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With the rapid growth of renewable energy sources, single-phase rooftop photovoltaic inverters connected to the distribution network have received widespread applications in recent years. In such a distribution network, asymmetric fault problems are likely to occur, and small-signal stability during asymmetric faults becomes important. The existing papers analyzed the sequence impedance and related stability issues during asymmetric faults in a three-phase three-wire system. In contrast, the SIs connected to three-phase four-wire systems requires consideration of the effect of zero-sequence components and the phase to phase coupling effect. Because both the zero-sequence component and phase coupling effect will affect the impedance characteristics of the inverter sub-system and thus the stability of the power system. Therefore, this paper established the $3\ast 3$ admittance model matrix for the inverter sub-system considering the frequency coupling effect and phase coupling effect under asymmetric fault. Based on the admittance model matrix, the main factors including phase-locked loop bandwidth and grid neutral inductance that affects the phase to phase coupling effect are also analyzed. In addition, this paper studies the effect of phase-locked loop bandwidth, short circuit fault degree, and short circuit location on system stability. The validity of theoretical analysis is further verified through the experimental results.

Abstract Iatrogenic injury to endometrial tissue is the main cause of intrauterine adhesions (IUA) and infection can also damage the endometrium. The microbiota plays an important role in the health of the female reproductive tract. However, the mechanism is still unclear. In total, 908 patients with IUA and 11,389 healthy individuals were retrospectively selected for this clinical study. Participant information including vaginal microecological results and human papillomavirus (HPV) status were collected. Univariate and multivariate logistic regression analyses were used to identify the factors related to IUA. Next, animal experiments were performed in a curettage-induced IUA rat model. After the procedure, rats in the experimental group received a vaginal infusion of a Candida albicans (C. albicans) fungal solution. On days 3, 7, and 14 after curettage and infusion, the expression levels of IL-6, fibrotic pathway-related factors (TGF-β1, Smad 2, and COL1), and estrogen receptor (ER) and progesterone receptor (PR) in rat endometrial tissues were assessed. Fungal infection of the reproductive tract was found to be an independent risk factor for IUA (P

Abstract Objectives To compare overall survival (OS) and cancer-specific survival (CSS) outcomes of surgery with radiotherapy in octogenarians with stage Ia non-small cell lung cancer (NSCLC). Materials and methods Patients aged ≥ 80 years with clinical stage Ia (T1N0M0) NSCLC between 2012 and 2017 were identified from the population-based Surveillance, Epidemiology, and End Results (SEER) database. Patients were assigned into surgery and radiotherapy groups. Multivariate Cox regression analysis was used to identify survival-associated factors. Treatment groups were adjusted by propensity score matching (PSM) analysis while OS and CSS outcomes were compared among groups by Kaplan–Meier analysis. Results A total of 1641 patients were identified, with 46.0% in the surgical group and 54.0% in the radiotherapy group. Compared to surgery, radiotherapy-treated patients were older, later diagnosed, had more often unmarried, more squamous cell carcinoma, more unknown grade and increased tumor sizes. Radiotherapy was associated with a significantly worse OS, compared to surgery (hazard ratio 2.426; 95% CI 2.003–2.939; P

Plutella xylostella endures Bt toxins with no performance costs. This study reveals how, depending on the presence of the toxin, this insect modifies MAPK phosphorylation to modulate the transcription factor FTZ-F1 binding, to up- or down- regulate Bt receptors or non-receptor (resistant) paralogs.

Objective: This study aims to compare the effectiveness and safety of perampanel and oxcarbazepine as monotherapy in children with focal epilepsy (FE).Methods: This is an ambispective, single-center, non-inferiority study comparing the effectiveness and safety of perampanel (PER) monotherapy and oxcarbazepine (OXC) monotherapy in children with newly diagnosed FE. The primary endpoint was a six-month seizure freedom rate. The secondary endpoints included retention, responder, and seizure freedom rates at 3, 6, and 12 months, respectively. Adverse events (AEs) were also recorded for both groups.Results: One hundred and thirty children and adolescents aged from 4 to 18years newly diagnosed with FE between May 2020 and November 2022 in Wuhan Children’s Hospital were included. There were 71 patients in the PER group and 59 patients in the OXC group. In the per protocol set (PPS), 50 (78.1%) in the PER group and 43 (78.2%) in the OXC group completed six months of treatment without seizures. The lower 95% CI (66.0%–87.5%) limit of PER was higher than the non-inferiority margin of 62.4% (80% of the 6-month seizure freedom rate in the OXC group); PER was non-inferior to OXC. The 3-month and 12-month seizure freedom rates were 77.1% and 82.9% for the PER group, respectively, while they were 80.4% and 75.8% for the OXC group. There were no serious adverse events in both groups.Conclusion: PER showed comparable effectiveness and safety compared with OXC in children with newly diagnosed focal epilepsy, which might be an effective and safe treatment for children and adolescents with newly diagnosed FE.Clinical Trial Registration: Identifier ChiCTR2300074696

The ketogenic diet (KD) has shown excellent performance in the treatment of refractory epilepsy, but how it works is not yet fully understood. Gut microbiota is associated with various neurological disorders through the brain-gut axis. Different dietary patterns have different effects on the composition and function of gut microbiota. Here, by analyzing fecal samples from some patients with mitochondrial epilepsy before and after KD treatment through 16SrRNA sequencing, we found that KD intervention reduced the abundance of Firmicutes in the patient’s gut, while the abundance of Bacteroidota increased in the KD group. LefSe analysis showed that Actinobacteriota, Phascolarctobacterium had significant advantages in the control group, while Bacteroides increased significantly after KD intervention, especially Bacteroides fragilis. Functional analysis showed that there were significant differences in 12 pathways in level 3. These changes suggest that KD can change the composition and diversity of the gut microbiota in patients and affect their function. Changes in specific bacterial groups in the gut may serve as biomarkers for the therapeutic effects of KD on epilepsy.

Abstract Antibacterial dynamic therapy (ADT) triggered by reactive oxygen species (ROS) is promising for diabetic infectious disease treatment. However, the limited local O2/H2O2 production and post‐treatment inflammation remain long‐standing issues. To address these challenges, a novel H2‐evolving bio‐heterojunction enzyme (Bio‐HJzyme) consisting of graphite‐phase carbon nitride/copper sulfide (CN/Cu2−xS) heterojunction and glucose oxidase (GOx) is created. The Bio‐HJzyme offers glutathione peroxidase (GPx), peroxidase (POD), and catalase (CAT) mimetic activities; provides anti‐pathogen properties via programmed light activation; and effectively promotes diabetic wound healing. Specifically, its GPx‐mimetic activity and the presence of GOx significantly enhance the yield of H2O2, which can be catalyzed through POD‐mimetic activity to produce highly germicidal •OH. The H2O2 can also be catalyzed to H2O and O2, assisted by the CAT‐mimetic activity. The catalyzed products can then be catalyzed into germicidal •OH and •O2− under NIR light irradiation, giving enhanced ADT. Further, CN can split water to form H2 under solar light, which dramatically suppresses the inflammation caused by excessive ROS. In vivo evaluation confirms that Bio‐HJzyme promotes the regeneration of diabetic infectious skin through killing bacteria, enhancing angiogenesis, promoting wound bed epithelialization, and reinforcing anti‐inflammatory responses; hence, providing a revolutionary approach for diabetic wounds healing.

Polymer solid electrolytes (SEs) with high safety and flexibility are ideal for advanced lithium‐metal solid‐state batteries (SSBs). Among various polymer SEs, polyvinylidene fluoride‐co‐hexafluoropropylene (PVDF‐HFP) polymer SEs have gained increased attention for their high dielectric constants, high ionic conductivity, and excellent flexibility. However, severe side reactions at the interface caused by the decomposition of residual DMF solvent significantly reduce the cycle life of PVDF‐HFP‐based SSBs. Herein, La2O3 nanoparticles are used as new inorganic fillers to form a PVDF‐HFP/LiFSI/La2O3‐40% composite polymer electrolyte (PVDF‐HFP/La2O3 CPE). Benefiting from the interaction between La2O3 and N,N‐dimethylformamide (DMF) solvent molecules, the cell cycling stability is greatly improved. In addition, the PVDF‐HFP/LiFSI solid electrolyte (PVDF‐HFP SE) containing 40 wt% La2O3 has the highest ionic conductivity of 1.33 × 10−3 S cm−1 at 25 °C. It also exhibits a higher lithium‐ion transference number of 0.52 and lower polarization. The PVDF‐HFP/La2O3 CPE here ensures high ionic conductivity and stable interface chemistry in SSB, demonstrating a promising application potential.

IntroductionSystemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank.MethodsExpression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts.ResultsThree preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells.DiscussionIn conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

Crisis communication plays a crucial role in preserving the national reputation during significant national crises. From the perspective of Situational Crisis Communication Theory (SCCT), this research paper analyzed over 1,790,816 YouTube comments from Chinese-speaking audiences, using sentiment analysis alongside the Difference-in-Differences (DiD) model, in order to investigate the influence of strategic crisis communication on public perceptions during public health crises. The study findings indicate that during this public health crisis, YouTube Chinese media, whose audience mainly consists of overseas Chinese-speaking users, primarily incorporated the enhancing strategies, succeeded by the diminish strategies, with limited application of deny strategies, while the use of rebuild strategies was virtually absent in this context. In addition, the research analysis confirms that Chinese media effectively increased the public’s positive perceptions of crisis events through crisis communication. Particularly, enhancing strategies proved most effective in improving public perceptions, followed by diminish strategies. In contrast, deny strategies failed to influence public perceptions of the crisis, and rebuild strategies demonstrated a negative impact on public perception. Thus, the research findings of this paper extend essential insights for effectively managing potential public health crises in the future.

The phase-field method, coupled with the micro-elastic model and irradiation-induced cascade mixing model, has been employed to investigate the spinodal decomposition in U-Mo and U-Mo-Zr alloys. The microstructure evolution of U-Mo or U-Mo-Zr alloys under different initial conditions, such as the alloy composition, aging temperature and irradiation intensity, were simulated to study the effect of cascade mixing on the miscibility gap, morphology and volume fraction of the decomposed phases. The simulation results demonstrate that irradiation-induced cascade mixing impedes the process of spinodal decomposition, and that irradiation shrinks the composition range of the miscibility gap in the alloys. Irradiation-induced cascade mixing slows down the anisotropic growth rate of the spinodal decomposition, yet this phenomenon can be weakened with increasing aging temperature. Adding an appropriate amount of Zr to a U-Mo alloy can effectively prevent the contraction of the miscibility gap caused by irradiation.

Abstract The closed pore has been considered as the key structure for Na ion storage in hard carbon. However, the traditional view is that closed pores can only be formed by the curling of graphite‐like crystallites in the case of high temperature carbonization. Ingenious designing of closed pore structures at lower temperature is still blank. Herein, for the first time, engineering the wall thickness and number of closed pores in waste rosewood‐derived hard carbon was successfully achieved at a low temperature of 1100°C by removing the lignin and hemicellulose components in wood precursor. When applied as an anode material, the optimum sample exhibits a high capacity of 326 mAh/g at 20 mA/g and a remarkable rate capability of 230 mAh/g at 5000 mA/g, significantly higher than those of the untreated sample (only 33 mAh/g at 5000 mA/g). The significantly improved Na storage performance should be attributed to abundant closed pores that provide sufficient spaces for Na storage and thin pore wall structure that is beneficial to the diffusion of Na+ in the bulk phase. This work provides a new idea for the future application of biomass‐based hard carbon for advanced Na ion batteries.

Precise control over flow rate and flow pattern is critical for investigating the contribution of shear force in cellular responses, biofluidic transport, and living matter in a flowing environment. Generation and control over the ultralow flow fields at microscale are, however, difficult, due to thermal agitation and fluctuations in the surrounding environment. Herein, pa novel microfluidic flow field generator is proposed, capable of generating stable flow field down to the limit of thermal noise. Integrated with a customized MATLAB program controlling timely open–close of 18 monolithic PDMS valves, the flow generator outperforms the existing methods by both achievable low flow rate, that is, 0.01 nL s−1, temporal resolution of flow rate fluctuation down to 100 ms, and provides complex flow patterns. Moreover, unlike external devices (e.g., the syringe pump), the design can be easily integrated into any fluidic chip and sealed from the disturbance of experimental conditions, for example, the airflow and the movement of connected pipelines. The methodology is, therefore, suitable for biological and biophysical studies requiring a well‐defined flowing environment.

PurposeThe development of tuberculosis and inflammatory status are closely related. The aim of this study was to investigate the prognostic value of inflammatory biomarkers in patients with rifampicin/multidrug-resistant tuberculosis (RR/MDR-TB).Patients and methodsThis study recruited 504 patients with RR/MDR-TB from Wuhan Jinyintan Hospital. A total of 348 RR/MDR patients from January 2017 to December 2019 were defined as training set, the rest of patients as validation set. The patients were divided into three-risk degrees according to the levels of inflammatory biomarkers (median, 85th percentile). Kaplan-Meier curve and log-rank test were used to assess survival differences among the groups. Cox proportion risk regression was used to identify risk factors for RR/MDR-TB mortality.ResultsIn training set, cox proportion risk regression analysis showed that high age (≥60 years) [OR (95%CI):1.053(1.03188-1.077)], smoking [OR (95%CI):2.206(1.191-4.085)], and bronchiectasia [OR (95%CI):2.867(1.548-5.311)] were prognostic factors for RR/MDR-TB patients. In addition, lower survival rates were observed in high CAR group [OR (95%CI):1.464(1.275-1.681)], high CPR group[OR (95%CI):1.268(1.101-1.459)], high CLR group[OR (95%CI):1.004(1.002-1.005)], high NLR group[OR (95%CI):1.103(1.069-1.139)], high PLR group[OR (95%CI):1.003(1.002-1.004)], and high MLR group[OR (95%CI):3.471(2.188-5.508)].Furthermore, AUCs of age, smoking, bronchiectasia, CAR, CPR, CLR, NLR, PLR, and MLR for predicting mortality in RR/MDR-TB patients were 0.697(95%CI:0.618-0.775), 0.603(95%CI:0.512-0.695), 0.629(95%CI:0.538-0.721), 0.748(95%CI:0.675-0.821, P

Quiescent prostate cancer (PCa) cells are common in tumors but are often resistant to chemotherapy. Quiescent PCa cells are also enriched for a stem-like tumor initiating population, and can lead to recurrence after dormancy. Unfortunately, quiescent PCa cells are difficult to identify and / or target with treatment in part because the relevant markers are intracellular and regulated by protein stability. We addressed this problem by utilizing PCa cells expressing fluorescent markers for CDKN1B (p27) and CDT1, which can separate viable PCa cells into G0, G1, or combined S/G2/M populations. We used FACS to collect G1 and G0 PC3 PCa cells, isolated membrane proteins, and analyzed protein abundance in G0 vs G1 cells by gas chromatography mass spectrometry. Enrichment analysis identified nucleocytoplasmic transport as the most significantly different pathway. To identify cell surface proteins potentially identifying quiescent PCa cells for future patient samples or for antibody based therapeutic research, we focused on differentially abundant plasma membrane proteins, and identified ERBB2 (HER2) as a cell surface protein enriched on G0 PCa cells. High HER2 on the cell membrane is associated with quiescence in PCa cells and likely induced by the bone microenvironment. Using a drug conjugated anti-HER2 antibody (trastuzumab emtansine) in a mouse PCa xenograft model delayed metastatic tumor growth, suggesting approaches that target HER2-high cells may be beneficial in treating PCa. We propose that HER2 is deserving of further study in PCa as a target on quiescent cells to prevent recurrence, decrease chemotherapy resistance, or eradicate minimal residual disease.

The chytrid fungal pathogens Batrachochytrium salamandrivorans (Bsal) and B. dendrobatidis (Bd) are driving amphibian extinctions and population declines worldwide. As their origins are believed to be in East/Southeast Asia, this region is crucial for understanding their ecology. However, Bsal screening is relatively limited in this region, particularly in hotspots where Bd lineage diversity is high. To address this gap, we conducted an extensive Bsal screening involving 1101 individuals from 36 amphibian species, spanning 17 natural locations and four captive facilities in the biodiversity-rich Guangxi Zhuang Autonomous Region (GAR). Our PCR assays yielded unexpected results, revealing the complete absence of Bsal in all tested samples including 51 individuals with Bd presence. To understand the potential distribution of Bsal, we created niche models, utilizing existing occurrence records from both Asia and Europe. These models estimated potential suitable habitats for Bsal largely in the northern and southwestern parts of the GAR. Although Bsal was absent in our samples, the niche models identified 10 study sites as being potentially suitable for this pathogen. Interestingly, out of these 10 sites, Bd was detected at 8. This suggests that Bsal and Bd could possibly co-exist in these habitats, if Bsal were present. Several factors seem to influence the distribution of Bsal in Asia, including variations in temperature, local caudate species diversity, elevation, and human population density. However, it is climate-related factors that hold the greatest significance, accounting for a notable 60% contribution. The models propose that the specific climatic conditions of arid regions, primarily seen in the GAR, play a major role in the distribution of Bsal. Considering the increased pathogenicity of Bsal at stable and cooler temperatures (10–15 °C), species-dependent variations, and the potential for seasonal Bd-Bsal interactions, we emphasize the importance of periodic monitoring for Bsal within its projected range in the GAR. Our study provides deeper insights into Bsal’s ecological niche and the knowledge generated will facilitate conservation efforts in amphibian populations devastated by chytrid pathogens across other regions of the world.

The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.

Abstract Background Biopesticides and transgenic crops based on Bacillus thuringiensis (Bt) toxins are extensively used to control insect pests, but the rapid evolution of insect resistance seriously threatens their effectiveness. Bt resistance is often polygenic and complex. Mutations that confer resistance occur in midgut proteins that act as cell surface receptors for the toxin, and it is thought they facilitate its assembly as a membrane-damaging pore. However, the mechanistic details of the action of Bt toxins remain controversial. Results We have examined the contribution of two paralogous ABC transporters and two aminopeptidases N to Bt Cry1Ac toxicity in the diamondback moth, Plutella xylostella, using CRISPR/Cas9 to generate a series of homozygous polygenic knockout strains. A double-gene knockout strain, in which the two paralogous ABC transporters ABCC2 and ABCC3 were deleted, exhibited 4482-fold resistance to Cry1A toxin, significantly greater than that previously reported for single-gene knockouts and confirming the mutual functional redundancy of these ABC transporters in acting as toxin receptors in P. xylostella. A double-gene knockout strain in which APN1 and APN3a were deleted exhibited 1425-fold resistance to Cry1Ac toxin, providing the most direct evidence to date for these APN proteins acting as Cry1Ac toxin receptors, while also indicating their functional redundancy. Genetic crosses of the two double-gene knockouts yielded a hybrid strain in which all four receptor genes were deleted and this resulted in a > 34,000-fold resistance, indicating that while both types of receptor need to be present for the toxin to be fully effective, there is a level of functional redundancy between them. The highly resistant quadruple knockout strain was less fit than wild-type moths, but no fitness cost was detected in the double knockout strains. Conclusion Our results provide direct evidence that APN1 and APN3a are important for Cry1Ac toxicity. They support our overarching hypothesis of a versatile mode of action of Bt toxins, which can compensate for the absence of individual receptors, and are consistent with an interplay among diverse midgut receptors in the toxins’ mechanism of action in a super pest.

Abstract Background Ketogenic diet (KD) therapy is one of the main treatments for drug-resistant epilepsy. However, the KD therapy has been applied in only a small number of infantile spasm cases. In this large multicenter study, we investigated the efficacy of KD therapy in the treatment of infantile spasms. Methods In this retrospective, multicenter cohort study, clinical data from main epilepsy centers were analyzed. Patients were classified into different groups according to age, type of drug and whether glucocorticoid was used before initiation of KD. Results From October 2014 to March 2020, 481 patients (308 males and 173 females) with infantile spasms were treated with the KD therapy. The age of the patients ranged from 2 months to 20 years, with a mean age of 1 year and 10 months. The number of anti-seizure medications (ASMs) used before KD initiation ranged 0–6, with a median of 3. In different time from initiation(1, 3, 6, and 12 months), the rates of seizure freedom after KD were 6.9, 11.6, 16.0 and 16.8%, respectively (χ 2 = 27.1772, P 0.05). Two hundred and eighteen patients (45.3%) failed to respond to corticotropin or glucocorticoid before initiation. There was no significant difference in the effectiveness rate at different time points between the group of KD therapy after glucocorticoid failure and the group after non-hormone failure (χ 2 = 0.8613, P = 0.8348). The rate of adverse events of KD in 1, 3, 6, and 12 months after KD initiation were 22.3, 21.7, 16.8 and 6.9%, respectively. The adverse events mainly occurred during the first 3 months of KD, and the main adverse events were gastrointestinal disturbance and constipation. Conclusion The efficacy of the KD treatment for infantile spasms was not affected by age, medication, and glucocorticoid use before initiation. KD is one of the effective treatments for infantile spasms. Trial registration ChiCTR-IIR-16008342. Registered on 22 April, 2016 - Retrospectively registered, https://www.chictr.org.cn .

Abstract Super-refractory status epilepticus (SRSE) is a serious and life-threatening neurological condition. Ketogenic diet (KD) is a diet characterized by high fat, low carbohydrate, and moderate protein. As KD shows effectiveness in controlling seizures in more than half of SRSE patients, it can be a treatment option for SRSE. Currently, KD treatment for SRSE is based on personal experience and observational evidence has been published. In the context of a lack of a validated guideline, we convened a multicenter expert panel within the China Association Against Epilepsy (CAAE) Ketogenic Diet Commission to work out the Chinese expert recommendations on KD for SRSE. We summarize and discuss the latest clinical practice of KD for SRSE in critical care settings. Recommendations are given on patient selection, the timing of KD, diet implementation, and follow-up. More research data are needed in this area to support better clinical practice.

Abstract Background Bacterial infections are common complications in patients with cirrhosis or liver failure and are correlated with high mortality. Clinical practice guideline (CPG) is a reference used to help clinicians make decisions. This systematic appraisal aimed to evaluate the methodological quality and summarize the recommendations of reported CPGs in these patients. Methods We systematically searched CPGs published from 2008 to 2019. The methodological quality of the included CPGs was assessed using the AGREE II instrument. We extracted and compared recommendations for prophylactic and empirical treatment strategies. Results Fourteen CPGs with a median overall score of 56.3% were included. The highest domain score was Clarity of Presentation (domain 4, 85.4%), and the lowest was for Stakeholder Involvement (domain 2, 31.3%). Three CPGs had an overall score above 80%, and 6 CPGs had a score above 90% in domain 4. Prophylaxis should be strictly limited to patients with varicose bleeding, low ascites protein levels and a history of spontaneous bacterial peritonitis. Fluoroquinolones (norfloxacin and ciprofloxacin), third-generation cephalosporins (G3) (ceftriaxone and cefotaxime) and trimethoprim–sulfamethoxazole (SXT) are recommended for preventing infections in patients with cirrhosis or liver failure. G3, β-lactam/β-lactamase inhibitor combinations (BLBLIs) and carbapenems are recommended as the first choice in empirical treatment according to local epidemiology of bacterial resistance. Conclusions The methodological quality of CPGs focused on patients with cirrhosis or liver failure evaluated by the AGREE II instrument is generally poor. Three CPGs that were considered applicable without modification and 6 CPGs that scored above 90% in domain 4 should also be paid more attention to by healthcare practitioners. Regarding recommendations, norfloxacin, ciprofloxacin, ceftriaxone, cefotaxime, and SXT are recommended for prophylactic treatment appropriately. G3, BLBLIs, and carbapenems are recommended for use in empirical treatment strategies.

In the present work, a phase-field model was developed to investigate the influence of recrystallization on bubble evolution during irradiation. Considering the interaction between bubbles and grain boundary (GB), a set of modified Cahn-Hilliard and Allen-Cahn equations, with field variables and order parameters evolving in space and time, was used in this model. Both the kinetics of recrystallization characterized in experiments and point defects generated during cascade were incorporated in the model. The bubble evolution in recrystallized polycrystalline of U–Mo alloy was also investigated. The simulation results showed that GB with a large area fraction generated by recrystallization accelerates the formation and growth of bubbles. With the formation of new grains, gas atoms are swept and collected by GBs. The simulation results of bubble size and distribution are consistent with the experimental results.

Natural killer (NK) cells have emerged as key mediators of obesity-related adipose tissue inflammation. However, the phenotype of NK cell subsets residing in human adipose tissue are poorly defined, preventing a detailed understanding of their role in metabolic disorders. In this study, we applied multicolor flow cytometry to characterize CD56bright and CD56dim NK cells in blood and adipose tissue depots in individuals with obesity and identified surface proteins enriched on adipose tissue-resident CD56bright NK cells. Particularly, we found that adipose tissue harbored clusters of tissue-resident CD56bright NK cells signatured by the expression of CD26, CCR5 and CD63, possibly reflecting an adaptation to the microenvironment. Together, our findings provide broad insights into the identity of NK cells in blood and adipose tissue in relation to obesity.

Abstract Background Brain aging is an important risk factor in many human diseases, such as Alzheimer’s disease (AD). The production of excess reactive oxygen species (ROS) mediated by nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and the maturation of inflammatory cytokines caused by activation of the NOD-like receptor protein 1 (NLRP1) inflammasome play central roles in promoting brain aging. However, it is still unclear when and how the neuroinflammation appears in the brain during aging process. Methods In this study, we observed the alterations of learning and memory impairments, neuronal damage, NLRP1 inflammasome activation, ROS production and NOX2 expression in the young 6-month-old (6 M) mice, presenile 16 M mice, and older 20 M and 24 M mice. Results The results indicated that, compared to 6 M mice, the locomotor activity, learning and memory abilities were slightly decreased in 16 M mice, and were significantly decreased in 20 M and 24 M mice, especially in the 24 M mice. The pathological results also showed that there were no significant neuronal damages in 6 M and 16 M mice, while there were obvious neuronal damages in 20 M and 24 M mice, especially in the 24 M group. Consistent with the behavioral and histological changes in the older mice, the activity of β-galactosidase (β-gal), the levels of ROS and IL-1β, and the expressions of NLRP1, ASC, caspase-1, NOX2, p47phox and p22phox were significantly increased in the cortex and hippocampus in the older 20 M and 24 M mice. Conclusion Our study suggested that NLRP1 inflammasome activation may be closely involved in aging-related neuronal damage and may be an important target for preventing brain aging.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients.Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83–17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens.Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml.Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

The experimental studies to understand the superconductivity of superhydrides remain scarce. Here, the authors report pressure and magnetic field dependence of superconductivity in LaH10, and indicate lattice vibrations strongly affect superconducting coupling.

Abstract Background Unplugged programming is proved to be an effective means to foster the learner-centered programming learning. In addition to the final tests, learners’ programming knowledge, skills, and capacities are primarily demonstrated throughout the programming process, particularly in the situation when they encounter challenges and problems. However, few studies examine how learners engage in the programming processes and to what extent unplugged programming fosters learning. This research used a quasi-experimental design to investigate two instructional modes in China’s secondary education, namely, the instructor-directed lecturing and the learner-centered unplugged programming. Based on an analytical framework, this research used mixed methods to compare learners’ knowledge, behaviors, and attitudes under these two instructional modes. Results The research results revealed discrepancies between two instructional modes. First, learners in the unplugged programming class achieved significantly higher scores on the programming knowledge assessment, compared to learners in the traditional lecturing class. Second, compared to the traditional lecturing class, learners in the unplugged programming class had higher test scores of the computational thinking skills, particularly on the cooperativity dimension. Next, discrepancies of in-class behaviors showed that learners in the unplugged programming class had frequent behaviors of listening to the instructor’s instructions and discussing with peers, while learners in the instructor-directed class had frequent behaviors of listening to instructor, taking notes, and irrelevant activities. Learners’ self-reported attitudes in the unplugged programming indicated a higher level of confidence than learners in the traditional lecturing class. Overall, this research revealed that the learner-centered unplugged programming had potential to improve learners’ programming knowledge, behaviors, and attitudes compared to the traditional instructor-directed lecturing of programming. Conclusions As a feasible and easy-to-use instructional activity in computer science education, unplugged programming is encouraged to be integrated in formal education to increase learners’ programming interests, motivations, and qualities. This quasi-experimental research compared learners’ programming knowledge, behaviors, and attitudes under two instructional modes. The results revealed critical discrepancies between two instructional modes on learners’ knowledge gains, in-class behaviors, and changes of attitudes towards programming. Pedagogical and analytical implications were provided for future instructional design and learning analytics of computer programming education.

Abstract Aqueous Zn‐ion batteries (AZIBs) are regarded as a promising alternative to the widely used lithium‐ion batteries in large‐scale energy storage systems. The researches on the development of novel aqueous electrolyte to improve battery performance have also attracted great interest since the electrolyte is a key component for Zn2+ migration between cathode and anode. Herein, we briefly summarized and illuminated the recent development tendency of aqueous electrolyte for AZIBs, then deeply analyzed its existing issues (water decomposition, cathode dissolution, corrosion and passivation, and dendrite growth) and discussed the corresponding optimization strategies (pH regulation, concentrated salt solution, electrolyte composition design, and functional additives). The internal mechanisms of these strategies were further revealed and the relationships between issues and solutions were clarified, which could guide the future development of aqueous electrolytes for AZIBs.

ObjectiveThe aim of this study was to build a nomogram based on clinical markers for predicting the malignancy of ovarian tumors (OTs).MethodA total of 1,268 patients diagnosed with OTs that were surgically removed between October 2017 and May 2019 were enrolled. Clinical markers such as post-menopausal status, body mass index (BMI), serum human epididymis protein 4 (HE4) value, cancer antigen 125 (CA125) value, Risk of Ovarian Malignancy Algorithm (ROMA) index, course of disease, patient-generated subjective global assessment (PG-SGA) score, ascites, and locations and features of masses were recorded and analyzed (p 0.05). Significant variables were further selected using multivariate logistic regression analysis and were included in the decision curve analysis (DCA) used to assess the value of the nomogram model for predicting OT malignancy.ResultThe significant variables included post-menopausal status, BMI, HE4 value, CA125 value, ROMA index, course of disease, PG-SGA score, ascites, and features and locations of masses (p 0.05). The ROMA index, BMI (≥ 26), unclear/blurred mass boundary (on magnetic resonance imaging [MRI]/computed tomography [CT]), mass detection (on MRI/CT), and mass size and features (on type B ultrasound [BUS]) were screened out for multivariate logistic regression analysis to assess the value of the nomogram model for predicting OT malignant risk (p 0.05). The DCA revealed that the net benefit of the nomogram’s calculation model was superior to that of the CA125 value, HE4 value, and ROMA index for predicting OT malignancy.ConclusionWe successfully tailored a nomogram model based on selected clinical markers which showed superior prognostic predictive accuracy compared with the use of the CA125, HE4, or ROMA index (that combines both HE and CA125 values) for predicting the malignancy of OT patients.

ObjectiveTo analyze the genotypes and phenotypes of mosaic male patients with PCDH19-related epilepsy (PCDH19-RE) and explore the correlation between genotype, variant allele frequency (VAF), and phenotypic severity.MethodsClinical data and peripheral blood samples of 11 male mosaic patients were collected and analyzed in our study. The VAF of the PCDH19 gene from peripheral blood was quantified using amplicon-based deep sequencing. Additional 20 mosaic male patients with PCDH19-RE were collected from the published literature, with 10 patients whose VAFs of the PCDH19 gene were available for analytic purposes.ResultsIn our cohort of 11 patients, 10 variants were identified, and four were novel. The VAF of the PCDH19 gene from peripheral blood ranged from 27 to 90%. The median seizure onset age was 6 months (range: 4–9 months). Clinical manifestations included cluster seizures (100%), fever sensitivity (73%), focal seizures (91%), developmental delay/intellectual disability (DD/ID, 82%), and autistic features (45%). Thirty-one mosaic male patients collected from our cohort and the literature developed seizures mostly (87%) within one year of age. Variant types included missense variants (42%), truncating variants (52%), splice variants (3%), and whole PCDH19 deletion (3%). Among 21 patients with a definite VAF from our cohort and the literature, nine had a low VAF ( ≤ 50%) and 12 had a high VAF (> 50%). Seventy-five percent of variants from the high VAF group were missense, whereas 89% of those from the low VAF group were truncations. The median seizure onset age was 6 months in the low VAF group and 9 months in the high VAF group (p = 0.018). Forty-four percent (4/9) of patients from the low VAF group achieved seizure-free for ≥1 year, whereas none of the 12 patients from the high VAF group did (p = 0.021). DD/ID was present in 83% (10/12) of the high VAF group and 56% (5/9) of the low VAF group (p = 0.331).ConclusionThe predominant variant types were truncating and missense variants. Missense variants tended to have higher VAFs. Patients with a high VAF were more likely to have a more severe epileptic phenotype. Our findings shed light on the phenotypic implications of VAF in mosaic males with PCDH19-RE.

Background: To develop a population pharmacokinetic (PPK) model for caspofungin, identify parameters influencing caspofungin pharmacokinetics, and assess the required probability of target attainment (PTA) and cumulative fraction of response (CFR) for various dosing regimens of caspofungin in all patients and intensive care unit (ICU)-subgroup patients.Method: The general PPK model was developed based on data sets from all patients (299 patients). A ICU-subgroup PPK model based on data sets from 136 patients was then analyzed. The effects of demographics, clinical data, laboratory data, and concomitant medications were tested. Monte-Carlo simulations (MCS) were used to evaluate the effectiveness of different caspofungin dosage regimens.Results: One-compartment model best described the data of all patients and ICU patients. Clearances (CL) were 0.32 L/h and 0.40 L/h and volumes of distribution (V) were 13.31 L and 10.20 L for the general and ICU-subgroup PPK models, respectively. In the general model, CL and V were significantly associated with albumin (ALB) concentration and body weight (WT). In the ICU-subgroup model, CL was associated with WT. The simulated exposure in ICU patients was lower than that in all patients (p < 0.05). MCS indicated that higher caspofungin maintenance doses of 70–150 mg may achieve target CFR of >90% for patients with higher WT (>70 kg) or with C. albicans or C. parapsilosis infections, and especially for ICU patients with hypoalbuminaemia.Conclusion: The PPK model and MCS presented in the study demonstrated that the recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure.

ObjectiveTo evaluate the oncologic outcomes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian sex cord-stromal tumors (SCSTs) who underwent fertility-sparing surgery (FSS) and the independent risk factors affecting overall survival (OS) and cancer-specific survival (CSS).MethodsData were acquired from the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2018. A total of 240 patients diagnosed with stage I ovarian SCSTs were divided into the definitive surgery group (N=116) and FSS group (N=124). The Kaplan-Meier analysis and Cox model were used to evaluate the overall survival (OS) and cancer-specific survival (CSS) of the two groups and assess the independent risk factors respectively. The Fine-Gray model evaluated cancer-specific mortality (CSM) and the independent risk factors that affected CSM.ResultsKaplan-Meier survival analysis showed no statistically significant differences in OS and CSS between the two groups (P>0.05). Univariate analysis of the Fine-Gray model also showed that there was no difference in the CSS between the two groups (P>0.05). However, from the 15th year postoperatively, the CSS of the FSS group decreased by 13.21% compared with that of the control group and by 17.49% in the 20th and 25th years postoperatively. The Cox proportional hazards model found that surgical methods (“defined surgery” vs “FSS”; HR=0.03259, P=0.0196) and FIGO stage (“stage IA” vs “stage IC”; HR=0.03073, P=0.0300) were independent risk factors for OS. The multivariate analysis of Fine-Gray model showed that the cancer-specific mortality of patients receiving definitive surgery was 40.1% lower than that of patients receiving FSS (“definitive surgery” vs “FSS”; HR=0.599, P=0.005), indicating that FSS might lead to higher tumor-specific mortality and lower CSS. However, age, race, laterality, history, FIGO stage, and tumor size had no significant influence on the tumor-specific mortality (P>0.05).ConclusionsFSS is considered for patients with stage I SCSTs with reproductive needs, but the follow-up period should not be less than 15 years. For patients with stage IC disease, FSS should be selected carefully, and close follow-up is necessary. Perhaps, definitive surgery after birth is a means to improve long-term survival rates.

In order to study the oil–gas two-phase flow characteristics of an aero-engine bearing chamber and improve the scavenge effect of lubricating oil, the two-phase flow solution model of a bearing chamber based on the Euler–Euler method was established. Three improvement schemes were proposed for the ventilation structure and scavenge structure of the bearing chamber. The flow characteristics and scavenge characteristics of a conventional bearing chamber and three improvement schemes under different working conditions were analyzed in depth. The results show that after the conventional bearing chamber ventilation structure is embedded (Embed) and improved, with the increase in the embedding depth, the oil in the cavity is further blocked in the cavity, the amount of oil flowing out from the vent is further reduced, and the scavenge efficiency is further improved. After the slope improvement of the scavenge structure of the conventional bearing chamber, due to the increase in the depth of the oil return groove, the drag effect of the air shear force in the cavity on the oil in the oil return groove is further weakened, and the oil accumulation area on the right side of the scavenge port is further suppressed. The volume fraction of the oil in the cavity is further reduced, and the scavenge efficiency is further improved. The combined improvement scheme (ES) can take into account the advantages of embedding and slope improvement schemes, and further improve the scavenge efficiency. Compared to the conventional bearing chamber, when the oil flow rate is 200 L/h and the speed is 15,000 r/min, the oil return efficiency of the embedded (h = 12 mm), slope (l = 56 mm) and combined improvement schemes are increased by 20.19%, 13.43%, and 37.94%, respectively.

Aqueous zinc-ion batteries (ZIBs) are an appealing rechargeable battery technology for next-generation energy storage devices, known for their low cost and high safety. Among the promising cathode materials used for aqueous ZIBs, anthraquinone (AQ) stands out due to its high theoretical specific capacity, low cost, and environmental friendliness. In this study, we investigate the cyclic stability of AQ in aqueous ZIBs. We demonstrate that AQ exhibits a good capacity retention at a high current density even after 1000 charge–discharge cycles, while more obvious capacity fading is observed at a low current density. Density functional theory calculations reveal that the mechanism of the rapid capacity fading under a low current density is due to the significant structural deformation of AQ crystal during Zn insertion into the AQ bulk. Furthermore, the energy barrier of Zn ions that diffuse into the AQ bulk is much higher than the diffuse on the AQ surface, leading to an irreversible Zn insertion. However, under a high current density, Zn ions prefer to adsorb and diffuse on the AQ surface without bulk insertion and structural deformation, rending a higher cycling stability. These insights into the factors influencing the cycling stability of AQ-based electrodes offer a guidance to improve their performance for practical applications.

Abstract To understand the role of intracellular zinc ion (Zn2+) dysregulation in mediating age-related neurodegenerative changes, particularly neurotoxicity resulting from the generation of excessive neurotoxic amyloid-β (Aβ) peptides, this study aimed to investigate whether N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a Zn2+-specific chelator, could attenuate Aβ25–35-induced neurotoxicity and the underlying electrophysiological mechanism. We used the 3-(4, 5-dimethyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay to measure the viability of hippocampal neurons and performed single-cell confocal imaging to detect the concentration of Zn2+ in these neurons. Furthermore, we used the whole-cell patch-clamp technique to detect the evoked repetitive action potential (APs), the voltage-gated sodium and potassium (K+) channels of primary hippocampal neurons. The analysis showed that TPEN attenuated Aβ25–35-induced neuronal death, reversed the Aβ25–35-induced increase in intracellular Zn2+ concentration and the frequency of APs, inhibited the increase in the maximum current density of voltage-activated sodium channel currents induced by Aβ25–35, relieved the Aβ25–35-induced decrease in the peak amplitude of transient outward K+ currents (I A) and outward-delayed rectifier K+ currents (I DR) at different membrane potentials, and suppressed the steady-state activation and inactivation curves of I A shifted toward the hyperpolarization direction caused by Aβ25–35. These results suggest that Aβ25–35-induced neuronal damage correlated with Zn2+ dysregulation mediated the electrophysiological changes in the voltage-gated sodium and K+ channels. Moreover, Zn2+-specific chelator-TPEN attenuated Aβ25–35-induced neuronal damage by recovering the intracellular Zn2+ concentration.

Abstract This study presents a study of fault‐tolerant operation for a brushless doubly fed reluctance generator (BDFRG) system under a converter switch fault. The topology of the dual converter fed open‐winding BDFRG is adopted to improve post‐fault operation capacity. For post‐fault operation, the appropriate voltage vectors of control winding are selected to directly adjust the active and reactive power of power winding based on the direct power control theory. Switching tables are formulated under different switch faults. The simulation and experimental results demonstrate the feasibility of the proposed strategy.

Abstract Background Circular RNAs (circRNAs) have been reported to be important regulators of the development and progression of various carcinomas. However, the role of circRNA_100290 in gastric cancer (GC) is still unclear. This study aimed to investigate the role of circRNA_100290 in GC invasion and metastasis and the possible underlying mechanism. Methods The expression of circRNA_100290 in GC cells and tissues was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The role of circRNA_100290 in cell proliferation, migration, and invasion was evaluated in the AGS and HGC-27 cell lines in vitro. Bioinformatics tools, dual-luciferase reporter assays, Western blot assays and qRT-PCR were used to explore the pathways downstream of circRNA_100290. The mechanism underlying the regulation of circRNA_100290 expression was explored using RNA immunoprecipitation, qRT-PCR, and Western blot assays. Results The expression of circRNA_100290 was significantly upregulated in GC cells and 102 GC tissues, and high circRNA_100290 expression in GC was closely related to Borrmann’s type, lymph node metastasis and tumour-node-metastasis stage. In vitro, knockdown of circRNA_100290 in AGS and HGC-27 cells significantly inhibited cell proliferation, migration, and invasion. Mechanistically, a dual-luciferase reporter assay confirmed the direct interaction between circRNA_100290 and miR-29b-3p, which targets ITGA11, an oncogene that is closely related to epithelial–mesenchymal transition (EMT). In addition, EIF4A3, an RNA-binding protein (RBP), could inhibit the formation of circRNA_100290 by binding to the flanking sites of circRNA_100290. Low EIF4A3 expression in GC was related to a poor prognosis. Conclusions Elevated circRNA_100290 expression in GC promotes cell proliferation, invasion and EMT via the miR-29b-3p/ITGA11 axis and might be regulated by EIF4A3. CircRNA_100290 might be a promising biomarker and target for GC therapy. Graphical abstract

This quantitative synthesis included 48 qualified studies with a total sample of 116,051 K-12 students. Aligned with previous meta-analyses, the findings suggested that formative assessment generally had a positive though modest effect (ES = + 0.19) on students’ reading achievement. Meta-regression results revealed that: (a) studies with 250 or less students yielded significantly larger effect size than large sample studies, (b) the effects of formative assessment embedded with differentiated instruction equated to an increase of 0.13 SD in the reading achievement score, (c) integration of teacher and student directed assessment was more effective than assessments initiated by teachers. Our subgroup analysis data indicated that the effect sizes of formative assessment intervention on reading were significantly different between Confucian-heritage culture and Anglophone culture and had divergent effective features. The result cautions against the generalization of formative assessment across different cultures without adaptation. We suggest that effect sizes could be calculated and intervention features be investigated in various cultural settings for practitioners and policymakers to implement tailored formative assessment.

BackgroundThe ketogenic diet (KD) is increasingly used to treat drug-resistant epilepsy because of its favorable effect on seizure reduction. Patients with mitochondrial diseases tend to experience seizures. Therefore, this study aimed to test the efficacy of the KD on participants with mitochondrial diseases in a controlled trial.MethodsParticipants from fourteen clinical centers who were diagnosed with mitochondrial disease were semi-randomized to either the intervention (KD) or control group. The KD group followed a 3-month KD intervention, while the control group received a 1-month normal diet initially and then a 3-month KD intervention. The primary outcome measure was seizure reduction. Biomarker changes, cognitive impairments, and side effects were also recorded, if available.ResultA total of 33 participants were assigned to the KD (n = 22) and control groups (n = 11). In the KD group, 31.8% (7/22) of participants achieved ≥50% seizure reduction after 1 month of diet intervention, which increased to 40.9% (9/22) at 3 months. In the control group, only 18.2% (2/11) of the participants had ≥50% seizure reduction during the normal diet period. After the control group was transferred to the KD, 63.6% (7/11) of participants had >50% seizure reduction, and this rate increased to 72.7% (8/11) at 3 months. The KD also showed high efficacy in participants with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or pathogenic variants in mitochondrial DNA (mtDNA) (90% and 93.3% response rates, respectively). The most frequent side effects reported at the 3-month review were vomiting, cold, hyperlipidemia, and bloating.ConclusionThe KD is a safe and effective therapy for seizure control in mitochondrial diseases, especially MELAS and pathogenic variants of mtDNA. KD intervention can be considered in the management of these patients.

Developmental and epileptic encephalopathies (DEEs) have high genetic heterogeneity, and DEE due to the potassium voltage-gated channel subfamily C member 2 (KCNC2) variant remains poorly understood, given the scarcity of related case studies. We report on two unrelated Chinese patients, an 11-year-old boy and a 5-year-old girl, diagnosed with global developmental delay (GDD), intellectual disability (ID), and focal impaired awareness seizure characterized by generalized spike and wave complexes on electroencephalogram (EEG) in the absence of significant brain lesions. Whole-exome sequencing (WES) and electrophysiological analysis were performed to detect genetic variants and evaluate functional changes of the mutant KCNC2, respectively. Importantly, we identified a novel gain-of-function KCNC2 variant, R405G, in both patients. Previously reported variants, V471L, R351K, T437A, and T437N, and novel R405G were found in multiple unrelated patients with DEE, showing consistent genotype–phenotype associations. These findings emphasize that the KCNC2 gene is causative for DEE and facilitates treatment and prognosis in patients with DEE due to KCNC2 mutations.

In white-throated sparrows, two alternative morphs differing in plumage and behavior segregate with a large chromosomal rearrangement. As with sex chromosomes such as the mammalian Y, the rearranged version of chromosome two (ZAL2m) is in a near-constant state of heterozygosity, offering opportunities to investigate both degenerative and selective processes during the early evolutionary stages of ‘supergenes.’ Here, we generated, synthesized, and analyzed extensive genome-scale data to better understand the forces shaping the evolution of the ZAL2 and ZAL2m chromosomes in this species. We found that features of ZAL2m are consistent with substantially reduced recombination and low levels of degeneration. We also found evidence that selective sweeps took place both on ZAL2m and its standard counterpart, ZAL2, after the rearrangement event. Signatures of positive selection were associated with allelic bias in gene expression, suggesting that antagonistic selection has operated on gene regulation. Finally, we discovered a region exhibiting long-range haplotypes inside the rearrangement on ZAL2m. These haplotypes appear to have been maintained by balancing selection, retaining genetic diversity within the supergene. Together, our analyses illuminate mechanisms contributing to the evolution of a young chromosomal polymorphism, revealing complex selective processes acting concurrently with genetic degeneration to drive the evolution of supergenes.

Background: As a cause of respiratory tract infections in humans, influenza remains with high morbidity and mortality, with associated significant healthcare burden and increased financial burden. Traditional Chinese medicine injections (TCMIs) combined with oseltamivir (TCMIs + oseltamivir) are the representative therapeutic strategies for influenza, which is a compliant with clinical applications in China. The aim of this study was to describe the comparative efficacy and safety of TCMIs + oseltamivir in patients with influenza, based on the current evidence.Methods: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, VIP information resource integration service platform databases, and the Chinese biomedical literature service system were searched to find randomized controlled trials where TCMIs + oseltamivir are the representative therapeutic strategies for influenza, from inception until October 2021, without language restriction. Two investigators independently screened eligibility criteria, extracted data, and appraised the risk of bias with the same criteria. We conducted a network meta-analysis using the Bayesian random method for each outcome and performed the sensitivity analysis, meta-regression, and Egger’s and Begg’s tests for the reliability and robustness of our results.Results: Thirty-one trials including 2,893 participants proved eligible and reported on four TCMIs + oseltamivir versus oseltamivir. Network meta-analysis showed Yanhuning (YHN) +oseltamivir (MD = −1.7, 95% CrI: −2.5 to −0.88; SUCRA = 0.89; low certainty of evidence) in fever disappearance time, Tanreqing (TRQ) +oseltamivir (MD = −1.9, 95% CrI: −2.8 to −1; SUCRA = 0.97; low certainty of evidence) in cough disappearance time, and Xiyanping (XYP) +oseltamivir (OR = 5.9, 95% CrI: 3.1 to 11; SUCRA = 0.82; very low certainty of evidence) in the response rate to be more efficacious than oseltamivir alone with the best SUCRA. Based on the combined SUCRA value for primary outcomes, TRQ + oseltamivir is probably better in cough disappearance time, and XYP + oseltamivir and YHN + oseltamivir may be better in fever disappearance time than others. No significant difference in safety between the treatments.Conclusion: In patients with influenza, TCMIs + oseltamivir only partially improve flu symptoms. Overall therapeutic efficacy and safety are inconclusive, based on low to very low certainty of evidence. However, the safety remains uncertain, and TCMI treatments for influenza should be considered with caution. More high-quality studies examining the efficacy and safety of TCMIs are needed.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021286994

Background: Advanced and recurrent endometrial cancer EC remains controversial. Immunotherapy will play a landmark role in cancer treatment, and alternative splicing (AS) of messenger RNA (mRNA) may offer the potential of a broadened target space.Methods: We downloaded the clinical information and mRNA expression profiles from The Cancer Genome Atlas (TCGA) database. Hub genes were extracted from 11 AS-related genes to analyze the correlation between clinical parameters and the tumor-immune microenvironment. We also analyzed the correlations between the copy numbers, gene expressions of hub genes, and immune cells. The correlation between the risk score and the six most important checkpoint genes was also investigated. The ESTIMATE algorithm was finally performed on each EC sample based on the high- and low-risk groups.Results: The risk score was a reliable and stable independent risk predictor in the Uterine Corpus Endometrial Carcinoma (UCEC) cohort. CYB561|42921|AP and FOLH1|15817|ES were extracted. The expression of CYB561 and FOLH1 decreased gradually with the increased grade and International Federation of Gynecology and Obstetrics (FIGO) stage (p < 0.05). Gene copy number changes in CYB561 and FOLH1 led to the deletion number of myeloid DC cells and T cell CD8+. Low expression of both CYB561 and FOLH1 was associated with poor prognosis (p < 0.001). The checkpoint genes, CTLA-4 and PDCD1, exhibited a negative correlation with the risk score of AS in UCEC.Conclusion: AS-related gene signatures were related to the immune-tumor microenvironment and prognosis. These outcomes were significant for studying EC’s immune-related mechanisms and exploring novel prognostic predictors and precise therapy methods.

We aim to establish an objective and accurate prediction model by evaluating the uterine cavity and correlate these key factors with the live birth rate after hysteroscopic adhesiolysis (HA). A total of 457 intrauterine adhesions (IUA) patients were retrospectively enrolled in this study. The participants underwent HA and second-look hysteroscopy at the Third Xiangya Hospital of Central South University. Pregnancy outcomes, including spontaneous live births and no live births (miscarriages and infertility), were followed. Clinical parameters, containing the number of visible uterine horns and tubal ostia, the length of the uterine cavity, among others, were measured and analyzed to determine the dominant variables in an attempt to establish the live birth rate, prediction models. Women in the no live birth group were older than that in the live birth group (P = 0.0002, OR = 0.895, 95% CI: 0.844–0.949) and were more likely to be 2 gravidity (P = 0.0136, OR = 2.558, 95% CI: 1.213–5.394). Uterine cavity length in pre-HA hysteroscopy was longer in the live birth group (P = 0.0018, OR = 1.735, 95% CI: 1.227–2.453), and adhesion scores in pre-HA hysteroscopy were more frequently above 6 (P = 0.0252, OR = 0.286, 95% CI: 0.096–0.856) in the no live birth group. During the second-look, hysteroscopy, visible bilateral fallopian tube ostia were more frequently observed in the live birth group (P = 0.0339, OR = 11.76, 95% CI: 1.207–114.611), and adhesion scores were 4–6 (P < 0.0001, OR = 0.032, 95% CI: 0.007–0.146) and above 6 (P < 0.0001, OR = 0.012, 95% CI: 0.002–0.073) in the no live birth group. The areas under the curves (AUCs) of the pre-HA and second-look hysteroscopy prediction models were 0.7552 and 0.8484, respectively. We established an objective and accurate method for evaluating the uterine cavity by hysteroscopy, and second-look hysteroscopy is more valuable than the fist hysteroscopy in predicting the live birth rate following HA. Visible bilateral fallopian tube ostia or adhesion scores were

Mono-allelic loss-of-function variants in ARFGEF1 have recently caused a developmental delay, intellectual disability, and epilepsy, with varying clinical expressivity. However, given the clinical heterogeneity and low-penetrance mutations of ARFGEF1-related neurodevelopmental disorder, the robustness of the gene-disease association requires additional evidence. In this study, five novel heterozygous ARFGEF1 variants were identified in five unrelated pediatric patients with neurodevelopmental disorders, including one missense change (c.3539T>G), two canonical splice site variants (c.917-1G>T, c.2850+2T>A), and two frameshift (c.2923_c.2924delCT, c.4951delG) mutations resulting in truncation of ARFGEF1. The pathogenic/likely pathogenic variants presented here will be highly beneficial to patients undergoing genetic testing in the future by providing an expanded reference list of disease-causing variants.

The soybean aphid poses a severe threat to soybean quality and yield by sucking phloem sap and transmitting plant viruses. An early-maturing and highly resistant soybean landrace, Fangzheng Moshidou, with markedly reduced aphid colonization has been identified by screening of aphid-resistant soybean accessions. In a population derived from the cross of Fangzheng Moshidou with the susceptible cultivar Beifeng 9, resistance was conferred by a single dominant gene. Three linked markers, Satt114, Satt334, and Sct_033, on chromosome 13 were identified by bulked-segregant analysis. Additional simple-sequence repeat and single-nucleotide polymorphism (SNP) markers were developed for gene mapping. The resistance of Fangzheng Moshidou was fine-mapped to the interval between the SNP markers YCSNP20 and YCSNP80, corresponding to 152.8 kb in the Williams 82 assembly 2 genome. This region was near the reported loci Rag2 and Rag5 but did not overlap the interval containing them. A unique haplotype is described for Fangzheng Moshidou that distinguishes it from soybean accessions PI 587972, PI 594879, and PI 567301B in the interval containing Rag2 and Rag5. These results indicate that Fangzheng Moshidou harbors a novel gene at a tightly linked resistance locus, designated as RagFMD. Fourteen candidate genes were annotated in the fine-mapping region, including seven NBS-LRR genes, which are usually considered resistance genes in plant defense. Most of these candidate genes showed variations distinguishing the resistant and susceptible parents and some genes also showed differences in expression between the two parental lines and at several times after aphid infestation. Isolation of RagFMD would advance the study of molecular mechanisms of soybean aphid resistance and contribute to precise selection of resistant soybeans.

Abstract Background Cocksfoot grass (Dactylis glomerata L.) with high biomass yield and rich cellulose can be used to produce bioethanol as fuel additive. In view of this, ultrasonic and hydrothermal pretreatments followed by successive alkali extractions were assembled into an integrated biorefinery process applied on cocksfoot grass to improve its enzymatic hydrolysis. In this work, the effects of ultrasonic and hydrothermal pretreatments followed by sequential alkali extractions on the enzymatic hydrolysis of cocksfoot grass were investigated. In addition, since large amount of hemicelluloses were released during the hydrothermal pretreatment and alkali extraction process, the yields, structural characteristics and differentials of water- and alkali-soluble hemicellulosic fractions isolated from different treatments were also comparatively explored. Results The integrated treatment significantly removed amorphous hemicelluloses and lignin, resulting in increased crystallinity of the treated residues. A maximum saccharification rate of 95.1% was obtained from the cellulose-rich substrate after the integrated treatment. In addition, the considerable hemicelluloses (31.4% water-soluble hemicelluloses and 53.4% alkali-soluble hemicelluloses) were isolated during the integrated treatment. The released water-soluble hemicellulosic fractions were found to be more branched as compared with the alkali-soluble hemicellulosic fractions and all hemicellulosic fractions were mixed polysaccharides mainly composed of branched xylans and β-glucans. Conclusion The combination of ultrasonic and hydrothermal pretreatments followed by successive alkali extractions can dramatically increase the enzymatic saccharification rate of the substrates and produce considerable amounts of hemicelluloses. Detailed information about the enzymatic hydrolysis rates of the treated substrates and the structural characteristics of the co-produced hemicelluloses will help the synergistic utilization of cellulose and hemicellulose in cocksfoot grass.

Meiotic recombination and the resulting novel allele combinations are fundamental to plant breeding and the identification of superior hybrids. However, the rate of meiotic crossovers is naturally suppressed below its potential ability, which prevents plant breeding efficiency. Nine suppressors of meiotic recombination have been identified in the model plant Arabidopsis and in other crop species. Mutations in these genes can lead to increased recombination frequency and could therefore potentially be used to create hyper-recombinant lines for ornamental breeding. In Gerbera hybrida, the anti-crossover factors remain elusive. In this study, we isolated and cloned TOP3α from flower buds of G. hybrida, and it encoded 935 amino acids with three conserved domains TOPRIM, TOP1Ac and zf-GR. Moreover, TOP3α was the highest expressed at the flower bud stage, which coincided with the occurrence of meiotic recombination, suggesting that TOP3α is associated with the regulation of meiotic recombination in G. hybrida.