Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer.

Despite the continuous developments and advancements in the treatment of gastric cancer (GC), which is one of the most prevalent types of cancer in China, the overall survival is still poor for most patients with advanced GC. In recent years, with the progress in tumor immunology research, attention has shifted toward immunotherapy as a therapeutic approach for GC. Programmed cell death protein 1 (PD-1) inhibitors, as novel immunosuppressive medications, have been widely utilized in the treatment of GC. However, many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy. To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy, to maximize the clinical activity of immunosuppressive drugs, and to elicit a lasting immune response, it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients. This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment, aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

The dose effectiveness of extracorporeal shockwave on plantar flexor spasticity of ankle in stroke patients: a randomized controlled trial.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) has been proven beneficial for post-stroke spasticity (PSS) of ankle plantar flexor muscles. This study aims to investigate the dose-response effectiveness of focused-ESWT and the duration of its effect on the treatment of ankle PSS in stroke patients. METHODS: In this double-blinded randomized controlled trial, stroke patients diagnosed with PSS in the ankle plantar flexor muscles were randomly assigned to two groups. The experimental group received double-dose ESWT (4000 pulses per session) targeting spastic calf muscles, while the control group received half the dose (2000 pulses per session). Both groups underwent four sessions over two weeks. The outcomes, including modified Ashworth Scale (MAS), modified Tardieu Scale (MTS), passive range of motion (PROM) of the ankle, Timed Up and Go (TUG) Test, Barthel index and strain elastography were evaluated at baseline, 1st, 4th, 12th, and 24th week after ESWT. RESULTS: Within-group analysis revealed significant improvements in MAS, PROM, TUG Test, and Barthel index for the double-dose ESWT group and improvements in Barthel index for the control group. Between-group analysis revealed greater improvements in TUG Test, Barthel Index and strain elastography for the double-dose ESWT group. Generalized estimating equations analysis indicated that the double-dose ESWT group achieved superior outcomes in the TUG Test, Barthel Index, and strain elastography across various time points and groups. CONCLUSIONS: Double-dose ESWT showed better functional improvement and elastography compared to the control group. ESWT demonstrated dose-response effectiveness for PSS of ankle-equinus. TRIAL REGISTRATION: NCT05878223.

Preconcentration of Cinnamic Acid Derivatives in Traditional Chinese Medicines by an Effective Dispersive Liquid-Liquid Microextraction Based on a Hydrophobic Deep Eutectic Solvent.

A dispersive liquid-liquid microextraction based on hydrophobic deep eutectic solvent (hDES) was developed for the extraction and quantification of four cinnamic acid derivatives in traditional Chinese medicines coupled with high-performance liquid chromatography-ultraviolet detection. In this method, a hDES (tetrabutylammonium chloride-hexanoic acid, molar ratio of 1:2) was prepared as the extractant. It only took 15 s to handle multiple samples simultaneously by hand-assisted dispersion. The use of a narrow-bore tube reduced the amount of the hydrophobic extractant with easier recovery. The approach was influenced by several key parameters, including the composition and consumption of the DES, sample phase pH, salt amount, extraction time, and centrifugation time, all of which had been investigated and optimized. Moreover, the formation of the DES was characterized by Fourier-transform infrared spectroscopy and differential scanning calorimetry. Under the optimal conditions, enrichment factors of the target analytes ranged from 135 to 220. Satisfactory linearities (r ≥ 0.9977), detection limits (0.2-0.4 ng/mL), precision (<8.5%), and accuracy (recoveries: 90.0%-104.6%) were obtained. The method has been successfully applied to the simultaneous extraction and preconcentration of four cinnamic acid derivatives in Chinese medicinal samples with rapidness, high efficiency, and convenience.

Huang-Lian-Jie-Du Decoction alleviates diabetic encephalopathy by regulating inflammation and pyroptosis via suppression of AGEs/RAGE/NF-κB pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated. AIM OF THE STUDY: To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice. STUDY DESIGN AND METHODS: A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice. RESULTS: Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways. CONCLUSION: Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.

Risk factor differences in five-year progression of Intracranial artery stenosis and cerebral small vessel disease in general population.

BACKGROUND: Intracranial artery stenosis (ICAS) and cerebral small vessel disease (CSVD) are associated with a heavy socioeconomic burden; however, their longitudinal changes remain controversial. METHODS: We conducted a longitudinal analysis on 756 participants of Shunyi Cohort who underwent both baseline and follow-up brain magnetic resonance imaging (MRI) and MR angiography in order to investigate the risk factors for ICAS and CSVD progression in community population. Incident ICAS was defined as new stenosis occurring in at least one artery or increased severity of the original artery stenosis. CSVD markers included lacunes, cerebral microbleeds (CMB), and white matter hyperintensities (WMH). RESULTS: After 5.58 ± 0.49 years of follow-up, 8.5% of the 756 participants (53.7 ± 8.0 years old, 65.1% women) had incident ICAS. Body mass index (BMI) (OR = 1.09, 95% CI = 1.01-1.17, p = 0.035) and diabetes mellitus (OR = 2.67, 95% CI = 1.44-4.93, p = 0.002) were independent risk factors for incident ICAS. Hypertension was an independent risk factor for incident lacunes (OR = 2.12, 95% CI = 1.20-3.77, p = 0.010) and CMB (OR = 2.32, 95% CI = 1.22-4.41, p = 0.011), while WMH progression was primarily affected by BMI (ß = 0.108, SE = 0.006, p = 0.002). A higher LDL cholesterol level was found to independently protect against WMH progression (ß = -0.076, SE = 0.027, p = 0.019). CONCLUSIONS: Modifiable risk factor profiles exhibit different in patients with ICAS and CSVD progression. Controlling BMI and diabetes mellitus may help to prevent incident ICAS, and antihypertensive therapy may conduce to mitigate lacunes and CMB progression. LDL cholesterol may play an inverse role in large arteries and small vessels.

Presence of Flazin in Miso and Identification of Four Tryptophan-Derived ß-Carbolines Formed during Fermentation.

In miso, due to the substantial presence of genistein, flazin is often overlapped and masked by genistein in HPLC analysis. Flazin in the miso extracts could be resolved with genistein through medium-pressure liquid chromatography run under a nonacidified methanol-water system and subsequently fractionated by semipreparative HPLC and identified by NMR spectroscopic analysis. As referenced, flazin was detected in all 11 locally marketed miso products, with contents ranging from 3.5 to 124.8 µg/g. In lab-made miso fermented at 28 and 37 °C for 8 weeks, flazin formed faster at 37 °C than at 28 °C. Based on the time-dependent HPLC chromatographic changes of the miso extracts during fermentation, the presence of tryptophan-derived ß-carboline intermediates was deduced. Tryptophan was then supplemented for miso fermentation, and four peak substances were targeted for isolation by sophisticated approaches. Four ß-carbolines were purified and instrumentally identified, i.e., P1: 1-(1,3,4,5-tetrahydroxypentyl)-9H- pyrido[3,4-b]indole, P2 (diastereomer of P1): 1-(1*,3,4,5-tetrahydroxypentyl)- 9H-pyrido[3,4-b]indole, and Miso 101: 1-(1,3,4,5-tetrahydroxypentyl)-9H- pyrido[3,4-b]indole 3-carboxylic acid, and Miso 111 (diastereomer of Miso 101): 1-(1*,3,4,5-tetrahydroxypentyl)-9H-pyrido[3,4-b]indole 3-carboxylic acid. Each of the purified ß-carbolines along with tryptophan and flazin exhibited varied ABTS·+ scavenging and xanthine oxidase inhibitory activities.

Vitexin Mitigates Haloperidol-Induced Orofacial Dyskinesia in Rats through Activation of the Nrf2 Pathway.

Vitexin (VTX), a C-glycosylated flavone found in various medicinal herbs, is known for its antioxidant, anti-inflammatory, and neuroprotective properties. This study investigated the protective effects of VTX against orofacial dyskinesia (OD) in rats, induced by haloperidol (HPD), along with the neuroprotective mechanisms underlying these effects. OD was induced by administering HPD (1 mg/kg i.p.) to rats for 21 days, which led to an increase in the frequency of vacuous chewing movements (VCMs) and tongue protrusion (TP). VTX (10 and 30 mg/kg) was given intraperitoneally 60 min after each HPD injection during the same period. On the 21st day, following assessments of OD, the rats were sacrificed, and nitrosative and oxidative stress, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptosis markers in the striatum were measured. HPD effectively induced OD, while VTX significantly reduced HPD-induced OD, decreased oxidative stress, enhanced antioxidant capacity, prevented mitochondrial dysfunction, and reduced neuroinflammatory and apoptotic markers in the striatum, and the protective effects of VTX on both behavioral and biochemical aspects of HPD-induced OD were significantly reduced when trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated pathway, was administered. These findings suggest that VTX provides neuroprotection against HPD-induced OD, potentially through the Nrf2 pathway, indicating its potential as a therapeutic candidate for the prevention or treatment of tardive dyskinesia (TD) in clinical settings. However, further detailed research is required to confirm these preclinical findings and fully elucidate VTX's therapeutic potential in human studies.

High-glucose impact on UVB responses in human epidermal keratinocytes: Insights on diabetic skin's resistance to photocarcinogenesis.

Ultraviolet (UV) B-induced damage in human epidermal keratinocytes (HEKs) initiates photocarcinogenesis. However, how diabetes influences photocarcinogenesis is not well understood. To investigate the impact of high-glucose environments on responses to UVB, we cultured HEKs in normal-glucose (NG) or high-glucose (HG) conditions (G6 and G26), followed by UVB irradiation at 25 mJ/cm2 (G6UVB and G26UVB). We performed next-generation sequencing and analyzed HEKs' expression profiles bioinformatically to identify candidate genes and cellular responses involved. We found UVB induced consistent responses in both NG- and HG-cultivated HEKs, but it also triggered certain distinct processes and pathways specifically in the HG groups. The 459 differentially expressed (DE) genes in the HG groups revealed their roles in chromatin remodeling, nucleosome assembly, and interferon signaling activation. Moreover, the 29 DE genes identified in G26UVB/G6UVB comparison, including the potent tumor suppressor gene TFPI2, were considered key genes contributing to HEKs' altered response to UVB in HG environments. UVB irradiation induced significantly higher TFPI2 expression in HG-cultivated HEKs than their NG-cultivated counterpart. Finally, HG-cultivation significantly increased oxidative stress, cyclobutane pyrimidine dimer formation, and apoptosis, while reducing HEKs' viability after UVB irradiation. These changes under HG conditions probably mediate cell fate toward death and tumor regression. Overall, our findings provide evidence and associated molecular basis on how HG conditions reduce keratinocytes' photocarcinogenic potential following UVB exposure.

The changing impacts of social determinants on youth mental health in Australia.

AIMS: Most lifetime mental health disorders begin by age 25 years, and the prevalence among young people has been increasing over recent years. We sought to understand what impact, if any, social determinants have had on this increase through the analysis of an Australian longitudinal dataset (with data from 2007 to 2021). METHODS: The analysis focused on five social determinants: loneliness and lack of social support, family relationships, participation in education and employment, receipt of government benefits and relative socio-economic status. We analysed cross-sectional changes in self-reported psychological distress between 2007 and 2021 (using the Kessler-10 item; K10 scores) and examined the effects of these five social determinants on psychological distress using weighted linear regression models. RESULTS: We identified a significant increase in psychological distress among Australians from 2007 to 2021, with the sharpest rise among those aged 15 to 25 years, who saw more than doubling in the percentage of high and very high K10. This period also saw an increase in the prevalence of social determinants such as loneliness and lack of social support, as well as poor family relationships, particularly in 2021 post COVID-19 pandemic. Regression models suggest loneliness and lack of social support had the most pronounced and increasing impact on psychological distress, followed by poor family relationships. DISCUSSION: The observed significant and steady increases in psychological distress and related social determinant factors, particularly loneliness and lack of social support among young people, highlight the urgent need for comprehensive actions. Coordinated research and community-based initiatives are needed to deliver intrapersonal, interpersonal and socially-focused interventions with a holistic approach to support psychosocial wellbeing. Policymakers must adopt a comprehensive shift in political commitment and a whole-of-government approach to address these challenges.

The I4790K mutation of the ryanodine receptor is responsible for anthranilic diamide resistance in field populations of Plutella xylostella (Lepidoptera: Plutellidae).

Insecticide resistance in Plutella xylostella (Linnaeus) (Lepidoptera: Plutellidae) is a major constraint on the global production of cruciferous crops. For effective management of insecticide resistance, it is necessary to develop a molecular detection tool for predicting insecticide resistance levels based on the mutation frequency of target sites. In this study, a susceptible strain (SHggt) of P. xylostella was subjected to chlorantraniliprole and tetraniliprole selection under laboratory conditions to obtain the CHLSel and TETSel strains, respectively, to determine their resistance development, cross-resistance and mutation frequencies of the P. xylostella ryanodine receptor (PxRyR). In addition, the tetraniliprole resistance and the mutation frequencies of the PxRyR from 7 field populations were evaluated. Continuous selection over 30 generations resulted in resistance ratios (RRs) of 7,073.2-fold and 6,971.0-fold for the CHLSel and TETSel strains, respectively, and thousandfold increases in cross-resistance to unexposed diamides, e.g., cyantraniliprole and flubendiamide, were observed. For the field populations, three out of seven populations have developed more than thousandfold resistance to tetraniliprole. Among the three investigated target site mutations in PxRyR, only I4790K was detected in both laboratory-selected strains. However, 2 mutations, I4790K and G4946E, were detected in field populations. A positive correlation between RRs and K allele frequencies was observed in the laboratory-selected/relaxed strains and field populations of P. xylostella. These results suggest a possible link between the development of anthranilic diamide resistance and the frequency of the PxRyR I4790K mutation, which can be used to develop effective strategies for diamide resistance management in P. xylostella.

Extragastrointestinal stromal tumors with diffuse membranous distribution with bleeding: A case report.

BACKGROUND: Extragastrointestinal stromal tumors (EGIST) and gastrointestinal stromal tumors are of similar pathological type and form. Here we report a rare case of EGIST diffusely distributed in membranous tissue in abdominal cavity, the feature of which included diffuse tumors at membranous tissue in entire abdominal cavity and spontaneous bleeding of the tumors. CASE SUMMARY: The patient was a 71-year man and hospitalized due to continuous pain at lower abdomen for more than 10 days. Upon physical examination, the patient had flat and tough abdomen with mild pressing pain at lower abdomen, no obvious abdominal mass was touchable, and shifting dullness was positive. Positron emission tomography-computed tomography (CT) showed that in his peritoneal cavity, there were multiple nodules of various sizes, seroperitoneum, multiple enlarged lymph nodes in abdominal/pelvic cavity and right external ilium as well as pulmonary nodules. Plain CT scanning at epigastrium/hypogastrium/pelvic cavity + enhanced three-dimensional reconstruction revealed multiple soft tissue nodules in abdominal/pelvic cavity, peritoneum and right groin. Tumor marker of carbohydrate antigen 125 was 808 U/mL, diffuse tuberous tumor was seen in abdominal/pelvic cavity during operation with hematocelia, and postoperative pathological examination confirmed EGIST. Imatinib was administered with better therapeutic effect. CONCLUSION: Gene testing showed breast cancer susceptibility gene 1 interacting protein C-terminal helicase 1 and KIT genovariation, and the patient was treated with imatinib follow-up visit found that his clinical symptoms disappeared and the tumor load alleviated obviously via imageological examination.

Non-invasive metabolic biomarkers in initial cognitive impairment in patients with diabetes: A systematic review and meta-analysis.

AIM: Diabetic cognitive impairment (DCI), considered one of the most severe and commonly overlooked complications of diabetes, has shown inconsistent findings regarding the metabolic profiles in DCI patients. This systematic review and meta-analysis aimed to identify dysregulated metabolites as potential biomarkers for early DCI, providing valuable insights into the underlying pathophysiological mechanisms. MATERIALS AND METHODS: A systematic search of four databases, namely PubMed, Embase, Web of Science and Cochrane, was conducted up to March 2024. Subsequently, a qualitative review of clinical studies was performed followed by a meta-analysis of metabolite markers. Finally, the sources of heterogeneity were explored through subgroup and sensitivity analyses. RESULTS: A total of 774 unique publications involving 4357 participants and the identification of multiple metabolites were retrieved. Of these, 13 clinical studies reported metabolite differences between the DCI and control groups. Meta-analysis was conducted for six brain metabolites and two metabolite ratios. The results revealed a significant increase in myo-inositol (MI) concentration and decreases in glutamate (Glu), Glx (glutamate and glutamine) and N-acetylaspartate/creatine (NAA/Cr) ratios in DCI, which have been identified as the most sensitive metabolic biomarkers for evaluating DCI progression. Notably, brain metabolic changes associated with cognitive impairment are more pronounced in type 2 diabetes mellitus than in type 1 diabetes mellitus, and the hippocampus emerged as the most sensitive brain region regarding metabolic changes associated with DCI. CONCLUSIONS: Our results suggest that MI, Glu, and Glx concentrations and NAA/Cr ratios within the hippocampus may serve as metabolic biomarkers for patients with early-stage DCI.

Factors associated with oropharyngeal dysphagia and unsuccessful nasogastric tube removal after endovascular thrombectomy for anterior circulation stroke.

PURPOSE: To identify the predictive variables for post-stroke dysphagia (PSD) among anterior circulation large vessel occlusion (LVO) stroke patients who underwent endovascular thrombectomy (EVT). METHODS: This retrospective cohort study enrolled hospitalized patients with anterior LVO stroke who underwent EVT between January 1, 2018 and October 31, 2022. PSD was defined as the unsuccessful removal of the nasogastric (NG) tube. Factors, such as premorbid characteristics, laboratory results, EVT, rehabilitation-related parameters, and neuro-imaging, were analyzed for correlations to PSD at 4 and 12 weeks. RESULTS: The study enrolled 136 patients, with a mean age of 72.9 ± 13.0 years, and 59 patients (43.4%) were male. At 4 weeks, 47.1% of the patients needed an NG tube, and at 12 weeks, 16.2% still required an NG tube. We found that lower albumin, lower body mass index (BMI), higher initial and 24-h post-EVT National Institute of Health Stroke Scale (NIHSS) scores, stroke-associated pneumonia, poor initial sitting balance and ability to sit up, insula or frontal operculum lesions, and bilateral hemisphere involvement were all associated with PSD at both 4 and 12 weeks in the univariate logistic regression. Multivariate analysis revealed that significant predictors of unsuccessful NG tube removal at 4 weeks included lower BMI (adjusted OR [aOR] 0.73, p = 0.005), hemorrhagic transformation (aOR 4.01, p = 0.0335), higher NIHSS scores at 24 h post-EVT (aOR 1.13, p = 0.0288), poor initial sitting ability (aOR 0.52, p = 0.0231), insular cortex ischemia (aOR 7.26, p = 0.0056), and bilateral hemisphere involvement (aOR 41.19, p < 0.0001). At 12 weeks, lower BMI (aOR 0.78, p = 0.0098), poor initial sitting balance (aOR 0.57, p = 0.0287), insular cortex lesions (aOR 4.83, p = 0.0092), and bilateral hemisphere involvement (aOR 4.07, p = 0.0139) remained significant predictors. CONCLUSIONS: In patients with anterior LVO following EVT, PSD was associated with lower BMI, higher NIHSS scores, poor initial sitting balance and sitting ability, insular lesions, and bilateral hemisphere involvement.

Vaccine optimization for highly pathogenic avian influenza: Assessment of antibody responses and protection for virus-like particle vaccines in chickens.

Background: Recent outbreaks of clade 2.3.4.4b highly pathogenic avian influenza (HPAI) H5N1 viruses in regions previously less affected since 2020 have raised global concerns. Implementing mass immunization or ring vaccination in poultry should be a countermeasure ready to contain disease outbreaks. This study focuses on developing a recombinant H5N2 vaccine based on virus-like particles (VLPs) against clade 2.3.4.4c, the predominant HPAI subclade in Taiwan since its emergence, leading to a large outbreak in 2015. Methods: The study aimed to confirm the effectiveness of clade 2.3.4.4c H5N2 VLPs in protecting chickens and identify the best adjuvants for the VLP vaccine. We used Montanide 71VG-adjuvanted inactivated RG6 to establish the immunization protocol, followed by prime-boost H5N2-VLP immunizations. We compared adjuvants: 71VG, 71VG with VP3, and Alum with VP3. Serum samples were tested for antibodies against homologous vaccine antigens and cross-clade antigens by hemagglutination inhibition (HI) assays. Finally, we evaluated the protective efficacy by lethally challenging immunized chickens with H5 viruses from clade 1 or 2.3.4.4c. Results: Poultry adjuvant 71VG significantly enhanced antibody responses in chickens with inactivated RG6 compared to unadjuvanted inactivated virus. While increasing antigen dosage enhanced 71VG adjuvanted RG6-induced antibody titers, the vaccine displayed minimal cross-reactivity against locally circulating HPAI H5N2. In contrast, H5N2-VLP containing the HA protein of clade 2.3.4.4c, adjuvanted with (FMDV) VP3 in 71VG, significantly promoted HI antibody responses. All H5N2-VLP immunized chickens survived lethal challenges with the local clade 2.3.4.4c H5 strain. Conclusion: The study demonstrated the immunogenic potential of the VLP vaccine in chickens. Our findings offer insights for optimizing VLP vaccines, allowing the incorporation of the HA of currently circulating H5 viruses to effectively mitigate the impact of the rapidly evolving clade 2.3.4.4 H5 outbreaks.

Exploration of the Mechanisms of Bu-Yang-Huan-Wu Decoction in the Treatment of Diabetic Peripheral Neuropathy by Integrating of Serum Pharmacochemistry and Network Pharmacology.

Diabetic peripheral neuropathy (DPN) is a significant and frequent complication of diabetes. Bu-Yang-Huan-Wu Decoction (BHD) is a classic traditional Chinese herbal prescription that is commonly used in modern clinical practice for the effective treatment of DPN, but the underlying mechanism is not yet clearly defined. The chemical constituents of BHD were characterized by UPLC-Q-Orbitrap HR MS/MS, and a total of 101 chemical components were identified, including 30 components absorbed into blood. An interaction network of "compound-target-disease" interactions was constructed based on the compounds detected absorbed in blood and their corresponding targets of diabetic neuropathy acquired from disease gene databases, and the possible biological targets and potential signalling pathways of BHD were predicted via network pharmacology analysis. Subsequently, methylglyoxal-induced (MGO-induced) Schwann cells (SCs) were used to identify the active ingredients in blood components of BHD and verify the molecular mechanisms of BHD. Through network topological analysis, 30 shared targets strongly implicated in the anti-DPN effects of BHD were identifed. Combined network pharmacology and in vitro cellular analysis, we found that the active ingredient of BHD may treat DPN by modulating the AGEs/RAGE pathway. This study provides valuable evidence for future mechanistic studies and potential therapeutic applications for patients with DPN.

Changes in Rates of Special Considerations in Higher Education Applications Pre- and During the COVID-19 Pandemic in Victoria, Australia.

BACKGROUND AND AIMS: Since the onset of the COVID-19 pandemic, a significant rise in mental ill health has been observed globally in young people, particularly those in their final years of secondary school. Students' negative experiences coincide with a critical transitional period which can disrupt milestones in social and educational development. This study aimed to use innovative population-level data to map the impact of the pandemic on students entering higher education. METHODS: Pre-pandemic (2019/2020) and pandemic (2020/2021) tertiary education application data were obtained from the Victorian Tertiary Admissions Centre. Prevalence of applications for special consideration related to mental ill health were compared between cohorts across various geographical areas and applicant demographic subgroups. Relative risk regression models were used to understand the role of different risk factors. RESULTS: Rates of mental health-related special consideration applications increased by 38% among all applications (pre-pandemic: 7.8%, n = 56 916; pandemic: 10.8%, n = 58 260). Highest increases were observed among students in areas with both extended and close-quarter lockdown experiences, and areas impacted by 2019/2020 black summer bushfires. The increases were higher among Year 12 students and students with other special consideration needs (e.g., physical condition, learning disability). Slightly higher increases were observed in areas with higher socio-economic status, which may potentially be related to inequality in mental health service access. CONCLUSION: As consequences of mental health difficulties and academic disruption in youth can be long lasting, it is critical to establish a mental health support framework both in and outside of higher education to facilitate young people's recovery from the pandemic.

Combining Ti4(embonate)6 anionic cages and π-conjugated coordination cations for highly effective optical limiting.

The integration of anionic Ti4L6 (L = embonate) cages and π-conjugated coordination cations into ordered structures can produce high-performance nonlinear optical (NLO) materials. More specifically, by employing Ti4L6 cages for assembly with mixed N,N-chelated and P,P-chelated type conjugated organic ligands and Ag+ ions, three cage-based structures have been synthesized and structurally characterized. Among them, an ion pair structure with strong π-π accumulation exhibits a significant third-order NLO response, and an excellent optical limiting effect has been experimentally verified. This work provides a promising material for NLO applications.

Primary and Orthotopic Murine Models of Nasopharyngeal Carcinoma Reveal Molecular Mechanisms Underlying its Malignant Progression.

Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein-Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV- (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC-associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene-edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV-coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV- and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.

Landscape genomics reveals genetic signals of environmental adaptation of African wild eggplants.

Crop wild relatives (CWR) provide a valuable resource for improving crops. They possess desirable traits that confer resilience to various environmental stresses. To fully utilize crop wild relatives in breeding and conservation programs, it is important to understand the genetic basis of their adaptation. Landscape genomics associates environments with genomic variation and allows for examining the genetic basis of adaptation. Our study examined the differences in allele frequency of 15,416 single nucleotide polymorphisms (SNPs) generated through genotyping by sequencing approach among 153 accessions of 15 wild eggplant relatives and two cultivated species from Africa, the principal hotspot of these wild relatives. We also explored the correlation between these variations and the bioclimatic and soil conditions at their collection sites, providing a comprehensive understanding of the genetic signals of environmental adaptation in African wild eggplant. Redundancy analysis (RDA) results showed that the environmental variation explained 6% while the geographical distances among the collection sites explained 15% of the genomic variation in the eggplant wild relative populations when controlling for population structure. Our findings indicate that even though environmental factors are not the main driver of selection in eggplant wild relatives, it is influential in shaping the genomic variation over time. The selected environmental variables and candidate SNPs effectively revealed grouping patterns according to the environmental characteristics of sampling sites. Using four genotype-environment association methods, we detected 396 candidate SNPs (2.5% of the initial SNPs) associated with eight environmental factors. Some of these SNPs signal genes involved in pathways that help adapt to environmental stresses such as drought, heat, cold, salinity, pests, and diseases. These candidate SNPs will be useful for marker-assisted improvement and characterizing the germplasm of this crop for developing climate-resilient eggplant varieties. The study provides a model for applying landscape genomics to other crops' wild relatives.

Level of empowerment of hospitalized patient in Taiwan clinical practice.

PURPOSE: In the health-care system within hospitals, Taiwanese patients usually play the role of passively cooperating with health-care professionals. Therefore, patients rarely make their own treatment decisions. This study evaluated the level of patient education and patient satisfaction in relation to empowerment level in Taiwan. METHODS: A cross-sectional survey by a self-administered structured questionnaire was carried out with 618 inpatients from the four hospitals. Statistical analyses were then conducted. Analysis of covariance and post-hoc comparison was used to compare differences between the level of patient empowerment, age, and education as covariates in the model. RESULTS: This study found that 21.2% and 35.6% of participants were highly empowered and well empowered, respectively. Years of education is a significant covariate in the counselling domain of patient education. Even after controlling for age and education level, the counselling, answer question and justifying action, providing information scores remain significant for all levels after adjusting for the effects of degree of patient empowerment. Patients with higher empowerment also having more-sufficient patient education, indicating a tendency toward higher patient satisfaction. Patient education and counselling practices in Taiwan's clinical practice could be improved to enhance patient empowerment and ensure health-care systems are person-centred. CONCLUSIONS: To move more toward highly patient empowerment, we suggest that health-care professionals advocate a patient-empowerment approach and to provide more counselling related to patients' illnesses and possible treatments.