CLigOpt: controllable ligand design through target-specific optimization.

MOTIVATION: A key challenge in deep generative models for molecular design is to navigate random sampling of the vast molecular space, and produce promising molecules that strike a balance across multiple chemical criteria. Fragment-based drug design (FBDD), using fragments as starting points, is an effective way to constrain chemical space and improve generation of biologically active molecules. Furthermore, optimization approaches are often implemented with generative models to search through chemical space, and identify promising samples which satisfy specific properties. Controllable FBDD has promising potential in efficient target-specific ligand design. RESULTS: We propose a controllable FBDD model, CLigOpt, which can generate molecules with desired properties from a given fragment pair. CLigOpt is a variational autoencoder-based model which utilizes co-embeddings of node and edge features to fully mine information from molecular graphs, as well as a multi-objective Controllable Generation Module to generate molecules under property controls. CLigOpt achieves consistently strong performance in generating structurally and chemically valid molecules, as evaluated across six metrics. Applicability is illustrated through ligand candidates for hDHFR and it is shown that the proportion of feasible active molecules from the generated set is increased by 10%. Molecular docking and synthesizability prediction tasks are conducted to prioritize generated molecules to derive potential lead compounds. AVAILABILITY AND IMPLEMENTATION: The source code is available via  https://github.com/yutongLi1997/CLigOpt-Controllable-Ligand-Design-through-Target-Specific-Optimisation.

SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1.

SIRT2, a cytoplasmic member of the Sirtuin family, has important roles in immunity and inflammation. However, its function in regulating the response to DNA virus infection remains elusive. Here, we find that SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS-STING-signaling pathway. SIRT2 is down-regulated after Herpes simplex virus-1 (HSV-1) infection, and SIRT2 deficiency markedly elevates the expression levels of type I interferon (IFN). SIRT2 inhibits the DNA binding ability and droplet formation of cGAS by interacting with and deacetylating G3BP1 at K257, K276, and K376, leading to the disassembly of the cGAS-G3BP1 complex, which is critical for cGAS activation. Administration of AGK2, a selective SIRT2 inhibitor, protects mice from HSV-1 infection and increases the expression of IFN and IFN-stimulated genes. Our study shows that SIRT2 negatively regulates cGAS activation through G3BP1 deacetylation, suggesting a potential antiviral strategy by modulating SIRT2 activity.

SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.

BACKGROUNDS: Pathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. METHODS: Mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. RESULTS: Our results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. CONCLUSIONS: This study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers.

While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are a new class of anticancer drugs comprising the coupling of antitumor mAbs with cytotoxic drugs. Compared with chemotherapeutic drugs, ADCs have the advantages of good tolerance, accurate target recognition, and small effects on noncancerous cells. ADCs occupy an increasingly important position in the therapeutic field. Currently, there are 13 Food and Drug Administration (FDA)‒approved ADCs and more than 100 ADC drugs at different stages of clinical trials. This review briefly describes the efficacy and safety of FDA-approved ADCs, and discusses the related problems and challenges to provide a reference for clinical work.

SPP1 represents a therapeutic target that promotes the progression of oesophageal squamous cell carcinoma by driving M2 macrophage infiltration.

BACKGROUND: Tumour-associated macrophages (TAMs) are an important component of the tumour microenvironment (TME). However, the crosstalk between oesophageal squamous cell carcinoma (ESCC) cells and TAMs remains largely unexplored. METHODS: Clinical samples and the TCGA database were used to evaluate the relevance of SPP1 and TAM infiltration in ESCC. Mouse models were constructed to investigate the roles of macrophages educated by SPP1 in ESCC. Macrophage phenotypes were determined using qRT‒PCR and immunohistochemical staining. RNA sequencing was performed to elucidate the mechanism. RESULTS: Increasing expression of SPP1 correlated with M2-like TAM accumulation in ESCC, and they both predicted poor prognosis in the ESCC cohort. Knockdown of SPP1 significantly inhibited the infiltration of M2 TAMs in xenograft tumours. In vivo mouse model experiments showed that SPP1-mediated education of macrophages plays an essential role in the progression of ESCC. Mechanistically, SPP1 recruited macrophages and promoted M2 polarisation via CD44/PI3K/AKT signalling activation and then induced VEGFA and IL6 secretion to sustain ESCC progression. Finally, blockade of SPP1 with RNA aptamer significantly inhibited tumour growth and M2 TAM infiltration in xenograft mouse models. CONCLUSIONS: This study highlights SPP1-mediated crosstalk between ESCC cells and TAMs in ESCC. SPP1 could serve as a potential target in ESCC therapy.

Screening of potential drugs for the treatment of diabetic kidney disease using single-cell transcriptome sequencing and connectivity map data.

OBJECTIVE: To explore the feasibility of screening potential drugs for the treatment of diabetic kidney disease (DKD) using a single-cell transcriptome sequencing dataset and Connectivity Map (CMap) database screening. METHODS: A DKD single-nucleus transcriptome sequencing dataset was analyzed using Seurat 4.0 to obtain specific podocyte subclusters and differentially expressed genes (DEGs) related to DKD. These DEGs were subsequently subjected to a search against the CMap database to screen for drug candidates. Cell and animal experiments were conducted to evaluate the efficacy of the top 3 drug candidates. RESULTS: Initially, we analyzed the DKD single-nucleus transcriptome sequencing dataset to obtain intrinsic renal cells such as podocytes, endothelial cells, mesangial cells, proximal tubular cells, collecting duct cells and immune cells. Podocytes were further divided into four subclusters, among which the proportion of POD_1 podcytes was significantly greater in DKD kidneys than in control kidneys (34.0 % vs. 3.4 %). The CMap database was searched using the identified DEGs in the POD_1 subcluster, and the drugs, including tozasertib, paroxetine, and xylazine, were obtained. Cell-based experiments showed that tozasertib, paroxetine and xylazine had no significant podocyte toxicity in the concentration range of 0.01-50 µM. Tozasertib, paroxetine, and xylazine all reversed the advanced glycation end products (AGEs)-induced decrease in podocyte marker levels, but the effect of paroxetine was more prominent. Animal experiments showed that paroxetine decreased urine ALB/Cr levels in DKD model mice by approximately 51.5 % (115.7 mg/g vs. 238.8 mg/g, P < 0.05). Histopathological assessment revealed that paroxetine attenuated basement membrane thickening, restored the number of foot processes of podocytes, and reduced foot process fusion. In addition, paroxetine also attenuated renal tubular-interstitial fibrosis. Mechanistically, paroxetine inhibited the expression of GRK2 and NLRP3, decreased the phosphorylation level of p65, restored NRF2 expression, and relieved inflammation and oxidative stress. CONCLUSION: This strategy based on single-cell transcriptome sequencing and CMap data can facilitate the identification and aid the rapid development of clinical DKD drugs. Paroxetine, screened by this strategy, has excellent renoprotective effects.

Optimized terahertz generation in BNA organic crystals with chirped Ti:sapphire laser pulses.

We report on the efficient generation of intense terahertz radiation from the organic crystal N-benzyl-2-methyl-4-nitroaniline pumped by chirped Ti:sapphire femtosecond laser pulses. The THz energy and spectrum as a function of the pump fluence and duration of the chirped laser pulses are studied systematically. For the appropriate positively chirped pump pulses, a significant boost in the THz generation efficiency by a factor of around 2.5 is achieved, and the enhancement of high-frequency components (>1 THz) shortens the THz pulse duration. Via complete characterization of THz properties and transmitted laser spectra, this nonlinear behavior is attributed to the extended effective interaction length for phase matching as a result of the self-phase modulation of the intense pump laser pulses. Numerical calculations well reproduce the experimental observation. Our results demonstrate a robust, efficient, strong-field (up to several MV/cm) THz source using the common sub-10 mJ and sub-100 fs Ti:sapphire laser systems without optical parametric amplifiers.

Electromagnetically Induced Transparency in the Strongly Relativistic Regime.

Stable transport of laser beams in highly overdense plasmas is of significance in the fast ignition of inertial confinement fusion, relativistic electron generation, and powerful electromagnetic emission, but hard to realize. Early in 1996, Harris proposed an electromagnetically induced transparency (EIT) mechanism, analogous to the concept in atomic physics, to transport a low-frequency (LF) laser in overdense plasmas aided by a high-frequency pump laser. However, subsequent investigations show that EIT cannot occur in real plasmas with boundaries. Here, our particle-in-cell simulations show that EIT can occur in the strongly relativistic regime and result in stable propagation of a LF laser in bounded plasmas with tens of its critical density. A relativistic three-wave coupling model is developed, and the criteria and frequency passband for EIT occurrence are presented. The passband is sufficiently wide in the strongly relativistic regime, allowing EIT to work sustainably. Nevertheless, it is narrowed to nearly an isolated point in the weakly relativistic regime, which can explain the quenching of EIT in bounded plasmas found in previous investigations.

Femtosecond Dynamics of Fast Electron Pulses in Relativistic Laser-Foil Interactions.

We report the femtosecond time-resolved dynamics of relativistic electron pulses in ultraintense laser-foil interactions, by characterizing the terahertz self-radiation with single-shot ultrabroadband interferometry. Experimental measurements together with theoretical modeling reveal that the electron pulses inherit the duration of the driving laser pulse. We also visualize the electron recirculation dynamics, where electrons remain trapped inside the self-generated electrostatic potential well and rebound back and forth around the thin foil for hundreds of femtoseconds. Our results not only demonstrate an in situ, real-time metrology scheme for electron bursts, but also have important implications for understanding and manipulating the time-domain properties of laser-driven particle and radiation sources.

Physiological and gene expression responses of Protohermes xanthodes (Megaloptera: Corydalidae) larvae to imidacloprid.

Megaloptera larvae are important bioindicator species and potential resource insects. To further cultivate their economic role, their living environment must be examined in more detail. In this study, we analyzed the physiological and biochemical effects of a sublethal dose of imidacloprid, a widely used neonicotinoid insecticide, on the larvae of Protohermes xanthodes. After treatment with imidacloprid, P. xanthodes larvae exhibited clear symptoms of poisoning, including the head curling up toward the ventral surface. Additionally, the activity of acetylcholinesterase was significantly inhibited following exposure. The activities of glutathione S-transferases initially continuously increased but showed a slight decrease after 8 days. Catalase activity initially increased and then decreased following imidacloprid treatment; superoxide dismutase activity fluctuated over time, and peroxidase activity continuously increased. The expression levels of HSP70s genes were evaluated using qRT-PCR. These results indicate that P. xanthodes larvae exhibit a toxic response to imidacloprid exposure, manifested as oxidative stress, as observed through behavioral and physiological indicators.

Bacillus phage phi18-2 is a novel temperate virus with an unintegrated genome present in the cytoplasm of lysogenic cells as a linear phage-plasmid.

Bacillus subtilis is a Gram-positive bacterium that is widely used in fermentation and in the pharmaceutical industry. Phage contamination occasionally occurs in various fermentation processes and causes significant economic loss. Here, we report the isolation and characterization of a temperate B. subtilis phage, termed phi18-2, from spore powder manufactured in a fermentation plant. Transmission electron microscopy showed that phi18-2 has a symmetrical polyhedral head and a long noncontractile tail. Receptor analysis showed that phi18-2 recognizes wall teichoic acid (WTA) for infection. The phage virions have a linear double-stranded DNA genome of 64,467 bp with identical direct repeat sequences of 309 bp at each end of the genome. In lysogenic cells, the phage genome was found to be present in the cytoplasm without integration into the host cell chromosome, and possibly as a linear phage-plasmid with unmodified ends. Our data may provide some insight into the molecular basis of the unique lysogenic cycle of phage phi18-2.

Masks As a New Hotspot for Antibiotic Resistance Gene Spread: Reveal the Contribution of Atmospheric Pollutants and Potential Risks.

The consumption of disposable surgical masks (DSMs) considerably increased during the coronavirus pandemic in 2019. Herein, we explored the spread of antibiotic resistance genes (ARGs) and the potential risks of antibiotic resistant bacteria (ARB) on DSMs. At environmentally relevant concentrations, the conjugate transfer frequency (CTF) of ARGs increased by 1.34-2.37 folds by 20 µg/m3 of atmospheric water-soluble inorganic ions (WSIIs), and it increased by 2.62-2.86 folds by 80 ng/m3 of polycyclic aromatic hydrocarbons (PAHs). Total suspended particulates (TSP) further promoted the CTF in combination with WSIIs or PAHs. Under WSII and PAH exposure, gene expression levels related to oxidative stress, cell membrane, and the adenosine triphosphate (ATP) were upregulated. WSIIs predominantly induced cellular contact, while PAHs triggered ATP formation and membrane damage. Molecular dynamics simulations showed that WSIIs and PAHs reduced membrane lipid fluidity and increased membrane permeability through interactions with the phosphatidylcholine bilayer. DSM filtering performance decreased, and the CTF of ARGs increased with the wearing time. The gut simulator test showed that ARB disrupted the human gut microbial community and increased total ARG abundance but did not change the ARG abundance carried by ARB themselves. A mathematical model showed that long-term WSII and PAH exposure accelerated ARG dissemination in DSMs.

Asian Screening Array and Next-Generation Sequencing Based Panels Applied to Preimplantation Genetic Testing for Monogenic Disorders Preclinical Workup in 294 Families: A Retrospective Analysis.

OBJECTIVE: Currently, the most commonly used methods for linkage analysis of pre-implantation genetic testing for monogenic disorders (PGT-M) are next generation sequencing (NGS) and SNP array. We aim to investigate whether the application efficacy of Asian screening array (ASA) in PGT-M preclinical workup for the Chinese population is superior to NGS based single nucleotide polymorphism (SNP) panels. METHODS: We conducted a retrospective analysis by reviewing 294 couples from a single center over the past 4 years and compared the detection results between NGS-based SNP panels and ASA. Using the numbers of informative SNPs upstream and downstream flanking of variants, we assessed the detection efficiency of both methods in monogenic diseases, chromosomal microdeletion syndrome and males with de novo variants, among other scenarios. RESULTS: Results indicate that ASA offers a greater number of informative SNPs compared with NGS-based SNP panels. Additionally, data analysis for ASA is generally more straightforward and may require less computational resources. While ASA can address most PGT-M challenges, we have also identified certain genes in previous tests that are not suitable for PGT-M using ASA. CONCLUSION: The application of ASA in PGT-M preclinical workup for Chinese populations has good practical value as it can perform linkage analysis for most genetic variants. However, for certain variants, NGS or other testing methods, such as mutated allele revealed by sequencing with aneuploidy and linkage analysis (MARSALA), may still be necessary for completion.

Preimplantation genetic testing in couples with balanced chromosome rearrangement: a four-year period real world retrospective cohort study.

BACKGROUND: Couples with balanced chromosome rearrangement (BCR) are at high risk of recurrent miscarriages or birth defects due to chromosomally abnormal embryos. This study aimed to provide real-world evidence of the euploidy rate of blastocysts from couples with BCR using preimplantation genetic testing (PGT) and to guide pretesting genetic counselling. METHODS: A continuous four-year PGT data from couples with BCR were retrospectively analyzed. Biopsied trophectoderm cells were amplified using whole genome amplification, and next-generation sequencing was performed to detect the chromosomal numerical and segmental aberrations. Clinical data and molecular genetic testing results were analyzed and compared among the subgroups. RESULTS: A total of 1571 PGT cycles with 5942 blastocysts were performed chromosomal numerical and segmental aberrations detection during the four years. Of them, 1034 PGT cycles with 4129 blastocysts for BCR couples were included; 68.96% (713/1034) PGT cycles had transferable euploid embryos. The total euploidy rate of blastocysts in couples carrying the BCR was 35.29% (1457/4129). Couples with complex BCR had euploid blastocyst rates similar to those of couples with non-complex BCR (46.15% vs. 35.18%, P > 0.05). Chromosome inversion had the highest chance of obtaining a euploid blastocyst (57.27%), followed by Robertsonian translocation (RobT) (46.06%), and the lowest in reciprocal translocation (RecT) (30.11%) (P < 0.05). Couples with males carrying RobT had higher rates of euploid embryo both in each PGT cycles and total blastocysts than female RobT carriers did, despite the female age in male RobT is significant older than those with female RobT (P < 0.05). The proportions of non-carrier embryos were 52.78% (95/180) and 47.06% (40/85) in euploid blastocysts from couples with RecT and RobT, respectively (P > 0.05). RecT had the highest proportion of blastocysts with translocated chromosome-associated abnormalities (74.23%, 1527/2057), followed by RobT (54.60%, 273/500) and inversion (30.85%, 29/94) (P < 0.05). CONCLUSIONS: In couples carrying BCR, the total euploidy rate of blastocysts was 35.29%, with the highest in inversion, followed by RobT and RecT. Even in couples carrying complex BCR, the probability of having a transferable blastocyst was 46.15%. Among the euploid blastocysts, the non-carrier ratios in RecT and RobT were 52.78% and 47.06%, respectively. RecT had the highest proportion of blastocysts with translocated chromosome-associated abnormalities.

Tranq Dope: Characterization of an ED cohort treated with a novel opioid withdrawal protocol in the era of fentanyl/xylazine.

BACKGROUND: Treating opioid use disorder has reached a new level of challenge. Synthetic opioids and xylazine have joined the non-medical opioid supply, multiplying the complexities of caring for individuals in emergency departments (ED). This combination, known as 'tranq dope,' is poorly described in literature. Inadequate withdrawal treatment results in a disproportionately high rate of patient-directed discharges (also known as against medical advice dispositions, or AMA). This study aimed to describe a cohort of individuals who received a novel order set for suspected fentanyl and xylazine withdrawal in the ED. METHODS: This is a descriptive study evaluating a cohort of ED patients who received withdrawal medications from a novel protocol and electronic health record order set. Individuals being assessed in the ED while suffering from withdrawal were eligible. Individuals under age 18, on stable outpatient MOUD or who were pregnant were excluded. Treatment strategies included micro-induction buprenorphine, short acting opioids, non-opioid analgesics, and other adjunctive medications. Data collected included: demographics including zip code, urine toxicology screening, order set utilization and disposition data. Clinical Opiate Withdrawal Scale (COWS) scores were recorded, where available, before and following exposure to the medications. RESULTS: There were 270 patient encounters that occurred between September 14, 2022, and March 9, 2023 included in the total study cohort. Of those, 66 % were male, mean age 37 with 71 % residing within Philadelphia zip codes. 100 % of urine toxicology screenings were positive for fentanyl. Of the 177 patients with both pre- and post-exposure COWS scores documented, constituting the final cohort, patients receiving medications had their COWS score decrease from a median of 12 to a median of 4 (p < 0.001). The AMA rate for this cohort was 3.9 %, whereas the baseline for the population with OUD was 10.7 %. Recorded adverse effects were few and resolved without complication. CONCLUSIONS: Fentanyl and xylazine withdrawal are challenging for patients and providers. A novel tranq dope withdrawal order set may reduce both COWS scores and rate of patient-directed discharge in this cohort of patients, though further investigation is needed to confirm findings.

Organosiloxane-Modified Auricularia Polysaccharide (Si-AP): Improved High-Temperature Resistance and Lubrication Performance in WBDFs.

This study introduces a novel organosilicon-modified polysaccharide (Si-AP) synthesized via grafting and comprehensively evaluates its performance in water-based drilling fluids (WBDFs). The molecular structure of Si-AP was characterized using Fourier-transform infrared spectroscopy (FTIR) and 1H-NMR experiments. Thermalgravimetric analysis (TGA) confirmed the good thermal stability of Si-AP up to 235 °C. Si-AP significantly improves the rheological properties and fluid loss performance of WBDFs. With increasing Si-AP concentration, system viscosity increases, API filtration rate decreases, clay expansion is inhibited, and drilling cuttings hydration dispersion is suppressed, especially under high-temperature conditions. Additionally, mechanistic analysis indicates that the introduction of siloxane groups can effectively inhibit the thermal degradation of AP chains and enhance their high-temperature resistance. Si-AP can form a lubricating film by adsorbing on the surface of clay particles, improving mud cake quality, reducing the friction coefficient, and significantly enhancing the lubricating performance of WBDFs. Overall, Si-AP exhibits a higher temperature-resistance limit compared to AP and more effectively optimizes the lubrication, inhibition, and control of the filtration rate of WBDFs under high-temperature conditions. While meeting the requirements of drilling fluid systems under high temperatures, Si-AP also addresses environmental concerns and holds promise as an efficient solution for the exploitation of deep-seated oil and gas resources.

[Immunological mechanism of Ermiao Powder improving inflammation in rats with collagen-induced arthritis through α7nAChR-JAK2/STAT3 pathway].

This study investigated the immunological mechanisms of Ermiao powder in the treatment of rheumatoid arthritis rats through the alpha 7 nicotinic acetylcholine receptor(α7nAChR)-Janus kinases 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling pathway. A total of 56 female Wistar rats were randomly divided into the normal group(HG, n=8), collagen-induced arthritis(CIA) model group(CM, n=8), vagotomy group(VA, n=8), sham group(SH, n=8), Ermiao Powder treatment model group(EM, n=8), Ermiao Powder treatment for vagotomy group(EV, n=8) and Ermiao Powder treatment for sham group(ES, n=8). Following the establishment of CIA models in all groups except the HG group, the rats underwent unilateral vagotomy and sham operation(only the vagus nerve was separated). Drug treatment was started 7 days after surgery and continued for 35 days. The body weight and joints of rats were recorded, the pathological changes of the spleen of rats were observed, the contents of interleukin-6(IL-6), interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in serum were detected by enzyme-linked immunosorbent assay(ELISA), and the mRNA and protein expression of α7nAChR-JAK2/STAT3 pathway core genes in spleen were detected by qRT-PCR, Western blot and immunohistochemistry. RESULTS:: showed that CM group(compared with HG group) and VA group(compared with CM group and SH group) had significantly decreased body weight(P<0.05, P<0.01), increased arthritis score(P<0.05, P<0.01), swollen ankle joints with deformity, and increased and enlarged lymph nodes in the spleen. There were also notable increases in the serum levels of IL-6, IL-1ß and TNF-α(P<0.05, P<0.01), and in the mRNA expressions of JAK2 and STAT3 in the spleen(P<0.05, P<0.01). The protein levels of phosphorylated JAK2(p-JAK2)/JAK2 and phospho-STAT3(p-STAT3)/STAT3 were significantly increased(P<0.05, P<0.01), and the number of JAK2, p-JAK2, STAT3 and p-STAT3 cells increased(P<0.05, P<0.01). EM group(compared with CM group) and ES group(compared with SH group) exhibited significantly increased body weight(P<0.01), decreased arthritis scores(P<0.05, P<0.01), reduced swelling of ankle joint, and decreased number and volume of lymph nodes in the spleen. Furthermore, serum levels of IL-6, IL-1ß, and TNF-α decreased(P<0.05, P<0.01), the mRNA expression of JAK2 and STAT3 in spleen decreased(P<0.05, P<0.01), the protein levels of p-JAK2/JAK2 and p-STAT3/STAT3 decreased(P<0.05, P<0.01), and the number of JAK2, p-JAK2, STAT3 and p-STAT3 cells decreased(P<0.05, P<0.01), whereas the mRNA and protein expressions of α7nAChR were significantly increased(P<0.01). Compared with the VA group, there was no significant differences in weight gain and arthritis scores in the EV group. The number of lymph nodes in the spleen was not significantly reduced and the volume was still large, suggesting the inflammation was not significantly improved. The serum levels of IL-6, IL-1ß and TNF-α were not significantly different, and there were no significant differences in α7nAChR, JAK2, and STAT3 mRNA expression in the spleen. The protein expression levels of p-JAK2/JAK2 and α7nAChR in spleen were lower(P<0.05, P<0.01), while p-STAT3/STAT3 protein expression was not significantly different. Besides, the two groups had no significant difference in the number of JAK2, p-JAK2, STAT3, and p-STAT3 cells. The results suggested that unilateral vagotomy promoted the increase of phosphorylated JAK2 and STAT3 expressions and exacerbated inflammation. In contrast, Ermiao Powder alleviated the inflammation in rheumatoid arthritis rats by activating the α7nAChR-mediated JAK2/STAT3 pathway through the vagus nerve, suggesting that the α7nAchR-JAK2/STAT3 pathway may be a potential target for the treatment of rheumatoid arthritis.

A long-read sequencing and SNP haplotype-based novel preimplantation genetic testing method for female ADPKD patient with de novo PKD1 mutation.

The autosomal dominant form of polycystic kidney disease (ADPKD) is the most common hereditary disease that causes late-onset renal cyst development and end-stage renal disease. Preimplantation genetic testing for monogenic disease (PGT-M) has emerged as an effective strategy to prevent pathogenic mutation transmission rely on SNP linkage analysis between pedigree members. Yet, it remains challenging to establish reliable PGT-M methods for ADPKD cases or other monogenic diseases with de novo mutations or without a family history. Here we reported the application of long-read sequencing for direct haplotyping in a female patient with de novo PKD1 c.11,526 G > C mutation and successfully established the high-risk haplotype. Together with targeted short-read sequencing of SNPs for the couple and embryos, the carrier status for embryos was identified. A healthy baby was born without the PKD1 pathogenic mutation. Our PGT-M strategy based on long-read sequencing for direct haplotyping combined with targeted SNP haplotype can be widely applied to other monogenic disease carriers with de novo mutation.

Assessing evidence accumulation and rule learning in humans with an online game.

Evidence accumulation, an essential component of perception and decision making, is frequently studied with psychophysical tasks involving noisy or ambiguous stimuli. In these tasks, participants typically receive verbal or written instructions that describe the strategy that should be used to guide decisions. Although convenient and effective, explicit instructions can influence learning and decision making strategies and can limit comparisons with animal models, in which behaviors are reinforced through feedback. Here, we developed an online video game and nonverbal training pipeline, inspired by pulse-based tasks for rodents, as an alternative to traditional psychophysical tasks used to study evidence accumulation. Using this game, we collected behavioral data from hundreds of participants trained with an explicit description of the decision rule or with experiential feedback. Participants trained with feedback alone learned the game rules rapidly and used strategies and displayed biases similar to those who received explicit instructions. Finally, by leveraging data across hundreds of participants, we show that perceptual judgments were well described by an accumulation process in which noise scaled nonlinearly with evidence, consistent with previous animal studies but inconsistent with diffusion models widely used to describe perceptual decisions in humans. These results challenge the conventional description of the accumulation process and suggest that online games provide a valuable platform to examine perceptual decision making and learning in humans. In addition, the feedback-based training pipeline developed for this game may be useful for evaluating perceptual decision making in human populations with difficulty following verbal instructions.NEW & NOTEWORTHY Perceptual uncertainty sets critical constraints on our ability to accumulate evidence and make decisions; however, its sources remain unclear. We developed a video game, and feedback-based training pipeline, to study uncertainty during decision making. Leveraging choices from hundreds of subjects, we demonstrate that human choices are inconsistent with popular diffusion models of human decision making and instead are best fit by models in which perceptual uncertainty scales nonlinearly with the strength of sensory evidence.

Two-field sequential color liquid crystal displays with deep learning-enabled real-time driving.

Two-field driving is the ultimate goal of field sequential color liquid crystal displays (FSC-LCDs) because it requires the lowest refresh rate and transmission bandwidth in addition to the intrinsic advantages of FSC-LCDs, e.g., tripled light efficiency and spatial resolution. However, fewer fields create a more significant challenge in controlling color breakup and distortion, as well as higher computational complexity in calculating LC signals. Regarding the difficulties, we propose a two-field FSC driving method that synchronously generates backlight and LC signals through two lightweight neural networks. The runtimes of the two networks are as fast as 1.23 and 1.79 ms per frame on a GeForce RTX 3090Ti graphic card, fully supporting real-time driving. Next, an over-partitioning approach is proposed to overcome the cross talk between backlight segments while processing high-resolution images. Besides the real-time feature, a reduction of 14.88% in color breakup concerning current methods and low distortion are verified. We also provide our open-source code.