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Aim: To observe the changes in corneal subepithelial nerve fibers (CNFs) and Langerhans cells (LCs) in patients with type 2 diabetes using corneal laser confocal microscopy (CLCM)., Methods: A total of 60 patients (64 eyes), including 40 patients with type 2 diabetes (DM group) and 20 subjects without diabetes (control group) were included with CLCM. Neuron J plugin of Image J software were used for quantitative analysis of CNF length (CNFL), CNF density (CNFD), corneal nerve branch fiber density (CNBD), main branch length density, branch length density, corneal nerve fiber tortuosity (NT) score, and LCs density. An independent samples t -test to analyze the variability between the two groups was performed, and Pearson correlation analysis was used to analyze the relationships between CNF and multiple biochemical indicators in the DM group. The predictive power of CNF for type 2 diabetes was assessed using the receiver operating characteristic (ROC) curve., Results: There were significant differences in the CNFL, CNFD, and main branch length density between two groups. The results of Pearson correlation analysis showed a significant negative correlation between CNFD and the duration of diabetes as well as triglyceride levels and total cholesterol, and a significant positive correlation between CNFD and serum albumin. In addition, the NT score showed a positive correlation and urea nitrogen, similar to the positive correlation observed between LC density and glycosylated hemoglobin (HbA1c) levels. CNFD showed the highest area under the curve (AUC of ROC) value, followed by main branch length density and CNFL. The AUC of the ROC curve under the logistic regression model also demonstrated good predictive values. The cut-off values of CNFD, CNFL, and main branch length density for diabetes showed 31.25, 18.85, and 12.56, respectively., Conclusion: In patients with type 2 diabetes, there is a notable reduction in both CNFL and CNFD. These measurements can be influenced by various blood biochemical factors. However, the compromised nerve fibers can serve as valuable indicators for predicting the onset of type 2 diabetes and also as biomarkers for detecting diabetic neuropathy and its related complications., Competing Interests: Conflicts of Interest: Meng LR, None; Chen H, None; Chen WQ, None; Gao Y, None; Li ZW, None; Ye Z, None; Li ZH, None., (International Journal of Ophthalmology Press.)

Congenital cataract is one of the leading causes of vision loss in children, and a large proportion of cases are related to genetics. In a Chinese family, we reported a new missense mutation in CRYBA2 (c.223T>C: p.Tyr75His), which can cause autosomal dominant congenital bilateral cataract. We collected blood samples from family members (mother and two sons) and extracted DNA. Through whole-exome sequencing, we discovered a novel unreported mutation. According to relevant ACMG guidelines, this mutation was determined to be a variant of unknown clinical significance. This article further expands the site information on the CRYBA2 mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Longitudinal evidence of long-term ozone exposure on heart rate variability (HRV, an early indicator of cardiovascular damage) is lacking and the potential mechanism remains largely unclear. Our objectives were to evaluate the cross-sectional and longitudinal associations of ozone exposure with HRV alteration, and the potential roles of protein carbonyl (PC, biomarker of oxidative protein damage) and transforming growth factor (TGF)-β1 in this association. This repeated-measures prospective study included 4138 participants with 6617 observations from the Wuhan-Zhuhai cohort. Ozone concentrations were estimated using a high temporospatial resolution model for each participant. HRV indices, PC, and TGF-β1 were also repeatedly measured. Cross-sectional and longitudinal relationships of ozone exposure with HRV alteration were evaluated by linear mixed model. Cross-sectionally, the strongest lag effect of each 10 ppb increment in short-term ozone exposure showed a 12.40 %, 8.47 %, 4.31 %, 8.03 %, 3.69 %, and 2.41 % decrement on very low frequency (VLF, lag 3 weeks), LF (lag 2 weeks), high frequency (HF, lag 0-7 days), total power (TP, lag 2 weeks), standard deviation of all normal-to-normal intervals (SDNN, lag 3 weeks), and square root of the mean squared difference between adjacent normal-to-normal intervals (lag 2 weeks), respectively. Longitudinally, each 10 ppb increment of annual average ozone was related with an annual change rate of -0.024 ms 2 /year in VLF, -0.009 ms 2 /year in LF, -0.013 ms 2 /year in HF, -0.014 ms 2 /year in TP, and -0.004 ms/year in SDNN. Mediation analyses indicated that PC mediated 20.77 % and 12.18 % of ozone-associated VLF and TP decline, respectively; TGF-β1 mediated 16.87 % and 27.78 % of ozone-associated VLF and SDNN reduction, respectively. Our study demonstrated that ozone exposure was cross-sectionally and longitudinally related with HRV decline in general Chinese urban adults, and oxidative protein damage and increased TGF-β1 partly mediated ozone exposure-related HRV reduction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The discovery of metal-organic frameworks (MOFs) with novel structures provides significant opportunities for developing porous solids with new properties and enriching the structural diversity of functional materials for various applications. The rational design of building units with specific geometric conformations is essential to direct the construction of MOFs with unique properties. Herein, we leverage a ligand desymmetrization approach to construct a series of new MOFs. A flexible tetratopic carboxylate ligand with a tetrahedral geometry was designed and assembled with a Zr6 cluster, generating four Zr-based MOF structures: NU-2600, NU-2700, NU-2800, and NU-1802, in which the ligand configurations and Zr6 cluster connectivities can be controlled by varying solvents and modulators during synthesis. Except for NU-1802, these represent entirely new topologies. Notably, NU-1802 exhibits structural flexibility, with up to a 74% reduction in the unit cell volume as confirmed by single-crystal X-ray diffraction studies. Given their microporous structures, we studied the adsorption behaviors of n-hexane and 2-chloroethyl ethyl sulfide to explore the structure-property relationships of these MOFs. Overall, this work highlights ligand desymmetrization as a powerful method to enrich MOF structural diversity and access complex MOFs with non-default topologies suitable for applications such as toxic gas capture., (© 2024 Wiley‐VCH GmbH.)

Nonylphenol (NP), an endocrine-disrupting compound (EDC) with accumulative properties, poses significant risks to human health and the environment. The pivotal role of probiotics in mitigating EDC toxicity has garnered increasing attention. In this study, we assessed the protective effects of Bifidobacterium longum CCFM1077, a probiotic with outstanding in vitro NP-binding ability, against NP-induced toxicity in rats. This analysis revealed that B. longum CCFM1077 effectively promoted the NP excretion and enhanced intestinal barrier integrity. Interestingly, B. longum CCFM1077, by modulating the structure and the function of gut microbiota, increased the abundance of Turicibacter, significantly elevated the level of butyric acid, and upregulated antioxidant-related metabolic pathways, thereby alleviating brain inflammation and ultimately improving behavioral disorders. This study elucidated a strategy to alleviate NP toxicity and lays a theoretical foundation for the development of novel intestinal protection strategies. It supports environmental sustainability by offering a strategy to combat NP bioaccumulation, aligning with global initiatives to minimize the environmental impact of industrial pollutants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1-F2 is a pathogenic factor in 15-18-month-old BALB/C mice (aged mice) but not in 6-8-week-old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1-F2-knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2'3'-cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2'3'-cGAMP to boost proinflammatory cytokine expression through STING-NF-κB signaling. We found that H7N9 PB1-F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA-cGAS-STING-NF-κB pathway. H7N9 PB1-F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V-dependent electron transport dysfunction, reverse electron transfer-dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS-STING-NF-κB signaling. PB1-F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1-F2-mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1-F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human-adapted descendants. Our findings provide one explanation to age-dependent pathogenesis of H7N9 infection., (© 2024 Wiley Periodicals LLC.)

Kuey teow is one of the delicacies of Guangdong, China and is a gluten-free noodle dish made from rice. It has a short storage period and extending the shelf life by quick freezing induces quality deterioration due to temperature fluctuations. To improve its freeze-thaw frozen storage quality, this paper examined the effects of hydroxypropyl corn starch (HCS), guar gum (GG), and compound phosphates (CP) on the quality of quick-frozen kuey teow during freeze-thaw cycles. The mechanism was investigated by identifying changes in the moisture status, aging degree of the starch, and textural and cooking characteristics. The results showed that all three additions improved the toughness, chewiness and steaming characteristics of the kuey teow, with CP significantly enhancing chewiness. XRD and FTIR results revealed that GG more significantly inhibited the decrease of starch crystallinity, while HCS inhibited starch aging. GG, HCS and CP all improved the hydration characteristics and water holding capacity of rice starch. GG enhances the ability of starch to bind more tightly with water, resulting in a more uniform water distribution and a more continuous and tight structure of the kuey teow. This study will provide a theoretical basis for compounding and optimizing the quick-freezing of kuey teow., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Tryptophan (Trp) metabolism involves three primary pathways: the kynurenine (Kyn) pathway (KP), the 5-hydroxytryptamine (serotonin, 5-HT) pathway, and the indole pathway. Under normal physiological conditions, Trp metabolism plays crucial roles in regulating inflammation, immunity, and neuronal function. Key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO), Trp-2,3-dioxygenase (TDO), and kynurenine monooxygenase (KMO) drive these metabolic processes. Imbalances in Trp metabolism are linked to various cancers and often correlate with poor prognosis and adverse clinical characteristics. Dysregulated Trp metabolism fosters tumor growth and immune evasion primarily by creating an immunosuppressive tumor microenvironment (TME). Activation of the KP results in the production of immunosuppressive metabolites like Kyn, which modulate immune responses and promote oncogenesis mainly through interaction with the aryl hydrocarbon receptor (AHR). Targeting Trp metabolism therapeutically has shown significant potential, especially with the development of small-molecule inhibitors for IDO1, TDO, and other key enzymes. These inhibitors disrupt the immunosuppressive signals within the TME, potentially restoring effective anti-tumor immune responses. Recently, IDO1 inhibitors have been tested in clinical trials, showing the potential to enhance the effects of existing cancer therapies. However, mixed results in later-stage trials underscore the need for a deeper understanding of Trp metabolism and its complex role in cancer. Recent advancements have also explored combining Trp metabolism inhibitors with other treatments, such as immune checkpoint inhibitors, chemotherapy, and radiotherapy, to enhance therapeutic efficacy and overcome resistance mechanisms. This review summarizes the current understanding of Trp metabolism and signaling in cancer, detailing the oncogenic mechanisms and clinical significance of dysregulated Trp metabolism. Additionally, it provides insights into the challenges in developing Trp-targeted therapies and future research directions aimed at optimizing these therapeutic strategies and improving patient outcomes., (© 2024. The Author(s).)

Patients with type 2 diabetes (T2D) are more susceptible to severe respiratory viral infections, but the underlying mechanisms remain elusive. Here, we show that patients with T2D and coronavirus disease 2019 (COVID-19) infections, and influenza-infected T2D mice, exhibit defective T helper 1 (Th1) responses, which are an essential component of anti-viral immunity. This defect stems from intrinsic metabolic perturbations in CD4 + T cells driven by hyperglycemia. Mechanistically, hyperglycemia triggers mitochondrial dysfunction and excessive fatty acid synthesis, leading to elevated oxidative stress and aberrant lipid accumulation within CD4 + T cells. These abnormalities promote lipid peroxidation (LPO), which drives carbonylation of signal transducer and activator of transcription 4 (STAT4), a crucial Th1-lineage-determining factor. Carbonylated STAT4 undergoes rapid degradation, causing reduced T-bet induction and diminished Th1 differentiation. LPO scavenger ameliorates Th1 defects in patients with T2D who have poor glycemic control and restores viral control in T2D mice. Thus, this hyperglycemia-LPO-STAT4 axis underpins reduced Th1 activity in T2D hosts, with important implications for managing T2D-related viral complications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development. Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied, the influence of neural signals, particularly those from the sympathetic nervous system, remains poorly understood. Here, using a mouse mammary gland model, we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development. Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty, adulthood, and pregnancy, accompanied by a reduction in mammary stem cell numbers. Through in vitro three-dimensional culture and in vivo transplantation analyses, we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration, while activation of sympathetic nervous signaling promotes these capacities. Mechanistically, sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the extracellular signal-regulated kinase signaling pathway. Collectively, our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity, offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development., (© The Author(s) (2024). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

The effects of environmental polycyclic aromatic hydrocarbons (PAHs) exposure on glycemic regulation and the underlying genetic mechanism were still unclear. This study aimed to analyze the longitudinal joint effects of PAHs exposure and genetic susceptibility on fasting plasma glucose (FPG) through a longitudinal study. We included 4104 observations (2383 baseline participants and 1721 6-year follow-up participants) from Wuhan-Zhuhai cohort. Ten urinary PAHs metabolites and FPG were measured at both baseline and follow-up. We constructed the polygenic risk scores (PRS) of FPG from the corresponding genome-wide association studies. Linear mixed models were used to explore the associations of urinary PAHs metabolites or FPG-PRS on FPG levels in the repeated-measure analysis. Besides, the longitudinal relationships of urinary PAHs metabolites, FPG-PRS, and their joint effects on FPG change over 6 years were evaluated by linear regression models. Compared with participants with persistent low levels of urinary total PAHs metabolites, hydroxynaphthalene, and hydroxyphenanthrene, participants with persistent high levels had average decreases of 0.180, 0.200, and 0.261 mmol/L for FPG change over 6 years, respectively. Each 1-unit increase of FPG-PRS was associated with a 0.521 mmol/L for FPG change over 6 years. Besides, compared with participants with high FPG-PRS and persistent low levels of urinary total hydroxynaphthalene, hydroxyfluorene, and hydroxyphenanthrene, participants with low FPG-PRS and persistent high levels had average decreases of 0.330, 0.557, and 0.421 mmol/L for FPG change over 6 years. Our findings demonstrated that high-level PAHs exposure was longitudinally associated with an average decrease of FPG over 6 years, and low FPG genetic risk can enhance the above associations. Our findings emphasized the hypoglycemic effect of PAHs exposure, shed new light on the complex effects between PAHs exposure and genetic factors in the prevention of high FPG, and might provide some clues for the development of potential hypoglycemic agents., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

Background: SHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects., Methods: Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18-45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55-80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg)., Results: Sixty-two (part 1/2, n = 50/12; age range, 18-42/55-63 years) and 30 subjects (age range, 18-42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2-60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed., Conclusions: A single intravenous dose of SHR-1707 at 2-60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development., Trial Registration: NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov., (© 2024. The Author(s).)

Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency., Competing Interests: Declaration of interests W.-J.C., Z.-Q.X., X.C., M.Z., Y.-H.Z., and L.C. have filed patents (CN2023113708968) to protect the application of CRACE therapy for the treatment of brain calcification., (Copyright © 2024 Elsevier Inc. All rights reserved.)

USP25 encodes ubiquitin-specific protease 25, a key member of the deubiquitinating enzyme family that is involved in neural fate determination. Although abnormal expression in Down's syndrome was reported previously, the specific role of USP25 in human diseases has not been defined. In this study, we performed trio-based whole exome sequencing in a cohort of 319 cases (families) with generalized epilepsy of unknown aetiology. Five heterozygous USP25 variants, including two de novo and three co-segregated variants, were determined in eight individuals affected by generalized seizures and/or febrile seizures from five unrelated families. The frequency of USP25 variants showed a significantly high aggregation in this cohort compared with the East Asian population and all populations in the gnomAD database. The mean age at onset of febrile and afebrile seizures were 10 months (infancy) and 11.8 years (juvenile), respectively. The patients achieved seizure freedom, except that one had occasional nocturnal seizures at the last follow-up. Two patients exhibited intellectual disability. Usp25 was expressed ubiquitously in mouse brain with two peaks, on embryonic Days 14-16 and postnatal Day 21, respectively. In human brain, likewise, USP25 is expressed in the fetus/early childhood stage and with a second peak at ∼12-20 years old, consistent with the seizure onset age in patients during infancy and in juveniles. To investigate the functional impact of USP25 deficiency in vivo, we established Usp25 knockout mice, which showed increased seizure susceptibility compared with wild-type mice in a pentylenetetrazol-induced seizure test. To explore the impact of USP25 variants, we used multiple functional detections. In HEK293 T cells, the variant associated with a severe phenotype (p.Gln889Ter) led to a significant reduction of mRNA and protein expressions but formed stable truncated dimers with an increment of deubiquitinating enzyme activities and abnormal cellular aggregations, indicating a gain-of-function effect. The p.Gln889Ter and p.Leu1045del variants increased neuronal excitability in mouse brain, with a higher firing ability in p.Gln889Ter. These functional impairments align with the severity of the observed phenotypes, suggesting a genotype-phenotype correlation. Hence, a moderate association between USP25 and epilepsy was noted, indicating that USP25 is potentially a predisposing gene for epilepsy. Our results from Usp25 null mice and the patient-derived variants indicated that USP25 would play an epileptogenic role via loss-of-function or gain-of-function effects. The truncated variant p.Gln889Ter would have a profoundly different effect on epilepsy. Together, our results underscore the significance of USP25 heterozygous variants in epilepsy, thereby highlighting the critical role of USP25 in the brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The frequent occurrence of mutations in the SARS-CoV-2 Spike (S) protein, with up to dozens of mutations, poses a severe threat to the current efficacy of authorized COVID-19 vaccines. Membrane (M) protein, which is the most abundant viral structural protein, exhibits a high level of amino acid sequence conservation. M protein ectodomain could be recognized by specific antibodies; however, the extent to which it is immunogenic and provides protection remains unclear., Methods: We designed and synthesized multiple peptides derived from coronavirus M protein ectodomains, and determined the secondary structure of specific peptides using circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect IgG responses against the synthesized peptides in clinical samples. To evaluate the immunogenicity of peptide vaccines, BALB/c mice were intraperitoneally immunized with peptide-keyhole limpet hemocyanin (KLH) conjugates adjuvanted with incomplete Freund's adjuvant (IFA). The humoral and T-cell immune responses induced by peptide-KLH conjugates were assessed using ELISA and ELISpot assays, respectively. The efficacy of the S2M2-30-KLH vaccine against SARS-CoV-2 variants was evaluated in vivo using the K18-hACE2 transgenic mouse model. The inhibitory effect of mouse immune serum on SARS-CoV-2 virus replication in vitro was evaluated using microneutralization assays. The subcellular localization of the M protein was evaluated using an immunofluorescent staining method, and the Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) activity of the S2M2-30-specific monoclonal antibody (mAb) was measured using an ADCC reporter assay., Results: Seroconversion rates for ectodomain-specific IgG were observed to be high in both SARS-CoV-2 convalescent patients and individuals immunized with inactivated vaccines. To assess the protective efficacy of the M protein ectodomain-based vaccine, we initially identified a highly immunogenic peptide derived from this ectodomain, named S2M2-30. The mouse serum specific to S2M2-30 showed inhibitory effects on the replication of SARS-CoV-2 variants in vitro . Immunizations of K18-hACE2-transgenic mice with the S2M2-30-keyhole limpet hemocyanin (KLH) vaccine significantly reduced the lung viral load caused by B.1.1.7/Alpha (UK) infection. Further mechanism investigations reveal that serum neutralizing activity, specific T-cell response and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) correlate with the specific immuno-protection conferred by S2M2-30., Discussion: The findings of this study suggest that the antibody responses against M protein ectodomain in the population most likely exert a beneficial effect on preventing various SARS-CoV-2 infections., Competing Interests: Author LD was employed by company Beijing Weimiao Biotechnology Co. Ltd. Authors LD, YT, SY, YC, CL, Z-WY, YH, and DL are inventors of the patent application related to this study Patent applicant: Hunan University; Application No.: CN202210366334.5. The remaining 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 Tang, Tang, Hu, Ye, Luo, Luo, Cao, Wang, Yue, Liu, Liu, Ge, Liu, Chen, Yuan and Deng.)

Competing Interests: Declaration of interests The authors declare no competing interests.

Background: This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men., Research Design and Methods: In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability., Results: HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (T max ) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged T max but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration., Conclusions: HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation., Trial Registration: ClinicalTrials.gov (NCT05638126).

Cellular therapies for type-1 diabetes can leverage cell encapsulation to dispense with immunosuppression. However, encapsulated islet cells do not survive long, particularly when implanted in poorly vascularized subcutaneous sites. Here we show that the induction of neovascularization via temporary controlled inflammation through the implantation of a nylon catheter can be used to create a subcutaneous cavity that supports the transplantation and optimal function of a geometrically matching islet-encapsulation device consisting of a twisted nylon surgical thread coated with an islet-seeded alginate hydrogel. The neovascularized cavity led to the sustained reversal of diabetes, as we show in immunocompetent syngeneic, allogeneic and xenogeneic mouse models of diabetes, owing to increased oxygenation, physiological glucose responsiveness and islet survival, as indicated by a computational model of mass transport. The cavity also allowed for the in situ replacement of impaired devices, with prompt return to normoglycemia. Controlled inflammation-induced neovascularization is a scalable approach, as we show with a minipig model, and may facilitate the clinical translation of immunosuppression-free subcutaneous islet transplantation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objective: Childhood is a crucial period for the formation of an individual's attachment type. Previous studies focused more on how to directly intervene in children's mental health problems such as depression, and less on how to improve children's mental health from the perspective of attachment relationship. Secure base, as one of the core concepts of attachment theory, plays an important role in the whole process of children's psychological development. In this article, we review the concept of the secure base, describe current clinical practice and suggest future directions., Methods: A literature search was performed within electronic databases such as Web of Science, PubMed, and CNKI. Chinese and English articles focusing on the secure base and attachment relationship among children were retrieved. Their publication dates were set from the inception of the database to August 6, 2024., Key Content and Findings: While the secure base significantly impacts early childhood, a safe base may also be established through group and teacher-student relationships to activate individual secure attachment schemas. Most prior studies concentrated on the mother-child bond, with limited exploration of the father's role in the family dynamic. Furthermore, children's secure attachment development is not only influenced by parents' secure base script knowledge (SBSK) but also by intergenerational transmission. The underlying structure of secure base scripting knowledge plays a distinct role in middle childhood mental health., Conclusions: The mechanism by which family structure, the functional division of family roles, and the potential structure of safe-base script knowledge influence children's secure attachment development at various stages warrants further elucidation, including investigating cross-gender and cross-cultural stability. To facilitate the development of children's secure attachment pathways, it is essential to consider different attachment styles within parents and diverse family structures (including those in lesbian, gay, bisexual). From a clinical psychotherapy perspective, this review offered novel insights and practical guidance on how the secure base mechanism impacts children's mental health, with the overarching goal of mitigating the risk of mental health problems., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-191/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Aims: Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients., Methods and Results: We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185  arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (<1185 AU in men and <850 AU in women), sub-severe (1185-2064 AU in men and 850-1274 AU in women), and severe (>2064 AU in men and >1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7-4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups., Conclusion: Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The pathogens causing unexplained pneumonia in both HIV-infected or HIV-unfected patients are likely to be complex. This retrospective study aimed to characterize the etiology of pneumonia in HIV-infected and HIV-uninfected patients using bronchoalveolar lavage fluid (BALF) analysis with metagenomic next-generation sequencing (mNGS) and X-pert MTB/RIF., Methods: Between January 2022 and May2024, 141 HIV-infected and 104 HIV-uninfected patients admitted to Nanjing Second Hospital with pneumonia were included. BALF samples were collected and analyzed using mNGS to detect bacteria, fungi, viruses, tuberculosis (TB) and non-tuberculous mycobacteria (NTM), and X-pert for TB detection. Clinical data including CD4 T-cell counts, comorbidities, and ART status were collected and analyzed., Results: HIV-uninfected patients were found to be older and exhibited a higher prevalence of comorbidities compared to HIV-infected patients. Despite higher median CD4 T-cell counts in HIV-uninfected individuals (412 cells/μL vs. 31 cells/μL in HIV-infected), TB detection rates using X-pert and mNGS were lower than anticipated, particularly in HIV-infected patients. Mixed-pathogen infections were significantly more prevalent in HIV-infected patients, especially those with lower CD4 T-cell counts. ART use showed variable impacts on pathogen diversity, with longer treatment durations associated with reduced infection complexity but persistent immunodeficiency in some cases.In patients with pneumonia, whether HIV-infected or HIV-uninfected, pathogens often exhibit complexity, underscoring the critical role of timely mNGS and X-pert analysis of BALF for early pathogen detection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Ophthalmology is a subject that highly depends on imaging examination. Artificial intelligence (AI) technology has great potential in medical imaging analysis, including image diagnosis, classification, grading, guiding treatment and evaluating prognosis. The combination of the two can realize mass screening of grass-roots eye health, making it possible to seek medical treatment in the mode of "first treatment at the grass-roots level, two-way referral, emergency and slow treatment, and linkage between the upper and lower levels". On the basis of summarizing the AI technology carried out by scholars and their teams all over the world in the field of ophthalmology, quite a lot of studies have confirmed that machine learning can assist in diagnosis, grading, providing optimal treatment plans and evaluating prognosis in corneal and conjunctival diseases, ametropia, lens diseases, glaucoma, iris diseases, etc . This paper systematically shows the application and progress of AI technology in common anterior segment ocular diseases, the current limitations, and prospects for the future., Competing Interests: Conflicts of Interest: Liu YH, None; Li LY, None; Liu SJ, None; Gao LX, None; Tang Y, None; Li ZH, None; Ye Z, None., (International Journal of Ophthalmology Press.)

With the acceleration of population aging, disability in older adults is a growing public health problem; however, little is known about the role of specific leisure-time activities in affecting disability. This study prospectively examined the association of leisure-time activities with disability among the Chinese oldest old. A total of 14 039 adults aged 80 years or older (median age of 89.8 years) were enrolled from the Chinese Longitudinal Healthy Longevity Survey from 1998 to 2014. Disability was defined as the presence of concurrent impairment in activities of daily living and physical performance. Cox proportional hazards models were used to estimate the associations between leisure-time activities and disability. During a mean of 4.2 years (2.7 years) of follow-up, 4487 participants developed disability. Compared with participants who never engaged in leisure-time activities, participants who engaged in almost daily activities, including gardening, keeping domestic animals or pets, playing cards or mahjong, reading books or newspapers, and watching TV or listening to the radio had a lower risk of disability, with HRs of 0.78 (0.69-0.88), 0.64 (0.58-0.70), 0.74 (0.63-0.86), 0.74 (0.65-0.84), and 0.84 (0.77-0.90), respectively. Moreover, the risk of disability gradually decreased with participation in an increasing number of those leisure-time activities (P for trend <0.001). Frequent engagement in leisure-time activities was associated with a lower risk of disability among the Chinese oldest old. This study highlights the importance of incorporating a broad range of leisure-time activities into the daily lives of older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated 172 , demonstrated broad-spectrum antiviral activity against multiple human pathogenic coronaviruses and different SARS-CoV-2 variants of concern. Mechanistic studies validated by reverse genetics showed that compound 172 inhibits the 3-chymotrypsin-like protease (3CLpro) by binding to an allosteric site and reduces 3CLpro dimerization. A drug synergistic checkerboard assay demonstrated that compound 172 can achieve drug synergy with nirmatrelvir in vitro . In vivo studies confirmed the antiviral activity of compound 172 in both Golden Syrian Hamsters and K18 humanized ACE2 mice. Overall, this study identified an alternative druggable site on the SARS-CoV-2 3CLpro, proposed a potential combination therapy with nirmatrelvir to reduce the risk of antiviral resistance and shed light on the development of allosteric protease inhibitors for treating a range of coronavirus diseases., Competing Interests: The authors have no conflict to declare., (© 2024 The Authors.)

Objective: The objective of this study is to assess the efficacy of auricular point acupressure in relieving postoperative pain and reducing anxiety among patients with perianal abscesses., Methods: We included 61 patients with perianal abscesses who were admitted to the Nantong First People's Hospital between July 2019 and June 2020 and were scheduled to undergo one-stage radical surgery. We divided them into the treatment group (n = 31), where patients were administered preoperative auricular acupressure targeting the bilateral Shenmen, subcortical, and other points. They were instructed to apply pressure five to six times per day, each time for about 3-5 min. Patients in the control group (n = 30) received routine preoperative preparation. The treatment duration for both groups was one week. We compared the two groups using the pain visual analog scale (VAS) scores, the use of additional postoperative analgesics, and scores on the Hamilton anxiety and depression scales pre- and post-surgery at 6 h, 24 h, 48 h, 72 h, and 1 week after surgery, as well as at the time of the first bowel movement., Results: Patients in the treatment group reported lower VAS scores than those of the control group at 48 h, 72 h, 1 week, and at the first defecation post-surgery, and the differences were statistically significant (all P < 0.05). Additional postoperative analgesics were used in seven patients in the treatment group (22.58 %) and in 10 patients in the control group (33.33 %). The difference between the two groups was not statistically significant (χ 2 = 0.88, P = 0.35). Postoperative scores for the Hamilton Anxiety Rating Scale (HAM-A) and the Hamilton Depression Rating Scale (HAM-D) in the treatment group were significantly lower than those in the control group (P < 0.05)., Conclusion: The results of this study demonstrated that auricular point acupressure was effective in alleviating postoperative pain in patients with perianal abscesses and simultaneously reduced their postoperative psychological stress reactions. This dual effect provided both pain relief and a reduction of anxiety with fewer adverse reactions, making it a safe and effective treatment option., (Copyright © 2024. Published by Elsevier Inc.)

Background: There are a few reports on the associations between fine particulate matter (PM 2.5 )-bound heavy metals and lung function., Objectives: To evaluate the associations of single and mixed PM 2.5 -bound heavy metals with lung function., Methods: This study included 316 observations of 224 Chinese adults from the Wuhan-Zhuhai cohort over two study periods, and measured participants' personal PM 2.5 -bound heavy metals and lung function. Three linear mixed models, including the single constituent model, the PM 2.5 -adjusted constituent model, and the constituent residual model were used to evaluate the association between single metal and lung function. Mixed exposure models including Bayesian kernel machine regression (BKMR) model, weighted quantile sum (WQS) model, and Explainable Machine Learning model were used to assess the relationship between PM 2.5 -bound heavy metal mixtures and lung function., Results: In the single exposure analyses, significant negative associations of PM 2.5 -bound lead, antimony, and cadmium with peak expiratory flow (PEF) were observed. In the mixed exposure analyses, significant decreases in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), maximal mid-expiratory flow (MMF), and forced expiratory flow at 75% of the pulmonary volume (FEF75) were associated with the increased PM 2.5 -bound heavy metal mixture. The BKMR models suggested negative associations of PM 2.5 -bound lead and antimony with lung function. In addition, PM 2.5 -bound copper was positively associated with FEV1/FVC, MMF, and FEF75. The Explainable Machine Learning models suggested that FEV1/FVC, MMF, and FEF75 decreased with the elevated PM 2.5 -bound lead, manganese, and vanadium, and increased with the elevated PM 2.5 -bound copper., Conclusions: The negative relationships were detected between PM 2.5 -bound heavy metal mixture and FEV1/FVC, MMF, as well as FEF75. Among the PM 2.5 -bound heavy metal mixture, PM 2.5 -bound lead, antimony, manganese, and vanadium were negatively associated with FEV1/FVC, MMF, and FEF75, while PM 2.5 -bound copper was positively associated with FEV1/FVC, MMF, and FEF75., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Perceived stress is an acknowledged risk factor for subthreshold depression (StD), and fluctuations in perceived stress are thought to disrupt the harmony of brain networks essential for emotional and cognitive functioning. This study aimed to elucidate the relationship between eye-open (EO) and eye-closed (EC) states, perceived stress, and StD. We recruited 27 individuals with StD and 33 healthy controls, collecting resting state fMRI data under both EC and EO conditions. We combined intrinsic connectivity and seed-based functional connectivity analyses to construct the functional network and explore differences between EC and EO conditions. Graph theory analysis revealed weakened connectivity strength in the right superior frontal gyrus (SFG) and right median cingulate and paracingulate gyrus (MCC) among participants with StD, suggesting an important role for these regions in the stress-related emotions dysregulation. Notably, altered SFG connectivity was observed to significantly relate to perceived stress levels in StD, and the SFG connection emerges as a neural mediator potentially influencing the relationship between perceived stress and StD. These findings highlight the role of SFG and MCC in perceived stress and suggest that understanding EC and EO states in relation to these regions is important in the neurobiological framework of StD. This may offer valuable perspectives for early prevention and intervention strategies in mental health disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The treatment of patients with metastatic prostate cancer (PCa) is considered to be a long‑standing challenge. Conventional treatments for metastatic PCa, such as radical prostatectomy, radiotherapy and androgen receptor‑targeted therapy, induce senescence of PCa cells to a certain extent. While senescent cells can impede tumor growth through the restriction of cell proliferation and increasing immune clearance, the senescent microenvironment may concurrently stimulate the secretion of a senescence‑associated secretory phenotype and diminish immune cell function, which promotes PCa recurrence and metastasis. Resistance to established therapies is the primary obstacle in treating metastatic PCa as it can lead to progression towards an incurable state of disease. Therefore, understanding the molecular mechanisms that underly the progression of PCa is crucial for the development of novel therapeutic approaches. The present study reviews the phenomenon of treatment‑induced senescence in PCa, the dual role of senescence in PCa treatments and the mechanisms through which senescence promotes PCa metastasis. Furthermore, the present review discusses potential therapeutic strategies to target the aforementioned processes with the aim of providing insights into the evolving therapeutic landscape for the treatment of metastatic PCa.

Purpose: To explore the correlation of endoplasmic reticulum stress (ERS) and oxidative stress (OS), and the protective effect of Sestrin2 (SESN2) on human lens epithelial cells (HLECs)., Methods: Tunicamycin (TM) was used to induce ERS in HLECs. 4-Phenylbutyric acid (4-PBA) was used to inhibit ERS. Eupatilin applied to HLECs as SESN2 agonist. SESN2 expression was knocked down via si-RNA in HLECs. The morphological changes of HLECs were observed by microscope. ER-tracker to evaluate ERS, ROS production assay to measure ROS, flow cytometry to calculate cell apoptosis rate. Immunofluorescence to observe Nrf2 translocation, and effects of TM or EUP on SESN2. Western blot and qPCR were used to evaluate the expression of GRP78, PERK, ATF4, CHOP, Nrf2, and SESN2 expression in HLECs with different treatment groups., Results: ERS can elevate the expression of ROS and Nrf2 to induce OS. Upregulation of SESN2 was observed in ERS-mediate OS. Overexpression of SESN2 can reduce the overexpression of ERS-related protein GRP78, PERK, ATF4, proapoptotic protein CHOP, OS-related protein Nrf2, as well as ROS, and alleviate ERS injury at the same time. Whereas knockdown of SESN2 can upregulate the expression of GRP78, PERK, ATF4, CHOP, Nrf2, ROS, and deteriorate ERS damage., Conclusions: ERS can induce OS, they form a vicious cycle to induce apoptosis in HLECs, which may contribute to cataract formation. SESN2 could protect HLECs against the apoptosis by regulating the vicious cycle between ERS and OS.

Long non‑coding RNAs serve a crucial role in autophagy of vascular smooth muscle cells (VSMCs). The present study aimed to investigate the effect of small nucleolar RNA host gene 1 (SNHG1) on autophagy in VSMCs and the associated underlying mechanisms. Rapamycin was used to induce autophagy in VSMCs and the effects of SNHG1 on the proliferation and migration of VSMCs and the change in phenotype were tested following overexpression and silencing of SNHG1. The target gene of SNHG1 was predicted and validated. SNHG1‑regulated autophagy of VSMCs via C‑type lectin domain family 7 member A (CLEC7A) was determined by combined silencing of SNHG1 and overexpression of CLEC7A. Rapamycin‑induced autophagy in VSMCs changed the cell phenotype from contractile to synthetic, with decreased expression of α‑smooth muscle actin and smooth muscle protein 22a and increased expression of osteopontin. Overexpression of SNHG1 caused the same change in phenotype while the opposite change was observed following SNHG1 silencing. Overexpression of SNHG1 promoted the proliferation and migration of VSMCs. CLEC7A was identified as a target gene of SNHG1 and a direct binding relationship between them was confirmed by RNA immunoprecipitation and RNA pull‑down assays. Overexpression of SNHG1 increased the expression of CLEC7A. The expression of both SNHG1 and CLEC7A was increased during autophagy of VSMCs. Overexpression of SNHG1 promoted autophagy of VSMCs and silencing of CLEC7A reduced this effect of SNHG1. In conclusion, SNHG1 and CLEC7A were increased in VSMCs following autophagy. SNHG1 promotes the conversion of VSMCs from a contractile phenotype to a synthetic phenotype by facilitating CLEC7A expression.

The long-term effectiveness of stabilized/solidified sediments (S/S sediments) is increasingly attracting attention. This study investigated the long-term leaching characteristics and mechanisms of S/S sediment through an 841-day tank leaching test, considering the influence of cement content, curing time, and zeolite. The results indicate significant correlations among pH, heavy metals, TN, NH 3 -N, and COD. The specimens with 6 % cement cured for 30 days (C6(30)) demonstrated considerable heavy metal stabilization, with stabilization rates for Cr, Ni, Cu, Zn, As, and Pb reaching 99.81 %, 99.06 %, 98.93 %, 99.61 %, 97.58 %, and 99.97 %, respectively. Compared to C6(30), partial replacement of cement with 10 % zeolite (C5 + Z0.5(30)) not only more effectively stabilized heavy metals except As, but also reduced the release of COD and NH 3 -N by 4.23 % and 10.04 %, respectively. However, there was a risk of TN, NH 3 -N, and COD exceeding permissible limits during long-term leaching. Microscopic analysis results suggested that hydration products and low porosity contributed to stabilization of heavy metals. Leaching mechanisms was revealed that surface wash-off controls the leaching of Cr and Pb, while diffusion controls the leaching of Ni, Cu, Zn, As, COD, TN, and NH 3 -N. Considering stabilization performance, cost and carbon emissions, C5 + Z0.5(30) is an effective strategy for reducing long-term environmental risks of S/S sediments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Flammulina velutipes, a widely cultivated species of edible fungus, exhibits diverse functional activities attributed to its polysaccharides. In this study, we employed an in vitro model to investigate the impact of F. velutipes polysaccharides (FVP) fermentation on gut microbiota, with a particular focus on Bacteroides. FVP fermentation resulted in the proliferation of microbiota associated with short-chain fatty acid (SCFA) metabolism and suppression of Escherichia-Shigella. Bacteroides emerged as potential primary degraders of FVP, with species-level analysis identifying the preference of B. thetaiotaomicron and B. intestinalis in FVP degradation. Metabolomics analysis revealed significant increases in hypoxanthine and 7-methyladenine contents, with histidine metabolism emerging as the most enriched pathway. B. nordii and B. xylanisolvens exhibited the most influence on amino acid and SCFA metabolism. Understanding the mechanisms by which gut microbiota metabolize FVP can provide valuable insights into the potential of FVP to promote intestinal health and disease prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glaucoma is the world's second-leading irreversible eye disease causing blindness. Although the pathogenesis of glaucoma is not particularly well understood, high intraocular pressure (IOP) is widely recognized as a significant risk factor. In clinical practice, various devices have been used to measure IOP, but most of them cannot provide continuous measurements for a long time. To meet the needs of glaucoma patients who experience frequent fluctuations in the IOP and require constant monitoring, we fabricated an implantable piezoresistive IOP sensor based on microfluidic technology. The sensor has a sensitivity of 0.00257 Ω/mbar and demonstrates excellent linearity, stability, and repeatability. According to the calibration data, the average measurement error is ±0.5 mbar. We implanted it into the vitreous of a rabbit and successfully detected its IOP fluctuations. The sensor is simple in design, easy to fabricate, and can be used for long-term continuous IOP measurements. It presents a new approach for microfluidic-based IOP sensors and offers a novel method for the daily care of patients with glaucoma.

This study aimed to determine the optimal high-sensitivity cardiac troponin I (hs-cTnI)-based algorithm for early diagnosis of non-ST-elevation myocardial infarction (NSTEMI) in Chinese patients. We prospectively enrolled 1,606 patients with suspected NSTEMI from three emergency departments across China, collecting blood samples at 0, 1, and 3 h post-admission. Patients were classified using the 0/1-h and 0/3-h algorithms. The 2015 and 2020 ESC 0/1-h algorithms rapidly triaged 70% of patients with high negative predictive value (NPV) (99.7%) and sensitivity (99.5%). The 0/3-h algorithm showed higher specificity (93.8%) but lower NPV (96.8%) and sensitivity (91.2%). An optimized 0/1-h algorithm improved specificity to 92.1% while maintaining high NPV (99.7%) and sensitivity (99.2%). Low 30-day and 180-day all-cause mortality and major adverse cardiac event (MACE) rates were observed in rule-out groups for all algorithms. The ESC 0/1-h algorithm is a safe and efficient triage method for patients with suspected NSTEMI, with optimization further enhancing specificity and efficiency for the Chinese population., Competing Interests: All authors declare no conflicts relevant to the contents of this article., (© 2024 The Authors.)

Abstract: Aneurysms are localized dilations of blood vessels, which can expand to 50% of the original diameter. They are more common in cardiovascular and cerebrovascular vessels. Rupture is one of the most dangerous complications. The pathophysiology of aneurysms is complex and diverse, often associated with progressive vessel wall dysfunction resulting from vascular smooth muscle cell death and abnormal extracellular matrix synthesis and degradation. Multiple studies have shown that long noncoding RNAs (lncRNAs) play a significant role in the progression of cardiovascular and cerebrovascular diseases. Therefore, it is necessary to find and summarize them. LncRNAs control gene expression and disease progression by regulating target mRNA or miRNA and are biomarkers for the diagnosis and prognosis of aneurysmal cardiovascular and cerebrovascular diseases. This review explores the role, mechanism, and clinical value of lncRNAs in aneurysms, providing new insights for a deeper understanding of the pathogenesis of cardiovascular and cerebrovascular aneurysms., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To explore the effect of silent information regulator factor 2-related enzyme 1 (SIRT1) on modulating apoptosis of human lens epithelial cells (HLECs) and alleviating lens opacification of rats through suppressing endoplasmic reticulum (ER) stress., Methods: HLECs (SRA01/04) were treated with varying concentrations of tunicamycin (TM) for 24h, and the expression of SIRT1 and C/EBP homologous protein (CHOP) was assessed using real-time quantitative polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. Cell morphology and proliferation was evaluated using an inverted microscope and cell counting kit-8 (CCK-8) assay, respectively. In the SRA01/04 cell apoptosis model, which underwent siRNA transfection for SIRT1 knockdown and SRT1720 treatment for its activation, the expression levels of SIRT1, CHOP, glucose regulated protein 78 (GRP78), and activating transcription factor 4 (ATF4) were examined. The potential reversal of SIRT1 knockdown effects by 4-phenyl butyric acid (4-PBA; an ER stress inhibitor) was investigated. In vivo , age-related cataract (ARC) rat models were induced by sodium selenite injection, and the protective role of SIRT1, activated by SRT1720 intraperitoneal injections, was evaluated through morphology observation, hematoxylin and eosin (H&E) staining, Western blotting, and RT-PCR., Results: SIRT1 expression was downregulated in TM-induced SRA01/04 cells. Besides, in SRA01/04 cells, both cell apoptosis and CHOP expression increased with the rising doses of TM. ER stress was stimulated by TM, as evidenced by the increased GRP78 and ATF4 in the SRA01/04 cell apoptosis model. Inhibition of SIRT1 by siRNA knockdown increased ER stress activation, whereas SRT1720 treatment had opposite results. 4-PBA partly reverse the adverse effect of SIRT1 knockdown on apoptosis. In vivo , SRT1720 attenuated the lens opacification and weakened the ER stress activation in ARC rat models., Conclusion: SIRT1 plays a protective role against TM-induced apoptosis in HLECs and slows the progression of cataract in rats by inhibiting ER stress. These findings suggest a novel strategy for cataract treatment focused on targeting ER stress, highlighting the therapeutic potential of SIRT1 modulation in ARC development., Competing Interests: Conflicts of Interest: Cui H, None; Sun D, None; Meng S, None; Ma TJ, None; Ye Z, None; Li ZH, None., (International Journal of Ophthalmology Press.)

The effective separation of aromatic and aliphatic hydrocarbons remains a notable challenge in the petrochemical industry. Herein, we report a self-healing three-dimensional B ← N-based hydrogen-bonded organic framework (HOF), BN-HOF-1, constructed from discrete B ← N inclusive dimers through weak C-H···F and C-H···N hydrogen-bonding interactions. To make use of the specific recognition of the B ← N inclusive dimers for the toluene molecules and the reversible ad/desorption nature of this novel HOF, BN-HOF-1 can exclusively recognize and separate toluene from the mixtures of toluene-methylcyclohexane, thus generating 99.6% pure toluene from its mixtures after gentle heating, the recorded value among any reported materials for toluene purification. After the toluene molecules were released from the framework, it becomes the condensed BN-HOF-1a, which can be further reused for the highly selective recognition and purification of toluene from its binary mixtures, through the reversible structural recovery back to BN-HOF-1. Single-crystal X-ray diffraction and molecular modeling studies reveal that the high specific toluene recognition is attributed to the complementary electrostatic potential between the host B ← N inclusive dimers and the guest toluene, while the self-healing and recovery nature of this HOF is attributed to weak intermolecular hydrogen-bonding interactions.

In this paper, we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors (SGLTis) for patients with type 2 diabetes who have heart failure with a preserved injection fraction, acute heart failure, atrial fibrillation, primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease, and acute myocardial infarction. We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1, 2020 and April 6, 2024 for our review. According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Rationale and Objectives: This study explored the intratumor heterogeneity (ITH) of esophageal squamous cell carcinoma (ESCC) using computed tomography (CT) and investigated the value of CT-based ITH in predicting the response to immune checkpoint inhibitor (ICI) plus chemotherapy in patients with ESCC., Materials and Methods: This retrospective study included 416 patients with ESCC who received ICI plus chemotherapy at two independent hospitals between January 2019 and July 2022. Multiparametric CT features were extracted from ESCC lesions and screened using hierarchical clustering and dimensionality reduction algorithms. Logistic regression and machine learning models based on selected features were developed to predict treatment response and validated in separate datasets. ITH was quantified using the score calculated by the best-performing model and visualized through feature clustering and feature contribution heatmaps. A gene set enrichment analysis (GSEA) was performed to identify the biological pathways underlying the CT-based ITH., Results: The extreme gradient boosting model based on CT-derived ITH had higher discriminative power, with areas under the receiver operating characteristic curve of 0.864 (95% confidence interval [CI]: 0.774-0.954) and 0.796 (95% CI: 0.698-0.893) in the internal and external validation sets. The CT-based ITH pattern differed significantly between responding and non-responding patients. The GSEA indicated that CT-based ITH was associated with immunity-, keratinization-, and epidermal cell differentiation-related pathways., Conclusion: CT-based ITH is an effective biomarker for identifying patients with ESCC who could benefit from ICI plus chemotherapy. Immunity-, keratinization-, and epidermal cell differentiation-related pathways may influence the patient's response to ICI plus chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Three preregistered experiments examined to what extent information about an epidemic situation provided by experts and information about anti-infection policies promoted by governments/media influenced anti-infection behaviors. The above effects were examined among populations from different countries (in Experiments 2 and 3) and across self-construals (in Experiment 3). In three experiments, participants (N =706) were presented with a scenario where experts provided (or did not provide) information about an epidemic situation and governments/media promoted (or did not promote) information about anti-infection policies. After that, participants indicated their willingness to adopt anti-infection behaviors. Results across three experiments showed that both types of information independently increased participants' anti-infection behaviors. In Experiments 2 and 3, we further found that the epidemic information had a larger impact on inducing anti-infection behaviors than the policy information, which was robust and consistent across countries and self-construals. Findings were discussed under the framework of social influence and in terms of practical implications for pandemic situations like the COVID-19.

Purpose: To investigate the capacity of critical flicker frequency (CFF) in discriminating cataract eyes with or without macula disease using trichromatic flickers, and to develop a model to predict postoperative best corrected visual acuity (BCVA)., Methods: Patients were divided into two groups based on the presence or absence of macular disease. CFF threshold measurements of red (R-CFF), green (G-CFF), and yellow (Y-CFF) flickers were conducted both preoperatively and postoperatively. A generalized estimating equations model (GEE) was employed to examine the relationship between CFF threshold and 3-month postoperative BCVA., Results: A total of 115 eyes were enrolled, with 59 eyes in the cataract alone group and 56 eyes in the cataract with macular disease group completing the follow-up. R-CFF was found to be consistent before and after cataract removal (P = 0.06), even in cases where OCT was not performed successfully (P > 0.05). Y-CFF showed the highest AUC (0.798) for differentiating ocular comorbidities. According to the GEE model, in patients with a CFF threshold below 26 Hz, the odds ratios for achieving a postoperative VA of 20/40 or better were 34.8% for R-CFF, 26.0% for G-CFF, and 24.5% for Y-CFF., Conclusion: CFF emerges as a promising tool for predicting postoperative BCVA, providing valuable supplementary insights when fundus examination is obstructed. R-CFF demonstrates the best resistance to cataracts, while Y-CFF exhibits the highest sensitivity both in identifying macular diseases and predicting postoperative BCVA of 20/40 or better., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

External stimuli triggering chemical reactions in cancer cells to generate highly reactive chemical species are very appealing for cancer therapy, in which external irradiation activating sensitizers to transfer energy or electrons to surrounding oxygen or other molecules is critical for generating cytotoxic reactive species. However, poor light penetration into tissue, low activity of sensitizers, and reliance on oxygen supply restrict the generation of cytotoxic chemical species in hypoxic tumors, which lowers the therapeutic efficacy. Here, this work presents galvanic cell nanomaterials that can directly release highly reactive electrons in tumors without external irradiation or photosensitizers. The released reactive electrons directly react with surrounding biomolecules such as proteins and DNA within tumors to destroy them or react with other surrounding (bio)molecules to yield cytotoxic chemical species to eliminate tumors independent of oxygen. Administering these nanogalvanic cells to mice results in almost complete remission of subcutaneous solid tumors and deep metastatic tumors. The results demonstrate that this strategy can further arouse an immune response even in a hypoxic environment. This method offers a promising approach to effectively eliminate tumors, similar to photodynamic therapy, but does not require oxygen or irradiation to activate photosensitizers., (© 2024 Wiley‐VCH GmbH.)

Objective: In this study, we compared the analgesic effects of intercostal nerve block (ICNB), ultrasound-guided paravertebral nerve block (PVB), and epidural block (EB) following single-port thoracoscopic lung surgery., Method: A total of 120 patients who underwent single-hole thoracoscopic lung surgery were randomly and equally divided into three groups: ICNB group, the PVB group, and the EB group. ICNB was performed under direct thoracoscopic visualization before the conclusion of the surgery in the ICNB group, while PVB and EB were performed after general anesthesia in the PVB and EB groups, respectively. Patient-controlled intravenous analgesia (PCIA) was used following the surgery in all the groups. The following indicators were recorded: Intraoperative sufentanil dosage, anesthesia awakening time, postoperative intubation time, nerve block operation time, postoperative visual analog scale (VAS) pain scores during resting and coughing at regular intervals of 0, 2, 4, 8, 24, and 48 h, the time until first PCIA, number of effective compressions within 24 h postoperatively, number of rescue analgesia interventions, and the side effects., Results: In comparison to the ICNB group, the PVB and EB groups had a lower intraoperative sufentanil dosage, significantly shorter anesthesia awakening time, and postoperative intubation time, but longer nerve block operation time, lower VAS scores when resting and coughing within 24 h postoperatively (all p-values less than 0.05). Conversely, there were no statistically significant differences in VAS scores during resting and coughing after 24 h (all p-values greater than 0.05). Time to first PCIA, number of effective compressions and number of rescue analgesia at the 24-hour mark postoperatively were significantly better in the PVB and EB groups than that in the ICNB group (P < 0.05). However, there was a higher incidence of side effects observed in the EB group (P < 0.05)., Conclusion: The analgesic effect of PVB and EB following single-port thoracoscopic lung surgery is better than that of ICNB. PVB causes fewer side effects and complications and is safer and more effective., (© 2024. The Author(s).)

Aim: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin., Methods: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24., Results: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia., Conclusions: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses., (© 2024 John Wiley & Sons Ltd.)

Reconfigurable intelligent surfaces (RIS) supply high-speed and in-depth coverage wireless networks for visible light communication (VLC) systems, improving the system adaptability to mobile scenarios. But the angle-related efficiency loss caused by the diffraction effect of RIS as well as the angular response of the lens-enhanced optical receiver severely affects the practical performance of the RIS-assisted VLC system, which have not draw the attention of researchers. By the influences of these adverse properties, the beam angle configuration method should be further explored. In this paper, a RIS-assisted optical receiver model that jointly considering the angle-related characteristics of both the RIS reflector and the receiver is proposed. Based on the model, the receiver property is characterized, and the beam angle optimization to achieve the maximum optical power is presented. The results of simulations verify the validity of the obtained optimal reflected angle, and test the practical detecting range of the optimally configured RIS-assisted receiver.

Hydrogels with strong adhesion to wet tissues are considered promising for wound dressings. However, the clinical application of adhesive hydrogel dressing remains a challenge due to the issues of secondary damage during dressing changes. Herein, we fabricated an adhesion-switchable hydrogel formed with poly(acrylamide)- co -poly( N -isopropyl acrylamide), quaternary ammonium chitosan and tannic acid. This hydrogel forms instant and robust adhesion to the skin at body temperature. However, as the temperature rises above the lower critical solution temperature (LCST), the hydrogel loses its adhesion towards the wound area due to the temperature-dependent volume phase transition of the copolymer, occurring around 45 °C. Consequently, the designed hydrogel can be easily detached from adhered tissues upon demand, providing a facile and effective method for painless dressing changes without secondary damage. This hydrogel holds great promise for long-term application in wound dressings.

The disturbance of ecological stability may take place in tropical regions due to the elevated biomass density resulting from heavy metal and other contaminant pollution. In this study, 62 valid soil samples were collected from Sanya. Source analysis of heavy metals in the area was carried out using absolute principal component-multiple linear regression receptor modelling (APCS-MLR); the comprehensive ecological risk of the study area was assessed based on pollution sources; the Monte-Carlo model was used to accurately predict the health risk of pollution sources in the study area. The results showed that: The average contents of soil heavy metals Cu, Ni and Cd in Sanya were 5.53, 6.56 and 11.66 times higher than the background values of heavy metals. The results of soil geo-accumulation index (I geo ) showed that Cr, Mo, Mn and Zn were unpolluted to moderately polluted, Cu and Ni were moderately polluted, and Cd was moderately polluted to strongly polluted. The main sources of heavy metal pollution were natural sources (57.99%), agricultural sources (38.44%) and traffic sources (3.57%). Natural and agricultural sources were jointly identified as priority control pollution sources and Cd was the priority control pollution element for soil ecological risk. Heavy metal content in Sanya did not pose a non-carcinogenic risk to the population, but there was a carcinogenic risk to children. The element Zn had a high carcinogenic risk to children, and was a priority controlling pollutant element for the risk of human health, with agricultural sources as the priority controlling pollutant source., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The gut microbiota is widely acknowledged as a crucial factor in regulating host health. The structure of dietary fibers determines changes in the gut microbiota and metabolic differences resulting from their fermentation, which in turn affect gut microbe-related health effects. β-Glucan (BG) is a widely accessible dietary fiber to humans, and its structural characteristics vary depending on the source. However, the interactions between different structural BGs and gut microbiota remain unclear. This study used an in vitro fermentation model to investigate the effects of BG on gut microbiota, and microbiomics and metabolomics techniques to explore the relationship between the structure of BG, bacterial communities, and metabolic profiles. The four sources of BG (barley, yeast, algae, and microbial fermentation) contained different types and proportions of glycosidic bonds, which differentially altered the bacterial community. The BG from algal sources, which contained only β(1 → 4) glycosidic bonds, was the least metabolized by the gut microbiota and caused limited metabolic changes. The other three BGs contain more diverse glycosidic bonds and can be degraded by bacteria from multiple genera, causing a wider range of metabolic changes. This work also suggested potential synergistic degradation relationships between gut bacteria based on BG. Overall, this study deepens the structural characterization-microbial-functional understanding of BGs and provides theoretical support for the development of gut microbiota-targeted foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)