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Abstract Background The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer’s disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. Methods We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. Results We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. Conclusions Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.

Summary: Major depressive disorder (MDD) is a prevalent mental disorder with serious impacts on life and health. Neuroimaging offers valuable diagnostic insights. However, traditional computer-aided diagnosis methods are limited by reliance on researchers’ experience. To address this, we proposed an evolutionary neural architecture search (M-ENAS) framework for automatically diagnosing MDD using multi-modal magnetic resonance imaging (MRI). M-ENAS determines the optimal weight and network architecture through a two-stage search method. Specifically, we designed a one-shot network architecture search (NAS) strategy to train supernet weights and a self-defined evolutionary search to optimize the network structure. Finally, M-ENAS was evaluated on two datasets, demonstrating that M-ENAS outperforms existing hand-designed methods. Additionally, our findings reveal that brain regions within the somatomotor network play important roles in the diagnosis of MDD, providing additional insight into the biological mechanisms underlying the disorder.

Background: LncRNA HOXB-AS3 are associated with tumor progression in several types of carcinomas, yet, its possibly biological role in gallbladder carcinoma(GBC) remains unclear. Therefore, this study aimed to investigate the biological function of HOXB-AS3 in GBC. Methods: To know the potential function of HOXB-AS3 in gallbladder carcinoma, real-time polymerase chain reaction was used to detected the expression of HOXB-AS3 in gallbladder carcinoma cells. The colony formation assay and cell counting kit-8 assay was performed to measured cell viability. Flow cytometry was to analyse cell apoptosis and cell cycle. Cell invasion and migration were determined by the transwell invasion assay and wound-healing assay. A nude mice xenograft tumor model was performed to investigate the biological function of HOXB-AS3 in vivo. Results: The results indicated that HOXB-AS3 was significantly elevated in gallbladder carcinoma tissues and cell lines. We used siHOXB-AS3 to knockdown the expression levels of HOXB-AS3. And knockdown HOXB-AS3 expression depressed gallbladder cancer cell viability and induced cell apoptosis. In addition, the gallbladder carcinoma cell cycle was obviously arrested at the G1 phase. Cell invasion and migration were markedly suppressed following knockdown HOXB-AS3 expression. Furthermore, the features of siHOXB-AS3 in gallbladder cancer cells could be reversed by the ERK1/2 phosphorylation agonist Ro 67–7476. Finally, we confirmed that HOXB-AS3 promoted the growth of transplanted tumors in vivo. Conclusion: HOXB-AS3 promoted gallbladder carcinoma cell proliferation, invasion and migration by activating the MEK/ERK signaling pathway. HOXB-AS3 contributed to gallbladder cancer tumorigenesis and metastasis, making it a viable therapeutic target for gallbladder cancer treatment.

[INLINE:1] Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited. Although regular exercise effectively improves learning and memory functions across multiple neurological diseases, its application in patients with epilepsy remains controversial. Here, we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy. Cognitive assays confirmed the improvement of object and spatial memory after endurance training, and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise. Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons, probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier. In summary, this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

In this study, the oral bioavailability of Pb, Cd, and As in three types of traditional Chinese medicines (TCMs) and TCM decoctions were investigated through in vitro PBET digestion/MDKC cell model. Furthermore, a novel cumulative risk assessment model associated with co-exposure of heavy metal(loid)s in TCM and TCM decoction based on bioavailability was developed using hazard index (HI) for rapid screening and target organ toxicity dose modification of the HI (TTD) method for precise assessment. The results revealed that the bioavailability of Pb, Cd, and As in three types of TCM and TCM decoction was 5.32–72.49% and 4.98–51.97%, respectively. After rapid screening of the co-exposure health risks of heavy metal(loid)s by the HI method, cumulative risk assessment results acquired by TTD method based on total metal contents in TCMs indicated that potential health risks associated with the co-exposure of Pb, Cd, and As in Pheretima aspergillum (E. Perrier) and Oldenlandia diffusa (Willd.) Roxb were of concern. However, considering both the factors of decoction and bioavailability, TTD-adjusted HI outcomes for TCMs in this study were

In order to safeguard the health of river ecosystems and maintain ecological balance, it is essential to rationally allocate water resources. This study utilized continuous runoff data from 1967 to 2020 at the Zhouqu Hydrological Station on the Bailong River. Five hydrological methods, tailored to the hydrological characteristics of the Zhouqu hydrological cross-section, were employed. These methods included the improved dynamic calculation method, the NGPRP method, the improved monthly frequency computation method, the improved RVA method, and the Tennant method. Ecological flow calculations were conducted to determine the ecological flow, with analysis carried out through the degree of satisfaction, economic benefits, and the nonlinear fitting of the GCAS model. We established an ecological flow threshold and early warning program for this specific hydrological cross-section. Ecological flow values calculated using different methods for each month of the year were compared. The improved RVA method and Tennant method resulted in small values ranging from 4.05 to 36.40 m3/s and 7.65 to 22.94 m3/s, respectively, with high satisfaction levels and economic benefits, but not conducive to ecologically sound development. In contrast, the dynamic calculation method, NGPRP method, and improved monthly frequency calculation method yielded larger ecological flow values in the ranges of 21.79–97.02 m3/s, 23.90–137.00 m3/s, and 28.50–126.00 m3/s, respectively, with poor fulfillment and economic benefits. Ecological flow thresholds were determined using the GCAS model, with values ranging from 16.72 to 114.58 m3/s during the abundant water period and from 5.03 to 63.63 m3/s during the dry water period. A three-level ecological warning system was proposed based on these thresholds, with the orange warning level indicating optimal sustainable development capacity for the Zhouqu Hydrological Station. This study provides valuable insights into the scientific management of water resources in the Bailong River Basin to ensure ecological security and promote sustainable development.

Major Depressive Disorder (MDD) is a common mental illness resulting in immune disorders and even thoughts of suicidal behavior. Neuroimaging techniques serve as a quantitative tool for the assessment of MDD diagnosis. In the domain of computer-aided magnetic resonance imaging diagnosis, current research predominantly focuses on isolated local or global information, often neglecting the synergistic integration of multiple data sources, thus potentially overlooking valuable details. To address this issue, we proposed a diagnostic model for MDD that integrates high-frequency and low-frequency information using data from diffusion tensor imaging (DTI), structural magnetic resonance imaging (sMRI), and functional magnetic resonance imaging (fMRI). First, we designed a meta-low-frequency encoder (MLFE) and a meta-high-frequency encoder (MHFE) to extract the low-frequency and high-frequency feature information from DTI and sMRI, respectively. Then, we utilized a multilayer perceptron (MLP) to extract features from fMRI data. Following the feature cross-fusion, we designed the ensemble learning threshold voting method to determine the ultimate diagnosis for MDD. The model achieved accuracy, precision, specificity, F1-score, MCC, and AUC values of 0.724, 0.750, 0.882, 0.600, 0.421, and 0.667, respectively. This approach provides new research ideas for the diagnosis of MDD.

Water resource management and natural vegetation distribution status are important for the sustainable development of agricultural, ecological and socio-economic systems in arid areas, and the carrying area of vegetation is limited by the established water resources. This study proposed the concept of natural vegetation area design in arid areas based on water resource design carrying capacity and took Minqin County belonging to a typical inland arid area as an example and socio-economic water consumption, ecological water consumption and water resource utilization efficiency in the study area as the main selected factors as well as reference indicators. By calculating the water ecological footprint, water resource carrying and water resource ecological pressure index of the main natural vegetation design area in Minqin County in 2017, we analyzed and evaluated its water resource carrying status and predicted the natural vegetation areas in 2025. The results showed that there was a large gap (the increase was 13.25–9.29%) between the actual area of various types of natural vegetation in 2017 and that in 2025. The water resource utilization was more effective in various types of natural vegetation in Minqin County under the stable development model, and the water ecological deficit was approaching 0, but the utilization of forest trees other than shrubs and herbaceous plants was in an insecure state, and the water ecological deficit was less than 0. The water resource allocation schemes under the restoration model and the optimization model were safer ecological development models for natural vegetation in Minqin County, which was in a state of water-ecological surplus, and the water-ecological surplus value was greater than 0. Thus, it could be seen that coordinating the water resource supply among various types of natural vegetation in an arid area was a preferred strategy to ensure the sustainable development of regional ecology as well as an effective countermeasure to improve the water use efficiency of natural vegetation in the county to a certain extent. This study aimed to evaluate the carrying capacity of a natural vegetation area and the water pressure index under certain water supply conditions, which could provide a reasonable theoretical reference for water resource management in arid areas.

Given the threats to the regional river ecological flow, including the sharp increase in per capita water demand, the increase in the number of hydraulic engineering, and the strong seasonal runoff of rainfall recharge channels, we clarified the appropriate ecological flow thresholds for the middle reaches of Bailong River of northwest China. Based on the monthly runoff data in the Wudu Hydrological Station of Bailong River from 1990 to 2020, seven suitable hydrological methods were used to couple the estimation of the ecological flow in the middle reaches of Bailong River, which were tested by runoff satisfaction level analysis, using quadratic fit and 95% confidence interval to determine the monthly ecological flow and threshold of the river in the study area. The results by using the single hydrological methods showed that the calculation results from the monthly minimum ecological runoff calculation method, the improved RVA method, the Tennant method, and the DC method were four better estimation methods, which had a satisfaction level of more than 90% in the whole year. The improved RVA method and the Tennant method were more suitable for the diversion power station whose main task aimed at power generation. Although the economic benefits of hydropower stations were better when the improved RVA method was used to calculate ecological flow, the calculation results from the improved RVA method were tested and analyzed by the Tennant method, which were extremely poor from November to April in the following year, and could not meet the minimum ecological water requirements for the biological community in the river channel. While the other five methods all meet this requirement. We suggest that the minimum ecological flow in the middle reaches of the Bailong River maintained at 27.28 m3⁄s, and the maximum retained at 116.33 m3⁄s. The calculation results were in line with the dynamics of runoff in the study area, which could improve the accuracy of water ecological protection. The calculation results of this study could be used for the middle reaches of the Bailong River and may provide a reference for follow-up ecological restoration research and management in similar ecological zones.

ObjectivesGastric cancer with liver metastasis (GCLM) is highly aggressive and has a poor prognosis. This study aims to evaluate the survival benefit of primary tumor resection (PTR) for gastric cancer with liver metastasis.MethodsData on patients with GCLM was extracted from the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. A 1:1 propensity score matching (PSM) analysis was performed to minimize the heterogeneity between the PTR and no-PTR groups. The Kaplan–Meier method and Cox regression analysis were used to assess the impact of primary tumor resection (PTR) on overall survival (OS) and cause-specific survival (CSS).ResultsA total of 3,001 patients with GCLM were included, with 328 patients treated with primary tumor resection (PTR), whereas the other 2,673 patients were not. Patients with PTR had a significantly higher OS and CSS rate than those without PTR in unmatched and PSM cohorts. In an unmatched cohort, the median OS was 12.0 months (95% CI, 10 months to 14 months) for those who underwent PTR and 4 months (95% CI, 4 months to 5 months) for those without PTR; the median CSS for those who underwent PTR was 12.0 months (95% CI, 10 months to14 months) and 4 months (95% CI, 4 months to 5 months) for those without PTR, respectively. After PMS, the median OS was 12.0 months (95% CI, 10 months to 17 months) for those who underwent PTR and 7 months (95% CI, 5 months to 10 months) for those without PTR, respectively; the median CSS for those who underwent PTR was 12.0 months (95% CI, 11 months to 17 months) and 7 months (95% CI, 5 months to 8 months) for those without PTR, respectively. In addition, multivariate Cox analysis in the PSM cohort showed that PTR, age, degree of tumor differentiation, and chemotherapy were independent prognostic factors for OS and CSS in GCLM. Specifically, PTR was a significant protective factor for OS (HR: 0.427; 95% CI, 0.325 to 0.561, P

The X-ray pulsar 1A 0535+262 exhibited a giant outburst in 2020, offering us a unique opportunity for X-ray polarimetry of an accreting pulsar in the supercritical state. Measurement with PolarLight yielded a nondetection in 3–8 keV; the 99% upper limit of the polarization fraction (PF) is found to be 0.34 averaged over spin phases, or 0.51 based on the rotating vector model. No useful constraint can be placed with phase-resolved polarimetry. These upper limits are lower than a previous theoretical prediction of 0.6–0.8, but consistent with those found in other accreting pulsars, like Her X-1, Cen X-3, 4U 1626−67, and GRO J1008−57, which were in the subcritical state, or at least not confidently in the supercritical state, during the polarization measurements. Our results suggest that the relatively low PF seen in accreting pulsars cannot be attributed to the source not being in the supercritical state, but could be a general feature.

Abstract The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.

In recent years, the escalation in emergency occurrences has underscored the pressing need for expedient responses in delivering essential supplies. Efficient integration and precise allocation of emergency resources under joint government–enterprise stockpiling models are pivotal for enhancing emergency response effectiveness and minimizing economic repercussions. However, current research predominantly focuses on contract coordination and cost-sharing within these joint reserve modes, overlooking significant discrepancies in emergency supply classification standards between government and enterprise sectors, as well as the asymmetry in cross-sectoral and cross-regional supply information. This oversight critically impedes the timeliness and accuracy of emergency supply responses. In practice, manual judgment has been used to match the same materials under differing classification standards between government and enterprise reserves. Still, this approach is inefficient and prone to high error rates. To mitigate these challenges, this study proposes a methodology leveraging the BERT pre-trained language model and TextCNN neural network to establish a robust mapping relationship between these classification criteria. The approach involves abstracting textual representations of both taxonomical classes, generating comparable sentence vectors via average pooling, and calculating cosine similarity scores to facilitate precise classification mapping. Illustrated with China’s Classification and Coding of Emergency Supplies standards and Global Product Classification standards, empirical validation on annotated data demonstrates the BERT-TextCNN model’s exceptional accuracy of 98.22%, surpassing other neural network methodologies such as BERT-CNN, BERT-RNN, BERT-BiLSTM, etc. This underscores the potential of advanced neural network techniques in enhancing emergency supply management across diverse sectors and regions.

Abstract Purpose There is a significant risk of DVT after TKA. We aim to evaluate the potential risk factors for postoperative DVT in the lower extremities in TKA patients over 60 years of age and provide a reference for the effective prevention of DVT. Methods This retrospective study included patients older than 60 who underwent TKA surgery in our hospital from May 2015 to May 2022 and compared and analyzed patients' personal characteristics and clinical data with or without postoperative DVT. Logistic regression analysis was performed to determine the potential risk factors for DVT after TKA. The sensitivity and specificity of each risk factor in the diagnosis of DVT were compared by the ROC curve, and the value of this model in the diagnosis of DVT was further investigated using a multivariable combined diagnosis ROC curve model. Results A total of 661 patients over 60 who underwent TKA were included. Preoperative Hematocrit (HCT), platelet count, anesthesia mode, postoperative D-dimer, ESR, diabetes mellitus, and other aspects of the DVT group and non-DVT group were statistically significant after TKA (P

Triple-negative breast cancer (TNBC) due to lack of clear target and notorious “cold” tumor microenvironment (TME) is one of the most intractable and lethal malignancies. Tuning “cold” TME into “hot” becomes an emerging therapeutic strategy to TNBC. Herewith, we report that integrin-targeting micellar gemcitabine and paclitaxel (ATN-mG/P, ATN sequence: Ac-PhScNK-NH2) cooperating with polymersomal CpG (NanoCpG) effectively “heated up” and treated TNBC. ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells, induced potent immunogenic cell death (ICD), and efficiently stimulated maturation of bone marrow-derived dendritic cells (BMDCs). Remarkably, in a postoperative TNBC model, ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses, showing a greatly augmented proportion of mature DCs and CD8+ T cells while reduced immune-suppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg), which led to complete inhibition of lung metastasis and 60% mice tumor-free. The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of “cold” tumors like TNBC.

Electron beam melting (EBM) additive manufacturing (AM) has grown rapidly in recent years due to its capability to manufacture high-performance metals and conductive ceramics. Whereas in-situ synchrotron X-ray imaging and diffraction have proven invaluable tools in understanding of laser powder bed fusion (L-PBF), the characterization of the EBM process lagged what has been accomplished in laser-based AM. This is principally due to the lack of an open architecture system. Here we report an open architecture EBM system for in-situ synchrotron X-ray monitoring with complementary high-speed visible light imaging and high-speed infrared (IR) imaging. We demonstrate that the developed system enables the characterization of sub-surface transient phenomena. The open architecture system reported here provides a powerful tool for studying the dynamics and mechanisms of EBM AM process. The promising results reported here may ignite more future research activities on using in-situ synchrotron x-ray techniques to study EBM AM processes.