Computational Mapping Identifies Localized Mechanisms for Ablation of Atrial Fibrillation

Atrial fibrillation (AF) is the most common heart rhythm disorder in the Western world and a common cause of hospitalization and death. Pharmacologic and non-pharmacologic therapies have met with limited success, in part due to an incomplete understanding of the underlying mechanisms for AF. AF is traditionally characterized by spatiotemporally disorganized electrical activation and, although initiating triggers for AF are described, it is unclear whether AF is sustained by spatially meandering continuous excitation (re-entrant waves), localized electrical sources within the atria, or some other mechanism. This has limited therapeutic options for this condition. Here we show that human AF is predominantly caused by a small number (1.8±0.9) of localized re-entrant waves or repetitive focal beats, that remain stable with limited spatial migration over prolonged periods of time. Radiofrequency ablation that selectively targeted the sites of these sources was able to immediately terminate fibrillation and eliminate the arrhythmia with high success. Our results show that human AF, despite apparent spatiotemporal disorganization, is often perpetuated by a few spatially-constrained and temporally conserved sources whose targeted ablation can eliminate this complex rhythm disorder.     

Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase associates with a protein super-complex integrating multiple metabolic pathways

Proteins involved in mitochondrial metabolic pathways engage in functionally relevant multi-enzyme complexes. We previously described an interaction between short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) and glutamate dehydrogenase (GDH) explaining the clinical phenotype of hyperinsulinism in SCHAD-deficient patients and adding SCHAD to the list of mitochondrial proteins capable of forming functional, multi-pathway complexes. In this work, we provide evidence of SCHAD's involvement in additional interactions forming tissue-specific metabolic super complexes involving both membrane-associated and matrix-dwelling enzymes and spanning multiple metabolic pathways. As an example, in murine liver, we find SCHAD interaction with aspartate transaminase (AST) and GDH from amino acid metabolic pathways, carbamoyl phosphate synthase I (CPS-1) from ureagenesis, other fatty acid oxidation and ketogenesis enzymes and fructose-bisphosphate aldolase, an extra-mitochondrial enzyme of the glycolytic pathway. Most of the interactions appear to be independent of SCHAD's role in the penultimate step of fatty acid oxidation suggesting an organizational, structural or non-enzymatic role for the SCHAD protein.     

Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms. Previous studies have shown aplysinopsin analogs to possess a variety of biological activities, including modulation of neurotransmissions. A series of fifty aplysinopsin analogs was synthesized and assayed for monoamine oxidase A and B inhibitory activity. Three compounds displayed significant MAO inhibitory activity and selectivity. The compound (E)-5-[(6-bromo-1H-indol-3-yl)methylene]-2-imino-1,3-dimethylimidazolidin-4-one (3x) possessed an IC(50) of 5.6 nM at MAO-A and had a selectivity index of 80.24. An SAR study revealed that multiple N-methylations, one of which should be at position N-2', and bromination at C-5 or C-6 are important factors for MAO-A potency and selectivity.     

Chemical mapping of mammalian cells by atom probe tomography

In atom probe tomography (APT), a technique that has been used to determine 3D maps of ion compositions of metals and semiconductors at sub-nanometer resolutions, controlled emissions of ions can be induced from needle-shaped specimens in the vicinity of a strong electric field. Detection of these ions in the plane of a position sensitive detector provides two-dimensional compositional information while the sequence of ion arrival at the detector provides information in the third dimension. Here we explore the use of APT technology for imaging biological specimens. We demonstrate that it is possible to obtain 3D spatial distributions of cellular ions and metabolites from unstained, freeze-dried mammalian cells. Multiple peaks were reliably obtained in the mass spectrum from tips with diameters of ~50 nm and heights of ~200 nm, with mass-to-charge ratios (m/z) ranging from 1 to 80. Peaks at m/z 12, 23, 28 and 39, corresponding to carbon, sodium, carbonyl and potassium ions respectively, showed distinct patterns of spatial distribution within the cell. Our studies establish that APT could become a powerful tool for mapping the sub-cellular distribution of atomic species, such as labeled metabolites, at 3D spatial resolutions as high as ~1 nm.     

Linking co-expression modules with phenotypes

The method for quantifying the association between co-expression module and clinical trait of interest requires application of dimensionality reduction to summaries modules as one dimensional (1D) vector. However, these methods are often linked with information loss. The amount of information lost depends upon the percentage of variance captured by the reduced 1D vector. Therefore, it is of interest to describe a method using analysis of rank (AOR) to assess the association between module and clinical trait of interest. This method works with clinical traits represented as binary class labels and can be adopted for clinical traits measured in continuous scale by dividing samples in two groups around median value. Application of the AOR method on test data for muscle gene expression profiles identifies modules significantly associated with diabetes status.     

Prospective role of insecticides of fungal origin: Review

Advances in the application of microbial‐based technology in insect pest management assist us to counter problems created by the application of chemical pesticides. These are mainly strong environmental effects, resistance development and high costs. Among the microbial pesticides, fungal pesticides are now preferred as they are target specific, ecofriendly, lacking in toxic residue and are economical. Being numerous with great diversification, entomopathogenic fungi therefore have great potential to control a large variety of insect pests. Fungi are applied directly in form of spores, mycelia or blastospores or by their metabolites (mycotoxins). Both approaches have very promising roles in insect pest management. However, there are three main obstacles in the development of fungal pesticides: (i) scant production of mycotoxins; (ii) carcinogenic mycotoxicosis in non‐target organisms; and (iii) slow effectiveness. Therefore, to eliminate these problems, attention has recently been paid to a synergistic approach to combating insecticide resistance. Next to synergism, genetic manipulation is also used to enhance the pathogenicity and virulence of fungal insecticides. However, the key risk associated with the release of recombinant microorganisms into the environment is that the novel organism may have unforeseen undesirable characteristics. Therefore, the introduction of synergists in pest control could have great benefit both economically and ecologically. An ideal synergistic approach is the mixing of more than two accelerating components together, i.e. tripartite or multiple synergism to enhance effectiveness. Thus, synergistic approaches have a bright future and require further research and financial support.     

In silico mining of EST-SSRs in <Emphasis Type="Italic">Arachis hypogaea</Emphasis> L. and their utilization for genetic structure and diversity analysis in cultivars/breeding lines in Odisha,India

A total of 26,685 unutilized public domain expressed sequence tags (ESTs) of Arachis hypogaea L. were analyzed to give a total of 4442 EST-SSRs, in which 517 ESTs contained more than one simple sequence repeat (SSR). Of these EST-SSRs, 2542 were mononucleotide repeats (MNRs), 803 were dinucleotide repeats (DNRs), 1043 were trinucleotide repeats (TNRs), 40 were tetranucleotide repeats (TtNRs), six were pentanucleotide repeats (PNRs) and eight were hexanucleotide repeats (HNRs). Out of these 4442 EST-SSRs, only 1160 were found to be successful in non-redundant primer design; 1060 were simple SSRs, while the remaining 100 were compound forms. Among all the motifs, MNRs were abundant, followed by TNRs and DNRs. The AAG/CTT motif was the most abundant (~33 %) TNR, while AG/CT was the most abundant DNR. For redundancy and novelty, a stringent criterion deploying three different strategies was used and a total of 782 novel EST-SSRs were added to the public domain of peanut. These novel EST-SSR markers will be useful for qualitative and quantitative trait mapping, marker-assisted selection and genetic diversity studies in cultivated peanut as well as related Arachis species. A subset of 30 novel EST-SSRs was further randomly selected for validation and genotyping studies with eight well-known cultivars and 32 advanced breeding lines (ADBX lines, ADBY lines and ADBZ lines) from Odisha state, India. The number of polymorphic markers among accessions of A. hypogaea was low; however, a set of informative EST-SSR markers detected considerable levels of genetic variability in peanut cultivars and uncharacterized breeding lines collected from Odisha. The 30 newly developed EST-SSRs from Arachis spp. showed ~97 % amplification in Cicer arientinum and 93 % in pigeon pea. Thus, the EST-SSRs developed in this study will be a very useful asset for genetic analysis, comparative genome mapping, population genetic structure and phylogenetic inferences among wild and allied species of Arachis.     

Amblyceps waikhomi,a New Species of Catfish (Siluriformes: Amblycipitidae) from the Brahmaputra Drainage of Arunachal Pradesh,India

Amblyceps waikhomi sp. nov. is described from the Nongkon stream which drains into the Noa Dehing River, a tributary of the Brahmaputra River, in Arunachal Pradesh, India. The new species can be distinguished from congeners (except A. torrentis) in having a deeper body depth at anus. It further differs from congeners (except A. mangois and A. serratum) in having fewer vertebrae, from A. mangois in lacking (vs. having) strongly-developed projections on the proximal lepidotrichia of the median caudal-fin rays, and in having a longer, wider, and deeper head; and from A. serratum in having a posteriorly smooth (vs. with 4–5 serrations) pectoral spine, and unequal jaw length (lower jaw longer and weakly-projecting anteriorly vs. equal upper and lower jaws). It additionally differs from A. murraystuarti, A. torrentis, A. apangi, A. laticeps, and A. cerinum in having a deeply forked (vs. emarginate or truncate) caudal fin. This species is the seventh amblycipitid species known to occur in the Ganga-Brahmaputra River system.