HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), ...Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.
As most viruses remain uncultivated, metagenomics is currently the main method for virus discovery. Detecting viruses in metagenomic data is not trivial. In the past few years, many bioinformatic ...virus identification tools have been developed for this task, making it challenging to choose the right tools, parameters, and cutoffs. As all these tools measure different biological signals, and use different algorithms and training and reference databases, it is imperative to conduct an independent benchmarking to give users objective guidance.
We compare the performance of nine state-of-the-art virus identification tools in thirteen modes on eight paired viral and microbial datasets from three distinct biomes, including a new complex dataset from Antarctic coastal waters. The tools have highly variable true positive rates (0-97%) and false positive rates (0-30%). PPR-Meta best distinguishes viral from microbial contigs, followed by DeepVirFinder, VirSorter2, and VIBRANT. Different tools identify different subsets of the benchmarking data and all tools, except for Sourmash, find unique viral contigs. Performance of tools improved with adjusted parameter cutoffs, indicating that adjustment of parameter cutoffs before usage should be considered.
Together, our independent benchmarking facilitates selecting choices of bioinformatic virus identification tools and gives suggestions for parameter adjustments to viromics researchers.
Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal ...residual disease by flow cytometry (FCM-MRD
) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10
/kg and were eventually settled at 1 × 10
/kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD
patients achieved MRD
. All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD
with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10
/kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.
The new Horizontal Wind Model (HWM07) provides a statistical representation of the horizontal wind fields of the Earth's atmosphere from the ground to the exosphere (0–500 km). It represents over 50 ...years of satellite, rocket, and ground‐based wind measurements via a compact Fortran 90 subroutine. The computer model is a function of geographic location, altitude, day of the year, solar local time, and geomagnetic activity. It includes representations of the zonal mean circulation, stationary planetary waves, migrating tides, and the seasonal modulation thereof. HWM07 is composed of two components, a quiet time component for the background state described in this paper and a geomagnetic storm time component (DWM07) described in a companion paper.
•A twinning and de-twinning model (TDT) is proposed to describe crystal plasticity.•Four mechanisms include nucleation, growth, shrinkage and re-twinning of twins.•Growth and shrinkage of twins are ...related with both matrix and twin domains.•TDT model can capture the key phenomena observed in experiments.
Together with slip, deformation twinning and de-twinning are the plastic deformation mechanisms in hexagonal close packed (HCP) crystals, which strongly affect texture evolution and anisotropic response. As a consequence, several twinning models have been proposed and implemented in the existing polycrystalline plasticity models. De-twinning is an inverse process with respect to twinning, which is relevant to cycling, fatigue and complex loads but is rarely incorporated into polycrystalline plastic models. In this paper, we propose a physics-based twinning and de-twinning (TDT) model that has the capability of dealing with both mechanisms during plastic deformation. The TDT model is characterized by four deformation mechanisms corresponding to twin nucleation, twin growth, twin shrinkage and re-twinning. Twin nucleation and twin growth are associated with deformation twinning, and twin shrinkage and re-twinning are associated with de-twinning. The proposed TDT model is implemented in the Elasto-Visco-Plastic Self-Consistent (EVPSC) model. We demonstrate the validity and the capability of the TDT model by simulating cyclic loading of magnesium alloys AZ31B plate and AZ31 bar. Comparison with the measurements indicates that the TDT model is able to capture the key features observed in experiments, implying that the mechanical response in the simulated materials is mainly associated with twinning and de-twinning.
► The response of Mg alloys is often characterized by inelastic behavior. ► Inelastic behavior originates from the alternation of deformation mechanisms. ► Inelastic behavior becomes pronounced when ...de-twinning is activated. ► Inelastic behavior for extruded bars is reduced under tension, but magnified under compression.
The inelastic behavior presenting in magnesium alloys during cyclic loading–unloading have been investigated through the finite strain elastic viscoplastic self-consistent (EVPSC) model for polycrystals (EVPSC-TDT), which has been updated by implementing the twinning and de-twinning (TDT) model. Corresponding to the existing experiments of extruded bars of Mg alloys, we constructed the extruded bars of magnesium alloys with different initial textures in our simulations to study the effects of initial textures and deformation processes (tension and compression) on inelastic behavior during cyclic loading and unloading. Taking the advantage of numerical modeling, the evolution of the instantaneous gradients, the activity of the deformation mechanisms and the evolution of twin volume fraction are characterized to interpret the inelastic behavior. We found that the alternation of deformation mechanisms corresponds to the inelastic behavior; in particular, the inelastic behavior becomes more pronounced when twinning and de-twinning are activated. Thus, a strong extrusion texture reduces the hysteresis loops of the loading–unloading cycle under uniaxial tension, while magnifies the inelastic behavior under uniaxial compression, because twinning and de-twinning are more active for extrude bars with the strong extrusion texture under compression. The simulated results are in agreement with the available experimental observations.
•The paper provides the first documented simulation of extruded Mg plate during the cyclic loading.•Correlations among the strain hardening plateau, subsequent rapid strain hardening, and twin ...reorientation are clarified.•Different CRSS values for twin nucleation and twin growth/detwinning are used in the EVPSC model.•The monotonic strength and strain hardening anisotropy are well-predicted along multiple directions.•Diffraction peak intensity evolutions and lattice strain evolutions are predicted during the cyclic loading.
A recently developed crystal plasticity model for describing twinning and detwinning behavior is employed to simulate the behavior of extruded Mg alloy, ZK60A. Notably, accounting for the initial texture and calibrating the model using tension and compression along one direction permits prediction of the strength anisotropy, strength asymmetry, and strain hardening behavior along other directions, for cases for which the contribution of twinning is large, small and intermediate. The model discriminates between the stress required to initiate twinning and that required to grow (thicken) previously existing twins. This enables the model to simulate the unusual stress–strain hysteresis behavior during twinning (e.g., sharp yielding behavior) as well as that of detwinning (characterized by quite gradual yielding). The strain hardening plateau which occurs during both twinning and detwinning are captured, as are the rapid hardening induced by the exhaustion of these mechanisms. Finally, the modeling is validated using previously published in-situ neutron diffraction data. The predicted diffracted intensity evolution, which is indicative of the volume fraction of twinning compares well with the experimental data. For the first time, the lattice strain evolutions during cyclic loading (involving twinning and detwinning) of an extruded magnesium alloy are predicted. Most features of the experimentally observed internal strain evolution are well-described. In particular, the inflections which may be associated with the initiation of particular deformation mechanisms: basal and non-basal slips, as well as deformation twinning are predicted. Careful analysis of the lattice strains reveals greater than expected load sharing by the precipitate phase.
The cyanobacterial phylum encompasses oxygenic photosynthetic prokaryotes of a great breadth of morphologies and ecologies; they play key roles in global carbon and nitrogen cycles. The chloroplasts ...of all photosynthetic eukaryotes can trace their ancestry to cyanobacteria. Cyanobacteria also attract considerable interest as platforms for “green” biotechnology and biofuels. To explore the molecular basis of their different phenotypes and biochemical capabilities, we sequenced the genomes of 54 phylogenetically and phenotypically diverse cyanobacterial strains. Comparison of cyanobacterial genomes reveals the molecular basis for many aspects of cyanobacterial ecophysiological diversity, as well as the convergence of complex morphologies without the acquisition of novel proteins. This phylum-wide study highlights the benefits of diversity-driven genome sequencing, identifying more than 21,000 cyanobacterial proteins with no detectable similarity to known proteins, and foregrounds the diversity of light-harvesting proteins and gene clusters for secondary metabolite biosynthesis. Additionally, our results provide insight into the distribution of genes of cyanobacterial origin in eukaryotic nuclear genomes. Moreover, this study doubles both the amount and the phylogenetic diversity of cyanobacterial genome sequence data. Given the exponentially growing number of sequenced genomes, this diversity-driven study demonstrates the perspective gained by comparing disparate yet related genomes in a phylum-wide context and the insights that are gained from it.
Objectives
The aim of this study was to estimate the relative risk of cardiovascular disease (CVD) among people living with HIV (PLHIV) compared with the HIV‐uninfected population.
Methods
We ...conducted a systematic review and meta‐analysis of studies from the peer‐reviewed literature. We searched the Medline database for relevant journal articles published before August 2010. Eligible studies were observational and randomized controlled trials, reporting CVD, defined as myocardial infarction (MI), ischaemic heart disease, cardiovascular and cerebrovascular events or coronary heart disease among HIV‐positive adults. Pooled relative risks were calculated for various groupings, including different classes of antiretroviral therapy (ART).
Results
The relative risk of CVD was 1.61 95% confidence interval (CI) 1.43–1.81 among PLHIV without ART compared with HIV‐uninfected people. The relative risk of CVD was 2.00 (95% CI 1.70–2.37) among PLHIV on ART compared with HIV‐uninfected people and 1.52 (95% CI 1.35–1.70) compared with treatment‐naïve PLHIV. We estimate the relative risk of CVD associated with protease inhibitor (PI)‐, nucleoside reverse transcriptase inhibitor‐ and nonnucleoside reverse transcriptase inhibitor‐based ART to be 1.11 (95% CI 1.05–1.17), 1.05 (95% CI 1.01–1.10) and 1.04 (95% CI 0.99–1.09) per year of exposure, respectively. Not all ART was associated with increased risk; specifically, lopinavir/ritonavir and abacavir were associated with the greater risk and the relative risk of MI for PI‐based versus non‐PI‐based ART was 1.41 (95% CI 1.20–1.65).
Conclusion
PLHIV are at increased risk of cardiovascular disease. Although effective in prolonging survival, ART (in particular PI‐based regimens) is related to further increased risk of CVD events among people at highest initial absolute risk of cardiovascular disease.
High-performance inversion-type enhancement- mode (E-mode) n-channel In 0.65 Ga 0.35 As MOSFETs with atomic-layer-deposited Al 2 O 3 as gate dielectric are demonstrated. A 0.4-mum gate-length MOSFET ...with an Al 2 O 3 gate oxide thickness of 10 nm shows a gate leakage current that is less than 5 times 10 -6 A/cm 2 at 4.0-V gate bias, a threshold voltage of 0.4 V, a maximum drain current of 1.05 A/mm, and a transconductance of 350 mS/mm at drain voltage of 2.0 V. The maximum drain current and transconductance scale linearly from 40 mum to 0.7 mum. The peak effective mobility is ~1550 cm 2 /V ldr s at 0.3 MV/cm and decreases to ~650 cm 2 /V ldr s at 0.9 MV/cm. The obtained maximum drain current and transconductance are all record-high values in 40 years of E-mode III-V MOSFET research.
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