UK-68,798, A Class III Antiarrhythmic Drug with Antifibrillatory Properties

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74787/1/j.1527-3466.1992.tb00244.x.pd

Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection

Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions

An optogenetic gene expression system with rapid activation and deactivation kinetics

Optogenetic gene expression systems can control transcription with spatial and temporal detail unequaled with traditional inducible promoter systems. However, current eukaryotic light-gated transcription systems are limited by toxicity, dynamic range, or slow activation/deactivation. Here we present an optogenetic gene expression system that addresses these shortcomings and demonstrate its broad utility. Our approach utilizes an engineered version of EL222, a bacterial Light-Oxygen-Voltage (LOV) protein that binds DNA when illuminated with blue light. The system has a large (\u3e100-fold) dynamic range of protein expression, rapid activation (\u3c 10 s) and deactivation kinetics (\u3c 50 s), and a highly linear response to light. With this system, we achieve light-gated transcription in several mammalian cell lines and intact zebrafish embryos with minimal basal gene activation and toxicity. Our approach provides a powerful new tool for optogenetic control of gene expression in space and time

Choosing Organic Pesticides over Synthetic Pesticides May Not Effectively Mitigate Environmental Risk in Soybeans

Background: Selection of pesticides with small ecological footprints is a key factor in developing sustainable agricultural systems. Policy guiding the selection of pesticides often emphasizes natural products and organic-certified pesticides to increase sustainability, because of the prevailing public opinion that natural products are uniformly safer, and thus more environmentally friendly, than synthetic chemicals. Methodology/Principal Findings: We report the results of a study examining the environmental impact of several new synthetic and certified organic insecticides under consideration as reduced-risk insecticides for soybean aphid (Aphis glycines) control, using established and novel methodologies to directly quantify pesticide impact in terms of biocontrol services. We found that in addition to reduced efficacy against aphids compared to novel synthetic insecticides, organic approved insecticides had a similar or even greater negative impact on several natural enemy species in lab studies, were more detrimental to biological control organisms in field experiments, and had higher Environmental Impact Quotients at field use rates. Conclusions/Significance: These data bring into caution the widely held assumption that organic pesticides are more environmentally benign than synthetic ones. All pesticides must be evaluated using an empirically-based risk assessment

Radically open-dialectical behavior therapy for adult anorexia nervosa: feasibility and outcomes from an inpatient program

Background Anorexia Nervosa (AN) is a highly life-threatening disorder that is extremely difficult to treat. There is evidence that family-based therapies are effective for adolescent AN, but no treatment has been proven to be clearly effective for adult AN. The methodological challenges associated with studying the disorder have resulted in recommendations that new treatments undergo preliminary testing prior to being evaluated in a randomized clinical trial. The aim of this study was to provide preliminary evidence on the effectiveness of a treatment program based on a novel adaptation of Dialectical Behavior Therapy (DBT) for adult Anorexia Nervosa (Radically Open-DBT; RO-DBT) that conceptualizes AN as a disorder of overcontrol. Methods Forty-seven individuals diagnosed with Anorexia Nervosa-restrictive type (AN-R; mean admission body mass index = 14.43) received the adapted DBT inpatient program (mean length of treatment = 21.7 weeks). Results Seventy-two percent completed the treatment program demonstrating substantial increases in body mass index (BMI; mean change in BMI = 3.57) corresponding to a large effect size (d = 1.91). Thirty-five percent of treatment completers were in full remission, and an additional 55% were in partial remission resulting in an overall response rate of 90%. These same individuals demonstrated significant and large improvements in eating-disorder related psychopathology symptoms (d = 1.17), eating disorder-related quality of life (d = 1.03), and reductions in psychological distress (d = 1.34). Conclusions RO-DBT was associated with significant improvements in weight gain, reductions in eating disorder symptoms, decreases in eating-disorder related psychopathology and increases in eating disorder-related quality of life in a severely underweight sample. These findings provide preliminary support for RO-DBT in treating AN-R suggesting the importance of further evaluation examining long-term outcomes using randomized controlled trial methodology

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

Phylogenomics: Gene Duplication, Unrecognized Paralogy and Outgroup Choice

Comparative genomics has revealed the ubiquity of gene and genome duplication and subsequent gene loss. In the case of gene duplication and subsequent loss, gene trees can differ from species trees, thus frequent gene duplication poses a challenge for reconstruction of species relationships. Here I address the case of multi-gene sets of putative orthologs that include some unrecognized paralogs due to ancestral gene duplication, and ask how outgroups should best be chosen to reduce the degree of non-species tree (NST) signal. Consideration of expected internal branch lengths supports several conclusions: (i) when a single outgroup is used, the degree of NST signal arising from gene duplication is either independent of outgroup choice, or is minimized by use of a maximally closely related post-duplication (MCRPD) outgroup; (ii) when two outgroups are used, NST signal is minimized by using one MCRPD outgroup, while the position of the second outgroup is of lesser importance; and (iii) when two outgroups are used, the ability to detect gene trees that are inconsistent with known aspects of the species tree is maximized by use of one MCRPD, and is either independent of the position of the second outgroup, or is maximized for a more distantly related second outgroup. Overall, these results generalize the utility of closely-related outgroups for phylogenetic analysis

Identification of conserved gene clusters in multiple genomes based on synteny and homology

<p>Abstract</p> <p>Background</p> <p>Uncovering the relationship between the conserved chromosomal segments and the functional relatedness of elements within these segments is an important question in computational genomics. We build upon the series of works on <it>gene teams</it> and <it>homology teams.</it></p> <p>Results</p> <p>Our primary contribution is a local sliding-window SYNS (SYNtenic teamS) algorithm that refines an existing family structure into orthologous sub-families by analyzing the neighborhoods around the members of a given family with a locally sliding window. The neighborhood analysis is done by computing conserved gene clusters. We evaluate our algorithm on the existing homologous families from the Genolevures database over five genomes of the Hemyascomycete phylum.</p> <p>Conclusions</p> <p>The result is an efficient algorithm that works on multiple genomes, considers paralogous copies of genes and is able to uncover orthologous clusters even in distant genomes. Resulting orthologous clusters are comparable to those obtained by manual curation.</p

The revised Bethesda guidelines: extent of utilization in a university hospital medical center with a cancer genetics program

<p>Abstract</p> <p>Background</p> <p>In 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution.</p> <p>Methods</p> <p>All HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients' electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution.</p> <p>Results</p> <p>A total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling.</p> <p>Conclusion</p> <p>This retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.</p