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Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinsons disease (PD), with 10-30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

Abstract Sleep difficulties affect up to 98% of Parkinson’s disease (PD) patients and are often not well treated. How globus pallidus internus (GPi)-DBS could help is less understood. We retrospectively analyzed sleep outcomes in 32 PD patients after GPi-DBS with a two-year follow-up. We observed high heterogeneity in sleep response to pallidal stimulation: 16 patients showed clinically meaningful improvement, 9 had minor changes, and 7 experienced worsened sleep quality, with no overall significant change on the Parkinson’s Disease Sleep Scale-2 (P = 0.19). Further analysis revealed that stimulation of the left sensorimotor GPi was significantly associated with sleep improvement. Fiber tracts from the left sensorimotor GPi to the bilateral sensorimotor cortex, right GPi, brainstem, and bilateral cerebellum were linked to better sleep, while projections to the left hippocampus correlated with worsened sleep. These findings may guide personalized GPi-DBS lead placement to optimize sleep outcomes in PD.

Abstract To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

Abstract Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson’s disease, Essential Tremor, Dystonia, Essential Tremor, Huntington’s disease, and Tourette’s syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder – BGOOSE. This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.

Aiming at the issue of crystallization and blockage of drainage system due to the massive calcium loss from the tunnel shotcrete, a self-designed tunnel seepage crystallization modelling system was developed. This system was produced in conjunction with the initial tunnel support shotcrete construction and drainage pipe installation, and is capable of simulating both the seepage process of groundwater in the shotcrete and the process of crystallization in the drainage pipe. Based on three different mechanisms of anti-crystallization, which include absorbing free calcium, reducing the porosity and increasing hydrophobicity, antialkali agent, nano-calcium carbonate, and silane were selected to test, respectively. Firstly, the suitable dosing ranges of these three external admixtures for resisting calcium loss in shotcrete were determined by single factor tests, which were 7%–11%, 4%–8%, and 0.3%–0.5%, respectively. Thereafter, the response surface method was employed to evaluate the interaction of antialkali agent, nano-calcium carbonate and silane on calcium loss in shotcrete, and to establish the relationship between them, and thus to determine the admixture ratio that can effectively reduce calcium loss crystallization in shotcrete, with the optimal admixture amounts of antialkali agent being 9.242%, nano-calcium carbonate 4.889% and silane 0.366%. Lastly, the reliability of the model test results was verified by the microscopic analysis, and the results showed that the total amount of calcium dissolution in the optimized group could be reduced by 75% compared with the blank control group, and was basically consistent with that derived from the response surface regression model, validating the high accuracy of the buildup response surface regression model. The present study can provide some ideas and references for reducing the seepage crystallization behavior of groundwater in the initial tunnel support shotcrete.

ObjectiveTo delineate the risk factors and causes of unplanned reoperations within 30 days following laparoscopic pancreaticoduodenectomy (LPD).MethodsA retrospective study reviewed 311 LPD patients at Ningbo Medical Center Li Huili Hospital from 2017 to 2024. Demographic and clinical parameters were analyzed using univariate and multivariate analyses, with P < 0.05 indicating statistical significance.ResultsOut of 311 patients, 23 (7.4%) required unplanned reoperations within 30 days post-LPD, primarily due to postoperative bleeding (82.6%). Other causes included anastomotic leakage, abdominal infection, and afferent loop obstruction. The reoperation intervals varied, with the majority occurring within 0 to 14 days post-surgery. Univariate analysis identified significant risk factors: diabetes, liver cirrhosis, elevated CRP on POD-3 and POD-7, pre-operative serum prealbumin < 0.15 g/L, prolonged operation time, intraoperative bleeding > 120 ml, vascular reconstruction, soft pancreatic texture, and a main pancreatic duct diameter ≤3 mm (all P < 0.05). Multivariate analysis confirmed independent risk factors: pre-operative serum prealbumin < 0.15 g/L (OR = 3.519, 95% CI 1.167-10.613), CRP on POD-7 (OR = 1.013, 95% CI 1.001-1.026), vascular reconstruction (OR = 9.897, 95% CI 2.405-40.733), soft pancreatic texture (OR = 5.243, 95% CI 1.628-16.885), and a main pancreatic duct diameter ≤3 mm (OR = 3.462, 95% CI 1.049-11.423), all associated with unplanned reoperation within 30 days post-LPD (all P < 0.05).ConclusionPostoperative bleeding is the primary cause of unplanned reoperations after LPD. Independent risk factors, confirmed by multivariate analysis, include low pre-operative serum prealbumin, elevated CRP on POD-7, vascular reconstruction, soft pancreatic texture, and a main pancreatic duct diameter of ≤3 mm. Comprehensive peri-operative management focusing on these risk factors can reduce the likelihood of unplanned reoperations and improve patient outcomes.

BackgroundEvidence of an association between maternal use of anti-seizure medication (ASM) during pregnancy and the risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children is conflicting. This systematic review and meta-analysis aimed to summarize the relationship between fetal exposure to ASM and the development of ASD or ADHD in offspring.MethodsA comprehensive literature search was conducted in PubMed and other databases to identify relevant epidemiological studies published from inception until 1 March 2024.ResultsSeven cohort studies were included in the meta-analysis. The results showed that maternal exposure to ASMs during pregnancy was associated with an increased risk of ASD [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.63–2.71; p

In this work a non-abelian gauge theory is reformulated in a rotating frame. With this new formalism, the influence of the background rotation on the color deconfinement transition for a pure SU(2) gluon system has been studied. The KvBLL caloron, which is a color neutral and topologically nontrivial solution of Yang-Mills equation at finite temperature, is reexamined under rotation and adopted as the confined vacuum of such a system. With rotation-modified solutions of the caloron's constituent solitons, i.e. dyons, the non-perturbative part of effective potential of the rotating system has been obtained. Combining with the perturbative potential by Gaussian fluctuations, the critical temperature of confinement-deconfinement phase transition is investigated. It is found that neither the rotational semi-classical potential nor Gaussian fluctuations can confine color charges more tightly when the rotation becomes faster. While only a stronger coupling constant is able to make the critical temperature increase with angular velocity, as what indicated in lattice simulations. And it is found a non-monotonic dependence of the critical temperature on the angular velocity is established because of the competition between these two contrary contributions.

Introduction The mechanisms underlying the protective effects of atrial natriuretic peptide (ANP) on the gut barrier during traumatic hemorrhagic shock (THS) remain elusive. This study aimed to explore the potential role of ANP in safeguarding against gut barrier dysfunction after THS, focusing on the PLC-γ1/ROS feedback loop. Methods In our THS rat model, we randomly allocated male Sprague-Dawley rats to receive intravenous ANP with or without a concurrent NADPH oxidase/p38 MAPK inhibitor during the shock phase. After 24 h, we assessed circulatory and jejunal ANP, ROS, intestinal tight junction proteins, and apoptosis to evaluate the effects of ANP on the gut barrier and its interplay with intestinal ANP and ROS. Rat small intestinal epithelial cells (IECs) were also treated with ANP and subjected to hypoxia/re-oxygenation injury, with or without PI3K/PLC inhibition, to elucidate the relationship between ANP/ROS signaling and PLC-γ1. Furthermore, we modulated PLC-γ1 expression in these IECs to examine its impact on ROS and ANP production. Results Intravenous ANP administration at 0.025 μg/kg/min during THS significantly increased intestinal ANP and ROS levels at 24 h. ANP treatment enhanced the expression of intestinal tight junction proteins and reduced IEC apoptosis. Inhibition of circulatory ROS diminished intestinal ANP levels, while suppression of circulatory ANP led to a reduction in intestinal ROS. Decreasing PLC-γ1 expression in hypoxia/re-oxygenation-treated IECs resulted in lower ROS and ANP levels, whereas augmenting PLC-γ1 expression did not alter these levels. Additionally, PI3K inhibition markedly decreased PLC-γ1 expression in these cells. Conclusion ANP-induced protection of the intestinal barrier in THS is mediated by an intrinsic PLC-γ1/ROS positive feedback loop. ANP preserves gut barrier integrity and reduces IEC apoptosis through this mechanism. Further studies are warranted to investigate the interaction between IECs and other cellular components within the PLC-γ1/ROS loop.

BackgroundGrowing evidence suggests that headache disorders and atopic dermatitis share similar pathological mechanisms and risk factors. The aim of this study was to assess the risk for headache disorders in patients with atopic dermatitis.MethodsWe systematically searched the PubMed and Embase databases from inception to December 1, 2023, for observational studies that examined risk of migraine in subjects with atopic dermatitis. Risk estimates from individual studies were pooled using random-effects models.ResultsTen studies with 12,717,747 subjects were included in the meta-analysis. Our results showed that patients with atopic dermatitis were associated with a higher risk of headache disorder (OR, 1.46, 95% CI = 1.36–1.56; P

Ischemic stroke (IS), which is the third foremost cause of disability and death worldwide, has inflammation and cell death as its main pathological features. IS can lead to neuronal cell death and release factors such as damage-related molecular patterns, stimulating the immune system to release inflammatory mediators, thereby resulting in inflammation and exacerbating brain damage. Currently, there are a limited number of treatment methods for IS, which is a fact necessitating the discovery of new treatment targets. For this review, current research on inflammation and cell death in ischemic stroke was summarized. The complex roles and pathways of the principal immune cells (microglia, astrocyte, neutrophils, T lymphocytes, and monocytes/macrophage) in the immune system after IS in inflammation are discussed. The mechanisms of immune cell interactions and the cytokines involved in these interactions are summarized. Moreover, the cell death mechanisms (pyroptosis, apoptosis, necroptosis, PANoptosis, and ferroptosis) and pathways after IS are explored. Finally, a summary is provided of the mechanism of action of natural pharmacological active ingredients in the treatment of IS. Despite significant recent progress in research on IS, there remain many challenges that need to be overcome.

Objective: Rare disease Background: Primary hepatic neuroendocrine neoplasms (PHNEN) are exceedingly rare tumors with atypical clinical manifestations, accounting for less than 0.5% of all neuroendocrine tumors. Currently, there is a lack of consensus on their management, and guidelines do not recommend postoperative chemotherapy for patients with stage G1/G2 disease after curative resection. We present a case report of PHNEN, outlining its diagnostic challenges, treatment strategy, and clinical outcomes. Case Report: A 31-year-old man presented with jaundice and was initially diagnosed with suspected IgG4-related disease, which initially appeared to respond to steroid therapy, but manifested worsening jaundice 4 months after initial treatment. Subsequent evaluation revealed a PHNEN NET G2 with lymph node metastasis and invasion of the right hepatic artery; and involvement of the hepatic duct at the hepatic hilum, primarily the left hepatic duct. The patient underwent extended left hemi-hepatectomy with caudate lobe resection, bile duct resection, and lymphadenectomy, followed by reconstruction of the right hepatic artery. Postoperatively, the patient received adjuvant chemotherapy consisting of capecitabine (1000 mg bid D1-14) and temozolomide (200 mg qn D10-14) for 6 cycles. Currently, the patient remains disease free 43 months after treatment. Conclusions: PHNEN presents diagnostic challenges due to its rarity and lack of specific markers. Surgical resection remains the cornerstone of treatment, with chemotherapy being considered in select cases with high-risk features. Further research is needed to refine treatment approaches and improve outcomes for patients with PHNEN. [ABSTRACT FROM AUTHOR]

Organic field‐effect transistors (OFETs) hold great promise for applications in non‐volatile memories, detectors, and artificial synapses due to the good flexibility and biocompatibility. However, certain drawbacks such as high operating voltages and significant degradation in endurance characteristics have hindered their practical implementations. Herein, a novel approach is proposed to enhance the performance of OFETs by incorporating a bi‐functional n‐type polymer semiconductor interlayer, Poly‐{[N,N'‐bis(2‐octyldodecyl)naphthalene‐1,4,5,8‐bis(dicarboximide)‐2,6‐diyl]‐alt‐5,5′‐(2,2′‐bithiophene)} (N2200), into a pentacene OFET structure. The device exhibits remarkable improvements, with reliable P/E operation cycles of over than 104 and a retention time of more than 10 years. On one hand, the inclusion of N2200 as an n‐type semiconductor effectively reduces the height of hole‐injection barrier for trapping and thus reducing the working voltage based on the electrostatic induction theory. On the other hand, n‐type semiconductor N2200 serves as a native hole‐consumption (or hole‐trapping) dielectric, and its narrower bandgap restrains the formation of deep hole‐traps, thus favoring the endurance characteristics of the OFET. [ABSTRACT FROM AUTHOR]

The fixed-total-pressure-based air-blowing method in free-jet wind tunnels only produces uniformity in a limited area for supersonic jets. To address the issue, we investigated the effect of total pressure on static pressures at the nozzle exit and test chamber. We proposed an air-blowing method for pressure matching and established corresponding equations while suggesting ways to determine its parameters. The pressure-matching method was experimentally verified to analyze and compare the effects of different air-blowing methods and pressure-matching parameters on jet uniformity. The results of the study are as follows: (1) The pressure-matching-based air-blowing method improved the uniformity of the flow field at Mach numbers (Ma) of 1.5, 2.0, and 3.0 by 445.5%, 275%, and 215.8%, respectively, when compared to the air-blowing method that maintains the total pressure above the designed value. (2) The pressure-matching-based air-blowing method reduced the root-mean-square deviation in the Ma of the flow field at a Ma of 2.0 by 47.1% compared to the air-blowing method that maintains the total pressure at the designed value. The findings indicate that the proposed air-blowing technique based on pressure matching can enhance the uniformity of the supersonic jet and the area of the uniform region in the flow field. This method is highly significant in improving the capabilities of free-jet wind tunnel facilities. [ABSTRACT FROM AUTHOR]

Component modulation endows Mn-based electrodes with prominent energy storage properties due to their adjustable crystal structure characteristics. Herein, ZnMn 2 (PO 4 ) 2 · n H 2 O (ZMP· n H 2 O) was obtained by a hydration reaction from ZnMn 2 (PO 4 ) 2 (ZMP) during an electrode-aging evolution. Benefiting from the introduction of lattice H 2 O molecules into the ZMP structure, the ion transmission path has been expanded along with the extended d-spacing, which will further facilitate the ZMP → ZMP· n H 2 O phase evolution and electrochemical reaction kinetics. Meanwhile, the hydrogen bond can be generated between H 2 O and O in PO 4 3- , which strengthens the structure stability of ZMP· n H 2 O and lowers the conversion barrier from ZMP to ZMP·4H 2 O during the Zn 2+ uptake/removal process. Thereof, ZMP· n H 2 O delivers enhanced electrochemical reaction kinetics with robust structure tolerance (106.52 mA h g -1 at 100 mA g -1 over 620 cycles). This high-energy aqueous Zn||ZMP· n H 2 O battery provides a facile strategy for engineering and exploration of high-performance ZIBs to realize the practical application of Mn-based cathodes.

The microplastics in aquatic ecosystems pose a serious threat to ecological security and environmental health, which have received widespread attention. To reveal the response of a water- Vallisneria natans -sediment system to microplastics exposure, the V. natans was exposed to polyethylene microplastics （PE-MPs） with different mass fractions （1%-5%, sediment wet mass fraction）, and the effects of PE-MPs on the physiochemical indicators of water quality, morphological characteristics of submerged plants, physiological characters, antioxidant system, and microbial community structure in sediments were studied respectively. The results showed that the physiochemical properties of the water body were not significantly changed in the PE-MPs treatment group, whereas the plant height, oxidative stress index, and antioxidant system were significantly inhibited. For the plant height, the 1% PE-MPs treatment group height was only 47.44% of that in the control group. Chlorophyll a content was 81.04% of that in the control group, and the activities of catalase （CAT）, malondialdehyde （MDA）, and peroxidase （POD） increased by 233.70%, 117.82%, and 61.62%, respectively. Different mass fractions of PE-MPs had a certain impact on microbial community structure in sediments. The above results are helpful to improve the evaluation system of PE-MPs ecological risk in the water-submerged plant-sediment system.