Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence

BACKGROUND: Previous studies have suggested that recent segmental duplications, which are often involved in chromosome rearrangements underlying genomic disease, account for some 5% of the human genome. We have developed rapid computational heuristics based on BLAST analysis to detect segmental duplications, as well as regions containing potential sequence misassignments in the human genome assemblies. RESULTS: Our analysis of the June 2002 public human genome assembly revealed that 107.4 of 3,043.1 megabases (Mb) (3.53%) of sequence contained segmental duplications, each with size equal or more than 5 kb and 90% identity. We have also detected that 38.9 Mb (1.28%) of sequence within this assembly is likely to be involved in sequence misassignment errors. Furthermore, we have identified a significant subset (199,965 of 2,327,473 or 8.6%) of single-nucleotide polymorphisms (SNPs) in the public databases that are not true SNPs but are potential paralogous sequence variants. CONCLUSION: Using two distinct computational approaches, we have identified most of the sequences in the human genome that have undergone recent segmental duplications. Near-identical segmental duplications present a major challenge to the completion of the human genome sequence. Potential sequence misassignments detected in this study would require additional efforts to resolve

Evolutionary plasticity in the allosteric regulator-binding site of pyruvate kinase isoform PykA from Pseudomonas aeruginosa.

Unlike many other well-characterized bacteria, the opportunistic human pathogen Pseudomonas aeruginosa relies exclusively on the Entner-Doudoroff pathway (EDP) for glycolysis. Pyruvate kinase (PK) is the main "pacemaker" of the EDP, and its activity is also relevant for P. aeruginosa virulence. Two distinct isozymes of bacterial PK have been recognized, PykA and PykF. Here, using growth and expression analyses of relevant PK mutants, we show that PykA is the dominant isoform in P. aeruginosa Enzyme kinetics assays revealed that PykA displays potent K-type allosteric activation by glucose 6-phosphate and by intermediates from the pentose phosphate pathway. Unexpectedly, the X-ray structure of PykA at 2.4 Å resolution revealed that glucose 6-phosphate binds in a pocket that is distinct from the binding site reported for this metabolite in the PK from Mycobacterium tuberculosis (the only other available bacterial PK structure containing bound glucose 6-phosphate). We propose a mechanism by which glucose 6-phosphate binding at the allosteric site communicates with the PykA active site. Taken together, our findings indicate remarkable evolutionary plasticity in the mechanism(s) by which PK senses and responds to allosteric signals.This work was funded by a PhD studentship from the Yousef Jameel Foundation (YA), a BBSRC studentship (to JG) and by BBSRC grant BB/M019411/1

Strongly coupled slow-light polaritons in one-dimensional disordered localized states

Cavity quantum electrodynamics advances the coherent control of a single quantum emitter with a quantized radiation field mode, typically piecewise engineered for the highest finesse and confinement in the cavity field. This enables the possibility of strong coupling for chip-scale quantum processing, but till now is limited to few research groups that can achieve the precision and deterministic requirements for these polariton states. Here we observe for the first time coherent polariton states of strong coupled single quantum dot excitons in inherently disordered one-dimensional localized modes in slow-light photonic crystals. Large vacuum Rabi splittings up to 311 {\mu}eV are observed, one of the largest avoided crossings in the solid-state. Our tight-binding models with quantum impurities detail these strong localized polaritons, spanning different disorder strengths, complementary to model-extracted pure dephasing and incoherent pumping rates. Such disorder-induced slow-light polaritons provide a platform towards coherent control, collective interactions, and quantum information processing.Comment: 17 pages, 5 figures and supplementary informatio

Drosophila expressing human SOD1 successfully recapitulates mitochondrial phenotypic features of familial amyotrophic lateral sclerosis

Mitochondrial pathology is a seminal pathogenic hallmark of familial amyotrophic lateral sclerosis (FALS) which is extensively manifested by human patients and mutant SOD1G93A mammalian models. Rodents expressing human FALS-associated mutations successfully mimic several human disease features; although they are not as amenable to genetic and therapeutic compound screenings as non-mammalian models. In this study, we report a newly generated and characterized Drosophila model that expresses human SOD1G93A in muscle fibers. Presence of SOD1G93A in thoracic muscles causes mitochondrial pathology and impairs normal motor behavior in these flies. Use of this new FALS-24B-SOD1G93A fly model holds promise for better understanding of the mitochondrial affectation process in FALS and for the discovery of novel therapeutic compounds able to reverse mitochondrial dysfunction in this fatal disease

Exploration of inositol 1,4,5-trisphosphate (IP3) regulated dynamics of N-terminal domain of IP3 receptor reveals early phase molecular events during receptor activation.

Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3 receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3 binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated 'clam closure' dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD - IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3 binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3 binding that lead to channel gating

Global geographical variations in ST-segment elevation myocardial infarction management and post-discharge mortality.

BACKGROUND: There is a shortage of information on regional variations in ST-segment elevation myocardial infarction (STEMI) management and prognosis at a global level. We aimed to compare patient profiles, in-hospital management and post-discharge mortality across several world regions. METHODS: In total, 11,559 patients with STEMI were enrolled in two prospective studies of acute coronary syndrome survivors: EPICOR (4943 patients from 555 hospitals in 20 countries in Europe and Latin America recruited between September 2010 and March 2011) and EPICOR Asia (6616 patients from 218 hospitals in eight Asian countries recruited between June 2011 and May 2012). Comparisons were performed by eight pre-defined regions: Northern Europe (NE), Southern Europe (SE), Eastern Europe (EE), Latin America (LA), China (CN), India (IN), Southeast Asia (SA), and South Korea/Hong Kong/Singapore (KS). RESULTS: Reperfusion therapy rates ranged between 53.9% (IN) and 81.2% (SE), primary percutaneous coronary intervention (PCI) between 24.8% (IN) and 65.6% (NE) and fibrinolysis between 8.1% (CN) and 34.2% (SA). Median time to primary PCI (h) ranged from 3.9 (NE) to 20.9 (IN) and to fibrinolysis from 2.4 (SE) to 6.3 (IN). Two-year mortality ranged between 2.5% in NE and 7.4% in LA. Regional variations in mortality persisted after adjustment for reperfusion therapy and known prognostic factors. CONCLUSIONS: Among patients with STEMI, there is a wide regional variation in clinical profiles, hospital care and mortality. Substantial room for improvement remains at a global level for increasing reperfusion rates, reducing delays and post-discharge mortality in patients with STEMI

Computational ligand–receptor docking simulation of piperine with apoptosis-associated factors

Although widely known for its antioxidant properties, piperine’s (a compound from the pepper plant) physiologic involvement in apoptosis (programmed cell death) is unclear. As a prerequisite to unravel its role in this process, computational approaches simulating ligand–receptor docking are sought. Herein, we report the simulated binding of piperine with major apoptotic proteins via combined deployment of AutoDock suite (AutoDock Vina), PyMOL, and LigPlot + software. Our results demonstrated varied binding affinity toward the different apoptosis-associated proteins with a higher to lower affinity pattern in the order of TNFR-1 > Caspase-3 > TNF-α > Caspase-8 > Bcl-2 > Caspase-9 > Bax. Docking scores for all receptor–ligand interactions indicate a strong likelihood of impromptu receptor–ligand binding. Molecularly, the simulated analysis revealed hydrophobic interactions in all receptor–ligand models studied. Receptor–piperine complexes involving TNFR-1 and Caspase-8 showed single hydrogen bonding whereas amino acid residues of TNF-α exhibited double hydrogen bonding to piperine. In the TNFR-1-piperine complex (receptor–ligand docked model with strongest binding affinity) the hydrophobic interaction involves amino acid residues of SER74, LYS75, ASN110 (2), THR94, CYS96, VAL95, and PHE112. Our findings provide novel in silico evidence of piperine’s binding affinity toward apoptosis-associated proteins and the high likelihood of its influence on apoptosis reaction via the extrinsic pathway

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Long-Term Antithrombotic Therapy and Clinical Outcomes in Patients with Acute Coronary Syndrome and Renal Impairment: Insights from EPICOR and EPICOR Asia.

BACKGROUND: Information is lacking on long-term management of patients with acute coronary syndrome (ACS) and chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2). OBJECTIVES: Our objectives were to describe antithrombotic management patterns and outcomes in patients with ACS with varying renal function from the EPICOR (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients; NCT01171404) and EPICOR Asia (NCT01361386) studies. METHODS: EPICOR and EPICOR Asia were prospective observational studies of patients who survived hospitalization for ACS and were enrolled at discharge in 28 countries across Europe, Latin America, and Asia. The studies were conducted from 2010 to 2013 and from 2011 to 2014, respectively. This analysis evaluated patient characteristics and oral antithrombotic management patterns and outcomes up to 2 years post-discharge according to admission eGFR: ≥ 90, 60-89, 30-59, or < 30 mL/min/1.73 m2. RESULTS: Among 22,380 patients with available data, eGFR < 60 mL/min/1.73 m2 was observed in 16.7%. Patients with poorer renal function were older, were at greater cardiovascular risk, and had more prior cardiovascular disease and bleeding. Patients with CKD underwent fewer cardiovascular interventions and had more in-hospital cardiovascular and bleeding events. Dual antiplatelet therapy was less likely at discharge in patients with eGFR < 30 (82.3%) than in those with ≥ 90 (91.3%) mL/min/1.73 m2 and declined more sharply during follow-up in patients with low eGFR (p < 0.0001). An adjusted proportional hazards model showed that patients with lower eGFR levels had a higher risk of cardiovascular events and bleeding. CONCLUSIONS: The presence of CKD in patients with ACS was associated with less aggressive cardiovascular management and an increased risk of cardiovascular events