Using gene and gene-set association tests to identify lethal prostate cancer genes.

BACKGROUND: Recent advances in the detection and treatment of prostate cancer (PCa) have reduced morbidity and mortality from this common cancer. Despite these improvements, PCa remains the second leading cause of cancer death in men in the United States. Further understanding of the genetic underpinnings of lethal PCa is required to drive risk detection and prevention and ultimately reduce mortality. We therefore set out to identify germline variants associated with cases of lethal prostate cancer (LPCa). METHODS: Using a two-stage study design, we compared whole-exome sequencing data of 550 LPCa patients to 488 healthy male controls. Men were classified as having LPCa based on medical record review. Candidate genes were identified using gene- and gene-set-based rare truncating variant association tests. Case-control burden testing through Firth's penalized logistic regression and case-gnomAD allelic burden testing through a one-sided mid-p Fisher's exact test were conducted. Each gene's p-values from these tests were combined into an omnibus p-value for candidate gene selection. In the subsequent validation stage, genes were assessed using the UK Biobank and Firth's penalized logistic regression for each ancestry, combined through meta-analysis. RESULTS: Gene-based rare variant association tests identified 12 genes nominally associated with LPCa. Rare-variant association tests identified a gene set with a significantly higher burden of truncating germline mutations in LPCa patients than controls. Combining gene- and gene-set test results, four nominally significant genes (PPP1R3A, TG, PPFIBP2, and BTN3A3) were selected as candidates. Subsequent validation using the UK Biobank found that PPP1R3A was significantly associated with LPCa risk (odds ratio 2.34, CI 1.20-4.59). Specifically, pGln662ArgfsTer7 was identified as the predominant variant in PPP1R3A among LPCa patients in our dataset. CONCLUSIONS: Both individual gene and gene-set analyses identified candidates associated with LPCa. The novel association of PPP1R3A and LPCa risk merits further investigation.

Anterior percutaneous full-endoscopic transcorporeal decompression for cervical disc herniation: a finite element analysis and long-term follow-up study.

OBJECTIVE: The purpose of this study was to investigate the long-term consequences on the cervical spine after Anterior transcorporeal percutaneous endoscopy cervical discectomy (ATc-PECD) from the biomechanical standpoint. METHODS: A three-dimensional model of the normal cervical spine C2-T1 was established using finite element method. Subsequently, a disc degeneration model and degeneration with surgery model were constructed on the basis of the normal model. The same loading conditions were applied to simulate flexion, extension, lateral bending and axial rotation of the cervical spine. We calculated the cervical range of motion (ROM), intradiscal pressure, and intravertebral body pressure under different motions for observing changes in cervical spine biomechanics after surgery. At the same time, we combined the results of a long-term follow-up of the ATc-PECD, and used imaging methods to measure vertebral and disc height and cervical mobility, the Japanese Orthopaedic Association (JOA) score and visual analog scale (VAS) score were used to assess pain relief and neurological functional recovery. RESULTS: The long-term follow-up results revealed that preoperative JOA score, neck VAS score, hand VAS score, IDH, VBH, and ROM for patients were 9.49 ± 2.16, 6.34 ± 1.68, 5.14 ± 1.48, 5.95 ± 0.22 mm, 15.41 ± 1.68 mm, and 52.46 ± 9.36° respectively. It changed to 15.71 ± 1.13 (P < 0.05), 1.02 ± 0.82 (P < 0.05), 0.77 ± 0.76 (P < 0.05), 4.73 ± 0.26 mm (P < 0.05), 13.67 ± 1.48 mm (P < 0.05), and 59.26 ± 6.72° (P < 0.05), respectively, at 6 years postoperatively. Finite element analysis showed that after establishing the cervical spondylosis model, the overall motion range for flexion, extension, lateral bending, and rotation decreased by 3.298°, 0.753°, 3.852°, and 1.131° respectively. Conversely, after establishing the bone tunnel model, the motion range for these actions increased by 0.843°, 0.65°, 0.278°, and 0.488° respectively, consistent with the follow-up results. Moreover, analysis of segmental motion changes revealed that the increased cervical spine mobility was primarily contributed by the surgical model segments. Additionally, the finite element model demonstrated that bone tunneling could lead to increased stress within the vertebral bodies and intervertebral discs of the surgical segments. CONCLUSIONS: Long-term follow-up studies have shown that ATc-PECD has good clinical efficacy and that ATc-PECD can be used as a complementary method for CDH treatment. The FEM demonstrated that ATc-PECD can lead to increased internal stresses in the vertebral body and intervertebral discs of the operated segments, which is directly related to cervical spine degeneration after ATc-PECD.

Supervisor's neuroticism and problematic Internet use among graduate students: the mediating role of supervisor-student relationship quality and the moderating role of fear of the supervisor's negative evaluation.

BACKGROUND: Graduate students exhibit vulnerability to problematic Internet use, which can result in adverse physical, psychological, and social consequences. However, limited studies have addressed this issue among graduate students, and even fewer have explored the unique factors contributing to their problematic Internet use. Therefore, to address this gap, the current study aims to probe the relationship between supervisor's neuroticism and problematic Internet use among graduate students, the mediating effect of the supervisor-student relationship quality, as well as the moderating effect of fear of the supervisor's negative evaluation. METHODS: A cross-sectional study was conducted in 2018 at three universities in Beijing, China. Anonymous data from 448 graduate students were collected regarding problematic Internet use, supervisor's neuroticism, supervisor-student relationship quality, and the fear of the supervisor's negative evaluation. A moderated mediation analysis was performed using Hayes' PROCESS macro (Model 14). RESULTS: Supervisor's neuroticism was positively linked to graduate students' problematic Internet use, supervisor-student relationship quality mediated the linkage, and fear of the supervisor's negative evaluation played a moderating role in the second stage. Specifically, for students lower in fear of the supervisor's negative evaluation, supervisor-student relationship quality negatively predicted students' problematic Internet use. While for the graduate students higher in fear of the supervisor's negative evaluation, supervisor-student relationship quality could not significantly predict students' problematic Internet use. The mediating effect was only significant for graduate students lower in fear of the supervisor's negative evaluation. CONCLUSIONS: This study established a theoretical model linking supervisor's neuroticism to graduate students' problematic Internet use, highlighting the potential roles of supervisor-student relationship quality and fear of the supervisor's negative evaluation. Reducing the neuroticism level of the supervisor, enhancing the quality of the supervisor-student relationship, and mitigating students' fear of the supervisor's negative evaluation will contribute to the reduction of problematic Internet use among graduate students.

Exploring new frontiers in type 1 diabetes through advanced mass-spectrometry-based molecular measurements.

Type 1 diabetes (T1D) is a devastating autoimmune disease for which advanced mass spectrometry (MS) methods are increasingly used to identify new biomarkers and better understand underlying mechanisms. For example, integration of MS analysis and machine learning has identified multimolecular biomarker panels. In mechanistic studies, MS has contributed to the discovery of neoepitopes, and pathways involved in disease development and identifying therapeutic targets. However, challenges remain in understanding the role of tissue microenvironments, spatial heterogeneity, and environmental factors in disease pathogenesis. Recent advancements in MS, such as ultra-fast ion-mobility separations, and single-cell and spatial omics, can play a central role in addressing these challenges. Here, we review recent advancements in MS-based molecular measurements and their role in understanding T1D.

Single-cell sequencing reveals that specnuezhenide protects against osteoporosis via activation of METTL3 in LEPR+ BMSCs.

BACKGROUND: Osteoporosis (OP) has garnered significant attention due to its substantial morbidity and mortality rates, imposing considerable health burdens on societies worldwide. However, the molecular mechanisms underlying osteoporosis pathogenesis remain largely elusive, and the available therapeutic interventions are limited. Therefore, there is an urgent need for innovative strategies in the treatment of osteoporosis. PURPOSE: The primary objective of this study was to elucidate the molecular mechanisms underlying osteoporosis pathogenesis using single-cell RNA sequencing (scRNA-seq), thereby proposing novel therapeutic agents. METHODS: The mice osteoporosis model was established through bilateral ovariectomy. Micro-computed tomography (µCT) and hematoxylin and eosin (H&E) staining were employed to assess the pathogenesis of osteoporosis. scRNA-seq was utilized to identify and analyze distinct molecular mechanisms and sub-clusters. Gradient dilution analysis was used to obtain specific sub-clusters, which were further validated by immunofluorescence staining and flow cytometry analysis. Molecular docking and cellular thermal shift assay (CETSA) were applied for screening potential agents in the TCMSPs database. Alkaline phosphatase (ALP) activity and alizarin red S (ARS) staining were performed to evaluate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Osteogenic organoids analysis was employed to assess the proliferation and sphere-forming ability of BMSCs. Quantitative real-time PCR (qRT-PCR) and western blot analysis were conducted to investigate signaling pathways. Wound healing assay and tube formation analysis were employed to evaluate the angiogenesis of endothelial cells. RESULTS: The scRNA-seq analysis revealed the crucial role of LEPR+ BMSCs in the pathogenesis of osteoporosis, which was confirmed by immunofluorescence staining of the epiphysis. Subsequently, the LEPR+ BMSCs were obtained by gradient dilution analysis and identified by immunofluorescence staining and flow cytometry. Accordingly, specnuezhenide (Spe) was screened and identified as a potential compound targeting METTL3 from the TCMSPs database. Spe promoted bone formation as evidenced by µ-CT, and H&E analysis. Additionally, Spe enhanced the osteogenic capacity of LEPR+ BMSCs through ALP and ARS assay. Notably, METTL3 pharmacological inhibitors S-Adenosylhomocysteine (SAH) attenuated the aforementioned osteo-protective effects of Spe. Particularly, Spe enhanced the LEPR+ BMSCs-dependent angiogenesis through the secretion of SLIT3, which was abolished by SAH in LEPR+ BMSCs. CONCLUSION: Collectively, these findings suggest that Spe could enhance the osteogenic potential of LEPR+ BMSCs and promote LEPR+ BMSCs-dependent angiogenesis by activating METTL3 in LEPR+ BMSCs, indicating its potential as an ideal therapeutic agent for clinical treatment of osteoporosis.

[Analysis of influencing factors of early femoral head necrosis after femoral neck fracture and construction of nomogram prediction model].

OBJECTIVE: To explore the risk factors of early femoral head necrosis in patients with femoral neck fracture after operation, and to establish a nomogram prediction model. METHODS: A total of 167 patients with femoral neck fracture from January 2020 to April 2022 were selected and divided into necrosis group and non-necrosis group according to whether femoral head necrosis occurred in the early postoperative period. There were 21 males and 17 females in the necrosis group, aged from 33 to 72 years old, with an average of (53.49±10.96) years old, and the time from injury to operation ranged from 40 to 67 hours, with average time of(53.46±7.23) hours. There were 72 males and 57 females in the non-necrosis group, aged from 18 to 83 years, with an average of (52.78±12.55) years old, and the time from injury to operation was 18 to 65 hours, with an average time of(39.88±7.79) hours. The potential influencing factors, including patient gender, diabetes mellitus, hypertension, chronic liver disease, posterior inclination angle of the femoral head, operation mode, fracture displacement, fracture line location, preoperative braking traction, screw arrangement mode, reduction quality, age, body mass index(BMI), and injury to operation time were subjected to single factor analysis. Logistic multivariate regression analysis was conducted for factors with a significance level of P<0.05. RESULTS: The incidence of femoral head necrosis in 167 patients with femoral neck fracture was 22.76%. The following factors were identified as independent risk factors for early postoperative femoral head necrosis in patients with femoral neck fractures:coexisting diabetes[OR=5.139, 95%CI(1.405, 18.793), P=0.013], displaced fracture [OR=3.723, 95%CI(1.105, 12.541), P=0.034], preoperative immobilization[OR=3.444, 95%CI(1.038, 11.427), P=0.043], quality of reduction [OR=3.524, 95%CI(1.676, 7.411), P=0.001], and time from injury to surgery[OR=1.270, 95%CI(1.154, 1.399), P=0.000]. The Hosmer-Lemeshow goodness-of-fit test(χ2=3.951, P=0.862), the area under the receiver operator characteristic(ROC) curve was 0.944[P<0.001, 95%CI(0.903, 0.987)], with a sensitivity of 89.50%, the specificity was 88.40%, the maximum Youden index was 0.779, and the overall trend of the model correction curve was close to the ideal curve. Model regression equation was Z=1.637 × diabetes + 1.314× fracture displacement+1.237 × preoperative braking traction+1.260 × reduction quality + 0.239×injury to operation time-18.310. CONCLUSION: The occurrence of early femoral head necrosis in patients with femoral neck fracture postoperatively is affected by multiple factors. The risk early warning model established according to the factors has good predictive efficacy.

Heterosis formation mechanism, prediction methods, and their application and prospect in pig production.

Heterosis is the phenomenon that the hybrid offspring outperform two-parent population. Hybridisation has been widely used in plant and animal production as it effectively improves the growth and developmental performance, reproductive performance and disease resistance of the offspring. Hybridization can effectively improve the growth and development performance, reproductive performance and disease resistance of offspring, so it is widely used in animal and plant production. Researchers have used cross-breeding techniques to cultivate excellent new agricultural and animal husbandry strains and supporting lines such as super-excellent Chaoyou 1000 hybrid rice, Xiaoyan No.6 hybrid wheat, Dumeng sheep, and Shanxia black pigs. However, there are still some urgent problems in the current hybrid dominance research: the existing hybrid dominance theory can only partially explain the phenomenon of plant and animal hybrid dominance, and the theory of animal hybrid dominance is less researched, and the accuracy of the existing hybrid dominance prediction methods is limited. China is the world's largest pork production and consumption country. Heterosis can effectively improve the production performance of pigs, and its application in the pig industry has important economic and research value. However, the existing research on pig hybrid production is in its infancy and needs to be further studied. In this review, we summarize the existing heterosis theory, heterosis prediction methods, and their application in pig production, to provide a reference for the application of heterosis in pig breeding.

Dapagliflozin and sacubitril on myocardial microperfusion in patients with post-acute myocardial infarction heart failure and type 2 diabetes.

BACKGROUND: Coronary heart disease and type 2 diabetes mellitus (T2DM) frequently coexist, creating a complex and challenging clinical scenario, particularly when complicated with acute myocardial infarction (AMI). AIM: To examine the effects of dapagliflozin combined with sakubactrovalsartan sodium tablets on myocardial microperfusion. METHODS: In total, 98 patients were categorized into control (n = 47) and observation (n = 51) groups. The control group received noxital, while the observation group was treated with dapagliflozin combined with noxital for 6 months. Changes in myocardial microperfusion, blood glucose level, cardiac function, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, growth differentiation factor-15 (GDF-15) level, and other related factors were compared between the two groups. Additionally, the incidence of major adverse cardiovascular events (MACE) and adverse reactions were calculated. RESULTS: After treatment, in the observation and control groups, the corrected thrombolysis in myocardial infarction frame counts were 37.12 ± 5.02 and 48.23 ± 4.66, respectively. The NT-proBNP levels were 1502.65 ± 255.87 and 2015.23 ± 286.31 pg/mL, the N-terminal pro-atrial natriuretic peptide (NT-proANP) levels were 1415.69 ± 213.05 and 1875.52 ± 241.02 ng/mL, the GDF-15 levels were 0.87 ± 0.43 and 1.21 ± 0.56 g/L, and the high-sensitivity C-reactive protein (hs-CRP) levels were 6.54 ± 1.56 and 8.77 ± 1.94 mg/L, respectively, with statistically significant differences (P < 0.05). The cumulative incidence of MACEs in the observation group was significantly lower than that in the control group (P < 0.05). The incidence of adverse reactions was 13.73% (7/51) in the observation group and 10.64% (5/47) in the control group, with no statistically significant difference (P > 0.05). CONCLUSION: Dapagliflozin combined with nocinto can improve myocardial microperfusion and left ventricular remodeling and reduce MACE incidence in patients with post-AMI heart failure and T2DM. The underlying mechanism may be related to the reduction in the expression levels of NT-proANP, GDF-15, and hs-CRP.

The source and accumulation of anthropogenic carbon in the U.S. East Coast.

The ocean has absorbed anthropogenic carbon dioxide (Canthro) from the atmosphere and played an important role in mitigating global warming. However, how much Canthro is accumulated in coastal oceans and where it comes from have rarely been addressed with observational data. Here, we use a high-quality carbonate dataset (1996-2018) in the U.S. East Coast to address these questions. Our work shows that the offshore slope waters have the highest Canthro accumulation changes (ΔCanthro) consistent with water mass age and properties. From offshore to nearshore, ΔCanthro decreases with salinity to near zero in the subsurface, indicating no net increase in the export of Canthro from estuaries and wetlands. Excesses over the conservative mixing baseline also reveal an uptake of Canthro from the atmosphere within the shelf. Our analysis suggests that the continental shelf exports most of its absorbed Canthro from the atmosphere to the open ocean and acts as an essential pathway for global ocean Canthro storage and acidification.

Activated dormant stem cells recover spermatogenesis in chemoradiotherapy-induced infertility.

Male infertility is a recognized side effect of chemoradiotherapy. Extant spermatogonial stem cells (SSCs) may act as originators for any subsequent recovery. However, which type of SSCs, the mechanism by which they survive and resist toxicity, and how they act to restart spermatogenesis remain largely unknown. Here, we identify a small population of Set domain-containing protein 4 (Setd4)-expressing SSCs that occur in a relatively dormant state in the mouse seminiferous tubule. Extant beyond high-dose chemoradiotherapy, these cells then activate to recover spermatogenesis. Recovery fails when Setd4+ SSCs are deleted. Confirmed to be of fetal origin, these Setd4+ SSCs are shown to facilitate early testicular development and also contribute to steady-state spermatogenesis in adulthood. Upon activation, chromatin remodeling increases their genome-wide accessibility, enabling Notch1 and Aurora activation with corresponding silencing of p21 and p53. Here, Setd4+ SSCs are presented as the originators of both testicular development and spermatogenesis recovery in chemoradiotherapy-induced infertility.

[Hypothetical Alcohol Consumption Interventions and Hepatic Steatosis: A Longitudinal Study in a Large Cohort]. / æ¨¡æ‹Ÿé¥®é ’å¹²é¢„ä¸Žè‚è„‚è‚ªå˜æ€§ï¼šä¸€é¡¹å¤§åž‹é˜Ÿåˆ—çš„çºµå‘ç ”ç©¶.

Objective: Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated fatty liver disease (ALD) are the most common chronic liver diseases. Hepatic steatosis is an early histological subtype of both NAFLD and ALD. Excessive alcohol consumption is widely known to lead to hepatic steatosis and subsequent liver damage. However, reported findings concerning the association between moderate alcohol consumption and hepatic steatosis remain inconsistent. Notably, alcohol consumption as a modifiable lifestyle behavior is likely to change over time, but most previous studies covered alcohol intake only once at baseline. These inconsistent findings from existing studies do not inform decision-making concerning policies and clinical guidelines, which are of greater interest to health policymakers and clinician-scientists. Additionally, recommendations on the types of alcoholic beverages are not available. Usually, assessing the effects of two or more hypothetical alcohol consumption interventions on hepatic steatosis provides answers to questions concerning the population risk of hepatic steatosis if everyone changes from heavy drinking to abstinence, or if everyone keeps on drinking moderately, or if everyone of the drinking population switches from red wine to beer? Thus, we simulated a target trial to estimate the effects of several hypothetical interventions, including changes in the amount of alcohol consumption or the types of alcoholic beverages consumed, on hepatic steatosis using longitudinal data, to inform decisions about alcohol-related policymaking and clinical care. Methods: This longitudinal study included 12687 participants from the UK Biobank (UKB), all of whom participated in both baseline and repeat surveys. We excluded participants with missing data related to components of alcohol consumption and fatty liver index (FLI) in the baseline and the repeat surveys, as well as those who had reported liver diseases or cancer at the baseline survey. We used FLI as an outcome indicator and divided the participants into non-, moderate, and heavy drinkers. The surrogate marker FLI has been endorsed by many international organizations' guidelines, such as the European Association for the Study of the Liver. The calculation of FLI was based on laboratory and anthropometric data, including triglyceride, gamma-glutamyl transferase, body mass index, and waist circumference. Participants responded to questions about the types of alcoholic beverages, which were defined in 5 categories, including red wine, white wine/fortified wine/champagne, beer or cider, spirits, and mixed liqueurs, along with the average weekly or monthly amounts of alcohol consumed. Alcohol consumption was defined as pure alcohol consumed per week and was calculated according to the amount of alcoholic beverages consumed per week and the average ethanol content by volume in each alcoholic beverage. Participants were categorized as non-drinkers, moderate drinkers, and heavy drinkers according to the amount of their alcohol consumption. Moderate drinking was defined as consuming no more than 210 g of alcohol per week for men and 140 g of alcohol per week for women. We defined the following hypothetical interventions for the amount of alcohol consumed: sustaining a certain level of alcohol consumption from baseline to the repeat survey (e.g., none to none, moderate to moderate, heavy to heavy) and changing from one alcohol consumption level to another (e.g., none to moderate, moderate to heavy). The hypothetical interventions for the types of alcoholic beverages were defined in a similar way to those for the amount of alcohol consumed (e.g., red wine to red wine, red wine to beer/cider). We applied the parametric g-formula to estimate the effect of each hypothetical alcohol consumption intervention on the FLI. To implement the parametric g-formula, we first modeled the probability of time-varying confounders and FLI conditional on covariates. We then used these conditional probabilities to estimate the FLI value if the alcohol consumption level of each participant was under a specific hypothetical intervention. The confidence interval was obtained by 200 bootstrap samples. Results: For the alcohol consumption from baseline to the repeat surveys, 6.65% of the participants were sustained non-drinkers, 63.68% were sustained moderate drinkers, and 14.74% were sustained heavy drinkers, while 8.39% changed from heavy drinking to moderate drinking. Regarding the types of alcoholic beverages from baseline to the repeat surveys, 27.06% of the drinkers sustained their intake of red wine. Whatever the baseline alcohol consumption level, the hypothetical interventions for increasing alcohol consumption from the baseline alcohol consumption were associated with a higher FLI than that of the sustained baseline alcohol consumption level. When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to moderate drinking, the mean ratio of FLI was 1.027 (95% confidence interval [CI]: 0.997-1.057). When comparing sustained non-drinking with the hypothetical intervention of changing from non-drinking to heavy drinking, the mean ratio of FLI was 1.075 (95% CI: 1.042-1.108). When comparing sustained heavy drinking with the hypothetical intervention of changing from heavy drinking to moderate drinking, the mean ratio of FLI was 0.953 (95% CI: 0.938-0.968). The hypothetical intervention of changing to red wine in the UKB was associated with lower FLI levels, compared with sustained consumption of other types of alcoholic beverages. For example, when comparing sustaining spirits with the hypothetical intervention of changing from spirits to red wine, the mean ratio of FLI was 0.981 (95% CI: 0.948-1.014). Conclusions: Regardless of the current level of alcohol consumption, interventions that increase alcohol consumption could raise the risk of hepatic steatosis in Western populations. The findings of this study could inform the formulation of future practice guidelines and health policies. If quitting drinking is challenging, red wine may be a better option than other types of alcoholic beverages in Western populations.

Dysrhythmic saliva microbiota in mobile phone addicts with sleep disorders and restored by acupuncture.

Background: Mobile phone addiction (MPA) greatly affects the biological clock and sleep quality and is emerging as a behavioral disorder. The saliva microbiota has been linked to circadian rhythms, and our previous research revealed dysrhythmic saliva metabolites in MPA subjects with sleep disorders (MPASD). In addition, acupuncture had positive effects. However, the dysbiotic saliva microbiota in MPASD patients and the restorative effects of acupuncture are unclear. Objectives: To probe the circadian dysrhythmic characteristics of the saliva microbiota and acupunctural restoration in MPASD patients. Methods: MPASD patients and healthy volunteers were recruited by the Mobile Phone Addiction Tendency Scale (MPATS) and the Pittsburgh Sleep Quality Index (PSQI). Saliva samples were collected every 4 h for 72 h. After saliva sampling, six MPDSD subjects (group M) were acupuncturally treated (group T), and subsequent saliva sampling was conducted posttreatment. Finally, all the samples were subjected to 16S rRNA gene sequencing and bioinformatic analysis. Results: Significantly increased MPATS and PSQI scores were observed in MPDSD patients (p< 0.01), but these scores decreased (p<0.001) after acupuncture intervention. Compared with those in healthy controls, the diversity and structure of the saliva microbiota in MPASD patients were markedly disrupted. Six genera with circadian rhythms were detected in all groups, including Sulfurovum, Peptostreptococcus, Porphyromonas and Prevotella. There were five genera with circadian rhythmicity in healthy people, of which the rhythmicities of the genera Rothia and Lautropia disappeared in MPASD patients but effectively resumed after acupuncture intervention. Conclusions: This work revealed dysrhythmic salivary microbes in MPASD patients, and acupuncture, as a potential intervention, could be effective in mitigating this ever-rising behavioral epidemic.

First report of Pseudopithomyces palmicola causing leaf spot on tobacco in China.

In July 2023, a new leaf spot disease emerged on tobacco leaves in Meitan County, Guizhou Province, China (27°20'18" - 28°12'30"N, 107°15'36" - 107°41'08"E, average altitude 972 meters). Initially, the symptoms showed raised yellow-brown spots; subsequently, the lesions expanded and became broken and perforated, leading to a significant loss of economic value, the prevalence rate exceeded 30%. For isolation, two tissue fragments (0.2 × 0.2 cm) of symptomatic leaves were sterilized in 75% ethanol for 30 s, 3% NaClO for 2 min, and were washed 3 times in sterilized distilled water, and were subsequently inoculated on potato dextrose agar (PDA), and incubated at 28°C for 9 days in the dark. The two strains CW16 and CW28 were isolated using the single hyphae method (Nouri et al. 2023). Both strains formed pale to yellow white colonies on PDA. Conidia had three constricted transverse septa and 1 to 2 longitudinal septa in the central cells, with thick and hyaline conidiophores and mostly globose, pale brown conidia with slightly constricted septa, their average size were measured as 13.4-22.4×8.358-13.347 µm (n = 50). Genomic DNA was extracted from the isolated strains CW16 and CW28. The internal transcribed spacer regions 1 and 2 as well as 5.8S nuclear ribosomal RNA (ITS), large subunit nrRNA (LSU), and partial DNA-directed RNA polymerase II second largest subunit (RPB2) genes were amplified using primers (Cui et al. 2023). The sequences had been deposited in GenBank under accession numbers ITS: PP024201, PP024205; LSU: PP024207, PP024209; RPB2: PP060480, PP060481. The sequences analysis revealed a high similarity of 99.74 to 100% between strains CW16 and CW28 with P. palmicola isolate KM42 (ITS OQ875842, LSU OQ875844, RPB2 OQ883943) in GenBank. Using BLAST for homology matching, two isolates (CW16, CW28) and with the sequences of the ten type isolates from GenBank, phylogenetic analysis was conducted using the Maximum Likelihood method in MEGA (11.0) software based on ITS, LSU and RPB2 sequences, which showed that strains CW16, CW28 clustered in the same score as the Pseudopithomyces palmicola, confirming the morphological and molecular characteristics identification. The pathogenicity tests were conducted on healthy tobacco plants with 4-5 leaves (Fig. S1B), the isolated strains, CW16 and CW28, were used to inoculate the healthy tobacco leaves, while blank PDA was used as a control. All plants were maintained in a greenhouse at 28°C with a relative humidity of 90%. After 9 days, necrotic spots were observed on all tobacco leaves inoculated with CW16 and CW28 fungal plugs, while the blank PDA-inoculated tobacco leaves showed no symptoms. Based on morphological and molecular characteristics, the same pathogen P. palmicola was identified from the inoculated leaves, fulfilling Koch's postulates. This study represents the first reported of tobacco leaf spot caused by P. palmicola in China and provides a theoretical basis for future prevention and control measures.

Single-molecule targeted therapy shrinks lung lesions and improves bone metastases: A case report.

RATIONALE: Bone metastasis is a common metastatic mode of advanced lung cancer and poses a great threat to the survival and quality of life of patients with this disease. However, the available literature has limited treatment options for advanced lung cancer with bone metastases. PATIENTS CONCERNS: A 76-year-old married male patient was underwent CT due to cough and sputum for 1 month. On CT, space-occupying lesions were found in the left inferior lobe of the lung, as well as multiple bone metastases in the vertebral body and ilium. DIAGNOSES: Pathologic sectioning of the lung lesion after puncture revealed invasive lung adenocarcinoma, and a genetic test revealed EGFR exon 21: L858R (64.60%). INTERVENTIONS: Considering that the disease was not suitable for radiotherapy (extensive metastasis) and could not be treated with chemotherapy (poor underlying condition), the patient was given molecularly targeted therapy with osimertinib. OUTCOMES: After 10 months of standard treatment (80 mg orally, once a day), the lung lesions of the patients became significantly smaller, and the bone metastases distinctly improved. And the patient's condition has not shown any signs of rebound with the one-year follow-up. LESSONS SUBSECTIONS: In the present case, the bone metastases from lung adenocarcinoma almost completely disappeared after treatment with a single molecular targeted therapy agent, increasing the confidence in the treatment of advanced lung cancer.

Effects of exercise training on glucose metabolism indicators and inflammatory markers in obese children and adolescents: A meta-analysis.

BACKGROUND: Obesity in children and adolescents is a serious problem, and the efficacy of exercise therapy for these patients is controversial. AIM: To assess the efficacy of exercise training on overweight and obese children based on glucose metabolism indicators and inflammatory markers. METHODS: The PubMed, Web of Science, and Embase databases were searched for randomized controlled trials related to exercise training and obese children until October 2023. The meta-analysis was conducted using RevMan 5.3 software to evaluate the efficacy of exercise therapy on glucose metabolism indicators and inflammatory markers in obese children. RESULTS: In total, 1010 patients from 28 studies were included. Exercise therapy reduced the levels of fasting blood glucose (FBG) [standardized mean difference (SMD): -0.78; 95% confidence interval (CI): -1.24 to -0.32, P = 0.0008], fasting insulin (FINS) (SMD: -1.55; 95%CI: -2.12 to -0.98, P < 0.00001), homeostatic model assessment for insulin resistance (HOMA-IR) (SMD: -1.58; 95%CI: -2.20 to -0.97, P < 0.00001), interleukin-6 (IL-6) (SMD: -1.31; 95%CI: -2.07 to -0.55, P = 0.0007), C-reactive protein (CRP) (SMD: -0.64; 95%CI: -1.21 to -0.08, P = 0.03), and leptin (SMD: -3.43; 95%CI: -5.82 to -1.05, P = 0.005) in overweight and obese children. Exercise training increased adiponectin levels (SMD: 1.24; 95%CI: 0.30 to 2.18, P = 0.01) but did not improve tumor necrosis factor-alpha (TNF-α) levels (SMD: -0.80; 95%CI: -1.77 to 0.18, P = 0.11). CONCLUSION: In summary, exercise therapy improves glucose metabolism by reducing levels of FBG, FINS, HOMA-IR, as well as improves inflammatory status by reducing levels of IL-6, CRP, leptin, and increasing levels of adiponectin in overweight and obese children. There was no statistically significant effect between exercise training and levels of TNF-α. Additional long-term trials should be conducted to explore this therapeutic perspective and confirm these results.

Polygenic Risk Score Informed Clinical Model for Improving Abdominal Aortic Aneurysm Screening.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disease with environmental and genetic risk factors. Polygenic risk scores (PRSs) based on disease-specific risk-associated single nucleotide variants (SNVs) have demonstrated effectiveness in stratifying individual-level disease risk for cardiovascular diseases. This prospective cohort study assessed associations of PRS of AAA (PRSAAA) with risk of incident AAA, analyzed the effectiveness of a combined clinical-genetic risk model, and explored the clinical utility of the model in identifying high-risk individuals for AAA screening. METHODS: PRSAAA was calculated using 911,440 SNVs and PRS of coronary artery disease was calculated using 2,324,683 SNVs derived from mixed ancestry genome-wide association studies. The UK Biobank was used as the study cohort. All individuals with complete genetic data available and no diagnosis of AAA at the time of recruitment were included in the analysis and followed prospectively to assess for incident AAA. A PRS-informed clinical model, Prob-AAA, was developed using clinically significant variables and PRSAAA. RESULTS: Four hundred eighty-one thousand one hundred 5 individuals were included in the analysis with 2,668 incident AAA cases. Incident AAA increased from 0.30 to 0.93% between the lowest and highest decile of PRSAAA; similarly, severe AAA, requiring surgery and/or presenting with rupture, increased from 23 to 39% of incident AAA cases across deciles. PRSAAA was a predictor of incident AAA diagnosis (hazard ratio 2.06 [1.70-2.48]) independent of other clinical risk factors including male sex, older age, and smoking history. Prob-AAA was an independent predictor of incident AAA (hazard ratio 1.92 [1.69-2.20]), and identified 9.6% of cases of incident AAA compared to only 4.2% by PRSAAA. Current screening guidelines captured 5.7% of the overall cohort, with an incident AAA rate of approximately 3.2%. Among males not included by current guidelines, Prob-AAA identified an additional cohort, approximately 2% of the overall cohort, with a similar rate of incident AAA. CONCLUSIONS: Prob-AAA, a PRS-informed clinical model for AAA, improved upon the predictive power of current, clinical risk factor-informed, screening guidelines for AAA.

CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma.

Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS.

Insights into the Understanding of the Nickel-Based Pre-Catalyst Effect on Urea Oxidation Reaction Activity.

Nickel-based catalysts are regarded as the most excellent urea oxidation reaction (UOR) catalysts in alkaline media. Whatever kind of nickel-based catalysts is utilized to catalyze UOR, it is widely believed that the in situ-formed Ni3+ moieties are the true active sites and the as-utilized nickel-based catalysts just serve as pre-catalysts. Digging the pre-catalyst effect on the activity of Ni3+ moieties helps to better design nickel-based catalysts. Herein, five different anions of OH-, CO32-, SiO32-, MoO42-, and WO42- were used to bond with Ni2+ to fabricate the pre-catalysts ß-Ni(OH)2, Ni-CO3, Ni-SiO3, Ni-MoO4, and Ni-WO4. It is found that the true active sites of the five as-fabricated catalysts are the same in situ-formed Ni3+ moieties and the five as-fabricated catalysts demonstrate different UOR activity. Although the as-synthesized five catalysts just serve as the pre-catalysts, they determine the quantity of active sites and activity per active site, thus determining the catalytic activity of the catalysts. Among the five catalysts, the amorphous nickel tungstate exhibits the most superior activity per active site and can catalyze UOR to reach 158.10 mA·cm-2 at 1.6 V, exceeding the majority of catalysts. This work makes for a deeper understanding of the pre-catalyst effect on UOR activity and helps to better design nickel-based UOR catalysts.

Sustainable Remediation of Soil and Water Utilizing Arbuscular Mycorrhizal Fungi: A Review.

Phytoremediation is recognized as an environmentally friendly technique. However, the low biomass production, high time consumption, and exposure to combined toxic stress from contaminated media weaken the potential of phytoremediation. As a class of plant-beneficial microorganisms, arbuscular mycorrhizal fungi (AMF) can promote plant nutrient uptake, improve plant habitats, and regulate abiotic stresses, and the utilization of AMF to enhance phytoremediation is considered to be an effective way to enhance the remediation efficiency. In this paper, we searched 520 papers published during the period 2000-2023 on the topic of AMF-assisted phytoremediation from the Web of Science core collection database. We analyzed the author co-authorship, country, and keyword co-occurrence clustering by VOSviewer. We summarized the advances in research and proposed prospective studies on AMF-assisted phytoremediation. The bibliometric analyses showed that heavy metal, soil, stress tolerance, and growth promotion were the research hotspots. AMF-plant symbiosis has been used in water and soil in different scenarios for the remediation of heavy metal pollution and organic pollution, among others. The potential mechanisms of pollutant removal in which AMF are directly involved through hyphal exudate binding and stabilization, accumulation in their structures, and nutrient exchange with the host plant are highlighted. In addition, the tolerance strategies of AMF through influencing the subcellular distribution of contaminants as well as chemical form shifts, activation of plant defenses, and induction of differential gene expression in plants are presented. We proposed that future research should screen anaerobic-tolerant AMF strains, examine bacterial interactions with AMF, and utilize AMF for combined pollutant removal to accelerate practical applications.

Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.

The phosphoinositide 3-kinase (PI3K)-Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K-Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K-Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1-Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K-Akt pathway and KRAS mutant cancer therapy.