Mulberry Leaf-Derived Morin Activates ß-Catenin by Binding to Frizzled7 to Promote Intestinal Stem Cell Expansion upon Heat-Stable Enterotoxin b Injury.

Intestinal stem cells (ISCs) sustain epithelial renewal by dynamically altering behaviors of proliferation and differentiation in response to various nutrition and stress inputs. However, how ISCs integrate bioactive substance morin cues to protect against heat-stable enterotoxin b (STb) produced by Escherichia coli remains an uncertain question with implications for treating bacterial diarrhea. Our recent work showed that oral mulberry leaf-derived morin improved the growth performance in STb-challenged mice. Furthermore, morin supplementation reinstated the impaired small-intestinal epithelial structure and barrier function by stimulating ISC proliferation and differentiation as well as supporting intestinal organoid expansion ex vivo. Importantly, the Wnt/ß-catenin pathway, an ISC fate commitment signal, was reactivated by morin to restore the jejunal crypt-villus architecture in response to STb stimulation. Mechanically, the extracellular morin-initiated ß-catenin axis is dependent or partially dependent on the Wnt membrane receptor Frizzled7 (FZD7). Our data reveal an unexpected role of leaf-derived morin, which represents molecular signaling targeting the FZD7 platform instrumental for controlling ISC regeneration upon STb injury.

Dimmed gene knockout shortens larval growth and reduces silk yield in the silkworm, Bombyx mori.

The bHLH domain transcription factor, Bombyx mori-derived dimmed (Bmdimm), is directly regulated by the JH-BmMet/BmSRC-BmKr-h1 pathway and plays a key role in regulating the expression of FibH, which codes the main component of silk protein. However, the other roles of Bmdimm in silk protein synthesis remain unclear. Here, we established a Bmdimm knockout (KO) line containing a 7-bp deletion via CRISPR/Cas9 system, which led to the absence of the bHLH domain. The expression level of silk protein genes and silk yield decreased significantly in the Bmdimm KO line. Moreover, knocking out Bmdimm led to shortened larval stages and significant weight loss in larvae and adults. Bmdimm was found to be highly expressed in the silk gland, but it was also expressed in the fat body. The expression level of Bmkr-h1 in the fat body was significantly downregulated in the Bmdimm KO line. Exogenous JHA treatment upregulated Bmkr-h1 and rescued the phenotype of larval growth in the Bmdimm KO line. In conclusion, knocking out Bmdimm led to a shortened larval stage via the inhibition of Bmkr-h1 expression, then reduced silk yield. These findings help to elucidate the regulatory mechanism of fibroin synthesis and larval development in silkworms.

Ligustroflavone mediates the resistance of non-small cell lung cancer to osimertinib by arresting G1/S phase / 药学学报

Natural products are an important source for the development of antitumor lead compounds, but the pharmacological effects and regulatory mechanisms of natural products in osimertinib resistance in non-small cell lung cancer (NSCLC) are not well understood. The natural product ligustroflavone was used as the research object to analyze its efficacy in osimertinib-resistant NSCLC cells by cell proliferation assay and cell cycle detection. The potential targets of ligustroflavone in osimertinib-resistant NSCLC cells were screened by public databases and bioinformatics, molecular docking and microscale thermophoresis were used to identify the interaction between privet and target molecules. Western blot was used to detect the effect of privet on the target molecules and their downstream pathways. Ligustroflavone reduced the proliferation of osimertinib-resistant NSCLC cells, and could arrest the cell cycle. Cyclin-dependent kinase 6 (CDK6) was the potential target of ligustroflavone in osimertinib-resistant NSCLC cells. Ligustroflavone inhibited the activation of CDK6-Rb axis. Together, ligustroflavone could regulate osimertinib resistance in NSCLC cells by binding cell cyclin-related molecules. This study provides a theoretical basis for the targeted drug resistance of NSCLC with natural products, and also provides a new idea for the development of clinical drug combination.

Impact of VA-ECMO combined with IABP and timing on outcome of patients with acute myocardial infarction complicated with cardiogenic shock / 中华心血管病杂志

Objective: To investigate the impact of combined use and timing of arterial-venous extracorporeal membrane oxygenation (VA-ECMO) with intra-aortic balloon pump (IABP) on the prognosis of patients with acute myocardial infarction complicated with cardiogenic shock (AMICS). Methods: This was a prospective cohort study, patients with acute myocardial infarction and cardiogenic shock who received VA-ECMO support from the Heart Center of Lanzhou University First Hospital from March 2019 to March 2022 in the registration database of the Chinese Society for Extracorporeal Life Support were enrolled. According to combination with IABP and time point, patients were divided into VA-ECMO alone group, VA-ECMO+IABP concurrent group and VA-ECMO+IABP non-concurrent group. Data from 3 groups of patients were collected, including the demographic characteristics, risk factors, ECG and echocardiographic examination results, critical illness characteristics, coronary intervention results, VA-ECMO related parameters and complications were compared among the three groups. The primary clinical endpoint was all-cause death, and the safety indicators of mechanical circulatory support included a decrease in hemoglobin greater than 50 g/L, gastrointestinal bleeding, bacteremia, lower extremity ischemia, lower extremity thrombosis, acute kidney injury, pulmonary edema and stroke. Kaplan-Meier survival curves were used to analyze the survival outcomes of patients within 30 days of follow-up. Using VA-ECMO+IABP concurrent group as reference, multivariate Cox regression model was used to evaluate the effect of the combination of VA-ECMO+IABP at different time points on the prognosis of AMICS patients within 30 days. Results: The study included 68 AMICS patients who were supported by VA-ECMO, average age was (59.8±10.8) years, there were 12 female patients (17.6%), 19 cases were in VA-ECMO alone group, 34 cases in VA-ECMO+IABP concurrent group and 15 cases in VA-ECMO+IABP non-concurrent group. The success rate of ECMO weaning in the VA-ECMO+IABP concurrent group was significantly higher than that in the VA-ECMO alone group and the VA-ECMO+IABP non-concurrent group (all P<0.05). Compared with the ECMO+IABP non-concurrent group, the other two groups had shorter ECMO support time, lower rates of acute kidney injury complications (all P<0.05), and lower rates of pulmonary edema complications in the ECMO alone group (P<0.05). In-hospital survival rate was significantly higher in the VA-ECMO+IABP concurrent group (28 patients (82.4%)) than in the VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (7 patients) (all P<0.05). The survival rate up to 30 days of follow-up was also significantly higher surviving patients within were in the ECMO+IABP concurrent group (26 cases) than in VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (4 patients) (all P<0.05). Multivariate Cox regression analysis showed that compared with the concurrent use of VA-ECMO+IABP, the use of VA-ECMO alone and non-concurrent use of VA-ECMO+IABP were associated with increased 30-day mortality in AMICS patients (HR=2.801, P=0.036; HR=2.985, P=0.033, respectively). Conclusions: When VA-ECMO is indicated for AMICS patients, combined use with IABP at the same time can improve the ECMO weaning rate, in-hospital survival and survival at 30 days post discharge, and which does not increase additional complications.

Impact of VA-ECMO combined with IABP and timing on outcome of patients with acute myocardial infarction complicated with cardiogenic shock / 中华心血管病杂志

Objective: To investigate the impact of combined use and timing of arterial-venous extracorporeal membrane oxygenation (VA-ECMO) with intra-aortic balloon pump (IABP) on the prognosis of patients with acute myocardial infarction complicated with cardiogenic shock (AMICS). Methods: This was a prospective cohort study, patients with acute myocardial infarction and cardiogenic shock who received VA-ECMO support from the Heart Center of Lanzhou University First Hospital from March 2019 to March 2022 in the registration database of the Chinese Society for Extracorporeal Life Support were enrolled. According to combination with IABP and time point, patients were divided into VA-ECMO alone group, VA-ECMO+IABP concurrent group and VA-ECMO+IABP non-concurrent group. Data from 3 groups of patients were collected, including the demographic characteristics, risk factors, ECG and echocardiographic examination results, critical illness characteristics, coronary intervention results, VA-ECMO related parameters and complications were compared among the three groups. The primary clinical endpoint was all-cause death, and the safety indicators of mechanical circulatory support included a decrease in hemoglobin greater than 50 g/L, gastrointestinal bleeding, bacteremia, lower extremity ischemia, lower extremity thrombosis, acute kidney injury, pulmonary edema and stroke. Kaplan-Meier survival curves were used to analyze the survival outcomes of patients within 30 days of follow-up. Using VA-ECMO+IABP concurrent group as reference, multivariate Cox regression model was used to evaluate the effect of the combination of VA-ECMO+IABP at different time points on the prognosis of AMICS patients within 30 days. Results: The study included 68 AMICS patients who were supported by VA-ECMO, average age was (59.8±10.8) years, there were 12 female patients (17.6%), 19 cases were in VA-ECMO alone group, 34 cases in VA-ECMO+IABP concurrent group and 15 cases in VA-ECMO+IABP non-concurrent group. The success rate of ECMO weaning in the VA-ECMO+IABP concurrent group was significantly higher than that in the VA-ECMO alone group and the VA-ECMO+IABP non-concurrent group (all P<0.05). Compared with the ECMO+IABP non-concurrent group, the other two groups had shorter ECMO support time, lower rates of acute kidney injury complications (all P<0.05), and lower rates of pulmonary edema complications in the ECMO alone group (P<0.05). In-hospital survival rate was significantly higher in the VA-ECMO+IABP concurrent group (28 patients (82.4%)) than in the VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (7 patients) (all P<0.05). The survival rate up to 30 days of follow-up was also significantly higher surviving patients within were in the ECMO+IABP concurrent group (26 cases) than in VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (4 patients) (all P<0.05). Multivariate Cox regression analysis showed that compared with the concurrent use of VA-ECMO+IABP, the use of VA-ECMO alone and non-concurrent use of VA-ECMO+IABP were associated with increased 30-day mortality in AMICS patients (HR=2.801, P=0.036; HR=2.985, P=0.033, respectively). Conclusions: When VA-ECMO is indicated for AMICS patients, combined use with IABP at the same time can improve the ECMO weaning rate, in-hospital survival and survival at 30 days post discharge, and which does not increase additional complications.

Regression analysis of percutaneous lymphatic contrast-enhanced ultrasound combined with clinicopathological features in the diagnosis of sentinel lymph nodes in breast cancer / 中华超声影像学杂志

Objective:To explore the diagnostic efficacy of percutaneous lymphatic contrast ultrasound (LCEUS) combined with clinicopathological features in the diagnosis of breast cancer sentinel lymph node (SLN).Methods:A total of 135 breast cancer patients who underwent sentinel lymph node biopsy and axillary lymph node radical resection were prospectively collected in the Affiliated Hospital of Nanjing University of Chinese Medicine from July 2018 to June 2021, and the breast masses and SLNs were evaluated by routine ultrasound, contrast-enhanced ultrasound and LCEUS within one week before surgery. The surgeons recorded the patients′ clinical characteristics before surgeries, and the pathology of the masses and SLNs were recorded after surgeries. Univariate analysis and multivariate Logistic regression analysis were used to explore the correlation between ultrasound clinicopathological features of breast cancer and SLN metastasis, then to establish a model, and evaluate the diagnostic efficacy of the model.Results:Univariate analysis showed that SLN metastasis of breast cancer was associated with age, axillary palpation of enlarged lymph nodes, pathological type of mass, clear hilum of lymph nodes, cortical thickening of lymph nodes, marginal blood flow in lymph nodes, and the appearances of LCEUS(all P<0.05). Multivariate Logistic regression analysis showed age, palpation of axillary lymph nodes and the appearances of LCEUS were independent predictors of SLN properties, the OR values were 6.90 ( P=0.030), 16.06 ( P<0.001) and 12.71 ( P<0.001), respectively. The regression equation was Logit(P)=0.887+ 1.932× axillary lymph node palpation + 2.776× marginal blood flow + 2.542×LCEUS. Conclusions:LCEUS combined with marginal blood flow in lymph nodes and palpation of axillary lymph nodes can help to determine the SLN state.

Rapid Identification of Characteristic Chemical Constituents of Panax ginseng, Panax quinquefolius, and Panax japonicus Using UPLC-Q-TOF/MS.

Saponins are the main active components in Panax ginseng C. A. Mey. (PG), Panax quinquefolius L. (PQ), and Panax japonicus C. A. Mey. (PJ), which belong to the genus Panax in the Araliaceae family. Because the chemical components in the three species are similar, they are often mixed and misused in functional foods and pharmaceuticals applications. Therefore, it is urgent to establish a method to quickly distinguish among PG, PQ, and PJ. Ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was combined with data postprocessing to identify the main characteristic fragments (CFs) and the related neutral losses (NLs) of protopanaxadiol (PPD), protopanaxatriol (PPT), oleanolic acid (OLE), and ocotillol- (OCO-) type saponins. By comparing the mass spectral data, it was possible to rapidly classify and identify saponins in PG, PQ, and PJ. A total of twenty-three chemical components were identified in the PG samples, twenty-three components were identified in the PQ samples, and twenty-seven components were identified in the PJ samples. Among them, OCO-type saponins were characteristic of PQ and PJ. Ginsenoside Rf, which was absent from PQ, allowed for differentiation between PQ and PJ. The CFs and NLs in the mass spectra of the characteristic components of PG, PQ, and PJ allowed for the rapid classification and identification of these species. Additionally, these results provide technical support for the quality evaluation of Chinese herbal medicine and for constructing a scientific regulatory system.

Recent progress on dissolution and absorption of amorphous solid dispersions / 药学学报

The amorphous solid dispersion is one of the most effective formulation approaches to enhance the oral bioavailability of poorly water-soluble drugs. However, the amorphous drugs tend to crystallize during storage or dissolution due to inadequate formulations, preparation techniques, storage and dissolution conditions, thus negating their advantages. Meanwhile, it is often difficult to establish in vitro-in vivo correlation for amorphous solid dispersions owing to the difference between dissolution media and physiological environments and between the apparent concentration and membrane transport flux, the dynamic process of the in vivo absorption, which put great challenges to the development of amorphous solid dispersion products. This review covers the recent progress on the mechanistic study of the in vitro dissolution and in vivo absorption of amorphous solid dispersions, aiming to provide guidance for the formulation development of poorly soluble drugs.

Diagnostic efficacy of indirect haemagglutination assay for detection of Schistosoma japonicum infections among boatmen and fishermen in the Dongting Lake region / 中国血吸虫病防治杂志

OBJECTIVE@#To evaluate the diagnostic efficacy of indirect haemagglutination assay (IHA) for detection of Schistosoma japonicum infections among boatmen and fishermen in Dongting Lake region, so as to provide insights into improving the schistosomiasis surveillance program among boatmen and fishermen.@*METHODS@#The boatmen and fishermen were detected for S. japonicum infections using IHA and Kato-Katz technique or miracidium hatching test nylon gauze simultaneously at schistosomiasis testing sites in the anchor sites for boatmen and fishermen in the Dongting Lake region during the period from 2014 to 2016, and using IHA for serological screening followed by parasitological testing of seropositives during the period from 2017 to 2019. The sensitivity and specificity of IHA were evaluated for detection of S. japonicum infections among boatmen and fishermen, with the 2014-2016 parasitological testing results as a gold standard. In addition, the seroprevalence of S. japonicum infections was compared among boatmen and fishermen with different characteristics and among years.@*RESULTS@#A total of 306 schistosomiasis testing sites were assigned for boatmen and fishermen, and a total of 143 360 person-time boatmen and fishermen were tested for S. japonicum infections in the Dongting Lake region from 2014 to 2019. The sensitivity and specificity of IHA were 69.9%, 97.3% and 96.1% (χ2 = 74.6, P < 0.05), and 70.9%, 74.5% and 71.9% for detection of S. japonicum infections from 2014 to 2016 (χ2 = 29.4, P < 0.05), respectively. The seroprevalence of S. japonicum infections reduced from 30.3% in 2014 to 1.8% in 2019 among boatmen and fishermen, appearing an overall tendency towards a decline (Z = 1 552.4, P < 0.05). In addition, male, individuals at ages of 45 to 60 years, full-time boatmen and fishermen were more likely to be seropositive for S. japonicum infections (all P values < 0.05).@*CONCLUSIONS@#The seroprevalence of S. japonicum infections appeared a tendency towards a decline among boatmen and fishermen in the Dongting Lake region year by year from 2014 to 2019. IHA presented a high efficacy for screening of S. japonicum infections among boatmen and fishermen in the Dongting Lake region.

Highly selective monoclonal antibody-based lateral flow immunoassay for visual and sensitive determination of conazole fungicides propiconazole in vegetables.

The conazole fungicide propiconazole is frequently found in vegetables although usage is not allowed. To overcome the high-cost and time-consuming labour requirements of instrumental methods, we developed a simple and visual lateral flow immunoassay for the sensitive determination of propiconazole. A hapten was carefully designed to raise a monoclonal antibody against propiconazole. Bal b/c mice were immunised with the hapten-carrier protein conjugate and a specific monoclonal antibody (mAb) was produced. Based on this mAb, a sensitive immunochromatographic strip assay (ICA) was established for rapid screening of propiconazole in vegetable samples. After optimisation of analytical parameters, the ICA strip showed a detection limit of 0.13 ng g-1 and a linear range from 0.5 to 80 ng g-1 using a strip reader. The assay also can be read by the naked eye with a visual limit of detection of 80 ng g-1. The recoveries for spiked vegetable samples by ICA ranged from 85.2% to 114.9%, with a coefficient of variation less than 11.7%. The assay time is within 45 min for a single sample including the sample pre-treatment. For spiked and blind samples, the detection capability of ICA was equivalent to liquid chromatography-mass spectrometry.

Arginine Methylation Regulates SARS-CoV-2 Nucleocapsid Protein Function and Viral Replication

Viral proteins are known to be methylated by host protein arginine methyltransferases (PRMTs) playing critical roles during viral infections. Herein, we show that PRMT1 methylates SARS-CoV-2 nucleocapsid (N) protein at residues R95 and R177 within RGG/RG sequences. Arginine methylation of N protein was confirmed by immunoblotting viral proteins extracted from SARS-CoV-2 virions isolated by cell culture. We demonstrate that arginine methylation of N protein is required for its RNA binding capacity, since treatment with a type I PRMT inhibitor (MS023) or substitution of R95K or R177K inhibited interaction with the 5-UTR of the SARS-CoV-2 genomic RNA. We defined the N interactome in HEK293 cells with or without MS023 treatment and identified PRMT1 and many of its RGG/RG substrates including the known interactor, G3BP1, and other components of stress granules (SG). Methylation of N protein at R95 regulates another function namely its property to suppress the formation of SGs. MS023 treatment or R95K substitution blocked N-mediated suppression of SGs. Also, the co-expression of methylarginine reader TDRD3 quenched N-mediated suppression of SGs in a dose-dependent manner. Finally, pre-treatment of VeroE6 cells with MS023 significantly reduced SARS-CoV-2 replication. With type I PRMT inhibitors being in clinical trials for cancer treatment, inhibiting arginine methylation to target the later stages of the viral life cycle such as viral genome packaging and assembly of virions may be an additional therapeutic application of these drugs.

Immunohistochemical detection of GluA1 subunit of AMPA receptor in the rat nucleus accumbens following cocaine exposure

α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are differentially regulated in the nucleus accumbens (NAcc) of the brain after cocaine exposure. However, these results are supported only by biochemical and electrophysiological methods, but have not been validated with immunohistochemistry. To overcome the restriction of antigen loss on the postsynaptic target molecules that occurs during perfusion-fixation, we adopted an immersion-fixation method that enabled us to immunohistochemically quantify the expression levels of the AMPA receptor GluA1 subunit in the NAcc. Interestingly, compared to saline exposure, cocaine significantly increased the immunofluorescence intensity of GluA1 in two sub-regions, the core and the shell, of the NAcc on withdrawal day 21 following cocaine exposure, which led to locomotor sensitization. Increases in GluA1 intensity were observed in both the extra-post synaptic density (PSD) and PSD areas in the two sub-regions of the NAcc. These results clearly indicate that AMPA receptor plasticity, as exemplified by GluA1, in the NAcc can be visually detected by immunohistochemistry and confocal imaging. These results expand our understanding of the molecular changes occurring in neuronal synapses by adding a new form of analysis to conventional biochemical and electrophysiological methods.

Potentiating CD8

Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

Pharmaceutical cocrystals are multicomponent systems in which at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients. Cocrystallization of a drug substance with a coformer is a promising and emerging approach to improve the performance of pharmaceuticals, such as solubility, dissolution profile, pharmacokinetics and stability. This review article presents a comprehensive overview of pharmaceutical cocrystals, including preparation methods, physicochemical properties, and applications. Furthermore, some examples of drug cocrystals are highlighted to illustrate the effect of crystal structures on the various aspects of active pharmaceutical ingredients, such as physical stability, chemical stability, mechanical properties, optical properties, bioavailability, sustained release and therapeutic effect. This review will provide guidance for more efficient design and manufacture of pharmaceutical cocrystals with desired physicochemical properties and applications.

Immunohistochemical detection of GluA1 subunit of AMPA receptor in the rat nucleus accumbens following cocaine exposure

α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are differentially regulated in the nucleus accumbens (NAcc) of the brain after cocaine exposure. However, these results are supported only by biochemical and electrophysiological methods, but have not been validated with immunohistochemistry. To overcome the restriction of antigen loss on the postsynaptic target molecules that occurs during perfusion-fixation, we adopted an immersion-fixation method that enabled us to immunohistochemically quantify the expression levels of the AMPA receptor GluA1 subunit in the NAcc. Interestingly, compared to saline exposure, cocaine significantly increased the immunofluorescence intensity of GluA1 in two sub-regions, the core and the shell, of the NAcc on withdrawal day 21 following cocaine exposure, which led to locomotor sensitization. Increases in GluA1 intensity were observed in both the extra-post synaptic density (PSD) and PSD areas in the two sub-regions of the NAcc. These results clearly indicate that AMPA receptor plasticity, as exemplified by GluA1, in the NAcc can be visually detected by immunohistochemistry and confocal imaging. These results expand our understanding of the molecular changes occurring in neuronal synapses by adding a new form of analysis to conventional biochemical and electrophysiological methods.

Broad-Spectrum Activity of Volatile Organic Compounds from Three Yeast-like Fungi of the Galactomyces Genus Against Diverse Plant Pathogens

The application of antagonistic fungi for plant protection has attracted considerable interest because they may potentially replace the use of chemical pesticides. Antipathogenic activities confirmed in volatile organic compounds (VOCs) from microorganisms have potential to serve as biocontrol agents against pre- and post-harvest diseases. In the present study, we investigated Galactomyces fungi isolated from rotten leaves and the rhizosphere of cherry tomato (Lycopersicon esculentum var. cerasiforme). VOCs produced by Galactomyces fungi negatively affected the growth of phytopathogenic fungi and the survival of nematodes. Mycelial growths of all nine examined phytopathogenic fungi were inhibited on agar plate, although the inhibition was more intense in Athelia rolfsii JYC2163 and Cladosporium cladosporioides JYC2144 and relatively moderate in Fusarium sp. JYC2145. VOCs also efficiently suppressed the spore germination and mycelial growth of A. rolfsii JYC2163 on tomatoes. The soil nematode Caenorhabditis elegans exhibited higher mortality in 24 h in the presence of VOCs. These results suggest the broad-spectrum activity of Galactomyces fungi against various plant pathogens and the potential to use VOCs from Galactomyces as biocontrol agents.

Effects of environmental factors on severity and mortality of COVID-19

BackgroundMost respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented. MethodsWe examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. FindingsMeta-analysis of the mortality risk in eight European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, p<0.001) and per increase in ambient temperature of one degree Celsius to be 0.854 (0.773-0.944, p=0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to Intensive Care Unit and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. InterpretationSeverity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation. Mucosal barrier and mucociliary clearance can significantly decrease viral load and disease progression, and their inactivation by low relative humidity of indoor air might significantly contribute to severity of the disease.

Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China.

The study aimed to investigate whether specific medications used in the treatment chronic diseases affected either the development and/ or severity of COVID-19 in a cohort of 610 COVID-19 cases and 48,667 population-based controls from Zheijang, China. Using a cohort of 578 COVID-19 cases and 48,667 population-based controls from Zheijang, China we tested the role of usage of cardiovascular, antidiabetic and other medications on risk and severity of COVID 19. Analyses were adjusted for age, sex and BMI and for presence of relevant comorbidities. Individuals with hypertension taking calcium channel blockers had significantly increased risk [odds ratio (OR)= 1.73 (95% CI 1.2-2.3)] of manifesting symptoms of COVID-19 whereas those taking angiotensin receptor blockers and diuretics had significantly lower disease risk (OR=0.22; 95%CI 0.15-0.30 and OR=0.30; 95%CI 0.19-0.58 respectively). Among those with type 2 diabetes, dipeptidyl peptidase-4 inhibitors (OR= 6.02; 95% CI 2.3-15.5) and insulin (OR= 2.71; 95% CI 1.6-5.5) were more and glucosidase inhibitors were less prevalent (OR= 0.11; 95% CI 0.1-0.3) among with COVID-19 patients. Drugs used in the treatment of hypertension and diabetes influence the risk of development of COVID-19, but, not its severity. Study highlightsO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSCardiovascular disease and Diabetes have been highlighted as comorbidities contributing to a more severe form of COVID-19 and medication to treat them may also influence the risk of COVID-19 and its clinical outcomes. What question did this study address?Does specific medications used in the treatment of chronic diseases influence the risk for the susceptibility to SARS CoV-2 infection of severity of COVID-19? What does this study add to our knowledge?The study confirms that higher BMI, diabetes and cardio/ cerebrovascular disease as independent risk factors for the development of COVID-19. Angtiotensin Receptor Blockers (ARBs) and diuretics were associated with reduced risk and Calcium Channel Blockers (CCBs) with increased risk of developing COVID-19. Among those with type 2 diabetes, dipeptidyl peptidase-4 and were associated with increased and glucosidase inhibitors with reduced risk development of COVID-19. None of the antihypertensive or anti-diabetic drugs were associated with increased risk of severe or critical form of the infection. Drugs used in the treatment of hypertension and diabetes influence the risk of development of COVID-19, but are not associated with severity of the disease. How might this change clinical pharmacology or translational science?Findings from the current large case-control study confirmed no evidence to alter ARBs or ACEIs therapy in the context of COVID-19 severity in clinical practice. Hypertension significantly increases the risk of severe or critical SARS-CoV-2 infection indicating that carefully controlled blood pressure should be a priority to reduce the healthcare burden of COVID-19.

Effect of gga-miR-155 on cell proliferation, apoptosis and invasion of Marek's disease virus (MDV) transformed cell line MSB1 by targeting RORA.

BACKGROUND: Marek's disease (MD) is caused by the oncogenic Marek's disease virus (MDV), and is a highly contagious avian infection with a complex underlying pathology that involves lymphoproliferative neoplasm formation. MicroRNAs (miRNAs) act as oncogenes or tumor suppressors in most cancers. The gga-miR-155 is downregulated in the MDV-infected chicken tissues or lymphocyte lines, although its exact role in tumorigenesis remains unclear. The aim of this study was to analyze the effects of gga-miR-155 on the proliferation, apoptosis and invasiveness of an MDV-transformed lymphocyte line MSB1 and elucidate the underlying mechanisms. RESULTS: The expression level of gga-miR-155 was manipulated in MSB1 cells using specific mimics and inhibitors. While overexpression of gga-miR-155 increased proliferation, decreased the proportion of G1 phase cells relative to that in S and G2 phases, reduced apoptosis rates and increased invasiveness. However, its downregulation had the opposite effects. Furthermore, gga-miR-155 directly targeted the RORA gene and downregulated its expression in the MSB1 cells. CONCLUSION: The gga-miR-155 promotes the proliferation and invasiveness of the MDV-transformed lymphocyte line MSB1 and inhibits apoptosis by targeting the RORA gene.

Identification and characterization of a Streptococcus suis immunogenic ornithine carbamoytransferase involved in bacterial adherence.

BACKGROUND: Streptococcus suis (SS) is a major swine pathogen and a serious zoonotic pathogen causing septicemia and meningitis in piglets and humans. Using an immunoproteomic approach, we previously brought evidence that ornithine carbamoytransferase (OCT) may represent a vaccine candidate to protect against S. suis biofilm-related and acute infections. METHOD: In this study, the gene encoding OCT was cloned into the expression vector pET-28a and the recombinant protein was expressed in Escherichia coli BL21. The immunogenicity and protective efficacy of the SS OCT was further investigated in a mouse model. RESULTS: The protein was found to be expressed in vivo and elicited high antibody titers following SS infections in mice. An animal challenge experiment with SS showed that 62.5% of mice immunized with the OCT protein were protected. Using an in vitro competitive adherence inhibition assay of adherence, evidence was obtained that OCT could significantly reduce the number of SS cells adhered to porcine kidney PK-15 cells. The bacterial levels recovered in mice of the OCT immunized group were significantly decreased in some organs, compared with the control group. CONCLUSION: In summary, our results suggest that the recombinant SS OCT protein, which is involved in bacterial adherence, may efficiently stimulate an immune response conferring protection against SS infections. It may therefore be considered as a potential vaccine candidate, although further studies are necessary to evaluate their use in swine.