[Abstract unavailable

Interferons (IFNs) are widely used in treating coronavirus disease 2019 (COVID-19) patients. However, a recent report of ACE2, the host factor mediating SARS-Cov-2 infection, identifying it as interferon-stimulated raised considerable safety concern. To examine the association between the use and timing of IFN-α2b and clinical outcomes, we analyzed in a retrospective multicenter cohort study of 446 COVID-19 patients in Hubei, China. Regression models estimated that early administration (≤5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. Among survivors, early IFN-α2b was not associated with hospital discharge or computed tomography (CT) scan improvement, whereas late IFN-α2b was associated with delayed recovery. Additionally, early IFN-α2b and umifenovir alone or together were associated with reduced mortality and accelerated recovery in comparison with treatment with lopinavir/ritonavir (LPV/r) alone. We concluded that administration of IFN-α2b during the early stage of COVID-19 could induce favorable clinical responses.

Recent reports have suggested that the gut microbiota is involved in the progression of colorectal cancer (CRC). The composition of gut microbiota in CRC precursors has not been adequately described. To characterize the structure of adherent microbiota in this disease, we conducted pyrosequencing-based analysis of 16S rRNA genes to determine the bacterial profile of normal colons (healthy controls) and colorectal adenomas (CRC precursors). Adenoma mucosal biopsy samples and adjacent normal colonic mucosa from 31 patients with adenomas and 20 healthy volunteers were profiled using the Illumina MiSeq platform. Principal coordinate analysis (PCoA) showed structural segregation between colorectal adenomatous tissue and control tissue. Alpha diversity estimations revealed higher microbiota diversity in samples from patients with adenomas. Taxonomic analysis illustrated that abundance of eight phyla (Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Chloroflexi, Cyanobacteria, Candidate-division TM7, and Tenericutes) was significantly different. In addition, Lactococcus and Pseudomonas were enriched in preneoplastic tissue, whereas Enterococcus, Bacillus, and Solibacillus were reduced. However, both PCoA and cluster tree analyses showed similar microbiota structure between adenomatous and adjacent non-adenoma tissues. These present findings provide preliminary experimental evidence supporting that colorectal preneoplastic lesion may be the most important factor leading to alterations in bacterial community composition.

Background: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, isolated from the traditional Chinese herb Artemisia annua, is recommended as the first-line anti-malarial drug with low toxicity. DHA has been shown to possess promising anticancer activities and induce cancer cell death through apoptotic pathways, although the molecular mechanisms are not well understood.

Situation Report-51 SITUATION IN NUMBERS total and new cases in last 24 hours Globally 118 319 confirmed (4620 new) 4292 deaths (280 new) China 80 955 confirmed (31 new) 3162 deaths (22 new) Outside of China 37 364 confirmed (4589 new) 1130 deaths (258 new) 113 countries/territories/ areas (4 new) WHO RISK ASSESSMENT China Very High Regional Level Very High Global Level Very High HIGHLIGHTS • WHO Director-General in his regular media briefing today stated that WHO has been assessing this outbreak around the clock and we are deeply concerned both by the alarming levels of spread and severity, and by the alarming levels of inaction. WHO therefore have made the assessment that COVID-19 can be characterized as a pandemic. For detailed information, please see here. • Four new countries/territories/areas (Bolivia [Plurinational State of], Jamaica, Burkina Faso and Democratic Republic of the Congo) have reported cases of COVID-19 in the past 24 hours. • The COVID-19 virus infects people of all ages. However, evidence to date suggests that two groups of people are at a higher risk of getting severe COVID-19 disease. These are older people; and those with underlying medical conditions. WHO emphasizes that all must protect themselves from COVID-19 in order to protect others. For more information, please see 'subject in focus'. • On 10 March, the IFRC, UNICEF and WHO issued a new guidance to help protect children and schools from transmission of the COVID-19 virus. The guidance provides critical considerations and practical checklists to keep schools safe. More information can be found here. Figure 1. Countries, territories or areas with reported confirmed cases of COVID-19, 11 March 2020 Erratum: 'Total cases' and 'new cases' for Bulgaria and Paraguay have been corrected. SUBJECT IN FOCUS: Risk Communication guidance-COVID-19, older adults and people with underlying medical conditions The virus that causes COVID-19 infects people of all ages. However, evidence to date suggests that two groups of people are at a higher risk of getting severe COVID-19 disease. These are older people (that is people over 60 years old); and those with underlying medical conditions (such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer). The risk of severe disease gradually increases with age starting from around 40 years. It's important that adults in this age range protect themselves and in turn protect others that may be more vulnerable. WHO has issued advice for these two groups and for community support to ensure that they are protected from COVID-19 without being isolated, stigmatized, left in a position of increased vulnerability or unable to access basic provisions and social care. This advice covers the subject of receiving visitors, planning for supplies of medication and food, going out safely in public and staying connected with others through phone calls or other means. It is essential that these groups are supported by their communities during the COVID-19 outbreak. WHO emphasizes that all people must p...

-l-phenylalanine 2-naphthylamide; LAMP1, lysosomal-associated membrane protein 1; Leup, leupeptin; MAP1LC3, microtubule-associated protein 1 light chain 3;MTOR, mechanistic target of rapamycin; RFP, red fluorescent protein; tfLC3, tandem fluorescence-tagged LC3.Autophagy is a catabolic lysosomal degradation process essential for cellular homeostasis and cell survival. Dysfunctional autophagy has been associated with a wide range of human diseases, e.g., cancer and neurodegenerative diseases. A large number of small molecules that modulate autophagy have been widely used to dissect this process and some of them, e.g., chloroquine (CQ), might be ultimately applied to treat a variety of autophagy-associated human diseases. Here we found that vacuolin-1 potently and reversibly inhibited the fusion between autophagosomes and lysosomes in mammalian cells, thereby inducing the accumulation of autophagosomes. Interestingly, vacuolin-1 was less toxic but at least 10-fold more potent in inhibiting autophagy compared with CQ. Vacuolin-1 treatment also blocked the fusion between endosomes and lysosomes, resulting in a defect in general endosomal-lysosomal degradation. Treatment of cells with vacuolin-1 alkalinized lysosomal pH and decreased lysosomal Ca 2C content. Besides marginally inhibiting vacuolar ATPase activity, vacuolin-1 treatment markedly activated RAB5A GTPase activity. Expression of a dominant negative mutant of RAB5A or RAB5A knockdown significantly inhibited vacuolin-1-induced autophagosome-lysosome fusion blockage, whereas expression of a constitutive active form of RAB5A suppressed autophagosome-lysosome fusion. These data suggest that vacuolin-1 activates RAB5A to block autophagosome-lysosome fusion. Vacuolin-1 and its analogs present a novel class of drug that can potently and reversibly modulate autophagy. IntroductionAmong 3 types of autophagy, including microautophagy, chaperone-mediated autophagy, and macroautophagy, in mammals, macroautophagy (hereafter referred as autophagy) is the most common type. Autophagy is an evolutionarily conserved catabolic degradation cellular process in which misfolded proteins or damaged organelles are first sequestered by a doublemembrane vesicle, called an autophagosome. Autophagosomes then fuse with lysosomes to form autolysosomes, inside which the sequestered contents are digested by lysosomal enzymes and recycled to maintain cellular homeostasis. Autophagy can also be markedly induced by a wide variety of stresses, e.g., nutrient starvation, infection, and aging, for cell survival. Dysfunctional autophagy has been associated with wide ranges of human diseases, e.g., cancer and neurodegenerative diseases. [1][2][3][4][5][6] Basal autophagy activity is essential for cell homeostasis, and it is tightly controlled by a complicated interplay among several key machineries, including ULK1 or ULK2 complexes and the class III phosphatidylinositol-3 kinase complexes. The MTOR (mechanistic target of rapamycin) Ser/Thr kinase suppresses autophagy by inhibiting the ULK1/2 comple...

Hypertriglyceridemia (HTG) aggravates the course of acute pancreatitis (AP). Intestinal barrier dysfunction is implicated in the pathogenesis of AP during which dysbiosis of intestinal microbiota contributes to the dysfunction in intestinal barrier. However, few studies focus on the changes in intestine during HTG-related acute necrotizing pancreatitis (ANP). Here, we investigated the changes in intestinal microbiota and Paneth cell antimicrobial peptides (AMPs) in HTG-related ANP (HANP) in rats. Rats fed a high-fat diet to induce HTG and ANP was induced by retrograde injection of 3.5% sodium taurocholate into biliopancreatic duct. Rats were sacrificed at 24 and 48 h, respectively. Pancreatic and ileal injuries were evaluated by histological scores. Intestinal barrier function was assessed by plasma diamine oxidase activity and D-lactate level. Systemic and intestinal inflammation was evaluated by tumor necrosis factor alpha (TNFα), interleukin (IL)-1β, and IL-17A expression. 16S rRNA high throughput sequencing was used to investigate changes in intestinal microbiota diversity and structure. AMPs (α-defensin5 and lysozyme) expression was measured by real-time polymerase chain reaction (PCR) and immunofluorescence. The results showed that compared with those of normal-lipid ANP (NANP) groups, the HANP groups had more severe histopathological injuries in pancreas and distal ileum, aggravated intestinal barrier dysfunction and increased TNFα, IL-1β, and IL-17A expression in plasma and distal ileum. Principal component analysis showed structural segregation between the HANP and NANP group. α-Diversity estimators in the HANP group revealed decreased microbiota diversity compared with that in NANP group. Taxonomic analysis showed dysbiosis of intestinal microbiota structure. In the HANP group, at phyla level, Candidatus_Saccharibacteria and Tenericutes decreased significantly, whereas Actinobacteria increased. At genus level, Allobaculum, Bifidobacterium, and Parasutterella increased significantly, while Alloprevotella, Anaerotruncus, Candidatus_Saccharimonas, Christensenellaceae_R-7_group, Rikenellaceae_RC9_gut_group, Ruminiclostridium_5, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-014 decreased. Compared with those in the NANP rats, mRNA expression of lysozyme and α-defensin5 and protein expression of lysozyme decreased significantly in the HANP rats. Moreover, in the NANP rats and the HANP rats, Allobaculum abundance was inversely correlated with lysozyme expression, while Anaerotruncus abundance was positively correlated with it by Spearman test. In conclusion, intestinal microbiota dysbiosis and decreased AMPs of Paneth cells might participate in the pathogenesis of intestinal barrier dysfunction in HANP.

Background: The role and mechanism of NAADP, an endogenous Ca2+ mobilizing nucleotide, in autophagic regulation remain to be determined.Results: Activation of NAADP/TPC2 signaling induced the accumulation of autophagosomes.Conclusion: The NAADP/TPC2 signaling inhibits autophagosomal-lysosomal fusion by alkalinizing lysosomal pH.Significance: Development of agonists or antagonists of NAADP should provide a novel approach to specifically manipulate autophagy.