Beneficial effect of taurine depletion on osmotic sodium and calcium loading during chemical hypoxia

Cellular sodium excess is cytotoxicbecause it increases both the intracellular osmotic load andintracellular calcium concentration ([Ca²⁺]_i). Because sodium levels rise duringhypoxia, it is thought to contribute to hypoxic injury. Thus thepresent study tested the hypothesis that taurine-linked reductions in[Na⁺]_i reduce hypoxia-induced cell injury.Taurine depletion was achieved by exposing isolated neonatalcardiomyocytes to medium containing the taurine analog -Alanine. Aspredicted, the -Alanine-treated cell exhibited less hypoxia-inducednecrosis and apoptosis than the control, as evidenced by lessswelling, shrinkage, TdT-mediated dUTP nick end labeling staining, andaccumulation of trypan blue. After 1 h of chemical hypoxia,[Na⁺]_i was 3.5-fold greater in the controlthan the taurine-deficient cell. Although more taurine was lost fromthe control cell than from the -Alanine-treated cell during hypoxia,the combined taurine and sodium osmotic load was lower in the-Alanine-treated cell. Taurine deficiency also reduced the degree ofhypoxia-induced calcium overload. Thus the observed resistance againsthypoxia-induced necrosis and apoptosis is probably related toan improvement in sodium and calcium handling.

     

Dynamics of chromatin position within the interphase nucleus

In this article we attempt to analyze the relationship between the processes, which occur in the nucleus, and the dynamics of chromatin, as well as to classify the changes in the position of chromatin in the cell nucleus during the lifetime of the cell. The proposed concept integrates possible types of chromatin movement within the nucleus.     

Signaling mechanisms and physiological functions of G‐protein Gα13 in blood vessel formation,bone homeostasis,and cancer

Heterotrimeric G‐proteins are cellular signal transducers. They mainly relay signals from G‐protein‐coupled receptors (GPCRs). GPCRs function as guanine nucleotide‐exchange factors to active these G‐proteins. Based on the sequence and functional similarities, these G‐proteins are grouped into four subfamilies: G_s, G_i, G_q, and G_12/13. The G_12/13 subfamily consists of two members: G₁₂ and G₁₃. G_12/13‐mediated signaling pathways play pivotal roles in a variety of physiological processes, while aberrant regulation of this pathway has been identified in various human diseases. Here we summarize the signaling mechanisms and physiological functions of Gα₁₃ in blood vessel formation and bone homeostasis. We further discuss the expanding roles of Gα₁₃ in cancers, serving as oncogenes as well as tumor suppressors.     

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

A series of camphecene and quinolizidine alkaloid (?)‐cytisine conjugates has been obtained for the first time using ‘click’ chemistry methodology. The cytotoxicity and virus‐inhibiting activity of compounds were determined against MDCK cells and influenza virus A/Puerto Rico/8/34 (H1N1), correspondingly, in in vitro tests. Based on the results obtained, values of 50 % cytotoxic dose (CC₅₀), 50 % inhibition dose (IC₅₀) and selectivity index (SI) were determined for each compound. It has been shown that the antiviral activity is affected by the length and nature of linkers between cytisine and camphor units. Conjugate 13 ((1R,5S)‐3‐(6‐{4‐[(2‐{(E)‐[(1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐ylidene]amino}ethoxy)methyl]‐1H‐1,2,3‐triazol‐1‐yl}hexyl)‐1,2,3,4,5,6‐hexahydro‐8H‐1,5‐methanopyrido[1,2‐a][1,5]diazocin‐8‐one), which contains cytisine fragment separated from triazole ring by –C₆H₁₂– aliphatic linker, showed the highest activity at relatively low toxicity (CC₅₀=168 μmol, IC₅₀=8 μmol, SI=20). Its selectivity index appeared higher than that of reference compound, rimantadine. According to theoretical calculations, the antiviral activity of the lead compound 13 can be explained by its influence on the functioning of neuraminidase.     

A Novel Reading Scheme for Assessing the Extent of Radiographic Abnormalities and Its Association with Disease Severity in Sputum Smear-Positive Tuberculosis: An Observational Study in Hyderabad/India

Background

Existing reading schemes for chest X-ray (CXR) used to grade the extent of disease severity at diagnosis in patients with pulmonary tuberculosis (PTB) are often based on numerical scores that summate specific radiographic features. However, since PTB is known to exhibit a wide heterogeneity in pathology, certain features might be differentially associated with clinical parameters of disease severity.

Objective

We aimed to grade disease severity in PTB patients at diagnosis and after completion of DOTS treatment by developing a reading scheme based on five different radiographic manifestations and analyze their association with the clinical parameters of systemic involvement and infectivity.

Methods

141 HIV-negative adults with newly diagnosed sputum smear-positive PTB were enrolled in a prospective observational study in Hyderabad, India. The presence and extent on CXRs of five radiographic manifestations, i.e., lung involvement, alveolar infiltration, cavitation, lymphadenopathy and pleural effusion, were classified using the new reading scheme by using a four-quadrant approach. We evaluated the inter-reader reliability of each manifestation, and its association with BMI and sputum smear positivity at diagnosis. The presence and extent of these radiographic manifestations were further compared with CXRs on completion of DOTS treatment.

Results

At diagnosis, an average lung area of 51.7% +/- 23.3% was affected by radiographic abnormalities. 94% of the patients had alveolar infiltrates, with 89.4% located in the upper quadrants, suggesting post primary PTB and in 34.8% of patients cavities were found. We further showed that the extent of affected lung area was a negative predictor of BMI (β value -0.035, p 0.019). No significant association of BMI with any of the other CXR features was found. The extent of alveolar infiltrates, along with the presence of cavitation, were strongly associated with sputum smear positivity. The microbiological cure rate in our cohort after 6 months of DOTS treatment was 95%. The extent of the affected lung area in these patients decreased from 56.0% +/- 21.5% to 31.0 +/- 20% and a decrease was also observed in the extent of alveolar infiltrates from 98.4% to 25.8% in at least one quadrant, presence of cavities from 34.8% to 1.6%, lymphadenopathy from 46.8% to 16.1%, and pleural effusion from 19.4% to 6.5%.

Conclusions

We established a new assessment scheme for grading disease severity in PTB by specifically considering five radiographic manifestations which were differently associated with the BMI and sputum smear positivity, changed to a different extent after 6 months of treatment and exhibited an excellent agreement between radiologists. Our results suggest that this reading scheme might contribute to the estimation of disease severity with respect to differences in disease pathology. Further studies are needed to determine a correlation with short and long-term pulmonary function impairment and whether there would be any benefit in lengthening or modulating therapy based on this CXR severity assessment.     

Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer’s disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, we show that Rab35 negatively regulates Aβ production by sorting amyloid precursor protein (APP) and β-secretase (BACE1) out of the endosomal network, where they interact to produce Aβ. Interestingly, Rab35 coordinates distinct intracellular trafficking steps for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we demonstrate that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress-related and AD-related amyloidogenesis.Subject terms: Cellular neuroscience, Alzheimer''s disease     

Drug Repositioning through Systematic Mining of Gene Coexpression Networks in Cancer

Gene coexpression network analysis is a powerful “data-driven” approach essential for understanding cancer biology and mechanisms of tumor development. Yet, despite the completion of thousands of studies on cancer gene expression, there have been few attempts to normalize and integrate co-expression data from scattered sources in a concise “meta-analysis” framework. We generated such a resource by exploring gene coexpression networks in 82 microarray datasets from 9 major human cancer types. The analysis was conducted using an elaborate weighted gene coexpression network (WGCNA) methodology and identified over 3,000 robust gene coexpression modules. The modules covered a range of known tumor features, such as proliferation, extracellular matrix remodeling, hypoxia, inflammation, angiogenesis, tumor differentiation programs, specific signaling pathways, genomic alterations, and biomarkers of individual tumor subtypes. To prioritize genes with respect to those tumor features, we ranked genes within each module by connectivity, leading to identification of module-specific functionally prominent hub genes. To showcase the utility of this network information, we positioned known cancer drug targets within the coexpression networks and predicted that Anakinra, an anti-rheumatoid therapeutic agent, may be promising for development in colorectal cancer. We offer a comprehensive, normalized and well documented collection of >3000 gene coexpression modules in a variety of cancers as a rich data resource to facilitate further progress in cancer research.