Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response.

Viral infection triggers the activation of transcription factor IRF3, and its activity is precisely regulated for robust antiviral immune response and effective pathogen clearance. However, how full activation of IRF3 is achieved has not been well defined. Herein, we identified BLK as a key kinase that positively modulates IRF3-dependent signaling cascades and executes a pre-eminent antiviral effect. BLK deficiency attenuates RNA or DNA virus-induced ISRE activation, interferon production and the cellular antiviral response in human and murine cells, whereas overexpression of BLK has the opposite effects. BLK-deficient mice exhibit lower serum cytokine levels and higher lethality after VSV infection. Moreover, BLK deficiency impairs the secretion of downstream antiviral cytokines and promotes Senecavirus A (SVA) proliferation, thereby supporting SVA-induced oncolysis in an in vivo xenograft tumor model. Mechanistically, viral infection triggers BLK autophosphorylation at tyrosine 309. Subsequently, activated BLK directly binds and phosphorylates IRF3 at tyrosine 107, which further promotes TBK1-induced IRF3 S386 and S396 phosphorylation, facilitating sufficient IRF3 activation and downstream antiviral response. Collectively, our findings suggest that targeting BLK enhances viral clearance via specifically regulating IRF3 phosphorylation by a previously undefined mechanism.

Phosphorylation of PPDPF via IL6-JAK2 activates the Wnt/ß-catenin pathway in colorectal cancer.

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to ß-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the ß-catenin destruction complex, decreasing the phosphorylation of ß-catenin, and activating the Wnt/ß-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/ß-catenin signaling pathway, providing a potential novel therapeutic target.

A Novel and Efficient Digital Pathology Classifier for Predicting Cancer Biomarkers Using Sequencer Architecture.

In digital pathology tasks, transformers have achieved state-of-the-art results, surpassing convolutional neural networks (CNNs). However, transformers are usually complex and resource intensive. This study developed a novel and efficient digital pathology classifier called DPSeq to predict cancer biomarkers through fine-tuning a sequencer architecture integrating horizontal and vertical bidirectional long short-term memory networks. Using hematoxylin and eosin-stained histopathologic images of colorectal cancer from two international data sets (The Cancer Genome Atlas and Molecular and Cellular Oncology), the predictive performance of DPSeq was evaluated in a series of experiments. DPSeq demonstrated exceptional performance for predicting key biomarkers in colorectal cancer (microsatellite instability status, hypermutation, CpG island methylator phenotype status, BRAF mutation, TP53 mutation, and chromosomal instability), outperforming most published state-of-the-art classifiers in a within-cohort internal validation and a cross-cohort external validation. In addition, under the same experimental conditions using the same set of training and testing data sets, DPSeq surpassed four CNNs (ResNet18, ResNet50, MobileNetV2, and EfficientNet) and two transformer (Vision Transformer and Swin Transformer) models, achieving the highest area under the receiver operating characteristic curve and area under the precision-recall curve values in predicting microsatellite instability status, BRAF mutation, and CpG island methylator phenotype status. Furthermore, DPSeq required less time for both training and prediction because of its simple architecture. Therefore, DPSeq appears to be the preferred choice over transformer and CNN models for predicting cancer biomarkers.

A facile double moving redox boundary model for visual electrophoresis titration of ascorbic acid.

In this work, we proposed a double moving redox boundary (MROB) model to realize the colorless analyte electrophoresis titration (ET) by the two steps of the redox reaction. Single MROB has been proposed for the development of ET sensing (Analyst, 2013, 138, 1137. ACS Sensor, 2019, 4, 126.), and faces great challenges in detecting the analyte without color change during redox reaction. Herein, a novel model of double-MROB electrophoresis, including its mechanisms, equations, and procedures, was developed for titration by using ascorbic acid as a model analyte. The first MROB was created with ferric iron (Fe3+) and iodide ion (I-) in which Fe3+ was reduced as Fe2+ and I- was oxidized as molecular iodine (I2) used as an indicator of visible MROB due to blue starch-iodine complex. The second boundary was then formed between the molecular iodine and model analyte of ascorbic acid. Under given conditions, there was a quantitative relationship between velocity of MROB (VMROB(ii)) and ascorbic acid concentration (CVit C) in the double-MROB system (1/VMROB(ii) = 0.6502CVit C + 4.5165, and R = 0.9939). The relevant relative standard deviation values of intraday and inter-day were less than ∼5.55% and ∼6.64%, respectively. Finally, the titration of ascorbic acid in chewable vitamin C tablets was performed by the developed method, the titration results agreed with those via the classic iodometric titration. All the results briefly demonstrated the validity of the double MROB model, in which Vit C was used as a model analyte. The developed method had potential use in quantitative analysis of redox-active species in biomedical samples.

Method for Measuring the Three-Dimensional Morphology of Near-Wall Bubbles and Droplets Based on LED Digital Holography.

Digital holography, recognized for its noncontact nature and high precision in three-dimensional imaging, is effectively employed to measure the morphology of bubbles and droplets. However, in terms of near-wall bubbles and droplets, such as confined bubbles in microfluidic chips, the measurement of the interface morphology of bubbles near the glass surface has not yet been resolved due to the coherent noise resulting from glass surface reflections in microfluidic chips. Accordingly, an off-axis digital holography system was devised by using Linnik interferometry. Measuring the confined bubble interface near the wall within a microfluidic chip and droplet evaporation on solid surfaces was studied. Partially coherent LED sources and reference light modulation techniques were employed in the optical setup to mitigate the coherent noise. Dual exposure and weighted least-squares unwrapping algorithms were introduced to correct phase distortions, enhancing image quality. Imaging two confined CO2 bubbles was done near the wall in silicon oil within a porous microfluidic chip, and contact angles of 4.7 and 4.5° were measured. Additionally, the measurement of the three-dimensional morphology of vertically evaporating deionized water droplets on a glass surface was done, due to which calculation of contact angles at various orientations was possible. This work offers a feasible new method for measuring the 3D interface morphology of bubbles and droplets, particularly in microfluidic visualization, addressing current measurement gaps.

Faecalibacterium prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis.

BACKGROUND: Despite available clinical management strategies, chronic kidney disease (CKD) is associated with severe morbidity and mortality worldwide, which beckons new solutions. Host-microbial interactions with a depletion of Faecalibacterium prausnitzii in CKD are reported. However, the mechanisms about if and how F prausnitzii can be used as a probiotic to treat CKD remains unknown. METHODS: We evaluated the microbial compositions in 2 independent CKD populations for any potential probiotic. Next, we investigated if supplementation of such probiotic in a mouse CKD model can restore gut-renal homeostasis as monitored by its effects on suppression on renal inflammation, improvement in gut permeability and renal function. Last, we investigated the molecular mechanisms underlying the probiotic-induced beneficial outcomes. RESULTS: We observed significant depletion of Faecalibacterium in the patients with CKD in both Western (n=283) and Eastern populations (n=75). Supplementation of F prausnitzii to CKD mice reduced renal dysfunction, renal inflammation, and lowered the serum levels of various uremic toxins. These are coupled with improved gut microbial ecology and intestinal integrity. Moreover, we demonstrated that the beneficial effects in kidney induced by F prausnitzii-derived butyrate were through the GPR (G protein-coupled receptor)-43. CONCLUSIONS: Using a mouse CKD model, we uncovered a novel beneficial role of F prausnitzii in the restoration of renal function in CKD, which is, at least in part, attributed to the butyrate-mediated GPR-43 signaling in the kidney. Our study provides the necessary foundation to harness the therapeutic potential of F prausnitzii for ameliorating CKD.

Safety of non-ionic contrast media in CT examinations for out-patients: retrospective multicenter analysis of 473,482 patients.

OBJECTIVES: This study aimed to explore the incidence of and potential risk factors for adverse drug reactions (ADRs) after non-ionic iodinated contrast media (NICM) administration for CT exams in out-patient settings in China. MATERIALS AND METHODS: A total of 473,482 out-patients who underwent intravenous NICM between January 1st, 2017, and Dec 31st, 2021, were retrospectively enrolled from three institutions. The occurrence of ADRs and clinical information were recorded. Chi-square test, Poisson regression, and logistic regression analyses were used to evaluate potential ADR risk factors and correlation with demographics, season, and NICM type. RESULTS: Among the 473,482 patients (mean age 55.22 ± 14.85; 253,499 male) who received intravenous NICM, the overall ADR incidence was 0.110% (522 of 473,482), with 0.099% acute-related drug reactions (469 of 473,482) and 0.0004% serious ADRs (two of 473,482). Iopromide was associated with a higher risk of acute ADRs. Late ADRs were more frequently observed with iodixanol 320. Multi-level logistic regression of patients with acute ADRs and a control group (matched 1:1 for age, gender, NICM, prescriber department, and institution) showed that summer (adjusted OR = 1.579; p = 0.035) and autumn (adjusted OR = 1.925; p < 0.001) were risk factors of acute ADRs. However, underlying disease and scanned body area were not related to a higher ADR incidence. CONCLUSION: The use of NICM for out-patients is in general safe with a low ADR incidence. The type of contrast medium (iopromide) and the seasons (summer and autumn) were associated with a higher risk of acute ADRs. Late ADRs were more often observed with iodixanol. CLINICAL RELEVANCE STATEMENT: In comparison to in-patients, out-patients may be exposed to higher risk due to a lack of extensive risk screening, less nursing care, and higher throughput pressure. Safety data about NICM from a large population may complement guidelines and avoid ambiguity. KEY POINTS: • The incidence and risk factors for adverse events after using non-ionic iodinated contrast media are complex in out-patients. • Non-ionic iodinated contrast media are safe for out-patients and the overall incidence of adverse drug reactions was 0.110%. • There is a higher risk of acute adverse drug reactions in summer and autumn.

Ruthenium-Catalyzed Meta-Selective Trifluoroisopropylation of Arenes.

This work reports the mild and efficient Ru-catalyzed trifluoroisopropylation of arenes using 2-bromo-1,1,1-trifluoropropane. Various bioactive molecules, such as purine and nucleoside derivatives, were well-suited for this transformation, affording the corresponding products in moderate-to-good yields. This method provides an efficient strategy for synthesizing trifluoroisopropyl molecules for drug discovery.

Multifunctional Ni-NPC Single-Atom Nanozyme for Removal and Smartphone-Assisted Visualization Monitoring of Carbamate Pesticides.

A multifunctional single-atom nanozyme, denoted as 3D Ni,N-codoped porous carbon (Ni-NPC), was devised that exhibits remarkable adsorption capabilities and a repertoire of enzyme mimetic functions (oxidase- and peroxidase-like). These attributes stem from the distinctive mesoporous thin-shell structure and well-dispersed Ni sites. The efficient adsorption capacity of Ni-NPC was assessed with respect to three carbamate pesticides (CMPs): metolcarb, carbaryl, and isoprocarb. Moreover, a colorimetric detection method for CMP was established based on its robust peroxidase-like catalytic activity and sequential catalytic interactions with acetylcholinesterase. Furthermore, a portable colorimetric sensor based on a hydrogel sphere integrated with a smartphone platform was devised. This sensor enables rapid, on-site, and quantitative assessment of CMP, boasting an extraordinarily low detection limit of 1.5 ng mL-1. Notably, this sensor was successfully applied to the analysis of CMP levels in lake water and vegetable samples (pakchoi and rape), propelling the progress of real-time detection technologies in food and environment monitoring.

Burden of cardiac arrhythmias in patients with acute myocardial infarction and their impact on hospitalization outcomes: insights from China acute myocardial infarction (CAMI) registry.

BACKGROUND: The coexistence of cardiac arrhythmias in patients with acute myocardial infarction (AMI) usually exhibits poor prognosis. However, there are few contemporary data available on the burden of cardiac arrhythmias in AMI patients and their impact on in-hospital outcomes. METHODS: The present study analyzed data from the China Acute Myocardial Infarction (CAMI) registry involving 23,825 consecutive AMI patients admitted to 108 hospitals from January 2013 to February 2018. Cardiac arrhythmias were defined as the presence of bradyarrhythmias, sustained atrial tachyarrhythmias, and sustained ventricular tachyarrhythmias that occurred during hospitalization. In-hospital outcome was defined as a composite of all-cause mortality, cardiogenic shock, re-infarction, stroke, or heart failure. RESULTS: Cardiac arrhythmia was presented in 1991 (8.35%) AMI patients, including 3.4% ventricular tachyarrhythmias, 2.44% bradyarrhythmias, 1.78% atrial tachyarrhythmias, and 0.73% ≥2 kinds of arrhythmias. Patients with arrhythmias were more common with ST-segment elevation myocardial infarction (83.3% vs. 75.5%, P < 0.001), fibrinolysis (12.8% vs. 8.0%, P < 0.001), and previous heart failure (3.7% vs. 1.5%, P < 0.001). The incidences of in-hospital outcomes were 77.0%, 50.7%, 43.5%, and 41.4%, respectively, in patients with ≥ 2 kinds of arrhythmias, ventricular tachyarrhythmias, bradyarrhythmias, and atrial tachyarrhythmias, and were significantly higher in all patients with arrhythmias than those without arrhythmias (48.9% vs. 12.5%, P < 0.001). The presence of any kinds of arrhythmia was independently associated with an increased risk of hospitalization outcome (≥ 2 kinds of arrhythmias, OR 26.83, 95%CI 18.51-38.90; ventricular tachyarrhythmias, OR 8.56, 95%CI 7.34-9.98; bradyarrhythmias, OR 5.82, 95%CI 4.87-6.95; atrial tachyarrhythmias, OR4.15, 95%CI 3.38-5.10), and in-hospital mortality (≥ 2 kinds of arrhythmias, OR 24.44, 95%CI 17.03-35.07; ventricular tachyarrhythmias, OR 13.61, 95%CI 10.87-17.05; bradyarrhythmias, OR 7.85, 95%CI 6.0-10.26; atrial tachyarrhythmias, OR 4.28, 95%CI 2.98-6.16). CONCLUSION: Cardiac arrhythmia commonly occurred in patients with AMI might be ventricular tachyarrhythmias, followed by bradyarrhythmias, atrial tachyarrhythmias, and ≥ 2 kinds of arrhythmias. The presence of any arrhythmias could impact poor hospitalization outcomes. REGISTRATION: Clinical Trial Registration: Identifier: NCT01874691.

Casticin induces apoptosis and cytoprotective autophagy while inhibiting stemness involving Akt/mTOR and JAK2/STAT3 pathways in glioblastoma.

Glioblastoma (GBM) is the most common malignant glioma. However, the current systemic drugs cannot completely cure GBM. Casticin is a methoxylated flavonol compound isolated from a traditional Chinese medicine Vitex rotundifolia L.f. and exhibits a strong antitumor activity in multiple human malignancies. This study was aimed to explore the effects and underlying mechanisms of casticin in GBM. The MTT assay and colony formation was used to evaluate the casticin-induced cell viability in GBM cells. Apoptosis was assessed by ANNEXIV/PI staining assay. Autophagy was analyzed by transmission electron microscopy and immunofluorescence assays. GBM stem cell (GSC) was analyzed by tumor-sphere formation assay and ALDEFLUOR assay. The anti-GBM effect of casticin was also determined by the U87MG xenograft model. Casticin inhibited tumor cell growth in vitro and in vivo, as well as significantly induced apoptosis and autophagy. Autophagy inhibition augmented casticin-induced apoptosis. Casticin also reduced the GSC population by suppressing Oct4, Nanog, and Sox2. Mechanistically, casticin inhibited Akt/mTOR and JAK2/STAT3 signal pathways. The antitumor effect of casticin in GBM was demonstrated by inducing apoptosis, autophagy, and reducing population of GSCs; thus, it may be a potential GBM therapeutic agent for future clinical usage.

Construction of a Colorimetric and Fluorescence Dual-Mode Immunoassay Detection of Alpha-Hemolysin in Milk.

Alpha-hemolysin (Hla) is a major virulence factor secreted by Staphylococcus aureus (S. aureus), which can lyse a variety of mammalian cells and help bacteria evade the host immune system or antibiotics, posing a safety hazard to human health. Therefore, it is critical to establish a quick-responsive and sensitive method for Hla detection to ensure food safety. In this work, a dual-mode immunoassay was developed with both colorimetric and fluorescent readouts for discriminative detection of Hla. The proposed sensing system consists of p-phenylenediamine (PPD) and fluorescein, where fluorescein functions as a fluorescent reporter, and PPD serves a dual function as a colorimetric reporter and fluorescence quencher. Subsequently, the reaction system of this method was optimized, and the detection limit, sensitivity, and specificity were evaluated. Under optimal conditions, the proposed method possesses excellent analytical performance in the range from 0.5 to 500 ng/mL with a limit of detection as low as 0.5 ng/mL. Noteworthy, this method was successfully employed for the detection of Hla in milk with good selectivity and high accuracy. Overall, the dual-mode immunoassay provides a superior platform for the on-site, quantitative, and accurate detection of Hla in food samples.

SensorNet: An Adaptive Attention Convolutional Neural Network for Sensor Feature Learning.

This work develops a generalizable neural network, SENSORNET, for sensor feature learning across various applications. The primary challenge addressed is the poor portability of pretrained neural networks to new applications with limited sensor data. To solve this challenge, we design SensorNet, which integrates the flexibility of self-attention with multi-scale feature locality of convolution. Moreover, we invent patch-wise self-attention with stacked multi-heads to enrich the sensor feature representation. SensorNet is generalizable to pervasive applications with any number of sensor inputs, and is much smaller than the state-of-the-art self-attention and convolution hybrid baseline (0.83 M vs. 3.87 M parameters) with similar performance. The experimental results show that SensorNet is able to achieve state-of-the-art performance compared with the top five models on a competition activity recognition dataset (SHL'18). Moreover, pretrained SensorNet in a large inertial measurement unit (IMU) dataset can be fine-tuned to achieve the best accuracy on a much smaller IMU dataset (up to 5% improvement in WISDM) and to achieve the state-of-the-art performance on an EEG dataset (SLEEP-EDF-20), showing the strong generalizability of our approach.

Factors Affecting Workers' Mental Stress in Handover Activities During Human-Robot Collaboration.

OBJECTIVE: This study investigated the effects of different approach directions, movement speeds, and trajectories of a co-robot's end-effector on workers' mental stress during handover tasks. BACKGROUND: Human-robot collaboration (HRC) is gaining attention in industry and academia. Understanding robot-related factors causing mental stress is crucial for designing collaborative tasks that minimize workers' stress. METHODS: Mental stress in HRC tasks was measured subjectively through self-reports and objectively through galvanic skin response (GSR) and electromyography (EMG). Robot-related factors including approach direction, movement speed, and trajectory were analyzed. RESULTS: Movement speed and approach direction had significant effects on subjective ratings, EMG, and GSR. High-speed and approaching from one side consistently resulted in higher fear, lower comfort, and predictability, as well as increased EMG and GSR signals, indicating higher mental stress. Movement trajectory affected GSR, with the sudden stop condition eliciting a stronger response compared to the constrained trajectory. Interaction effects between speed and approach direction were observed for "surprise" and "predictability" subjective ratings. At high speed, approach direction did not significantly differ, but at low speeds, approaching from the side was found to be more surprising and unpredictable compared to approaching from the front. CONCLUSION: The mental stress of workers during HRC is lower when the robot's end effector (1) approaches a worker within the worker's field of view, (2) approaches at a lower speed, or (3) follows a constrained trajectory. APPLICATION: The outcome of this study can serve as a guide to design HRC tasks with a low level of workers' mental stress.

Sentiment annotations for 3827 simplified Chinese characters.

Sentiment analysis in Chinese natural language processing has been largely based on words annotated with sentiment categories or scores. Characters, however, are the basic orthographic, phonological, and in most cases, semantic units in the Chinese language. This study collected sentiment annotations for 3827 characters. The ratings demonstrated high levels of reliability, and were validated through a comparison with the ratings of some characters' word equivalents reported in a previous norming study. Relations with other lexico-semantic variables and character processing efficiency were investigated. Furthermore, analyses of the association between constituent character valence and word valence revealed semantic compositionality and sentiment fusion characteristic of larger Chinese linguistic units. These ratings for characters, expanding current Chinese sentiment lexicons, can be utilized for the purposes of more precise stimuli assessment in research on Chinese character processing and more efficient sentiment analysis equipped with annotations of single-character words.

[Integrated strategy for mechanism of Shenling Baizhu San in treating ulcerative colitis based on colonic metabolomics and network pharmacology].

Shenling Baizhu San(SLBZS) is a commonly used medicine for the treatment of ulcerative colitis(UC). This study aims to explore the mechanism of SLBZS in treating UC by using colonic metabolomics and network pharmacology. BALB/c mice were randomly divided into four groups: a blank group, a model group, an SLBZS group, and a sulfasalazine group. UPLC-Q-TOF-MS/MS technology was utilized to analyze the metabolic profiles of colonic tissue in mice, and differential metabolites and related metabolic pathways were screened. Based on the online database, active ingredients, action targets, and UC disease targets of SLBZS were screened. The protein-protein interaction(PPI) network of core targets of SLBZS in treating UC was constructed using STRING and Cytoscape 3.9.1. Gene Ontology(GO) functional and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses were performed using the DAVID database. A "metabolite-reaction-enzyme-gene" network was constructed to conduct a combined analysis of metabolomics and network pharmacology. SLBZS reversed the levels of 25 metabolites involved in various pathways such as D-glutamine and D-glutamate metabolism, caffeine metabolism, sphingolipid metabolism, arginine biosynthesis, lysine degradation, alanine, aspartate, and glutamate metabolism, glycerophospholipid metabolism, and pyrimidine metabolism in UC colonic tissue. 47 core targets of SLBZS in treating UC were involved in pathways including the MAPK signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway, lipid and atherosclerosis, inflammatory bowel disease, and Th17 cell differentiation. Integrated analysis showed that glycerophospholipid metabolism and pyrimidine metabolism were key metabolic pathways in the treatment of UC with SLBZS. The results suggested that SLBZS improved colonic mucosal morphology by regulating colonic metabolites, down-regulated the expression of inflammation-related core target genes to reduce inflammation levels, and alleviated lipid metabolism disorders, thereby exerting a therapeutic effect on UC.

Aptamer-Linked Photonic Crystal Assay for High-Throughput Screening of HIV and SARS-CoV-2.

We present a microplate assay for the detection of HIV and SARS-CoV-2 which involves the preadsorption of carboxy-modified polystyrene microspheres to the microplate wells and their self-assembly leading to the formation of a photonic crystal colloidal array (PCCA). PCCA is then cross-linked with amino-modified aptamers selected for viral cell surface glycoproteins, i.e., S1-protein of SARS-CoV-2 and gp120 of the human immunodeficiency virus (HIV), to develop an aptamer-linked photonic crystal assay (ALPA). ALPA is then utilized as a proof-of-concept method for the detection of S1-protein, gp120, and two whole viruses, i.e., SARS-CoV-2 and HIV, as well. The aptamers are stable at room temperature and can bind with the viruses' proteins via hydrogen bonding. This binding leads to color generation from PCCA, and the signal can easily be measured and quantified by a UV/vis spectrometer. The assay carries the advantage of a two-step detection process by the addition of the virus sample directly to a 96-well microplate and incubation of 5 min followed by convenient detection through a UV/vis-spectrometer. The assay does not require any additional reagents and can be customized for similar viruses utilizing specific aptamers targeting their cell surface receptors.

Ni Single Atoms on MoS2 Nanosheets Enabling Enhanced Kinetics of Li-S Batteries.

The practical application of Li-S batteries is seriously hindered due to its shuttle effect and sluggish redox reaction, which requires a better functional separator to solve the problems. Herein, polypropylene separators modified by MoS2 nanosheets with atomically dispersed nickel (Ni-MoS2 ) are prepared to prevent the shuttle effect and facilitate the redox kinetics for Li-S batteries. Compared with pristine MoS2 nanosheets, Ni-MoS2 nanosheets exhibit both excellent adsorption and catalysis performance for overcoming the shuttle effect. Assembled with this novel separator, the Li-S batteries exhibit an admirable cycling stability at 2 C over 400 cycles with 0.01% per cycle decaying. In addition, even with a high sulfur loading of 7.5 mg cm-2 , the battery still provides an initial capacity of 6.9 mAh cm-2 and remains 5.9 mAh cm-2 after 50 cycles because of the fast convention of polysulfides catalyzed by Ni-MoS2 nanosheets, which is further confirmed by the density functional theory (DFT) calculations. Therefore, the proposed strategy is expected to offer a new thought for single atom catalyst applying in Li-S batteries.

SCEBE: an efficient and scalable algorithm for genome-wide association studies on longitudinal outcomes with mixed-effects modeling.

Genome-wide association studies (GWAS) using longitudinal phenotypes collected over time is appealing due to the improvement of power. However, computation burden has been a challenge because of the complex algorithms for modeling the longitudinal data. Approximation methods based on empirical Bayesian estimates (EBEs) from mixed-effects modeling have been developed to expedite the analysis. However, our analysis demonstrated that bias in both association test and estimation for the existing EBE-based methods remains an issue. We propose an incredibly fast and unbiased method (simultaneous correction for EBE, SCEBE) that can correct the bias in the naive EBE approach and provide unbiased P-values and estimates of effect size. Through application to Alzheimer's Disease Neuroimaging Initiative data with 6 414 695 single nucleotide polymorphisms, we demonstrated that SCEBE can efficiently perform large-scale GWAS with longitudinal outcomes, providing nearly 10 000 times improvement of computational efficiency and shortening the computation time from months to minutes. The SCEBE package and the example datasets are available at https://github.com/Myuan2019/SCEBE.

Sp1 promotes tumour progression by remodelling the mitochondrial network in cervical cancer.

BACKGROUND: Cervical cancer remains one of the most prevalent cancers worldwide. Accumulating evidence suggests that specificity protein 1 (Sp1) plays a pivotal role in tumour progression. The underlying role and mechanism of Sp1 in tumour progression remain unclear. METHODS: The protein level of Sp1 in tumour tissues was determined by immunohistochemistry. The effect of Sp1 expression on the biological characteristics of cervical cancer cells was assessed by colony, wound healing, transwell formation, EdU, and TUNEL assays. Finally, the underlying mechanisms and effects of Sp1 on the mitochondrial network and metabolism of cervical cancer were analysed both in vitro and in vivo. RESULTS: Sp1 expression was upregulated in cervical cancer. Sp1 knockdown suppressed cell proliferation both in vitro and in vivo, while overexpression of Sp1 had the opposite effects. Mechanistically, Sp1 facilitated mitochondrial remodelling by regulating mitofusin 1/2 (Mfn1/2), OPA1 mitochondrial dynamin-like GTPase (Opa1), and dynamin 1-like (Drp1). Additionally, the Sp1-mediated reprogramming of glucose metabolism played a critical role in the progression of cervical cancer cells. CONCLUSIONS: Our study demonstrates that Sp1 plays a vital role in cervical tumorigenesis by regulating the mitochondrial network and reprogramming glucose metabolism. Targeting Sp1 could be an effective strategy for the treatment of cervical cancer.