Genetic polymorphisms of VIP variants in the Tajik ethnic group of northwest China

BACKGROUND: Individual response to medications varies significantly among different populations, and great progress in understanding the molecular basis of drug action has been made in the past 50 years. The field of pharmacogenomics seeks to elucidate inherited differences in drug disposition and effects. While we know that different populations and ethnic groups are genetically heterogeneous, we have not found any pharmacogenomics information regarding minority groups, such as the Tajik ethnic group in northwest China. RESULTS: We genotyped 85 Very Important Pharmacogene (VIP) variants selected from PharmGKB in 100 unrelated, healthy Tajiks from the Xinjiang Uygur Autonomous Region and compared our data with HapMap data from four major populations around the world: Han Chinese (CHB), Japanese in Tokyo (JPT), Utah Residents with Northern and Western European Ancestry (CEU), and Yorubia in Ibadan, Nigeria (YRI). We found that Tajiks differed from CHB, JPT and YRI in 30, 32, and 32 of the selected VIP genotypes respectively (p < 0.005), while differences between Tajiks and CEU were found in only 6 of the genotypes (p < 0.005). Haplotype analysis also demonstrated differences between the Tajiks and the other four populations. CONCLUSION: Our results contribute to the pharmacogenomics database of the Tajik ethnic group and provide a theoretical basis for safer drug administration that may be useful for diagnosing and treating disease in this population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-014-0102-y) contains supplementary material, which is available to authorized users

Comprehensive comparison of three commercial human whole-exome capture platforms

BackgroundExome sequencing, which allows the global analysis of protein coding sequences in the human genome, has become an effective and affordable approach to detecting causative genetic mutations in diseases. Currently, there are several commercial human exome capture platforms; however, the relative performances of these have not been characterized sufficiently to know which is best for a particular study.ResultsWe comprehensively compared three platforms: NimbleGen's Sequence Capture Array and SeqCap EZ, and Agilent's SureSelect. We assessed their performance in a variety of ways, including number of genes covered and capture efficacy. Differences that may impact on the choice of platform were that Agilent SureSelect covered approximately 1,100 more genes, while NimbleGen provided better flanking sequence capture. Although all three platforms achieved similar capture specificity of targeted regions, the NimbleGen platforms showed better uniformity of coverage and greater genotype sensitivity at 30- to 100-fold sequencing depth. All three platforms showed similar power in exome SNP calling, including medically relevant SNPs. Compared with genotyping and whole-genome sequencing data, the three platforms achieved a similar accuracy of genotype assignment and SNP detection. Importantly, all three platforms showed similar levels of reproducibility, GC bias and reference allele bias.ConclusionsWe demonstrate key differences between the three platforms, particularly advantages of solutions over array capture and the importance of a large gene target set

Genome sequences reveal global dispersal routes and suggest convergent genetic adaptations in seahorse evolution

Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats.Fil: Chunyan, Li. Southern Marine Science and Engineering Guangdong Laboratory; China. Pilot National Laboratory for Marine Science and Technology; China. Chinese Academy of Sciences; República de ChinaFil: Olave, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; Argentina. University of Konstanz; AlemaniaFil: Hou, Yali. Chinese Academy of Sciences; República de ChinaFil: Geng, Qi. Chinese Academy of Sciences; República de China. Southern Marine Science and Engineering Guangdong Laboratory; ChinaFil: Schneider, Ralf. University Of Konstanz; Alemania. Helmholtz Centre for Ocean Research Kie; AlemaniaFil: Zeixa, Gao. Huazhong Agricultural University; ChinaFil: Xiaolong, Tu. Allwegene Technologies ; ChinaFil: Xin, Wang. Chinese Academy of Sciences; República de ChinaFil: Furong, Qi. China National Center for Bioinformation; China. University of Chinese Academy of Sciences; ChinaFil: Nater, Alexander. University of Konstanz; AlemaniaFil: Kautt, Andreas F.. University of Konstanz; Alemania. Harvard University; Estados UnidosFil: Wan, Shiming. Chinese Academy of Sciences; República de ChinaFil: Yanhong, Zhang. Chinese Academy of Sciences; República de ChinaFil: Yali, Liu. Chinese Academy of Sciences; República de ChinaFil: Huixian, Zhang. Chinese Academy of Sciences; República de ChinaFil: Bo, Zhang. Chinese Academy of Sciences; República de ChinaFil: Hao, Zhang. Chinese Academy of Sciences; República de ChinaFil: Meng, Qu ,. Chinese Academy of Sciences; República de ChinaFil: Shuaishuai, Liu. Chinese Academy of Sciences; República de ChinaFil: Zeyu, Chen. Chinese Academy of Sciences; República de China. University of Chinese Academy of Sciences; ChinaFil: Zhong, Jia. Chinese Academy of Sciences; República de ChinaFil: Zhang, He. BGI-Shenzhen; ChinaFil: Meng, Lingfeng. BGI-Shenzhen; ChinaFil: Wang, Kai. Ludong University; ChinaFil: Yin, Jianping. Chinese Academy of Sciences; República de ChinaFil: Huang, Liangmin. Chinese Academy of Sciences; República de China. University of Chinese Academy of Sciences; ChinaFil: Venkatesh, Byrappa. Institute of Molecular and Cell Biology; SingapurFil: Meyer, Axel. University of Konstanz; AlemaniaFil: Lu, Xuemei. Chinese Academy of Sciences; República de ChinaFil: Lin, Qiang. Chinese Academy of Sciences; República de China. Southern Marine Science and Engineering Guangdong Laboratory; China. Pilot National Laboratory for Marine Science and Technology; China. University of Chinese Academy of Sciences; Chin

Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Neuroprotective strategies for patients with acute myocardial infarction combined with hypoxic ischemic encephalopathy in the ICU

Background: We investigated neuroprotective treatment strategies for patients with acute myocardial infarction (AMI) complicated with hypoxic ischemic encephalopathy (HIE) in the ICU. Methods: The 83 cases diagnosed with secondary AMI were, for the first time, divided into an observation group (n = 43) and control group (n = 40). All of the patients underwent emergency or elective PCI. Patients in the control group were treated with mannitol to reduce intracranial pressure and cinepazide maleate to improve microcirculation in the brain as well as given a comprehensive treatment with oxygen inhalation, fluid infusion, acid-base imbalance correction and electrolyte disturbance. Patients in the observation group underwent conventional treatment combined with neuroprotective therapeutic strategies. The effects of the different treatment strategies were compared. Results: Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay were significantly shorter in the observation group compared with the control group (P < 0.05). After treatment, the jugular vein oxygen saturation (SjvO2) and blood lactate (JB-LA) levels of both groups were lower than before treatment and the cerebral oxygen utilization rate (O2UC) increased, with a significantly higher increase in the observation group (P < 0.05). After treatment, the activities of daily living (ADL) score was higher for both groups and the neural function defect (NIHS) score was lower. Conclusion: The neuroprotective strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen was effective for treating AMI patients with HIE and may be worth clinical promotion. Keywords: ICU, Acute myocardial infarction, Hypoxic ischemic encephalopathy, Neural protectio

Harmonic Vibrational Frequency Simulation of Pharmaceutical Molecules via a Novel Multi-Molecular Fragment Interception Method

By means of a computational method based on Density Functional Theory (DFT), using commercially available software, a novel method for simulating equilibrium geometry harmonic vibrational frequencies is proposed. Finasteride, Lamivudine, and Repaglinide were selected as model molecules to study the adaptability of the new method. Three molecular models, namely the single-molecular, central-molecular, and multi-molecular fragment models, were constructed and calculated by Generalized Gradient Approximations (GGAs) with the PBE functional via the Material Studio 8.0 program. Theoretical vibrational frequencies were assigned and compared to the corresponding experimental data. The results indicated that the traditional single-molecular calculation and scaled spectra with scale factor exhibited the worst similarity for all three pharmaceutical molecules among the three models. Furthermore, the central-molecular model with a configuration closer to the empirical structure resulted in a reduction of mean absolute error (MAE) and root mean squared error (RMSE) in all three pharmaceutics, including the hydrogen-bonded functional groups. However, the improvement in computational accuracy for different drug molecules using the central-molecular model for vibrational frequency calculation was unstable. Whereas, the new multi-molecular fragment interception method showed the best agreement with experimental results, exhibiting MAE and RMSE values of 8.21 cm−1 and 18.35 cm−1 for Finasteride, 15.95 cm−1 and 26.46 cm−1 for Lamivudine, and 12.10 cm−1 and 25.82 cm−1 for Repaglinide. Additionally, this work provides comprehensive vibrational frequency calculations and assignments for Finasteride, Lamivudine, and Repaglinide, which have never been thoroughly investigated in previous research

Abnormal grain growth under solution-aging treatments enables convergence mechanical properties of a Fe-Ni-Cr based austenitic alloy

In this study, systematic heat treatment routes including solution (980 °C to 1130 °C) and aging (675 °C to 775 °C) processes were used to tailor the microstructural evolution and mechanical performance of a Fe-Ni-Cr based austenitic alloy, strengthened by a γ ′ phase (Ni _3 (Ti, Al)). Grain growth was observed with increasing solution treatment temperature from nearly 90 μ m (980 °C) to nearly 200 μ m (1130 °C). Grain refinement during solution heat processes was found to ascribe to the solute drag effect and the pinning effect of nickel-titanium-enriched segregates and precipitates. During aging, the precipitation behavior of γ ′ is found to be almost independent of solution treatment temperatures. Interestingly, abnormal grain growth during aging was observed. The motion of grain boundaries was ascribed to the formation of nickel-titanium-enriched γ ′ in the austenitic matrix, thereby contributing to the dissolution of the previously enriched segregates and precipitates from grain boundaries. The studied alloy shows a wide range of mechanical properties, from tensile strength of 1131 MPa with ductility at 36%, to tensile strength of 880 MPa with ductility at 50%. The current study demonstrates that grain refinement of the alloy at solution treatment may not benefit the final mechanical properties

Physiological and Dual Transcriptional Analysis of Microalga Graesiella emersonii&ndash;Amoeboaphelidium protococcarum Pathosystem Uncovers Conserved Defense Response and Robust Pathogenicity

The underlying mechanisms of microalgal host&ndash;pathogen interactions remain largely unknown. In this study, we applied physiological and simultaneous dual transcriptomic analysis to characterize the microalga Graesiella emersonii&ndash;Amoeboaphelidium protococcarum interaction. Three infection stages were determined according to infection rate and physiological features. Dual RNA-seq results showed that the genes expression of G. emersonii and A. protococcarum were strongly dynamically regulated during the infection. For microalgal hosts, similar to plant defense response, the expression of defense genes involved in the pattern recognition receptors, large heat shock proteins, and reactive oxygen scavenging enzymes (glutathione, ferritin, and catalase) were significantly upregulated during infection. However, some genes encoding resistance proteins (R proteins) with a leucine-rich repeat domain exhibited no significant changes during infection. For endoparasite A. protococcarum, genes for carbohydrate-active enzymes, pathogen&ndash;host interactions, and putative effectors were significantly upregulated during infection. Furthermore, the genes in cluster II were significantly enriched in pathways associated with the modulation of vacuole transport, including endocytosis, phagosome, ubiquitin-mediated proteolysis, and SNARE interactions in vesicular transport pathways. These results suggest that G. emersonii has a conserved defense system against pathogen and that endoparasite A. protococcarum possesses a robust pathogenicity to infect the host. Our study characterizes the first transcriptomic profile of microalgae&ndash;endoparasite interaction, providing a new promising basis for complete understanding of the algal host defense strategies and parasite pathogenicity