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Abstract Neurofibromatosis type 1 (NF1) and schwannomatosis (SWN) are rare genetic disorders with distinct genetic etiologies. Both syndromes are predominantly characterized by the development of multiple benign nerve sheath tumors, which typically arise from cranial/peripheral nerves. The management of NF1/SWN-associated benign nerve sheath tumors pose a substantial clinical challenge. In recent years, immunotherapy has demonstrated significant efficacy in treating various tumors, but its application to NF1/SWN has not been explored. In this study, we first evaluated the feasibility of chimeric antigen receptor (CAR)-T cell therapy for the treatment of benign NF1/SWN-related nerve sheath tumor by analyzing the expression of multiple antigens in 85 tumor samples. Our findings revealed that epidermal growth factor receptor (EGFR/HER1) was highly expressed in most samples, indicating its potential as an ideal target for CAR-T cell therapy. Additionally, TGFβ1 and PDL1, key inhibitory regulators of T cell function within solid tumor microenvironment (TME), were universally overexpressed in these samples, highlighting the immunosuppressive nature of NF1/SWN tumors. To target HER1, we constructed CARs using three distinct scFvs (806, E2 and NEC). All three types of CAR-T cells demonstrated significant tumor-eliminating capability against NF1/SWN tumor cell lines, with 806 CAR-T cells showing the highest efficacy. Considering the immunosuppressive TME, we knocked out TGFBR2 and/or PDCD1 in 806 CAR-T cells using CRISPR/Cas9. Their anti-tumor efficacy was further evaluated using a 3D tumor spheroid model, and the gene-edited 806 CAR-T cells exhibited superior anti-tumor efficacy. In conclusion, we identified HER1 as a target for CAR-T cell therapy in NF1/SWN-related nerve sheath tumors, and developed anti-HER1 CAR-T cells that effectively eliminated NF1/SWN tumor cells, providing a promising therapeutic strategy for patients with these conditions.

Abstract Background With the intensification of aging, depression among the older adults has become a significant global health challenge, especially in developing countries where the problem is particularly severe. This study aims to explore the association between living arrangements and depression, with a specific focus on examining the mediating role of social support in rural northwest China. Methods Data were collected from 501 individuals aged 60 and above in rural Shaanxi Province, northwest China. Living arrangements were assessed based on co-residing family members. Depression was measured using the Geriatric Depression Scale-30, and social support was evaluated with the Social Support Rating Scale. Ordinary Least Squares Regression, Quantile Regression, Generalized Linear Regression, and Ordered Regression analyzed the association between living arrangements and depression. Hierarchical multiple linear regression examined the mediating role of social support. A heterogeneity analysis by gender and socio-economic status was also conducted. Results The depression rates were 51.84% for non-empty nests, 67.92% for individuals living alone, and 46.80% for individuals only living with a spouse. The regression analysis did not reveal a significant difference in depressive between empty nests compared to non-empty nests. However, older adults living alone exhibited a higher susceptibility to depression symptoms (β = 2.594, P

Abstract Background The increasing prevalence of cognitive impairment poses substantial risks to older adults, particularly those with chronic diseases. While existing studies have examined the connection between the empty nest phenomenon and cognitive function, few have attempted to consider endogeneity issues within this relationship, with limited attention given to older adults with chronic diseases. This study investigates the impact of empty nest status on cognitive function among rural Chinese older adults with chronic diseases and explores the possible mechanisms underlying this effect. Methods A cross-sectional study involved 365 older adults aged 60 or above with chronic diseases in rural areas of Shaanxi province, northwest China. Cognitive function was measured using the Mini-Mental State Examination. Multiple regression models and the instrumental variable (IV) method were employed to examine the association between empty nest and cognitive function. Results Among the 365 older adults aged 60 or above with chronic diseases, 43% experienced cognitive impairment. Results from both multiple regression and IV analyses consistently demonstrate a significant association between empty nest status and higher cognitive function scores (β = 1.757, p = 0.007; β = 3.682, p = 0.034, respectively). Mechanism analysis further supports that the positive association may arise from empty nesters receiving more social support from children and friends, and perceiving loneliness experiences as inadequate. Heterogeneity analysis reveals that the association between empty nest status and cognitive function is more pronounced among male adults with chronic diseases. Conclusions This study challenges the notion that empty nest status is a risk factor for cognitive decline in older adults with chronic diseases in rural China. The positive impact is attributed to the robust social relationships of empty nesters, encompassing sustained support from their social network, and the absence of an increase in loneliness. Therefore, future interventions aimed at improving cognitive function in older adults may benefit from promoting the development of social relationships.

Background Chimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous antigen expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable tumor antigen for targeted therapy due to its intestinal-restricted expression pattern in normal tissues and steady overexpression in gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive and long-lasting CAR-T cell targeting GUCY2C was investigated in this study.Methods Using constructed tumor cell lines with various GUCY2C expression densities, we screened out an antigen-sensitive single chain variable fragment (scFv) that enabled CAR-T cells to efficiently eradicate the GUCY2C lowly expressed tumor cells. CAR-T cells with different compositions of the hinge, transmembrane and costimulatory domains were also constructed for selection of the long-lasting CAR-T format with durable antitumor efficacy in vitro and in tumor-bearing mice. The underlying mechanism was further investigated based on mutation of the hinge and transmembrane domains.Results We found that the composition of the antigen-sensitive scFv, CD8α hinge, CD8α transmembrane, and CD28 costimulatory domains boosted CAR-T cells to rapidly kill tumors, maintain high expansion capacity, and long-term efficacy in various colorectal cancer models. The durable antitumor function was attributed to the optimal CAR tonic signaling that conferred CAR-T cells with autonomous activation, proliferation, survival and cytokine release in the absence of antigen stimulation. The tonic signaling was associated with the length and the cysteine residues in the CD8α hinge and transmembrane domains.Conclusions This study demonstrated a potent GUCY2C-targeted CAR-T cell for gastrointestinal tumor therapy and highlights the importance of adequate tonic signaling for effective CAR-T cell therapy against solid tumors.

Abstract Acute brain slices represent a workhorse model for studying the central nervous system (CNS) from nanoscale events to complex circuits. While slice preparation inherently involves tissue damage, it is unclear how microglia, the main immune cells and damage sensors of the CNS react to this injury and shape neuronal activity ex vivo. To this end, we investigated microglial phenotypes and contribution to network organization and functioning in acute brain slices. We reveal time-dependent microglial phenotype changes influenced by complex extracellular ATP dynamics through P2Y12R and CX3CR1 signalling, which is sustained for hours in ex vivo mouse brain slices. Downregulation of P2Y12R and changes of microglia-neuron interactions occur in line with alterations in the number of excitatory and inhibitory synapses over time. Importantly, functional microglia modulate synapse sprouting, while microglial dysfunction results in markedly impaired ripple activity both ex vivo and in vivo. Collectively, our data suggest that microglia are modulators of complex neuronal networks with important roles to maintain neuronal network integrity and activity. We suggest that slice preparation can be used to model time-dependent changes of microglia-neuron interactions to reveal how microglia shape neuronal circuits in physiological and pathological conditions.

Abstract Objectives In middle-income countries, poor physician-patient communication remains a recognized barrier to enhancing healthcare quality and patient satisfaction. This study investigates the influence of provider-patient communication skills on healthcare quality and patient satisfaction in the rural primary healthcare setting in China. Methods Data were collected from 504 interactions across 348 rural primary healthcare facilities spanning 21 counties in three provinces. Using the Standardized Patient method, this study measured physician-patient communication behaviors, healthcare quality, and patient satisfaction. Communication skills were assessed using the SEGUE questionnaire framework. Multivariate linear regression models and multivariate logistic regression models, accounting for fixed effects, were employed to evaluate the impact of physicians’ communication skills on healthcare quality and patient satisfaction. Results The findings indicated generally low provider-patient communication skills, with an average total score of 12.2 ± 2.8 (out of 24). Multivariate regression models, which accounted for physicians’ knowledge and other factors, demonstrated positive associations between physicians’ communication skills and healthcare quality, as well as patient satisfaction (P

Abstract Non-hydraulic root signals (nHRS) are affirmed as a unique positive response to soil drying, and play a crucial role in regulating water use efficiency and yield formation in dryland wheat production. Strigolactones (SLs) can enhance plant drought adaptability. However, the question of whether strigolactones enhance grain yield and water use efficiency by regulating nHRS and antioxidant defense systems in dryland wheat remains unanswered. In this study, pot experiments were conducted to investigate the effects of strigolactones on nHRS, antioxidant defense system, and grain yield and water use efficiency in dryland wheat. The results showed that external application of SLs increased drought-induced abscisic acid (ABA) accumulation and activated an earlier trigger of nHRS at 73.4% field capacity (FC), compared to 68.5% FC in the control group (CK). This phenomenon was mechanically associated with the physiological mediation of SLs. The application of SLs significantly enhanced the activities of leaf antioxidant enzymes, reduced ROS production, and mitigated oxidative damage to lipid membrane. Additionally, root biomass, root length density, and root to shoot ratio were increased under strigolactone treatment. Furthermore, exogenous application of SLs significantly increased grain yield by 34.9% under moderate drought stress. Water use efficiency was also increased by 21.5% and 33.3% under moderate and severe drought conditions respectively, compared to the control group (CK). The results suggested that the application of strigolactones triggered earlier drought-sensing mechanism and improved the antioxidant defense ability, thus enhancing grain yield and water use efficiency in dryland wheat production.

To analyze self-lubricating mechanism of copper-based graphite composites, the discrete element method (DEM) was used to study motion law of graphite particles of copper-based graphite composite/45 steel during friction. The research results show the film-forming particle layer was formed on the composite surface after a period of friction, which maintained dynamic balance depends on continuous supply of graphite in the composite. At different position, the trajectory of graphite particles is different, but the motion tendency of the graphite is the same, that is, the graphite x movement direction is consistent with the sliding direction of 45 steel, the graphite y movement direction is from the inside of the composite to the friction interface, and the motion displacement in y direction is greater than that in x direction. The load and sliding speed have an important influence on the motion law of graphite. Load or speed change the trajectory of graphite particles. However, the load and speed did not change the movement trend of graphite particles, which were consistent with motion trend at different position.

Abstract Smart sensors with excellent performance are accelerating the development of biomedicine and the Internet of Energy. Nanodielectrics exhibit unique electrical and mechanical properties. As the predominant materials in optical magnetic field sensor (MFS), they can not only exert the anti‐interference of optical sensing, but improve the measuring characteristics of optical sensors. For instance, the optical fibre quantum probe for the magnetic field can obtain a higher sensitivity of 0.57 nT/Hz1/2, while the measurement range of the sensor that uses Co‐doped ZnO nanorods as cladding is 17–180 mT. Here, these exciting recent achievements in the realm of optical sensing methods for magnetic field detection are reviewed, with a focus on nanodielectrics, which provide an emerging opportunity to achieve higher sensitivity and a wider measurement range of MFS.

Abstract Background Human papillomavirus (HPV) infection can cause cervical and other cancers, including vulva, vagina, penis, anus, or oropharynx. However, in China's northern Henan Province, data on the prevalence and genotype distribution of HPV among women attending gynecology clinics is limited. This study aimed to investigate the current prevalence and genotype distribution of HPV among women attending gynecology clinics in northern Henan Province. Methods This study included 15,616 women aged 16–81 years old who visited the Xinxiang central hospital's gynecology department between January 2018 and December 2019. HPV DNA was detected by a conventional PCR method followed by HPV type-specific hybridization, which was designed to detect 17 high-risk HPV (HR-HPV) genotypes and 20 low-risk HPV (LR-HPV) genotypes. HPV prevalence and corresponding 95% confidence intervals (95% CI) were calculated using SPSS 18.0. Results The overall HPV prevalence was 19.7% among women in northern Henan Province. Single, double, and multiple HPV infections accounted for 13.7%, 4.3%, and 1.8% of the total cases. Most infections were caused by HR-HPV (71.8%), and single genotype HPV infection (13.7%) was the most common pattern. The most common HR-HPV genotype was HPV16 (4.3%), followed by HPV52 (3.5%) and HPV58 (2.0%). The most common LR-HPV genotype was HPV6 (1.4%), followed by HPV61 (1.1%) and HPV81 (1.1%). Conclusions HPV infection is high among women attending gynecology clinics in northern Henan Province. The highest prevalence was found in women less than 20 years old. In northern Henan Province, the 9-valent HPV vaccine is strongly recommended for regular immunization.

The typical approach to electronics is to integrate sensors, power units, and controlling components on a printed circuit board (PCB). Here, the authors demonstrate a self-powered and fully integrated combination of sensors and controlling components that is woven, rather than integrated onto a PCB, allowing for wearable health monitoring.”

With the rapid advancements in flexible wearable electronics, there is increasing interest in integrated electronic fabric innovations in both academia and industry. However, currently developed plastic board-based batteries remain too rigid and bulky to comfortably accommodate soft wearing surfaces. The integration of fabrics with energy-storage devices offers a sustainable, eco-friendly, and pervasive energy solution for wearable distributed electronics. Fabric-type flexible energy-storage devices are particularly advantageous as they conform well to the curved body surface and the various movements associated with wearing habits such as running. This review presents a comprehensive overview of the advances in flexible fabric-type energy-storage devices for wearable electronics, including their significance, construction methods, structure design, hybrid forms with other energy sources, and the existing challenges and future directions. With worldwide efforts on materials and technologies, we hope that progress in this review will revolutionize our way of life.

Abstract Background Gastrointestinal stromal tumors (GISTs), a type of mesenchymal tumor in the gastrointestinal tract, are believed to be closely associated with PDGFRA and C-KIT mutations. Schwannoma in the stomach, which is an unusual location, is a rare disorder. The simultaneous occurrence of the two diseases is rarer than metachronous occurrences, and its pathological characteristics have not been reported to date. We present a case report on a patient with simultaneous coexistence of gastric schwannoma and GISTs. Case presentation A 39-year-old female visited our hospital complaining of intermittent abdominal pain for the previous 3 months. CT revealed a 3.4 cm slight homogeneous enhancement in the lesser curvature of the stomach; the mass was nodular soft tissue, which was removed by radical surgery. Two solid tumors with different volumes were located in the stomach. Histologically and immunohistochemically different, the larger tumor consisted of spindle cells surrounded by a peripheral lymphoid cuff, and was positive for S-100. The larger tumor was therefore classified as a gastric schwannoma. The smaller tumor was composed of medium-sized round, oval cells with amphiphilic granular cytoplasm; vacuolization was also observed. The tumor cells were positive for DOG1 and sporadically positive for CD34 and CD117. Hence, the smaller tumor was diagnosed as epithelioid GISTs. Sanger sequencing revealed that the GIST tumor cells contained a deletion mutation (c.2527_2538 del12,843–846del4), which was located in exon 18 of PDGFRA. Conclusion GISTs combined with gastric schwannoma are a considerably rare subgroup of gastric tumors. Related clinical research is comparatively weak, and the mechanism remains unknown. We reviewed related articles to provide knowledge to improve the correct identification, diagnosis and management of patients with gastric cancer. All pathologists involved in the diagnosis and clinicians involved in the treatment should be aware of this new kind of disease pattern to improve their understanding of the disease.

Objective:To observe the effect of simple reaction speed training on executive function of the elderly with mild cognitive impairment (MCI).Methods:A total of 64 elderly with MCI were selected by convenient sampling method from Xindu district of Chengdu City from January 2016 to June 2018, which were randomly divided into the control group and the observation group, with 32 cases in each group. The control group only received MCI health education, once every two weeks, continuous intervention for three months. The observation group received simple reaction speed training on the basis of the control group.④Decomposition training: walking on flat ground decomposition training, going up and down stairs decomposition training, crossing obstacles decomposition training, 10 times a group, two groups a day.④Complete training: walking on flat ground complete training, going up and down stairs complete training, 10 times a group, one group a day; crossing obstacles complete training, five times a group, one group a day.④Change training: according to the instruction of command or signal light, the subject makes corresponding actions or actions contrary to the instruction, three times a group, one group a day.④Sense of movement training: single training of walking on flat ground training, going up and down stairs training and crossing obstacles training, three times a group, one group a day. Each training time was 30-40 min, once a day, five times a week, continuous intervention for three months. The behavior rating inventory of executive function-adult version[BRIEF-A, including behavior regulation index (BRI), metacognitive index (MI)], behavioral assessment of dysexecutive syndrome[BADS, including rule switching card test (RSCT), action plan test (APT), key seek test (KST), time judgment test (TJT), zoo map test (ZMT), modified six-element test (MSET) ]and trail making test (TMT, including TMT-A and TMT-B) were used to evaluate the executive function of patients with MCI before and after intervention, respectively. Moreover, the serum brain-derived neurotrophic factor in the blood before and after intervention was detected by using enzyme linked immunosorbent assay (ELISA), respectively.Results:Compared with before intervention, the scores of conversion, working memory, planning, task monitoring, MI, total standard scores, TMT-B and interference in the observation group after intervention for three months were significantly lower, KST, TJT, ZMT, total standard scores and level of serum BDNF of the observation group after intervention were significantly higher (P< 0.05); compared with the control group, the scores of conversion, task initiation, working memory, planning, BRI, MI, total standard scores, TMT-B and interferences of the observation group were significantly lower, and RSCT, KST, TJT, ZMT, total standard scores and level of serum brain-derived neurotrophic factor (BDNF) of the observation group were significantly high (P< 0.05).Conclusion:Simple reaction speed training can improve the executive function, brain nerve function, and effectively delay cognitive decline of elderly with MCI.

Chimeric antigen receptor T (CAR-T) cell therapy has been applied successfully in treating hematologic malignancies; however, it shows very limited efficacy in treating solid tumors. Adenosine is one of the key immunosuppressive metabolites in tumor microenvironment (TME) of solid tumors. Although the effect of adenosine has been well studied using mouse CAR-T cells, its effect on human CAR-T cells has not been fully elucidated. In particular, there was no evaluation of the CAR-T cells with blocked adenosine signaling in tumor xenograft animal model, which is essential for determining the feasibility of future clinical trials. In this study, we found the expression of A2a receptor (A2AR) and A2b receptor (A2BR) both upregulated in human-derived CAR-T cells, and only A2AR was responsible for adenosine-induced impairment of CAR-T cell function. Disrupting A2AR gene in human CAR-T cells with CRISPR-Cas9 increased the anti-tumor function and prevented the exhaustion of CAR-T cells in vitro. Furthermore, CRL5826-CDX model and two patient-derived xenograft solid tumor models were applied to evaluate the efficacy of A2AR knock-out CAR-T cells, which showed superior capability of inhibiting tumor growth. Taken together, these results demonstrate that A2AR knock-out CAR-T cells have the potential of being an improved CAR-T cell therapy in treating solid tumors.

Bisphenol-A (BPA), a widely used synthetic compound in plastics, disrupts endocrine function and interferes with physiological actions of endogenous gonadal hormones. Chronic effects of BPA on reproductive function, learning and memory, brain structure, and social behavior have been intensively investigated. However, less is known about the influence of BPA on long-term potentiation (LTP), one of the major cellular mechanisms that underlie learning and memory. In the present study, for the first time we investigated the effect of different doses of BPA on hippocampal LTP in rat brain slices. We found a biphasic effect of BPA on LTP in the dentate gyrus: exposure to BPA at a low dose (100 nM) enhanced LTP and exposure to BPA at a high dose (1000 nM) inhibited LTP compared with vehicle controls. The rapid facilitatory effect of low-dose BPA on hippocampal LTP required membrane-associated estrogen receptor (ER) and involved activation of the extracellular signal-regulated kinase (ERK) signaling pathway. Coadministration of 17β-estradiol (E2, the primary estrogen hormone) and BPA (100 nM) abolished both the BPA-induced enhancement of LTP and the E2-induced enhancement of baseline fEPSP, suggesting a complex interaction between BPA- and E2-mediated signaling pathways. Our investigation implies that even nanomolar levels of endocrine disrupters (e.g., BPA) can induce significant effects on hippocampal LTP.

BACKGROUND: Currently, a constant shortage in the supply of platelets has become an important medical and society challenge, especially in developing country, and the in vitro production of megakaryocytic progenitor cells (MPs) from cord blood could represent an effective platelet substitute. In the present study, our objective was to determine the safety and feasibility of ex vivo generated MPs in patients. METHODS AND FINDINGS: MPs were produced and characterized from cord blood mononuclear cells under a serum free medium with cytokines. We investigated the feasibility of expansion and infusion of cord blood-derived MPs in 24 patients with advanced hematological malignancies. The primary end point was the safety and tolerability of the infusion of cord blood-derived MPs. No adverse effects were observed in patients who received ex vivo-generated cells at concentrations of up to a median value of 5.45 × 10(6)cells/kg of body weight. With one year follow-up, acute and chronic GVHD had not been observed among patients who received MPs infusion, even without ABO blood group and HLA typing matching. CONCLUSIONS: These initial results in patients are very encouraging. They suggest that infusion of cord blood-derived MPs appears safe and feasible for treatment of thrombocytopenia.

Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimer's disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3-to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brain's endogenous γ-oscillations through enhancing the function of PV+INs. [ABSTRACT FROM AUTHOR]

Subcortical white matter stroke (WMS) is a progressive disorder which is demarcated by the formation of small ischemic lesions along white matter tracts in the CNS. As lesions accumulate, patients begin to experience severe motor and cognitive decline. Despite its high rate of incidence in the human population, our understanding of the cause and outcome of WMS is extremely limited. As such, viable therapies for WMS remain to be seen. This study characterizes myelin recovery following stroke and motor learning-based rehabilitation in a mouse model of subcortical WMS. Following WMS, a transient increase in differentiating oligodendrocytes occurs within the peri-infarct in young male adult mice, which is completely abolished in male aged mice. Compound action potential recording demonstrates a decrease in conduction velocity of myelinated axons at the peri-infarct. Animals were then tested on one of three distinct motor learning-based rehabilitation strategies (skilled reach, restricted access to a complex running wheel, and unrestricted access to a complex running wheel) for their capacity to induce repair. These studies determined that unrestricted access to a complex running wheel alone increases the density of differentiating oligodendrocytes in infarcted white matter in young adult male mice, which is abolished in aged male mice. Unrestricted access to a complex running wheel was also able to enhance conduction velocity of myelinated axons at the peri-infarct to a speed comparable to naive controls suggesting functional recovery. However, there was no evidence of motor rehabilitation-induced remyelination or myelin protection. [ABSTRACT FROM AUTHOR]

In this paper, we propose a multi-stage HIV infection model with general incidence rate to describe the influence of raltegravir intensification on viral dynamics. The basic reproduction number R0 is established. The infection-free equilibrium E0 is locally asymptotically stable if R0 < 1. The infection equilibrium E* is locally asymptotically stable if R0 > 1. [ABSTRACT FROM AUTHOR]