Potential molecular mechanism for c-Src kinase-mediated regulation of intestinal cell migration

The ubiquitously expressed Src tyrosine kinases (c-Src, c-Yes, and c-Fyn) regulate intestinal cell growth and differentiation. Src activity is also elevated in the majority of malignant and premalignant tumors of the colon. The development of fibroblasts with the three ubiquitously expressed kinases deleted (SYF cells) has identified the role of Src proteins in the regulation of actin dynamics associated with increased cell migration and invasion. Despite this, unexpectedly nothing is known about the role of the individual Src kinases on intestinal cell cytoskeleton and/or cell migration. We have previously reported that villin, an epithelial cell-specific actin-modifying protein that regulates actin reorganization, cell morphology, cell migration, cell invasion, and apoptosis, is tyrosine-phosphorylated. In this report using the SYF cells reconstituted individually with c-Src, c-Yes, c-Fyn, and wild type or phosphorylation site mutants of villin, we demonstrate for the first time the absolute requirement for c-Src in villin-induced regulation of cell migration. The other major finding of our study is that contrary to previous reports, the nonreceptor tyrosine kinase, Jak3 (Janus kinase 3), does not regulate phosphorylation of villin or villin-induced cell migration and is, in fact, not expressed in intestinal epithelial cells. Further, we identify SHP-2 and PTP-PEST (protein-tyrosine phosphatase proline-, glutamate-, serine-, and threonine-rich sequence) as negative regulators of c-Src kinase and demonstrate a new function for these phosphatases in intestinal cell migration. Together, these data suggest that in colorectal carcinogenesis, elevation of c-Src or down-regulation of SHP-2 and/or PTP-PEST may promote cancer metastases and invasion by regulating villin-induced cell migration and cell invasion.     

Predicted metal binding sites for phytoremediation

Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP''s). Earlier work on MAP''s have shown that heavy metals accumulated by aromatic and medicinal plants do not appear in the essential oil and that some of these species are able to grow in metal contaminated sites. A pattern search against the UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high specificity of the motifs designed for the ions of nickel, lead, molybdenum, manganese, cadmium, zinc, iron, cobalt and xenobiotic compounds. Motifs were also studied against PDB structures. Results of the study suggested the presence of binding sites on the surface of protein molecules involved. PDB structures of proteins were finally predicted for the binding sites functionality in their respective phytoremediation usage. This was further validated through CASTp server to study its physico-chemical properties. Bioinformatics implications would help in designing strategy for developing transgenic plants with increased metal binding capacity. These metal binding factors can be used to restrict metal update by plants. This helps in reducing the possibility of metal movement into the food chain.     

Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study

Background

Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia.

Methods and Findings

We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy.

Conclusions

Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians. Please see later in the article for the Editors'' Summary     

Chikungunya: an overview

Chikungunya (CHIK), a mosquito borne debilitating disease, is caused by CHIK virus, an alphavirus belonging to the family Togaviridae. The sudden onset of very high fever along with rash, and severe arthralgia especially in the small joints of hands and toes are the characteristics of the disease. It was first reported from Tanzania in 1952–53 and spread subsequently to sub-Saharan Africa, South East Asia and Pacific causing large epidemics. The virus exists in three genotypes, the Asian, West African and East Central South African that are responsible for outbreaks in the respective areas. The first outbreak in Asia was in Bangkok in 1958 followed by other Asian countries. India experienced massive outbreaks of CHIK in the 1960s and early 70s mainly in cities. After a gap of 32 years an explosive outbreak of CHIK devastated the country affecting more than 1.4 million people in 13 states. The epidemic also witnessed many unusual clinico-pathological complications including CHIK associated deaths and mother to child transmission. High morbidity with severe arthralgia persisted for several months made the people mentally and physically weak. This review describes CHIK in general and highlights the various clinico-pathological aspects observed during the recent outbreak.     

Blockchain for IoV in 6G environment: review solutions and challenges

Cluster Computing - In this era of modern digital technologies, the Internet of Vehicles (IoVs) is omnipresent and can be used for varied purposes. However, these devices have scalability,...     

Dimerization and actin-bundling properties of villin and its role in the assembly of epithelial cell brush borders

Villin is a major actin-bundling protein in the brush border of epithelial cells. In this study we demonstrate for the first time that villin can bundle actin filaments using a single F-actin binding site, because it has the ability to self-associate. Using fluorescence resonance energy transfer, we demonstrate villin self-association in living cells in microvilli and in growth factor-stimulated cells in membrane ruffles and lamellipodia. Using sucrose density gradient, size-exclusion chromatography, and matrix-assisted laser desorption ionization time-of-flight, the majority of villin was identified as a monomer or dimer. Villin dimers were also identified in Caco-2 cells, which endogenously express villin and Madin-Darby canine kidney cells that ectopically express villin. Using truncation mutants of villin, site-directed mutagenesis, and fluorescence resonance energy transfer, an amino-terminal dimerization site was identified that regulated villin self-association in parallel conformation as well as actin bundling by villin. This detailed analysis describes for the first time microvillus assembly by villin, redefines the actin-bundling function of villin, and provides a molecular mechanism for actin bundling by villin, which could have wider implications for other actin cross-linking proteins that share a villin-like headpiece domain. Our study also provides a molecular basis to separate the morphologically distinct actin-severing and actin-bundling properties of villin.     

Peeling off the Mask: Pseudo Myocardial Infarction Pattern on Electrocardiogram During AICD Implantation

Lead induced transient right bundle branch block is not uncommon during pacemaker implantation. We describe a patient with old anterior wall myocardial infarction with severe left ventricular dysfunction presenting with recurrent ventricular tachycardia who developed transient right bundle branch block and pseudomyocardial infacrction pattern during AICD implantation.Key words: Pseudo Myocardial Infarction, AICD implantation     

Patterns in Benthic Biodiversity Link Lake Trophic Status to Structure and Potential Function of Three Large,Deep Lakes

Relative to their scarcity, large, deep lakes support a large proportion of the world’s freshwater species. This biodiversity is threatened by human development and is in need of conservation. Direct comparison of biodiversity is the basis of biological monitoring for conservation but is difficult to conduct between large, insular ecosystems. The objective of our study was to conduct such a comparison of benthic biodiversity between three of the world’s largest lakes: Lake Tahoe, USA; Lake Hövsgöl, Mongolia; and Crater Lake, USA. We examined biodiversity of common benthic organism, the non-biting midges (Chironomidae) and determined lake trophic status using chironomid-based lake typology, tested whether community structure was similar between the three lakes despite geographic distance; and tested whether chironomid diversity would show significant variation within and between lakes. Typology analysis indicated that Lake Hövsgöl was ultra-oligotrophic, Crater Lake was oligotrophic, and Lake Tahoe was borderline oligotrophic/mesotrophic. These results were similar to traditional pelagic measures of lake trophic status for Lake Hövsgöl and Crater Lake but differed for Lake Tahoe, which has been designated as ultra-oligotrophic by traditional pelagic measures such as transparency found in the literature. Analysis of similarity showed that Lake Tahoe and Lake Hövsgöl chironomid communities were more similar to each other than either was to Crater Lake communities. Diversity varied between the three lakes and spatially within each lake. This research shows that chironomid communities from these large lakes were sensitive to trophic conditions. Chironomid communities were similar between the deep environments of Lake Hövsgöl and Lake Tahoe, indicating that chironomid communities from these lakes may be useful in comparing trophic state changes in large lakes. Spatial variation in Lake Tahoe’s diversity is indicative of differential response of chironomid communities to nutrient enrichment which may be an indication of changes in trophic state within and across habitats.     

The Role of Hemosiderin Excision in Seizure Outcome in Cerebral Cavernous Malformation Surgery: A Systematic Review and Meta-Analysis

Background and Purpose

Whether the excision of hemosiderin surrounding cerebral cavernous malformations (CCMs) is necessary to achieve a seizure-free result has been the subject of debate. Here, we report a systematic review of related literature up to Jan 1, 2015 including 594 patients to assess the effect of hemosiderin excision on seizure outcome in patients with CCMs by meta-analysis.

Methods

Ten studies comparing extended hemosiderin excision with only lesion resection were identified by searching the English-language literature. Meta-analyses, subgroup analyses and sensitivity analysis were conducted to determine the association between hemosiderin excision and seizure outcome after surgery.

Results

Seizure outcome was significantly improved in the patients who underwent an extended excision of the surrounding hemosiderin (OR, 0.62; 95% CI: 0.42–0.91; P = 0.01). In subgroup analysis, studies from Asia (OR, 0.42; 95% CI: 0.25–0.71; P = 0.001), male-majority (female ratio < 50%) studies (OR, 0.56; 95% CI: 0.33–0.96; P = 0.04), low occurrence rate of multiple CCMs (OR, 0.37; 95% CI: 0.20–0.71; P = 0.003), cohort studies (OR, 0.44; 95% CI: 0.28–0.68; P = 0.78), longer duration of seizure symptoms (> 1 year) before surgery (OR, 0.43; 95% CI: 0.22–0.84; P = 0.01), lesion diameter > 2 cm (OR, 0.41; 95% CI: 0.19–0.87; P = 0.02) and short-term (< 3 years) follow-up (OR, 0.48; 95% CI: 0.29–0.80; P = 0.005) tended to correlate with a significantly favorable outcome.

Conclusion

Patients who underwent extended surrounding hemosiderin excision could exhibit significantly improved seizure outcomes compared to patients without hemosiderin excision. However, further well-designed prospective multiple-center RCT studies are still needed.