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This paper primarily determined the suitable technique for the preparation of WS2/C coating by the analytical hierarchy process (AHP) with a keen focus on the criteria of coating property, deposition process, resource and equipment. Further, some cutting performances of six cutting tools with different treatments, including cutting forces, cutting temperatures, wear mechanisms, tool life, etc. were investigated in dry cutting AISI1045 steel. The optimal lubricating condition for dry cutting process was obtained when using the cutting tools configured with the combination of WS2/C coating and shark-skin-inspired structures. Finally, the sustainability assessment was carried out by the calculation of the product sustainability index (PSI). The highest PSI of 78.6% was obtained in case of the dry cutting experiment using WMT-2-N tools, which provided a suggested favorable alternative considering both product and manufacturing process. Thus, dry cutting AISI1045 steel using WMT-2-N tools seems to be an environmentally-friendly machining process and would be helpful to enhance sustainability.

The effect of surface wettability on the friction properties of Al2O3/TiC ceramic was investigated to improve the friction and wear of Al2O3/TiC ceramic tool surfaces. The surface wettability of Al2O3/TiC ceramic was changed by preparing different microgroove arrays on its surface. The surface contact angles of the different samples were measured to characterize surface wettability. The reciprocating linear friction tests were implemented under liquid lubrication by a ball-disc type friction machine and the friction coefficient was measured. The worn surface characteristics of Al2O3/TiC ceramic were observed using SEM. Results showed that the surface wettability effectively improved the friction and wear properties of Al2O3/TiC ceramic. The friction coefficient of Al2O3/TiC ceramics decreased as surface wettability was enhanced. The surface wettability enhancement of 86.8% corresponds to a reduction in the friction coefficient of 73.6%. The better the wettability, the smoother the worn surface. The mechanism responsible was explained as micro-textures promoted capillary adsorption of lubricating fluid on the surface of Al2O3/TiC ceramic. The additional capillary adsorption force reduced the solid-liquid interfacial tension, thereby enhancing the surface wettability of the Al2O3/TiC ceramic, which promoted spreading ability of lubricating fluid. Therefore, the lubricating fluid can form a continuous lubricating film at the friction interface to achieve the effect of reducing the friction.

The friction between textured surfaces was investigated by reciprocating sliding tests under similar operating conditions of sliding guideways. Micro-grooves parallel, perpendicular and 45° to sliding orientation were fabricated on the contacting surfaces of upper and/or lower guideways, and their tribological performance was evaluated with non-textured guideways as control group. The reduction of friction coefficient was observed for all the textured guideways, except for those with textures parallel to the sliding orientation. Lowest friction coefficient was achieved for both-side-textured guideways, while only-one-side textures were more effective in preventing stick-slip motion. The occlusal contact was found to be the main hindrance for improving tribological behavior by both-side texturing.

In this paper, linear micro textures that parallel to the sawtooth edge were fabricated on the surface of the high-speed steel W6Mo5Cr4V2 circular saw blade by laser engraving. Furthermore, cutting performance of micro textured circular saw blade (TCS) and traditional circular saw blade (CS), including sawing arc length, sawing force, sawing temperature, machined surface roughness, and wear mechanism, were investigated in sawing 304 stainless steel pipes under the cutting fluid condition. Results showed that the largest sawing arc length and sawing force were occurred on the circular saw blade sawing outward from the inner wall. In addition, TCS exhibited better cutting performance mainly due to the following two aspects, on the one hand, the effective sawtooth-chip contact length was reduced due to the micro textures fabricated on the sawtooth surface; on the other hand, cutting fluid can be better penetrated into the micro textures and formed stable lubrication film in sawtooth-chip contact interface.

Derivative cutting often happens when micro textures perform cutting action on the chip bottom side, which hinders the effectiveness of micro textured tools in dry machining. The effects of derivative cutting on machining performance need to be comprehensively studied in terms of cutting forces, tool wear and chip formation. Dry cutting tests on AISI H13 steel were carried out using the micro textured tools (TT) and conventional tools (CT) over a range of cutting velocities from 95 to 237 m/min. Results show that the derivative cuttings occurred during machining with the TT tools in this range of cutting velocity. The effects of derivative cutting are analyzed based on the results and reflected in the following observations. On the one hand, derivative cutting can generate a great deal of heat on the textured rake face, increasing cutting temperature. On the other hand, derivative cutting can produce intensive material removal and plowing action on the chip bottom side, increasing cutting force. Overall, derivative cutting can accelerate texture wear, which in turn aggravates derivative cutting. This leads to a severer tool-chip friction, which should be minimized when machining with textured cutting tools.

This paper aims to provide a method in improving tribological properties of Al2O3/TiC ceramics. Biomimetic shark skin was produced on Al2O3/TiC ceramic surfaces by laser surface texturing. Then WS2 coating was deposited on the biomimetic skin by electrohydrodynamic atomization and its dry friction behaviours and wear mechanisms were investigated. Results revealed that the synergy effect of biomimetic shark skin and WS2 coatings has an effective influence on the tribological properties of Al2O3/TiC ceramics. The friction coefficient reduced to ∼0.3 and ∼0.07 after texturing biomimetic shark skin and depositing WS2 coatings, which reduced by 29% and 84%, respectively, compared with those of only polished Al2O3/TiC ceramics. The contribution of biomimetic shark skin was primarily decreasing the friction surface, reducing shear stress and trapping wear debris. Moreover, the grooves acted as lubricant reservoir could keep a thicker trio-film and realize continuous lubrication for a longer friction time.

Severe friction at the cutter-chip interface increases tool surface wear and reduces tool life. The friction could be reduced by introducing cutting fluids between cutter and chip. The lubrication of cutting fluids depends on its penetration. The ability of cutting fluids to penetrate into the cutting zone can be enhanced by the surface texture of the cutters. In this paper, microgroove-liked textures with different groove width were fabricated on the rake-face of the cemented carbide YS8 cutters with femtosecond laser. The effect of micro-textures on the lubrication of cutting fluids in cutting zone was investigated in cutting H13 hot die steel tests with textured and non-textured cutters under full lubrication. Results showed that micro-textures enhanced penetration of the cutting fluid, improved the lubrication in the cutter-chip interface, and significantly reduced cutting force and tool wear compared to untextured tools. The micro-textured tool with groove width of 50 μm had the best performance among all tested tools. Mechanism responsible was found that cutting fluids can continuously penetrate into the cutting contact area through the sufficient space provided by the microgrooves on the rake-face.

The combination of WS2 films and surface textures were investigated for improving the friction and wear properties of sol-gel ZrO2 coatings. Grid-like grooves with different groove pitch were fabricated by laser surface texturing technology. All the textured coatings showed improved hydrophilicity (the contact angle of ZrO2 coatings decreased by ~ 3.5–22.8% after texturing). WS2 films were deposited on the ZrO2 coatings by electrohydrodynamic atomization technology. The dry sliding friction and wear properties of samples with surface textures or/and WS2 films additive were evaluated. Both the coefficient of friction of ZrO2 coatings and steel ball wear rate were affected by laser surface texturing and WS2 films additive. The textured samples with the texture coverage of 0.679 showed the lowest friction coefficient and lowest steel ball wear rate, decreasing by ~ 16% and ~ 70%, respectively, when comparing with those of the untextured samples. The further improved antifriction and antiwear properties were obtained by the synergistic combination of surface textures and deposited WS2 films. Additionally, laser surface micro-texturing could contribute to prolong the WS2 films wear life and magnify its lubricating effect.

Advanced ceramics after sintering are almost processed by grinding or non-traditional machining. Nevertheless, these methods are limited by complexity of processing efficiency, tool wear and economic effectiveness. So machining green ceramics before sintering is introduced, it is environmentally friendly, efficient and cheap with high removal rate of materials. During dry turning green ceramics, flank-wear of tools and processing quality of compacts are two main elements to evaluate cutting performance of tools. The processing efficiency and economic effectiveness are mainly effected by the cutting performance of tools. In this paper, polished tool, tool with nano-scale textured flank-face, tool with TiAlN coating deposited on polished flank-face, and tool with TiAlN coating deposited on nano-scale textured flank-face were prepared. Effect of nano-scale texture pretreatment on wear-resistance of WC/Co tools with/without TiAlN coated flank-face was studied in turning of green Al2O3 ceramics. Results displayed that nano-scale textures on the flank-face had prominent effects on the enhancement of flank-wear resistance of tools. Relevant mechanisms were explored that nano-scale textures exhibited “derivative cutting” to protect unworn face from abrasion, and nano-scale textures pretreated on the flank-face could enhance the adhesion strength between coating and matrix. These developed tools could also significantly improve the processing quality of machined surfaces.

In this paper, linear micro textures that parallel to the sawtooth edge were fabricated on the surface of the high speed steel W6Mo5Cr4V2 circular saw blade by laser engraving. Further, cutting performance of micro textured circular saw blade (TCS) and traditional circular saw blade (CS), including sawing arc length, sawing force, sawing temperature, machined surface roughness and wear mechanism, were investigated in sawing 304 stainless steel pipes under the cutting fluid condition. Results showed that the largest sawing arc length and sawing force were occurred on the circular saw blade sawing outward from the inner wall. In addition, TCS circular saw blade exhibited better cutting performance and the mechanisms were found, on the one hand, the effective sawtooth-chip contact length was reduced due to the micro textures fabricated on the sawtooth surface, on the other hand, cutting fluid can be better penetrated into the micro textures and formed stable lubrication film in sawtooth-chip contact interface.

Correction for ‘High-resolution DNA size enrichment using a magnetic nano-platform and application in non-invasive prenatal testing’ by Bo Zhang et al., Analyst, 2020, 145, 5733–5739, DOI: 10.1039/D0AN00813C.

WS2 coating additive and surface micro texturing were investigated in order to improve the tribological properties of the cemented carbide tool surfaces. Laser surface texturing technology (LST) was employed to fabricate three kinds of textures (dimple array, line array and four-leaf clover array) on cemented carbide surfaces. Characterizations such as micromorphology, surface roughness, wettability of the surfaces with different micro-textures were examined. Electrohydrodynamic atomization technology (EHDA) was used to deposit WS2 coatings on the substrate surfaces. The influence of the atomization parameters (flow rate, operating voltage and atomizing distance) on the characteristics of deposited coatings was examined. Uniform and dense coating, with a thickness of ~20 μm, was produced under the optimized conditions. The friction and wear properties of textured surfaces before and after depositing WS2 coatings were evaluated by reciprocating sliding friction tests. The coating-substrate adhesion was evaluated by scratch tests. The results show that the friction and wear properties would be improved by EHDA deposited WS2 coating or micro-textures, and the samples combined with deposited WS2 coatings and textured surfaces exhibited the best efficiency. Additionally, laser surface micro-texturing can improve the coating-substrate adhesion strength and then prolong the wear life of WS2 coatings.

Tool wear and surface quality are the most important problems in green ceramic processing. This paper fabricated textures with different texture parameters on the flank face of carbide tools by femtosecond laser, to enhance the wear resistance of carbide tools and surface quality of machined compacts. The wear resistance of textured tools and quality of machined surface were evaluated in cutting tests of the green Al2O3 ceramics with these different flank-faced textured tools. Results showed that better flank wear resistance of textured tools and better quality of machined surfaces could be obtained by flank-faced textured tools than that by conventional tool (WT-0). The parameters of flank-faced textures had a significant effect on the flank wear resistance of textured tools and surface quality of machined workpieces. To achieve best wear resistance of cutting tool and surface quality of workpieces within the experiment parameters, the best parameters of the textures were chosen that width of the texture groove was 75 µm, spacing of texture groove was 100 µm, and distance of texture groove to main cutting edge was 75 µm. “Derivative cutting” to the hard inclusions in the surface of workpieces was happened at the textured grooves’ lower edge. It contributed to enhancement of wear resistance and the surface quality in a certain parameter of texture grooves.

To enhance the tribological properties of the TiAlSiN coatings, two types of micro-textures were fabricated on the AISI 1045 steel substrates by laser texturing and ultrasonic rolling texturing prior to coating deposition. The mechanical properties and tribological behaviors of different samples were evaluated. Results revealed that the micro-textures improved the tribological properties of TiAlSiN coatings under dry friction and lubricant conditions. Under dry friction conditions, the friction coefficient and steel ball wear rate of the coatings decreased by ~16.9% and ~44.2%, respectively, after ultrasonic rolling texturing pretreatment, when compared with the coatings deposited on the polished substrates. Under lubricant conditions, the two values were reduced by ~27.8% and ~73.4%, respectively. The contribution of micro-textures was primarily to amplify lubrication, trap wear debris, decrease contact area and improve bearing capacity. The modification mechanism of the ultrasonic rolling texturing also benefited from the enhanced mechanical properties.

Derivative cutting of micro-textured tool refers to the additional cutting to the bottom side of the chip with the micro-surface textures on the tool surface. In our previous research, it has been proved that piling up of chip in the microgroove of textures is caused by derivative cutting, resulting in structural function failure of the textured tool face. Hence, derivative-cutting behavior needs to be understood and implemented in models. In this study, an analytical approach for the orthogonal cutting process is developed to determinate derivative-chip formation by predictions of the uncut derivative-chip thickness (UDCT) and minimum uncut derivative-chip thickness (MUDCT) values according to cutting parameters, tool geometry, workpiece material properties, and positional and geometrical parameters of textures. The analytical approach is experimentally validated using a 1045 steel workpiece with the textures of different distances to the main cutting edge on the tool rake face. Subsequently, the responses of the UDCT and MUDCT to cutting speed and texture parameters including its geometry and position are quantified on the basis of the proposed approach. Results show that reasonable enlarging of texture-edge radius and proper increasing of cutting speed both are feasible ways to prevent derivative-cutting from derivative-chip formation.

Derivative cutting is a texture-edge cutting of chip bottom side, which happens all the time in machining with textured tools. Two new types of textured tools are developed and fabricated: a micro-textured tool with chamfered texture edge (CTE) tool and a multiscale textured (MSTT) tool with the texture surface below the rake face. The effectiveness of the tools on inhibiting derivative cutting is investigated at different cutting velocities. For the CTE tool, the inhibiting effect is more pronounced with the increase in the chamfer angle, but the severe rake face wear eventually leads to the occurrence of derivative cutting. Compared with the CTE tool, the multiscale textures of the MSTT tool provide more sustainable effectiveness in inhibiting derivative cutting. The inhibition mechanisms of the two types of textured tools are discussed.

WS2 coatings were prepared by electrohydrodynamic atomization method, and graphite was introduced in order to improve their mechanical properties and oxidation resistance. The influence of graphite on the microstructure, anti-oxidation capability, mechanical performances and tribological properties of the composite coatings were systematically analysed. The sharkskin-like biomimetic textures were fabricated on the substrates by laser machining. The results showed that the sharkskin-like biomimetic textures increased the compressive stresses and surface energies of substrates, resulting in improved adhesion strength between deposited coatings and substrates. The improved adhesion strength and oxidation resistance of the WS2/C coatings as well as the antifriction capability of micro/nano-textures aided in keeping a low stabilized friction coefficient down to 0.05 for a long sliding time. The WS2/C (4:1) composite coatings deposited on the sharkskin-like biomimetic textured substrates presented the longest wear life of ~2800 s, which was ~2.3 times longer than that of the pure WS2 coatings on the polished substrates. The wear rate of WS2/C (4: 1) coating deposited on the textured substrate was ~3.1 × 10−7 mm3/N mm, which was about three-fifths of that of the pure WS2 coating deposited on the polished substrate. The micro/nano-grooves, which acted as reservoirs for WS2 lubricating material, could support the formation of the low-friction tribo-films.

This paper aims to demonstrate an effective surface texturing fabrication approach in improving the tribological properties of AISI 1045 hardened steel surface. Ultrasonic surface rolling technology was employed to fabricate strengthened surface and line array textured surface on substrates. Characterizations such as morphology, surface residual stress, microhardness, elasticity modulus and surface roughness with different surfaces were examined. Ball-on disk reciprocating sliding dry friction tests were performed. Results indicate that textured surfaces with good quality and accuracy were fabricated by ultrasonic rolling treatment. Increased microhardness and residual compressive stress of surfaces treated by ultrasonic rolling were obtained. Textured surfaces played a positive role in improving tribological performance. The surface with line array textures presented the best efficiency of anti-friction and anti-wear while sliding against GCr15 steel ball, the friction coefficient and sliding ball wear rate decreased by 79% and 98%, respectively, compared with the polished ones. Additionally, the possible tribological mechanism of ultrasonic rolling texturing was discussed. Multistage structure with mm/micro/nano-textures combined with a strengthened layer caused by ultrasonic rolling technology, increased the mechanical and tribological properties of surfaces. The synergistic combination of strengthened layer and texture structure could contribute to prolonging the friction and wear life of materials.

Summary Background Matrix metalloproteinase-9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. Aim To evaluate the safety and efficacy of GS-5745, a fully humanised anti-matrix metalloproteinase-9 monoclonal antibody, in moderately-to-severely active ulcerative colitis. Methods We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS-5745 or placebo. Multiple-dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS-5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS-5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS-5745. Exploratory analyses in the multiple-dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS-5745 were explored using histological and molecular approaches. Results Twenty-three of the 42 patients (55%) receiving multiple doses of GS-5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS-5745 showed target-mediated drug disposition, approximately dose-proportional increases in maximum plasma concentration and more than dose-proportional increases in the area under the plasma drug concentration-time curve. Clinical response occurred in 18/42 patients (43%) receiving GS-5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS-5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS-5745 had reductions in matrix metalloproteinase-9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. Conclusion This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS-5745 in the treatment of ulcerative colitis.

This paper aims to provide a simple and rapid fabricating method for solution-based ZrO2 thin films. The ZrO2 thin film was firstly deposited on a 316L stainless steel substrate by electrohydrodynamic atomization. Then the crystallization process was carried out by a 4W Nd:YAG laser with a wavelength of 1064 nm. The morphology, structure and evolution of chemical bonds (Zr and O) were evaluated by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. After laser annealing, the O 1s (O-containing ions in ZrO2) fraction rose from 22.6% to 51.1%, and the principal tetragonal phase composition was obtained. The large temperature gradients that derived from the photothermal effect contribute to the fast crystallization during the laser treatments. The tribological and electrochemical corrosion experiments reveal that the laser crystallized films have significantly well wear and corrosion resistance, close to those of conventionally crystallized films. This fabricating method is simple, energy-saving and could achieve the spatially-resolved crystallization of films with a minimal temperature increase on the underlying substrates.

Individualized assessment of hepatocellular carcinoma (HCC) risk in chronic liver disease remains challenging. Serum biomarkers including cytokines may offer helpful adjuncts to standard parameters for risk prediction. Our aim was to identify markers associated with increased HCC incidence. This was a prospective cohort study of 282 patients with both viral or non-viral chronic liver disease. Baseline serum cytokines and other markers were measured in multiplex with a commercially-available Luminex-based system. Patients were followed until death or HCC diagnosis. We performed Lasso-based survival analysis to determine parameters associated with HCC development. Cytokine mean florescence intensity (MFI) was the primary predictor and HCC development the primary outcome. 25 patients developed HCC with total follow-up of 1,363 person-years. Parameters associated with increased HCC incidence were cirrhosis, hepatic decompensation, and soluble serum intercellular adhesion molecule 1 (sICAM-1) MFI. No other molecules increased predictive power for HCC incidence. On univariate analysis, the parameters associated with HCC incidence in patients with cirrhosis were age, antiviral treatment, and high sICAM-1 MFI; on multivariate analysis, sICAM-1 remained associated with HCC development (adjusted HR = 2.75). On unbiased screening of serum cytokines and other markers in a diverse cohort, baseline sICAM-1 MFI is associated with HCC incidence.

Based on bounded rationality, a linear dynamic system is proposed in this work for the duopoly game of renewable resource extraction. This dynamics reflects the decision-makers’ dynamical output strategy consisting of all the Nash equilibriums in every two adjacent periods. The resource growth rate, the discount rate and the expected extraction rate are the major parameters in this system. The system stability and the equilibrium characteristics of the stable state are analyzed. Numerical simulations are made to show the influence of all the parameters on the speed for the system to approaches its stable equilibrium. By the mathematical analysis we find that, if the discount is smaller or the expected extraction rate is larger, the system will converge in shorter time and approach a stable state with lager resource reserve and with larger resource output. So we draw the conclusion that decision-makers’ focusing on the long-term profits is helpful to sustainable development on natural resource market in the long run.

Background Protease inhibitors for the treatment of HCV can cause mild and reversible elevations of unconjugated bilirubin. We sought to characterize genetic determinants of bilirubin elevations using a genome-wide approach among patients with genotype 1 HCV who received combination therapy that included GS-9256, a novel potent inhibitor of HCV NS3 serine protease, as part of a Phase IIb trial. Methods Of the 200 patients sampled, 176 had confirmed European ancestry and were included in the analysis. Infinium HumanOmni5BeadChip (Illumina, Inc., San Diego, CA, USA) was used for genotyping. A categorical analysis of low (grade 0–1) versus high (grade 2–4) bilirubin toxicity grade and a quantitative trait locus mapping of peak bilirubin concentrations was performed. Results A total of 4,466,809 genetic markers were analysed. No single variant showed a statistically significant association with observed bilirubin elevations in this patient population. In a targeted analysis of single nucleotide polymorphisms in genes known to be involved in bilirubin transport, no significant differences in allele frequency between high and low bilirubin toxicity grade were observed. Conclusions These results indicate that risk for bilirubin elevation in patients receiving GS-9256 is unlikely to be strongly influenced by common genetic variants with large effects. The current study cannot rule out a role for common variants of weak effect, or a more complex model, including multiple contributing factors, such as rare variants and as yet unidentified environmental influences.

Cytokines play an important role in the pathogenesis of cirrhosis and hepatocellular carcinoma (HCC), most cases of which are related to either hepatitis B virus (HBV) or hepatitis C virus (HCV). Prior studies have examined differences in individual cytokine levels in patients with chronic liver disease, but comprehensive cytokine profiling data across different clinical characteristics are lacking. We examined serum cytokine profiles of 411 patients with HCC (n = 102: 32% HBV, 54% HCV, 14% non-viral) and without HCC (n = 309: 39% HBV, 39% HCV, 22% non-viral). Multiplex analysis (Luminex 200 IS) was used to measure serum levels of 51 common cytokines. Random forest machine learning was used to obtain receiver operator characteristic curves and to determine individual cytokine importance using Z scores of mean fluorescence intensity for individual cytokines. Among HCC and non-HCC patients, cytokine profiles differed between HBV and HCV patients (area under curve (AUC) 0.82 for HCC, 0.90 for non-HCC). Cytokine profiles did not distinguish cirrhotic HBV patients with and without HCC (AUC 0.503) or HCV patients with and without HCC (AUC 0.63). In conclusion, patients with HBV or HCV infection, with or without HCC, have distinctly different cytokine profiles, suggesting potential differences in disease pathogenesis and/or disease characteristics.

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC −46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, ∼11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors. © 2012 The American Society of Human Genetics.

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10−17, poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of

Background & Aims Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×10 9 /L and an absolute neutrophil count (ANC) ⩾1500/mm 3 . Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). Results 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p =10 −10 ). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction ( p =10 −12 , p =10 −7 ) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p =10 −17 ) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Conclusions Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.