High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

Dynamic Surface Intelligent Robust Control of Nonlinear Systems With Fixed-Time Sliding-Mode Observer.

The high tracking control precision and fast finite-time convergence for nonlinear systems is a significant challenge due to complex nonlinearity and unknown disturbances. To address this challenge, a dynamic surface intelligent robust control strategy with fixed-time sliding-mode observer (DSIRC-SMO) is proposed to improve the tracking control performance in a finite time. First, adaptive fuzzy neural network based on a predictor (P-AFNN) is designed to imitate the complex nonlinearity. In particular, the weight adaptive law is formulated by utilizing the prediction error information, which improves the accuracy of approximating the nonlinear system. Second, the fixed-time sliding-mode observer (SMO) is integrated into the dynamic surface control technique to deal with unknown disturbances and modeling errors in a fixed time. This integration allows for timely updates the dynamic surface using observation information, thereby enhancing the system's anti-interference capability. Then, the fixed-time convergence of SMO is proven. Third, the proposed DSIRC-SMO can be effectively implemented and the finite-time convergence of DSIRC-SMO is proven in detail based on the fixed-time convergence of SMO. Finally, numerical simulation and actual wastewater treatment processes simulation are conducted to validate the effectiveness of DSIRC-SMO.

Comprehensive analysis of paraspeckle-associated gene modules unveils prognostic signatures and immunological relevance in multi-cancers.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, characterized by high rates of angiogenesis and immune evasion. Paraspeckle genes, involved in gene regulation and RNA metabolism, have recently been linked to tumor progression. This study aims to elucidate the relationship between paraspeckle genes and HCC prognosis, focusing on SFPQ, DDX39B, and UBAP2. METHODS: We analyzed HCC (LIHC) and prostate cancer (PRAD) samples from the TCGA database to explore the correlation between paraspeckle genes and angiogenesis. We conducted unsupervised clustering, risk scoring, and survival analysis to identify distinct patient groups and their clinical outcomes. Gene expression data were used to perform differential analysis and Gene Ontology (GO) enrichment. RESULTS: Our analysis identified significant correlations between paraspeckle genes and angiogenesis across multiple cancer types. Elevated expression levels of SFPQ, DDX39B, and UBAP2 were associated with poor prognosis in HCC patients, and all of them has statistical significance. Unsupervised clustering of HCC samples based on paraspeckle gene expression revealed two distinct clusters, with high-risk patients exhibiting stronger immune suppression and tumor immune evasion. GO enrichment highlighted critical pathways related to angiogenesis and immune regulation. Additionally, a risk scoring model based on these genes effectively distinguished high-risk and low-risk patient groups, providing valuable prognostic insights. CONCLUSION: This study demonstrates that SFPQ, DDX39B, and UBAP2 are significantly associated with poor prognosis in HCC, likely due to their roles in promoting angiogenesis and immune suppression. These findings highlight the potential of paraspeckle genes as prognostic biomarkers and therapeutic targets, offering new avenues for personalized treatment strategies in HCC. Further research into their functional mechanisms and clinical applicability is crucial for advancing HCC treatment and improving patient outcomes.

Low Absolute Lymphocyte Count Correlates with Lymph Node Metastases and Worse Survival of Patients with Gastric Cancer.

BACKGROUND: Several studies have found that the absolute lymphocyte (ALC) or neutrophil count predicts the survival of patients with solid tumors, and that the neutrophil-to-lymphocyte ratio and the prognostic nutritional index are useful markers of gastric cancer prognosis. However, it remains unclear whether the ALC is prognostic of lymph node (LN) metastasis in patients with gastric cancer. In this study, we aimed to explore the impact of ALC on prognosis and distinctive clinical characteristics in patients with gastric cancer. PATIENTS AND METHODS: The medical records of patients with gastric adenocarcinomas who underwent radical gastrectomy with curative intent at Seoul St. Mary's Hospital and Yeouido St. Mary's Hospital between January 2010 and December 2017 were reviewed. Of these, 4149 patients for whom preoperative white blood cell, neutrophil, and lymphocyte counts were available were enrolled. RESULTS: In all 4149 patients, ALC gradually decreased as the pN stage increased. Those with an ALC of less than 1360 cells/µL were defined as a low-ALC group, and advanced cT and cN stages were the strongest risk factors for LN metastasis in both univariate and multivariate analyses; undifferentiated tumor histology and a low ALC were also significant risk factors. Patients of all stages in the ALC-low group exhibited poorer prognoses. The ALC-low group also exhibited a higher recurrence rate in a greater proportion of LNs. CONCLUSIONS: In patients with gastric cancer, as the preoperative ALC decreases, the incidence of LN metastasis increases. A low ALC is associated with a high recurrence rate, particularly in LNs.

Qiliqiangxin Alleviates Imbalance of Inflammatory Cytokines in Patients with Dilated Cardiomyopathy: A Randomized Controlled Trial.

OBJECTIVE: Qiliqiangxin (QLQX) capsule- a traditional Chinese medicine used for treating heart failure (HF), can modulate inflammatory cytokines in rats with myocardial infarction. However, its immune-regulating effect on dilated cardiomyopathy (DCM) remains unknown. The aim of this study was to investigate whether QLQX has a unique regulatory role in the imbalance of pro- and anti-inflammatory cytokines in patients with DCM. METHODS: The QLQX-DCM is a randomized- double-blind trial conducted at 24 tertiary hospitals in China. A total of 345 patients with newly diagnosed virus-induced DCM were randomly assigned to receive QLQX capsules or placebo while receiving optimal medical therapy for HF. The primary endpoints were changes in plasma inflammatory cytokines and improvements in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) over the 12-month treatment. RESULTS: At the 12-month follow-up, the levels of IFN-γ, IL-17, TNF-α, and IL-4 decreased significantly, while the level of IL-10 increased in both groups compared with baselines (all P<0.0001). Furthermore-these changes, coupled with improvements in LVEF, NT-proBNP and New York Heart Association (NYHA) functional classification, excluding the LVEDd in the QLQX group, were greater than those in the placebo group (all P<0.001). Additionally, compared with placebo, QLQX treatment also reduced all-cause mortality and rehospitalization rates by 2.17% and 2.28%, respectively, but the difference was not statistically significant. CONCLUSION: QLQX has the potential to alleviate the imbalance of inflammatory cytokines in patients with DCM, potentially leading to further improvements in cardiac function when combined with anti-HF standard medications.

Data-Driven Tube-Based Robust Predictive Control for Constrained Wastewater Treatment Process.

The wastewater treatment process (WWTP) is characterized by unknown nonlinearity and external disturbances, which complicates the tracking control of dissolved oxygen concentration (DOC) within operational constraints. To address this issue, a data-driven tube-based robust predictive control (DTRPC) strategy is proposed to achieve stable tracking control of DOC and satisfy the system constraints. First, a tube-based robust predictive control (TRPC) strategy is designed to deal with system constraints and external disturbances. Specifically, a nominal controller is designed to ensure that the nominal output accurately tracks the set-point under tightened constraints, while an auxiliary feedback controller is designed to suppress disturbances and restore the nominal performance of the disturbed WWTP. Second, two fuzzy neural network identifiers are employed to provide accurate predictive outputs for the control process, overcoming the challenges of modeling the WWTP with strong nonlinearity and unknown dynamics. Third, the generalized multiplier method is utilized to solve the constrained optimization problem to obtain the nominal control law, and the gradient descent algorithm is used to obtain the auxiliary control law. The implementation of this composite controller ensures the satisfaction of the system constraints and the effective suppression of disturbances. Finally, the feasibility and stability of the proposed DTRPC strategy are guaranteed through rigorous theoretical analysis, and its effectiveness is demonstrated through the simulations on the benchmark simulation model No.1.

ROCK2 increases drug resistance in acute myeloid leukemia via metabolic reprogramming and MAPK/PI3K/AKT signaling.

Rho-associated coiled-coil kinase 2 (ROCK2) is classified as a member of the serine/threonine protein kinase family and has been identified as a key driver of the development of various forms of cancer. The cause of ROCK2's impact on acute myeloid leukemia (AML) is still unknown. We found that ROCK2 expression was higher in AML patients, leading to lower complete response rates and worse overall survival. Additionally, ROCK2 expression was elevated in the doxorubicin-resistant leukemia cell line HL-60/ADM when compared to their individual parent cells. Moreover, the suppression or inhibition of ROCK2 leads to enhanced drug sensitivity in both AML cell lines and primary AML specimens, along with a notable decrease in downstream signaling pathways. Furthermore, the suppression of ROCK2 caused disruption of cellular energy production pathways by directly affecting the functionality of proteins within the mitochondrial electron transport chain. Finally, we discovered that TRIM26, a specific E3 ligase, is capable of ubiquitylating ROCK2, and the upregulation of TRIM26 within HL-60/ADM cells resulted in heightened sensitivity to the drug and reduced resistance. Thus, our study presents a new strategy for overcoming drug resistance in AML through targeting ROCK2/AKT/MAPK signaling pathway.

Anatomical Feasibility of Percutaneous Arteriovenous Fistula Formation in Korea.

INTRODUCTION: Currently, there are two types of percutaneous arteriovenous fistula (pAVF) formation systems approved by the FDA: Ellipsys and WavelinQ. Although these systems are already in use in Europe or the United States, they have not been approved for use in Korea yet. For this reason, this study aimed to check anatomical feasibility of these systems for Korean population prior to their actual use. METHODS: Consecutive patients who received ultrasound vein mapping for arteriovenous fistula formation from June 2021 to June 2022 were included. The anatomical feasibility of each system was confirmed according to the manufacturer's instructions for use (IFU). RESULTS: Upper extremity ultrasonography was performed for a total of 83 patients to determine their feasibility for pAVF formation. Of these patients, 65.1% were feasible for pAVF formation with appropriate deep communicating vein (DCV) and outflow. Among them, 57.8% were feasible for the Ellipsys system and 54.2% were feasible for the WavelinQ system. Most patients who were infeasible for pAVF formation had a DCV of small size. Ulnar vessels were more suitable than radial vessel for WavelinQ (54.2% vs 33.7%, P-value = .012). The most common reason for not meeting the criteria was a small vein size at the access site. CONCLUSIONS: More than half of all patients were feasible for pAVF formation in this study. Ellipsys had a higher feasibility than WavelinQ, although they showed no significant difference in the feasibility. If these devices are imported into Korea, it will be a good opportunity for many patients to reduce the surgical burden and create AVFs more easily through these procedures.

[Dynamic and Static Complementary Balance Theory-Based Functional Exercise Combined With Stepwise Rehabilitation Training Improves Postoperative Hip Function Recovery in Patients Undergoing Total Hip Replacement]. / åŠ¨é™äº’è¡¥å¹³è¡¡è®ºåŠŸèƒ½é”»ç‚¼ç»“åˆé˜¶æ¢¯æ€§åº·å¤è®­ç»ƒåˆ©äºŽå ¨é«‹å ³èŠ‚ç½®æ¢è€ æœ¯åŽé«‹å ³èŠ‚åŠŸèƒ½æ¢å¤.

Objective: To analyze the application value of dynamic and static complementary balance theory-based functional exercise combined with stepwise rehabilitation training in postoperative hip function recovery in patients undergoing total hip replacement (THR). Methods: The clinical data of 118 inpatients undergoing THR between June 2022 and June 2023 were retrospectively collected. Among the patients, 57 were given perioperative stepwise rehabilitation training (the control group), and 61 were given a combination of functional exercise based on static and dynamic complementary balance theory and stepwise rehabilitation training during the perioperative period (the combination group). The postoperative recovery status and the incidence of postoperative complications in the two groups were recorded. During postoperative recovery, the patients were assessed for pain with the visual analogue scale (VAS) and for self-efficacy with the Self-Efficacy for Rehabilitation Outcome Scale (SER). Hip function was measured and compared between the two groups at 2 weeks, 4 weeks and 8 weeks after surgery. Results: With regard to the primary outcome indicator, the postoperative length-of-stay was (7.63±1.36) d in the combination group, which was shorter than the (8.22±1.48) d in the control group, and the difference was statistically significant (t=2.257, P=0.026). As for the secondary outcome indicators, no statistically significant difference was observed in the incidence of postoperative complications between the two groups (4.92% vs. 14.04%) (P>0.05). The perioperative VAS scores in the two groups showed an interaction effect according to the repeated measurement variance test (P<0.05). The postoperative VAS scores in both groups declined significantly compared to the preoperative scores (P<0.05), and the VAS score decreased gradually over time after surgery (P<0.05). The VAS scores in the combination group at 7 and 14 days after surgery were lower than those in the control group (P<0.05). At 14 days after surgery, the scores for the coping and the task dimensions and the total score of SER increased in both groups compared with those at 3 days after surgery (P<0.05), with the combination group showing higher scores than the control group did (P<0.05). After surgery, the scores for the dimensions of deformity, pain, function, and joint mobility and the total score of the Harris Hip Scale revealed interaction effects in the two groups according to the repeated measurement variance test (P<0.05), with these scores increasing gradually over time after surgery (P<0.05), and the scores in the combination group were higher at 4 and 8 weeks after surgery compared to those in the control group (P<0.05). Conclusion: The combination of functional exercise based on dynamic and static complementary balance theory and stepwise rehabilitation training shows an advantage over stepwise rehabilitation training alone in enhancing the self-efficacy of THR patients, relieving the postoperative pain, shortening the length-of-stay, and improving the hip function in patients.

Cullin 4B-RING E3 ligase negatively regulates the immunosuppressive capacity of mesenchymal stem cells by suppressing iNOS.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-ß signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-ß signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

O-Carboxymethyl chitosan nanoparticles: A novel approach to enhance water stress tolerance in maize seedlings.

Water stress, a significant abiotic stressor, significantly hampers crop growth and yield, posing threat to food security. Despite the promising potential of nanoparticles (NPs) in enhancing plant stress tolerance, the precise mechanisms underlying the alleviation of water stress using O-Carboxymethyl chitosan nanoparticles (O-CMC-NPs) in maize remain elusive. In this study, we synthesized O-CMC-NPs and delved into their capacity to mitigate water stress (waterlogging and drought) in maize seedlings. Structural characterization revealed spherical O-CMC-NPs with a size of approximately 200 nm. These NPs accumulated near the seed embryo and root tip, resulting in a substantial increase in fresh and dry weights. The application of O-CMC-NPs to water-stressed maize seedlings remarkedly elevated the chlorophyll content and activity of various antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol oxidase (PPO). The malondialdehyde (MDA) content was significantly reduced compared to the untreated control. Additionally, the expression of stress-responsive genes, such as ZmSOD, ZmCAT, ZmPOD, ZmTIFY, ZmACO, ZmPYL2, ZmNF-YC12, and ZmEREB180, were significantly upregulated in the O-CMC-NPs treated seedlings. These findings unveil the novel role of O-CMC-NPs in enhancing plant stress tolerance, suggesting their potential application in safeguarding maize seedlings under water stress conditions and facilitating the recovery from oxidative damage.

Peptide degrader-based targeting of METTL3/14 improves immunotherapy response in cutaneous melanoma.

METTL3 has emerged as a promising therapeutic target in cancer treatment, although its oncogenic functions in melanoma development and potential for therapeutic targeting drug have not been fully explored. In this study, we define the oncogenic role of METTL3 in melanoma development and progression. Building on this insight, we examine our recently designed peptide inhibitor RM3, which targets the binding interface of METTL3/14 complex for disruption and subsequent ubiquitin-mediated proteasomal degradation via the E3 ligase STUB1. RM3 treatment reduces proliferation, migration, and invasion, and induces apoptosis in melanoma cells in vitro and in vivo. Subsequent transcriptomic analysis identified changes in immuno-related genes following RM3-mediated suppression of METTL3/14 N6-methyladenosine (m6A) methyltransferase activity, suggesting a potential for interaction with immunotherapy. A combination treatment of RM3 with anti-PD-1 antibody results in significantly higher beneficial tumor response in vivo, with a good safety profile. Collectively, these findings not only delineate the oncogenic role of METTL3 in melanoma but also showcase RM3, acting as a peptide degrader, as a novel and promising strategy for melanoma treatment.

Ischemia-reperfusion responses in human lung transplants at the single-cell resolution.

Ischemia-reperfusion is an unavoidable step of organ transplantation. Development of therapeutics for lung injury during transplantation has proved challenging; understanding lung injury from human data at the single-cell resolution is required to accelerate the development of therapeutics. Donor lung biopsies from 6 human lung transplant cases were collected at the end of cold preservation and 2-hour reperfusion and underwent single-cell RNA sequencing. Donor and recipient origin of cells from the reperfusion timepoint were deconvolved. Gene expression profiles were: (1) compared between each donor cell type between timepoints and (2) compared between donor and recipient cells. Inflammatory responses from donor lung macrophages were found after reperfusion with upregulation of multiple cytokines and chemokines, especially IL-1ß and IL-1α. Significant inflammatory responses were found in alveolar epithelial cells (featured by CXCL8) and lung endothelial cells (featured by IL-6 upregulation). Different inflammatory responses were noted between donor and recipient monocytes and CD8+ T cells. The inflammatory signals and differences between donor and recipient cells observed provide insight into the cellular and molecular mechanisms of ischemia-reperfusion induced lung injury. Further investigations may lead to the development of novel targeted therapeutics.

A smart mask for exhaled breath condensate harvesting and analysis.

Recent respiratory outbreaks have garnered substantial attention, yet most respiratory monitoring remains confined to physical signals. Exhaled breath condensate (EBC) harbors rich molecular information that could unveil diverse insights into an individual's health. Unfortunately, challenges related to sample collection and the lack of on-site analytical tools impede the widespread adoption of EBC analysis. Here, we introduce EBCare, a mask-based device for real-time in situ monitoring of EBC biomarkers. Using a tandem cooling strategy, automated microfluidics, highly selective electrochemical biosensors, and a wireless reading circuit, EBCare enables continuous multimodal monitoring of EBC analytes across real-life indoor and outdoor activities. We validated EBCare's usability in assessing metabolic conditions and respiratory airway inflammation in healthy participants, patients with chronic obstructive pulmonary disease or asthma, and patients after COVID-19 infection.

Morbidity and Mortality After Laparoscopy-Assisted Distal Gastrectomy and Totally Laparoscopic Distal Gastrectomy to Treat Gastric Cancer: An Interim Report: A Phase III Multicenter, Prospective, Randomized Trial (The KLASS-07 Trial).

PURPOSE: We conducted a randomized prospective trial (KLASS-07 trial) to compare laparoscopy-assisted distal gastrectomy (LADG) and totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. In this interim report, we describe short-term results in terms of morbidity and mortality. METHODS AND METHODS: The sample size was 442 participants. At the time of the interim analysis, 314 patients were enrolled and randomized. After excluding patients who did not undergo planned surgeries, we performed a modified per-protocol analysis of 151 and 145 patients in the LADG and TLDG groups, respectively. RESULTS: The baseline characteristics, including comorbidity status, did not differ between the LADG and TLDG groups. Blood loss was somewhat higher in the LADG group, but statistical significance was not attained (76.76±72.63 vs. 62.91±65.68 mL; P=0.087). Neither the required transfusion level nor the operation or reconstruction time differed between the 2 groups. The mini-laparotomy incision in the LADG group was significantly longer than the extended umbilical incision required for specimen removal in the TLDG group (4.79±0.82 vs. 3.89±0.83 cm; P<0.001). There were no between-group differences in the time to solid food intake, hospital stay, pain score, or complications within 30 days postoperatively. No mortality was observed in either group. CONCLUSIONS: Short-term morbidity and mortality rates did not differ between the LADG and TLDG groups. The KLASS-07 trial is currently underway. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03393182.

Randomized, double-blind, placebo-controlled trial of aripiprazole oral solution in children and adolescents with Tourette's disorder.

BACKGROUND: Aripiprazole is the most frequently recommended antipsychotic for the treatment of tics in children and adolescents with Tourette's disorder (TD). However, to date, a randomized controlled trial for aripiprazole oral solution has not been conducted despite being widely preferred by children. Therefore, we examined whether aripiprazole oral solution is effective for treating tics. METHODS: All patients received a flexible dose of aripiprazole oral solution (1 mg/mL, range: 2-20 mg) with a starting dose of 2 mg. The target dose for patients weighing < 50 kg was 2, 5, and 10 mg/day, and that for patients weighing ≥ 50 kg was 5, 10, 15, and 20 mg/day. The primary efficacy endpoint was the mean change in the Yale Global Tic Severity Scale-total tic score (YGTSS-TTS) from baseline to week 8. RESULTS: Of the 121 patients enrolled, 59 patients (96.7%) in the aripiprazole group and 53 patients (88.3%) in the placebo group completed the study. The aripiprazole group showed significantly greater improvement in the YGTSS-TTS from baseline to week 8 than the placebo group (least squares mean difference [95% confidence interval (CI)] -5.5 [95% CI - 8.4 to - 2.6]). At week 8, the response rate (i.e., percentage of patients with a Tourette's Syndrome Clinical Global Impression-Improvement score of 1 or 2) of the aripiprazole group (86.4%) was significantly higher than that of the placebo group (56.6%; odds ratio: 3.6, p < 0.001). The incidence of treatment-emergent adverse events (TEAEs) reported in at least one patient was 86.9% in the aripiprazole group and 65.5% in the placebo group. All TEAEs were mild or moderate in severity. No serious adverse events or deaths occurred during the study. CONCLUSIONS: Our findings suggest that aripiprazole oral solution is an effective, well-tolerated, and safe treatment for children and adolescents with TD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03487783. Registered 4 April 2018.

High-throughput sensitive screening of small molecule modulators of microexon alternative splicing using dual Nano and Firefly luciferase reporters.

Disruption of alternative splicing frequently causes or contributes to human diseases and disorders. Consequently, there is a need for efficient and sensitive reporter assays capable of screening chemical libraries for compounds with efficacy in modulating important splicing events. Here, we describe a screening workflow employing dual Nano and Firefly luciferase alternative splicing reporters that affords efficient, sensitive, and linear detection of small molecule responses. Applying this system to a screen of ~95,000 small molecules identified compounds that stimulate or repress the splicing of neuronal microexons, a class of alternative exons often disrupted in autism and activated in neuroendocrine cancers. One of these compounds rescues the splicing of several analyzed microexons in the cerebral cortex of an autism mouse model haploinsufficient for Srrm4, a major activator of brain microexons. We thus describe a broadly applicable high-throughput screening system for identifying candidate splicing therapeutics, and a resource of small molecule modulators of microexons with potential for further development in correcting aberrant splicing patterns linked to human disorders and disease.

Retrospective analysis of the clinical utility of multi-cytokine profiles in smear-negative pulmonary tuberculosis.

OBJECTIVES: To evaluate cytokine profiles and interferon-gamma release assay (IGRA) for their diagnostic capabilities in the differentiation of tuberculosis (TB) from non-TB conditions, as well as smear-negative pulmonary tuberculosis (SNPT) from smear-positive pulmonary tuberculosis (SPPT). METHODS: A total of 125 participants were included, 77 of whom had TB and 48 who didn't, and demographic, clinical, and laboratory data were collected, including cytokine levels and IGRA results. The TB patients were further divided into 2 subgroups: SNPT (n=42) and SPPT (n=35). RESULTS: Compared to non-TB, the TB group had lower BMI, higher WBC, neutrophils, monocytes, ESR and CRP (p<0.05). TB patients showed higher IL-2, IL-6, IFN-γ, IL-8 (p<0.001) and higher IGRA positivity (88.3% versus [vs.] 29.2%, p<0.001). Between SNPT and SPPT, moderate effect sizes were observed for IFN-α, IL-2, IL-10, IL-8 (Cohen's d 0.59-0.76), with lower IGRA positivity in SNPT (81.0% vs. 97.1%, p=0.015). ROC analysis indicated IFN-α, IL-2, IL-10, IL-8 had moderate accuracy for SNPT diagnosis (AUCs 0.668-0.734), and combining these improved accuracy (AUC 0.759, 80% sensitivity, 64.2% specificity). CONCLUSION: A multi-biomarker approach combining these cytokines demonstrates enhanced diagnostic accuracy for tuberculosis.

Bacterial outer membrane vesicle nanorobot.

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains.

Robust Model Free Adaptive Predictive Control for Wastewater Treatment Process With Packet Dropouts.

External disturbances and packet dropouts will lead to poor control performance for the wastewater treatment process (WWTP). To address this issue, a robust model-free adaptive predictive control (RMFAPC) strategy with a packet dropout compensation mechanism (PDCM) is proposed for WWTP. First, a dynamic linearization approach (DLA), relying only on perturbed process data, is employed to approximate the system dynamics. Second, a predictive control strategy is introduced to avoid a short-sighted control decision, and an extended state observer (ESO) is used to attenuate the disturbance effectively. Furthermore, a PDCM strategy is designed to handle the packet dropout problem, and the stability of RMFAPC is rigorously analyzed. Finally, the correctness and effectiveness of RMFAPC are verified through extensive simulations. The simulation results indicate that RMFAPC can significantly reduce IAE by 0.0223 and 0.1976 in two scenarios, regardless of whether the expected value remains constant or varies. This comparison to MFAPC demonstrates the superior robustness of RMFAPC against disturbances. The ablation experiment on PDCM further confirms its capability in handling the packet dropout problem.