Transcriptional Interference Regulates the Evolutionary Development of Speech

The human capacity to speak is fundamental to our advanced intellectual, technological and social development. Yet so very little is known regarding the evolutionary genetics of speech or its relationship with the broader aspects of evolutionary development in primates. In this study, we describe a large family with evolutionary retrograde development of the larynx and wrist. The family presented with severe speech impairment and incremental retrograde elongations of the pisiform in the wrist that limited wrist rotation from 180◦ to 90◦ as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene TOSPEAK had been disrupted in the family. TOSPEAK emerged de novo in an ancestor of extant primates across a 540 kb region of the genome with a pre-existing highly conserved long-range laryngeal enhancer for a neighbouring bone morphogenetic protein gene GDF6. We used transgenic mouse modelling to identify two additional GDF6 long-range enhancers within TOSPEAK that regulate GDF6 expression in the wrist. Disruption of TOSPEAK in the affected family blocked the transcription of TOSPEAK across the 3 GDF6 enhancers in association with a reduction in GDF6 expression and retrograde development of the larynx and wrist. Furthermore, we describe how TOSPEAK developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of TOSPEAK in gibbon. This repeat subsequently expanded incrementally in higher hominids to form an overlapping series of Sp1/KLF transcription factor consensus binding sites in human that correlated with incremental increases in the promoter strength of TOSPEAK with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in TOSPEAK transcriptional interference of GDF6 enhancers in the incremental evolutionary development of the wrist and larynx in hominids and the human capacity to speak and their retrogression with the reduction of TOSPEAK transcription in the affected family

L-DOPA Neurotoxicity Is Mediated by Up-Regulation of DMT1−IRE Expression

2008-2009 > Academic research: refereed > Publication in refereed journalpublished_fina

Numerical study of inflow equivalence ratio inhomogeneity on oblique detonation formation in hydrogen-air mixtures

In this study, numerical simulations using Euler equations with detailed chemistry are performed to investigate the effect of fuel-air composition inhomogeneity on the oblique detonation wave (ODW) initiation in hydrogen-air mixtures. This study aims for a better understanding of oblique detonation wave engine performance under practical operating conditions, among those is the inhomogeneous mixing of fuel and air giving rise to a variation of the equivalence ratio (ER) in the incoming combustible flow. This work focuses primarily on how a variable equivalence ratio in the inflow mixture affects both the formation and characteristic parameters of the oblique detonation wave. In this regard, the present simulation imposes initially a lateral linear distribution of the mixture equivalence ratio within the initiation region. The variation is either from fuel-lean or fuel-rich to the uniform stoichiometric mixture condition above the oblique shock wave. The obtained numerical results illustrate that the reaction surface is distorted in the cases of low mixture equivalence ratio. The so-called &quot;V-shaped&quot; flame is observed but differed from previous results that it is not coupled with any compression or shock wave. Analyzing the temperature and species density evolution also shows that the fuel-lean and fuel-rich inhomogeneity have different effects on the combustion features in the initiation region behind the oblique shock wave. Two characteristic quantities, namely the initiation length and the ODW surface position, are defined to describe quantitatively the effects of mixture equivalence ratio inhomogeneity. The results show that the initiation length is mainly determined by the mixture equivalence ratio in the initiation region. Additional computations are performed by reversing ER distribution, i.e., with the linear variation above the initiation region of uniform stoichiometric condition and results also demonstrate that the ODW position is effectively determined by the ER variation before the ODW, which has in turn only negligible effect on the initiation length. (C) 2017 Elsevier Masson SAS. All rights reserved.</p

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus

The Impact of Imputation on Meta-Analysis of Genome-Wide Association Studies

Genotype imputation is often used in the meta-analysis of genome-wide association studies (GWAS), for combining data from different studies and/or genotyping platforms, in order to improve the ability for detecting disease variants with small to moderate effects. However, how genotype imputation affects the performance of the meta-analysis of GWAS is largely unknown. In this study, we investigated the effects of genotype imputation on the performance of meta-analysis through simulations based on empirical data from the Framingham Heart Study. We found that when fix-effects models were used, considerable between-study heterogeneity was detected when causal variants were typed in only some but not all individual studies, resulting in up to ∼25% reduction of detection power. For certain situations, the power of the meta-analysis can be even less than that of individual studies. Additional analyses showed that the detection power was slightly improved when between-study heterogeneity was partially controlled through the random-effects model, relative to that of the fixed-effects model. Our study may aid in the planning, data analysis, and interpretation of GWAS meta-analysis results when genotype imputation is necessary

Increasing the simulation performance of large-scale evacuations using parallel computing techniques based on domain decomposition

Evacuation simulation has the potential to be used as part of a decision support system during large-scale incidents to provide advice to incident commanders. To be viable in these applications, it is essential that the simulation can run many times faster than real time. Parallel processing is a method of reducing run times for very large computational simulations by distributing the workload amongst a number of processors. This paper presents the development of a parallel version of the rule based evacuation simulation software buildingEXODUS using domain decomposition. Four Case Studies (CS) were tested using a cluster, consisting of 10 Intel Core 2 Duo (dual core) 3.16 GHz CPUs. CS-1 involved an idealised large geometry, with 20 exits, intended to illustrate the peak computational speed up performance of the parallel implementation, the population consisted of 100,000 agents; the peak computational speedup (PCS) was 14.6 and the peak real-time speedup (PRTS) was 4.0. CS-2 was a long area with a single exit area with a population of 100,000 agents; the PCS was 13.2 and the PRTS was 17.2. CS-3 was a 50 storey high rise building with a population of 8000/16,000 agents; the PCS was 2.48/4.49 and the PRTS was 17.9/12.9. CS-4 is a large realistic urban area with 60,000/120,000 agents; the PCS was 5.3/6.89 and the PRTS was 5.31/3.0. This type of computational performance opens evacuation simulation to a range of new innovative application areas such as real-time incident support, dynamic signage in smart buildings and virtual training environments

Climate Variability and Hemorrhagic Fever with Renal Syndrome Transmission in Northeastern China

Background: The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by climatic variables. However, few studies have examined the quantitative relationship between climate variation and HFRS transmission. ---------- Objective: We examined the potential impact of climate variability on HFRS transmission and developed climate-based forecasting models for HFRS in northeastern China. ---------- Methods: We obtained data on monthly counts of reported HFRS cases in Elunchun and Molidawahaner counties for 1997–2007 from the Inner Mongolia Center for Disease Control and Prevention and climate data from the Chinese Bureau of Meteorology. Cross-correlations assessed crude associations between climate variables, including rainfall, land surface temperature (LST), relative humidity (RH), and the multivariate El Niño Southern Oscillation (ENSO) index (MEI) and monthly HFRS cases over a range of lags. We used time-series Poisson regression models to examine the independent contribution of climatic variables to HFRS transmission. ----------- Results: Cross-correlation analyses showed that rainfall, LST, RH, and MEI were significantly associated with monthly HFRS cases with lags of 3–5 months in both study areas. The results of Poisson regression indicated that after controlling for the autocorrelation, seasonality, and long-term trend, rainfall, LST, RH, and MEI with lags of 3–5 months were associated with HFRS in both study areas. The final model had good accuracy in forecasting the occurrence of HFRS. ---------- Conclusions: Climate variability plays a significant role in HFRS transmission in northeastern China. The model developed in this study has implications for HFRS control and prevention

Effects of Combined Aspirin and Clopidogrel Therapy on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis

BACKGROUND: Aspirin and clopidogrel monotherapies are effective treatments for preventing vascular disease. However, new evidence has emerged regarding the use of combined aspirin and clopidogrel therapy to prevent cardiovascular events. We therefore performed a comprehensive systematic review and meta-analysis to evaluate the benefits and harms of combined aspirin and clopidogrel therapy on major cardiovascular outcomes. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies to fit our analysis. Eligible studies were randomized controlled trials assessing the effect of combined aspirin and clopidogrel therapy compared with aspirin or clopidogrel monotherapy. We identified 7 trials providing data with a total of 48248 patients. These studies reported 5134 major cardiovascular events, 1626 myocardial infarctions, 1927 strokes, and 1147 major bleeding events. Overall, the addition of aspirin to clopidogrel therapy as compared to single drug therapy resulted in a 9% RR reduction (95%CI, 2 to 17) in major cardiovascular events, 14% RR reduction (95%CI, 3 to 24) in myocardial infarction, 16% RR reduction (95%CI, 1 to 28) in stroke, and 62% RR increase (95%CI, 26 to 108) in major bleeding events. We also present the data as ARR to explore net value as the reduction in cardiovascular events. Overall, we observed that combined therapy yielded 1.06% decrease (95%CI, 0.23% to 1.99%) in major cardiovascular events and 1.23% increase (95%CI, 0.52% to 2.14%) in major bleeding events. CONCLUSION/SIGNIFICANCE: Although the addition of aspirin to clopidogrel resulted in small relative reductions in major cardiovascular events, myocardial infarction, and stroke, it also resulted in a relative increase in major bleeding events. In absolute terms the benefits of combined therapy, a 1.06% reduction in major cardiovascular events, does not outweigh the harms, a 1.23% increase in major bleeding events

Potential Tumor Suppressor NESG1 as an Unfavorable Prognosis Factor in Nasopharyngeal Carcinoma

BACKGROUND:Recently we identified nasopharyngeal epithelium specific protein 1 (NESG1) as a potential tumor suppressor in nasopharyngeal carcinoma (NPC). The purpose of this study is to investigate the involvement of NESG1 in tumor progression and prognosis of human NPC. METHODOLOGY/PRINCIPAL FINDINGS:NESG1 protein expression in NPC was examined. Survival analysis was performed using Kaplan-Meier method. The effect of NESG1 on cell proliferation, migration, and invasion were also investigated. RESULTS:NESG1 expression was downregulated in atypical hyperplasia and NPC samples compared to normal and squamous nasopharynx tissues. Reduced protein expression was negatively associated with the status of NPC progression. Patients with lower NESG1 expression had a shorter overall survival and disease-free time than did patients with higher NESG1 expression. Multivariate analysis suggested NESG1 expression as an independent prognostic indicator for NPC patient survival. Proliferation, migration, and invasion ability were significantly increased in cell lines following lentiviral-mediated shRNA suppression of NESG1 expression. Microarray analysis indicated that NESG1 participated in multiple pathways, including MAPK signaling and cell cycle regulation. Finally, DNA methylation microarray examination revealed a lack of hypermethylation at the NESG1 promoter, suggesting other mechanisms are involved in suppressing NESG1 expression in NPC. CONCLUSION:Our studies are the first to demonstrate that decreased NESG1 expression is an unfavorable prognostic factor for NPC