPD.Methods: UC tissue was collected from a healthy donor, followed by propagation at the Stem Cell Core Facility at Vinmec Research Institute of Stem Cell and Gene Technology. UC-MSC culture was conducted under xeno- and serum-free conditions. Four patients with established BPD were enrolled in this study between May 25, 2018, and December 31, 2018. All four patients received two intravenous doses of allo-UC-MSCs (1 million cells/kg patient body weight (PBW) per dose) with an intervening interval of 7 days. Safety and patient conditions were evaluated during hospitalization and at 7 days and 1, 6 and 12 months postdischarge.Results: No intervention-associated severe adverse events or prespecified adverse events were observed in the four patients throughout the study period. At the time of this report, all patients had recovered from BPD and were weaned off of oxygen support. Chest X-rays and CT scans confirmed the progressive reductions in fibrosis.Conclusions: Allo-UC-MSC administration is safe in preterm infants with established BPD. Trial registration This preliminary study was approved by the Vinmec International Hospital Ethics Board (approval number: 88/2019/QĐ-VMEC; retrospectively registered March 12, 2019). [ABSTRACT FROM AUTHOR]

Background: Delirium tremens is a severe form of alcohol withdrawal syndrome. Literature documenting acute coronary events in the setting of alcohol withdrawal remains scarce. An accepted hypothesis for the underlying process is focused on the hyperadrenergic state that leads to coronary vasospasm and increased myocardial oxygen demand.Case Presentation: A 47-year-old Caucasian man with a past medical history of tobacco and alcohol abuse, hypertension, and anxiety presented to the emergency department for crampy epigastric abdominal pain with intractable nausea and vomiting for the past 2 days. His reported last alcoholic intake was about 10 days prior; however, outpatient records indicated otherwise. He was admitted for electrolyte replacement and fluid resuscitation secondary to gastrointestinal losses from presumed early alcohol withdrawal syndrome. The following night, he developed acute substernal chest pain with elevated cardiac enzymes. Electrocardiography showed an acute inferoposterior infarct with reciprocal changes in leads V1-V4. The patient was taken for emergent catheterization, and a drug-eluting stent was placed in the middle of the left anterior descending artery. Postcatheterization electrocardiography showed sustained inferolateral ST elevations consistent with acute injury pattern. The patient had not required any benzodiazepines until this point. On the morning of catheterization, the patient's Clinical Institute Withdrawal Assessment for Alcohol-Revised score was 19 with a high of 25, and he was actively hallucinating. He was treated for delirium tremens and an acute coronary event along with an incidental pneumonia. He did not require any benzodiazepines during the last 4 days of admission, and he made a full recovery.Conclusions: The prevalence of alcohol dependence in hospitalized patients is substantial. Although our patient was being treated with the standard protocols for alcohol withdrawal, he rapidly developed delirium tremens, which led to an acute inferior ST-elevation myocardial infarction in the setting of nonoccluded coronary vessels. This case report adds to the sparse literature documenting acute coronary events in the setting of alcohol withdrawal and suggests that our patient's ST-elevation myocardial infarction is not fully explained by the current coronary vasospasm hypothesis, but rather was in part the result of direct catecholamine-associated myocardial injury. Further research should be conducted on prophylactic agents such as β-blockers and calcium channel blockers. [ABSTRACT FROM AUTHOR]

Targeted nanoparticle delivery is a promising strategy for increasing efficacy and limiting side effects of therapeutics. When designing a targeted liposomal formulation, the in vivo biodistribution of the particles must be characterized to determine the value of the targeting approach. Peroxisome proliferator-activated receptor (PPAR) agonists effectively treat metabolic syndrome by decreasing dyslipidemia and insulin resistance but side effects have limited their use, making them a class of compounds that could benefit from targeted liposomal delivery. The adipose targeting sequence peptide (ATS) could fit this role, as it has been shown to bind to adipose tissue endothelium and induce weight loss when delivered conjugated to a pro-apoptotic peptide. To date, however, a full assessment of ATS in vivo biodistribution has not been reported, leaving important unanswered questions regarding the exact mechanisms whereby ATS targeting enhances therapeutic efficacy. We designed this study to evaluate the biodistribution of ATS-conjugated liposomes loaded with the PPARα/γ dual agonist tesaglitazar in leptin-deficient ob/ob mice. The ATS-liposome biodistribution in adipose tissue and other organs was examined at the cellular and tissue level using microscopy, flow cytometry, and fluorescent molecular tomography. Changes in metabolic parameters and gene expression were measured by target and off-target tissue responses to the treatment. Unexpectedly, ATS targeting did not increase liposomal uptake in adipose relative to other tissues, but did increase uptake in the kidneys. Targeting also did not significantly alter metabolic parameters. Analysis of the liposome cellular distribution in the stromal vascular fraction with flow cytometry revealed high uptake by multiple cell types. Our findings highlight the need for thorough study of in vivo biodistribution when evaluating a targeted therapy. [ABSTRACT FROM AUTHOR]

Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design. [ABSTRACT FROM AUTHOR]

Carbapenemase-producing Enterobacteriaceae (CPE) are well known to cause many serious infections resulting in increasing mortality rate, treatment cost, and prolonged hospitalization. Among the widely recognized types of carbapenemases, New Delhi β-lactamase (NDM) and Klebsiella pneumoniae carbapenemase (KPC) are the most important enzymes. However, in Vietnam, there are only scattered reports of CPE due to the lack of simple and affordable methods that are suitable to laboratory conditions. This study aims to survey the characteristics of carbapenem-resistant E. coli and K. pneumoniae (CR-E/K) at two hospitals in Southern Vietnam and perform some simple methods to detect the two enzymes. A total of 100 CR-E/K strains were collected from clinical isolates of Gia Dinh People's Hospital and Dong Nai General Hospital, Vietnam, from November 2017 to May 2018. The patient-related information was also included in the analysis. We conducted real-time polymerase chain reaction (PCR), Modified Hodge Test (MHT), and combined disk test (CDT) on all isolates. Carbapenemase-encoding genes were detected in 47 isolates (36 NDM, 10 KPC, and one isolate harboring both genes). The E. coli strain carrying simultaneously these two genes was the first case reported here. Most of isolates were collected from patients in ICU, Infectious Disease Department, and Department of Urologic Surgery. Urine and sputum were two common specimens. The true positive rate (sensitivity, TPR) and specificity (SPC) of the imipenem–EDTA (ethylen diamine tetra acetic acid) for NDM detection and the imipenem–PBA (phenylboronic acid) for KPC detection on E. coli were 93.8%, 97.1% and 66.7%, 95.7%, respectively. Meanwhile, the imipenem–EDTA for NDM detection and the imipenem–PBA for KPC detection among K. pneumonia achieved 90.5%, 100% and 100%, 92.9% TPR and SPC, respectively. However, MHT showed low sensitivity and specificity. Our findings showed that CP-E/K were detected with high prevalence in the two hospitals. We suggest that CDT can be used as a low-priced and accurate method of detection. [ABSTRACT FROM AUTHOR]

A copper-organic framework Cu-CPO-27 was synthesized, and utilized as a recyclable heterogeneous catalyst for the direct C H amination of quinoxalin-2(1 H )-ones with amines to produce 3-aminoquinoxalin-2(1 H )-ones. High yields were achieved in the presence of molecular oxygen as the oxidant. This framework was more catalytically active than a number of MOF-based catalysts. The Cu-CPO-27 also displayed higher performance than CuFe 2 O 4 nanoparticles. The copper-organic framework catalyst could be reutilized in the synthesis of 3-aminoquinoxalin-2(1 H )-ones via the direct C H amination reaction without a remarkable deterioration in catalytic performance. To our best knowledge, this is the first heterogeneous catalytic protocol to generate 3-aminoquinoxalin-2(1 H )-ones. [ABSTRACT FROM AUTHOR]

Summary The adenosine A 1 receptor (A 1 -AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A 1 -AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A 2A receptor (A 2A -AR) structure. Mutational and computational analysis of A 1 -AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain. [ABSTRACT FROM AUTHOR]

NADH cytochrome b5 reductase 3 (CYB5R3) is critical for reductive reactions such as fatty acid elongation, cholesterol biosynthesis, drug metabolism and methemoglobin reduction. While the physiological and metabolic importance of CYB5R3 has been established in hepatocytes and erythrocytes, emerging investigations suggest that CYB5R3 is critical for nitric oxide signaling and vascular function. However, advancement toward fully understanding CYB5R3 function has been limited due to a lack of potent small molecule inhibitors. Because of this restriction, we modeled the binding mode of propylthiouracil (PTU), a weak inhibitor of CYB5R3 (IC50= ~275 µM), and used it as a guide to predict thiouracil-biased inhibitors from the set of commercially available compounds in the ZINC database. Using this approach, we validated two new potent derivatives of PTU, ZINC05626394 (IC50 = 10.81 µM) and ZINC39395747 (IC50 = 9.14 µM), both of which inhibit CYB5R3 activity in cultured cells. Moreover, we found that ZINC39395747 significantly increased NO bioavailability in renal vascular cells, augmented renal blood flow and decreased systemic blood pressure in response to vasoconstrictors in spontaneously hypertensive rats. These compounds will serve as a new tool to examine the biological functions of CYB5R3 in physiology and disease and also as a platform for new drug development. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is a degenerative retinal disease involving progressive loss of rod and cone photoreceptor function. It represents the most common form of registered blindness among the working aged populations of developed countries. Given the immense genetic heterogeneity associated with this disease, parameters influencing cone photoreceptor survival (preservation of daytime vision) that are independent of primary mutations are exceedingly important to identify from a therapeutic standpoint. Here we identify C1q, the primary component of the classical complement pathway, as a cone photoreceptor neuronal survival factor. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms contribute to the regulation of cell differentiation and function. Vascular smooth muscle cells (SMCs) are specialized contractile cells that retain phenotypic plasticity even after differentiation. Here, by performing selective demethylation of histone H3 lysine 4 di-methylation (H3K4me2) at SMC-specific genes, we uncovered that H3K4me2 governs SMC lineage identity. Removal of H3K4me2 via selective editing in cultured vascular SMCs and in murine arterial vasculature led to loss of differentiation and reduced contractility due to impaired recruitment of the DNA methylcytosine dioxygenase TET2. H3K4me2 editing altered SMC adaptative capacities during vascular remodeling due to loss of miR-145 expression. Finally, H3K4me2 editing induced a profound alteration of SMC lineage identity by redistributing H3K4me2 toward genes associated with stemness and developmental programs, thus exacerbating plasticity. Our studies identify the H3K4me2-TET2-miR145 axis as a central epigenetic memory mechanism controlling cell identity and function, whose alteration could contribute to various pathophysiological processes. [Display omitted] • Gene-selective epigenome editing reveals that H3K4me2 controls SMC lineage identity • H3K4me2 editing induces loss of contractility and exacerbates phenotypic plasticity • H3K4me2 interacts with TET2 and mediates TET-dependent gene activation • Loss of H3K4me2 impairs SMC-mediated vascular remodeling due to miR-145 deficiency Regulating the contractile states of smooth muscle cells (SMCs) is critical for vascular homeostasis. Liu et al. find that the H3K4me2 modification is required to maintain SMC lineage identity and contractile state, serving as a genomic footprint for TET2-mediated DNA demethylation. H3K4me2 alteration in SMCs may contribute to cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Highly trained vascular sonographers make up a significant cost of abdominal aortic aneurysm (AAA) ultrasound screening. However, they are over-trained for this very limited task. Others have reported that health workers (e.g. emergency room staff and nurses) with far less training may be able to perform these scans. The national AAA screening programme in the UK uses staff with limited training. Whether individuals without a health professional qualification could be trained to perform the scan accurately to improve cost-effectiveness is not known. We aimed to investigate whether a short, well-supervised course in ultrasonography could train novices to detect AAA for screening purposes.Methods: Three novices were trained by an experienced sonographer for 15 days to perform abdominal aortic ultrasound examinations and detect AAA using a portable ultrasound system. The examination included four anterior-posterior aortic measurements: a maximal diameter in the coronal plane and three diameters of the suprarenal, mid and distal infrarenal aorta in the transverse plane. The novices independently scanned 215 subjects following training; experienced sonographers repeated the measurements on the same subject in the same session. Using Bland-Altman plots and CUSUM analysis, the novices' and experienced sonographers' accuracy and efficiency measurements were compared. Factors influencing performance were recorded.Results: The novices measured the maximal coronal aortic diameter accurately, to within 0.46-0.52 cm of the true diameter; 85-97% of their coronal measurements were within 0.5 cm of the assessors; kappa statistic and Bland-Altman plots show a high agreement with the assessor's measurements. However, the novices' measurements of the three diameters in the transverse plane were outside clinically acceptable limits. Assuming a referral policy for a second scan for scans recorded as 'difficult', only one novice missed a 3.13 cm aneurysm.A CUSUM quality improvement analysis demonstrated substantial improvements in the scanning efficiency of the novices with continued scanning experience.Conclusion: This study showed that novices could be trained to screen for AAA over 15 days. However, the need for continuing quality improvement is critical, especially in more technically demanding cases. Measuring the maximal infrarenal diameter instead of specific segmental diameters may be more appropriate for AAA screening using novices. [ABSTRACT FROM AUTHOR]