One-Pot Synthesis of Alkyl Functionalized Reduced Graphene Oxide Nanocomposites as the Lubrication Additive Enabling Enhanced Tribological Performance.

Recently, aiming for the enhanced dispersibility of graphene-based nanomaterials in lubricating oil matrices to serve as highly efficient lubricant additives, numerous modification approaches have been extensively studied. However, these previous modification routes usually involve a tedious multistep modification process or multitudinous toxic reagents, restricting their extensive practical application. In this work, novel graphene oxide (GO) nanoadditives (RGO-g-BO) featuring excellent durable dispersion capability and remarkable tribological performance were successfully prepared via an environmentally friendly one-step approach consisting of surface grafting of long-chain bromooctadecane (BO) and in situ chemical reduction. Benefiting from the greatly improved lipophilicity (resulting from the introduction of hydrophobic long-chain alkane groups and chemical reduction), along with the miniaturization effect, RGO-g-BO exhibits superior long-term dispersion stability in the finished oil. Moreover, the tribological properties results demonstrated that the finished oil filled with RGO-g-BO nanolubricants achieved an outstanding friction-reducing and antiwear performance. Particularly, under the optimum content of RGO-g-BO (as low as 0.005 wt%), the friction coefficient as well as the wear volume of the composite finished oil were greatly reduced by 13% and 53%, respectively, as compared with nascent finished oil. Therefore, in view of the advantages of low-cost, one-step facile synthesis, desirable dispersion capability, and remarkable tribological performance, RGO-g-BO holds great prospects as a highly efficient lubrication additive in the tribology field.

Structural design and preparation of Ti3C2Tx MXene/polymer composites for absorption-dominated electromagnetic interference shielding.

Electromagnetic interference (EMI) is a pervasive and harmful phenomenon in modern society that affects the functionality and reliability of electronic devices and poses a threat to human health. To address this issue, EMI-shielding materials with high absorption performance have attracted considerable attention. Among various candidates, two-dimensional MXenes are promising materials for EMI shielding due to their high conductivity and tunable surface chemistry. Moreover, by incorporating magnetic and conductive fillers into MXene/polymer composites, the EMI shielding performance can be further improved through structural design and impedance matching. Herein, we provide a comprehensive review of the recent progress in MXene/polymer composites for absorption-dominated EMI shielding applications. We summarize the fabrication methods and EMI shielding mechanisms of different composite structures, such as homogeneous, multilayer, segregated, porous, and hybrid structures. We also analyze the advantages and disadvantages of these structures in terms of EMI shielding effectiveness and the absorption ratio. Furthermore, we discuss the roles of magnetic and conductive fillers in modulating the electrical properties and EMI shielding performance of the composites. We also introduce the methods for evaluating the EMI shielding performance of the materials and emphasize the electromagnetic parameters and challenges. Finally, we provide insights and suggestions for the future development of MXene/polymer composites for EMI shielding applications.

Exploring the target and molecular mechanism of Astragalus membranaceus in the treatment of vascular cognitive impairment based on network pharmacology and molecular docking.

Astragalus membranaceus (AM) is a traditional Chinese herbal medicine extensively utilized in vascular cognitive impairment (VCI) treatment. However, due to the complex components of AM, its exact molecular mechanism remains unclear. Therefore, this study investigated the target and molecular mechanism of AM to treat VCI based on network pharmacology and molecular docking. Firstly, the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, STITCH, and SwissTargetPrediction were utilized to gather the primary active ingredients of AM. The potential therapeutic targets of VCI were collected through GeneCards, OMIM, and DisGeNET databases. Secondly, the protein-protein interaction network was built using the STRING database. The enrichment analysis of gene ontology and the Kyoto Encyclopedia of Genes and Genome pathways was carried out in the R language. Finally, The network topology calculation of Cytoscape software was combined with module analysis to predict the binding properties of its active ingredients and targets. Twenty effective compounds and 733 targets were screened from AM, among which 158 targets were seen as possible targets of AM to treat VCI. MAPK3 and MMP9 were the critical targets of AM intervention in VCI. The crucial pathways include PI3K/Akt, MAPK, Rap1, and Ras signaling pathways. Besides, calycosin and quercetin might be the potential active compounds of AM for VCI treatment. AM intervenes in VCI through a multi-ingredient, multi-target, and multi-pathway coordination mechanism. These findings provide a foundation for a deeper understanding of the molecular mechanisms by which AM is effective in treating VCI.

Development of Electromagnetic-Wave-Shielding Polyvinylidene Fluoride-Ti3C2Tx MXene-Carbon Nanotube Composites by Improving Impedance Matching and Conductivity.

Absorption-dominated electromagnetic interference (EMI) shielding is attained by improving impedance matching and conductivity through structural design. Polyvinylidene fluoride (PVDF)-Ti3C2Tx MXene-single-walled carbon nanotubes (SWCNTs) composites with layered heterogeneous conductive fillers and segregated structures were prepared through electrostatic flocculation and hot pressing of the PVDF composite microsphere-coated MXene and SWCNTs in a layer-by-layer fashion. Results suggest that the heterogeneous fillers improve impedance matching and layered coating, and hot compression allows the MXene and SWCNTs to form a continuous conducting network at the PVDF interface, thereby conferring excellent conductivity to the composite. The PVDF-MXene-SWCNTs composite showed a conductivity of 2.75 S cm-1 at 2.5% MXene and 1% SWCNTs. The EMI shielding efficiency (SE) and contribution from absorption loss to the total EMI SE of PVDF-MXene-SWCNTs were 46.1 dB and 85.7%, respectively. Furthermore, the PVDF-MXene-SWCNTs composite exhibited excellent dielectric losses and impedance matching. Therefore, the layered heteroconductive fillers in a segregated structure optimize impedance matching, provide excellent conductivity, and improve absorption-dominated electromagnetic shielding.

Interrogating the Human Diplome: Computational Methods, Emerging Applications, and Challenges.

Human DNA sequencing protocols have revolutionized human biology, biomedical science, and clinical practice, but still have very important limitations. One limitation is that most protocols do not separate or assemble (i.e., "phase") the nucleotide content of each of the maternally and paternally derived chromosomal homologs making up the 22 autosomal pairs and the chromosomal pair making up the pseudo-autosomal region of the sex chromosomes. This has led to a dearth of studies and a consequent underappreciation of many phenomena of fundamental importance to basic and clinical genomic science. We discuss a few protocols for obtaining phase information as well as their limitations, including those that could be used in tumor phasing settings. We then describe a number of biological and clinical phenomena that require phase information. These include phenomena that require precise knowledge of the nucleotide sequence in a chromosomal segment from germline or somatic cells, such as DNA binding events, and insight into unique cis vs. trans-acting functionally impactful variant combinations-for example, variants implicated in a phenotype governed by compound heterozygosity. In addition, we also comment on the need for reliable and consensus-based diploid-context computational workflows for variant identification as well as the need for laboratory-based functional verification strategies for validating cis vs. trans effects of variant combinations. We also briefly describe available resources, example studies, as well as areas of further research, and ultimately argue that the science behind the study of human diploidy, referred to as "diplomics," which will be enabled by nucleotide-level resolution of phased genomes, is a logical next step in the analysis of human genome biology.

Robust and Multifunctional 3D Graphene-Based Aerogels Reinforced by Hydroxyapatite Nanowires for Highly Efficient Organic Solvent Adsorption and Fluoride Removal.

In view of the serious perniciousness and complex diversity of actual wastewater systems, exploiting a robust and multifunctional adsorbent material featuring high sorption efficiency, broad-spectrum applicability, and excellent recyclability in treating multifarious pollutants in water (such as oils and fluoride ions) is highly required; however, it is still a daunting goal to pursue to date. In this work, novel mechanically robust and exceptional graphene oxide/hydroxyapatite nanowire (GO/HAPNW) aerogels (RGHAs/polydopamine (PDA)@RGHAs) with adjustable surface wettability were developed through a facile sol-gel self-assembly technology and subsequently optional bioinspired hydrophilic modification. Thanks to the reinforcing effect of HAPNWs with higher aspect ratio, a remarkably improved mechanical robustness (including superior compressibility and superelasticity) was acquired for the resulting aerogels. Based on the cooperative effect of the favorable selective wetting properties (i.e., hydrophobic/oleophilic for RGHAs) and the excellent mechanic stability, the aerogels displayed an outstanding sorption performance for diverse oils/organic solvents accompanied with a prominent recyclability. Specifically, a fairly high adsorption capacity of as high as 191 times of its own mass (for pump oil) was achieved based on a fast adsorption kinetic process. More importantly, superamphiphilic three-dimensional (3D) PDA@RGHAs revealed an extraordinary removal capability for water-soluble fluoride ions, exhibiting a superior equilibrium adsorption capacity (qe, 9.93 mg/g), which is distinctly superior to those of low-dimensional fluorine adsorbent materials recently reported. Accordingly, the as-prepared 3D aerogels combining both superior oil/organic solvent adsorption and excellent defluorination capability reveal a competitive application prospect toward effective intricate oily wastewater purification.

miR-122-5p regulates proliferation and apoptosis of chicken granulosa cells of hierarchal follicles by targeting MAPK3.

Chicken follicles plays a crucial role in the reproductive performance, especially in laying period. Recently, miR-122-5p has been found to be differentially expressed in the ovaries of rats with polycystic ovary syndrome and normal rats, indicating the potential role of miR-122-5p in the development of granulosa cells (GCs). In present study, we found that miR-122-5p was highly expressed in chicken atrophic ovaries. Herein, we investigated its function on GC proliferation and apoptosis of chicken in vitro. We found that overexpression of miR-122-5p significantly inhibited proliferation and promoted apoptosis of GCs, whereas the opposite effects were detected in miR-122-5p knockdown GCs. Meanwhile, mitogen-activated protein kinase 3 (MAPK3) was confirmed as a new target gene of miR-122-5p by bioinformatics software prediction and the dual-luciferase reporter assay verification. Furthermore, after knockdown of MAPK3, the function of MAPK3 for GC proliferation and apoptosis was opposite to that of miR-122-5p. Collectively, our results indicated that miR-122-5p impeded chicken GC proliferation and promoted apoptosis through the post-transcriptional downregulation of MAPK3.

Robust Graphene/Poly(vinyl alcohol) Janus Aerogels with a Hierarchical Architecture for Highly Efficient Switchable Separation of Oil/Water Emulsions.

Given the complexity and diversity of actual oily sewages, developing multifunctional separation materials with features of high separation efficiency and low energy consumption for separating diverse oil/water emulsions is urgently needed, yet it remains a formidable challenge till now. Herein, a superior graphene/poly(vinyl alcohol) Janus aerogel (J-CGPA), showing an intriguing three-dimensional (3D) hierarchical architecture (a dense skin-layer and a larger internal cell network) and desirable asymmetric wettability, was exploited via a simple direct freeze-shaping technique and subsequent mussel-inspired hydrophilic modification. Benefiting from the controlled unilateral decoration of dopamine, the resultant aerogels displayed completely opposite superwettability on two antithetic sides, i.e., one side is highly hydrophobic (water contact angle (WCA), 143°), whereas the other side is superhydrophilic. On the basis of the favorable 3D hierarchical structure and binary cooperative superwetting properties, the Janus aerogels achieved a remarkable switchable separation performance for both highly emulsified oil-in-water and water-in-oil emulsions as well as stratified oil/water mixtures accompanied with outstanding separation efficiencies. Particularly, an ultrahigh permeation flux of 1306 L m-2 h-1 along with a high rejection efficiency of 99.7% was acquired solely under the driving of gravity (<1 kPa), which is 1-2 order of magnitude higher than that of pioneering two-dimensional Janus polymeric/inorganic membranes recently reported. Moreover, together with robust reusability, this novel 3D Janus aerogel indicates a promising practical application for high-performance oily wastewater remediation.

Facile construction of gas diode membrane towards in situ gas consumption via coupling two chemical reactions.

Controlling the bubbles' behavior on a solid surface is significant for exploring more related applications and thus recently has attracted increased investigations. Based on this, a Janus poly (l-lactic acid) (PLLA) membrane with definitely opposite water wettability in air and opposite bubble wettability underwater was successfully fabricated in this work. The obtained Janus membrane exhibited unidirectional transport for air bubble underwater from the superaerophilic side to superaerophobic side, meanwhile prevented the permeation of water medium from both sides under low pressure. This special membrane was designed to couple two chemical reactions. During the designed chemical reaction process, the feature of bubble unidirectional transport allowed the carbon dioxide (CO2) produced in one reaction system to transport through the resultant membrane into another reaction system, wherein it could be consumed. Meanwhile, the anti-water-permeation function of the membrane guaranteed that the two chemical reactions could be performed independently. We believe that the present research could broaden the potential applications of membranes with super-wetting character for gas bubbles.

Facile fabrication of long-chain alkyl functionalized ultrafine reduced graphene oxide nanocomposites for enhanced tribological performance.

Due to their ultrathin 2D laminated structure as well as excellent mechanical and thermal stabilities, ultrafine graphene-based nanoparticles exhibit fascinating advantages as highly-efficient lubricant additives. However, it remains a daunting challenge to achieve good and durable dispersion of these graphene-based nanoparticles in lubricating oils. Herein, we report a facile and efficient integration strategy involving particle size miniaturization, surface grafting with octadecyl alcohol (OA), and partial chemical reduction to prepare a novel long-chain alkyl functionalized ultrafine reduced graphene oxide (RGO-g-OA) with highly-dispersive capacity and superior tribological performance. The chemical composition and structural characteristics, microstructural morphology, and particle size distribution of RGO-g-OA were systematically investigated. Combining significantly improved lipophilicity derived from the long-chain alkyl grafting and partial chemical reduction with the small-size effect gave rise to outstanding long-term dispersion stability (as long as one month) of RGO-g-OA in the finished oil. Moreover, the friction coefficient and wear volume of finished oil with merely 0.005 wt% RGO-g-OA greatly reduced to 0.065 and 10 316 µm3, decreased by 9.7% and 44%, respectively, compared to those of pristine finished oil, demonstrating remarkable friction reduction and anti-wear performances. Consequently, owing to the characteristics of facile fabrication, durable dispersion stability, and superior tribological performance at an extremely low content, this novel nanoadditive shows a promising application potential in the tribology field.

Flexible Polydimethylsilane Nanocomposites Enhanced with a Three-Dimensional Graphene/Carbon Nanotube Bicontinuous Framework for High-Performance Electromagnetic Interference Shielding.

High-performance electromagnetic interference (EMI)-shielding materials featuring lightweight, flexibility, excellent conductivity, and shielding properties, as well as superior mechanical robustness, are highly required, yet their development still remains a daunting challenge. Here, a flexible and exceptional EMI-shielding polydimethylsilane/reduced graphene oxide/single-wall carbon nanotube (PDMS/rGO/SWCNT) nanocomposite was developed by a facile backfilling approach utilizing a preformed rGO/SWCNT aerogel as the three-dimensional (3D) conducting and reinforcement skeleton. Pristine SWCNTs acting as secondary conductive fillers showed intriguing advantages, whose intrinsically high conductivity could be well preserved in the composites because of no surface acidification treatment. The robust and interconnected 3D network can not only serve as fast channels for electron transport but also effectively transfer external load. Accordingly, a prominent electrical conductivity of 1.2 S cm-1 and an outstanding EMI-shielding effectiveness of around 31 dB over the X-band frequency range were achieved for the resultant composite with an ultralow loading of 0.28 wt %, which is among the best results for currently reported conductive polymer nanocomposites. Moreover, the composite displayed excellent mechanical properties and bending stability; for example, a 233% increment in the compression strength was obtained compared with that of neat PDMS. These observations indicate the unrivalled effectiveness of 3D rGO/SWCNT aerogel as a reinforcement to endow the polymer composites with outstanding conductive and mechanical properties toward high-performance EMI-shielding application.

Polyols-Infused Slippery Surfaces Based on Magnetic Fe3O4-Functionalized Polymer Hybrids for Enhanced Multifunctional Anti-Icing and Deicing Properties.

High durability, low cost, and superior anti-icing and active deicing multifunctional surface coatings, especially in the extreme environment, are highly desired to inhibit and/or eliminate the detriment of icing in many fields, such as automobile, aerospace, and power transmission. Herein, we first report a facile and versatile strategy to prepare novel slippery polyols-infused porous surfaces (SPIPS's) with the inexpensive polyols as the lubricant liquids. These SPIPS's are fabricated by a spray-coating approach based on amino-modified magnetic Fe3O4 nanoparticles (MNP@NH2) and amphiphilic P(poly(ethylene glycol) methyl ether methacrylate- co-glycidyl methacrylate) copolymer covalent cross-linked hybrids, followed by infusion with various polyols. The as-prepared surface exhibits excellent antifrosting property, that is, it can greatly postpone frost formation as long as 2700 s at -18 °C. Meanwhile, differential scanning calorimetry results clearly demonstrate that SPIPS's show a remarkable freezing point depression capacity and the crystallization point of water can be decreased as low as -36.8 °C. The SPIPS also displays an extremely low ice adhesion strength (0.1 kPa) due to its unique surface characteristics. Moreover, outstanding active thermal deicing property is achieved for these slippery surfaces because of intrinsically photothermal effect of magnetic Fe3O4 nanoparticle. Hence, these results indicate that this kind of multifunctional bioinspired slippery surface, with superb stability, good cost effectiveness, and easy fabrication, can be used as a promising candidate for anti-icing and deicing applications.

Association of single nucleotide polymorphisms of APOBEC3G with susceptibility to HIV-1 infection and disease progression among men engaging in homosexual activity in northern China.

Men who have sex with men (MSM) are at high risk of HIV infection. The APOBEC3G (apolipoprotein B mRNA editing catalytic polypeptide 3G) protein is a component of innate antiviral immunity that inhibits HIV-1 replication. In the present study, a total of 483 HIV-1 seropositive men and 493 HIV-1 seronegative men were selected to investigate the association between single nucleotide polymorphisms (SNPs) of the APOBEC3G gene and susceptibility to HIV-1 infection and AIDS progression among MSM residing in northern China. Genotyping of four SNPs (rs5757465, rs3736685, rs8177832, and rs2899313) of the APOBEC3G was performed using the SNPscan™ Kit, while the rs2294367 polymorphism was genotyped using the SNaPshot multiplex system. Our results disclosed no association between the SNPs of APOBEC3G and susceptibility to HIV-1, or effects of these polymorphisms on the CD4+ T cell count or clinical phase of disease. A meta-analysis of 1624 men with HIV-1 infection and 1523 controls suggested that the association between rs8177832 and susceptibility was not significant. However, we observed a trend towards association with HIV-1 infection for haplotype TTACA (p = 0.082). The potential role of variants of APOBEC3G in HIV-1/AIDS warrants further investigation.

Silicone Oil-Infused Slippery Surfaces Based on Sol-Gel Process-Induced Nanocomposite Coatings: A Facile Approach to Highly Stable Bioinspired Surface for Biofouling Resistance.

Slippery liquid-infused surfaces (SLIPS) have aroused widespread attention due to their excellent liquid-repellency properties associated with broad applications in various fields. However, the complicated preparation processes and the vulnerable surface lubricant layers severely restrict the practical applications of SLIPS. In this work, robust transparent slippery hybrid coatings (SHCs) were easily fabricated by the infusion of sol-gel-derived nanocomposite coatings in silicone oils of varying viscosity. The prepared silicone oil-infused surfaces exhibited outstanding long-term slippery stability even under extreme operating conditions such as high shear rate, elevated evaporation, and flowing aqueous immersion. Static bacteria culture tests confirmed that the SHCs could significantly inhibit biofilm formation. In addition, bovine serum albumin adhesion experiments were conducted after lubricant loss tests, showing significantly less protein absorption and a long service life of the SLIPS. The unique ultralow bacterial attachment and remarkably long-term protein-resistant performance render the as-prepared SLIPS as a promising candidate for biomedical applications even under harsh environmental conditions.

Novel Fluorinated Polymers Containing Short Perfluorobutyl Side Chains and Their Super Wetting Performance on Diverse Substrates.

Because the emission of perfluorooctanoic acid (PFOA) was completely prohibited in 2015, the widely used poly- and perfluoroalkyl substances with long perfluoroalkyl groups must be substituted by environmentally friendly alternatives. In this study, one kind of potential alternative (i.e., fluorinated polymers with short perfluorobutyl side chains) has been synthesized from the prepared monomers {i.e., (perfluorobutyl)ethyl acrylate (C4A), (perfluorobutyl)ethyl methacrylate (C4MA), 2-[[[[2-(perfluorobutyl)]sulfonyl]methyl]amino]ethyl acrylate (C4SA), and methacrylate (C4SMA)}, and the microstructure, super wetting performance, and applications of the synthesized fluorinated polymers were systematically investigated. The thermal and crystallization behaviors of the fluoropolymer films were characterized by differential scanning calorimetry and wide-angle X-ray diffraction analysis, respectively. Dynamic water-repellent models were constructed. The stable low surface energy and dynamic water- and oil-repellent properties of these synthesized fluorinated polymers with short perfluorobutyl side chains were attributed to the synergetic effect of amorphous fluorinated side chains in perfluoroalkyl acrylate and crystalline hydrocarbon pendant groups in stearyl acrylate. Outstanding water- and oil-repellent properties of fabrics and any other substrates could be achieved by a facile dip-coating treatment using a fluorinated copolymer dispersion. As a result, we believe that our prepared fluorinated copolymers are potential candidates to replace the fluoroalkylated polymers with long perfluorinated chains in nonstick and self-cleaning applications in our daily life.

The polymorphisms of MSH6 gene are associated with AIDS progression in a northern Chinese population.

It has been reported that DNA repair genes play an important role in HIV-1 infection and AIDS progression. One DNA repair pathway, the mismatch repair (MMR) is associated with a wide variety of tumors. However, the role of single nucleotide polymorphisms (SNPs) in the MMR genes and their importance in HIV-1 infection and AIDS progression remain unclear. In the present study, 479 HIV-1-infected and 487 healthy individuals from northern China were genotyped for nine SNPs in the MSH2 gene (rs13019654, rs4608577, rs4952887, rs6726691, rs10191478, rs12999145, rs1981929, rs2042649, rs2303428) and five SNPs in the MSH6 gene (rs2348244, rs3136245, rs3136329, rs2072447, rs7562048). Our results showed that the rs7562048 G allele frequency was significantly higher in the cases with the CD4(+) T-lymphocyte count <200cells/µl than those with >200cells/µl (P=0.001, OR=1.811, 95% CI 1.255-2.614), which is in agreement with the result of the Bonferroni correction. The frequencies of the rs2348244 C allele and rs3136245 T allele were higher in the cases at clinical phase IV than those at clinical phase I+II+III (P=0.026, OR=1.591, 95% CI 1.056-2.398 and P=0.019, OR=1.749, 95% CI 1.096-2.791, respectively); however, this difference is not supported by the Bonferroni correction. There were no significant differences in the frequency of allele, genotype and haplotype of the 14 SNPs between HIV-1-infected individuals and healthy controls (P>0.05). These results suggest that the rs7562048 is associated with the clinical features and that the MSH6 gene polymorphisms likely play an important role in the progression of AIDS in the northern Chinese population.

Ultralow Oil-Fouling Heterogeneous Poly(ether sulfone) Ultrafiltration Membrane via Blending with Novel Amphiphilic Fluorinated Gradient Copolymers.

A novel amphiphilic fluorinated gradient copolymer was prepared by semibatch reversible addition-fragmentation chain transfer (RAFT) method using poly(ethylene glycol) methyl ether methacrylate (PEGMA) and 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl acrylate (TFOA) as monomers. The resultant amphiphilic copolymers were then incorporated into the poly(ether sulfone) (PES) to fabricate PES blend membranes via the non-solvent-induced phase separation method (NIPS). During the phase inversion process, both hydrophilic (PEGMA) and low surface energy (TFOA) segments significantly enriched on the membrane surface by surface segregation to form an amphiphilic surface, which was demonstrated by surface wetting properties and X-ray photoelectron spectroscopy (XPS) measurements. According to the filtration experiments of oil-in-water emulsion, the heterogeneous membranes exhibited superior oil-fouling resistant properties, that is, low flux decay (as low as 15.4%) and high flux recovery (almost 100%), compared to the pure PES membrane. The synergistic effect of fouling-resistant and fouling-release mechanisms was found to be responsible for the excellent antifouling capacities. The findings of this study offer a facile and robust strategy for fabricating ultralow oil-fouling membranes that might be used for effective oil/water separation.

Associations between two single-nucleotide polymorphisms (rs1801278 and rs2943641) of insulin receptor substrate 1 gene and type 2 diabetes susceptibility: a meta-analysis.

The objective of the study is to assess the association between rs1801278 and rs2943641 of insulin receptor substrate 1 gene (IRS1) and the susceptibility to type 2 diabetes. A literature search strategy was conducted to identify all references lists of relevant studies. The fixed or random effect model was used to calculate the pooled ORs on the basis of heterogeneity. Further analyses were performed to explore the sources of heterogeneity by sensitivity analysis, meta-regression analysis, and subgroup analysis. There was significant association between rs1801278 and type 2 diabetes risk in recessive model (AA vs. GA + GG, p = 0.043) and codominant model (AA vs. GG, p = 0.007). Subgroup analysis showed that the association between rs1801278 and type 2 diabetes risk was significant in dominant model (GA + AA vs. GG, p = 0.044), codominant model (GA vs. GG, p = 0.039), codominant model (AA vs. GG, p = 0.044), overdominant model (GG + AA vs. GA, p = 0.037) in Asian and codominant model (AA vs. GG, p = 0.039) in Caucasian of rs1801278. The association between rs2943641 and type 2 diabetes risk was significant in codominant model (CT vs. CC, p = 0.023) in Caucasian. This meta-analysis suggests that rs1801278 may play a role in type 2 diabetes risk, especially in Asian. It also indicates that rs2943641 may be associated with type 2 diabetes risk in Caucasian. Further larger studies should be performed to warrant confirmation.

Gain-of-function ADCY5 mutations in familial dyskinesia with facial myokymia.

OBJECTIVE: To identify the cause of childhood onset involuntary paroxysmal choreiform and dystonic movements in 2 unrelated sporadic cases and to investigate the functional effect of missense mutations in adenylyl cyclase 5 (ADCY5) in sporadic and inherited cases of autosomal dominant familial dyskinesia with facial myokymia (FDFM). METHODS: Whole exome sequencing was performed on 2 parent-child trios. The effect of mutations in ADCY5 was studied by measurement of cyclic adenosine monophosphate (cAMP) accumulation under stimulatory and inhibitory conditions. RESULTS: The same de novo mutation (c.1252C>T, p.R418W) in ADCY5 was found in both studied cases. An inherited missense mutation (c.2176G>A, p.A726T) in ADCY5 was previously reported in a family with FDFM. The significant phenotypic overlap with FDFM was recognized in both cases only after discovery of the molecular link. The inherited mutation in the FDFM family and the recurrent de novo mutation affect residues in different protein domains, the first cytoplasmic domain and the first membrane-spanning domain, respectively. Functional studies revealed a statistically significant increase in ß-receptor agonist-stimulated intracellular cAMP consistent with an increase in adenylyl cyclase activity for both mutants relative to wild-type protein, indicative of a gain-of-function effect. INTERPRETATION: FDFM is likely caused by gain-of-function mutations in different domains of ADCY5-the first definitive link between adenylyl cyclase mutation and human disease. We have illustrated the power of hypothesis-free exome sequencing in establishing diagnoses in rare disorders with complex and variable phenotype. Mutations in ADCY5 should be considered in patients with undiagnosed complex movement disorders even in the absence of a family history.

Chip-based direct genotyping of coding variants in genome wide association studies: utility, issues and prospects.

There is considerable debate about the most efficient way to interrogate rare coding variants in association studies. The options include direct genotyping of specific known coding variants in genes or, alternatively, sequencing across the entire exome to capture known as well as novel variants. Each strategy has advantages and disadvantages, but the availability of cost-efficient exome arrays has made the former appealing. Here we consider the utility of a direct genotyping chip, the Illumina HumanExome array (HE), by evaluating its content based on: 1. functionality; and 2. amenability to imputation. We explored these issues by genotyping a large, ethnically diverse cohort on the HumanOmniExpressExome array (HOEE) which combines the HE with content from the GWAS array (HOE). We find that the use of the HE is likely to be a cost-effective way of expanding GWAS, but does have some drawbacks that deserve consideration when planning studies.