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Background: Primary Sjögren syndrome (pSjS) is one of the most prevalent systemic autoimmune diseases and characterized with hyperactivation of B cell and the abundant presence of autoantibodies in sera. The salivary gland epithelial cells (SGECs) release autoantigens to evoke autoimmunity through releasing elevated apoptosis or secreting autoantigen-containing exosomes, thus identifying autoantibodies directly to SGECs might provide insights into disease related biomarkers as well as further elucidating pathogenesis mechanisms. The present study was undertaken to identify autoantibodies to SGECs and to evaluate its clinical values in Chinese pSjS., Methods: Cell-based indirect immunofluorescence and immunostaining, two-dimensional electrophoresis and liquid chromatograph-tandem mass spectrometry were conducted to identify the autoantibodies to human salivary gland cell line A253 in pSjS sera. Enzyme-linked immunosorbent assay (ELISA) was applied to identify autoantibody titer in pSjS cohort and healthy controls. The prevalence and clinical significance of the identified autoantibodies was further assessed in pSjS population., Results: Anti-calreticulin (CALR) antibody was identified as a new autoantibody directly to SGECs in sera from pSjS patients. Anti-CALR antibody were detected in 37 of 120 pSjS patients (30.83 %) and 1 of 54 healthy controls (1.85 %). It was found in 40.85 % pSjS with anti-SSA positive, 53.85 % with anti-SSB positive, and 14.7 % in sero-negative pSjS. Anti-CALR antibody was associated with clinical manifestations including weight loss(p = 0.045), vasculitis (p = 0.031), and laboratory parameters including erythrocyte sedimentation rate (ESR) (r = 0.056, p = 0.021), Krebs von den Lungen-6 (KL-6) (r = 0.121, p = 0.035), IgG (r = 0.097, p < 0.001), IgG2 (r = 0.142, p = 0.022), IgG3 (r = 0.287, p < 0.001), fibrinogen (r = 0.084, p = 0.016), D-Dimer (r = 0.086, p = 0.012) and fibrinogen degradation production (r = 0.150, p = 0.002). The expression of CALR in salivary glands was related to lymphocytes infiltration into salivary glands in pSjS patients (r = 0.7076, p = 0.0034)., Conclusion: To our knowledge, this was the first study to investigate the prevalence and clinical significance of anti-CALR antibody in Chinses pSjS patients. The present study identified an autoimmune antibody, anti-CALR antibody, as a good autoimmune biomarker for sero-negative pSjS., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Messenger RNA (mRNA)-based immunotherapies and protein in situ production therapies hold great promise for addressing theoretically all the diseases characterized by aberrant protein levels. The safe, stable, and precise delivery of mRNA to target cells via appropriate pharmaceutical strategies is a prerequisite for its optimal efficacy. In this review, we summarize the structural characteristics, mode of action, development prospects, and limitations of existing mRNA delivery systems from a pharmaceutical perspective, with an emphasis on the impacts from formulation adjustments and preparation techniques of non-viral vectors on mRNA stability, target site accumulation and transfection efficiency. In addition, we introduce strategies for synergistical combination of mRNA and small molecules to augment the potency or mitigate the adverse effects of mRNA therapeutics. Lastly, we delve into the challenges impeding the development of mRNA drugs while exploring promising avenues for future advancements., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Pharmaceutical Strategies for Optimized mRNA Expression”., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Adoptive cell therapy (ACT) emerged as a promising approach for cancer treatment, yet its application in solid tumors faced challenges such as inadequate tumor infiltration and cellular dysfunction. Histone acetylation is reported to play a crucial role in restoring T-cell function within tumor tissues. Building upon previous research, a novel strategy involving the co-loading of two drugs, G3C12 and vorinostat (SAHA), into PLGA microspheres to form G3C12+SAHA@PLGA is developed for intratumoral injection. The G3C12 peptide enhances adoptive T-cell recruitment to the tumor site by modulating the binding state of IFN-γ. While SAHA, a histone deacetylase inhibitor, promotes memory phenotypes of infiltrating T-cells and prevents their transition to an exhausted state. This synergistic approach effectively augmentes the efficacy of ACT in the "cold" tumor model (4T1) or the "hot" tumor model (CT26). These findings highlight the potential of combining epigenetic regulation with recruitment signaling as a means to enhance the therapeutic impact of ACT in treating solid tumors., (© 2024 Wiley‐VCH GmbH.)

The NSP14 protein of SARS-CoV-2 not only facilitates viral replication but also plays a pivotal role in activating the host immune system by enhancing cytokine production. In this study, we found that NSP14 markedly activated the activator protein 1 (AP-1) pathway by increasing the phosphorylation of ERK (p-ERK), which enters the nucleus and promotes AP-1 transcription. The screening of the main proteins of the ERK pathway revealed that NSP14 could interact with MEK, a kinase of ERK, and increase the level of phosphorylated MEK. The addition of the MEK inhibitor U0126 suppressed the level of p-ERK induced by NSP14 and partly blocked cytokine production, suggesting that NSP14 activates MEK to enhance AP-1 signaling. Further investigation demonstrated that the ExoN domain of NSP14 might be crucial for the interaction and activation of MEK. These results suggest a novel mechanism by which NSP14 of SARS-CoV-2 induces a proinflammatory response in the host., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4 + T cells, and rejuvenation of dendritic cells along with CD8 + T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases., 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.)

This study aimed to examine the relationships among family function, psychological resilience, and social network of patients with chronic disease in the community and to further identify whether psychological resilience played a mediating role in the relationship between family function and social network. A cross-sectional survey including 460 convenient samples of patients with chronic disease in four Chinese communities was conducted using a general characteristics questionnaire, the Family APGAR Index, the Connor-Davidson Resilience Scale, and the Lubben Social Network Scale 6. Data were analyzed using descriptive analysis, Student's t-test, one-way ANOVA, Pearson/Spearman correlation, hierarchical multiple regression analysis, and mediation analysis using the PROCESS macro. Family function, psychological resilience, and social network were significantly related. Psychological resilience partially mediated the relationship between family function and social network. Interventions designed to enhance family function and psychological resilience may improve social network among patients with chronic disease in the community., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Spectral-domain OCT angiography (SD-OCTA) scans were tested in an algorithm developed for use with swept-source OCT angiography (SS-OCTA) scans to determine if SD-OCTA scans yielded similar results for the detection and measurement of persistent choroidal hypertransmission defects (hyperTDs)., Design: Retrospective study., Participants: Forty pairs of scans from 32 patients with late-stage nonexudative age-related macular degeneration (AMD)., Methods: Patients underwent both SD-OCTA and SS-OCTA imaging at the same visit using the 6 × 6 mm OCTA scan patterns. Using a semiautomatic algorithm that helped with outlining the hyperTDs, 2 graders independently validated persistent hyperTDs, which are defined as having a greatest linear dimension ≥250 μm on the en face images generated using a slab extending from 64 to 400 μm beneath Bruch's membrane. The number of lesions and square root (sqrt) total area of the hyperTDs were obtained from the algorithm using each imaging method., Main Outcome Measures: The mean sqrt area measurements and the number of hyperTDs were compared., Results: The number of lesions and sqrt total area of the hyperTDs were highly concordant between the 2 instruments (r c  = 0.969 and r c  = 0.999, respectively). The mean number of hyperTDs was 4.3 ± 3.1 for SD-OCTA scans and 4.5 ± 3.3 for SS-OCTA scans ( P  = 0.06). The mean sqrt total area measurements were 1.16 ± 0.64 mm for the SD-OCTA scans and 1.17 ± 0.65 mm for the SS-OCTA scans ( P < 0.001). Because of the small standard error of the differences, the mean difference between the scans was statistically significant but not clinically significant., Conclusions: Spectral-domain OCTA scans provide similar results to SS-OCTA scans when used to obtain the number and area measurements of persistent hyperTDs through a semiautomated algorithm previously developed for SS-OCTA. This facilitates the detection of atrophy with a more widely available scan pattern and the longitudinal study of early to late-stage AMD., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology.)

Cracking of Akebia trifoliata fruit at maturity is problematic for the cultivation of the horticultural crop, shortening shelf-life quality and compromising commercial value. However, the molecular mechanisms underlying this feature of A. trifoliata are not known. Genes involved in cell wall metabolism were identified by genome and transcriptome sequencing, which may play important roles in fruit cracking. One of the galactose metabolism related genes, β-galactosidase (AtrBGAL2), was identified in A. trifoliata, and overexpression (OE) of AtrBGAL2 resulted in early fruit cracking, higher water-soluble pectin contents, and lower acid-soluble pectin, cellulose, and hemicellulose content compared to the wild type. Whereas silencing of AtrBGAL2 in trifoliata by virus induced gene silencing showed opposite trends. The levels of AtrBGAL2 transcripts were 24.6 and 66.0-fold higher in OE A. trifoliata and tomato fruits, respectively, and the cell wall-related genes were also gradually greater than in control plants during fruit ripening. Whereas the expression levels of AtrBGAL2 was significantly down-regulated by 54.1 % and 73.7 % in gene silenced A. trifoliata and CRISPR/Cas9 tomato mutant plants, respectively, and cell wall-related genes were also significantly reduced. These results demonstrate that AtrBGAL2 plays important roles in regulating fruit cracking during fruit ripening., Competing Interests: Declaration of competing interest The authors declare that this study was conducted without commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Male breast cancer (MBC) is a rare disease. Although several large-scale studies have investigated MBC patients in other countries, the features of MBC patients in China have not been fully explored. This study aims to explore the features of Chinese MBC patients comprehensively., Methods: We retrospectively collected data of MBC patients from 36 centers in China. Overall survival (OS) was evaluated by the Kaplan-Meier method, log-rank test, and Cox regression analyses. Multivariate Cox analyses were used to identify independent prognostic factors of the patients., Results: In total, 1119 patients were included. The mean age at diagnosis was 60.9 years, and a significant extension over time was observed (P < 0.001). The majority of the patients (89.1 %) received mastectomy. Sentinel lymph node biopsy was performed in 7.8 % of the patients diagnosed in 2009 or earlier, and this percentage increased significantly to 38.8 % in 2020 or later (P < 0.001). The five-year OS rate for the population was 85.5 % [95 % confidence interval (CI), 82.8 %-88.4 %]. Multivariate Cox analysis identified taxane-based [T-based, hazard ratio (HR) = 0.32, 95 % CI, 0.13 to 0.78, P = 0.012] and anthracycline plus taxane-based (A + T-based, HR = 0.47, 95 % CI, 0.23 to 0.96, P = 0.037) regimens as independent protective factors for OS. However, the anthracycline-based regimen showed no significance in outcome (P = 0.175)., Conclusion: As the most extensive MBC study in China, we described the characteristics, treatment and prognosis of Chinese MBC population comprehensively. T-based and A + T-based regimens were protective factors for OS in these patients. More research is required for this population., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hereditary white matter disease is a series of progressive genetic diseases that mainly affect the white matter of the central nervous system. The development of molecular genetics enables the clinical diagnosis, carrier detection, and prenatal diagnosis of hereditary white matter disease. Here, we block the transmission of pathogenic variants in ABCD1 and NOTCH3 in a family with cerebral white matter disease via preimplantation genetic testing (PGT). Pathogenic genes were identified based on clinical manifestations, genetic background, and the results of targeted gene capture sequencing. A blastocyst biopsy was performed, and multiple annealing and looping-based amplification (MALBAC), next-generation sequencing (NGS), and single nucleotide polymorphism (SNP) arrays were used to analyze ploidy and the state of the gene mutations. The proband (III:1) had hemizygous mutations in ABCD1 (c.323C>A (p.Ser108 *) and c.775C>T (p.Arg259Trp)) and heterozygous mutations in NOTCH3 (c.1630C>T (p.Arg544Cys)), which were maternally inherited (II:2). After genetic analysis, a euploid blastocyst without ABCD1 and NOTCH3 variations was transferred. A healthy male baby was born at full term, and the results of prenatal diagnosis by amniocentesis in the second trimester verified the results of PGT. To our knowledge, this is the first report of simultaneously blocking the transmission of pathogenic variants in ABCD1 and NOTCH3 via PGT. This report highlights the feasibility and effectiveness of PGT in preventing cerebral adrenoleukodystrophy (cALD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and provides valuable insights for the diagnosis and treatment of similar cases., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Council of Human Research in Xiamen Maternal and Child Health Care Hospital issued approval KY-2019-059. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (international and national) and with the Helsinki Declaration. Informed consent was obtained from all study participants. Participant identifiers have been removed, so the persons described are not identifiable. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Huang et al.)

The efficacy and safety of mRNA vaccines both rely on a fine-tuning of specific humoral and cellular immune responses. Instead of adjustments in vaccine component, we proposed a concept of chronological management of adjuvant effect to modulate the adaptive immune potency and preference inspired by natural virus infection. By simulating type I interferon expression dynamics during viral infection, three vaccine strategies employing distinct exposure sequences of adjuvant and mRNA have been developed, namely Precede , Coincide , and Follow . Follow , the strategy of adjuvant administration following mRNA, effectively suppressed tumor progression, which was attributed to enhanced mRNA translation, augmented p-MHC I expression, and elevated CD8 + T cell response. Meanwhile, Follow exhibited improved biosafety, characterized by reduced incidences of cardiac and liver toxicity, owing to its alteration to the vaccination microenvironment between successive injections. Our strategy highlights the importance of fine-tuning adjuvant effect dynamics in optimizing mRNA vaccines for clinical application.

Objective: To investigate the alleviating effect of chlorogenic acid (CGA) on oxidative damage in high glucose (HG)-induced HK-2 cells and to explore its potential mechanisms., Methods: We cultured the human proximal tubular cell line HK-2 and divided them into the control group and different concentrations of CGA groups (0, 5, 10, 25, 50, 100, 200 μM). The trypan blue dye test was used to detect CGA's potential cytotoxicity on HK-2 cells. Then, we treated HK-2 with HG and CGA; the Cell Counting Kit-8 (CCK-8) method was used to detect the cell viability of HK-2 cells in each group. Flow cytometry was employed to measure the apoptosis rate of cells. Western blot was performed to detect the expression of apoptosis proteins B-cell lymphoma-2 (BCL-2), BCL-2-associated X protein (BAX), cysteinyl aspartate specific proteinase (CASPASE)-9, and CASPASE-3. In addition, enzymatic activities, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and lipid peroxide (LPO), were measured with the corresponding detection kits. 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) assay and flow cytometry were performed to detect reactive oxygen species (ROS) production. Western blot analysis and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) were conducted to evaluate protein and mRNA expressions of the Kelch-like ECH-associated protein-1 (KEAP1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Antioxidant Response Elements (ARE) signaling pathway., Results: The outcomes showed that, in a dose-dependent way, CGA dramatically increased the vitality of HK-2 induced by HG. Furthermore, CGA significantly reduced the HG-stimulated HK-2 cell apoptosis, which may be linked to the promotion of BCL-2 and the suppression of BAX, cleaved-CASPASE-3, and cleaved-CASPASE-9 expression. In HK-2 cells, CGA reduced the formation of ROS generated by HG levels and markedly boosted the activity of the antioxidant enzymes SOD, GSH-Px, and CAT. Furthermore, compared with the HG group, CGA significantly raised NRF2 nuclear expression and downregulated NRF2 cytosolic expression and increased the mRNA expression of NRF2 and its target genes, heme oxygenase-1 ( HO-1 ), KEAP1 , and NAD(P)H dehydrogenase quinone 1 ( NQO1 )., Conclusion: These results show that CGA might be useful in managing oxidative damage in HG-induced HK-2 cells.

Lipopeptides, a class of compounds consisting of a peptide ring and a fatty acid chain, are secondary metabolites produced by Bacillus spp. As their hydrophilic and oleophilic properties, lipopeptides are widely used in food, medicine, environment and other industrial or agricultural fields. Compared with artificial synthetic surfactants, microbial lipopeptides have the advantages of low toxicity, high efficiency and versatility, resulting in urgent market demand and broad development prospect of lipopeptides. However, due to the complex metabolic network and precursor requirements of synthesis, the specific and strict synthesis pathway, and the coexistence of multiple homologous substances, the production of lipopeptides by microorganisms has the problems of high cost and low production efficiency, limiting the mass production of lipopeptides and large-scale application in industry. This review summarizes the types of Bacillus -produced lipopeptides and their biosynthetic pathways, introduces the versatility of lipopeptides, and describes the methods to improve the production of lipopeptides, including genetic engineering and optimization of fermentation conditions.

Thromboangiitis obliterans (TAO) is a non-atherosclerotic segmental inflammatory occlusive disease with a high recurrence rate, high disability rate, difficulty to cure, and poor prognosis. It has been clinically proven that Mailuoshutong pill (MLSTP) is an effective traditional Chinese medicine for treating TAO. As MLSTP contains hundreds of chemical components, the quality control of which is a challenge in the development of reliable quality evaluation metrics. This study aimed to evaluate the quality uniformity of MLSTP by establishing a multi-strategy platform. In the present study, the key targets and signaling pathways of MLSTP treating TAO were predicted by network pharmacology. It was further shown by in vivo validation experiments that MLSTP exerted therapeutic effects on TAO by modulating the PI3K-AKT signaling pathway, VEGF signaling pathway, and HIF-1 signaling pathway. In addition, UPLC fingerprints of MLSTP were established and screened for potential Q-markers of MLSTP in combination with network pharmacology results. Six components, including chlorogenic acid, liquiritin, paeoniflorin, calycosin-7-glucoside, berberine, and formononetin, were selected as potential quality markers (Q-markers) in MLSTP. Finally, the quantitative analysis of multi-components by single marker (QAMS) method was established to quantitatively analyze the six potential Q-markers, and the results were consistent with those obtained by the external standard method (ESM). Taken together, the multi-strategy platform established in this study would be conducive to the Q-markers screening and quality control of MLSTP, improving the quality standard of MLSTP and providing favorable assurance for the clinical management of TAO., 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.)

Background: Stroke is a complex physiological process associated with intestinal flora dysbiosis and metabolic disorders. Dan-deng-tong-nao capsule (DDTN) is a traditional Chinese medicine used clinically to treat cerebral ischemia-reperfusion injury (CIRI) for many years. However, little is known about the effects of DDTN in the treatment of CIRI from the perspective of gut microbiota and metabolites., Purpose: This study aimed to investigate the regulatory roles of DDTN in endogenous metabolism and gut microbiota in CIRI rats, thus providing a basis for clinical rational drug use and discovering natural products with potential physiological activities in DDTN for the treatment of CIRI., Methods: The chemical composition of DDTN in vitro and in vivo was investigated using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLCHRMS), followed by target prediction using reverse molecular docking. Secondly, a biological evaluation of DDTN ameliorating neural damage in CIRI was performed at the whole animal level. Then, an integrated omics approach based on UHPLCHRMS and 16S rRNA sequencing was proposed to reveal the anti-CIRI effect and possible mechanism of DDTN. Finally, exploring the intrinsic link between changes in metabolite profiles, changes in the intestinal flora, and targets of components to reveal DDTN for the treatment of CIRI., Results: A total of 112 chemical components of DDTN were identified in vitro and 10 absorbed constituents in vivo. The efficacy of DDTN in the treatment of CIRI was confirmed by alleviating cerebral infarction and neurological deficits. After the DDTN intervention, 21 and 26 metabolites were significantly altered in plasma and fecal, respectively. Based on the fecal microbiome, a total of 36 genera were enriched among the different groups. Finally, the results of the network integration analysis showed that the 10 potential active ingredients of DDTN could mediate the differential expression of 24 metabolites and 6 gut microbes by targeting 25 target proteins., Conclusion: This study was the first to outline the landscapes of metabolites as well as gut microbiota regulated by DDTN in CIRI rats using multi-omics data, and comprehensively revealed the systematic relationships among ingredients, targets, metabolites, and gut microbiota, thus providing new perspectives on the mechanism of DDTN in the treatment of CIRI., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest., (Copyright © 2023. Published by Elsevier GmbH.)

Background: Affiliate stigma experienced by family caregivers of individuals with dementia may seriously affect home care and prognosis of these patients. This study aimed to explore the levels of perceived affiliate stigma and its influencing factors among family caregivers of patients with dementia in mainland China, which remains a relatively unexplored topic., Methods: In this cross-sectional study, purposive sampling was used to recruit dementia family caregivers from an online communication group between April and May 2022. A total of 727 eligible caregivers were included and asked to complete the demographic questionnaire, the affiliate stigma scale, and the caregiver burden inventory. Descriptive statistics, independent sample t-test, one-way analysis of variance, Pearson correlation analysis, and multiple linear regression were used to explore the factors that influence perceived affiliate stigma among dementia family caregivers., Results: The mean score for affiliate stigma of dementia family caregivers was 48.09 ± 16.38 (range: 22-86). Whether there were regular breaks during patient care, time-dependent burden, developmental burden, physical burden, and social burden were significant factors influencing the affiliate stigma of dementia family caregivers., Conclusion: Dementia family caregivers showed a moderate to high level of affiliate stigma. Those who had regular breaks during patient care, higher time-dependent burden, developmental burden, and physical burden and lower social burden exhibited higher levels of affiliate stigma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shi, Dong, Liang, Xie, Zhang, Li and Li.)

Background: To investigate the clinical and immune characteristics of patients with primary Sjögren's syndrome (pSS) who were negative for anti-Sjögren's-syndrome-related antigen A antibodies (anti-SSA) and anti-Sjögren's-syndrome-related antigen B antibodies (anti-SSB) in Chinese population., Methods: A retrospective study were performed and 232 patients with pSS were analyzed. Patients positive for anti-SSA or/and anti-SSB were termed as seropositive pSS, and these negative for both anti-SSA and anti-SSB (non-antinuclear antibodies) as seronegative pSS. Clinical manifestations and laboratory findings were compared between the two groups., Results: Among the 232 patients with pSS, 192 (82.8%) were seropositive pSS and 40 (17.2%) were seronegative pSS. Compared to seropositive pSS, seronegative pSS were older and with higher percentage of low disease activity (ESSDAI < 5), xerostomia and xerophthalmia, with higher platelet count and level of creatine kinase. This subgroup was with lower levels of gamma globulin, immunoglobulin G, immunoglobulin A and autoantibodies including rheumatoid factor and antinuclear antibody in serum, and less immunoglobulin G deposition in labial gland., Conclusion: Seronegative pSS was a distinct subtype of pSS different from seropositive pSS. Clinical manifestations in seronegative pSS subgroup were restricted to exocrine gland and less B lymphocyte activation, while seropositive pSS were prone to present with systemic involvement and high disease activity. Specific underlying pathogenesis mechanisms and therapeutic strategies in this subgroup needed to be further studied., (© 2024. The Author(s).)

ABSTACTThe medicinal properties of genetic drugs are highly dependent on the design of delivery systems. Ionizable cationic lipids are considered core materials in delivery systems. However, there has not yet been a widespread consensus on the relationship between the wide diversity of lipid structure design and gene delivery efficiency. The aims of the research work were to synthesize ionizable cholesterol derivatives (iChol-lipids) and to evaluate their potential applications as gene delivery vector. A series of iChol-lipids with different head groups were synthesized with carbamate bond spacer. The chemical structures were characterized by 1 H NMR, MS, melting range, and p K a . The interactions between iChol-lipids and MALAT1-siRNA were studied by molecular dynamics simulations and compared with market available DC-Chol, which revealed that hydrogen bonds, salt-bridge, and electrostatic interaction were probably involved. The self-assemble behaviors of these lipids were intensively investigated and evaluated by dynamic laser scattering in the presence of different helper lipids and PEGylated lipids. Their plasmid binding ability, transfection efficiency, hemolytic toxicity, and cytotoxicity were fully studied. IZ-Chol-LNPs was proved to be highly potential to effectively complex with DNA, and endosome escape mechanisms mediated by proton sponge effect was verified by pH-sensitive fluorescence probe BCFL.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

Arsenic, a ubiquitous environmental toxicant with various forms and complex food matrix interactions, can reportedly exert differential effects on the liver compared to drinking water exposure. To examine its specific liver-related harms, we targeted the liver in C57BL/6 J mice (n=48, 8-week-old) fed with arsenic-contaminated food (30 mg/kg) for 60 days, mimicking the rice arsenic composition observed in real-world scenarios (iAs V : 7.3%, iAs III : 72.7%, MMA: 1.0%, DMA: 19.0%). We then comprehensively evaluated liver histopathology, metabolic changes, and the potential role of the gut-liver axis using human hepatocellular carcinoma cells (HepG2) and microbiota/metabolite analyses. Rice arsenic exposure significantly altered hepatic lipid (fatty acids, glycerol lipids, phospholipids, sphingolipids) and metabolite (glutathione, thioneine, spermidine, inosine, indole-derivatives, etc.) profiles, disrupting 33 metabolic pathways (bile secretion, unsaturated fatty acid biosynthesis, glutathione metabolism, ferroptosis, etc.). Pathological examination revealed liver cell necrosis/apoptosis, further confirmed by ferroptosis induction in HepG2 cells. Gut microbiome analysis showed enrichment of pathogenic bacteria linked to liver diseases and depletion of beneficial strains. Fecal primary and secondary bile acids, short-chain fatty acids, and branched-chain amino acids were also elevated. Importantly, mediation analysis revealed significant correlations between gut microbiota, fecal metabolites, and liver metabolic alterations, suggesting fecal metabolites may mediate the impact of gut microbiota and liver metabolic disorders. Gut microbiota and its metabolites may play significant roles in arsenic-induced gut-liver injuries. Overall, our findings demonstrate that rice arsenic exposure triggers oxidative stress, disrupts liver metabolism, and induces ferroptosis., 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 Authors. Published by Elsevier Inc. All rights reserved.)

The primary objective of this investigation was to elucidate the manner in which ginsenoside Rg 5 (Rg 5 ) ameliorates nonalcoholic fatty liver disease (NAFLD) via the modulation of the gut microbiota milieu. We administered either a standard diet (ND) or a high-fat diet (HFD), coupled with 12-week treatment employing two distinct doses of Rg 5 (50 and 100 mg/kg/d), to male C57BL/6J mice. In comparison to the HFD cohort, the Rg 5 -treated group demonstrated significant enhancements in biochemical parameters, exemplified by a substantial decrease in lipid concentrations, as well as the reduced expression of markers indicative of oxidative stress and liver injury. This signifies a mitigation of hepatic dysfunction induced by an HFD. Simultaneously, Rg 5 demonstrates the capacity to activate the LKB1/AMPK/mTOR signaling pathway, instigating energy metabolism and consequently hindering the progression of NAFLD. Furthermore, we underscored the role of Rg 5 in the treatment of NAFLD within the gut-microbiota-liver axis. Analysis via 16S rRNA sequencing unveiled that Rg 5 intervention induced alterations in gut microbiota composition, fostering an increase in beneficial bacteria, such as Bacteroides and Akkermansia , while concurrently reducing the relative abundance of detrimental bacteria, exemplified by Olsenella . Furthermore, employing fecal microbiota transplantation (FMT) experiments, we observed analogous outcomes in mice subjected to fecal bacterial transplants, providing additional verification of the capacity of Rg 5 to mitigate NAFLD in mice by actively participating in the restoration of gut microbiota via FMT. Drawing from these data, the regulation of the gut microbiota is recognized as an innovative strategy for treating or preventing NAFLD and metabolic syndrome. Consequently, these research findings suggest that Rg 5 holds promise as a potential therapeutic agent for NAFLD management.

Both the gut microbiome and their host participate in arsenic (As) biotransformation, while their exact roles and mechanisms in vivo remain unclear and unquantified. In this study, as3mt -/- zebrafish were treated with tetracycline (TET, 100 mg/L) and arsenite (iAs III ) exposure for 30 days and treated with probiotic Lactobacillus rhamnosus GG (LGG, 1 × 10 8 cfu/g) and iAs III exposure for 15 days, respectively. Structural equation modeling analysis revealed that the contribution rates of the intestinal microbiome to the total arsenic (tAs) and inorganic As (iAs) metabolism approached 44.0 and 18.4%, respectively. Compared with wild-type, in as3mt -/- zebrafish, microbial richness and structure were more significantly correlated with tAs and iAs, and more differential microbes and microbial metabolic pathways significantly correlated with arsenic metabolites ( P < 0.05). LGG supplement influenced the microbial communities, significantly up-regulated the expressions of genes related to As biotransformation ( gss and gst ) in the liver, down-regulated the expressions of oxidative stress genes ( sod1 , sod2 , and cat ) in the intestine, and increased arsenobetaine concentration ( P < 0.05). Therefore, gut microbiome promotes As transformation and relieves As accumulation, playing more active roles under iAs stress when the host lacks key arsenic detoxification enzymes. LGG can promote As biotransformation and relieve oxidative stress under As exposure.

The kynurenine pathway (KP) is the principal metabolic route for the essential amino acid tryptophan (TRP). Recent advances have highlighted a pivotal role for several KP metabolites in inflammatory diseases, including ulcerative colitis (UC). However, the alterations of KP enzymes and their functional impact in UC remain poorly defined. Here, we focused on kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which serve as critical branching enzymes in the KP. We observed that dextran sodium sulfate (DSS)-induced colitis mice exhibited disturbed TRP metabolism along with KMO and KYNU upregulated. In patients with active UC, both the expression of KMO and KYNU were positively correlated with inflammatory factors TNF-α and IL-1β. Pharmacological blockade of KMO or genetic silencing of KYNU suppressed IL-1β-triggered proinflammatory cytokines expression in intestinal epithelial cells. Furthermore, blockage of KMO by selective inhibitor Ro 61-8048 alleviated the symptoms of DSS-induced colitis in mice, accompanied by an expanded NAD + pool and redox balance restoration. The protective role of Ro 61-8048 may be partly due to its effect on KP regulation, particularly in enhancing kynurenic acid production. In summary, our study provides new evidence for the proinflammatory property of KMO and KYNU in intestinal inflammation, hinting at a promising therapeutic approach in UC through targeting these enzymes., 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 © 2023. Published by Elsevier B.V.)

Designing and constructing supramolecular photosensitizer nanosystems with highly efficient photodynamic therapy (PDT) is vital in the nanomedical field. Despite recent advances in forming well-defined superstructures, the relationship between molecular arrangement in nanostructures and photodynamic properties has rarely been involved, which is crucial for developing stable photosensitizers for highly efficient PDT. In this work, through a microemulsion-assisted self-assembly approach, indium porphyrin (InTPP) was used to fabricate a series of morphology-controlled self-assemblies, including nanorods, nanospheres, nanoplates, and nanoparticles. They possessed structure-dependent 1 O 2 generation efficiency. Compared with the other three nanostructures, InTPP nanorods featuring strong π-π stacking, J -aggregation, and high crystallinity proved to be much more efficient at singlet oxygen ( 1 O 2 ) production. Also, theoretical modeling and photophysical experiments verified that the intermolecular π-π stacking in the nanorods could cause a decreased singlet-triplet energy gap (Δ E ST ) compared with the monomer. This played a key role in enhancing intersystem crossing and facilitating 1 O 2 generation. Both in vitro and in vivo experiments demonstrated that the InTPP nanorods could trigger cell apoptosis and tumor ablation upon laser irradiation (635 nm, 0.1 W/cm 2 ) and exhibited negligible dark toxicity and high phototoxicity. Thus, the supramolecular self-assembly strategy provides an avenue for designing high-performance photosensitizer nanosystems for photodynamic therapy and beyond.

Background: Scrophulariae Radix (SR) is a commonly used medicinal plant. Alzheimer's disease (AD) is a neurodegenerative disease for which there is no effective treatment. This study aims to initially clarify the potential mechanism of SR in the treatment of AD based on network pharmacology and molecular docking techniques., Methods: The principal components and corresponding protein targets of SR were conducted by HPLC analysis and searched on TCMSP. AD targets were searched on DrugBank, Chemogenomics, TTD, OMIM and GeneCards databases. The compound-target network was constructed by Cytoscape3.8.2. The intersection of compound target and disease target was obtained and the coincidence target was imported into STRING database to construct a PPI network. We further performed GO and KEGG enrichment analysis on the targets. Meanwhile, molecular docking study and cell experiments were approved for the core target and the active compound., Results: Through multidatabase retrieval and integration, it was found that 17 components of SR could exert anti-AD effects against 40 targets. KEGG enrichment analysis indicated that Alzheimer's disease (hsa05010) was one of the most significant AD enrichment signalling pathways. Combined with the gene expression profile information in the AlzData database, 15 targets were found to be associated with tau or beta-amyloid protein (Aβ). GO analysis indicated that the primary molecular functions of SR in the treatment of AD were neurotransmitter receptor activity (GO:0007268), postsynaptic neurotransmitter receptor activity (GO:0070997), and acetylcholine receptor activity (GO:0050435). Moreover, we explored the anti-AD effects of SR extract and ursolic acid (UA) using SH-SY5Y cells. Treatment of SH-SY5Y cells with 20 μM UA significantly reduced the oxidative damage to these neuronal cells., Conclusion: This study reveals the active ingredients and potential molecular mechanism of SR in the treatment of AD, and provides a theoretical basis for further basic research and clinical application., 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 Published by Elsevier Ltd.)

Obesity often leads to severe medical complications. However, existing FDA-approved medications to combat obesity have limited effectiveness in reducing adiposity and often cause side effects. These medications primarily act on the central nervous system or disrupt fat absorption through the gastrointestinal tract. Adipose tissue enlargement involves adipose hyperplasia and hypertrophy, both of which correlate with increased reactive oxygen species (ROS) and hyperactivated X-box binding protein 1 (XBP1) in (pre)adipocytes. In this study, we demonstrate that KT-NE, a nanoemulsion loaded with the XBP1 inhibitor KIRA6 and α-Tocopherol, simultaneously alleviates aberrant endoplasmic reticulum stress and oxidative stress in (pre)adipocytes. As a result, KT-NE significantly inhibits abnormal adipogenic differentiation, reduces lipid droplet accumulation, restricts lipid droplet transfer, impedes obesity progression, and lowers the risk of obesity-associated non-alcoholic fatty liver disease in female mice with obesity. Furthermore, diverse administration routes of KT-NE impact its in vivo biodistribution and contribute to localized and/or systemic anti-obesity effectiveness., (© 2024. The Author(s).)

Plants are commonly exposed to abiotic stressors, which can affect their growth, productivity, and quality. Previously, the maize transcription factor ZmCCT was shown to be involved in the photoperiod response, delayed flowering, and quantitative resistance to Gibberella stalk rot. In this study, we demonstrate that ZmCCT can regulate plant responses to drought. ZmCCT physically interacted with ZmFra a 1, ZmWIPF2, and ZmAux/IAA8, which localized to the cell membrane, cytoplasm, and nucleus, respectively, both in vitro and in vivo in a yeast two-hybrid screen in response to abiotic stress. Notably, ZmCCT recruits ZmWIPF2 to the nucleus, which has strong E3 self-ubiquitination activity dependent on its RING-H2 finger domain in vitro. When treated with higher indole-3-acetic acid/abscisic acid ratios, the height and root length of Y331-ΔTE maize plants increased. Y331-ΔTE plants exhibited increased responses to exogenously applied auxin or ABA compared to Y331 plants, indicating that ZmCCT may be a negative regulator of ABA signalling in maize. In vivo, ZmCCT promoted indole-3-acetic acid biosynthesis in ZmCCT-overexpressing Arabidopsis. RNA-sequencing and DNA affinity purification-sequencing analyses showed that ZmCCT can regulate the expression of ZmRD17, ZmAFP3, ZmPP2C, and ZmARR16 under drought. Our findings provide a detailed overview of the molecular mechanism controlling ZmCCT functions and highlight that ZmCCT has multiple roles in promoting abiotic stress tolerance., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Dendrobium officinale polysaccharides (DOP) has been reported to possess remarkable effects on improving renal function, oxidative stress damage and fibrotic diseases. However, the role and mechanism of DOP in preventing and treating renal fibrosis remain unclear. The purpose of this paper was to explore the therapeutic effects and underlying mechanisms of DOP on renal fibrosis. Firstly, renal fibrosis model was induced by unilateral ureteral obstruction operation (UUO) in male BALB/c mice. Subsequently, the anti-renal fibrosis effect of DOP was evaluated. It turned out that DOP significantly attenuated UUO induced renal fibrosis. The beneficial effects of DOP on renal fibrosis were concretely manifested in the relief of clinical symptoms, improvement of renal function, reduction of extracellular matrix collagen aggregation, attenuation of structural damage and inflammation, and decrement of profibrotic factors secretion. Meanwhile, DOP could also alleviate oxidative stress injury and inhibit the AhR/NOX4 pathway proteins expression. Furthermore, multivariate statistical analysis, AhR interference and overexpression experiments showed that the effect of DOP on alleviating renal fibrosis was closely related to the improvement of oxidative stress injury mediated by the AhR/NOX4 pathway. Overall, the data in the present paper indicated that DOP could alleviate renal fibrosis through improving AhR/NOX4 mediated oxidative stress injury., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: To explore the role of anti-Mullerian hormone (AMH) in predicting the need to step up recombinant FSH (rFSH) dose following long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovarian syndrome (PCOS) women., Methods: This is a retrospective cohort study of 825 PCOS women undergoing long GnRH agonist protocol enrolled from Jan 2019 to Dec 2021. The daily rFSH dose at which the first response to rFSH were recorded. The dose at which the first response to rFSH was based on folliculometry during follow up in which two or more follicles reached ≥ 11 mm. A receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict the need to step up initial rFSH dose., Results: PCOS women who needed to step up initial rFSH dose had a significantly higher AMH compared with those didn't step up initial rFSH dose (11.37 ± 3.25ng/ml vs. 8.69 ± 3.16ng/ml, p < 0.001). In multivariate logistic regression analysis, increased AMH level was an independent factor for the need to step up initial rFSH dose in PCOS patients after adjusted for confounding factors. ROC curve analysis showed AMH could predict the need to step up initial rFSH dose (AUC = 0.738, 95%CI: 0.704-0.773), having 75.4% specificity and 63% sensitivity when the threshold AMH concentration was 9.30ng/ml. 58.8% PCOS women with AMH > 9.30 ng/ml required increased rFSH dose compared to 18.8% of women with AMH ≤ 9.30ng/ml (p < 0.001). Although the clinical pregnancy rate and live birth rate were not significantly different, there was a higher incidence of OHSS among women with AMH > 9.30 ng/ml vs. AMH ≤ 9.30ng/ml (20.8% vs. 15.3%, p = 0.043)., Conclusion: PCOS women with AMH > 9.30 ng/ml were resistant to rFSH stimulation and require increased dose for the cycle recruitment of ovarian follicles., (© 2023. The Author(s).)

Enterovirus D68 (EV-D68), a member of Enterovirus genus of the Picornaviridae family, mainly causes respiratory system-related diseases as well as neurological complications in some patients. At present, there is no effective vaccine or treatment for the virus. The aim of this research was to systematically analyse the molecular epidemiology, recombination and changes in the epitope of EV-D68 in China from 2008 to 2022. Through phylogenetic analysis based on VP1 sequences, it was found that there was limited information about EV-D68 infection before 2011 and that EV-D68 infection was dominated by the A2 gene subtype from 2011 to 2013 and the B3 genotype from 2014 to 2018, during which A2 and B3 were coprevalent and alternately prevalent. We also constructed a phylogenetic tree using the EV-D68 full-length genome sequences, and the genotype of each sequence was consistent with that of the VP1 sequence evolutionary tree. Recombination analysis showed that MH341715 underwent intertypic recombination with the A2 genotype MH341729 at the 5' untranslated region (5'UTR) and that P1-P3 underwent recombination with the B3 genotype MH341712. The capsid protein VP1 is one of the most important structural proteins. In VP1, the BC-loop (89-105 amino acids) and DE-loop (140-152 amino acids) are the most variable domains on the surface of the virus and are associated with epitopes. In this study, it was found that the dominant amino acid composition of the BC-loop and DE-loop continued to change with the epidemic of the virus; the amino acid composition also differed in different regions of the same genotypes. The ongoing genomic and molecular epidemiology of EV-D68 remains important for predicting emergence of new viruses and preventing major outbreaks of respiratory diseases., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aims to investigate the status and influencing factors of two-way social support among old adults. A cross-sectional study of 408 convenient samples of old adults was conducted using socio-demographic questionnaire, Brief 2-Way Social Support Scale, Modified Barthel index, General Well-being Schedule, Family APGAR Index, and Lubben Social Network Scale 6. The two-way social support score for old adults in China was (43.74±7.86), with the receiving and giving social support scoring (22.80±4.06) and (20.94±4.52), respectively. The multiple linear regression analysis revealed that family care, residence place, socioeconomic status, and social network were associated with both receiving and giving social support. Chronic diseases and religious beliefs were related to receiving social support, while gender, general well-being, and residence form were related to giving social support. Tailored interventions based on the distinct influencing factors are needed to enhance old adults' social support both as recipients and providers., 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 © 2023 Elsevier Inc. All rights reserved.)

Electrolytic manganese residue (EMR) stockpiles contain significant amounts of Mn 2+ and NH 4 + -N which pose a risk of environmental pollution. For EMR safe disposal, an innovative approach is proposed that involves direct sodium silicate-sodium hydroxide (Na 2 SiO 3 -NaOH) collaborative technology. This approach utilises Na 2 SiO 3 and NaOH as the solidifying agent and activator, respectively, to treat EMR without hazardous effects. The study also provides insights into the kinetics of Mn 2+ leaching under the effect of Na 2 SiO 3 -NaOH. Leaching efficiency was determined by varying parameters such as stirring rate, reaction temperature, pH of the initial solution, Na 2 SiO 3 concentration, and reaction time to investigate the efficacy of this method. The study indicates that the co-treatment technology of Na 2 SiO 3 -NaOH can achieve maximum solidification efficiencies of 99.7% and 98.2% for Mn 2+ and NH 4 + -N, respectively. The process can successfully solidify Mn 2+ by synthesising Mn(OH) 2 and MnSiO 3 in an alkaline environment under optimal conditions including stirring rate of 450 rpm, initial solution pH of 8, test temperature of 40 °C, test time of 420 min, and Na 2 SiO 3 content of 5%. The findings of this study have confirmed that surface chemistry plays a vital role in regulating the test rate and the proposed equation accurately describes Mn 2+ leaching kinetics. Overall, the co-treatment technology involving Na 2 SiO 3 -NaOH is a viable solution for EMR resource utilisation without compromising environmental safety. This method has the potential to be implemented for other waste streams with comparable compositions, ultimately promoting the sustainable management of waste., 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 © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The appearance and growth of persistent choroidal hypertransmission defects (hyperTDs) detected on en face swept-source optical coherence tomography (SS-OCT) images from eyes with intermediate age-related macular degeneration (iAMD) were studied to determine if they could serve as novel clinical trial endpoints., Design: Post hoc subgroup analysis of a prospective study., Methods: Subjects with iAMD underwent 6 × 6 mm SS-OCT angiography imaging at their baseline and follow-up visits. The drusen volumes were obtained using a validated SS-OCT algorithm. Two graders independently evaluated all en face structural images for the presence of persistent hyperTDs. The number and area of all hyperTDs along with drusen volume were obtained from all SS-OCT angiography scans. Eyes were censored from further follow-up once exudative AMD developed., Results: A total of 171 eyes from 121 patients with iAMD were included. Sixty-eight eyes developed at least 1 hyperTD. Within 1 year after developing a hyperTD, 25% of eyes developed new hyperTDs for an average of 0.44 additional hyperTDs. Over 2 years, as hyperTDs appeared, enlarged, and merged, the average area growth rate was 0.220 mm/yr using the square-root transformation strategy. A clinical trial design using the onset and enlargement of these hyperTDs for the study of disease progression in eyes with iAMD is proposed., Conclusions: The appearance and growth of persistent choroidal hyperTDs in eyes with iAMD can be easily detected and measured using en face OCT imaging and can serve as novel clinical trial endpoints for the study of therapies that may slow disease progression from iAMD to late AMD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Over the past 70 years, China has advanced significantly in the prevention and treatment of infectious diseases while simultaneously undergoing a socioeconomic transformation, making it a useful source of data for analysing relationships between public health policy and the control of infectious diseases., Methods: We collected data on the incidence of notifiable infectious diseases and associated fatalities in Jiangsu province in southeast China from the Provincial Center for Disease Control and Prevention, Provincial Institute of Parasitic Diseases, and the Nationwide Notifiable Infectious Diseases Reporting Information System. We compared data from different historical periods using descriptive statistical methods, joinpoint regression, and correlation analysis., Results: During 1950-2022, 75 754 008 cases of 46 notifiable infectious diseases were reported in Jiangsu, with an average annual incidence was 1679.49 per 100 000 population and a fatality rate of 1.82 per 1000 persons. The incidence of classes A-B decreased (average annual percent change (AAPC) = -2.1) during the entire study period, while the incidence of class C increased (AAPC = 10.8) after 2004. The incidence of intestinal diseases (AAPC = -4.4) and vector-borne and zoonotic diseases (AAPC = -8.1) decreased rapidly, while the incidence of sexually transmitted and blood-borne diseases (AAPC = 1.8) increased. The number of medical and health institutions and the per capita gross domestic product correlated negatively with the annual incidence of diseases in classes A-B, but not with fatality rates., Conclusions: Although the annual incidence of many severe infectious diseases has decreased in Jiangsu since 1950, the incidence of sexually transmitted and blood-borne diseases increased. Socioeconomic growth and sustainable investment in health systems are associated with better control of infectious diseases., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

Type 2 diabetes mellitus (T2DM), a complex metabolism disease, which was characterized by metabolic disorders including hyperglycemia, has become a major health problem due to the increasing prevalence worldwide. γ-glutamylcysteine (γ-GC) as an immediate precursor of glutathione (GSH) was originally used for the treatment of sepsis, inflammation bowel disease, and senescence. Here, we evaluated the capacity of γ-GC on diabetes-related metabolic parameters in db/db mice and insulin resistance (IR) amelioration in cells induced by palmitic acid (PA). Our data suggested that γ-GC treatment decreased body weight, reduced adipose tissue size, ameliorated ectopic fat deposition in liver, increased the GSH content in liver, improved glucose control and other diabetes-related metabolic parameters in vivo. Moreover, in vitro experiments showed that γ-GC could maintain the balance of free fatty acids (FFAs) and glucose uptake through regulating the translocation of CD36 and GLUT4 from cytoplasm to plasma membrane. Furthermore, our finding also provided evidence that γ-GC could activate Akt not only via adenylate cyclase (AC)/cAMP/PI3K signaling pathway, but also via IGF-1R/IRS1/PI3K signaling pathway to improve IR and hepatic steatosis. Blocking either of two signaling pathways could not activate Akt activation induced by γ-GC. This unique characteristic ensures the important role of γ-GC in glucose metabolism. Collectively, these results suggested that γ-GC could serve as a candidate dipeptide for the treatment of T2DM and related chronic diabetic complications via activating AC and IGF-1R/IRS1/PI3K/Akt signaling pathways to regulate CD36 and GLUT4 trafficking., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Glaucoma is the third leading cause of blindness worldwide and is primarily characterized by elevated intraocular pressure (IOP). Common risk factors such as age, myopia, ocular trauma, and hypertension all increase the risk of elevated IOP. Prolonged high IOP not only causes physiological discomfort like headaches, but also directly damages retinal cells and leads to retinal ischemia, oxidative imbalance, and accumulation of reactive oxygen species (ROS) in the retina. This oxidative stress causes the oxidation of proteins and unsaturated lipids, leading to peroxide formation and exacerbating retinal damage. While current clinical treatments primarily target reducing IOP through medication or surgery, there are currently no effective methods to mitigate the retinal cell damage associated with glaucoma. To address this gap, we developed a novel nanoemulsion to co-delivery latanoprost and α-tocopherol (referred to as LA@VNE later) that prolongs ocular retention and enhances retinal permeability through localized administration. By encapsulating latanoprost, an IOP-lowering drug, and α-tocopherol, a potent antioxidant, we effectively reduced ROS accumulation (>1.5-fold in vitro and 2.5-fold in vivo), retinal ganglion cell (RGC) apoptosis (>9 fold), and inflammatory cell infiltration (>1.6 fold). Our approach showed strong biocompatibility and significant potential for clinical translation, providing a promising platform for the treatment of glaucoma., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Correlations between low luminance visual acuity deficits (LLVADs) and central choriocapillaris perfusion deficits were investigated to help explain how increases in LLVAD scores at baseline predict annual growth rates of geographic atrophy (GA)., Design: Prospective cross-sectional study., Methods: Photopic luminance best-corrected visual acuity (PL-BCVA) and low luminance BCVA (LL-BCVA) were measured using the Early Treatment Diabetic Retinopathy Study chart. LL-BCVA was measured using a 2.0-log unit neutral density filter. LLVADs were calculated as the difference between PL-BCVA and LL-BCVA. Within a fovea-centered 1-mm circle, the percentage of choriocapillaris flow deficits (CC FD%), drusen volume, optical attenuation coefficient (OAC) elevation volume, and outer retinal layer (ORL) thickness were assessed., Results: In all 90 eyes (30 normal eyes; 31 drusen-only eyes; 29 non-foveal GA eyes), significant correlations were found between the central CC FD% and PL-BCVA (r = -0.393, P < .001), LL-BCVA (r = -0.534, P < .001), and the LLVAD (r = 0.439, P < .001). Central cube root (cubrt) drusen volume, cubrt OAC elevation volume, and ORL thickness were correlated with PL-BCVA, LL-BCVA, and LLVADs (all P < .05). Stepwise regression models showed that central cubrt OAC elevation volume and ORL thickness were associated with PL-BCVA (R 2  = 0.24, P < .05); central CC FD%, cubrt OAC elevation volume, and ORL thickness were associated with LL-BCVA (R 2  = 0.44, P < .01); and central CC FD% and ORL thickness were associated with LLVAD (R 2  = 0.24, P < .01)., Conclusions: The significant correlations between central CC FD% and LLVAD support the hypothesis that the ability of LLVAD to predict the growth of GA is mediated through a decrease in macular choriocapillaris perfusion., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The formation of black and odorous water is a complex process influenced by various factors such as organic matter and environmental conditions. However, there are limited studies on the role of microorganisms in water and sediment during the blackening and odorization process. In this study, we investigated the characteristics of black and odorous water formation by simulating organic carbon-driven black and odorous water through indoor experiments. The study revealed that the water turned black and odorous when DOC reached 50 mg/L and the microbial community structure in the water changed significantly during this process, with the relative abundance of Desulfobacterota increasing significantly and Desulfovibrio being the main dominant genus in Desulfobacterota. Additionally, we observed a notable decrease in the α-diversity of the microbial community in water and a considerable increase in microbial function of sulfur compounds respiration in water. In contrast, the sediment microbial community changed slightly, and the main functions of the sediment microbial community remained unchanged. The partial least squares path model (PLS-PM) suggested that organic carbon will drive the blackening and odorization process by affecting DO levels and microbial community structure and that the contribution of Desulfobacterota in water to the formation of black and odorous water was higher than that in sediment. Overall, our study provides insights into the characteristics of black and odorous water formation and suggests potential ways to prevent its formation by controlling DOC and inhibiting the growth of Desulfobacterota in water bodies., 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 © 2023 Elsevier Inc. All rights reserved.)

Metabolic-associated fatty liver disease (MAFLD) and alcoholic hepatitis (AH) are among the most prevalent liver diseases worldwide, and their coexistence is common in clinical practice. However, currently established models of MAFLD-AH coexistence do not fully replicate their pathological characteristics and require sophisticated experimental techniques. Therefore, we aimed to develop an easily replicable model that mimics obesity-induced MAFLD-AH in patients. Our goal was to establish a murine model that replicates MAFLD and AH coexistence, resulting in significant liver injury and inflammation. To this end, we administered a single ethanol gavage dose to ob/ob mice on a chow diet. The administration of a single dose of ethanol led to elevated serum transaminase levels, increased liver steatosis, and apoptosis in ob/ob mice. Furthermore, ethanol binge caused a significant increase in oxidative stress in ob/ob mice, as measured via 4-hydroxynonenal. Importantly, the single dose of ethanol also markedly exacerbated liver neutrophil infiltration and upregulated the hepatic mRNA expression of several chemokines and neutrophil-related proteins, including Cxcl1, Cxcl2, and Lcn2. Whole-liver transcriptomic analysis revealed that ethanol-induced changes in gene expression profile shared similar features with AH and MAFLD. In ob/ob mice, a single dose of ethanol binge caused significant liver injury and neutrophil infiltration. This easy-to-replicate murine model successfully mimics the pathological and clinical features of patients with coexisting MAFLD and AH and closely resembles the transcriptional regulation seen in human disease.

Purpose: The symmetry of major macular fundus features in both eyes of the same patient with age-related macular degeneration (AMD) was investigated using swept-source(SS)-OCT., Design: Retrospective review of a prospective study., Participants: Patients with AMD., Methods: Grading was performed on the first SS-OCT images obtained on the patients. Two graders diagnosed the presence of drusen, geographic atrophy (GA), and exudative AMD (eAMD) in each eye. Medical records were reviewed to assess prior exudation. To assess symmetry, 1 eye of each patient was randomly selected as the index eye and compared with the fellow eye. The kappa statistic (κ) was used to assess the symmetry of diagnosis. The intraclass correlation coefficient (ICC) was used to assess the symmetry of drusen area and volume., Main Outcome Measures: Interocular symmetry of the AMD stages: drusen, GA, and eAMD., Results: A total of 1310 patients with AMD were included. The average age was 78 years (range, 50-102; 60% women). Of the 1310 subjects, 54% (701) presented with symmetric disease: 20% with bilateral drusen, 11% with bilateral GA, and 22% with bilateral eAMD. Only 0.5% of the subjects had both GA and eAMD in both eyes. Of the randomly selected index eyes, 825 (47%) were right eyes. Overall, limited interocular agreement was observed between the index and fellow eyes (54%; κ = 0.29). Kappa coefficients were poor (< 0.4) for index eyes diagnosed with drusen (κ = 0.27), eAMD (κ = 0.17), and mixed disease (κ = 0.03). There was moderate agreement between the index and fellow eyes for GA (κ = 0.50). Of the 265 patients with bilateral drusen, the symmetry of drusen area measurements had moderate ICC values of 0.70, 0.71, and 0.70 in the 3- and 5-mm diameter foveal-centered circles and in the total scan area, respectively. The ICC values for the drusen volumes were 0.65, 0.66, and 0.64, respectively., Conclusions: Interocular symmetry was poor for eyes with drusen, eAMD, and mixed disease, but moderate for GA. Although the diagnosis of drusen was not very symmetric between eyes, when present in both eyes, the drusen area and volume measurements were moderately symmetric., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In plant-pathogen interactions, Magnaporthe oryzae causes blast disease on more than 50 species of 14 monocot plants, including important crops such as rice, millet, and most 15 recently wheat. M. oryzae is a model fungus for studying plant-microbe interaction, and the main source for fungal pathogenesis in the field. Here we report that MoJMJD6 is required for conidium germination and appressorium formation in M. oryzae. We obtained MoJMJD6 mutants (ΔMojmjd6) using a target gene replacement strategy. The MoJMD6 deletion mutants were delayed for conidium germination, glycogen, and lipid droplets utilization and consequently had decreased virulence. In the ΔMojmjd6 null mutants, global histone methyltransferase modifications (H3K4me3, H3K9me3, H3K27me3, and H3K36me2/3) of the genome were unaffected. Taken together, our results indicated that MoJMJD6 function as a nuclear protein which plays an important role in conidium germination and appressorium formation in the M. oryzae. Our work provides insights into MoJMJD6-mediated regulation in the early stage of pathogenesis in plant fungi.

A series of thin film composite (TFC) membranes was prepared with piperazine (PIP) and m -phenylenediamine (MPD) in different ratios, and the magnesium-lithium separation performance of TFC membranes in salt-lake brine with the magnesium-lithium ratio of 28 were systematically compared. The prepared TFC membranes exhibited high rejection of magnesium ions and negative rejection of lithium ions with high water flux, enabling high magnesium-lithium separation efficiency. The characterisation using FTIR spectroscopy, XPS, zeta potential measurements, and SEM techniques indicated that the composition and surface morphology of the membrane prepared with dual aqueous monomers were found to be different from those prepared with single aqueous monomers under the similar conditions. The interfacial polymerization process of different monomers and the structure-performance mechanism of TFC membranes were further discussed., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In this work, the electrolytic manganese residues (EMR) were used as sulfate activators for fly ash and granulated blast-furnace slag to fabricate highly reactive supplementary cementitious materials (SCMs). The findings promote the implementation of a win-win strategy for carbon reduction and waste resource utilisation. The effects of EMR dosing on the mechanical properties, microstructure and CO 2 emission of the EMR-doped cementitious materials are investigated. The results show that low dosing EMR (5 %) produced more ettringite, fostering early strength development. The fly ash-doped mortar strength increases and then decreases with the addition of EMR from 0 to 5 % to 5-20 %. It was found that blast furnace slag contributes less to strength than fly ash. Moreover, the sulfate activation and the micro-aggregate effect compensate for the EMR-induced dilution effect. The significant increase in strength contribution factor and direct strength ratio at each age verifies the sulfate activation of EMR. The lowest EIF 90 value of 5.4 kg∙MPa -1 ∙m 3 was achieved for the fly ash-doped mortar with 5 % EMR, suggesting the synergistic effect between fly ash and EMR optimised the mechanical properties while maintaining lower CO 2 emissions., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled, “Feasibility of electrolytic manganese residue for low-carbon and low-environmental impact supplementary cementitious materials”., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The incidence of hepatitis B virus (HBV) has decreased year by year in China after the expansion of vaccination, but there is still a high disease burden in Jiangsu Province of China., Methods: The year-by-year incidence data of HBV in Jiangsu Province from 1990 to 2021 were collected. The incidence rates of males and females age groups were clustered by systematic clustering, and the incidence rates of each age group were analyzed and studied by using Joinpoint regression model and age-period-cohort effect model (APC)., Results: Joinpoint regression model and APC model showed a general decrease in HBV prevalence in both males and females. In addition, the results of the APC model showed that the age, period, and cohort effects of patients all affected the incidence of HBV, and the incidence was higher in males than in females. The incidence is highest in the population between the ages of 15 and 30 years (mean: 21.76/100,000), especially in males (mean: 31.53/100,000) than in females (mean:11.67/100,000). Another high-risk group is those over 60 years of age (mean: 21.40/100,000), especially males (mean: 31.17/100,000) than females (mean: 11.63/100,000). The period effect of the APC model suggests that HBV vaccination is effective in reducing the incidence of HBV in the population., Conclusions: The incidence of HBV in Jiangsu Province showed a gradual downward trend, but the disease burden in males was higher than that in females. The incidence is higher and increasing rapidly in the population between the ages of 15 and 30 years and people over 60 years of age. More targeted prevention and control measures should be implemented for males and the elderly., 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., (© 2023 The Authors.)

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in the cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumour cells. In the present study, we found that SIRT3 was highly expressed in colorectal cancer cells with mitochondrial dysfunction, leading to PINK1/Parkin-mediated mitophagy. Excessive activation of mitophagy enhanced DNA damage repair, therefore promoting the resistance of tumour cells to radiation. Mechanistically, mitophagy resulted in decreased RING1b expression, which led to a reduction in the ubiquitination of histone H2A at K119, thereby enhancing the repair of DNA damage caused by radiation. Additionally, high expression of SIRT3 was related to a poor tumour regression grade in rectal cancer patients treated with neoadjuvant radiotherapy. These findings suggest that restoring mitochondrial function could be an effective method for increasing the radiosensitivity of patients with colorectal cancer., (© 2023 Federation of European Biochemical Societies.)

Ferroptosis, featuring an iron-dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin-1 but not Z-VAD-FMK (a pan-caspase inhibitor), Necrostatin-1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA-induced ferroptosis. Altogether, our findings reveal that PA engages in anti-cancer properties by activating ER stress/ER calcium release/TF-dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Compared to fixed orthodontic appliances with brackets, thermoplastic invisible orthodontic aligners offer several advantages, such as high aesthetic performance, good comfort, and convenient oral health maintenance, and are widely used in orthodontic fields. However, prolonged use of thermoplastic invisible aligners may lead to demineralization and even caries in most patients' teeth, as they enclose the tooth surface for an extended period. To address this issue, we have created PETG composites that contain piezoelectric barium titanate nanoparticles (BaTiO 3 NPs) to obtain antibacterial properties. First, we prepared piezoelectric composites by incorporating varying amounts of BaTiO 3 NPs into PETG matrix material. The composites were then characterized using techniques such as SEM, XRD, and Raman spectroscopy, which confirmed the successful synthesis of the composites. We cultivated biofilms of Streptococcus mutans ( S. mutans ) on the surface of the nanocomposites under both polarized and unpolarized conditions. We then activated piezoelectric charges by subjecting the nanocomposites to 10 Hz cyclic mechanical vibration. The interactions between the biofilms and materials were evaluated by measuring the biofilm biomass. The addition of piezoelectric nanoparticles had a noticeable antibacterial effect on both the unpolarized and polarized conditions. Under polarized conditions, nanocomposites demonstrated a greater antibacterial effect than under unpolarized conditions. Additionally, as the concentration of BaTiO 3 NPs increased, the antibacterial rate also increased, with the surface antibacterial rate reaching 67.39% (30 wt% BaTiO 3 NPs). These findings have the potential for application in wearable, invisible appliances to improve clinical services and reduce the need for cleaning methods.

Pharmaceuticals have been developed for the treatment of a wide range of bone diseases and disorders, but suffer from problematic delivery to the bone marrow. Neutrophils are naturally trafficked to the bone marrow and can cross the bone marrow-blood barrier. Here we report the use of neutrophils for the targeted delivery of free drugs and drug nanoparticles to the bone marrow. We demonstrate how drug-loaded poly(lactic-co-glycolic acid) nanoparticles are taken up by neutrophils and are then transported across the bone marrow-blood barrier to boost drug concentrations in the bone marrow. We demonstrate application of this principle to two models. In a bone metastasis cancer model, neutrophil delivery is shown to deliver cabazitaxel and significantly inhibit tumour growth. In an induced osteoporosis model, neutrophil delivery of teriparatide is shown to significantly increase bone mineral density and alleviate osteoporosis indicators., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Black-odorous water is a severe environmental issue that has received continuous attention. The major purpose of the present study was to propose an economical, practical, and pollution-free treatment technology. In this study, the in situ remediation of black-odorous water was conducted by applying different voltages (2.5, 5, and 10 V) to improve oxidation conditions of the surface sediments. The study investigated the effects of voltage intervention on water quality, gas emissions, and microbial community dynamics in surface sediments during the remediation process. The results indicated that the voltage intervention can effectively increase the oxidation-reduction potential (ORP) of the surface sediments and inhibit the emissions of H 2 S, NH 3 , and CH 4 . Moreover, the relative abundances of typical methanogens (Methanosarcina and Methanolobus) and sulfate-reducing bacteria (Desulfovirga) decreased because of the increase in ORP after the voltage treatment. The microbial functions predicted by FAPROTAX also demonstrated the inhibition of methanogenesis and sulfate reduction functions. On the contrary, the total relative abundances of chemoheterotrophic microorganisms (e.g., Dechloromonas, Azospira, Azospirillum, and Pannonibacter) in the surface sediments increased significantly, which led to enhanced biochemical degradability of the black-odorous sediments as well as CO 2 emissions.