441 research outputs found
Evolutionary algorithms for the selection of single nucleotide polymorphisms
BACKGROUND: Large databases of single nucleotide polymorphisms (SNPs) are available for use in genomics studies. Typically, investigators must choose a subset of SNPs from these databases to employ in their studies. The choice of subset is influenced by many factors, including estimated or known reliability of the SNP, biochemical factors, intellectual property, cost, and effectiveness of the subset for mapping genes or identifying disease loci. We present an evolutionary algorithm for multiobjective SNP selection. RESULTS: We implemented a modified version of the Strength-Pareto Evolutionary Algorithm (SPEA2) in Java. Our implementation, Multiobjective Analyzer for Genetic Marker Acquisition (MAGMA), approximates the set of optimal trade-off solutions for large problems in minutes. This set is very useful for the design of large studies, including those oriented towards disease identification, genetic mapping, population studies, and haplotype-block elucidation. CONCLUSION: Evolutionary algorithms are particularly suited for optimization problems that involve multiple objectives and a complex search space on which exact methods such as exhaustive enumeration cannot be applied. They provide flexibility with respect to the problem formulation if a problem description evolves or changes. Results are produced as a trade-off front, allowing the user to make informed decisions when prioritizing factors. MAGMA is open source and available at . Evolutionary algorithms are well suited for many other applications in genomics
Use of a cAMP BRET Sensor to Characterize a Novel Regulation of cAMP by the Sphingosine 1-Phosphate/G13 Pathway
Regulation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP) is integral in mediating cell growth, cell differentiation, and immune responses in hematopoietic cells. To facilitate studies of cAMP regulation we developed a BRET (bioluminescence resonance energy transfer) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc), which can quantitatively and rapidly monitor intracellular concentrations of cAMP in vivo. This sensor was used to characterize three distinct pathways for modulation of cAMP synthesis stimulated by presumed Gs-dependent receptors for isoproterenol and prostaglandin E2. Whereas two ligands, uridine 5'-diphosphate and complement C5a, appear to use known mechanisms for augmentation of cAMP via Gq/calcium and Gi, the action of sphingosine 1-phosphate (S1P) is novel. In these cells, S1P, a biologically active lysophospholipid, greatly enhances increases in intracellular cAMP triggered by the ligands for Gs-coupled receptors while having only a minimal effect by itself. The enhancement of cAMP by S1P is resistant to pertussis toxin and independent of intracellular calcium. Studies with RNAi and chemical perturbations demonstrate that the effect of S1P is mediated by the S1P2 receptor and the heterotrimeric G13 protein. Thus in these macrophage cells, all four major classes of G proteins can regulate intracellular cAMP
Role of N-methyl-D-aspartate receptors in action-based predictive coding deficits in schizophrenia
Published in final edited form as:Biol Psychiatry. 2017 March 15; 81(6): 514ā524. doi:10.1016/j.biopsych.2016.06.019.BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.
METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.
RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohenās d = 1.14) and schizophrenia (Cohenās d = .85).
CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. (AstraZeneca for an investigator-initiated study (DHM); R01 MH-58262 - National Institute of Mental Health; T32 MH089920 - National Institute of Mental Health; UL1RR024139 - Yale Center for Clinical Investigation; P50AA012879 - US National Institute on Alcohol Abuse and Alcoholism)Accepted manuscrip
Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal
INTRODUCTION: Prothrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation. METHODS: Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety. RESULTS: Seventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, pā<ā0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, pā=ā0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, pā=ā1.00), mortality, length of hospital stay, or cost. CONCLUSIONS: Based on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa
Associations among ancestry, geography and breast cancer incidence, mortality, and survival in Trinidad and Tobago
Breast cancer (BC) is the most common newly diagnosed cancer among women in Trinidad and Tobago (TT) and BC mortality rates are among the highest in the world. Globally, racial/ethnic trends in BC incidence, mortality and survival have been reported. However, such investigations have not been conducted in TT, which has been noted for its rich diversity. In this study, we investigated associations among ancestry, geography and BC incidence, mortality and survival in TT. Data on 3767 incident BC cases, reported to the National Cancer Registry of TT, from 1995 to 2007, were analyzed in this study. Women of African ancestry had significantly higher BC incidence and mortality rates (Incidence: 66.96; Mortality: 30.82 per 100,000) compared to women of East Indian (Incidence: 41.04, Mortality: 14.19 per 100,000) or mixed ancestry (Incidence: 36.72, Mortality: 13.80 per 100,000). Geographically, women residing in the North West Regional Health Authority (RHA) catchment area followed by the North Central RHA exhibited the highest incidence and mortality rates. Notable ancestral differences in survival were also observed. Women of East Indian and mixed ancestry experienced significantly longer survival than those of African ancestry. Differences in survival by geography were not observed. In TT, ancestry and geographical residence seem to be strong predictors of BC incidence and mortality rates. Additionally, disparities in survival by ancestry were found. These data should be considered in the design and implementation of strategies to reduce BC incidence and mortality rates in TT
High-resolution experimental phases for tryptophanyl-tRNA synthetase (TrpRS) complexed with tryptophanyl-5ā²AMP
Synergistic Ca^(2+) Responses by GĪ±_i- and GĪ±_q-coupled G-protein-coupled Receptors Require a Single PLCĪ² Isoform That Is Sensitive to Both GĪ²_Ī³ and GĪ±_q
Cross-talk between GĪ±_i- and GĪ±_q-linked G-protein-coupled receptors yields synergistic Ca^(2+) responses in a variety of cell types. Prior studies have shown that synergistic Ca^(2+) responses from macrophage G-protein-coupled receptors are primarily dependent on phospholipase CĪ²3 (PLCĪ²3), with a possible contribution of PLCĪ²2, whereas signaling through PLCĪ²4 interferes with synergy. We here show that synergy can be induced by the combination of GĪ²Ī³ and GĪ±q activation of a single PLCĪ² isoform. Synergy was absent in macrophages lacking both PLCĪ²2 and PLCĪ²3, but it was fully reconstituted following transduction with PLCĪ²3 alone. Mechanisms of PLCĪ²-mediated synergy were further explored in NIH-3T3 cells, which express little if any PLCĪ²2. RNAi-mediated knockdown of endogenous PLCĪ²s demonstrated that synergy in these cells was dependent on PLCĪ²3, but PLCĪ²1 and PLCĪ²4 did not contribute, and overexpression of either isoform inhibited Ca^(2+) synergy. When synergy was blocked by RNAi of endogenous PLCĪ²3, it could be reconstituted by expression of either human PLCĪ²3 or mouse PLCĪ²2. In contrast, it could not be reconstituted by human PLCĪ²3 with a mutation of the Y box, which disrupted activation by GĪ²Ī³, and it was only partially restored by human PLCĪ²3 with a mutation of the C terminus, which partly disrupted activation by GĪ±_q. Thus, both GĪ²Ī³ and GĪ±_q contribute to activation of PLCĪ²3 in cells for Ca^(2+) synergy. We conclude that Ca^(2+) synergy between GĪ±_i-coupled and GĪ±_q-coupled receptors requires the direct action of both GĪ²Ī³ and GĪ±q on PLCĪ² and is mediated primarily by PLCĪ²3, although PLCĪ²2 is also competent
The sleep of elite athletes at sea level and high altitude: A comparison of sea-level natives and high-altitude natives (ISA3600)
Background Altitude exposure causes acute sleep disruption in non-athletes, but little is known about its effects in elite athletes. The aim of this study was to examine the effects of altitude on two groups of elite athletes, that is, sea-level natives and high-altitude natives. Methods Sea-level natives were members of the Australian under-17 soccer team (n=14). High-altitude natives were members of a Bolivian under-20 club team (n=12). Teams participated in an 18-day (19 nights) training camp in Bolivia, with 6 nights at near sea level in Santa Cruz (430 m) and 13 nights at high altitude in La Paz (3600 m). Sleep was assessed on every day/night using activity monitors. Results The Australiansā sleep was shorter, and of poorer quality, on the first night at altitude compared with sea level. Sleep quality returned to normal by the end of the first week at altitude, but sleep quantity had still not stabilised at its normal level after 2 weeks. The quantity and quality of sleep obtained by the Bolivians was similar, or greater, on all nights at altitude compared with sea level. The Australians tended to obtain more sleep than the Bolivians at sea level and altitude, but the quality of the Boliviansā sleep tended to be better than that of the Australians at altitude. Conclusions Exposure to high altitude causes acute and chronic disruption to the sleep of elite athletes who are sea-level natives, but it does not affect the sleep of elite athletes who are high-altitude natives
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