Use of Implantable Loop Recorders to Unravel the Cause of Unexplained Syncope

Syncope is a symptom of many underlying disease states, which range from the relatively benign to the life threatening. There are numerous investigations done for patients with recurrent unexplained syncope which may have very low yield when it comes to making a definitive diagnosis. Recently, the implantable loop recorder (ILR) for continuous monitoring of the cardiac rhythm has been launched in India. This review will briefly discuss these current availabel strategies and focus on the usefulness of an ILR in the definitive diagnosis and treatment of patients with a recurrent unexplained syncope.     

Increase in Nitrate Reductase Activity in Bean Leaves by Light Involves a Regulator Protein

Nitrate reductase activity, assayed either in vivo or in vitro was considerably higher in bean (Phaseolus vulgaris L.) leaves from 7-day-old light grown seedlings than those from dark grown, both in the absence as well as presence of nitrate. Cytochrome c reductase activity was however similar in both regimes, while peroxidase was lower in light than in dark. The light stimulated increase in nitrate reductase activity in leaf segments from dark grown seedlings was inhibited by cycloheximide, DNP, chloramphenicol, and sodium tungstate and was unaffected by lincomycin and DCMU. Under similar conditions, the increase in total chlorophyll was inhibited completely by cycloheximide and DNP, partially by chloramphenicol and lincomycin, and was unaffected by tungstate and DCMU. A supply of 1~5 mm reduced glutathione increased enzyme activity in the dark and also to some extent in light. The substrate induction of enzyme activity started after a lag of one hr in light or dark and continued for either 5 hr in the dark or 8 hr in light. Two proteinaceous inhibitors (Factors I and II) of nitrate reductase were isolated by ammonium sulfate precipitation and Sephadex gel filtration. The amount of Factor I was higher in the dark than in light. The amount and activity of Factor II was however, almost equal in light and dark. The inhibition of enzyme activity by these inhibitors increased with their concentration. It is proposed that light increases nitrate reductase activity by decreasing the amount of a nitrate reductase inhibitor.     

Minocycline,levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.     

Integrating multi-platform genomic data using hierarchical Bayesian relevance vector machines

Background

Recent advances in genome technologies and the subsequent collection of genomic information at various molecular resolutions hold promise to accelerate the discovery of new therapeutic targets. A critical step in achieving these goals is to develop efficient clinical prediction models that integrate these diverse sources of high-throughput data. This step is challenging due to the presence of high-dimensionality and complex interactions in the data. For predicting relevant clinical outcomes, we propose a flexible statistical machine learning approach that acknowledges and models the interaction between platform-specific measurements through nonlinear kernel machines and borrows information within and between platforms through a hierarchical Bayesian framework. Our model has parameters with direct interpretations in terms of the effects of platforms and data interactions within and across platforms. The parameter estimation algorithm in our model uses a computationally efficient variational Bayes approach that scales well to large high-throughput datasets.

Results

We apply our methods of integrating gene/mRNA expression and microRNA profiles for predicting patient survival times to The Cancer Genome Atlas (TCGA) based glioblastoma multiforme (GBM) dataset. In terms of prediction accuracy, we show that our non-linear and interaction-based integrative methods perform better than linear alternatives and non-integrative methods that do not account for interactions between the platforms. We also find several prognostic mRNAs and microRNAs that are related to tumor invasion and are known to drive tumor metastasis and severe inflammatory response in GBM. In addition, our analysis reveals several interesting mRNA and microRNA interactions that have known implications in the etiology of GBM.

Conclusions

Our approach gains its flexibility and power by modeling the non-linear interaction structures between and within the platforms. Our framework is a useful tool for biomedical researchers, since clinical prediction using multi-platform genomic information is an important step towards personalized treatment of many cancers. We have a freely available software at: http://odin.mdacc.tmc.edu/~vbaladan.

     

Aldose Reductase Inhibition Prevents Allergic Airway Remodeling through PI3K/AKT/GSK3β Pathway in Mice

Background

Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA)-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs).

Methods

Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling.

Results

In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.

Conclusion

Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.     

An efficient algorithm for protein structure comparison using elastic shape analysis

Background

Protein structure comparison play important role in in silico functional prediction of a new protein. It is also used for understanding the evolutionary relationships among proteins. A variety of methods have been proposed in literature for comparing protein structures but they have their own limitations in terms of accuracy and complexity with respect to computational time and space. There is a need to improve the computational complexity in comparison/alignment of proteins through incorporation of important biological and structural properties in the existing techniques.

Results

An efficient algorithm has been developed for comparing protein structures using elastic shape analysis in which the sequence of 3D coordinates atoms of protein structures supplemented by additional auxiliary information from side-chain properties are incorporated. The protein structure is represented by a special function called square-root velocity function. Furthermore, singular value decomposition and dynamic programming have been employed for optimal rotation and optimal matching of the proteins, respectively. Also, geodesic distance has been calculated and used as the dissimilarity score between two protein structures. The performance of the developed algorithm is tested and found to be more efficient, i.e., running time reduced by 80–90 % without compromising accuracy of comparison when compared with the existing methods. Source codes for different functions have been developed in R. Also, user friendly web-based application called ProtSComp has been developed using above algorithm for comparing protein 3D structures and is accessible free.

Conclusions

The methodology and algorithm developed in this study is taking considerably less computational time without loss of accuracy (Table 2). The proposed algorithm is considering different criteria of representing protein structures using 3D coordinates of atoms and inclusion of residue wise molecular properties as auxiliary information.

     

CRYβA3/A1-Crystallin Knockout Develops Nuclear Cataract and Causes Impaired Lysosomal Cargo Clearance and Calpain Activation

βA3/A1-crystallin is an abundant structural protein of the lens that is very critical for lens function. Many different genetic mutations have been shown to associate with different types of cataracts in humans and in animal models. βA3/A1-crystallin has four Greek key-motifs that organize into two crystallin domains. It shown to bind calcium with moderate affinity and has putative calcium-binding site. Other than in the lens, βA3/A1 is also expressed in retinal astrocytes, retinal pigment epithelial (RPE) cells, and retinal ganglion cells. The function of βA3/A1-crystallin in the retinal cell types is well studied; however, a clear understanding of the function of this protein in the lens has not yet been established. In the current study, we generated the βA3/A1-crystallin knockout (KO) mouse and explored the function of βA3/A1-crystallin in lens development. Our results showed that βA3-KO mice develop congenital nuclear cataract and exhibit persistent fetal vasculature condition. At the cellular level KO lenses show defective lysosomal clearance and accumulation of nuclei, mitochondria, and autophagic cargo in the outer cortical region of the lens. In addition, the calcium level and the expression and activity of calpain-3 were increased in KO lenses. Taken together, these results suggest the lack of βA3-crystallin function in lenses, alters calcium homeostasis which in turn causes lysosomal defects and calpain activation. These defects are responsible for the development of nuclear cataract in KO lenses.     

Isolation and characterization of biosurfactant producing <Emphasis Type="Italic">Bacillus</Emphasis> sp. from diesel fuel-contaminated site

Among hydrocarbon pollutants, diesel oil is a complex mixture of alkanes and aromatic compounds which are often encountered as soil contaminants leaking from storage tanks and pipelines or as result of accidental spillage. One of the best ecofriendly approaches is to restore contaminated soil by using microorganisms able to degrade those toxic compounds in a bioremediation process. In the present study, nineteen bacteria were isolated by enrichment culture technique from diesel spilled soil collected from electric generator shed of NBAIM, Mau. All the isolates were subjected to screening for lipase production and twelve isolates were found to be positive for lipase. When the isolates were screened for biosurfactant production using CTAB-methylene blue agar plates, only one isolate viz. 2NBDSH3 was found positive which was found to be phylogenetically closely related with Bacillus flexus. Despite having low emulsification index, the bacterium could degrade 88.6% of diesel oil in soil. Biosurfactant from the isolate was extracted and characterized through infra-red spectroscopy which indicated its possible lipopeptide nature which was further supported by strong absorption in UV range in the UV-Vis spectrum. The results of the present study indicated that the isolate either does not produce any bioemulsifier or produces very low amount of emulsifier rather it produces a lipopeptide biosurfactant which helps in degradation of diesel oil by lowering the surface tension. The bacterium thus isolated and characterized can serve as a promising solution for ecofriendly remediation of bacterium diesel contaminated soils.     

Endophytes of opium poppy differentially modulate host plant productivity and genes for the biosynthetic pathway of benzylisoquinoline alkaloids

Planta - Endophytes reside in different parts of the poppy plant and perform the tissue-specific functions. Most leaf endophytes modulate photosynthetic efficiency, plant growth, and productivity...