LncRNA NONRATT021972 involved the pathophysiologic processes mediated by P2X<Subscript>7</Subscript> receptors in stellate ganglia after myocardial ischemic injury

Adenosine triphosphate (ATP) acts on P2X receptors to initiate signal transmission. P2X₇ receptors play a role in the pathophysiological process of myocardial ischemic injury. Long noncoding RNAs (lncRNAs) participate in numerous biological functions independent of protein translation. LncRNAs are implicated in nervous system diseases. This study investigated the effects of NONRATT021972 small interference RNA (siRNA) on the pathophysiologic processes mediated by P2X₇ receptors in stellate ganglia (SG) after myocardial ischemic injury. Our results demonstrated that the expression of NONRATT021972 in SG was significantly higher in the myocardial ischemic (MI) group than in the control group. Treatment of MI rats with NONRATT021972 siRNA, the P2X₇ antagonist brilliant blue G (BBG), or P2X₇ siRNA improved the histology of injured ischemic cardiac tissues and decreased the elevated concentrations of serum myocardial enzymes, creatine kinase (CK), CK isoform MB (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) compared to the MI rats. NONRATT021972 siRNA, BBG, or P2X₇ siRNA treatment in MI rats decreased the expression levels of P2X₇ immunoreactivity, P2X₇ messenger RNA (mRNA), and P2X₇ protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) in the SG compared to MI rats. NONRATT021972 siRNA treatment prevented the pathophysiologic processes mediated by P2X₇ receptors in the SG after myocardial ischemic injury.     

Detection and characterization of diverse alpha- and betacoronaviruses from bats in China

Bats have been implicated as important reservoir hosts of alpha- and betacoronaviruses. In this study, diverse coronaviruses (CoVs) were detected in 50 of 951 (positive rate 5.3%) intestinal specimens of eight bat species collected in four provinces and the Tibet Autonomous Region of China by pan-coronavirus RT-PCR screening. Based on 400-nt RNA-dependent RNA polymerase (RdRP) sequence analysis, eight belonged to genus Alphacoronavirus and 42 to Betacoronavirus. Among the 50 positive specimens, thirteen gave rise to CoV full-length RdRP gene amplification for further sequence comparison, of which three divergent sequences (two from a unreported province) were subjected to full genome sequencing. Two complete genomes of betacoronaviruses (JTMC15 and JPDB144) and one nearly-complete genome of alphacoronavirus (JTAC2) were sequenced and their genomic organization predicted. The present study has identified additional numbers of genetically diverse bat-borne coronaviruses with a wide distribution in China. Two new species of bat CoV, identified through sequence comparison and phylogenetic analysis, are proposed.

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A Questionnaire Survey of the Type of Support Required by <Emphasis Type="Italic">Yogo</Emphasis> Teachers to Effectively Manage Students Suspected of Having an Eating Disorder

Background

Many studies have focused on the decreasing age of onset of eating disorders (EDs). Because school-age children with EDs are likely to suffer worse physical effects than adults, early detection and appropriate support are important. The cooperation of Yogo teachers is essential in helping these students to find appropriate care. To assist Yogo teachers, it is helpful to clarify the encounter rates (the proportion of Yogo teachers who have encountered ED students) and kinds of requested support (which Yogo teachers felt necessary to support ED students). There are no studies that have surveyed the prevalence rates of ED children by ED type as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), nor were we able to find any quantitative study surveying the kinds of support Yogo teachers feel helpful to support ED students.

Methods

A questionnaire survey was administered to 655 Yogo teachers working at elementary/junior high/senior high/special needs schools in Chiba Prefecture. The questionnaire asked if the respondents had encountered students with each of the ED types described in DSM-5 (anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), avoidant/restrictive food intake disorder (ARFID), and other types of EDs (Others)), and the kinds of support they felt necessary to support these students. The encounter rates and the kinds of requested were obtained and compared, taking their confidence intervals into consideration.

Results

The encounter rates for AN, BN, BED, ARFID, and Others were 48.4, 14.0, 8.4, 10.7, and 4.6 %, respectively. When classified by school type, AN, BN, BED, and ARFID had their highest encounter rates in senior high schools. Special needs schools had the highest rate for Others. The support most required for all ED types was “a list of medical/consultation institutions.”

Conclusions

Our results have clarified how to support Yogo teachers in the early detection and support of ED students. We found that the encounter rate of AN was the highest, and that it is effective to offer “a list of medical/consultation institutions” to junior and senior high schools where the encounter rates for AN are high.

     

Crystal structure of human S100A8 in complex with zinc and calcium

Background

S100 proteins are a large family of calcium binding proteins present only in vertebrates. They function intra- and extracellularly both as regulators of homeostatic processes and as potent effectors during inflammation. Among these, S100A8 and S100A9 are two major constituents of neutrophils that can assemble into homodimers, heterodimers and higher oligomeric species, including fibrillary structures found in the ageing prostate. Each of these forms assumes specific functions and their formation is dependent on divalent cations, notably calcium and zinc. In particular, zinc appears as a major regulator of S100 protein function in a disease context. Despite this central role, no structural information on how zinc bind to S100A8/S100A9 and regulates their quaternary structure is yet available.

Results

Here we report two crystallographic structures of calcium and zinc-loaded human S100A8. S100A8 binds two zinc ions per homodimer, through two symmetrical, all-His tetracoordination sites, revealing a classical His-Zn binding mode for the protein. Furthermore, the presence of a (Zn)₂-cacodylate complex in our second crystal form induces ligand swapping within the canonical His₄ zinc binding motif, thereby creating two new Zn-sites, one of which involves residues from symmetry-related molecules. Finally, we describe the calcium-induced S100A8 tetramer and reveal how zinc stabilizes this tetramer by tightening the dimer-dimer interface.

Conclusions

Our structures of Zn²⁺/Ca²⁺-bound hS100A8 demonstrate that S100A8 is a genuine His-Zn S100 protein. Furthermore, they show how zinc stabilizes S100A8 tetramerization and potentially mediates the formation of novel interdimer interactions. We propose that these zinc-mediated interactions may serve as a basis for the generation of larger oligomers in vivo.

     

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.     

Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice

Combined methylmalonic aciduria with homocystinuria (cblC type) is a rare disease caused by mutations in the MMACHC gene. MMACHC encodes an enzyme crucial for intracellular vitamin B₁₂ metabolism, leading to the accumulation of toxic metabolites e.g. methylmalonic acid (MMA) and homocysteine (Hcy), and secondary disturbances in folate and one-carbon metabolism when not fully functional. Patients with cblC deficiency often present in the neonatal or early childhood period with a severe multisystem pathology, which comprises a broad spectrum of treatment-resistant ophthalmological phenotypes, including retinal degeneration, impaired vision, and vascular changes. To examine the potential function of MMACHC in the retina and how its loss may impact disease, we performed gene expression studies in human and mouse, which showed that local expression of MMACHC in the retina and retinal pigment epithelium is relatively stable over time. To study whether functional MMACHC is required for retinal function and tissue integrity, we generated a transgenic mouse lacking Mmachc expression in cells of the peripheral retina. Characterization of this mouse revealed accumulation of cblC disease related metabolites, including MMA and the folate-dependent purine synthesis intermediates AICA-riboside and SAICA-riboside in the retina. Nevertheless, fundus appearance, morphology, vasculature, and cellular composition of the retina, as well as ocular function, remained normal in mice up to 6 or 12 months of age. Our data indicates that peripheral retinal neurons do not require intrinsic expression of Mmachc for survival and function and questions whether a local MMACHC deficiency is responsible for the retinal phenotypes in patients.     

Long-Term Exposure to Primary Traffic Pollutants and Lung Function in Children: Cross-Sectional Study and Meta-Analysis

Background

There is widespread concern about the possible health effects of traffic-related air pollution. Nitrogen dioxide (NO₂) is a convenient marker of primary pollution. We investigated the associations between lung function and current residential exposure to a range of air pollutants (particularly NO₂, NO, NOx and particulate matter) in London children. Moreover, we placed the results for NO₂ in context with a meta-analysis of published estimates of the association.

Methods and Findings

Associations between primary traffic pollutants and lung function were investigated in 4884 children aged 9–10 years who participated in the Child Heart and Health Study in England (CHASE). A systematic literature search identified 13 studies eligible for inclusion in a meta-analysis. We combined results from the meta-analysis with the distribution of the values of FEV₁ in CHASE to estimate the prevalence of children with abnormal lung function (FEV₁<80% of predicted value) expected under different scenarios of NO₂ exposure. In CHASE, there were non-significant inverse associations between all pollutants except ozone and both FEV1 and FVC. In the meta-analysis, a 10 μg/m³ increase in NO₂ was associated with an 8 ml lower FEV₁ (95% CI: -14 to -1 ml; p: 0.016). The observed effect was not modified by a reported asthma diagnosis. On the basis of these results, a 10 μg/m³ increase in NO₂ level would translate into a 7% (95% CI: 4% to 12%) increase of the prevalence of children with abnormal lung function.

Conclusions

Exposure to traffic pollution may cause a small overall reduction in lung function and increase the prevalence of children with clinically relevant declines in lung function.     

Vibrio coralliilyticus Strain OCN008 Is an Etiological Agent of Acute Montipora White Syndrome

Identification of a pathogen is a critical first step in the epidemiology and subsequent management of a disease. A limited number of pathogens have been identified for diseases contributing to the global decline of coral populations. Here we describe Vibrio coralliilyticus strain OCN008, which induces acute Montipora white syndrome (aMWS), a tissue loss disease responsible for substantial mortality of the coral Montipora capitata in Kāne‘ohe Bay, Hawai‘i. OCN008 was grown in pure culture, recreated signs of disease in experimentally infected corals, and could be recovered after infection. In addition, strains similar to OCN008 were isolated from diseased coral from the field but not from healthy M. capitata. OCN008 repeatedly induced the loss of healthy M. capitata tissue from fragments under laboratory conditions with a minimum infectious dose of between 10⁷ and 10⁸ CFU/ml of water. In contrast, Porites compressa was not infected by OCN008, indicating the host specificity of the pathogen. A decrease in water temperature from 27 to 23°C affected the time to disease onset, but the risk of infection was not significantly reduced. Temperature-dependent bleaching, which has been observed with the V. coralliilyticus type strain BAA-450, was not observed during infection with OCN008. A comparison of the OCN008 genome to the genomes of pathogenic V. coralliilyticus strains BAA-450 and P1 revealed similar virulence-associated genes and quorum-sensing systems. Despite this genetic similarity, infections of M. capitata by OCN008 do not follow the paradigm for V. coralliilyticus infections established by the type strain.