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Abstract Among the many far-reaching consequences of the potential existence of a magnetic monopole, it induces a topological zero mode in the Dirac equation, which was derived by Jackiw and Rebbi 48 years ago and has been elusive ever since. Here, we show that the monopole and multi-monopole solutions can be constructed in the band theory by gapping the three-dimensional Dirac points in hedgehog mass configurations. We then experimentally demonstrate such a monopole bound state in an optimized Dirac acoustic crystal structurally modulated in full solid angles. The monopole mode exhibits the optimal scaling behavior — whose modal spacing is inversely proportional to the cubic root of the modal volume. This work completes the kink-vortex-monopole zero-mode trilogy and paves the way for exploring higher-dimensional bulk-topological-defect correspondence.

Abstract Cancer-associated fibroblasts (CAFs), integral components of the tumor microenvironment, play a pivotal role in tumor proliferation, metastasis, and clinical outcomes. However, its specific roles in Kidney Renal Clear Cell Carcinoma (KIRC) remain poorly understood. Employing the established Seurat single-cell analysis pipeline, we identified 21 CAFs marker genes. Subsequently, a prognostic signature consisting of 6 CAFs marker genes (RGS5, PGF, TPM2, GJA4, SEPT4, and PLXDC1) was developed in a cohort through univariate and LASSO Cox regression analyses. The model’s efficacy was then validated in an external cohort, with a remarkable predictive performance in 1-, 3-, and 5-year. Patients in the high-risk group exhibited significantly inferior survival outcomes (p

Background/Aims Metabolic dysfunction-associated steatohepatitis (MASH) is an unmet clinical challenge due to the rapid increased occurrence but lacking approved drugs. Autophagy-related protein 16-like 1 (ATG16L1) plays an important role in the process of autophagy, which is indispensable for proper biogenesis of the autophagosome, but its role in modulating macrophage-related inflammation and metabolism during MASH has not been documented. Here, we aimed to elucidate the role of ATG16L1 in the progression of MASH. Methods Expression analysis was performed with liver samples from human and mice. MASH models were induced in myeloid-specific Atg16l1-deficient and myeloid-specific Atg16l1-overexpressed mice by high-fat and high-cholesterol diet or methionine- and choline-deficient diet to explore the function and mechanism of macrophage ATG16L1 in MASH. Results Macrophage-specific Atg16l1 knockout exacerbated MASH and inhibited energy expenditure, whereas macrophage-specific Atg16l1 transgenic overexpression attenuated MASH and promotes energy expenditure. Mechanistically, Atg16l1 knockout inhibited macrophage lipophagy, thereby suppressing macrophage β-oxidation and decreasing the production of 4-hydroxynonenal, which further inhibited stimulator of interferon genes(STING) carbonylation. STING palmitoylation was enhanced, STING trafficking from the endoplasmic reticulum to the Golgi was promoted, and downstream STING signaling was activated, promoting proinflammatory and profibrotic cytokines secretion, resulting in hepatic steatosis and hepatic stellate cells activation. Moreover, Atg16l1-deficiency enhanced macrophage phagosome ability but inhibited lysosome formation, engulfing mtDNA released by pyroptotic hepatocytes. Increased mtDNA promoted cGAS/STING signaling activation. Moreover, pharmacological promotion of ATG16L1 substantially blocked MASH progression. Conclusions ATG16L1 suppresses MASH progression by maintaining macrophage lipophagy, restraining liver inflammation, and may be a promising therapeutic target for MASH management.

Aspergillus niger is an efficient cell factory for organic acids production, particularly l-malic acid, through genetic manipulation. However, the traditional method of collecting A. niger spores for inoculation is labor-intensive and resource-consuming. In our study, we used the CRISPR-Cas9 system to replace the promoter of brlA, a key gene in Aspergillus conidiation, with a xylose-inducible promoter xylP in l-malic acid-producing A. niger strain RG0095, generating strain brlAxylP. When induced with xylose in submerged liquid culture, brlAxylP exhibited significant upregulation of conidiation-related genes. This induction allowed us to easily collect an abundance of brlAxylP spores (>7.1 × 106/mL) in liquid xylose medium. Significantly, the submerged conidiation approach preserves the substantial potential of A. niger as a foundational cellular platform for the biosynthesis of organic acids, including but not limited to l-malic acid. In summary, our study offers a simplified submerged conidiation strategy to streamline the preparation stage and reduce labor and material costs for industrial organic acid production using Aspergillus species.

This paper proposes an improved analysis method based on the theory of structural vulnerability, which incorporates structural redundancy and comprehensively analyzes structural vulnerability and robustness by considering the changes in structural stiffness and redundancy after damage to structural members under conventional loading. The improved method takes into account the changes in the strain energy of the structure after the damage of the structural members, which can be more in line with the actual situation of continuity collapse, and solves the complex process of traditional structural vulnerability theory that requires clustering and unclustering, greatly reducing the workload as well as solving the problem of not being able to find the critical members of the structure. The improved method is used to analyze the vulnerability of a 5-story dropped-story steel frame structure, to find the critical members of the structure based on the test data simulated by ABAQUS, to evaluate the robustness, and to propose improvement measures. The results show that the improved vulnerability assessment method is more reasonable and effective and can be applied to different steel frame structures.

Cancer, including gastric cancer, has become a serious disease that jeopardizes public life. Currently, the main treatment methods are surgery, radiation therapy, and chemotherapy. One of the primary causes of death for patients with gastric cancer is drug resistance. Several mechanisms of anticancer drugs resistance have been reported, including changes in drugs transport and metabolism, mutations in drug targets, changes in DNA repair systems, inhibition of cell apoptosis and autophagy, gastric cancer stem cells, invasion and migration. It is becoming more widely known that non-coding RNAs, like circRNAs, play a critical role in the resistance of drugs used to treat gastric cancer. CircRNAs have a unique structure and function that is related to gastric cancer resistance, cell proliferation, apoptosis, autophagy, DNA repair systems, migration, and invasion. A clear understanding of the molecular mechanism of circRNAs mediated the resistance of gastric cancer drugs will open a new window for the treatment and management of gastric cancer. Therefore, in this review, we will summarize the current mechanism of drug resistance, and finally discuss the molecular mechanism of circRNAs in regulating the development of drug resistance in gastric cancer.

Objective Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis.Design In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients.Results Our findings highlight the pivotal role of POSTN+ CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN+ CAFs and SPP1+ macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN+ CAFs and SPP1+ macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN+ CAFs and SPP1+ macrophages achieved less therapeutic benefit in an immunotherapy cohort.Conclusion Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.

Copper is a microelement with important physiological functions in the body. However, the excess copper ion (Cu2+) may cause severe health problems, such as hair cell apoptosis and the resultant hearing loss. Therefore, the assay of Cu2+ is important. We integrate ionic imprinting technology (IIT) and structurally colored hydrogel beads to prepare chitosan-based ionically imprinted hydrogel beads (IIHBs) as a low-cost and high-specificity platform for Cu2+ detection. The IIHBs have a macroporous microstructure, uniform size, vivid structural color, and magnetic responsiveness. When incubated in solution, IIHBs recognize Cu2+ and exhibit a reflective peak change, thereby achieving label-free detection. In addition, benefiting from the IIT, the IIHBs display good specificity and selectivity and have an imprinting factor of 19.14 at 100 μmol·L−1. These features indicated that the developed IIHBs are promising candidates for Cu2+ detection, particularly for the prevention of hearing loss.

Abstract The principal aim of this investigation is to identify pivotal biomarkers linked to the prognosis of osteosarcoma (OS) through the application of artificial intelligence (AI), with an ultimate goal to enhance prognostic prediction. Expression profiles from 88 OS cases and 396 normal samples were procured from accessible public databases. Prognostic models were established using univariate COX regression analysis and an array of AI methodologies including the XGB method, RF method, GLM method, SVM method, and LASSO regression analysis. Multivariate COX regression analysis was also employed. Immune cell variations in OS were examined using the CIBERSORT software, and a differential analysis was conducted. Routine blood data from 20,679 normal samples and 437 OS cases were analyzed to validate lymphocyte disparity. Histological assessments of the study's postulates were performed through immunohistochemistry and hematoxylin and eosin (HE) staining. AI facilitated the identification of differentially expressed genes, which were utilized to construct a prognostic model. This model discerned that the survival rate in the high-risk category was significantly inferior compared to the low-risk cohort (p

Abstract Gastric cancer (GC), known for its high incidence and poor prognosis, urgently necessitates the identification of reliable prognostic biomarkers to enhance patient outcomes. We scrutinized data from 375 GC patients alongside 32 non-cancer controls, sourced from the TCGA database. A univariate Cox Proportional Hazards Model (COX) regression was employed to evaluate expressions of ferroptosis-related genes. This was followed by the application of Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate COX regression for the development of prognostic models. The composition of immune cell subtypes was quantified utilizing CIBERSORT, with their distribution in GC versus control samples being comparatively analyzed. Furthermore, the correlation between the expressions of Cystathionine Gamma-Lyase (CTH) and Microtubule Associated Protein 1 Light Chain 3 Beta (MAP1LC3B) and the abundance of immune cell subtypes was explored. Our bioinformatics findings underwent validation through immunohistochemical analysis. Our prognostic models integrated CTH and MAP1LC3B. Survival analysis indicated that patients categorized as high-risk, as defined by the model, exhibited significantly lower survival rates compared to their low-risk counterparts. Notably, CTH expression inversely correlated with monocyte levels, while MAP1LC3B expression showed an inverse relationship with the abundance of M2 macrophages. Immunohistochemical validation corroborated lower expressions of CTH and MAP1LC3B in GC tissues relative to control samples, in concordance with our bioinformatics predictions. Our study suggests that the dysregulation of CTH, MAP1LC3B, and the accompanying monocyte-macrophage dynamics could be pivotal in the prognosis of GC. These elements present potential targets for prognostic assessment and therapeutic intervention.

Abstract Dipterocarpoideae species form the emergent layer of Asian rainforests. They are the indicator species for Asian rainforest distribution, but they are severely threatened. Here, to understand their adaptation and population decline, we assemble high-quality genomes of seven Dipterocarpoideae species including two autotetraploid species. We estimate the divergence time between Dipterocarpoideae and Malvaceae and within Dipterocarpoideae to be 108.2 (97.8‒118.2) and 88.4 (77.7‒102.9) million years ago, and we identify a whole genome duplication event preceding dipterocarp lineage diversification. We find several genes that showed a signature of selection, likely associated with the adaptation to Asian rainforests. By resequencing of two endangered species, we detect an expansion of effective population size after the last glacial period and a recent sharp decline coinciding with the history of local human activities. Our findings contribute to understanding the diversification and adaptation of dipterocarps and highlight anthropogenic disturbances as a major factor in their endangered status.

Receptor-like cytoplasmic kinase OsBSK1-2 was reported to play an important role in regulation of response to rice blast, but the signaling pathway remained unknown. In this study, we identified OsMAPKKK18 and previously uncharacterized MAPKKKs OsMAPKKK16 and OsMAPKKK19 that interact with OsBSK1-2. Expression of all three MAPKKKs was induced by Magnaporthe oryzae infection, and all three induced cell death when transiently expressed in Nicotiana benthamiana leaves. Knockout of OsMAPKKK16 and OsMAPKKK18 compromised blast resistance and overexpression of OsMAPKKK19 increased blast resistance, indicating that all three MAPKKKs are involved in regulation of rice blast response. Furthermore, both OsMAPKKK16 and OsMAPKKK19 interacted with and phosphorylated OsMKK4 and OsMKK5, and chitin-induced MAPK activation was suppressed in osmapkkk16 and osbsk1-2 mutants. OsMAPKKK18 was earlier reported to interact with and phosphorylate OsMKK4 and affect chitin-induced MAPK activation, suggesting that OsBSK1-2 is involved in regulation of immunity through multiple MAPK signaling pathways. Unlike BSK1 in Arabidopsis, OsBSK1-2 was not involved in response to avirulent M. oryzae strains. Taken together, our results revealed important roles of OsMAPKKK16/18/19 and a OsBSK1-2-OsMAPKKK16/18/19-OsMKK4/5 module in regulating response to rice blast.

BackgroundThe interplay between teaching engagement and performance has garnered attention in both theoretical and empirical research, primarily due to its influence on student academic achievement, teacher well-being, and the realization of institutional goals. This is especially pertinent in the realm of preschool education, where the scope of learning extends beyond academic content to encompass the broader socialization of children. Drawing from Affective Neuroscience research, this study investigates the role of affective tendencies as mediators in the relationship between work engagement and job performance.ObjectiveThe primary aim of this research is to examine a chain mediation model that hypothesizes the predictive role of teacher engagement. This model posits the intermediary influence of four basic emotions—CARING, SEEKING, ANGER, and FEAR—followed by the mediating effect of job satisfaction on teacher job performance.MethodThe study utilized a sample of 842 Chinese preschool teachers. Data were collected through an online questionnaire, employing a time-lagged design. The analysis was conducted using Model 80 of the PROCESS Macros.ResultsThe findings reveal that both positive and negative emotions significantly predict teachers’ job satisfaction. However, job satisfaction does not influence job performance. The analysis confirmed the direct and total effects of teacher engagement, as well as the indirect effects, particularly through the positive emotion of Caring.ImplicationsThe results are instrumental in informing and refining interventions designed to enhance teacher engagement and performance, underscoring the importance of emotional factors in the educational environment.

Abstract Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation.

ABSTRACT Endocytosis has been extensively studied in yeasts, where it plays crucial roles in growth, signaling regulation, and cell-surface receptor internalization. However, the biological functions of endocytosis in pathogenic filamentous fungi remain largely unexplored. In this study, we aimed to functionally characterize the roles of EdeA, an ortholog of the Saccharomyces cerevisiae endocytic protein Ede1, in Aspergillus fumigatus. EdeA was observed to be distributed as patches on the plasma membrane and concentrated in the subapical collar of hyphae, a localization characteristic of endocytic proteins. Loss of edeA caused defective hyphal polarity, reduced conidial production, and fewer sites of endocytosis initiations than that of the parental wild type. Notably, the edeA null mutant exhibited increased sensitivity to cell wall-disrupting agents, indicating a role for EdeA in maintaining cell wall integrity in A. fumigatus. This observation was further supported by the evidence showing that the thickness of the cell wall in the ΔedeA mutant increased, accompanied by abnormal activation of MpkA, a key component in the cell wall integrity pathway. Additionally, the ΔedeA mutant displayed increased pathogenicity in the Galleria mellonella wax moth infection model, possibly due to alterations in cell wall morphology. Site-directed mutagenesis identified the conserved residue E348 within the third EH (Eps15 homology) domain of EdeA as crucial for its subcellular localization and functions. In conclusion, our results highlight the involvement of EdeA in endocytosis, hyphal polarity, cell wall integrity, and pathogenicity in A. fumigatus.IMPORTANCEAspergillus fumigatus is a significant human pathogenic fungus known to cause invasive aspergillosis, a disease with a high mortality rate. Understanding the basic principles of A. fumigatus pathogenicity is crucial for developing effective strategies against this pathogen. Previous research has underscored the importance of endocytosis in the infection capacity of pathogenic yeasts; however, its biological function in pathogenic mold remains largely unexplored. Our characterization of EdeA in A. fumigatus sheds light on the role of endocytosis in the development, stress response, and pathogenicity of pathogenic molds. These findings suggest that the components of the endocytosis process may serve as potential targets for antifungal therapy.

Abstract Hereditary deafness is a common neurosensory disorder, and 148 non‐syndromic deafness genes have been identified to date. Gene therapy has been used to treat a variety of genetic diseases, but no gene therapy drug for hereditary deafness has been approved for clinical use. At present, several clinical trials of gene therapy for hereditary deafness are underway. However, few normative documents have been issued to guide the standardization of gene therapy for hearing loss, and this document is the first global gene therapy guideline for hereditary hearing loss. The guidelines were jointly developed and drafted by experienced audiologists, virologists and biologists who are vigorously involved in inner ear gene therapy research in the Hearing, Speech and Communication Subsociety of Biophysical Society of China, Audiology Development Foundation Of China and Audiology Subsociety of Jiangsu Medical Association. These guidelines cover preclinical research and clinical practice of gene therapy for hereditary deafness, including indications, key points of pre‐clinical research, patient selection criteria, pre‐clinical preparation, drug efficacy, drug safety evaluation criteria, ethical review, etc. We hope that the guidelines will promote the standardization of clinical practice related to gene therapy for hereditary deafness in China and around the world.

ABSTRACTAzoles are the primary antifungal drugs used to treat infections caused by Aspergillus fumigatus. However, the emergence of azole resistance in A. fumigatus has become a global health concern despite the low proportion of resistant isolates in natural populations. In bacteria, antibiotic resistance incurs a fitness cost that renders strains less competitive in the absence of antibiotics. Consequently, fitness cost is a key determinant of the spread of resistant mutations. However, the cost of azole resistance and its underlying causes in A. fumigatus remain poorly understood. In this observation, we revealed that the 10 out of 15 screened azole-resistant isolates, which possessed the most common azole-targeted cyp51A mutations, particularly the presence of tandem repeats in the promoter region, exhibit fitness cost when competing with the susceptible isolates in azole-free environments. These results suggest that fitness cost may significantly influence the dynamics of azole resistance, which ultimately contributes to the low prevalence of azole-resistant A. fumigatus isolates in the environment and clinic. By constructing in situ cyp51A mutations in a parental azole-susceptible strain and reintroducing the wild-type cyp51A gene into the azole-resistant strains, we demonstrated that fitness cost is not directly dependent on cyp51A mutations but is instead associated with the evolution of variable mutations related to conidial germination or other unknown development-related processes. Importantly, our observations unexpectedly revealed that some azole-resistant isolates showed no detectable fitness cost, and some even exhibited significantly increased competitive fitness in azole-free environments, highlighting the potential risk associated with the prevalence of these isolates.IMPORTANCEAzole resistance in the human fungal pathogen Aspergillus fumigatus presents a global public health challenge. Understanding the epidemic trends and evolutionary patterns of azole resistance is critical to prevent and control the spread of azole-resistant isolates. The primary cause is the mutation of the drug target 14α-sterol-demethylase Cyp51A, yet its impact on competitive ability remains uncertain. Our competition assays revealed a diverse range of fitness outcomes for environmental and clinical cyp51A-mutated isolates. We have shown that this fitness cost is not reliant on cyp51A mutations but might be linked to unknown mutations induced by stress conditions. Among these isolates, the majority displayed fitness costs, while a few displayed enhanced competitive ability, which may have a potential risk of spread and the need to closely monitor these isolates. Our observation reveals the variation in fitness costs among azole-resistant isolates of A. fumigatus, highlighting the significant role of fitness cost in the spread of resistant strains.

Abstract Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno‐associated virus (AAV)‐mediated OTOF gene replacement therapy is extensively validated in Otof‐deficient mice. However, the clinical safety and efficacy of AAV‐OTOF is not reported. Here, AAV‐OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non‐human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV‐OTOF is delivered into one cochlea of a 5‐year‐old deaf patient and into the bilateral cochleae of an 8‐year‐old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure‐tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5‐year‐old patient can be restored to the normal range at 1 month after AAV‐OTOF injection, while the 8‐year‐old patient can hear the conversational sounds. Most importantly, the 5‐year‐old patient can hear and recognize speech only through the AAV‐OTOF‐injected ear. This study is the first to demonstrate the safety and efficacy of AAV‐OTOF in patients, expands and optimizes current OTOF‐related gene therapy and provides valuable information for further application of gene therapies for deafness.

Background. An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic occurred throughout China from December 2022 to January 2023, and the vast majority of those infected individuals were mild. The symptom characteristics of mildly infected individuals in this epidemic wave of the Omicron variant have not been well described. Methods. We conducted a nationwide survey of symptomatic characteristics of nonhospitalized individuals with mild Omicron infection through a WeChat app. Results. Respondents (68.6% female) were aged 18–87 years (42.6 ± 13.1 years), of whom 79.8% were diagnosed by SARS-CoV-2 PCR or antigen test. Of the 19 symptoms predefined in the questionnaire, an average of 7.8 symptoms was reported. The most common symptoms included cough (81.2%), fever (79.9%), fatigue (73.8%), muscle soreness (62.2%), headache (59.2%), and phlegm (55.1%). Painful swallowing was present in 38.3% of the participants and was one of the most severe symptoms perceived by the participants. Also, we found that young people were more likely to have symptoms such as fever, painful swallowing, and headache compared to the elderly population. 36.9% of respondents graded their symptoms as severe, and the severity of symptoms was higher in young people than in older adults, with fever, cough, painful swallowing, fatigue, and headache being the most severe. In addition, women experienced a significantly higher prevalence of symptoms than men, but there was no significant difference in the severity of most symptoms. The presence of comorbidities did not increase the incidence or severity of symptoms in those with mildly infected individuals. Conclusions. The symptom profile of mild COVID-19 cases in the nationwide Omicron wave in China was markedly different from previous reports, featuring a high incidence of symptoms, multiple symptoms, and heavy symptoms. The symptoms of mild Omicron infection cases are not mild and are more pronounced in young people.

Abstract Noise‐induced hearing loss (NIHL) is a common outcome of excessive reactive oxygen species in the cochlea, and the targeted delivery of antioxidants to the inner ear is a potential therapeutic strategy. In this paper, a novel natural biomaterials‐derived multifunctional delivery system using silk fibroin‐polydopamine (PDA)‐composited inverse opal microcarriers (PDA@SFMCs) is presented for inner ear drug delivery and NIHL therapy. Due to their large specific surface area and interpenetrating nanochannels, PDA@SFMCs can rapidly load active biomolecules making them a convenient medium for the storage and delivery of such molecules. In addition, surface modification of PDA enables the microcarriers to remain in the round window niche, thus facilitating the precise local and directed delivery of loaded drugs. Based on these features, it is demonstrated here that n‐acetylcysteine‐loaded silk microcarriers have satisfactory antioxidant properties on cells and can successfully prevent NIHL in guinea pigs. These results indicate that the natural multifunctional silk microcarriers are promising agents for local inner ear drug delivery in the clinic.

Abstract Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is limited due to drug resistance and toxic side‐effects. It is urgently required to establish the effective biosynthetic strategy for developing novel and safe antifungal molecules economically. Echinocandins become a promising option as a mainstay family of antifungals, due to specifically targeting the fungal specific cell wall. To date, three kinds of echinocandins for caspofungin, anidulafungin, and micafungin, which derived from pneumocandin B0, echinocandin B, and FR901379, are commercially available in clinic and have shown potential in managing invasive fungal infections in a cost‐effective manner. However, current echinocandins‐derived precursors all are produced by environmental fungal isolates with long fermentation cycle and low yields, which challenge the production efficacy of these precursors in industry. Therefore, understanding their biosynthetic machinery is of great importance for improving antifungal titres and creating new echinocandins‐derived products. With the development of genome‐wide sequencing and establishment of gene‐editing technology, there are a growing number of reports on echinocandins‐derived products and their biosynthetic gene clusters. This review briefly summarizes the discovery and development history of echinocandins, compares their structural characteristics and biosynthetic processes, and sums up existed strategies for improving their production. Moreover, the genomic analysis of related biosynthetic gene clusters of echinocandins is discussed, highlighting the similarities and differences among the clusters. Last, the biosynthetic processes of echinocandins are compared, focusing on the activation and attachment of side‐chains and the formation of the hexapeptide core. This review aims to provide insights into the development and production of new echinocandin drugs by modifying the structure of echinocandin‐derived precursors and/or optimizing the fermentation processes; and achieve a new microbial chassis for efficient production of echinocandins in heterologous hosts.

Abstract OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in [Ctrp4.sup.-/-] mice compared with WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naive [CD4.sup.+] T cells into Th17 cells in vitro. Mechanistically, CTRP4 interfered with the interaction between IL-6 and the IL-6 receptor (IL-6R) by directly competing to bind with IL-6R, leading to suppression of IL-6-induced activation of the STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor- signaling pathway, may be a potential therapeutic intervention for Th17-driven autoimmune diseases., Introduction Multiple sclerosis (MS) is an inflammatory disorder of the CNS identified by chronic demyelination and axonal damage. Upon activation in the peripheral lymphoid organs, the autoimmune T cells enter [...]

Aims: The population pharmacokinetic (PPK) model-based machine learning (ML) approach offers a novel perspective on individual concentration prediction. This study aimed to establish a PPK-based ML model for predicting tacrolimus (TAC) concentrations in Chinese renal transplant recipients. Methods: Conventional TAC monitoring data from 127 Chinese renal transplant patients were divided into training (80%) and testing (20%) datasets. A PPK model was developed using the training group data. ML models were then established based on individual pharmacokinetic data derived from the PPK basic model. The prediction performances of the PPK-based ML model and Bayesian forecasting approach were compared using data from the test group. Results: The final PPK model, incorporating hematocrit and CYP3A5 genotypes as covariates, was successfully established. Individual predictions of TAC using the PPK basic model, postoperative date, CYP3A5 genotype, and hematocrit showed improved rankings in ML model construction. XGBoost, based on the TAC PPK, exhibited the best prediction performance. Conclusion: The PPK-based machine learning approach emerges as a superior option for predicting TAC concentrations in Chinese renal transplant recipients. [ABSTRACT FROM AUTHOR]

To investigate the diversity of wild fungi in the Helan mountains of Inner Mongolia, the fruiting body morphology, the surface characteristics of the cap, the appendage characteristics of the cap, the characteristics of the stalk, and the gill characteristics of the cap were analyzed. The following conclusions were obtained. Similarities exist between different fruiting bodies, phenotypic diversity also exists in the same germ fruiting bodies, and the morphological characteristics of fruiting bodies and their constituent parts are independent of each other. Four constituent parts' characteristics showed that intraspecific diversity was less than interspecific diversity. The morphological characteristics of the cap and the gill were significantly or extremely significant correlated with the overall characteristics of the fruiting body. The morphological characteristics of cap appendages and the stalk did not correlate with the fruiting body. Additionally, 141, 44, and 4 species showed low, middle, and high diversity, respectively. [ABSTRACT FROM AUTHOR]

Background: Tousled-like kinase 2 (TLK2) is integral to DNA repair, replication, and cell cycle regulation, crucial for maintaining genome stability and integrity. However, the expression and prognostic value of TLK2 in hepatitis B viral (HBV)-related hepatocellular carcinoma (HCC) remains unclear. Methods: We examined TLK2 expression and prognostic implications in pancancer by using diverse databases. Subsequently, TLK2 expression in HBV-related HCC tissues and adjacent tissues was assessed using quantitative real-time PCR and immunohistochemistry. The prognostic value of TLK2 was assessed through ROC curves, time-dependent ROC curves, Cox regression, Kaplan-Meier curve, and decision curve analysis. Additionally, analyses of immune infiltration, proteinprotein interactions, key molecules of tumor-related signaling pathways, molecular subtypes, and TLK2-associated differentially expressed genes (DEGs) were conducted, along with GO/KEGG and GSEA enrichment analyses. Results: TLK2 expression was significantly higher in HCC tissues compared to adjacent tissues and correlated with gender, AFP levels, albumin-bilirubin (ALBI) grade, microvascular invasion (MVI), maximum tumor diameter, tumor number, and TNM stage. TLK2 overexpression emerged as an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in HBV-related HCC patients. An integrated OS nomogram model, incorporating TLK2, age, ALBI grade, MVI, and tumor number, displayed enhanced prognostic capability (C-index: 0.765, 95% CI: 0.732-0.798) in predicting OS and has a higher net benefit than the TNM stage. Moreover, TLK2 expression correlated closely with immune cell infiltration and key molecules of signaling pathways. Functional enrichment analyses highlighted significant associations with DNA duplex unwinding, double-strand break repair, DNA replication, cell cycle, E2F targets, G2M checkpoint, and MYC targets V1. Conclusion: TLK2 is notably overexpressed in HBV-related HCC and emerges as a promising prognostic biomarker, necessitating further validation. [ABSTRACT FROM AUTHOR]

Eight new 12,8-eudesmanolide sesquiterpenes, eutypellaolides A-H (1-8), and two new eudesmane-type sesquiterpenes, eutypellaolides I-J (9-10), along with four known 12,8-eudesmanolide compounds 11-14, were isolated from the culture extract of the polar fungus Eutypella sp. D-1 by one strain many compounds (OSMAC) approach. The structures of these compounds were determined through comprehensive spectroscopic data and experimental and calculated ECD analysis. Antibacterial, immunosuppressive, and PTP1B inhibition activities of these compounds were evaluated. Compounds 1 and 11 exhibited strong inhibitory activities against Bacillus subtilis and Staphylococcus aureus, with each showing an MIC value of 2 µg/mL. Compound 9 displayed weak immunosuppressive activity against ConA-induced T-cell proliferation with an inhibitory rate of 61.7% at a concentration of 19.8 µM. Compounds 5, 11, and 14 exhibited weak PTP1B inhibition activities with IC50 values of 44.8, 43.2, and 49.5 µM, respectively. [ABSTRACT FROM AUTHOR]

Biphenyl fused alicyclic tetracarboxylic dianhydride, 6,6′,7,7′‐tetracarboxylic dianhydride‐5,5′,6,6′,7,7′,8,8′‐octahydro‐2,2′‐binaphthalene (OHBNDA) was successfully synthesized from biphenyltetracarboxylic dianhydride (BPDA) through hydrolysis, reduction, bromination, and Diels–Alder reaction. Three OHBNDA‐based polyimides (PIs) were synthesized by one‐step polycondensation at high temperature with 9,9‐bis(4‐aminophenyl)fluorene (BAFL), 2,2′‐bis(trifluoromethyl)‐4,4′‐diaminobiphenyl (TFMB), and 4,4′‐diamino‐2,2′‐dimethyl‐1,1′‐biphenyl (m‐TolDA) diamines, respectively. These PIs have moderate molecular weights and good solubility in polar organic solvents, such as N,N‐dimethylformamide, dimethylacetamide (DMAc), and dimethyl sulfoxide (DMSO). OHBNDA‐TFMB, OHBNDA‐m‐TolDA, and OHBNDA‐BAFL display glass transition temperatures (Tgs) of 309, 329, and 377°C from differential scanning calorimetry (DSC) curves, and the decomposition temperatures at 5% weight loss (Td5) of as high as 522, 507, and 548°C under nitrogen, respectively. Meanwhile, these PI films also show good optical transparency with the cut‐off wavelength <315 nm and the transmittance >75% at 400 nm. These results confirm that aryl‐fused alicyclic tetracarboxylic dianhydrides can afford transparent/colorless PIs with high thermal stability, especially the higher decomposition temperatures than the wholly alicyclic dianhydrides. [ABSTRACT FROM AUTHOR]

Thyroid radiofrequency ablation and microwave ablation are widely adopted minimally invasive treatments for diverse thyroid conditions worldwide. Fundamental skills such as the trans-isthmic approach and the moving shot technique are crucial for performing thyroid ablation, and advanced techniques, including hydrodissection and vascular ablation, improve safety and efficacy and reduce complications. Given the learning curve associated with ultrasound-guided therapeutic procedures, operators need training and experience. While training models exist, limited attention has been given to ultrasound maneuvers in ablation needle manipulation. This article introduces two essential maneuvers, the zigzag moving technique and the alienate maneuver, while also reviewing the latest ultrasound techniques in thyroid ablation, contributing valuable insights into this evolving field. [ABSTRACT FROM AUTHOR]

A wideband circularly polarized (CP) dipole antenna with compact size and wide beamwidth is proposed. To achieve a wide half‐power beamwidth (HPBW), the dipole is designed to be a folded bowtie, and four rotationally symmetric vertical metal plates are placed on the square ground plane. A circular parasitic patch above the dipole arms improves the impedance bandwidth. By using a 3‐dB coupler, the proposed antenna achieves wideband CP performance. The measured results show that an impedance bandwidth for VSWR ≤ 2 and a 3‐dB axial‐ratio (AR) bandwidth are from 0.76 to 2.1 GHz (93.7%). Moreover, a bandwidth of HPBW ≥ 102° is from 0.76 to 1.8 GHz (81.2%). [ABSTRACT FROM AUTHOR]

Abstract Preserving pulp viability and promoting pulp regeneration in pulpitis have attracted widespread attention. Restricted by the oxidative stress microenvironment of dental pulpitis, excessive reactive oxygen and nitrogen species (RONS) trigger uncontrolled inflammation and exacerbate pulp tissue destruction. However, modulating redox homeostasis in inflamed pulp tissue to promote pulp regeneration remains a great challenge. Herein, this work proposes an effective antioxidative system (C-NZ/GelMA) consisting of carbon dot nanozymes (C-NZ) with gelatin methacryloyl (GelMA) to modulate the pulpitis microenvironment for dental pulp regeneration by utilizing the antioxidant properties of C-NZ and the mechanical support of an injectable GelMA hydrogel. This system effectively scavenges RONS to normalize intracellular redox homeostasis, relieving oxidative stress damage. Impressively, it can dramatically enhance the polarization of regenerative M2 macrophages. This study revealed that the C-NZ/GelMA hydrogel promoted pulp regeneration and dentin repair through its outstanding antioxidant, antiapoptotic, and anti-inflammatory effects, suggesting that the C-NZ/GelMA hydrogel is highly valuable for pulpitis treatment.

Abstract Background The ratio (E/Ea) of mitral Doppler inflow velocity to annular tissue Doppler wave velocity by transthoracic echocardiography and diaphragmatic excursion (DE) by diaphragm ultrasound have been confirmed to predict extubation outcomes. However, few studies focused on the predicting value of E/Ea and DE at different positions during a spontaneous breathing trial (SBT), as well as the effects of △E/Ea and △DE (changes in E/Ea and DE during a SBT). Methods This study was a reanalysis of the data of 60 difficult-to-wean patients in a previous study published in 2017. All eligible participants were organized into respiratory failure (RF) group and extubation success (ES) group within 48 h after extubation, or re-intubation (RI) group and non-intubation (NI) group within 1 week after extubation. The risk factors for respiratory failure and re-intubation including E/Ea and △E/Ea, DE and △DE at different positions were analyzed by multivariate logistic regression, respectively. The receiver operating characteristic (ROC) curves of E/Ea (septal, lateral, average) and DE (right, left, average) were compared with each other, respectively. Results Of the 60 patients, 29 cases developed respiratory failure within 48 h, and 14 of those cases required re-intubation within 1 week. Multivariate logistic regression showed that E/Ea were all associated with respiratory failure, while only DE (right) and DE (average) after SBT were related to re-intubation. There were no statistic differences among the ROC curves of E/Ea at different positions, nor between the ROC curves of DE. No statistical differences were shown in △E/Ea between RF and ES groups, while △DE (average) was remarkably higher in NI group than that in RI group. However, multivariate logistic regression analysis showed that △DE (average) was not associated with re-intubation. Conclusions E/Ea at different positions during a SBT could predict postextubation respiratory failure with no statistical differences among them. Likewise, only DE (right) and DE (average) after SBT might predict re-intubation with no statistical differences between each other.

Abstract Background Physical disability is an important cause of affecting the quality of life in the elderly. The association between standing height and physical disability is less studied. Purpose The purpose of this study is to investigate the possible link between standing height and physical disability among U.S. adults aged 60 years and older. Methods The cross-sectional data were obtained from the US National Health and Nutrition Examination Survey (NHANES) 2015–2018. Physical disability was assessed by six questions: “Have serious difficulty hearing (SDH)?”, “Have serious difficulty seeing (SDS)?”, “Have serious difficulty concentrating (SDC)?”, “Have serious difficulty walking (SDW)?”, “Have difficulty dressing or bathing (DDB)?” and “Have difficulty doing errands alone (DDEA)?”. Responses to these questions were “yes” or “no”. Answer yes to one of the above six questions was identified as physical disability. Standing height (cm) was measured with an altimeter. Multivariate logistic regression was performed to examine the possible link between standing height and physical disability after adjustment for all covariates. Results A total of 2624 participants aged ≥ 60 years were included in our study, including 1279 (48.7%) females and 1345 (51.3%) males. The mean age of participants was 69.41 ± 6.82 years. After adjusting for all potential confounders, the inverse relationship between standing height and all physical disability (APD) was statistically significant (OR = 0.976, 95%CI:0.957–0.995). In addition, among six types of physical disability (SDH, SDS, SDC, SDW, DDB, DDEA), standing height was also a protective factor for SDW (OR = 0.961, 95%CI:0.939–0.983) and DDEA (OR = 0.944, 95%CI:0.915–0.975) in the full-adjusted model. Conclusion The cross-sectional population based study demonstrates that standing height is a protective factor for physical disability among U.S. adults aged 60 years and older.

Abstract Objective Bayesian network (BN) models were developed to explore the specific relationships between influencing factors and type 2 diabetes mellitus (T2DM), coronary heart disease (CAD), and their comorbidities. The aim was to predict disease occurrence and diagnose etiology using these models, thereby informing the development of effective prevention and control strategies for T2DM, CAD, and their comorbidities. Method Employing a case-control design, the study compared individuals with T2DM, CAD, and their comorbidities (case group) with healthy counterparts (control group). Univariate and multivariate Logistic regression analyses were conducted to identify disease-influencing factors. The BN structure was learned using the Tabu search algorithm, with parameter estimation achieved through maximum likelihood estimation. The predictive performance of the BN model was assessed using the confusion matrix, and Netica software was utilized for visual prediction and diagnosis. Result The study involved 3,824 participants, including 1,175 controls, 1,163 T2DM cases, 982 CAD cases, and 504 comorbidity cases. The BN model unveiled factors directly and indirectly impacting T2DM, such as age, region, education level, and family history (FH). Variables like exercise, LDL-C, TC, fruit, and sweet food intake exhibited direct effects, while smoking, alcohol consumption, occupation, heart rate, HDL-C, meat, and staple food intake had indirect effects. Similarly, for CAD, factors with direct and indirect effects included age, smoking, SBP, exercise, meat, and fruit intake, while sleeping time and heart rate showed direct effects. Regarding T2DM and CAD comorbidities, age, FBG, SBP, fruit, and sweet intake demonstrated both direct and indirect effects, whereas exercise and HDL-C exhibited direct effects, and region, education level, DBP, and TC showed indirect effects. Conclusion The BN model constructed using the Tabu search algorithm showcased robust predictive performance, reliability, and applicability in forecasting disease probabilities for T2DM, CAD, and their comorbidities. These findings offer valuable insights for enhancing prevention and control strategies and exploring the application of BN in predicting and diagnosing chronic diseases.

Abstract In order to alleviate environmental problems and reduce CO2 emissions, geopolymers had drew attention as a kind of alkali-activated materials. Geopolymers are easier access to raw materials, green and environment friendly than traditional cement industry. Its special reaction mechanism and gel structure show excellent characteristics such as quick hardening, high strength, acid and alkali resistance. In this paper, geopolymer pastes were made with metakaolin (MK) and ground granulated blast furnace slag (GGBFS) as precursors. The effects of liquid–solid ratio (L/S) and modulus of sodium silicate (Ms) on the performances of MK-GGBFS based geopolymer paste (MSGP) were characterized by workability, strength and microstructural tests. The regression equations were obtained by central composite design method to optimize the mix design of MSGP. The goodness of fit of all the equations were more than 98%. Based on the results of experiments, the optimum mix design was found to have L/S of 0.75 and Ms of 1.55. The workability of MSGP was significantly improved while maintaining the strength under the optimum mix design. The initial setting time of MSGP decreased by 71.8%, while both of the fluidity and 28-d compressive strength increased by 15.3%, compared with ordinary Portland cement pastes. Therefore, geopolymers are promising alternative cementitious material, which can consume a large amount of MK and GGBFS and promote green and clean production.

The composition and dynamics of wetland plant communities play a critical role in maintaining the functionality of wetland ecosystems and serve as important indicators of wetland degradation and restoration. Accurately identifying wetland plant communities using remote sensing techniques remains challenging due to the complex environment and cloud contamination. Here, we applied a sample migration method based on change vector analysis and a random forest (RF) classifier incorporating SHapley Additive exPlanations (SHAP) to explore the spatiotemporal changes of wetland plant communities in the western Songnen Plain of China between 2016 and 2022, and to better understand the decision logic of the RF model. Our work achieved accurate annual wetland classification at the community scale, with an average overall accuracy of 89.5% and an average kappa coefficient of 0.87. Our analysis revealed different spatiotemporal change characteristics of wetland plant communities in the western Songnen Plain and three national nature reserves. The SHAP model showed that MOS_IRECI is the most important feature determining the prediction results of the RF model, and the importance of the features differs at global and local levels. This study confirms the feasibility of annual dynamic monitoring of wetland plant communities at a regional scale. The results are expected to provide a reference for the fine and sustainable management of wetland resources in the western Songnen Plain, as well as valuable data support for related wetland ecology research.

Pre-disaster protection strategies are essential for enhancing the resilience of electric power systems against natural disasters. Considering the budgets for protection strategies, the dependency of other infrastructure systems on electricity, and the uncertainty of disaster scenarios, this paper develops risk-neutral and risk management models of strategies for pre-disaster protection. The risk-neutral model is a stochastic model designed to maximize the expected value of resilience (EVR) of the integrated system. The risk management model is a multi-objective model prioritizing the minimization of risk metrics as a secondary goal alongside maximizing the EVR. A case study conducted on the energy infrastructure systems in the Greater Toronto Area (GTA) validates the effectiveness of the models. The findings reveal the following: (i) increasing the budget enhances the EVR of the integrated system; however, beyond a certain budget threshold, the incremental benefits to the EVR significantly diminish; (ii) reducing the value of the downside risk often results in an increase in the EVR, with the variation in Pareto-optimal solutions between the two objectives being non-linear; and (iii) whether for the risk-neutral or risk management protection strategies, there are reasonable budgets when considering disaster intensity and the cost of protection measures. The models can help decision-makers to select effective protection measures for natural disasters.

Objectives: Burnout influences students’ academic performance and mental health. This study analyzed the relationship between professional identity, self-directed learning ability, and burnout, and examined the mediating effect of self-directed learning ability between professional identity and burnout among nursing students. Methods: 884 nursing students were recruited at two medical universities in China. Demographic information, Academic Burnout Scale, Professional Identity Questionnaire for Nursing Students, and Self-directed Learning Instrument were distributed to collect data. Results: Both professional identity (β = −0.17) and self-directed learning ability (β = −0.43) showed negative associations with students’ burnout. Meanwhile, there was a partial mediating effect of self-directed learning ability between professional identity and burnout (−0.24, 95% CI = −0.30, −0.20). Conclusions: Nursing educators should emphasize on developing effective strategies to improve nursing students’ professional identity and self-directed learning ability to prevent or reduce their burnout.