Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement.

Inhibition of the receptor tyrosine kinase MerTK by small molecules has the potential to augment the immune response to tumors. Potent, selective inhibitors with high levels of in vivo target engagement are needed to fully evaluate the potential use of MerTK inhibitors as cancer therapeutics. We report the discovery and optimization of a series of pyrazinamide-based type 1.5 MerTK inhibitors bearing an azetidine-benzoxazole substituent. Compound 31 potently engages the target in vivo and demonstrates single agent activity in the immune-driven MC-38 murine syngeneic tumor model.

Baicalein induces apoptosis by targeting ribosomes in Candida auris.

The emergence of the "super fungus" Candida auris poses a significant threat to human health, given its multidrug resistance and high mortality rates. Therefore, developing a new antifungal strategy is necessary. Our previous research showed that Baicalein (BE), a key bioactive compound from the dried root of the perennial herb Scutellaria baicalensis Georgi, has strong fungistatic properties against C. auris. Nevertheless, the antifungal activity of BE against C. auris and its mechanism of action requires further investigation. In this study, we explored how BE affects this fungus using various techniques, including scanning electron microscopy (SEM), Annexin V-FITC apoptosis detection, CaspACE FITC-VAD-FMK In Situ Marker, reactive oxygen species (ROS) assay, singlet oxygen sensor green (SOSG) fluorescent probe, enhanced mitochondrial membrane potential (MMP) assay with JC-1, DAPI staining, TUNEL assay and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Our findings revealed that BE induced several apoptotic features, including phosphatidylserine (PS) externalization, metacaspase activation, nuclear condensation and DNA fragmentation. BE also increased intracellular ROS levels and altered mitochondrial functions. Additionally, transcriptomic analysis and RT-qPCR validation indicated that BE may induce apoptosis in C. auris by affecting ribosome-related pathways, suggesting that ribosomes could be new targets for antifungal agents, in addition to cell walls, membranes, and DNA. This study emphasizes the antifungal activity and mechanism of BE against C. auris, offering a promising treatment strategy for C. auris infection.

Inflammatory protein associations with brain MRI measures: Framingham Offspring Cohort.

INTRODUCTION: Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study. METHODS: Dementia and stroke-free participants underwent OLINK Proteomics profiling and MRI measurements within 5 years. Pairwise cross-sectional analysis assessed 68 biomarkers with 13 brain MRI volumes, adjusting for covariates and familial correlations. RESULTS: Elevated CDCP1, IL6, OPG, and 4E.BP1 were related to smaller total cerebral brain volume (TCBV), whereas higher HGF, IL8, and MMP10 were associated with smaller TCBV, total and frontal white matter volumes. Higher SCF and TWEAK were associated with larger TCBV. In sex-stratified analyses, associations were observed exclusively among males. DISCUSSION: We report several associations between inflammatory biomarkers and brain volumes, highlighting different associations within sex subgroups. HIGHLIGHTS: Higher CDCP1, IL6, OPG, and 4E.BP1 levels were associated with smaller TCBV. Higher levels of HGF, IL8 and MMP10 were associated with smaller TCBV, CWV and FWV. Higher levels of SCF and TWEAK, were associated with larger TCBV. Significance diminished in models adjusting for CVD risk factors. Associations were observed exclusively in males.

Transcriptomics analysis reveals the effect of Pulsatilla decoction butanol extract on endoplasmic reticulum and peroxisome function of Candida albicans in hyphal state.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula known as Pulsatilla decoction was utilized to treat conditions such as bacterial dysentery, ulcerative colitis, and fungal infections like vulvovaginal candidiasis (VVC) caused by Candida albicans (C. albicans). In our prior research, it was shown that the n-butanol extract from Pulsatilla Decoction (BEPD) exhibited effective inhibition of C. albicans. Nevertheless, the exact mechanism by which BEPD hinders hyphal growth, a critical virulence factor of C. albicans, remains unclear. AIM OF THE STUDY: In the present study, the inhibitory effect and mechanism of the BEPD on C. albicans hyphal growth was predicted by transcriptome analysis, and further verified by in vitro and in vivo experiments. MATERIALS AND METHODS: The BEPD was prepared and C. albicans was cultured to induce the hyphal state. Transcriptome analysis was conducted to predict the significant difference in enrichment genes and signaling pathways in the inhibitory effect of BEPD on C. albicans hyphae. Various methods, such as spot assay, time-growth curve analysis, Confocal laser scanning microscope (CLSM), scanning electron microscope (SEM), transmission electron microscope (TEM), flow cytometry, and spectrophotometer, were used to assess the effect of BEPD on hyphal structure and growth activity, lipid peroxidation level, peroxidase (CAT) activity, superoxide dismutase (SOD) activity, and apoptosis of C. albicans. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to examine the expression levels of genes associated with endoplasmic reticulum and peroxisome function. The VVC model was employed to evaluate the influence of BEPD on the growth of C. albicans hyphae in vivo. RESULT: The growth of C. albicans hyphae on solid culture media was significantly inhibited by BEPD. CLSM showed that the length of C. albicans hyphae was decreased and their vitality was lowered. SEM indicated that the hyphae of C. albicans were fractured, while TEM revealed damage to the organelles within the cells. GO enrichment and KEGG pathways analysis from transcriptomic data demonstrated that BEPD effectively suppressed the functioning of the endoplasmic reticulum and peroxisomes in C. albicans hyphae. RT-qPCR verified the decreased expression of genes associated with endoplasmic reticulum and peroxisome function by BEPD. Investigation of the endoplasmic reticulum revealed that BEPD elevated levels of reactive oxygen species (ROS) and apoptosis, indicating endoplasmic reticulum stress, as well as malondialdehyde (MDA), a marker of oxidative stress. Additionally, BEPD was shown to lower the activities of catalase (CAT) and superoxide dismutase (SOD). In animal trials, BEPD effectively hindered the growth of C. albicans hyphae in the vaginas of mice with VVC, thus reducing immune inflammatory damage to the vaginal mucosa of these mice. CONCLUSION: This study demonstrates that BEPD has an inhibitory effect on hyphae, which are an important virulence factor of C. albicans. This effect may be related to BEPD's inhibitory effect on endoplasmic reticulum (ER) and peroxisome function. The findings suggest that BEPD could potentially play a therapeutic role in C. albicans infectious diseases by inhibiting hyphae.

Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

Progress and recommendations of developing occupational exposure limits for noise-A systematic review.

Objective: Noise exposure limit is one of the critical measures to prevent noise-induced hearing loss (NIHL). This review aimed to review the progress and recommendations for developing occupational exposure limits (OELs) for workplace noise. Methods: A systematic review was used. Thirty-eight national or international organizations' noise exposure standards (including OEL) and laws, regulations, and guidelines for noise exposure control were analyzed. Articles on recommendations for revising noise OEL standards between 2000 and 2023 were selected. Results: The definition of different noise types (especially for non-steady and impulsive noise) varied worldwide, and the used 8-h OEL varied from 80 to 90 dB(A). Maximum sound pressure level (Lmax) and noise dose for industrial noise and peak sound pressure level (Lpeak) for impulsive noise have been incorporated into the OELs. Countries developed noise risk management measures based on OELs, action levels (ALs), and exposure risk ratio or classification. The risk of co-exposure to noise and ototoxic organic substances and the effects of noise on susceptible populations were concerns in EU country standards. Scholars suggested revising the existing noise exposure standards based on noise's temporal structure (expressed by kurtosis), effective noise level, impulsive noise OEL, action level, and key factors of risk assessment. Conclusions: Indicators such as Lmax, noise dose, Lpeak, and action level can be incorporated into noise OELs. Developing noise OEL standards should consider the co-exposure of noise and ototoxic substances, HPD's noise attenuation, susceptible groups, and noise's temporal structure.

Developing a Framework for Industrial Noise Risk Management Based on Noise Kurtosis and Its Adjustment.

OBJECTIVES: Noise risk control or management based on noise level has been documented, but noise risk management based on a combination of noise level and noise's temporal structure is rarely reported. This study aimed to develop a framework for industrial noise risk management based on noise kurtosis (reflecting noise's temporal structure) and its adjustment for the noise level. DESIGN: A total of 2805 Chinese manufacturing workers were investigated using a cross-sectional survey. The noise exposure data of each subject included LEX,8h, cumulative noise exposure (CNE), kurtosis, and kurtosis-adjusted LEX,8h (LEX,8h-K). Noise-induced permanent threshold shifts were estimated at 3, 4, and 6 kHz frequencies (NIPTS346) and 1, 2, 3, and 4 kHz frequencies (NIPTS1234). The prevalence of high-frequency noise-induced hearing loss prevalence (HFNIHL%) and noise-induced hearing impairment (NIHI%) were determined. Risk346 or Risk1234 was predicted using the ISO 1999 or NIOSH 1998 model. A noise risk management framework based on kurtosis and its adjustment was developed. RESULTS: Kurtosis could identify the noise type; Kurtosis combining noise levels could identify the homogeneous noise exposure group (HNEG) among workers. Noise kurtosis was a risk factor of HFNIHL or NIHI with an adjusted odds ratio of 1.57 or 1.52 (p < 0.01). At a similar CNE level, the NIPTS346, HFNIHL%, NIPTS1234, or NIHI% increased with increasing kurtosis. A nonlinear regression equation (expressed by logistic function) could rebuild a reliable dose-effect relationship between LEX,8h-K and NIPTS346 at the 70 to 95 dB(A) noise level range. After the kurtosis adjustment, the median LEX,8h was increased by 5.45 dB(A); the predicted Risk346 and Risk1234 were increased by 11.2 and 9.5%, respectively; NIPTS346-K of complex noise at exposure level <80, 80 to 85, and 85 to 90 dB(A), determined from the nonlinear regression equation, was almost the same as the Gaussian noise. Risk management measures could be recommended based on the exposure risk rating or the kurtosis-adjusted action levels (e.g., the lower and upper action levels were 80 and 85 dB(A), respectively). CONCLUSIONS: The kurtosis and its adjustment for noise levels can be used to develop an occupational health risk management framework for industrial noise. More human studies are needed to verify the risk management framework.

Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases.

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.

Anti-inflammatory and anti-lung cancer activities of low-molecular-weight and high-sulfate-content sulfated polysaccharides extracted from the edible fungus Poria cocos.

Sulfated polysaccharides (SPSs) have excellent physicochemical properties, attracting research interest in the pharmaceutical industry. A previous study extracted SPS (named Suc40) from the edible fungus, Poria cocos and demonstrated that it exhibited anti-inflammatory and anticancer activities. In this study, three fractions of Suc40, Suc40 F1, Suc40 F2, and Suc40 F3, with different molecular weights and sulfate contents were prepared through gel-filtration column chromatography. The molecular weights of F1, F2, and F3 were approximately 616.23, 82.57, and 6.21 kDa, respectively, and their sulfate content were 0.23, 1.65, and 1.90 mmol/g, respectively. The fractions' anti-inflammatory activities were determined by assessing their ability to suppress inflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Suc40 F2 and Suc40 F3 suppressed interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production by 60 % and 35 %, respectively. Suc40 F2 and Suc40 F3 suppressed protein kinase B (AKT)/p38 and p38 signaling, which resulted in anti-inflammatory effects. The fractions' anti-lung cancer activity was evaluated by assessing their H1975 cell proliferation inhibition. Suc40 F3 at a concentration of 800 µg/ml exhibited maximal cell proliferation inhibition. The low molecular weight and high sulfate content of Suc40 F3 were associated with its enhanced anti-inflammatory and anti-lung cancer activities.

Insulin-like growth factor-binding protein7 exacerbates inflammatory response and lipid metabolism imbalance in alcohol-associated liver disease.

Alcohol-associated liver disease(ALD), caused by excessive alcohol consumption, are often associated with inflammatory outbreaks and lipid deposition in the liver. The role of Insulin-like growth factor-binding protein 7 (IGFBP7), an important metabolic regulator, in ALD, its underlying regulatory mechanism, and its potential implication in anti-ALD therapies remain unknown. We investigated the effects of IGFBP7 on hepatic inflammation and lipid metabolism disruption in a mouse model of ALD. Mice were fed by chronic ethanol feeding plus a single binge of ethanol feeding(chronic-plus-single-binge model). In addition, ethanol exposure modeling studies were performed on cultured hepatocytes to verify molecular correlations. The results showed that IGFBP7 expression was significantly elevated in the livers of mice and hepatocytes after chronic ethanol exposure. Subsequently, the results of a study by specific knockout of IGFBP7(IGFBP7-cKO) in mouse hepatocytes and lentiviral silencing of IGFBP7 in vivo suggested that IGFBP7 deletion could improve liver function levels in alcohol-fed mice; It also attenuated the outbreak of hepatitis factor and the disorder of lipid metabolism in mice.Using RNA-seq sequencing of mouse liver tissue, we found that IGFBP7 affects several downstream metabolic signaling pathways, including PPAR, MAPK, FoxO, etc. Then, we used the PPARα plasmid in hepatocytes and discovered that overexpressing PPARα reversed the impact of IGFBP7 on lipid metabolism disorders in hepatocytes. In conclusion, IGFBP7 deficiency in alcohol-associated liver disease alleviates the decline in liver function and the imbalance of lipid metabolism in mice, attenuates the inflammatory outbreak, and affects a variety of downstream lipid metabolism factors by regulating PPARα. Hence, IGFBP7 may be an effective therapeutic target in the treatment of ALD.

The influences of ApoE isoforms on endothelial adherens junctions and actin cytoskeleton responding to mCRP.

Apolipoprotein E4 (ApoE4) plays an important role responding to monomeric C-reactive protein (mCRP) via binding to CD31 leading to cerebrovascular damage and Alzheimer's disease (AD). Using phosphor-proteomic profiling, we found altered cytoskeleton proteins in the microvasculature of AD brains, including increased levels of hyperphosphorylated tau (pTau) and the actin-related protein, LIMA1. To address the hypothesis that cytoskeletal changes serve as early pathological signatures linked with CD31 in brain endothelia in ApoE4 carriers, ApoE4 knock-in mice intraperitoneal injected with mCRP revealed that mCRP increased the expressions of phosphorylated CD31 (pCD31) and LIMA1, and facilitate the binding of pCD31 to LIMA1. mCRP combined with recombinant APOE4 protein decreased interaction of CD31 and VE-Cadherin at adherens junctions (AJs), along with altered the expression of various actin cytoskeleton proteins, causing microvasculature damage. Notably, the APOE2 protein attenuated these changes. Overall, our study demonstrates that ApoE4 responds to mCRP to disrupt the endothelial AJs which link with the actin cytoskeleton and this pathway could play a key role in the barrier dysfunction leading to AD risk.

Sigmoid colon cancer presenting as a large abdominal mass accompanied by abscess and rupture: a case report and literature review.

Introduction and Importance: Colon cancer presenting as a large abdominal mass accompanied by abscess and rupture is rare and prone to be misdiagnosed and delayed. In addition, the treatment plan is not clear when combined with abdominal wall metastasis. Case Presentation: A 79-year-old woman presented with a large abdominal mass accompanied by abscess and rupture. It was misdiagnosed as a soft tissue infection in a local hospital, and after a comprehensive examination, it was diagnosed as sigmoid colon cancer with abdominal wall metastasis and abscess formation. The patient underwent a one-stage surgery, including en bloc resection of the tumor and invaded abdominal wall, as well as autologous tissue abdominal wall reconstruction, with a good clinical prognosis. Clinical Discussion: For the diagnosis of large abdominal masses, abdominal CT, and pus culture are more valuable than ultrasound. For colon cancer with abdominal wall metastasis, one-stage surgery to completely remove the tumor and full-thickness of the abdominal wall, and the use of autologous tissue abdominal wall reconstruction technology to repair defects is feasible. Conclusion: This case highlights the importance of using colon cancer as one of the differential diagnoses for the diagnosis for large abdominal mass accompanied by abscess and rupture in elderly patients, as well as the possibility of one-stage surgical resection of the tumor and invasion of the abdominal wall and reconstruction of the abdominal wall with autologous tissue when there is abdominal wall metastasis.

A lipidomic study on the lens epithelial cells of patients with age related cataracts.

Age related cataracts (ARC) represent the main reason for blindness globally. The lens epithelial cells (LECs) participate not only in the metabolism of many substances in the lens but also in maintaining lens transparency. This study used lipidomics to investigate the metabolic differences in LECs of ARC patients with different severity, aiming at identifying potential metabolic biomarkers of ARC. Patients diagnosed with ARC and underwent cataract surgery at Shanghai Tongren Hospital were selected to participate in this study, which were classified as mild ARC group and severe ARC group. During their cataract surgery, anterior lens capsules(LCs) containing LECs were obtained. The lipidomics of LECs were analyzed using the liquid chromatography­mass spectrometry (LC-MS). Potential pathways of lipids were searched for using databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and MetaboAnalyst platform. In LEC lipids, 26 lipids have been identified as potential biomarkers between mild ARC and severe ARC, with AUC values of 0.67-0.94. The pathway analysis results revealed that the Glycerophospholipid (GPL) metabolism was significantly influenced, indicating that these metabolic markers contribute significantly to regulating this pathway. The LEC metabolic spectrum demonstrates a proficient ability to differentiate between patients with varying levels of cataracts. Herein, we have successfully identified potential metabolic biomarkers and pathways that have proven to be valuable in enhancing our understanding of ARC pathogenesis. The finding has translational value for developing new cataract treatment methods in the future.

UFMylation is involved in serum inflammatory cytokines generation and splenic T cell activation induced by lipopolysaccharide.

UFMylation, a novel ubiquitin-like protein modification system, has been recently found to be activated in inflammation. However, the effects of UFMylation activation on inflammation in vivo remains unclear. In the present study, we generated a UFMylation activated mice using transgenic (TG) techniques. Lipopolysaccharide (LPS) was used to induce systemic inflammation in both TG and non-transgenic (NTG) mice. Serum cytokines were detected using a Mouse Cytokine Array, and the proportions of splenic NK, B and T cells were determined by using flow cytometry. We found that TG mice showed increased serum G-CSF, TNF RII and decreased serum TCA-3, CD30L, bFGF, IL-15 and MIG compared with NTG mice at baseline. Furthermore, serum cytokines in TG mice exhibited different responses to LPS compared to NTG mice. LPS up-regulated serum TNF RII, G-CSF, MCP-5, RANTES, KC, BLC, MIG and down-regulated IL-1b, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-15, IL-17, IFN-γ, TCA-3, Eotaxin-2, LIX, MCP-1, TNFα, GM-CSF in NTG mice, whereas LPS up-regulated G-CSF, MCP-5, RANTES, KC, BLC, MIG, ICAM-1, PF4, Eotaxin, CD30L, MIP-1a, TNFRI and down-regulated IL-1b, IL-3, LIX, MCP-1, TNFα, GM-CSF in TG mice. Data from flow cytometry indicated that LPS significantly reduced the percentages of NK and NKT cells in NTG mice, whereas UFMylation activation inhibited LPS-induced NKT cell decrease. The proportions of B cells, total CD4+ and total CD8+ T cells were comparable between TG and NTG mice in response to LPS treatment, whereas the percentages of CD4+CD69+ and CD8+CD69+T cells were lower in TG mice. These findings suggest that UFMylation may alter LPS-induced serum cytokine profile and participate in splenic T cell activation in vivo.

Overcoming Microstructural Defects at the Buried Interface of Formamidinium-Based Perovskite Solar Cells.

Since the advent of formamidinium (FA)-based perovskite photovoltaics (PVs), significant performance enhancements have been achieved. However, a critical challenge persists: the propensity for void formation in the perovskite film at the buried perovskite-interlayer interface has a deleterious effect on device performance. With most emerging perovskite PVs adopting the p-i-n architecture, the specific challenge lies at the perovskite-hole transport layer (HTL) interface, with previous strategies to overcome this limitation being limited to specific perovskite-HTL combinations; thus, the lack of universal approaches represents a bottleneck. Here, we present a novel strategy that overcomes the formation of such voids (microstructural defects) through a film treatment with methylammonium chloride (MACl). Specifically, our work introduces MACl via a sequential deposition method, having a profound impact on the microstructural defect density at the critical buried interface. Our technique is independent of both the HTL and the perovskite film thickness, highlighting the universal nature of this approach. By employing device photoluminescence measurements and conductive atomic force microscopy, we reveal that when present, such voids impede charge extraction, thereby diminishing device short-circuit current. Through comprehensive steady-state and transient photoluminescence spectroscopy analysis, we demonstrate that by implementing our MACl treatment to remedy these voids, devices with reduced defect states, suppressed nonradiative recombination, and extended carrier lifetimes of up to 2.3 µs can be prepared. Furthermore, our novel treatment reduces the stringent constraints around antisolvent choice and dripping time, significantly extending the processing window for the perovskite absorber layer and offering significantly greater flexibility for device fabrication.

Probiotics-regulated lithocholic acid suppressed B-cell differentiation in neuromyelitis optica spectrum disorder.

Intestinal microbes play a crucial role in gut health and the immune-mediated central nervous system through the "gut-brain" axis. However, probiotic safety and efficacy in Neuromyelitis optica spectrum disorder (NMOSD) are not well-explored. A pilot clinic trial for NMOSD with probiotic intervention revealed alterations in the microbiota (increased Anaerostipes, Bacteroides; decreased Granulicatella, Streptococcus, Rothia). Metabolite analysis showed elevated 2-methylbutyric and isobutyric acids, reduced lithocholic acid (LCA), and glycodeoxycholic acid (GDCA). Immune markers Interleukin (IL-7), vascular endothelial growth factor (VEGF-A), and B lymphocyte chemoattractant (BLC) decreased, while plasma cells and transitional B cells increased post-probiotics, suggesting potential immunomodulatory effects on NMOSD.

Female-Specific Association between the Apolipoprotein E E4 Allele and Age at Diagnosis of Glaucoma in UK Biobank.

OBJECTIVE: To explore the impact of the apolipoprotein E (APOE) E4 allele in the gender-specific aging process in glaucoma by illustrating the interaction between risk factors, including the APOE E4 allele, gender, and intraocular pressure (IOP), for age at diagnosis (AAD) of glaucoma. DESIGN: A cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis. Data were analyzed in December 2023. PARTICIPANTS: Two thousand two hundred thirty-six glaucoma patients and 103 232 controls. METHODS: We evaluated multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele (0: absence; 1: presence), and IOP using linear mixed model (LMM) analyses across groups stratified by AAD of mean age of menopause (50 years) and gender. MAIN OUTCOMES MEASURES: Age at diagnosis of glaucoma, APOE E4 allele, and IOP. RESULTS: Patients with glaucoma were older and had a higher percentage of males and a higher mean IOP compared to controls (all P < 0.001). Further stratifying the patients with glaucoma by AAD of 50 and gender, lower IOP (model 1 adjusted by age, ßIOP = -0.096 ± 0.041, P = 0.019), and positive APOE E4 allele (model 2 adjusted by age and IOP, ße4 = 1.093 ± 0.488, P = 0.026) were associated with an older AAD in females with an AAD <50 years under univariate LMM. In multivariate LMM adjusted by age (model 3), the effect size of both factors increased in the multivariate model as the beta-value increased (ßIOP = -0.111 ± 0.040, P = 0.007; ße4 = 1.235 ± 0.485, P = 0.012) (model 1 vs. model 3: P = 0.011). In females with an AAD ≥50 years, only positive APOE E4 allele (adjusted by age and IOP, ße4 = -1.121 ± 0.412, P = 0.007) was associated with a younger AAD. In males, only higher IOP was associated with an older AAD in those with an AAD ≥50 years (ßIOP = 0.088 ± 0.032, P = 0.006). CONCLUSIONS: Apolipoprotein E E4 allele may initially delay and later accelerate the development of glaucoma in females around the transition period of 50 years, which is the mean age of menopause, and importantly, this is independent of IOP. Understanding the specific transition states and modifiable factors within each age phase is crucial for developing interventions or strategies that promote healthy aging. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Promising strategies for smart insulin delivery system: Glucose-sensitive microneedle.

The diabetes treatment landscape is rapidly evolving towards intelligent and precise therapeutic interventions. Among these advancements, glucose-sensitive microneedle patches (GSMPs), which can automatically adjust the transdermal release rate of insulin based on glucose concentrations, are emerging as a promising strategy. In this work, a new classification method has been proposed for GSMPs, categorizing them into integrated, all-in-one, and core-shell structures. The working mechanism and performance of GSMPs are thoroughly analyzed to compare the advantages and disadvantages of these three forms. The correlation between glucose-sensitive performance and normal blood glucose maintenance time (NGT) is further explored. Our findings indicate that all-in-one GSMPs demonstrate a positive correlation between in vitro glucose-sensitive controlled-release performance and NGT, unlike assembled GSMPs, where the performance is influenced by the matrix material and crosslinking factors. Simultaneously, challenges in clinical translation and future development trends are discussed from a patient's perspective. In summary, the new classification method, in-depth explanation of mechanisms, and analysis of challenges in this work contribute to a better understanding of the field of GSMPs and provide guidance for the development of more advanced and efficient GSMPs.

GLIM criteria-based identification of severe malnutrition and its relationship with the risk of mortality among older Chinese adults with arthritis or rheumatism.

BACKGROUND: Malnutrition is a well-known risk factor for mortality among older adults. Arthritis and rheumatism are characterized by chronic inflammation and are also related to malnutrition as diagnosed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. This study was thus developed to examine the associations linking malnutrition and all-cause death among older adults in China, employing the GLIM criteria to assess malnutrition. METHODS: Two waves of the China Health and Retirement Longitudinal Study from 2013 and 2018 were used to conduct this study. Moderate malnutrition was defined as low BMI (< 18.5 and < 20 for individuals < 70 and 70 + years of age, respectively), an unintended 10-20% decrease in weight, or low muscle mass based on the sex-specific lowest 20% of the height-adjusted muscle mass as < 5.039 kg/m2 in women and < 6.866 kg/m2 in men. Severe malnutrition was defined as a > 20% unintended decrease in weight only or the combination of both low muscle mass and an unintended reduction of over 10% in weight. Associations between malnutrition and the risk of all-cause death were assessed through Cox regression analyses. RESULTS: Overall, this study enrolled 1766 subjects 60 + years of age, of whom 57.36% (1033/1766) were female. Malnutrition was estimated to affect 418 (23.67%) of these individuals at baseline, with 21.06% and 2.60% affected by moderate and severe malnutrition, respectively. Over the 5-year follow-up, 189 of these individuals died. Covariate-adjusted Cox regression analyses confirmed a significant association between severe malnutrition and the risk of death in this cohort (HR = 2.196, 95%CI 1.125-4.286, P = 0.021). CONCLUSIONS: Severe malnutrition, identified through screening based on the GLIM criteria, was associated with an increased risk of all-cause death among older Chinese adults with arthritis or rheumatism.