Studies of natural selection, followed by functional validation, are shedding light on understanding of genetic mechanisms underlying human evolution and adaptation. Classic methods for detecting selection, such as the integrated haplotype score (iHS) and Fay and Wu's H statistic, are useful for candidate gene searching underlying positive selection. These methods, however, have limited capability to localize causal variants in selection target regions. In this study, we developed a novel method based on conditional coalescent tree to detect recent positive selection by counting unbalanced mutations on coalescent gene genealogies. Extensive simulation studies revealed that our method is more robust than many other approaches against biases due to various demographic effects, including population bottleneck, expansion, or stratification, while not sacrificing its power. Furthermore, our method demonstrated its superiority in localizing causal variants from massive linked genetic variants. The rate of successful localization was about 20-40% higher than that of other state-of-the-art methods on simulated data sets. On empirical data, validated functional causal variants of four well-known positive selected genes were all successfully localized by our method, such as ADH1B, MCM6, APOL1, and HBB. Finally, the computational efficiency of this new method was much higher than that of iHS implementations, that is, 24-66 times faster than the REHH package, and more than 10,000 times faster than the original iHS implementation. These magnitudes make our method suitable for applying on large sequencing data sets. Software can be downloaded from https://github.com/wavefancy/scct.
Bio-electrospraying (BES) is a technique for directly jetting living cells that has significant implications for tissue engineering and regenerative medicine. However, the effect of BES on human adipose-derived stem cells (hASCs) remains unknown. Here, we show that an hASC suspension was successfully electrosprayed via a continuous, stable and linearly directed electrospray at 10 kV and at 3 ml/h. Morphological observations and Trypan Blue and CCK-8 assays revealed that the cells remained viable and proliferated at a rate similar to that of the controls (0 kV). However, at 20 kV, BES became unstable and cell viability was reduced. Moreover, hASCs electrosprayed at 10 kV retained their multilineage potential, successfully differentiating into chondrogenic, osteogenic and neurogenic lineages. Thus, BES does not significantly affect cell morphology, viability or multipotency.
The title compound, C4H8O4Te, crystallized from a solution of Te(4+) in ethyl-ene glycol. The Te(IV) atom is in a distorted seesaw coordination defined by four O atoms from two different ethyl-eneglycate ligands. The C atoms of the ethyl-eneglycate ligands are disorderd over two positions, with population parameters of 50.3?(6) and 49.7?(6)% indicating a statistical distribution. Due to the possibility to transform the primitive monoclinic unit cell into a metrically ortho-rhom-bic C unit cell, the data are twinned and were refined with the twin law -100/0-10/101 with the relative scale factor refining to 1.82?(4)% for the minor component.
The electrodeposition of germanium from the ionic liquid 1-butyl-1-methylpyrrolidinium dicyanamide ([BMP][DCA]) and a mixture of [BMP][DCA] and 1-butyl-1-methylpyrrolidinium chloride ([BMP]Cl) was studied using cyclic voltammetry and using an electrochemical quartz crystal microbalance (EQCM). [GeCl4(BuIm)2] (BuIm = N-butylimidazole) was used as germanium source as it has a solubility of 0.47 M, up to 13 times the solubility of GeCl4 in [BMP][DCA]. Cyclic voltammograms show an irreversible electrochemical behavior and two reduction waves were observed. The wave at the more positive potential was assigned to the reduction of Ge(4+) to Ge(2+). The wave at the more negative potential was attributed to the formation of Ge(0). The diffusion coefficient of Ge(4+) in [BMP][DCA] containing 0.1 M [GeCl4(BuIm)2] is 1.1 × 10(-12) m(2) s(-1), and the exchange current density is 2 × 10(-4) A m(-2) at 50 °C. Polymerization of dicyanamide anions took place at the anode in the solution of [BMP][DCA]. The polymerization reaction could be avoided by using an equimolar [BMP]Cl-[BMP][DCA] mixture as electrolyte. Smooth, porous germanium films were electrodeposited on both copper and silicon substrates.
Context. Modified Chaihu Shugan powder (MCSP) is a popular traditional Chinese herbal formula for functional dyspepsia, which is revised from Chaihu Shugan San and recorded in a medical classic works of China. However, its role and effect in treating functional dyspepsia have not been well established. Objective. To assess the effect and safety of modified Chaihu Shugan powder for functional dyspepsia. Methods. We searched the published and unpublished studies up to August 2012. Only RCTs of modified Chaihu Shugan powder with or without prokinetic drugs versus prokinetic drugs in the patients diagnosed with functional dyspepsia were included. Results. Twenty-two clinical trials involving 1998 participants were included. There were evidences that modified Chaihu Shugan powder (RR = 1.20, 95%, CI 1.14 to 1.27) and modified Chaihu Shugan powder plus prokinetic drugs (RR = 1.18, 95%, CI 1.11 to 1.25) were significantly better treatment options than prokinetic drugs alone in improving symptoms. No serious adverse events were described in the included trials. Conclusions. This meta-analysis showed that modified Chaihu Shugan powder alone or in combination with prokinetic drugs might be more effective than prokinetic drugs alone. However, with poor methodological quality, all the included trials were at high risk of bias. Further large-scale high-quality trials are required for assessment.
Hepatitis B virus (HBV) is an important infectious agent that causes widespread concern because billions of people are infected by at least 8 different HBV genotypes worldwide. However, reconstruction of the phylogenetic relationship between HBV genotypes is difficult. Specifically, the phylogenetic relationships among genotypes A, B, and C are not clear from previous studies because of the confounding effects of genotype recombination. In order to clarify the evolutionary relationships, a rigorous approach is required that can effectively explore genetic sequences with recombination.
Testing for random mating of a population is important in population genetics, because deviations from randomness of mating may indicate inbreeding, population stratification, natural selection, or sampling bias. However, current methods use only observed numbers of genotypes and alleles, and do not take advantage of the fact that the advent of sequencing technology provides an opportunity to investigate this topic in unprecedented detail. To address this opportunity, a novel statistical test for random mating is required in population genomics studies for which large sequencing datasets are generally available. Here, we propose a Monte-Carlo-based-permutation test (MCP) as an approach to detect random mating. Computer simulations used to evaluate the performance of the permutation test indicate that its type I error is well controlled and that its statistical power is greater than that of the commonly used chi-square test (CHI). Our simulation study shows the power of our test is greater for datasets characterized by lower levels of migration between subpopulations. In addition, test power increases with increasing recombination rate, sample size, and divergence time of subpopulations. For populations exhibiting limited migration and having average levels of population divergence, the statistical power approaches 1 for sequences longer than 1 Mbp and for samples of 400 individuals or more. Taken together, our results suggest that our permutation test is a valuable tool to detect random mating of populations, especially in population genomics studies.
Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (K(i)) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600?M, 2.600?M, 3.200?M, 3.600?M and 3.600?M, respectively. To elucidate the structural features of potent inhibitors, docking-based three-dimensional structure-activity relationship (3D-QSAR) analyses were performed. Satisfactory agreement between experiment and theory suggests that comparative molecular similarity index analysis (CoMSIA) modeling exhibit much better correlation and predictive power. The cross-validated q(2) value is 0.638 while no-validation r(2) value is 0.930. Integrated with docking-based 3D-QSAR CoMSIA modeling, molecular surface property (electrostatic and steric) mapping and molecular dynamics simulation, a set of receptor-ligand binding models and bio-affinity predictive models for rational design of more potent inhibitors of GLO I are established.
Human cerebral malaria causes neurological and behavioral deficits which persist long after resolution of infection and clearance of parasites with antimalarial drugs. Previously, we demonstrated that during active infection, mice with cerebral malaria demonstrated negative behavioral outcomes. Here we used a chloroquine treatment model of cerebral malaria to determine whether these abnormal outcomes would be persistent in the mouse model. C57BL/6 mice were infected with Plasmodium berghei ANKA, and treated for ten days. After cessation of chloroquine, a comprehensive assessment of cognitive and motor function demonstrated persistence of abnormal behavioral outcomes, 10 days after successful eradication of parasites. Furthermore, these deficits were still evident forty days after cessation of chloroquine, indicating persistence long after successful treatment, a hallmark feature of human cerebral malaria. Thus, cognitive tests similar to those used in these mouse studies could facilitate the development of adjunctive therapies that can ameliorate adverse neurological outcomes in human cerebral malaria.
We report a new complex Eu(tta)(3).bpt (tta = thenoyltrifluoroacetonate; bpt = 2-(N,N-di-ethylanilin-4-yl)-4,6-bis(pyrazol-1-yl)-1,3,5-triazine) with excellent long-wavelength sensitized luminescent properties, in which four hydrogen atoms replace the methyl groups at the 3,3- and 5,5-positions of the pyrazolyl rings in a previously reported complex Eu(tta)(3).dpbt. Upon visible-light excitation (lambda(ex) = 410 nm) at 295 K, the quantum yield (Phi(Ln)(L)) of Eu(3+) luminescence of Eu(tta)(3).bpt is higher by 23% than that of Eu(tta)(3).dpbt. Different from the case of Eu(tta)(3).dpbt, Phi(Ln)(L) of Eu(tta)(3).bpt increases linearly with the decrease in temperature. Because of the different coordination environments around Eu(3+) ion, the fine structure of the hypersensitive (5)D(0)-->(7)F(2) emission band of Eu(tta)(3).bpt is quite different from that of Eu(tta)(3).dpbt, with the strongest emission line locating at 620 nm rather than 613 nm where the strongest emission line of Eu(tta)(3).dpbt appears. The excitation window of Eu(tta)(3).bpt is much broader than that of Eu(tta)(3).dpbt with a red edge extending up to 450 nm in a dilute toluene solution (1.0 x 10(-5) M) and 500 nm in a toluene solution (1.0 x 10(-2) M). Eu(tta)(3).bpt also exhibits excellent two-photon-excitation luminescent properties.
Glyoxalase I (GLOI) is a key metalloenzyme in glycolytic pathway by detoxifying reactive alpha-ketoaldehydes such as methylglyoxal. Recent studies demonstrate that the nature product curcumin is an efficient inhibitor of GLOI, but its binding mechanism towards GLOI is still unclear. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to better understand the inhibitory mechanism of curcumin towards GLOI. The enol form of curcumin coordinates with the catalytic zinc ion of GLOI and forms a strong hydrogen bond with Glu 172, whereas its keto tautomer displays unfavorable electrostatic interactions with Glu 172 and Glu 99. The calculated binding free energies suggest that GLOI prefers the primary enol form (DeltaG=-30.38kcal/mol) to the keto tautomer (DeltaG=-24.16kcal/mol). The present work also reveals that bisdemethoxycurcumin binds to GLOI in a similar manner as curcumin and exhibits a slightly less negative predicted binding free energy, which is further validated by our comparative kinetics analysis (Ki=18.2 and 10.3muM for bisdemethoxycurcumin and curcumin, respectively). Results of the study can provide an insight into the development of novel and more effective GLOI inhibitors.
Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3?) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3? activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3? inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3? with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3? signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM.
To investigate the association between vasculopathy and survival during experimental cerebral malaria (ECM), and to determine whether targeting the endothelin-1 (ET-1) pathway alone or in combination with the anti-malaria drug artemether (a semi-synthetic derivative of artemisinin) will improve microvascular hemorrhage and survival.
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