Time-Dependent Potentiation of the PERK Branch of UPR by GPR68 Offers Protection in Brain Ischemia.

BACKGROUND: In ischemia, acidosis occurs in/around injured tissue and parallels disease progression. Therefore, targeting an acid-sensitive receptor offers unique advantages in achieving the spatial and temporal specificity required for therapeutic interventions. We previously demonstrated that increased expression of GPR68 (G protein-coupled receptor 68), a proton-sensitive G protein-coupled receptor, mitigates ischemic brain injury. Here, we investigated the mechanism underlying GPR68-dependent protection. METHODS: We performed biochemical and molecular analyses to examine poststroke signaling. We used in vitro brain slice cultures and in vivo mouse transient middle cerebral artery occlusion (tMCAO) models to investigate ischemia-induced injuries. RESULTS: GPR68 deletion reduced PERK (protein kinase R-like ER kinase) expression in mouse brain. Compared with the wild-type mice, the GPR68-/- (knockout) mice exhibited a faster decline in eIF2α (eukaryotic initiation factor-2α) phosphorylation after tMCAO. Ogerin, a positive modulator of GPR68, stimulated eIF2α phosphorylation at 3 to 6 hours after tMCAO, primarily in the ipsilateral brain tissue. Consistent with the changes in eIF2α phosphorylation, Ogerin enhanced tMCAO-induced reduction in protein synthesis in ipsilateral brain tissue. In organotypic cortical slices, Ogerin reduced pH 6 and oxygen-glucose deprivation-induced neurotoxicity. Following tMCAO, intravenous delivery of Ogerin reduced brain infarction in wild-type but not knockout mice. Coapplication of a PERK inhibitor abolished Ogerin-induced protection. Delayed Ogerin delivery at 5 hours after tMCAO remained protective, and Ogerin has a similar protective effect in females. Correlated with these findings, tMCAO induced GPR68 expression at 6 hours, and Ogerin alters post-tMCAO proinflammatory/anti-inflammatory cytokine/chemokine expression profile. CONCLUSIONS: These data demonstrate that GPR68 potentiation leads to neuroprotection, at least in part, through enhancing PERK-eIF2α activation in ischemic tissue but has little impact on healthy tissue.

Marine Streptomyces-Derived Novel Alkaloids Discovered in the Past Decade.

Natural alkaloids originating from actinomycetes and synthetic derivatives have always been among the important suppliers of small-molecule drugs. Among their biological sources, Streptomyces is the highest and most extensively researched genus. Marine-derived Streptomyces strains harbor unconventional metabolic pathways and have been demonstrated to be efficient producers of biologically active alkaloids; more than 60% of these compounds exhibit valuable activity such as antibacterial, antitumor, anti-inflammatory activities. This review comprehensively summarizes novel alkaloids produced by marine Streptomyces discovered in the past decade, focusing on their structural features, biological activity, and pharmacological mechanisms. Future perspectives on the discovery and development of novel alkaloids from marine Streptomyces are also provided.

The incidence and risk factors of unplanned removal of peripherally inserted central catheters among adult patients: A multi-centre cohort study.

AIMS AND OBJECTIVES: (i) To estimate the national incidence of unplanned removal of peripherally inserted central catheters (PICCs) in China. (ii) To explore the associated risk factors to provide evidence for the prevention. DESIGN: A multi-centre prospective cohort study. METHODS: A representative sample of 3222 Chinese adult patients with successful PICC insertion was recruited for the PICC Safety Management Research (PATH) using a two-stage cluster sampling method from December 2020 to June 2022. Sixty hospitals from seven Chinese provinces representing all geographical regions were selected. Demographic information and PICC characteristics were collected using a standard online case report form. Risk factors for the unplanned removal of PICCs were assessed using a cause-specific hazard model and verified using a sub-distribution hazard model. STROBE guidelines were followed in reporting this study. RESULTS: Three thousand one hundred and sixty-six patients were included in the final analysis with a mean age of 59 years and a total of 344,247 catheter days. The incidence of unplanned removal was 10.04%. Female, with thrombosis history, PICC insertion due to infusion failure, valved catheter and double-lumen catheter were risk factors, whereas longer insertion and exposure length were protective factors in the cause-specific hazard model. Higher BMI became an independent risk factor in the sub-distribution hazard model. CONCLUSIONS: Unplanned removal of PICCs is a serious clinical challenge in China. Our findings call for prevention strategies targeting the identified risk factors. RELEVANCE TO CLINICAL PRACTICE: Our study characterised the epidemiology of unplanned removal of PICCs among Chinese adult inpatients, highlighting the need for prevention among this population and providing a basis for the formulation of relevant prevention strategies. PATIENT OR PUBLIC CONTRIBUTION: Patients contributed through sharing their information required for the case report form. Healthcare professionals who provide direct care to the patient at each medical centre contributed by completing the online case report form.

Profiling of serum oxylipins identifies distinct spectrums and potential biomarkers in young people with very early onset gout.

OBJECTIVE: Oxylipins modulate inflammation via complex pathways. The oxylipin profile in gout remains unexplored. In this study, we systemically profiled oxylipins in young men and identified new oxylipin biomarkers for clinical use in differentiating gout from hyperuricaemia. MATERIAL AND METHODS: Oxylipin profiling was performed in 90 men (30 very early onset gout, 30 asymptomatic hyperuricaemia [HU] and 30 normouricaemia [NU], all aged <20 years) divided into discovery and validation sample sets. The dataset was analysed based on orthogonal projection to latent structure-discriminant analysis. Correlation network and pathway enrichment were conducted to reveal potential oxylipin-involved pathways of gout. Candidate oxylipins were further evaluated and optimized in the validation cohort, and differential oxylipin biomarkers combined with or without serum urate were applied to construct diagnostic models. RESULTS: In discovery stage, 21 differential oxylipins in the gout vs HU comparisons and 14 differential oxylipins in the gout vs NU comparisons were discovered. Correlation network analysis was performed and 14(S)-HDHA (14S-hydroxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid) was identified as a hub metabolite in both comparisons. Seven down-regulated oxylipins in the gout vs HU group and five down-regulated oxylipins in the gout vs NU group were validated. Diagnostic models were constructed with the above oxylipins, with 14(S)-HDHA alone having an area under the curve of 1 (95% CI, 1, 1) in both comparisons. CONCLUSIONS: Young men with very early onset gout have distinct oxylipin spectrums, especially those derived from arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid. Differential oxylipins could serve as candidate serum biomarkers in differentiating gout from hyperuricaemia.

Elevated serum CA72-4 predicts gout flares during urate lowering therapy initiation: a prospective cohort study.

OBJECTIVE: Gout flares during urate-lowering therapy (ULT) initiation are common, but predictors of these flares are poorly understood. The aim of this study was to determine whether serum CA72-4 is an independent predictor for gout flares during ULT initiation. METHODS: A prospective cohort study was conducted between March 2021 and January 2022. Men with gout, at least one gout flare in the past year, and at least three serum CA72-4 measurements in the previous six months were enrolled. Participants were grouped according to their highest recorded serum CA72-4 levels (above or within the normal range). All participants took oral febuxostat 20 mg daily without flare prophylaxis therapy, and attended face-to-face visits every four weeks until 24 weeks. The incidence of gout flare was compared between the two groups. Backward stepwise logistic regression analyses were used to identify risk factors associated with flares. Receiver operating characteristic curve analysis was used to evaluate prediction efficacy. RESULTS: A total of 193 completed the study (79 with high CA72-4; 114 with normal CA72-4). The cumulative incidence of at least one gout flare was 48.1% (62.1% in the high CA72-4 group, 38.4% in the normal CA72-4 group, P = 0.001), and recurrent (≥2) flares was 33.0% (47.1% in the high CA72-4 group, 23.2% in the normal CA72-4, P < 0.001). High CA72-4, disease duration, intra-articular tophus size, glucose, high-density lipoprotein-cholesterol and ESR were independent risk factors for gout flares. Serum CA72-4 alone predicted recurrent flares with an area under the curve of 0.63 (95% CI = 0.54, 0.71), and 0.78 (95% CI = 0.71, 0.85) when combined with other independent variables. CONCLUSION: High serum CA72-4 predicts the risk of gout flares during ULT initiation. TRIAL REGISTRATION: ChiCTR; https://www.chictr.org.cn/; ChiCTR2100043573.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model.

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Ultrasensitive Detection of Aqueous Uranyl Based on Uranyl-Triggered Protein Photocleavage.

The detection of environmental uranyl is attracting increasing attention. However, the available detection strategies mainly depend on the selective recognition of uranyl, which is subject to severe interference by coexisting metal ions. Herein, based on the unique uranyl-triggered photocleavage property, the protein BSA is labelled with fluorescent molecules that exhibit an aggregation-induced emission effect for uranyl detection. Uranyl-triggered photocleavage causes the separation of the fluorescent-molecule-labelled protein fragments, leading to attenuation of the emission fluorescence, which is used as a signal for uranyl detection. This detection strategy shows high selectivity for uranyl and an ultralow detection limit of 24 pM with a broad detection range covering five orders of magnitude. The detection method also shows high reliability and stability, making it a promising technique for practical applications in diverse environments.

Effects of fenofibrate therapy on renal function in primary gout patients.

OBJECTIVE: To investigate the incidence and potential risk factors for development of fenofibrate-associated nephrotoxicity in gout patients. METHODS: A total of 983 gout patients on fenofibrate treatment who visited the dedicated Gout Clinic at the Affiliated Hospital of Qingdao University between September 2016 and June 2020 were retrospectively enrolled from the electronic records system. Fenofibrate-associated nephrotoxicity was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dl within 6 months of fenofibrate initiation. The change trend of SCr and uric acid levels during the treatment period were assessed by a generalised additive mixed model (GAMM). Multivariate analysis was performed for risk factors affecting elevated SCr. RESULTS: A total of 100 (10.2%) patients experienced an increase in SCr ≥0.3 mg/dl within 6 months after fenofibrate initiation. The median change of SCr in the whole cohort was 0.11 mg/dl [interquartile range (IQR) 0.03-0.20], whereas it was 0.36 (0.33-0.45) in the fenofibrate-associated nephrotoxicity group. In a multivariable regression model, chronic kidney disease (CKD) [odds ratio (OR) 2.39 (95% CI 1.48, 3.86)] and tophus [OR 2.29 (95% CI 1.39, 3.78)] were identified to be risk predictors, independent of measured covariates, of fenofibrate-associated nephrotoxicity. During the treatment period, although SCr temporarily increased, serum urate and triglyceride concentrations decreased using the interaction analysis of GAMM. Of those with fenofibrate withdrawal records, the SCr increase in 65% of patients was reversed after an average of 49 days off the drug. CONCLUSIONS: This observational study implied that fenofibrate-associated nephrotoxicity occurs frequently in gout patients, especially in patients with tophi or CKD. The potential renal risks of fenofibrate usage in gout needs additional research.

The efficacy and safety of citrate mixture vs sodium bicarbonate on urine alkalization in Chinese primary gout patients with benzbromarone: a prospective, randomized controlled study.

OBJECTIVES: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment. METHODS: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12). RESULTS: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred. CONCLUSION: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks. TRIAL REGISTRATION: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.

A cross-sectional study on uric acid levels among Chinese adolescents.

BACKGROUND: The prevalence of hyperuricemia is increasing in adults, while the prevalence among adolescents is seldom reported. METHODS: A cross-sectional survey by multistage, stratified sampling method was carried out in Shandong Province during 2017-2018. A total of 9371 adolescents aged from 13 to 19 years were randomly sampled and analyzed in this survey. RESULTS: The overall mean serum uric acid (sUA) concentration was 6.08 ± 1.57 mg/dL and overall hyperuricemia prevalence was 25.4% and 60.5% (when hyperuricemia was defined as sUA ≥ 7 mg/dL or ≥ 5.5 mg/dL). Prevalence were 42.3% (male) and 8.0% (female) when limit was 7 mg/dL and prevalence were 82.1% (male) and 38.4% (female) when limit was 5.5 mg/dL. Male gender, increased body mass index, increased waist circumstance, increased triglycerides, increased fasting blood glucose, increased systolic blood pressure, decreased estimated glomerular filtration rate, and positive family gout history were associated with the enhanced risk of hyperuricemia according to univariate and/or multivariate logistic regression analysis. Food intake frequency of carbonate beverage, mutton, and other kinds varied between hyperuricemia adolescents and normal sUA ones. CONCLUSIONS: The studied adolescent population showed sUA level and hyperuricemia prevalence which are even higher than those of adults in China. The epidemic of youth hyperuricemia may pose a future threat of gout attacks and other hyperuricemia-related diseases, which alarms the public, health professionals and health policy makers to prepare the future health challenges.

Spidroin-Inspired, High-Strength, Loofah-Shaped Protein Fiber for Capturing Uranium from Seawater.

The unique three-dimensional structure of spidrion determines the outstanding mechanical properties of the spider silk fiber. Inspired by the similarity of the three-dimensional structure of superb-uranyl binding protein (SUP) to that of spidroin, a dual-SUP (DSUP) chimeric protein fiber with high tensile strength is designed. The DSUP hydrogel fiber exhibits a loofah-shape structure by the cross-interaction of the protein nanofiber. Full exposure of abundant functional uranyl-binding sites in the stretchable loofah-shape hydrogel protein fiber give the DSUP fiber a groundbreaking uranium extraction capacity of 17.45 mg g-1 with an ultrashort saturation time of 3 days in natural seawater. This work reports the design of an adsorbent with ultrahigh uranium extraction capacity and explores a strategy for fabricating artificial high-strength functional non-spidroin protein fiber.

Isatin inhibits SH-SY5Y neuroblastoma cell invasion and metastasis through MAO/HIF-1α/CXCR4 signaling.

Isatin was reported to possess anticancer activities through its effect on tumor proliferation, apoptosis, and metastasis in vitro and in vivo. This study aimed to elucidate the underlying mechanism behind isatin's ability to inhibit neuroblastoma cell metastasis. Our results demonstrated that isatin could inhibit neuroblastoma cell proliferation, invasion, and migration in a dose-dependent manner. Moreover, isatin inhibited the expression level of monoamine oxidase A as well as that of its downstream protein hypoxia-inducible factor 1α. Further study indicated that isatin inhibited reactive oxygen species production, extracellular signal-regulated kinase activation, vascular endothelial growth factor receptor-1 phosphorylation, and chemokine receptor type 4 expression. All results support the potential antimetastatic effect of isatin in neuroblatoma cells.

[Discussion on efficacy evaluation thought and method for innovation medicine of Chinese herbal compound formula based on clinical application characteristics].

The Chinese herbal compound formula preparation was made based on theory of Chinese medicine, which was confirmed by long period clinical application, and with multi-compound and multi-target characteristics. During the exploitation process of innovation medicine of Chinese herbal compound formula, selecting and speeding up the research development of drugs with clinical value shall be paid more attention, and as request of rules involved in new drug research and development, the whole process management should be carried out, including project evaluation, manufacturing process determination, establishment of quality control standards, evaluation for pharmacological and toxic effect, as well as new drug application process. This reviews was aimed to give some proposals for pharmacodynamics research methods involved in exploration of Chinese herbal compound formula preparation, including： ①the endpoint criteria should meet the clinical attribution of new drugs; ②the pre-clinical pharmacodynamics evaluation should be carried on appropriate animal models according to the characteristics of diagnosis and therapy of Chinese medicine and observation indexes; ③during the innovation of drug for infants and children, information on drug action conforming to physiological characteristics of infants and children should be supplied, and the pharmacodynamics and toxicology research shall be conducted in immature rats according to the body weight of children. In a summary, the clinical application characteristics are the important criteria for evaluation of pharmacological effect of innovation medicine of Chinese herbal compound formula.

Synaptic plasticity in the facial nucleus in rats following infraorbital nerve manipulation after facial nerve injury.

The aim of this study is to investigate the effect of sensory input on the neural plasticity in the facial nucleus following facial nerve injury. Adult male Wistar rats were randomly assigned to four groups: (1) sham control; (2) facial nerve crush (FNC); (3) nerve crush plus daily manual vibrissal stimulation (FMS); and (4) nerve crush with infraorbital nerve transection plus daily manual stimulation (FIMS). Plasticity related proteins in the facial nucleus were evaluated by western blot at 7, 14, and 28 days postsurgery (n = 6/group per timepoint). Synaptophysin-positive terminals were evaluated by immunohistochemistry in a second set of animals (n = 6/group) at 14 days. Quantitation of synaptophysin immunostaining showed that rats in the FNC group had a significantly lower mean number of pixels compared to control animals (29.1 ± 2.6 × 10(6) vs. 34.2 ± 2.3 × 10(6); P < 0.05). Values in the FMS group (33.2 ± 1.7 × 10(6)) were similar to that of the control group, while the mean number in the FIMS group (26.5 ± 2.4 × 10(6)) was significantly lower than in the control group. Synapsin I phosphorylation was reduced to 70-83 % in FNC rats, but increased to 121-132 % in the FMS group (P < 0.05 vs. controls). Phosphorylation of cAMP response element-binding protein was similarly reduced by facial nerve crush, which was delayed in FMS animals (P < 0.05 vs. controls at 28 days). Expression and phosphorylation of all proteins were reduced to the lowest in the FIMS group (all P < 0.05). Sensory input from the IoN have a strong effect on synaptic plasticity within the facial nucleus, which is necessary to achieve the benefit of manual stimulation.

Synthesis of p-O-Alkyl Salicylanilide Derivatives as Novel EGFR Inhibitors.

Preclinical Research Epidermal growth factor receptor (EGFR), a validated target for anticancer drugs, plays a critical role in tumorigenesis and tumor development. A series of p-O-alkyl salicylanilide derivatives were designed and synthesized as novel EGFR inhibitors using a salicylic acid scaffold. A simulated six-membered ring strategy formed through intramolecular hydrogen bonds was employed to mimic the planar quinazoline of the EGFR antagonist, gefitinib. The derived compounds with hydroxyl at the ortho position were more potent than ones with methoxyl group. In particular, compounds 5d and 5b displayed significant EGFR inhibitory (IC50 values = 0.30 and 0.45 µM, respectively) activity as well as potent antiproliferative activity in A431 and HCT-116 tumor cells. These salicylanilides could be considered as promising lead compounds for developing novel EGFR inhibitors.

Blockade of Salusin-ß in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats.

Salusin-ß, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-ß in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-ß blocker, antisalusin-ß IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and ß-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-ß in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy.

A description of the complete mitochondrial genomes of Amphiporus formidabilis, Prosadenoporus spectaculum and Nipponnemertes punctatula (Nemertea: Hoplonemertea: Monostilifera).

We sequenced the complete mitochondrial genomes (mitogenomes) of three Hoplonemertea species, Amphiporus formidabilis, Prosadenoporus spectaculum and Nipponnemertes punctatula, which are 14,616, 14,655 and 15,354 bp in length, respectively. Each of the three circular mitogenomes consists of 37 typical genes and some non-coding regions. The nucleotide composition of the coding strand is biased toward T, almost a half of total nucleotides in these mitogenomes. There are many poly-T tracts across these mitogenomes, which exhibit T-number variation within different clones of protein-coding genes, mainly resulting from false PCR amplification. The major non-coding regions have tandem repeat motifs and hairpin-like structures that may be associated with the initiation of replication or transcription. Data published to date for nemerteans show that Palaeonemertea species usually bear the largest mitogenomes, while representatives in the more recently derived Distromatonemertea clade bear the smallest ones; and that the gene arrangement of mitogenomes seems to be variable within the phylum Nemertea, but stable within either of Heteronemertea and Hoplonemertea.

The health context paradox in the relationship between victimization, classroom bullying attitudes, and adolescent depression: An analysis based on the hlm model.

From the perspective of the health context paradox, this study examined the relationship between adolescent victimization and depression based on the diathesis-stress model and attribution theory using a nested model. A survey was conducted on 3743 Chinese adolescents using the Bullying & Victimization Scale, Rumination Scale, Beck Depression Inventory, and Bullying Attitude Scale. The results disclosed that victimization had a positive impact on depression, rumination played a mediating role between victimization and depression, and classroom anti-bullying attitudes heightened the correlation between victimization and developing depression as well as between victimization and engaging in rumination thinking. This study provides a new cross-level perspective to reduce the occurrence of depression among bullied adolescents and further validates the health context paradox, expanding its applicability range. It also provides new experimental research references for reducing depression among bullied adolescents from a more comprehensive, cross-level perspective in the future.

Nanopore-based DNA long-read sequencing analysis of the aged human brain.

Aging disrupts cellular processes such as DNA repair and epigenetic control, leading to a gradual buildup of genomic alterations that can have detrimental effects in post-mitotic cells. Genomic alterations in regions of the genome that are rich in repetitive sequences, often termed "dark loci," are difficult to resolve using traditional sequencing approaches. New long-read technologies offer promising avenues for exploration of previously inaccessible regions of the genome. Using nanopore-based long-read whole-genome sequencing of DNA extracted from aged 18 human brains, we identify previously unreported structural variants and methylation patterns within repetitive DNA, focusing on transposable elements ("jumping genes") as crucial sources of variation, particularly in dark loci. Our analyses reveal potential somatic insertion variants and provides DNA methylation frequencies for many retrotransposon families. We further demonstrate the utility of this technology for the study of these challenging genomic regions in brains affected by Alzheimer's disease and identify significant differences in DNA methylation in pathologically normal brains versus those affected by Alzheimer's disease. Highlighting the power of this approach, we discover specific polymorphic retrotransposons with altered DNA methylation patterns. These retrotransposon loci have the potential to contribute to pathology, warranting further investigation in Alzheimer's disease research. Taken together, our study provides the first long-read DNA sequencing-based analysis of retrotransposon sequences, structural variants, and DNA methylation in the aging brain affected with Alzheimer's disease neuropathology.

Predictors of Inadequate Serum Urate Response to Low-Dose Febuxostat in Male Patients with Gout.

Objective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables. Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA<6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set. Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR. Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.