Facile route to bulk ultrafine-grain steels for high strength and ductility.

Steels with sub-micrometre grain sizes usually possess high toughness and strength, which makes them promising for lightweighting technologies and energy-saving strategies. So far, the industrial fabrication of ultrafine-grained (UFG) alloys, which generally relies on the manipulation of diffusional phase transformation, has been limited to steels with austenite-to-ferrite transformation1-3. Moreover, the limited work hardening and uniform elongation of these UFG steels1,4,5 hinder their widespread application. Here we report the facile mass production of UFG structures in a typical Fe-22Mn-0.6C twinning-induced plasticity steel by minor Cu alloying and manipulation of the recrystallization process through the intragranular nanoprecipitation (within 30 seconds) of a coherent disordered Cu-rich phase. The rapid and copious nanoprecipitation not only prevents the growth of the freshly recrystallized sub-micrometre grains but also enhances the thermal stability of the obtained UFG structure through the Zener pinning mechanism6. Moreover, owing to their full coherency and disordered nature, the precipitates exhibit weak interactions with dislocations under loading. This approach enables the preparation of a fully recrystallized UFG structure with a grain size of 800 ± 400 nanometres without the introduction of detrimental lattice defects such as brittle particles and segregated boundaries. Compared with the steel to which no Cu was added, the yield strength of the UFG structure was doubled to around 710 megapascals, with a uniform ductility of 45 per cent and a tensile strength of around 2,000 megapascals. This grain-refinement concept should be extendable to other alloy systems, and the manufacturing processes can be readily applied to existing industrial production lines.

Contrasting functions of ATP hydrolysis by MDA5 and LGP2 in viral RNA sensing.

Cytosolic long dsRNA, among the most potent proinflammatory signals, is recognized by melanoma differentiation-associated protein 5 (MDA5). MDA5 binds dsRNA cooperatively forming helical filaments. ATP hydrolysis by MDA5 fulfills a proofreading function by promoting dissociation of shorter endogenous dsRNs from MDA5 while allowing longer viral dsRNAs to remain bound leading to activation of interferon-ß responses. Here, we show that adjacent MDA5 subunits in MDA5-dsRNA filaments hydrolyze ATP cooperatively, inducing cooperative filament disassembly. Consecutive rounds of ATP hydrolysis amplify the filament footprint, displacing tightly bound proteins from dsRNA. Our electron microscopy and biochemical assays show that LGP2 binds to dsRNA at internal binding sites through noncooperative ATP hydrolysis. Unlike MDA5, LGP2 has low nucleic acid selectivity and can hydrolyze GTP and CTP as well as ATP. Binding of LGP2 to dsRNA promotes nucleation of MDA5 filament assembly resulting in shorter filaments. Molecular modeling identifies an internally bound MDA5-LGP2-RNA complex, with the LGP2 C-terminal tail forming the key contacts with MDA5. These contacts are specifically required for NTP-dependent internal RNA binding. We conclude that NTPase-dependent binding of LGP2 to internal dsRNA sites complements NTPase-independent binding to dsRNA ends, via distinct binding modes, to increase the number and signaling output of MDA5-dsRNA complexes.

Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678. FINDINGS: 14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29). INTERPRETATION: In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective. FUNDING: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Publisher Correction: Enhanced strength and ductility in a high-entropy alloy via ordered oxygen complexes.

Change history: In this Letter, owing to a production error, all the data points (except the two points for O-2 and N-2, respectively) were missing in Fig. 1b. The figure has been corrected online.

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity.

BACKGROUND: Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. METHODS: Summary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR). RESULTS: Through preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy. CONCLUSIONS: This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

CD137 expression and signal function drive pleiotropic γδ T-cell effector functions that inhibit intracellular M. tuberculosis growth.

Co-activation signal that induces/sustains pleiotropic effector functions of antigen-specific γδ T cells remains unknown. Here, Mycobacteria tuberculosis (Mtb) tuberculin administration during tuberculosis (TB) skin test resulted in rapid expression of co-activation signal molecules CD137 and CD107a by fast-acting Vγ2Vδ2 T cells in TB-resistant subjects (Resisters), but not patients with active TB. And, anti-CD137 agonistic antibody treatment experiments showed that CD137 signaling enabled Vγ2Vδ2 T cells to produce more effector cytokines and inhibit intracellular Mtb growth in macrophages (Mɸ). Consistently, Mtb antigen (Ag) HMBPP stimulation induced sustainable high-level CD137 expression in fresh and activated Vγ2Vδ2 T cells from uninfected subjects, but not TB patients. CD137+Vγ2Vδ2 T-cell subtype predominantly displayed central memory phenotype and mounted better proliferative responses than CD137-Vγ2Vδ2 T-cells. In response to HMBPP, CD137+Vγ2Vδ2 T-cell subtype rapidly differentiated into greater numbers of pleiotropic effector cells producing anti-Mtb cytokines compared to CD137-Vγ2Vδ2 T subtype, with the non-canonical NF-κB pathway involved. CD137 expression in Vγ2Vδ2 T cells appeared to signal anti-Mtb effector functions leading to intracellular Mtb growth inhibition in Mɸ, and active TB disrupted such CD137-driven anti-Mtb effector functions. CD137+Vγ2Vδ2 T-cells subtype exhibited an epigenetic-driven high-level expression of GM-CSF and de novo production of GM-CSF critical for Vγ2Vδ2 T-cell controlling of Mtb growth in Mϕ. Concurrently, exosomes produced by CD137+Vγ2Vδ2 T cells potently inhibited intracellular mycobacterial growth. Furthermore, adoptive transfer of human CD137+Vγ2Vδ2 T cells to Mtb-infected SCID mice conferred protective immunity against Mtb infection. Thus, our data suggest that CD137 expression/signaling drives pleiotropic γδ T-cell effector functions that inhibit intracellular Mtb growth.

Cascading Energy Transfer for Highly Efficient Deep-Red OLED Emission with Cyclometalated [3+2+1] Iridium Complexes.

The promising cyclometalated iridium (III) complexes have been proved to possess great potential in vacuum-deposited organic light-emitting diodes (OLEDs) applications for full-color displays and white solid-state lighting sources. Herein, based on the unique bidentate ligand of dibenzo[a,c]phenazine (dbpz) group with strong conjugated effect of aromatic rings for red emission, four novel [3+2+1] coordinated iridium (III) emissive materials have been rationally designed and synthesized. The monodentate ligands of -CN and -OCN have been effectively employed to tune the deep-red emission of 628-675 nm with high photoluminescence quantum yields up to 98%. Moreover, all devices displayed deep-red color coordinates ranging from (0.675, 0.325) to (0.716, 0.284), which is close to the standard-red color coordinates of (0.708, 0.292), as recommended by International Telecommunication Union Radiocommunication (ITU-R) BT.2020. The device based on nBuIr(dbpz)CN with an exciplex cohost has exhibited maximum external quantum efficiencies of 20.7% and good stability. With nBuIr(dbpz)CN as an effective sensitizer, the nBuIr(dbpz)OCN based phosphorescent OLED devices have successfully demonstrated cascading energy transfer processes, contributing to pure red emission with maximum luminance as high as 6471 cd m-2. Therefore, this work has been successfully demonstrated rational molecular design strategy of [3+2+1] iridium complexes to obtain highly efficient deep-red electrophosphorescent emission.

Superior radiation tolerance via reversible disordering-ordering transition of coherent superlattices.

Materials capable of sustaining high radiation doses at a high temperature are required for next-generation fission and future fusion energy. To date, however, even the most promising structural materials cannot withstand the demanded radiation environment due to irreversible radiation-driven microstructure degradation. Here we report a counterintuitive strategy to achieve exceptionally high radiation tolerance at high temperatures by enabling reversible local disordering-ordering transition of the introduced superlattice nanoprecipitates in metallic materials. As particularly demonstrated in martensitic steel containing a high density of B2-ordered superlattices, no void swelling was detected even after ultrahigh-dose radiation damage at 400-600 °C. The reordering process of the low-misfit superlattices in highly supersaturated matrices occurs through the short-range reshuffling of radiation-induced point defects and excess solutes right after rapid, ballistic disordering. This dynamic process stabilizes the microstructure, continuously promotes in situ defect recombination and efficiently prevents the capillary-driven long-range diffusion process. The strategy can be readily applied into other materials and pave the pathway for developing materials with high radiation tolerance.

Polarization self-compensation in a laser-driven interferometric fiber optic gyroscope with high long-term stability.

We present a laser-driven interferometric fiber optic gyroscope (IFOG) with polarization self-compensation to achieve high scale-factor stability, sensitivity, and long-term stability. Coherent light with 200kHz linewidth is employed to keep the scale factor stable. The optical scheme ensures polarization reciprocity as well as the optimal working point for good sensitivity. Furthermore, a hybrid machine learning loop (MLL) method, combining the advantages of PID fast response and artificial neural network (ANN) dynamic search, can control a liquid crystal rotator (LCR) to dynamically compensate for slow drift induced by polarization coupling. In open environment, when the sensitivity is 0.005 ∘/h, the bias instability (BI) is significantly optimized from 0.6723°/h at 60s (PID) to 0.3869°/h at 200s (MLL), which is close to the Sagnac interferometric limit (SIL). Such IFOG can meet the real-time and robust requirements for inertial navigation systems in long-term measurement.

NFIC mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to represses malignant phenotype of non-small cell lung cancer cells.

BACKGROUND: Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. METHODS: The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. RESULTS: Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3'UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. CONCLUSIONS: Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.

Diaph1 knockout inhibits mouse primordial germ cell proliferation and affects gonadal development.

BACKGROUND: Exploring the molecular mechanisms of primordial germ cell (PGC) migration and the involvement of gonadal somatic cells in gonad development is valuable for comprehending the origins and potential treatments of reproductive-related diseases. METHODS: Diaphanous related formin 1 (Diaph1, also known as mDia1) was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). Subsequently, the CRISPR-Cas9 technology was used to construct Diaph1 knockout mice to investigate the role of Diaph1 in gonad development. RESULTS: Based on data from public databases, a differentially expressed gene Diaph1, was identified in the migration of mouse PGC. Additionally, the number of PGCs was significantly reduced in Diaph1 knockout mice compared to wild type mice, and the expression levels of genes related to proliferation (Dicer1, Mcm9), adhesion (E-cadherin, Cdh1), and migration (Cxcr4, Hmgcr, Dazl) were significantly decreased. Diaph1 knockout also inhibited Leydig cell proliferation and induced apoptosis in the testis, as well as granulosa cell apoptosis in the ovary. Moreover, the sperm count in the epididymal region and the count of ovarian follicles were significantly reduced in Diaph1 knockout mice, resulting in decreased fertility, concomitant with lowered levels of serum testosterone and estradiol. Further research found that in Diaph1 knockout mice, the key enzymes involved in testosterone synthesis (CYP11A1, 3ß-HSD) were decreased in Leydig cells, and the estradiol-associated factor (FSH receptor, AMH) in granulosa cells were also downregulated. CONCLUSIONS: Overall, our findings indicate that the knockout of Diaph1 can disrupt the expression of factors that regulate sex hormone production, leading to impaired secretion of sex hormones, ultimately resulting in damage to reproductive function. These results provide a new perspective on the molecular mechanisms underlying PGC migration and gonadal development, and offer valuable insights for further research on the causes, diagnosis, and treatment of related diseases.

A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts.

BACKGROUND: Lipid metabolism plays essential roles in skin barrier formation and the regulation of skin inflammation. Moreover, lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia, and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES: To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS: Whole-exome sequencing was performed to identify the underlying genetic variants. Quantitative PCR, western blot, and immunofluorescent staining were employed to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of the mutant SREBP-1 was determined by luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS: Two patients of different ethnicities presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts, and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in the SREBF1 gene in both patients. The variant encoded a truncated protein which showed preferential nucleus localization, in contrast to wild-type SREBP-1 which is mainly localized in cytoplasm in sterol-sufficient conditions. Luciferase reporter assay revealed that the Ser430* mutant exhibited an enhanced transcriptional activity. The primary cultured melanocytes from the patient showed increased melanin synthesis compared to those from normal controls. The Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes at 35 days post-fertilization. CONCLUSIONS: We demonstrated that a gain-of-function variant in SREBF1 caused a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development and paves the way for developing novel therapeutic targets for skin dyspigmentation or cataracts.

Exploring optimal settings for safe and effective thulium fibre laser lithotripsy in a kidney model.

OBJECTIVES: To explore the optimal laser settings and treatment strategies for thulium fibre laser (TFL) lithotripsy, namely, those with the highest treatment efficiency, lowest thermal injury risk, and shortest procedure time. MATERIALS AND METHODS: An in vitro kidney model was used to assess the efficacy of TFL lithotripsy in the upper calyx. Stone ablation experiments were performed on BegoStone phantoms at different combinations of pulse energy (EP ) and frequency (F) to determine the optimal settings. Temperature changes and thermal injury risks were monitored using embedded thermocouples. Experiments were also performed on calcium oxalate monohydrate (COM) stones to validate the optimal settings. RESULTS: High EP /low F settings demonstrated superior treatment efficiency compared to low EP /high F settings using the same power. Specifically, 0.8 J/12 Hz was the optimal setting, resulting in a twofold increase in treatment efficiency, a 39% reduction in energy expenditure per unit of ablated stone mass, a 35% reduction in residual fragments, and a 36% reduction in total procedure time compared to the 0.2 J/50 Hz setting for COM stones. Thermal injury risk assessment indicated that 10 W power settings with high EP /low F combinations remained below the threshold for tissue injury, while higher power settings (>10 W) consistently exceeded the safety threshold. CONCLUSIONS: Our findings suggest that high EP /low F settings, such as 0.8 J/12 Hz, are optimal for TFL lithotripsy in the treatment of COM stones. These settings demonstrated significantly improved treatment efficiency with reduced residual fragments compared to conventional settings while keeping the thermal dose below the injury threshold. This study highlights the importance of using the high EP /low F combination with low power settings, which maximizes treatment efficiency and minimizes potential thermal injury. Further studies are warranted to determine the optimal settings for TFL for treating kidney stones with different compositions.

A New Fingerprint and Graph Hybrid Neural Network for Predicting Molecular Properties.

Machine learning plays a role in accelerating drug discovery, and the design of effective machine learning models is crucial for accurately predicting molecular properties. Characterizing molecules typically involves the use of molecular fingerprints and molecular graphs. These are input into a multilayer perceptron (MLP) and variants of graph neural networks, such as graph attention networks (GATs). Due to the diverse types and large dimension of fingerprints, models may contain many features that are relatively irrelevant or redundant; meanwhile, although the GAT excels in handling heterogeneous graph tasks, it lacks the ability to extract collaborative information from neighboring nodes, which is crucial in scenarios where it cannot capture the joint influence of adjacent groups on atoms. To overcome these challenges, we introduce a hybrid model, combining improved GAT and MLP. In GAT, the recurrent neural network is employed to capture collaborative information. To address the dimensionality issue, we propose a feature selection algorithm, which is based on the principle of maximizing relevance while minimizing redundancy. Through experiments on 13 public data sets and 14 breast cell lines, our model demonstrates superior performance compared to state-of-the-art deep learning and traditional machine learning algorithms. Additionally, a series of ablation experiments were conducted to demonstrate the advantages of our improved version, as well as its antinoise capability and interpretability. These results indicate that our model holds promising prospects for practical applications.

Insights into the antimicrobial effects of tafenoquine against Enterococcus and its biofilms.

AIM: The purpose of this study is to assess the in vitro antimicrobial and anti-biofilm effects of the anti-protozoal agent tafenoquine (TAF) on Enterococcus and elucidate its underlying mode of action. METHODS AND RESULTS: The present work investigated the susceptibility of TAF on 3 type strains and 11 clinical isolates of enterococci. The results indicated that TAF exhibited powerful antimicrobial activity against both of Enterococcus faecalis and Enterococcus faecium with minimum inhibitory and bactericidal concentrations ranging from 8 to 16 µg ml-1. Meanwhile, biofilm inhibition and eradication assays showed that TAF exhibited potent anti-biofilm activity against E. faecalis ATCC 29212 and E. faecium ATCC 19434. Ultra-microscopic observations revealed significant changes in bacterial morphology and structure caused by TAF, particularly for the disruption of plasma membrane. Mechanistic investigations also revealed that TAF altered both membrane permeability and potential while also impacting adenosine triphosphate production as well as reactive oxygen species generation. In addition, no detectable cytotoxicity of TAF on human cells was observed at concentrations near the minimal inhibitory concentration. CONCLUSIONS: In summary, this study confirmed that TAF could effectively inhibit Enterococcus as well as its biofilm formation.

Enhanced strength and ductility in a high-entropy alloy via ordered oxygen complexes.

Oxygen, one of the most abundant elements on Earth, often forms an undesired interstitial impurity or ceramic phase (such as an oxide particle) in metallic materials. Even when it adds strength, oxygen doping renders metals brittle1-3. Here we show that oxygen can take the form of ordered oxygen complexes, a state in between oxide particles and frequently occurring random interstitials. Unlike traditional interstitial strengthening4,5, such ordered interstitial complexes lead to unprecedented enhancement in both strength and ductility in compositionally complex solid solutions, the so-called high-entropy alloys (HEAs)6-10. The tensile strength is enhanced (by 48.5 ± 1.8 per cent) and ductility is substantially improved (by 95.2 ± 8.1 per cent) when doping a model TiZrHfNb HEA with 2.0 atomic per cent oxygen, thus breaking the long-standing strength-ductility trade-off11. The oxygen complexes are ordered nanoscale regions within the HEA characterized by (O, Zr, Ti)-rich atomic complexes whose formation is promoted by the existence of chemical short-range ordering among some of the substitutional matrix elements in the HEAs. Carbon has been reported to improve strength and ductility simultaneously in face-centred cubic HEAs12, by lowering the stacking fault energy and increasing the lattice friction stress. By contrast, the ordered interstitial complexes described here change the dislocation shear mode from planar slip to wavy slip, and promote double cross-slip and thus dislocation multiplication through the formation of Frank-Read sources (a mechanism explaining the generation of multiple dislocations) during deformation. This ordered interstitial complex-mediated strain-hardening mechanism should be particularly useful in Ti-, Zr- and Hf-containing alloys, in which interstitial elements are highly undesirable owing to their embrittlement effects, and in alloys where tuning the stacking fault energy and exploiting athermal transformations13 do not lead to property enhancement. These results provide insight into the role of interstitial solid solutions and associated ordering strengthening mechanisms in metallic materials.

Impact of epilepsy surgery on developmental trajectories of children under 3 years of age.

AIM: To investigate the developmental effects of epilepsy surgery in young children. METHOD: This study retrospectively reviewed 315 consecutive children under 3 years of age, and ultimately included 89 children (48 males, 41 females) with pre- and postsurgery developmental evaluations. RESULTS: The mean general quotient before surgery was 46.7 (SD 24.7). Before surgery, the general quotient decreased in 77.6% of patients, while after surgery it increased in 55.1%. Furthermore, 70% of those 20 patients whose presurgical general quotient decreased by more than 10 points experienced positive changes. General quotient scores decreased in 15 out of the 22 patients classified in the normal/marginal presurgical category. Children who underwent surgery before the age of 12 months had a median gain in general quotient score by 7.6. Short-term general quotient scores were highly correlated with long-term scores (r = 0.909, p < 0.001). INTERPRETATION: Surgical intervention was more inclined to positively impact developmental trajectories within a short postsurgical period, particularly among those affected by severe epileptic activity. However, in children with relatively typical development, certain developmental setbacks may arise. Postsurgical short-term developmental outcomes could predict longer-term outcomes.

RP11-495P10.1 promotes HCC cell proliferation by regulating reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis.

The incidence and related death of hepatocellular carcinoma (HCC) have increased over the past decades. However, the molecular mechanisms underlying HCC pathogenesis are not fully understood. Long noncoding RNA (lncRNA) RP11-495P10.1 has been proven to be closely associated with the progression of prostate cancer, but its role and specific mechanism in HCC are still unknown. Here, we identify that RP11-495P10.1 is highly expressed in HCC tissues and cells and contributes to the proliferation of HCC cells. Moreover, this study demonstrates that RP11-495P10.1 affects the proliferation of HCC by negatively regulating the expression of nuclear receptor subfamily 4 group a member 3 (NR4A3). Glycometabolism reprogramming is one of the main characteristics of tumor cells. In this study, we discover that RP11-495P10.1 regulates glycometabolism reprogramming by changing the expression of pyruvate dehydrogenase kinase 1 (PDK1) and pyruvate dehydrogenase (PDH), thus contributing to the proliferation of HCC cells. Furthermore, knockdown of RP11-495P10.1 increases enrichment of H3K27Ac in the promoter of NR4A3 by promoting the activity of PDH and the production of acetyl-CoA, which leads to the increased transcription of NR4A3. Altogether, RP11-495P10.1 promotes HCC cell proliferation by regulating the reprogramming of glucose metabolism and acetylation of the NR4A3 promoter via the PDK1/PDH axis, which provides an lncRNA-oriented therapeutic strategy for the diagnosis and treatment of HCC.

Accurate and robust auto-segmentation of head and neck organ-at-risks based on a novel CNN fine-tuning workflow.

PURPOSE: Obvious inconsistencies in auto-segmentations exist among various AI software. In this study, we have developed a novel convolutional neural network (CNN) fine-tuning workflow to achieve precise and robust localized segmentation. METHODS: The datasets include Hubei Cancer Hospital dataset, Cetuximab Head and Neck Public Dataset, and Québec Public Dataset. Seven organs-at-risks (OARs), including brain stem, left parotid gland, esophagus, left optic nerve, optic chiasm, mandible, and pharyngeal constrictor, were selected. The auto-segmentation results from four commercial AI software were first compared with the manual delineations. Then a new multi-scale lightweight residual CNN model with an attention module (named as HN-Net) was trained and tested on 40 samples and 10 samples from Hubei Cancer Hospital, respectively. To enhance the network's accuracy and generalization ability, the fine-tuning workflow utilized an uncertainty estimation method for automatic selection of candidate samples of worthiness from Cetuximab Head and Neck Public Dataset for further training. The segmentation performances were evaluated on the Hubei Cancer Hospital dataset and/or the entire Québec Public Dataset. RESULTS: A maximum difference of 0.13 and 0.7 mm in average Dice value and Hausdorff distance value for the seven OARs were observed by four AI software. The proposed HN-Net achieved an average Dice value of 0.14 higher than that of the AI software, and it also outperformed other popular CNN models (HN-Net: 0.79, U-Net: 0.78, U-Net++: 0.78, U-Net-Multi-scale: 0.77, AI software: 0.65). Additionally, the HN-Net fine-tuning workflow by using the local datasets and external public datasets further improved the automatic segmentation with the average Dice value by 0.02. CONCLUSION: The delineations of commercial AI software need to be carefully reviewed, and localized further training is necessary for clinical practice. The proposed fine-tuning workflow could be feasibly adopted to implement an accurate and robust auto-segmentation model by using local datasets and external public datasets.