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Articular cartilage defect therapy is still dissatisfactory in clinic. Direct cell implantation faces challenges, such as tumorigenicity, immunogenicity, and uncontrollability. Extracellular vesicles (EVs) based cell-free therapy becomes a promising alternative approach for cartilage regeneration. Even though, EVs from different cells exhibit heterogeneous characteristics and effects. The aim of the study was to discover the functions of EVs from the cells during chondrogenesis timeline on cartilage regeneration. Here, bone marrow mesenchymal stem cells (BMSCs)-EVs, juvenile chondrocytes-EVs, and adult chondrocytes-EVs were used to represent the EVs at different differentiation stages, and fibroblast-EVs as surrounding signals were also joined to compare. Fibroblasts-EVs showed the worst effect on chondrogenesis. While juvenile chondrocyte-EVs and adult chondrocyte-EVs showed comparable effect on chondrogenic differentiation as BMSCs-EVs, BMSCs-EVs showed the best effect on cell proliferation and migration. Moreover, the amount of EVs secreted from BMSCs were much more than that from chondrocytes. An injectable decellularized extracellular matrix (dECM) hydrogel from small intestinal submucosa (SIS) was fabricated as the EVs delivery platform with natural matrix microenvironment. In a rat model, BMSCs-EVs loaded SIS hydrogel was injected into the articular cartilage defects and significantly enhanced cartilage regeneration in vivo. Furthermore, protein proteomics revealed BMSCs-EVs specifically upregulated multiple metabolic and biosynthetic processes, which might be the potential mechanism. Thus, injectable SIS hydrogel loaded with BMSCs-EVs might be a promising therapeutic way for articular cartilage defect. [ABSTRACT FROM AUTHOR]

Implementing the rural revitalization strategy is crucial for ensuring and enhancing the livelihoods of the vast rural population. The upgrading of rural consumption reflects the gradual realization of rural residents' pursuit of a better life, and the rapid development of digital inclusive finance provides strong support for this. Based on the Digital Inclusive Finance Index released by Peking University and panel data from 30 provinces across the country, this study examines the role of digital inclusive finance in optimizing rural consumption structure through the mediation effect model and analyzes its spatial spillover effects using the spatial Durbin model. The research shows that narrowing the development gap in digital inclusive finance is crucial for upgrading the rural consumption structure, which helps to promote rural residents' transition to higher-level consumption. Through the analysis of the spatial Durbin model, this study finds spatial spillover effects in this process, meaning that financial development in a particular region promotes local development but inhibits development in neighboring areas. Among various dimensions, the impact of breadth of coverage is the most significant. This trend of financial development affects consumption structure by increasing agricultural productivity and rural residents' operational income, particularly highlighting its impact on operational income. However, there are significant differences between the eastern and central-western regions in optimizing rural consumption structure, with the eastern region benefiting more while the effects in the central-western region are limited and sometimes even negative. Therefore, regional characteristics should be fully considered in policy formulation to narrow the development gap in digital inclusive finance and achieve high-quality and sustainable development. [ABSTRACT FROM AUTHOR]

Background: BMPR1A‐mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene. Objective: This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC. Methods: Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next‐generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line. Results: A novel nonsense variant (c.1114A > T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense‐mediated mRNA decay. Read‐through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway. Conclusion: The identification of the novel BMPR1A variant enriched the genotype–phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC‐targeting therapy for BMPR1A‐mediated JPS and CRC. [ABSTRACT FROM AUTHOR]

Background: The perfect repair of damaged skin has always been a constant goal for scientists; however, the repair and reconstruction of skin is still a major problem and challenge in injury and burns medicine. Human amniotic membrane (hAM), with its good mechanical properties and anti‐inflammatory, antioxidant and antimicrobial benefits, containing growth factors that promote wound healing, has evolved over the last few decades from simple skin sheets to high‐tech dressings, such as being made into nanocomposites, hydrogels, powders, and electrostatically spun scaffolds. This paper aims to explore the historical development, applications, trends, and research hotspots of hAM in wound healing. Methods: We examined 2660 publications indexed in the Web of Science Core Collection (WoSCC) from January 1, 1975 to July 12, 2023. Utilizing bibliometric methods, we employed VOSviewer, CiteSpace, and R‐bibliometrix to characterize general information, identify development trends, and highlight research hotspots. Subsequently, we identified a collection of high‐quality English articles focusing on the roles of human amniotic epithelial stem cells (hAESCs), human amniotic mesenchymal stem cells (hAMSCs), and amniotic membrane (AM) scaffolds in regenerative medicine and tissue engineering. Results: Bibliometric analysis identified Udice–French Research Universities as the most productive affiliation and Tseng S.C.G. as the most prolific author. Keyword analysis, historical direct quotations network, and thematic analysis helped us review the historical and major themes in this field. Our examination included the knowledge structure, global status, trends, and research hotspots regarding the application of hAM in wound healing. Our findings indicate that contemporary research emphasizes the preparation and application of products derived from hAM. Notably, both hAM and the cells isolated from it – hADSCs and hAESCs are prominent and promising areas of research in regenerative medicine and tissue engineering. Conclusion: This research delivers a comprehensive understanding of the knowledge frameworks, global dynamics, emerging patterns, and primary research foci in the realm of hAM applications for wound healing. The field is rapidly evolving, and our findings offer valuable insights for researchers. Future research outcomes are anticipated to be applied in clinical practice, enhancing methods for disease prevention, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Context: The human TSPY1 (testis-specific protein, Y-linked 1) gene is critical for spermatogenesis and male fertility. However, there have been difficulties with studying the mechanism underlying its function, partly due to the presence of the Tspy1 pseudogene in mice. Aims: TSPYL5 (TSPY-like 5), an autosomal homologous gene of TSPY1 showing a similar expression pattern in both human and mouse testes, is also speculated to play a role in male spermatogenesis. It is beneficial to understand the role of TSPY1 in spermatogenesis by investigating Tspyl5 functions. Methods: Tspyl5 -knockout mice were generated to investigate the effect of TSPYL5 knockout on spermatogenesis. Key results: Tspyl5 deficiency caused a decline in fertility and decreased the numbers of spermatogonia and spermatozoa in aged male mice. Trancriptomic detection of spermatogonia derived from aged Tspyl5 -knockout mice revealed that the Pcna -mediated DNA replication pathway was downregulated. Furthermore, Tspyl5 was proven to facilitate spermatogonia proliferation and upregulate Pcna expression by promoting the ubiquitination-degradation of the TRP53 protein. Conclusions: Our findings suggest that Tspyl5 is a positive regulator for the maintenance of the spermatogonia pool by enhancing Pcna -mediated DNA replication. Implications: This observation provides an important clue for further investigation of the spermatogenesis-related function of TSPY1. The mammalian Y chromosome is crucial for spermatogenesis, in addition to controlling male sex determination. In order to elucidate the specific role of the TSPY1 gene in spermatogenesis, we used CRISPR/Cas9 technology to generate Tspyl5 -deficient mice (TSPY1 homologous gene). Tspyl5 -deficient mice showed significant decreases in sperm count and fertility. This important discovery suggests these genes are crucial for male reproduction. [ABSTRACT FROM AUTHOR]

NR0B1 is frequently activated in hepatocellular carcinoma (HCC). However, the role of NR0B1 is controversial in HCC. In this study, we observed that NR0B1 was an independent poor prognostic factor, negatively correlated with the overall survival of HCC and the relapse‐free survival of patients treated with sorafenib. Meanwhile, NR0B1 promoted the proliferation, migration, and invasion of HCC cells, inhibited sorafenib‐induced apoptosis, and elevated the IC50 of sorafenib in HCC cells. NR0B1 was further displayed to increase sorafenib‐induced autophagic vesicles and activate Beclin1/LC3‐II‐dependent autophagy pathway. Finally, NR0B1 was revealed to transcriptionally suppress GSK3β that restrains AMPK/mTOR‐driven autophagy and increases BAX‐mediated apoptosis. Collectively, our study uncovered that the ectopic expression of NR0B1 augmented sorafenib‐resistance in HCC cells by activating autophagy and inhibiting apoptosis. Our findings supported that NR0B1 was a detrimental factor for HCC prognosis. [ABSTRACT FROM AUTHOR]

Objective: The precise intervention of K‐Cl cotransporter isoform 2 (KCC2) as a promising target for drug‐resistant epilepsy remains elusive. Methods: Here, we used a CRISPRa system delivered by adeno‐associated viruses to specifically upregulate KCC2 in the subiculum to confirm its therapeutic potential in various in vivo epilepsy models. Calcium fiber photometry was used to reveal the role of KCC2 in the restoration of impaired GABAergic inhibition. Results: CRISPRa system effectively upregulated KCC2 expression both in in vitro cell culture and in vivo brain region. Delivery of CRISPRa with adeno‐associated viruses resulted in upregulating the subicular KCC2 level, contributing to alleviating the severity of hippocampal seizure and facilitating the anti‐seizure effect of diazepam in a hippocampal kindling model. In a kainic acid‐induced epilepticus status model, KCC2 upregulation greatly increased the termination percentage of diazepam‐resistant epilepticus status with the broadened therapeutic window. More importantly, KCC2 upregulation attenuated valproate‐resistant spontaneous seizure in a kainic acid‐induced chronic epilepsy model. Finally, calcium fiber photometry showed CRISPRa‐mediated KCC2 upregulation partially restored the impaired GABAA‐mediated inhibition in epilepsy. Interpretation: These results showed the translational potential of adeno‐associated viruses‐mediated delivery of CRISPRa for treating neurological disorders by modulating abnormal gene expression that is directly associated with neuronal excitability, validating KCC2 as a promising therapeutic target for treating drug‐resistant epilepsy. ANN NEUROL 2023;94:91–105 [ABSTRACT FROM AUTHOR]

Individual chemotherapeutic drugs usually suffered drug resistance in the cancer treatment, and the combination therapy has aroused great interest which can reduce the resistance. Glutamine inhibitor (V9302) and chemotherapy drug doxorubicin (DOX) were combined for the first time to construct a pH‐sensitive multi‐mode synergistic treatment system BSA@CDs‐V9302/DOX. The synergistic rate CI value of the drugs was less than 1, indicating the combination therapy showed a synergistic effect on reducing cancerous cell viability. In addition, compared with the high toxicity and rapid release of free drug DOX and the poor solubility of glutamine inhibitor V9302, the BSA@CDs‐V9302/DOX administration system not only retains the pharmacological activity of V9302 and DOX, but also has an excellent time‐dependence which is more suitable for continuous treatment. BSA@CDs‐V9302/DOX drug delivery system has excellent long‐term tracing ability, which has a high application value in biomedical field. [ABSTRACT FROM AUTHOR]

This study aims to determine the serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and phosphorylated neurofilament heavy chain (pNFH) in amyotrophic lateral sclerosis (ALS) patients, and to explore their feasibility as valid biomarkers for quantifying disease progression and predicting individual prognosis. 52 patients with ALS and 30 controls with noninflammatory neurological diseases were included. NFL and pNFH levels in serum and CSF were measured by enzyme‐linked immunosorbent assay. Our findings showed that serum and CSF levels of NFL and pNFH in ALS patients were significantly increased. These values were negatively correlated with disease duration (except CSF NFL with disease duration) and ALSFRS‐r score, and positively correlated with disease progression rate (DPR) and upper motor neuron (UMN) score, but did not correlate with bilateral median and ulnar nerve compound muscle action potential (cMAP) amplitudes (except a weak correlation between CSF NFL and cMAP amplitudes). The optimal cut‐off values with high sensitivity and specificity were obtained in ROC curve analysis to discriminate ALS from controls. Kaplan‐Meier survival curves illustrated that survival was significantly shorter for patients with higher neurofilament levels at diagnosis. The Cox proportional hazards regressions confirmed that NFL and pNFH were significant predictors of survival. Overall, NFL and pNFH in serum and CSF can be used as reliable biomarkers in ALS. [ABSTRACT FROM AUTHOR]

• Dominant-acting heterozygous missense mutations in SLC12A6 can cause Charcot–Marie–Tooth disease with a milder clinical presentation than HMSN/ACC. • Causative mutation identification and co-segregation analyses were conducted in different inheritance models. • A structure model of the mutated protein based on homology modeling was generated, demonstrating damaged stability of the protein via modification of the number of H-bonds. • Our study is the first report of a dominant-acting heterozygous mutation in SLC12A6 in Chinese CMT patients. • A wider clinical spectrum is associated with SLC12A6 mutations. Charcot-Marie-Tooth disease (CMT) represents a phenotypically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been reported as the cause of autosomal-recessive (AR) hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). Here we identified an autosomal-dominant (AD) heterozygous mutation in SLC12A6 in a Chinese patient with intermediate CMT. The patient presented with slowly progressive distal muscle weakness and atrophy. Electrophysiological examination showed a mixed axonal/demyelinating neuropathy. Cognition and brain MRI were normal. A single heterozygous missense mutation c.620G> A (p.R207H) in exon 5 of SLC12A6 was identified as the likely pathogenic mutation by whole-exome sequencing consistent with two previously published cases. It affects evolutionarily highly conserved amino acid residue and is predicted to be deleterious by using in silico tools. Modelling of the mutant KCC3 cotransporter showed altered formation of hydrogen bonds and weakened interaction force between the mutated site and its surrounding amino acid residues. Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 mutations from AR-HMSN/ACC to AD-CMT. The differences in the inheritance pattern might be associated with a dominant-negative pathomechanism. [ABSTRACT FROM AUTHOR]

In this paper, we model topology control through transmission switching as a recourse action in the day-ahead operation of power systems with large-scale renewable generation resources. We prove that transmission switching could only reduce the linear objective value of direct current optimal power flow when congestion exists. However, we also show, through a simple example, that unit commitment cost could be reduced by transmission switching even in the absence of congestion. To solve the stochastic unit commitment with topology control within reasonable computational time, we proposed a heuristic that first decomposes a practical system into zones and then solves the problem for each zone in parallel. The benefit of topology control recourse is demonstrated on a network representing the Central European System. We compare the costs of the network with different loading and renewable generation conditions. The cost reduction of the test system can reach 3.34% with heavy load and large-scale renewable generation while in a single zone the cost reduction can be above 7%. [ABSTRACT FROM PUBLISHER]

For the cultural heritage gardens in the urban environment, modern high-rise buildings inevitably change their original landscape and form a new landscape experience with visual impact. Whether cultural heritage gardens and modern cities can coexist harmoniously is one of the critical issues to achieve their sustainable development. This research aimed to find an indicator of landscape morphology, which can predict the visitor's cognition for such cultural landscape forms. This study surveyed tourists' preferences in six selected cultural heritage gardens in Tokyo. We used hemispheric panoramas to calculate the view factors of certain elements of the landscape at the observation points. The results showed that Sky View Factor was a positive predictor of tourists' preference, and this predictability did not change significantly with the attributes of tourists. We also found that tourists' attitudes towards the high-rise buildings outside the gardens have become more tolerant and diverse. These findings could be applied to predict visitors' perception preference of cultural heritage landscape in the context of urban renewal, contributing to the sustainable development of cultural heritage landscape and urbanization. [ABSTRACT FROM AUTHOR]

In recent years, research on landscape perception has been generally overoptimistic about the use of virtual reality (VR); however, few have questioned the validity of VR. It is necessary to examine whether on-site stimulation can be substituted by VR. The purpose of this study was to assess the degree of agreement between on-site survey and VR for landscape perception. The sample included 11 representative landscapes from Tsuchiura city and Tsukuba city, Japan. On-site survey data was collected for 17 items related to aesthetic preference and landscape cognition. The same scenes were produced by VR and same survey data as on-site was collected. The agreement of both the overall mean of all landscapes and the ratings of all individuals in each landscape confirmed the high level of concordance of most cognitive attributes between the two stimuli. The findings support immersive VR as a reliable tool for assessing landscape cognition. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Competitive antagonists (CAs) of ionotropic GABA receptors (GABARs) reportedly exhibit insecticidal activity and have potential for development as novel insecticides for overcoming emerging resistance to traditional GABAR-targeting insecticides. Our previous studies demonstrated that 4,5-disubstituted 3-isoxazolols or 3-isothiazolols are an important class of insect GABAR CAs. In the present study, we synthesized a series of 4-aryl-5-carbamoyl-3-isoxazolols and examined their antagonism of insect GABARs expressed in Xenopus oocytes. Several of these 3-isoxazolols exhibited potent antagonistic activities against housefly and common cutworm GABARs, with IC 50 values in the low-micromolar range in both receptors. 4-(3-Amino-4-methylphenyl)-5-carbamoyl-3-isoxazolol (3u) displayed the highest antagonism, with IC 50 values of 2.0 and 0.9 μM in housefly and common cutworm GABARs, respectively. Most of the synthesized 3-isoxazolols showed moderate larvicidal activities against common cutworms, with more than 50% mortality at 100 μg/g. These results indicate that 4-monocyclic aryl-5-carbamoyl-3-isoxazolol is a promising scaffold for insect GABAR CA discovery and provide important information for the design and development of GABAR-targeting insecticides with a novel mode of action. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship., Methods: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes., Results: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits., Conclusion: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Wang, Yi, Xie, Zhang, Tao, Liu and Yang.)

Predatory hunting is an innate appetite-driven and evolutionarily conserved behavior essential for animal survival, integrating sequential behaviors including searching, pursuit, attack, retrieval, and ultimately consumption. Nevertheless, neural circuits underlying hunting behavior with different features remain largely unexplored. Here, we deciphered a novel function of lateral hypothalamus (LH) calcium/calmodulin-dependent protein kinase II α (CaMKII α + ) neurons in hunting behavior and uncovered upstream/downstream circuit basis. LH CaMKII α + neurons bidirectionally modulate novelty-seeking behavior, predatory attack, and eating in hunting behavior. LH CaMKII α + neurons integrate hunting-related novelty-seeking information from the medial preoptic area (MPOA) and project to the ventral periaqueductal gray (vPAG) to promote predatory eating. Our results demonstrate that LH CaMKII α + neurons are the key hub that integrate MPOA-conveyed novelty-seeking signals and encode predatory eating in hunting behavior, which enriched the neuronal substrate of hunting behavior., Competing Interests: All authors declare that they have no competing interests., (Copyright © 2022 Na Tan et al.)

Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal limb weakness, elevated creatine kinase (CK) levels, and myofiber necrosis without or with only a small amount of inflammatory cell infiltrate. There is only 1 report of hypothyroidism combined with antibody-negative IMNM to date. We aimed to describe a rare case of hypothyroidism combined with anti-signal recognition particle (SRP) IMNM for the first time and review the previous literature. A 50-year-old male, who had a 4-year history of hypothyroidism treated with levothyroxine replacement therapy, presented with progressive symmetrical proximal muscle weakness. Laboratory testing showed an elevated CK level of 6,106 U/L. Electrophysiological examination elicited carpal tunnel syndrome and myogenic damage. Muscle MRI revealed diffuse abnormal signals in both lower limbs. Given that muscle symptoms are widely recognized among hypothyroid patients, hypothyroid myopathy was initially suspected, and thyroid hormone tablets were added for a week. However, muscle weakness persisted along with an even higher CK (7,020 U/L). Quadriceps muscle biopsy was performed and indicated inflammatory myopathy. Myositis specific antibodies (MSAs) detection revealed that anti-SRP was positive. A diagnosis of hypothyroidism combined with anti-SRP IMNM was finally made. Treatment of corticosteroid and immunosuppressive agents achieved a positive clinical and biochemical response. This case indicates that hypothyroidism combined with anti-SRP IMNM is a rare clinical entity, possibly caused by a general immunologic dysregulation.