Association of age at diagnosis of diabetes with subsequent risk of age-related ocular diseases and vision acuity.

BACKGROUND: The importance of age on the development of ocular conditions has been reported by numerous studies. Diabetes may have different associations with different stages of ocular conditions, and the duration of diabetes may affect the development of diabetic eye disease. While there is a dose-response relationship between the age at diagnosis of diabetes and the risk of cardiovascular disease and mortality, whether the age at diagnosis of diabetes is associated with incident ocular conditions remains to be explored. It is unclear which types of diabetes are more predictive of ocular conditions. AIM: To examine associations between the age of diabetes diagnosis and the incidence of cataract, glaucoma, age-related macular degeneration (AMD), and vision acuity. METHODS: Our analysis was using the UK Biobank. The cohort included 8709 diabetic participants and 17418 controls for ocular condition analysis, and 6689 diabetic participants and 13378 controls for vision analysis. Ocular diseases were identified using inpatient records until January 2021. Vision acuity was assessed using a chart. RESULTS: During a median follow-up of 11.0 years, 3874, 665, and 616 new cases of cataract, glaucoma, and AMD, respectively, were identified. A stronger association between diabetes and incident ocular conditions was observed where diabetes was diagnosed at a younger age. Individuals with type 2 diabetes (T2D) diagnosed at < 45 years [HR (95%CI): 2.71 (1.49-4.93)], 45-49 years [2.57 (1.17-5.65)], 50-54 years [1.85 (1.13-3.04)], or 50-59 years of age [1.53 (1.00-2.34)] had a higher risk of AMD independent of glycated haemoglobin. T2D diagnosed < 45 years [HR (95%CI): 2.18 (1.71-2.79)], 45-49 years [1.54 (1.19-2.01)], 50-54 years [1.60 (1.31-1.96)], or 55-59 years of age [1.21 (1.02-1.43)] was associated with an increased cataract risk. T2D diagnosed < 45 years of age only was associated with an increased risk of glaucoma [HR (95%CI): 1.76 (1.00-3.12)]. HRs (95%CIs) for AMD, cataract, and glaucoma associated with type 1 diabetes (T1D) were 4.12 (1.99-8.53), 2.95 (2.17-4.02), and 2.40 (1.09-5.31), respectively. In multivariable-adjusted analysis, individuals with T2D diagnosed < 45 years of age [ß 95%CI: 0.025 (0.009,0.040)] had a larger increase in LogMAR. The ß (95%CI) for LogMAR associated with T1D was 0.044 (0.014, 0.073). CONCLUSION: The younger age at the diagnosis of diabetes is associated with a larger relative risk of incident ocular diseases and greater vision loss.

Synthesis and Preliminary Evaluation of an ASGPr-Targeted Polycationic ß-Cyclodextrin Carrier for Nucleosides and Nucleotides.

Most antiviral and anticancer nucleosides are prodrugs that require stepwise phosphorylation to their triphosphate nucleotide form for biological activity. Monophosphorylation may be rate-limiting, and the nucleotides may be unstable and poorly internalized by target cells. Effective targeting and delivery systems for nucleoside drugs, including oligonucleotides used in molecular therapeutics, could augment their efficacy. The development of a carrier designed to effect selective transmembrane internalization of nucleotides via the asialoglycoprotein receptor (ASGPr) is now reported. In this work, the polycationic, polygalactosyl drug delivery carrier heptakis[6-amino-6-deoxy-2-O-(3-(1-thio-ß-D-galactopyranosyl)-propyl)]-ß-cyclodextrin hepta-acetate salt (GCyDAc), potentially a bifunctional carrier of (poly)nucleotides, was modeled by molecular docking in silico as an ASGPr-ligand, then synthesized for testing. The antivirals arabinosyl adenine (araA, vidarabine, an early generation antiviral nucleoside), arabinosyl adenine 5'-monophosphate (araAMP), and 12-mer-araAMP (p-araAMP) were selected for individual formulation with GCyDAc to develop this concept. Experimentally, beta cyclodextrin was decorated with seven protonated amino substituents on the primary face, and seven thiogalactose residues on its secondary face. AraA, araAMP, and p-araAMP were individually complexed with GCyDAc and complex formation for each drug was confirmed by differential scanning calorimetry (DSC). Finally, the free drugs and their GCyDAc complexes were evaluated for antiviral activity using ASGPr-expressing HepAD38 cells in cell culture. In this model, araA, araAMP, and p-araAMP showed relative antiviral potencies of 1.0, 1.1, and 1.2, respectively. In comparison, GCyDAc-complexes of araA, araAMP, and p-araAMP were 2.5, 1.3, and 1.2 times more effective than non-complexed araA in suppressing viral DNA production. The antiviral potencies of these complexes were minimally supportive of the hypothesis that ASGPr-targeted, CyD-based charge-association complexation of nucleosides and nucleotides could effectively enhance antiviral efficacy. GCyDAc was non-toxic to mammalian cells in cell culture, as determined using the MTS proliferation assay.

Chromosome-level genome provides insight into the evolution and conservation of the threatened goral (Naemorhedus goral).

BACKGROUND: Gorals Naemorhedus resemble both goats and antelopes, which prompts much debate about the intragenus species delimitation and phylogenetic status of the genus Naemorhedus within the subfamily Caprinae. Their evolution is believed to be linked to the uplift of the Qinghai-Tibet Plateau (QTP). To better understand its phylogenetics, the genetic information is worth being resolved. RESULTS: Based on a sample from the eastern margin of QTP, we constructed the first reference genome for Himalayan goral Naemorhedus goral, using PacBio long-read sequencing and Hi-C technology. The 2.59 Gb assembled genome had a contig N50 of 3.70 Mb and scaffold N50 of 106.66 Mb, which anchored onto 28 pseudo chromosomes. A total of 20,145 protein-coding genes were predicted in the assembled genome, of which 99.93% were functionally annotated. Phylogenetically, the goral was closely related to muskox on the mitochondrial genome level and nested into the takin-muskox clade on the genome tree, rather than other so-called goat-antelopes. The cladogenetic event among muskox, takin and goral occurred sequentially during the late Miocene (~ 11 - 5 Mya), when the QTP experienced a third dramatic uplift with consequent profound changes in climate and environment. Several chromosome fusions and translocations were observed between goral and takin/muskox. The expanded gene families in the goral genome were mainly related to the metabolism of drugs and diseases, so as the positive selected genes. The Ne of goral continued to decrease since ~ 1 Mya during the Pleistocene with active glaciations. CONCLUSION: The high-quality goral genome provides insights into the evolution and valuable information for the conservation of this threatened group.

GAS6-AS1, a long noncoding RNA, functions as a key candidate gene in atrial fibrillation related stroke determined by ceRNA network analysis and WGCNA.

BACKGROUND: Stroke attributable to atrial fibrillation (AF related stroke, AFST) accounts for 13 ~ 26% of ischemic stroke. It has been found that AFST patients have a higher risk of disability and mortality than those without AF. Additionally, it's still a great challenge to treat AFST patients because its exact mechanism at the molecular level remains unclear. Thus, it's vital to investigate the mechanism of AFST and search for molecular targets of treatment. Long non-coding RNAs (lncRNAs) are related to the pathogenesis of various diseases. However, the role of lncRNAs in AFST remains unclear. In this study, AFST-related lncRNAs are explored using competing endogenous RNA (ceRNA) network analysis and weighted gene co-expression network analysis (WGCNA). METHODS: GSE66724 and GSE58294 datasets were downloaded from GEO database. After data preprocessing and probe reannotation, differentially expressed lncRNAs (DELs) and differentially expressed mRNAs (DEMs) between AFST and AF samples were explored. Then, functional enrichment analysis and protein-protein interaction (PPI) network analysis of the DEMs were performed. At the meantime, ceRNA network analysis and WGCNA were performed to identify hub lncRNAs. The hub lncRNAs identified both by ceRNA network analysis and WGCNA were further validated by Comparative Toxicogenomics Database (CTD). RESULTS: In all, 19 DELs and 317 DEMs were identified between the AFST and AF samples. Functional enrichment analysis suggested that the DEMs associated with AFST were mainly enriched in the activation of the immune response. Two lncRNAs which overlapped between the three lncRNAs identified by the ceRNA network analysis and the 28 lncRNAs identified by the WGCNA were screened as hub lncRNAs for further validation. Finally, lncRNA GAS6-AS1 turned out to be associated with AFST by CTD validation. CONCLUSION: These findings suggested that low expression of GAS6-AS1 might exert an essential role in AFST through downregulating its downstream target mRNAs GOLGA8A and BACH2, and GAS6-AS1 might be a potential target for AFST therapy.

Survey the effect of drug treatment on modulation of cytokines gene expression in allergic rhinitis.

Allergic rhinitis as common airway disease has high prevalence in all peoples worldwide. In allergic diseases, Th2 cells release type 2 cytokines that support the inflammation in airways. All the drugs used for allergic rhinitis do not cure completely, and the choice of drugs according to cost and efficacy is very important in all groups of atopic patients. Therefore, in this study, the effect of commercial drugs on cytokine gene expression has been studied. Male Balb/c mice were divided into six groups. Allergic rhinitis was induced in five of the six groups with ovalbumin, and four of these five groups were treated with salbutamol, budesonide, theophylline, and montelukast. The fifth group was used as positive control group and the sixth group as negative control group. For the survey, RNA was extracted, cDNA was synthesized, and quantitative real-time PCR was done for 21 genes. The four drugs had different effects on mRNA expression of cytokines (IL-1b, 2, 4, 5, 7, 8, 9, 11, 12, 13, 17, 18, 22, 25, 31, 33, 37, IFN-γ, TNF-α, TGF-ß1, and eotaxin) in the allergic rhinitis groups. Salbutamol can be used during pregnancy and breastfeeding, but it has some side effects. Budesonide in the inhaled form is generally safe in pregnancy. Theophylline cannot control allergic attack in the long run. Montelukast is not useful in the treatment of acute allergic attacks. Immunomodulatory and anti-inflammatory effects of drugs in control of allergic rhinitis via Th2 cytokines can be new approaches in molecular medicine.

The Smad3-dependent microRNA let-7i-5p promoted renal fibrosis in mice with unilateral ureteral obstruction.

Renal fibrosis is a common feature of all types of chronic kidney disease (CKD) and is tightly regulated by the TGF-ß/Smad3 pathway. Let-7i-5p belongs to the let-7 microRNA family with diverse biological functions. It has been reported that let-7i-5p suppresses fibrotic disease in the heart, lungs, and blood vessels, while the role of let-7i-5p in renal fibrosis remains limited. In this study, we aimed to investigate the role of let-7i-5p in renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) and TGF-ß1-stimulated renal tubular cell line TCMK1. The RNA-targeting CRISPR/Cas13d system was used to knock down let-7i-5p. Renal injury and fibrosis were determined by histological analysis, RT-PCR, Western blot, and immunostaining. Our results have shown that in the kidneys after UUO, the expression of let-7i-5p was significantly increased along with notable tubular injury and interstitial fibrosis. Electroporation of let-7i-targeting Cas13d plasmid efficiently knocked down let-7i-5p in kidneys after UUO with reduced tubular injury, fibrotic area, and expression of fibrotic marker genes α-SMA, fibronectin, and Col1a1. In TGF-ß1-stimulated TCMK1 cells, knockdown of let-7i-5p by Cas13d plasmid transfection also blunted the expression of fibrotic marker genes. Most importantly, the genomic locus of let-7i showed enriched binding of Smad3 as revealed by chromatin immunoprecipitation. In TCMK1 cells, the overexpression of Smad3 can directly induce the expression of let-7i-5p. However, the deletion of Smad3 abolished TGF-ß1-stimulated let-7i-5p expression. Collectively, these findings suggest that let-7i-5p is a Smad3-dependent microRNA that plays a pathogenic role in renal fibrosis. Let-7i-5p could be a promising target for the treatment of CKD-associated renal fibrosis.

The Association Between Subclinical Thyroid Dysfunction and Recurrence of Atrial Fibrillation After Catheter Ablation.

Objective: The aim of this study was to evaluate the association between subclinical thyroid dysfunction and the recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). Methods: We examined the association between subclinical thyroid dysfunction and the recurrence of AF at a large university-affiliated cardiac arrhythmia center in China. Data were collected from consecutive patients who underwent RFCA for AF, excluding those with a history of hypothyroidism, hyperthyroidism, or ongoing medical treatment for hypothyroidism or hyperthyroidism, biochemically defined overt thyroid disease, and long-term use of amiodarone before admission. The primary end point was the recurrence of AF in a time-to-event analysis. We compared outcomes in patients who had subclinical hyperthyroidism or hypothyroidism with those who had euthyroid state, using a multivariable Cox model with inverse probability weighting and propensity score matching. Results: In all, 93 patients were excluded from 435 consecutive patients who underwent RFCA for AF. Of the remaining 342 patients for the analysis, the prevalence of subclinical hyperthyroidism and subclinical hypothyroidism were 26 (7.6%) and 41 (12.0%), respectively; during a median follow-up of 489 days, 91 patients (26.6%) developed a primary end point event. In the main analysis of the multivariable Cox model, only subclinical hyperthyroidism [hazard ratio: 3.07, 95% confidence interval (CI): 1.54-6.14] was associated with an increased risk of end point event after adjusting for potential confounders. However, the association between subclinical hypothyroidism and the end point event was not significant (hazard ratio: 0.66, 95% CI: 0.31-1.43). Results were consistent either in multiple sensitivity analyses or across all subgroups of analysis. Compared with individuals with free triiodothyronine (fT3) in the lowest quintile, those with fT3 in the highest quintile had an HR of 2.23 (95% CI: 1.16-4.28) for recurrence of AF. With the increase of thyroid-stimulating hormone (TSH), a reduction in the risk of recurrence of AF was detected in the adjusted model, and the hazard ratio (HR) per standard deviation (SD) increase was 0.82 (95% CI: 0.68-0.98). Conclusion: In this retrospective cohort study involving patients who underwent RFCA for AF, patients with subclinical hyperthyroidism were associated with a markedly higher prevalence of recurrence of AF, whereas patients with subclinical hypothyroidism had a similar recurrence rate of AF compared to those with the euthyroid state.

Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents.

Solid tumours are often poorly oxygenated, which confers resistance to standard treatment modalities. Targeting hypoxic tumours requires compounds, such as nitroimidazoles (NIs), equipped with the ability to reach and become activated within diffusion limited tumour niches. NIs become selectively entrapped in hypoxic cells through bioreductive activation, and have shown promise as hypoxia directed therapeutics. However, little is known about their mechanism of action, hindering the broader clinical usage of NIs. Iodoazomycin arabinofuranoside (IAZA) and fluoroazomycin arabinofuranoside (FAZA) are clinically validated 2-NI hypoxic radiotracers with excellent tumour uptake properties. Hypoxic cancer cells have also shown preferential susceptibility to IAZA and FAZA treatment, making them ideal candidates for an in-depth study in a therapeutic setting. Using a head and neck cancer model, we show that hypoxic cells display higher sensitivity to IAZA and FAZA, where the drugs alter cell morphology, compromise DNA replication, slow down cell cycle progression and induce replication stress, ultimately leading to cytostasis. Effects of IAZA and FAZA on target cellular macromolecules (DNA, proteins and glutathione) were characterized to uncover potential mechanism(s) of action. Covalent binding of these NIs was only observed to cellular proteins, but not to DNA, under hypoxia. While protein levels remained unaffected, catalytic activities of NI target proteins, such as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the detoxification enzyme glutathione S-transferase (GST) were significantly curtailed in response to drug treatment under hypoxia. Intraperitoneal administration of IAZA was well-tolerated in mice and produced early (but transient) growth inhibition of subcutaneous mouse tumours.

Safety and Efficacy Evaluation of Antithrombotic Therapy with Rivaroxaban and Clopidogrel After PCI in Chinese Patients.

OBJECTIVE: To investigate the efficacy and safety of the antithrombotic therapy using the oral anticoagulant rivaroxaban and clopidogrel in Chinese patients with acute coronary syndrome complicated with atrial fibrillation after percutaneous coronary intervention. METHODS: A total of 100 patients were selected. Patients were randomly divided into two groups: the treatment group (rivaroxaban group) received a therapy of rivaroxaban and clopidogrel. The control group (warfarin group) receivied a combined treatment of warfarin, clopidogrel, and aspirin. The primary outcome endpoint was evaluated based on the adverse cardiac and cerebrovascular events within 12 months. RESULTS: A total of 8 (8.00%) main adverse cardiac and cerebrovascular events occurred during the 12 months of follow-up, including 5 (9.80%) in the warfarin group and 3 (6.10%) in the rivaroxaban group. The risk of having main adverse cardiac and cerebrovascular events in the two groups was comparable (P = 0.479). A total of 9 patients (9.00%) were found to have bleeding events, among which 8 patients (15.7%) were in the warfarin group, whereas only 1 patient (2.00%) was in the rivaroxaban group. Therefore, the risk of bleeding in the warfarin group was significantly higher than that in the rivaroxaban group (P = 0.047). CONCLUSIONS: In Chinese patients with acute coronary syndrome complicated with atrial fibrillation, the efficacy of the dual therapy of oral anticoagulant rivaroxaban plus clopidogrel after percutaneous coronary intervention was similar to that of the traditional triple therapy combined with warfarin, aspirin and clopidogrel, but it has a better safety property, which has potential to widely apply to antithrombotic therapy after PCI.

Species divergence and phylogeography of Corylus heterophylla Fisch complex (Betulaceae): Inferred from molecular, climatic and morphological data.

Historical geo-climatic changes have shaped the geographical distributions and genetic diversity of numerous plant taxa in East Asia, which promote species divergence and ultimately speciation. Here, we integrated multiple approaches, including molecular phylogeography, ecological niche modeling, and morphological traits to examine the nucleotide diversity and interspecific divergence within Corylus heterophylla complex (C. heterophylla, C. kweichowensis, and C. yunnanensis). These three sibling taxa harbored similar high levels of nucleotide diversity at the species level. The molecular data (SCNG and cpDNA) unanimously supported the division of C. heterophylla complex into two major clades, with C. yunnanensis diverged earlier from the complex, whereas C. heterophylla and C. kweichowensis could hardly be separated. The split between the two clades (c. 12.89 Ma) coincided with the formation of Sichuan Basin in the middle Miocene, while the divergence among and within the five subclades (YUN1-YUN3, HK1-HK2) occurred from the late Miocene to the Pleistocene. C. heterophylla of northern China experienced glacial contraction and interglacial expansion during the Quaternary, whereas C. kweichowensis and C. yunnanensis of southern China presented population expansion even during the last glacial maximum. Despite of high levels of genetic admixture between C. heterophylla and C. kweichowensis, significant ecological and morphological discrepancy as well as incomplete geographic isolation indicated that adaptive evolution triggered by divergent selection may have played important roles in incipient ecological speciation.

Nano-Aromatic Drugs Based on Mesoporous Silica Nanoparticles and Bergamot Essential Oil for Anti-Depression.

Depression is a mental disorder characterized by low mood as the main pathological feature. Current medications for depression have long treatment cycles and serious side effects. Aromatherapy can alleviate depression in a "moistening things silently" way, but the fast evaporation rate of aromatic drugs weakens the effect of aromatherapy. In this study, we designed and prepared nano-aromatic drugs with slow release for anti-depressant application. We first synthesized rod-shaped mesoporous silica nanoparticles (MSNs) and encapsulated bergamot essential oil. These nanoaromatic drugs were named BEO@MSNs. Subsequently, we analyzed the pore properties of MSNs and BEO@MSNs. Further, we explored the thermal stability, encapsulation efficiency, and slow-release properties of bergamot essential oil in BEO@MSNs. Finally, we used BEO@MSNs to alleviate depression in mice while constructing depression model mice via corticosterone. The results showed that BEO@MSNs had excellent anti-depressant effects and biosafety.

Next generation sequencing of RB1gene for the molecular diagnosis of ethnic minority with retinoblastoma in Yunnan.

BACKGROUND: Retinoblastoma is a rare intraocular malignancy and typically initiated by inactivating biallelic mutations of RB1 gene. Each year, ~ 8000 children worldwide are diagnosed for retinoblastoma. In high-income countries, patient survival is over 95% while low-income countries is ~ 30%.If disease is diagnosed early and treated in centers specializing in retinoblastoma, the survival might exceed 95% and many eyes could be safely treated and support a lifetime of good vision. In China, approximate 1100 newly diagnosed cases are expected annually and 28 hospitals covering 25 provinces established centers classified by expertise and resources for better treatment options and follow-up. Comparing with other province of eastern China, Yunnan province is remote geographically. This might result that healthcare staff have low awareness of the role of genetic testing in management and screening in families. METHODS: The patients with retinoblastoma were selected in Yunnan. DNA from blood was used for targeted gene sequencing. Then, an in-house bioinformatics pipeline was done to detect both single nucleotide variants and small insertions/deletions. The pathogenic mutations were identified and further confirmed by conventional methods and cosegregation in families. RESULTS: Using our approach, targeted next generation sequencing was used to detect the mutation of these 12 probands. Bioinformatic predictions showed that nine mutations were found in our study and four were novel pathogenic variants in these nine mutations. CONCLUSIONS: It's the first report to describe RB1 mutations in Yunnan children with retinoblastoma. This study would improve role of genetic testing for management and family screening.

The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial-to-mesenchymal transition and lipid-derived energy production in prostate cancer cells.

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid-binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial-to-mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid ß-oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12's role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP-PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Effectiveness of Atorvastatin in the Treatment of Asymptomatic Heart Failure After Myocardial Infarction: A Clinical Study.

INTRODUCTION: Silent heart failure after myocardial infarction has not been effectively treated. Atorvastatin has certain efficacy in the treatment of heart failure. Our clinical study aimed to investigate the effectiveness of atorvastatin in patients with asymptomatic heart failure after myocardial infarction. METHODS: A total of 162 patients with asymptomatic heart failure after myocardial infarction in our hospital from August 2018 to August 2019 were randomly divided into the observation group (81 cases were treated with atorvastatin on the basis of routine therapy) and the control group (81 cases were treated with routine symptomatic treatment). The clinical curative effect, the level of related inflammatory cytokines, cardiac function index, and vascular endothelial function were compared between the two groups. RESULTS: Before intervention, there was no significant difference in tumor necrosis factor (TNFα), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), plasma N-terminal B-type natriuretic peptide (NT-ProBNP), left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular posterior wall thickness (LVPWT), asymmetric dimethyarginine (ADMA), activity of nitric oxide synthase (NOS), nitric oxide (NO) and flow-mediated dilation (FMD) between the two groups. After intervention, TNFα, hs-CRP, IL-6, NT-ProBNP, LVEF, LVEDD, LVESD, LVPWT, ADMA, NOS, NO, and FMD were improved in both groups. The clinical curative effect, TNFα, hs-CRP, IL-6, NT-ProBNP, LVEF, LVEDD, LVESD, LVPWT, ADMA, NOS, NO, and FMD in the observation group showed significantly greater results than those in the control group (P < 0.05). CONCLUSION: Atorvastatin exerted a great effect in treating asymptomatic heart failure after myocardial infarction, which can evidently reduce the level of related inflammatory cytokines, improve cardiac function, and regulate vascular endothelial function. Hence, atorvastatin is considered a valid and alternative approach in clinical practice.

A COVID-19 case report from asymptomatic contact: implication for contact isolation and incubation management.

BACKGROUND: As of 2 March, 2020, at least 80 151 coronavirus disease 2019 (COVID-19) cases were reported in China. Most of the patients had a history of visiting Hubei Province or contacting with people who had ever stayed in or passed by Hubei Province or were exposed to symptoms. Some patients got infected through only asymptomatic contact. This study aimed to report the epidemic features and lab identification of a patient confirmed with COVID-19 infection through only asymptomatic contact. CASE PRESENTATION: A 44-year-old man, who lived in Nanchang, Jiangxi Province, China until 6 March 2020, suffered from cough on 27 January 2020. Fever symptoms appeared on 28 January, with a maximum temperature of 38.8 °C, accompanied by cough, sore throat, headache, fatigue, muscle ache, joint ache, and other symptoms. The symptoms continued until he was hospitalized on 30 January. Coronavirus conventional polymerase chain reaction assay was positive for the throat swab sample. The patient, along with his wife and son, drove from Nanchang to back to Honghu City, Hubei Province, on 23 January 2020. After staying with his parents and brother's family for 3 days, the patient drove back to Nanchang and arrived on 25 January. On the way back home, they stopped by Tongshan service area, Hubei Province, without any close contact with other people. After arriving home in Nanchang City, Jiangxi Province, none of them left their residence. In addition, his parents stayed at home for 20 days with his younger brother's family before they got back. His younger brother and one of his brother's children visited Wuhan on 5 January and came home on 6 January 2020. CONCLUSIONS: This report suggested that, in the early phase of COVID-19 pneumonia, routine screening could miss patients who were virus carriers. Highlighting travel history is of paramount importance for the early detection and isolation of severe acute respiratory syndrome coronavirus 2 cases.

Short-term efficacy and safety of levosimendan in patients with chronic systolic heart failure.

The objective was to investigate and evaluate the short-term efficacy and safety of levosimendan in patients with chronic systolic heart failure. Forty-nine patients with chronic systolic heart failure during acute decompensation were randomly divided into a levosimendan group (26 cases) and a control group (23 cases). The control group received only routine treatment, while the levosimendan group received a levosimendan bolus with a load of 12 µg/kg, in addition to the same routine treatment as the control group. After 48 hours of treatment, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in the levosimendan group were significantly lower than those in the control group. In addition, the left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) cardiac function scores of the levosimendan group were significantly higher and more improved than those of the control group seven days after treatment, but there was no significant difference in the left ventricular end-diastolic diameter between the two groups. Furthermore, 48 hours after treatment, there were no significant differences in potassium, haemoglobin, haematocrit and creatinine levels between the levosimendan and control groups. During the whole hospitalisation, there was one case of sudden death in the control group and one case of palpitations in the levosimendan group, and no hypotension or severe hypokalaemia occurred in either group. Levosimendan significantly improved NT-proBNP and LVEF in patients with chronic systolic heart failure, and improved NYHA cardiac function classification without significant cardiovascular events. Levosimendan is therefore effective and safe in the short-term treatment of chronic systolic heart failure.

Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists.

STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2'3'-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2'3'-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections.

Two new steroidal saponins from Neolamarckia cadamba.

Two new steroidal saponins, ß-sitosterol-3-O-α-l-glucopyranoside (3) and ß-sitosterol-3-O-ß-d-glucopyranosyl-(1→6)-ß-d-glucopyranoside (4), were isolated and identified from the bark of Neolamarckia cadamba, along with 13 known compounds. Their structures were established on the basis of spectral data.

Adropin and glucagon-like peptide-2 are associated with glucose metabolism in obese children.

BACKGROUND: The interaction of adropin, glucagon-like peptide-2 (GLP2), angiopoietin-like protein 4 (ANGPTL4), and with childhood obesity and glucose metabolism is inconsistent. This study is to evaluate the association of the three cytokines and glucose homeostasis. METHODS: This was a cross-sectional study of children with obesity ranging from 5 to 14 years compared to age- and sex-matched children of normal weight. Fasting plasma glucose (FPG), oral glucose tolerance test 2-hour plasma glucose (OGTT2hPG), and insulin (INS) were measured, and serum adropin, GLP2, and ANGPTL4 levels were measured by enzyme-linked immunosorbent assay. The body mass index (BMI), BMI-Z scores, waist-to-hip ratio (WHR), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. RESULTS: Thirty-nine children (9.70 ± 1.71 years, 18 females) with obesity and 29 normal weight children (8.98 ± 1.98 years, 16 females) were assessed. The levels of INS, HOMA-IR and GLP2 of the obesity group were significantly higher than the controls (P < 0.05). Pearson correlation analysis showed that serum GLP2 was positively associated with WHR, FPG, and OGTT2hPG, and adropin was negatively associated with BMI, BMI-Z, WHR, INS, and HOMA-IR (all P < 0.05). Furthermore, GLP2 were negatively associated with adropin and ANGPTL4 (both P < 0.05). By binary logistic regression, adropin and GLP2 were found to be independent markers of obesity. Multiple linear regression showed that GLP2 was associated with OGTT2hPG, and adropin was associated with INS and HOMA-IR (all P < 0.05). CONCLUSIONS: Obese children had elevated GLP2 concentrations, and adropin and GLP2 associated with both childhood obesity and glucose homeostasis. Furthermore, there may be a physiologic interplay between adropin and GLP2 in obese children.