Tsutsugamushi fever in the Kuril Islands]

The authors present the results of a 6-year study of tsutsugamushi fever at the Kuril islands. The area of the disease proved to include Southern Kuril islands - Shikotan and Kunashir. The principal natural carriers of tsutsugamushi among the mouse-like rodents and trombiculidae larvae were revealed; highly virulent strains were found to prevail among the tsutsugamushi rickettsia strains. Tsutsugamushi fever in the population is characterized by a benign course, pyrexia, primary affects and lymphadenitis.     

Precursors and propeptides of neurotrophic factors as modulators of the biological activity of mature forms

Problems of the maturation of neurotrophic factors, the role of their precursors (proneurotrophins), and the contribution of elements that are removed in the course of maturation (propeptides) to the biological functions of these growth factors, are reviewed.     

Natural focal infections in the north of the Far East. I. The detection of natural foci of infections in Chukot]

Results of a 3-year complex (zoo-parasitological, viral, bacteriological, and serological) studies of mammals and birds in Chukotka demonstrated the presence of natural foci of pseudo-tuberculosis, intestinal yersinosis, salmonellosis (heidelberg), and of tick-borne encephalitis. The existence of natural foci of tularemia and endemic rickettsioses is supposed on the basis of serological data.     

Rif1 regulates telomere length through conserved HEAT repeats

In budding yeast, Rif1 negatively regulates telomere length, but the mechanism of this regulation has remained elusive. Previous work identified several functional domains of Rif1, but none of these has been shown to mediate telomere length. To define Rif1 domains responsible for telomere regulation, we localized truncations of Rif1 to a single specific telomere and measured telomere length of that telomere compared to bulk telomeres. We found that a domain in the N-terminus containing HEAT repeats, Rif1_177–996, was sufficient for length regulation when tethered to the telomere. Charged residues in this region were previously proposed to mediate DNA binding. We found that mutation of these residues disrupted telomere length regulation even when Rif1 was tethered to the telomere. Mutation of other conserved residues in this region, which were not predicted to interact with DNA, also disrupted telomere length maintenance, while mutation of conserved residues distal to this region did not. Our data suggest that conserved amino acids in the region from 436 to 577 play a functional role in telomere length regulation, which is separate from their proposed DNA binding function. We propose that the Rif1 HEAT repeats region represents a protein-protein binding interface that mediates telomere length regulation.     

Cytotoxic effect of co-expression of human hepatitis A virus 3C protease and bifunctional suicide protein FCU1 genes in a bicistronic vector

Recent reports on various cancer models demonstrate a great potential of cytosine deaminase/5-fluorocytosine suicide system in cancer therapy. However, this approach has limited success and its application to patients has not reached the desirable clinical significance. Accordingly, the improvement of this suicide system is an actively developing trend in gene therapy. The purpose of this study was to explore the cytotoxic effect observed after co-expression of hepatitis A virus 3C protease (3C) and yeast cytosine deaminase/uracil phosphoribosyltransferase fusion protein (FCU1) in a bicistronic vector. A set of mono- and bicistronic plasmid constructs was generated to provide individual or combined expression of 3C and FCU1. The constructs were introduced into HEK293 and HeLa cells, and target protein synthesis as well as the effect of 5-fluorocytosine on cell death and the time course of the cytotoxic effect was studied. The obtained vectors provide for the synthesis of target proteins in human cells. The expression of the genes in a bicistronic construct provide for the cytotoxic effect comparable to that observed after the expression of genes in monocistronic constructs. At the same time, co-expression of FCU1 and 3C recapitulated their cytotoxic effects. The combined effect of the killer and suicide genes was studied for the first time on human cells in vitro. The integration of different gene therapy systems inducing cell death (FCU1 and 3C genes) in a bicistronic construct allowed us to demonstrate that it does not interfere with the cytotoxic effect of each of them. A combination of cytotoxic genes in multicistronic vectors can be used to develop pluripotent gene therapy agents.     

Clinical characteristics and analysis of risk factors for disease progression of COVID-19: A retrospective Cohort Study

Objective: Since December 2019, an outbreak of coronavirus disease 2019 (COVID 19) has been experienced from Wuhan, China to the world. A retrospective cohort study was conducted to summarize the clinical characteristics of patients with COVID-19 and to explore the risk factors affecting the disease duration in Jiangan Fangcang shelter hospital, Wuhan, China.Methods: Clinical characteristics of 409 patients with COVID-19 were retrospectively analyzed. We describe the clinical characteristics and distribution of discharge time or transfer time for each patient. Then we performed univariate and multivariate Cox regression analysis to identify potential risk factors for progression from non-severe to severe COVID-19 or death.Results: The median disease duration of all patients was 23 days (IQR 19-28). The main symptoms of the patient were fever (95.6%), cough (74.3%), tiredness (21.5%), and so on. Comorbidities mainly included hypertension (30.6%) diabetes (17.6%) and heart disease (12.5%). The univariate Cox regression analysis showed that old age, number of symptoms, the combination of hypertension, heart disease and pulmonary disease were associated with the progression of disease. The multivariate Cox regression analysis showed that old age (HR: 7.294; 95% CI: 1.442-36.888; P = 0.016), the combination of hypertension (HR: 2.230; 95% CI: 1.090-4.562; P = 0.028) and heart disease (HR: 2.650; 95% CI: 1.079-6.510; P = 0.034) were independent risk factors for progression of COVID-19.Conclusions: The age of the patient, the combination of hypertension and heart disease were independent risk factors for the progression of COVID-19. Cautions should be raised for patients with these risk factors.     

Effect of monovalent and bivalent cations and anions on the properties of ATPase from rabbit small intestine mucosa

The effects of monovalent cations and anions on the ATPase activity of rabbit small intestine mucosa membranes was studied. It was shown that the small intestine mucosa contains the ATPase activity sensitive to NaCl and NaHCO3. This activity, in contrast to the HCO3--ATPase activity, is inhibited by ethacrinic acid, is practically insensitive to thyocyanate, has a pH optimum of 6.2, is unstable upon storage and is not inhibited by 2 mM EDTA. The catalytic and regulatory properties of HCO3--ATPase and NaCl/NaHCO3-stimulated ATPase were compared; their possible involvement in secretion in small intestine epithelium is discussed.     

Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease

In the last decade, treatment for castration-resistant prostate cancer has changed markedly, impacting symptom control and longevity for patients. However, a large proportion of cases progress despite androgen deprivation therapy and chemotherapy, while still being fit enough for several more lines of treatment. Overstimulation of the androgen receptor (AR) activity is the main driver of this cancer. Targeting biological functions of the AR or its co-regulators has proven very effective in this disease and led to the development of several highly effective drugs targeting the AR signalling axis. Drugs such as enzalutamide demonstrated that the improvement in anti-tumour efficacy is closely correlated with an affinity for the AR and its activity and have established the paradigm that AR remains activity in aggressive disease. However, as importantly, key insights into mechanisms of resistance are guiding the development of the next generation of AR-targeted drugs. This review outlines the historical development of these highly specific agents, their mechanism of action in the context of defective AR activity, and explores the potential for the upcoming next-generation AR inhibitors (ARI) for prostate cancer by targeting the alternative domains of AR, rather than by the conventional ligand-binding domain approach. There is huge potential in these approaches to develop new drugs with high clinical activity and further improve the outlook for patients.