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Abstract To address immune escape, multi-specific CAR-T-cell strategies use natural ligands that specifically bind multiple receptors on malignant cells. In this context, we propose a split CAR design comprising a universal receptor expressed on T cells and ligand-based switch molecules, which preserves the natural trimeric structure of ligands like APRIL and BAFF. Following optimization of the hinges and switch labeling sites, the split-design CAR-T cells ensure the native conformation of ligands, facilitating the optimal formation of immune synapses between target cancer cells and CAR-T cells. Our CAR-T-cell strategy demonstrates antitumor activities against various B-cell malignancy models in female mice, potentially preventing immune escape following conventional CAR-T-cell therapies in the case of antigen loss or switching. This ligand-based split CAR design introduces an idea for optimizing CAR recognition, enhancing efficacy and potentially improving safety in clinical translation, and may be broadly applicable to cellular therapies based on natural receptors or ligands.

Abstract Background Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. Methods Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase–activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. Results CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. Conclusions These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization. Graphical abstract

There were many problems in the methodological theory of the formulation of clinical practice guidelines in in the real world situation, and the lack of consideration of the actual situation leads to the decline of the guidance for the formulation of guidelines. Through an in-depth analysis of the various difficulties related to theory and practice in the formulation of the guidelines, including the deviation between methodological theory and practice in the formulation of guidelinesn, lack of empirical studies of large samples related to guideline development, after the empirical application of methodological theory, the reports of limitations and future research recommendations were insufficient and not standardized. To improve the guidance of future guidelines, our team put forward a number of methodology recommendations, including advocating for empirical research that validates methodological theories, develop large sample empirical research and comparative research, standardize the content and form of reports on limitations and future research recommendations after empirical research, in order to provide reference for guidelines develop methodology researchers and guideline development groups.

The microstructure evolution and hardness change of Fe-1.4C-1.5Cr-Alx ultra-high carbon steel with 2%-6% aluminum content added during quenching and tempering were analyzed. It is found that the addition of Al reduces the precipitation amount of proeutectoid carbides during cooling， and helps to inhibit the formation of network carbides around grain boundaries. After adding 4% -6% Al， the tempering hardness of ultra-high carbon steel is stable between 62HRC -65HRC at 200 ℃-400 ℃， and after adding Al element， the decomposition temperature of nanoscale carbide in the tempering process of the test steel is increased， the tempering resistance stability is improved， and the martensitic decomposition temperature is increased， and the greater the amount of Al element added， the better of the tempering stability and temperature resistance of ultra-high carbon steel.

The genus Micryletta is widely distributed in South China and Southeast Asia. Although significant progress has been made in the diversity and taxonomy of this genus over the past few years, the distribution range and taxonomy of some species still remain controversial, especially in M. inornata sensu lato. Consequently, limitations at national borders have resulted in a lack of comparative research on species from different countries. To resolve the classification dispute, assess species diversity, and determine the distribution range of Micryletta, a series of specimens were collected from the Yunnan Province of China and Thailand during herpetological surveys from 2009 to 2020. Subsequent analyses based on morphological and molecular data revealed a distinct and previously unknown lineage from western Thailand, which we formally describe as a new species. Furthermore, our study confirms that M. ‘inornata’, previously known from Mengla, Yunnan, was actually M. menglienica, and further extends its distribution range to Thailand and Laos. In addition, our findings extend the latitudinal distribution of M. inornata and M. subaraji northward into southern Thailand. Notably, this study brings the total number of known species in the genus Micryletta from 13 to 14, with the count rising from three to six species in Thailand and from one to three in Laos. Our study further confirms that species diversity within the genus Micryletta is underestimated and emphasizes the important role that international collaborations play in taxonomy. Intensifying field surveys in other regions (e.g., Myanmar, Vietnam, and Guangxi of China) will be extremely necessary in the future to clarify any taxonomic questions and reevaluate the distribution range of these species.

AimThis study aims to create and validate a novel systematic immune-inflammation-nutrition (SIIN) score to provide a non-invasive and accurate prognostic tool for head and neck squamous cell carcinoma (HNSCC) patients.Methods259 participants diagnosed with HNSCC from the First Affiliated Hospital of Xi’an Jiaotong University between 2008 and 2017 was included in this retrospective study. Patients were assigned to training (n=181) and validation (n=78) sets. A LASSO Cox regression model was employed to identify significant biomarkers for constructing a SIIN nomogram and to create SIIN score from this nomogram. The prognostic accuracy of the SIIN score was assessed by exploiting receiver operating characteristic (ROC) analysis, Kaplan-Meier survival analysis, Cox proportional hazard regression models, calibration and DCA curves.ResultsThe SIIN score was formulated based on six biomarkers-platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), albumin-bilirubin index (ALBI), fibrinogen (FIB) and monocyte count-identified by LASSO regression analysis. (1)The SIIN score demonstrated superior predictive value, achieving area under the ROC curve (AUC) values of 0.736 and 0.700 for 3- and 5-year OS. For recurrence-free survival (RFS), the AUC values were 0.752 for 3-year and 0.701 5-year RFS, as assessed in the training set. Validated as an independent prognostic factor in both cohorts, the SIIN score showed strong correlation with adverse clinicopathological outcomes.ConclusionThe SIIN score is a promising prognostic tool that integrates immune, inflammatory, and nutritional factors for predicting clinical outcomes in HNSCC patients. It offers enhanced predictive accuracy compared to existing markers and has the potential to guide personalized treatment strategies and clinical decision-making.

The genus of Polypedates Tschudi, 1838 currently comprises 25 recognised species with four of these species reported in Yunnan, China. Dubois (1987) speculated the distribution of P. teraiensis in China; however, there was no study carried out to confirm its distribution in the region.We herein describe P. teraiensis as a new national record, based on a specimen collected from Yunnan border region. Phylogenetically, our sequence clustered with the sequences of recognised P. teraiensis specimens from Bangladesh, Myanmar and India. The uncorrected pairwise distances between the specimens from China and other P. teraiensis localities was small, ranging from 0.0-0.7%, based on 16S rRNA gene. Therefore, we report P. teraiensis as a new species record for China.

BackgroundTo identify the cognitive load of different turning tasks in simulated flight, a flight experiment was designed based on real “preliminary screening” training modules for pilots.MethodsHeart Rate Variability (HRV) and flight data were collected during the experiments using a flight simulator and a heart rate sensor bracelet. The turning behaviors in flight were classified into climbing turns, descending turns, and level flight turns. A recognition model for the cognitive load associated with these turning behaviors was developed using machine learning and deep learning algorithms.Resultspnni_20, range_nni, rmssd, sdsd, nni_20, sd1, triangular_index indicators are negatively correlated with different turning load. The LSTM-Attention model excelled in recognizing turning tasks with varying cognitive load, achieving an F1 score of 0.9491.ConclusionSpecific HRV characteristics can be used to analyze cognitive load in different turn-ing tasks, and the LSTM-Attention model can provide references for future studies on the selection characteristics of pilot cognitive load, and offer guidance for pilot training, thus having significant implications for pilot training and flight safety.

Abstract Conductive polymer hydrogels exhibit unique electrical, electrochemical, and mechanical properties, making them highly competitive electrode materials for stretchable high‐capacity energy storage devices for cutting‐edge wearable electronics. However, it remains extremely challenging to simultaneously achieve large mechanical stretchability, high electrical conductivity, and excellent electrochemical properties in conductive polymer hydrogels because introducing soft insulating networks for improving stretchability inevitably deteriorates the connectivity of rigid conductive domain and decreases the conductivity and electrochemical activity. This work proposes a distinct confinement self‐assembly and multiple crosslinking strategy to develop a new type of organic–inorganic hybrid conductive hydrogels with biphase interpenetrating cross‐linked networks. The hydrogels simultaneously exhibit high conductivity (2000 S m−1), large stretchability (200%), and high electrochemical activity, outperforming existing conductive hydrogels. The inherent mechanisms for the unparalleled comprehensive performances are thoroughly investigated. Elastic all‐hydrogel supercapacitors are prepared based on the hydrogels, showing high specific capacitance (212.5 mF cm−2), excellent energy density (18.89 µWh cm−2), and large deformability. Moreover, flexible self‐powered luminescent integrated systems are constructed based on the supercapacitors, which can spontaneously shine anytime and anywhere without extra power. This work provides new insights and feasible avenues for developing high‐performance stretchable electrode materials and energy storage devices for wearable electronics.

Abstract Traditional vision screenings in schools are limited to simple visual tasks, yet students in their daily learning face more complex visual environments. Binocular rivalry tasks can partially simulate the visual challenges of real visual environments and activate advanced visual processing mechanisms that simple visual tasks cannot. Therefore, by superimposing binocular rivalry-state tasks onto simple visual tasks, we have developed an innovative vision screening program to rapidly and extensively assess students’ visual performance in complex environments. This is a cross-sectional study in which we investigated the performance of 1126 grade 1–6 students from a primary school in Wuxi, China, in rivalry-state stereoscopic vision tasks. The correlation between the screening results of 1044 students and their academic achievements was also statistically analyzed. The study results revealed pass rates of 53.5–60.5% across various visual tests. Specifically, for first-grade students, there was a statistically significant difference in standardized Chinese scores between the group that failed and the group that passed the rivalry-state stereoscopic vision test (− 0.49 ± 3.42 vs. 0.22 ± 0.58, t = − 2.081, P = 0.04). This result underscores the importance of focusing on the visual adaptability of first graders in complex environments. Trail registration: Ethics Committee of Affiliated Children’s Hospital of Jiangnan University-Certificate number: WXCH2022-04-027

To address the cracking issues that often occur between laser cladding coatings and substrates on brake disc surfaces, methods including microhardness testing, scanning electron microscopy (SEM), and X-ray stress testing were employed. These techniques were used to study the high-temperature dry sliding friction and wear behavior of Ni60A coating on the 20CrNiMo alloy surface treated by laser shock peening (LSP) and its bonding zone. The results indicate that LSP can significantly enhance the microhardness of the coating and bonding zone, refine the microstructure, and form residual compressive stress without generating new phases. The weight loss due to wear and the average coefficient of friction for the substrate, the cladding alloy, and the LSP-treated alloy demonstrate a trend of first decreasing and then increasing with the rise in temperature. The high-temperature friction and wear performance of the LSP-treated alloy is excellent. This is particularly true at 400 °C, where its wear resistance reaches its peak. Furthermore, after strengthening by LSP, the wear mechanism of the alloy at high temperatures transitions from spalling, oxidation, and adhesive wear to primarily oxidation and abrasive wear.

BACKGROUND:Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. METHODOLOGY/PRINCIPAL FINDINGS:We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. CONCLUSIONS/SIGNIFICANCE:As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

BackgroundThe prognostic value of an effective biomarker, pan-immune-inflammation value (PIV), for head and neck squamous cell carcinoma (HNSCC) patients after radical surgery or chemoradiotherapy has not been well explored. This study aimed to construct and validate nomograms based on PIV to predict survival outcomes of HNSCC patients.MethodsA total of 161 HNSCC patients who underwent radical surgery were enrolled retrospectively for development cohort. The cutoff of PIV was determined using the maximally selected rank statistics method. Multivariable Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed to develop two nomograms (Model A and Model B) that predict disease-free survival (DFS). The concordance index, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to evaluate the nomograms. A cohort composed of 50 patients who received radiotherapy or chemoradiotherapy (RT/CRT) alone was applied for generality testing of PIV and nomograms.ResultsPatients with higher PIV (≥123.3) experienced a worse DFS (HR, 5.01; 95% CI, 3.25–7.72; p

BackgroundThyroid hormones (THs) have been found that it is closely associated with the onset and progression of non-alcoholic fatty liver disease (NAFLD). However, the current study could not verify the intrinsic relationship between thyroid hormones and NAFLD, which requires further research.MethodsThe searches of studies reported both TH level in serum and NAFLD were performed in PubMed, Web of Science, Cochrane Library, and Embase databases. We combined an overall meta-analysis with a dose-response meta-analysis to assess the correlation and dose-response relationship between thyroid function levels and the risk of NAFLD.ResultsOverall, 10 studies were included with a total of 38,425 individuals. We found that the non-linear dose-response model showed that for every 1 ng/dL increase in FT4, the risk of NAFLD was reduced by 10.56% (p=0.003). The odds ratios (ORs) for NAFLD with high free triiodothyronine (FT3) exposure compared to those with low FT3 were 1.580 (95% CI 1.370 to 1.830, I2 = 0.0%, p

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Psoralen (PSO) is the main pharmacological component identified from Bu-Shen-Fang-Chuan formula which has been traditionally used in treatment of COPD, yet its efficacy in COPD inflammation were unreported. In this study, we aimed to elucidate the anti-inflammatory potential of PSO in COPD and unravel the underlying mechanisms, focusing on T lymphocyte recruitment and the modulation of chemokines, namely monokine induced by interferon-gamma (CXCL9), interferon inducible protein 10 (CXCL10), and interferon inducible T-Cell alpha chemoattractant (CXCL11). In vitro, RAW264.7 was stimulated by interferon (IFN)-γ + cigarette smoke extract (CSE) and were treated with PSO (2.5, 5, 10 μM), then the levels of chemokines and the activation of Janus kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) pathway were analyzed by real time PCR and western blot. In vivo, a murine model was established by intraperitoneal injection of CSE on day 1, 8, 15, and 22, then treated with PSO (10 mg/kg). Our experiments in vitro illustrated that PSO reduced the levels of CXCL9, CXCL10, and CXCL11, and decreased the protein phosphorylation levels of JAK2 and STAT1. Additionally, PSO effectively improved inflammatory infiltration and decreased the proportion of CD8+ T cells in CSE-exposed mice. Furthermore, PSO reduced the levels of CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid (BALF) and lung tissue, and decreased the protein phosphorylation levels of JAK2 and STAT1. In conclusion, our results revealed the therapeutic potential of PSO for COPD inflammation, possibly mediated through the regulation of CD8+ T cell recruitment and chemokines via the JAK2/STAT1 signaling pathway.

Abstract Objective To analyze the oxidative stress status and its association with tissue neutrophilia and oral steroid response in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. Methods The levels of total oxidant status (TOS) were detected in the sinonasal tissues by using specific assay kits. Tissue neutrophil was examined by immunohistochemical staining, and oxidant status index (OSI) was evaluated in polyps tissues, and the messenger RNA (mRNA) levels of superoxide dismutase 2 (SOD2), aldehyde dehydrogenase 1 (ALDH1A1), and microsomal glutathione S‐transferase 1 (MGST1) were examined using quantitative real‐time polymerase chain reaction in the sinonasal tissues. The receiver operating characteristics (ROCs) curve of ALDH1A1, MGST1, and SOD2 mRNA levels were evaluated to determine the steroid response of CRSwNP patients. Results The levels of TOS and OSI were significantly higher in CRSwNP and CRSsNP than in normal controls, and OSI in polyps tissues was positively associated with tissue neutrophilia and poor steroid response. The ALDH1A1, MGST1, and SOD2 mRNA levels showed comparable accuracy as predictors of poor steroid response indicated by the area under the curve. Conclusion These findings provided evidence that the increased level of oxidative stress contributes to enhanced tissue neutrophilia and poor steroid response in CRSwNP patients.

This study was carried out in order to explore the effect of ultrasonic treatment at different temperatures (0, 20, 40 and 60 ℃) on the ability of maize starch to form a complex with lipid. Scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), X-ray diffractometry (XRD), laser confocal micro-Raman spectroscopy and were used to characterize the changes in the multilevel structure of maize starch granules before and after treatment, and the mechanism for the change in its lauric acid complexing capacity was analyzed. The results showed that the lipid complexing capacity of maize starch was significantly (P < 0.05) reduced by ultrasonic treatment, and the complexing index decreased from 27.9% to 15.0% with increasing temperature from 0 to 60 ℃; the enthalpy change (ΔH), relative crystallinity, degree of short-range order and relative content of resistant starch declined. Through the multi-level structure analysis, it was found that the molecular chain of the starch was depolymerized by ultrasonic treatment, and ultrasonic treatment at 60 ℃ caused the leaching of amylose from starch granules, thereby damaging their integrity and making the surface rough. In conclusion, ultrasonic treatment at different temperatures can reduce the lipid complexing capacity of starch by changing its multilevel structure.

Abstract Background Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different sex and reproductive status populations. Methods This cross-sectional study included 880 patients (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively, and the following parameters were obtained: liver stiffness measurement (LSM), controlled attenuation parameter (CAP), waist circumference (WC), body mass index (BMI), percent body fat (PBF), visceral fat area (VFA), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat mass (FM), fat free mass (FFM), and FFM to FM ratio (FFM/FM). Multiple ordinal logistic regression (MOLR) was used to analyze the independent correlation between body composition indicators and liver steatosis grade and fibrosis stage in different sex and menopausal status populations. Results Men had higher WC, ASM, ASMI, FFM, and FFM/FM than pre- or post-menopausal women, while pre-menopausal women had higher PBF, VFA, and FM than the other two groups (p

In recent years, the types and quantities of fentanyl analogs have increased rapidly. It has become a hotspot in the illicit drug control field of how to quickly identify novel fentanyl analogs and to shorten the blank regulatory period. At present, the identification methods of fentanyl analogs that have been developed mostly rely on reference materials to target fentanyl analogs or their metabolites with known chemical structures, but these methods face challenges when analyzing new compounds with unknown structures. In recent years, emerging machine learning technology can quickly and automatically extract valuable features from massive data, which provides inspiration for the non-targeted screening of fentanyl analogs. For example, the wide application of instruments like Raman spectroscopy, nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and other instruments can maximize the mining of the characteristic data related to fentanyl analogs in samples. Combining this data with an appropriate machine learning model, researchers may create a variety of high-performance non-targeted fentanyl identification methods. This paper reviews the recent research on the application of machine learning assisted non-targeted screening strategy for the identification of fentanyl analogs, and looks forward to the future development trend in this field.

For improving the friction properties of GH05 superalloy in high temperature and high pressure water environment, Cr/DLC and CrN coatings were prepared on the alloy surface via ion source assisted unbalanced magnetron sputtering and multi - arc ion plating respectively. FGD autoclave was used to conduct the high temperature and high pressure test of the coatings, and scanning electron microscope (SEM) was used to observe the surfaces and cross - sectional morphologies of the coatings. Moreover, a high temperature UMT tribometer and a step height tester were used to study the friction and wear properties of the coatings, and a nanoindenter was employed to measure the hardness and elastic modulus of the two kinds of coatings before and after high temperature and high pressure test. Results showed that the surface morphology and mechanical properties of the CrN coating after high temperature and high pressure test changed slightly in comparison with that before such test. However, the Cr/DLC coating suffered remarkable oxidation. The coating structure became loose, and the bonding force as well as the hardness of the coating significantly decreased. On the other hand, the high temperature and high pressure test led to an increase of the friction coefficient of Cr/DLC and CrN coatings in both dry and water environments, which might be attributed to the oxidation of the coatings’ surfaces and the deterioration of mechanical properties of the coatings. Compared with the sharp decrease of friction properties for the Cr/DLC coating, CrN coating still maintained good friction and wear properties after high temperature and high pressure test. Especially, the wear rate of CrN coating in water environment was only 1.40 × 10-7 mm3/N·m, which was only 1.60% of that of the Cr/DLC coating under the same test condition (i.e., 8.73× 10-6 mm3/N·m). Overall, the CrN coating could greatly improve the service performance of the superalloy under severe working conditions.

TRPM3 belongs to the melastatin sub-family of transient receptor potential (TRPM) cation channels and has been shown to function as a steroid-activated, heat-sensitive calcium ion (Ca2+) channel. A missense substitution (p.I65M) in the TRPM3 gene of humans (TRPM3) and mice (Trpm3) has been shown to underlie an inherited form of early-onset, progressive cataract. Here, we model the pathogenetic effects of this cataract-causing mutation using ‘knock-in’ mutant mice and human cell lines. Trpm3 and its intron-hosted micro-RNA gene (Mir204) were strongly co-expressed in the lens epithelium and other non-pigmented and pigmented ocular epithelia. Homozygous Trpm3-mutant lenses displayed elevated cytosolic Ca2+ levels and an imbalance of sodium (Na+) and potassium (K+) ions coupled with increased water content. Homozygous TRPM3-mutant human lens epithelial (HLE-B3) cell lines and Trpm3-mutant lenses exhibited increased levels of phosphorylated mitogen-activated protein kinase 1/extracellular signal-regulated kinase 2 (MAPK1/ERK2/p42) and MAPK3/ERK1/p44. Mutant TRPM3-M65 channels displayed an increased sensitivity to external Ca2+ concentration and an altered dose response to pregnenolone sulfate (PS) activation. Trpm3-mutant lenses shared the downregulation of genes involved in insulin/peptide secretion and the upregulation of genes involved in Ca2+ dynamics. By contrast, Trpm3-deficient lenses did not replicate the pathophysiological changes observed in Trpm3-mutant lenses. Collectively, our data suggest that a cataract-causing substitution in the TRPM3 cation channel elicits a deleterious gain-of-function rather than a loss-of-function mechanism in the lens.

This study aimed to study the entrapment of Enterococcus faecalis HZNU S1 using a mixture of flaxseed protein isolate (FPI) and sodium alginate (SA) as an encapsulation agent. The characteristics of free and encapsulated cells during storage and under in vitro gastrointestinal conditions were investigated. The survival rate of encapsulated cells did not decline after 2 h exposure to pH 2.5 simulated gastric juice (SGJ), while viable free probiotics treated at the same conditions, were not found. After encapsulated probiotics were exposed to SGJ pH 2.0 for 2.0 h, the viability decreased from 10.01 to 8.01 Log CFU/g. After exposure to 1.0% and 2.0% bile salt solutions for 2 h, the viable amounts of encapsulated probiotics were still higher 8.0 Log CFU/g, whereas, viable free cells were not observed after treatment at the same conditions. Encapsulated probiotics were fully released from the microbeads in simulated intestinal juice (SIJ) in around 4 h. The viable numbers of encapsulated probiotics were only reduced 0.5 Log CFU/g after two weeks of storage (4 °C), and the viable amounts of encapsulated probiotics were reduced to 8.2 Log CFU/g at 25 °C after eight days of storage. However, the viable amounts of free cells were reduced from 10.01 to 8.8 Log CFU/mL (4 °C), and 4.0 Log CFU/mL (25 °C) during the investigated storage period, respectively. Encapsulated E. faecalis HZNU S1 showed enhanced resistance to environmental conditions, allowing the delivery of probiotics that could be used to increase foods added value.

Rhododendron meddianum is a critically endangered species with important ornamental value and is also a plant species with extremely small populations. In this study, we used double digest restriction-site-associated DNA sequencing (ddRAD) technology to assess the genetic diversity, genetic structure and demographic history of the three extant populations of R. meddianum. Analysis of SNPs indicated that R. meddianum populations have a high genetic diversity (π = 0.0772 ± 0.0024, HE = 0.0742 ± 0.002). Both FST values (0.1582–0.2388) and AMOVA showed a moderate genetic differentiation among the R. meddianum populations. Meanwhile, STRUCTURE, PCoA and NJ trees indicated that the R. meddianum samples were clustered into three distinct genetic groups. Using the stairway plot, we found that R. meddianum underwent a population bottleneck about 70,000 years ago. Furthermore, demographic models of R. meddianum and its relative, Rhododendron cyanocarpum, revealed that these species diverged about 3.05 (2.21–5.03) million years ago. This divergence may have been caused by environmental changes that occurred after the late Pliocene, e.g., the Asian winter monsoon intensified, leading to a drier climate. Based on these findings, we recommend that R. meddianum be conserved through in situ, ex situ approaches and that its seeds be collected for germplasm.

Ampelopsis grossedentata (AG) is mainly distributed in Chinese provinces and areas south of the Yangtze River Basin. It is mostly concentrated or scattered in mountainous bushes or woods with high humidity. Approximately 57 chemical components of AG have been identified, including flavonoids, phenols, steroids and terpenoids, volatile components, and other chemical components. In vitro studies have shown that the flavone of AG has therapeutic properties such as anti-bacteria, anti-inflammation, anti-oxidation, enhancing immunity, regulating glucose and lipid metabolism, being hepatoprotective, and being anti-tumor with no toxicity. Through searching and combing the related literature, this paper comprehensively and systematically summarizes the research progress of AG, including morphology, traditional and modern uses, chemical composition and structure, and pharmacological and toxicological effects, with a view to providing references for AG-related research.

Primula filchnerae, an endangered plant endemic to China, has drawn people’s attention in recent years due to its ornamental value in flower. It was rarely recorded since being described in 1902, but it was rediscovered in 2009 and is now known from a limited number of sites located in Hubei and Shaanxi Provinces. Since the species is still poorly known, a number of unanswered questions arise related to it: How has P. filchnerae responded to past climate change and how might it respond in the future? Why was P. filchmerae so rarely collected during the past century? We assembled geographic coordinates for P. filchnerae through the field surveys and website searches, and then used a maximum entropy model (MaxEnt) to simulate its potential suitable distribution in six periods with varied carbon emission levels by combining bioclimatic and environmental factors. MaxEnt showed that Min Temperature of the Coldest Month (bio6) and Precipitation of the Coldest Quarter (bio19) affected P. filchnerae’s distribution most, with an aggregate contribution >60% and suitable ranges above −5 °C and below 40 mm, respectively. We also analyzed potential habitat distribution in various periods with differing impacts of climate change compared to today’s suitable habitats, and in most cases, Shaanxi and Sichuan remained the most stable areas and with possible expansion to the north under various carbon emission scenarios, but the 2050s SSP5-8.5 scenario may be an exception. Moreover, we used MaxEnt to evaluate population shifts, with various scenarios indicating that geometric center would be concentrated in Sichuan Province in China. Finally, conservation strategies are suggested, including the creation of protected areas, long-term monitoring, raising public awareness of plant conservation, situ conservation measures, assisted migration, and species introduction. This study demonstrates how P. filchnerae may have adapted to changes in different periods and provides a scientific basis for germplasm conservation and management.

In recent years, growing interest has been paid to the exploration of the concepts of entropy, heat and information, which are closely related to the symmetry properties of the physical systems in quantum theory. In this paper, we follow this line of research on the the validity of the concepts in quantum field theory by studying Landauer’s principle for a Dirac field interacting perturbatively with an Unruh–DeWitt detector in a 1+1-dimensional MIT bag cavity. When the field is initially prepared in the vacuum state, we find that the field always absorbs heat, while the Unruh–DeWitt detector can either gain or lose entropy, depending on its motion status, as a result of the Unruh effect. When the field is initially prepared in the thermal state and the detector remains still, the heat transfer and entropy change can be obtained under two additional but reasonable approximations: (i) one is where the duration of the interaction is turned on for a sufficiently long period, and (ii) the other is where the Unruh–DeWitt detector is in resonance with one of the field modes. Landauer’s principle is verified for both considered cases. Compared to the results of a real scalar field, we find that the formulas of the vacuum initial state differ solely in the internal degree of freedom of the Dirac field, and the distinguishability of the fermion and anti-fermion comes into play when the initial state of the Dirac field is thermal. We also point out that the results for a massless fermionic field can be obtained by taking the particle mass m→0 straightforwardly.

Extracellular membrane proteins are crucial for mediating cell attachment, recognition, and signal transduction in the testicular microenvironment, particularly germline stem cells. Cadherin 18 (CDH18), a type II classical cadherin, is primarily expressed in the nervous and reproductive systems. Here, we investigated the expression of CDH18 in neonatal porcine prospermatogonia (ProSGs) and murine spermatogonial stem cells (SSCs). Disruption of CDH18 expression did not adversely affect cell morphology, proliferation, self-renewal, or differentiation in cultured porcine ProSGs, but enhanced cell adhesion and prolonged cell maintenance. Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion. To further elucidate the function of CDH18 in germ cells, Cdh18 knockout mice were generated, which exhibited normal testicular morphology, histology, and spermatogenesis. Transcriptomic analysis showed increased expression of genes associated with adhesion, consistent with the observations in porcine ProSGs. The interaction of CDH18 with β-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency. Collectively, these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs. Understanding this regulatory mechanism provides significant insights into the testicular niche. [ABSTRACT FROM AUTHOR]

Abstract. Background:. Many Parkinson disease (PD) patients complain about chronic fatigue and sleep disturbances during the night. The objective of this study is to determine the relationship between fatigue and sleep disturbances by using polysomnography (PSG) in PD patients. Methods:. Two hundred and thirty-two PD patients (152 with mild fatigue and 80 with severe fatigue) were recruited in this study. Demographic information and clinical symptoms were collected. Fatigue severity scale (FSS) was applied to evaluate the severity of fatigue, and PSG was conducted in all PD patients. FSS ≥4 was defined as severe fatigue, and FSS

The materials used in variable temperature conditions are required to have excellent thermal fatigue performance. The effects of laser shock processing (LSP), solid solution and aging treatment (T6), and cryogenic treatment (CT) on both microstructure and thermal fatigue performance of ZCuAl10Fe3Mn2 alloys were studied. Microstructure and crack morphology were then examined by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). The result showed that, after being subjected to the combination treatment of T6+CT+LSP, the optimal mechanical properties and thermal fatigue performance were obtained for the ZCuAl10Fe3Mn2 alloy with the tensile strength, hardness, and elongation of 720 MPa, 300.16 HB, and 16%, respectively, and the thermal fatigue life could reach 7,100 cycles when the crack length was 0.1 mm. Moreover, the ZCuAl10Fe3Mn2 after combination treatment shows high resistance to oxidation, good adhesion between the matrix and grain boundaries, and dramatically reduced growth rate of crack. During thermal fatigue testing, under the combined action of thermal and alternating stresses, the microstructure around the sample notch oxidized and became loose and porous, which then converted to micro-cracks. Fatigue crack expanded along the grain boundary in the early stage. In the later stage, under the cyclic stress accumulation, the oxidized microstructure separated from the matrix, and the fatigue crack expanded in both intergranular and transgranular ways. The main crack was thick, and the path was meandering.

Prostate cancer (PCa) is one of the most common malignancies in Western countries. Studies have shown that androgen contributes to the progression of PCa, but how androgen promotes PCa remains largely unknown. Here, we demonstrated that androgen suppressed the expression of miR-760 depending on the interaction between androgen and androgen receptor (AR). miR-760 was downregulated in prostate cancer tissues compared with normal tissues. Functional experiments showed that miR-760 downregulation promoted the proliferation and growth of LNCaP and 22rv1 cells. In contrast, miR-760 ectopic expression inhibited the proliferation of LNCaP and 22rv1 cells. DNA synthesis was suppressed by miR-760. Mechanistically, miR-760 bound to the 3'UTR of interleukin 6 (IL6 ). A mutation in the binding site disrupted their interaction. In addition, silencing ofIL 6 suppressed the proliferation of LNCaP and 22rv1 cells. IL6 was upregulated in PCa tissues. Our study reveals that androgen downregulates miR-760 to promote the growth of PCa cells by regulating IL6.

Epstein-Barr virus (EBV) tegument proteins BBRF2 and BSRF1 have been suggested to form a hetero-complex. Here, He et al. provide the crystal structures of BBRF2 alone and in complex with BSRF1 and suggest that the complex tethers EBV nucleocapsids to the Golgi membrane, facilitating secondary envelopment.

Objective: To evaluate the efficacy and safety of Morinda officinalis oligosaccharide (MOO) capsules for depressive disorder. Methods: Eight electronic databases were searched for relevant studies from inception to April 19, 2020. Randomized controlled trials comparing MOO capsules with antidepressants were included. Data analysis was conducted using Review Manager 5.3 software. The risk of bias was assessed using the Cochrane Risk of Bias Tool, and the quality of the studies was evaluated by two researchers using the Grading of Recommendation, Assessment, Development and Evaluations (GRADE) software. Results: Seven studies involving 1,384 participants were included in this study. The effect of MOO capsules for moderate depressive disorder was not different from that of antidepressants (risk ratio [RR] = 0.99, 95%CI 0.92-1.06). Regarding adverse events, no significant difference was found between MOO capsules and antidepressants (RR = 0.84, 95%CI 0.65-1.07). In addition, the quality of evidence related to these adverse events was rated as low. Conclusion: This systematic review suggests that the efficacy of MOO capsules in the treatment of mild to moderate depression is not inferior to that of conventional antidepressants, which may provide a new direction for clinical alternative selection of antidepressants. However, more high-quality research and detailed assessments are needed.