The Complete Genomic Sequence of Microbial Transglutaminase Producer, Streptomyces mobaraensis DSM40587.

Actinomycetes are remarkable natural sources of active natural molecules and enzymes of considerable industrial value. Streptomyces mobaraensis is the first microorganism found to produce transglutaminase with broad industrial applications. Although transglutaminase in S. mobaraensis has been well studied over the past three decades, the genome of S. mobaraensis and its secondary metabolic potential were poorly reported. Here, we presented the complete genome of S. mobaraensis DSM40587 obtained from the German Collection of Microorganisms and Cell Cultures GmbH. It contains a linear chromosome of 7,633,041 bp and a circular plasmid of 23,857 bp. The chromosome with an average GC content of 73.49% was predicted to harbour 6683 protein-coding genes, seven rRNA and 69 tRNA genes. Comparative genomic analysis reveals its meaningful genomic characterisation. A comprehensive bioinformatics investigation identifies 35 putative BGCs (biosynthesis gene clusters) involved in synthesising various secondary metabolites. Of these, 13 clusters showed high similarity (> 55%) to known BGCs coding for polyketides, nonribosomal peptides, hopene, RiPP (Ribosomally synthesized and post-translationally modified peptides), and others. Furthermore, these BGCs with over 65% similarity to the known BGCs were analysed in detail. The complete genome of S. mobaraensis DSM40587 reveals its capacity to yield diverse bioactive natural products and provides additional insights into discovering novel secondary metabolites.

Hyperhubeins A-I, Bioactive Sesquiterpenes with Diverse Skeletons from Hypericum hubeiense.

Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.

Associations of grip strength, walking pace, and the risk of incident dementia: A prospective cohort study of 340212 participants.

INTRODUCTION: Grip strength and walking pace have been linked to cognitive dysfunction. Their relationships, however, demand further clarification as the evidence is derived primarily from less-comprehensive investigations. METHODS: A total of 340212 UK Biobank participants without dementia and cardiovascular diseases at baseline were analyzed. Cox proportional hazard models assessed the longitudinal associations. RESULTS: Over a mean follow-up of 8.51 ± 2.68 years, 2424 incident dementia cases were documented. A 5 kg increment of absolute grip strength was associated with lower risks of all-cause dementia (hazard ratio [HR] 0.857), Alzheimer's disease (HR 0.874), and vascular dementia (HR 0.788). The patterns of associations remained similar when grip strength was expressed in relative terms and quintiles. A slow walking pace demonstrated consistent associations with increased risks of all dementia types. DISCUSSION: Our findings provide amplified evidence and suggest that muscle fitness, reflected by objective grip strength measures and self-reported walking pace, may be imperative for estimating the risks of dementia.

A Novel Tumor Staging System Incorporating Tumor Regression Grade (TRG) With Lymph Node Status (ypN-Category) Results in Better Prognostication Than ypTNM Stage Groups After Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups. BACKGROUND: Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups. METHODS: A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system. RESULTS: In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors. CONCLUSION: TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups.

Efficient Experimental Verification of Quantum Gates with Local Operations.

Verifying the correct functioning of quantum gates is a crucial step toward reliable quantum information processing, but it becomes an overwhelming challenge as the system size grows due to the dimensionality curse. Recent theoretical breakthroughs show that it is possible to verify various important quantum gates with the optimal sample complexity of O(1/ε) using local operations only, where ε is the estimation precision. In this Letter, we propose a variant of quantum gate verification (QGV) that is robust to practical gate imperfections and experimentally realize efficient QGV on a 2-qubit controlled-not gate and a 3-qubit Toffoli gate using only local state preparations and measurements. The experimental results show that, by using only 1600 and 2600 measurements on average, we can verify with 95% confidence level that the implemented controlled-not gate and Toffoli gate have fidelities of at least 99% and 97%, respectively. Demonstrating the superior low sample complexity and experimental feasibility of QGV, our work promises a solution to the dimensionality curse in verifying large quantum devices in the quantum era.

Absence of Vaccine-enhanced Disease With Unexpected Positive Protection Against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by Inactivated Vaccine Given Within 3 Days of Virus Challenge in Syrian Hamster Model.

BACKGROUND: Mass vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing amidst widespread transmission during the coronavirus disease-2019 (COVID-19) pandemic. Disease phenotypes of SARS-CoV-2 exposure occurring around the time of vaccine administration have not been described. METHODS: Two-dose (14 days apart) vaccination regimen with formalin-inactivated whole virion SARS-CoV-2 in golden Syrian hamster model was established. To investigate the disease phenotypes of a 1-dose regimen given 3 days prior (D-3), 1 (D1) or 2 (D2) days after, or on the day (D0) of virus challenge, we monitored the serial clinical severity, tissue histopathology, virus burden, and antibody response of the vaccinated hamsters. RESULTS: The 1-dose vaccinated hamsters had significantly lower clinical disease severity score, body weight loss, lung histology score, nucleocapsid protein expression in lung, infectious virus titers in the lung and nasal turbinate, inflammatory changes in intestines, and a higher serum neutralizing antibody or IgG titer against the spike receptor-binding domain or nucleocapsid protein when compared to unvaccinated controls. These improvements were particularly noticeable in D-3, but also in D0, D1, and even D2 vaccinated hamsters to varying degrees. No increased eosinophilic infiltration was found in the nasal turbinate, lung, and intestine after virus challenge. Significantly higher serum titer of fluorescent foci microneutralization inhibition antibody was detected in D1 and D2 vaccinated hamsters at day 4 post-challenge compared to controls despite undetectable neutralizing antibody titer. CONCLUSIONS: Vaccination just before or soon after exposure to SARS-CoV-2 does not worsen disease phenotypes and may even ameliorate infection.

Improving Outcome of Superior Mediastinal Lymph Node Dissection During Esophagectomy: A Novel Approach Combining Continuous and Intermittent Recurrent Laryngeal Nerve Monitoring.

OBJECTIVE: This study aimed at demonstrating the effects and learning curve of utilizing combined intermittent and continuous recurrent laryngeal nerve (RLN) monitoring for lymphadenectomy during esophagectomy. BACKGROUND: RLN lymphadenectomy is oncologically important but is technically demanding. Vocal cord (VC) palsy as a result from RLN injury, carries significant morbidities. METHODS: This is a retrospective study of consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent transthoracic esophagectomy from 2010 to 2020. Combined nerve monitoring (CNM) included: CNM which involved a periodic stimulating left vagal electrode and intermittent nerve monitoring which utilized a stimulating probe to identify the RLNs. The integrity of the RLNs was assessed both intermittently and continuously. This technique was introduced in 2014. Patients were divided into "before CNM" and "CNM" groups. The primary outcome was the difference in number of RLN lymph nodes harvested and VC palsy rate. Learning curves were demonstrated by cumulative sum (CUSUM) analysis. RESULTS: Two hundred and fifty-five patients were included with 157 patients in "CNM" group. The mean number of RLN lymph nodes harvested was significantly higher (4.31 vs 0.45, P < 0.0001) for the "CNM" group. VC palsy rates were significantly lower (17.8% vs 32.7%, P = 0.007). There was an initial increase in VC palsy rate, peaked at around 46 cases. The increase in lymph nodes harvested above the mean plateaued at around 96 cases. CONCLUSIONS: CNM helped improve bilateral RLN lymphadenectomy. Lymph node harvesting was increased with reduction of VC palsy after a learning curve.

Neoadjuvant Chemoradiotherapy Using Cisplatin and 5-Fluorouracil (PF) Versus Carboplatin and Paclitaxel (CROSS Regimen) for Esophageal Squamous Cell Carcinoma (ESCC): A Propensity Score-matched Study.

OBJECTIVE: This study compared the efficacy of PF-based and CROSS-based neoadjuvant chemoradiotherapy for ESCC. BACKGROUND: PF-based regimen has been a standard regimen for ESCC, but it has been replaced by the CROSS regimen in the past few years, despite no prospective head-to-head comparative study has been performed. METHODS: This is a single center retrospective study. Records of all ESCC patients who have received neoadjuvant PF with 40 Gy radiotherapy in 20 daily fractions (PFRT Group) or CROSS with 41.4 Gy radiotherapy in 23 daily fractions (CROSS Group) during the period 2002 to 2019 were retrieved. Propensity score matching (1:1) was performed to minimize baseline differences. The primary and secondary endpoints were overall survival and clinicopathological response. Subgroup analysis ("CROSS Eligibility") was performed based on tumor length, cT-stage, cM-stage, age, and performance status. RESULTS: One hundred (out of 109) patients (CROSS group) and propensity score matched 100 (out of 210) patients (PFRT group) were included. Esophagectomy rates in CROSS and PFRT group were 69% and 76%, respectively (P = 0.268). R0 resection rates were 85.5% and 81.6% (P = 0.525) and the pathological complete remission rates were 24.6% and 35.5% (P = 0.154). By intention-to-treat, the median survival was 16.7 and 32.7 months (P = 0.083). For "CROSS Eligible subgroup," the median survival of the CROSS and PFRT group was 21.6 versus 44.9 months (P = 0.093). CONCLUSIONS: There is no statistically difference in survival or clinicopathological outcome between both groups, but the trend favors PFRT. Prospective head-to-head comparison and novel strategies to improve the outcomes in resectable ESCC are warranted.

[A new phenolic compound from endophytic fungus Aspergillus fumigatus of Euphorbia royleana].

This research was carried out to study the secondary metabolites of endophytic fungus Aspergillosis fumigatus from Euphorbia royleana. The endophytic fungus A. fumigatus was fermented by solid fermentation,and purified by various chromatographic methods after extraction. The structures of the compounds were identified by1 H-NMR,13 C-NMR and HSQC,HMBC spectra and physicchemical properties. Three compounds were isolated and their structures were identified as 3-( 3,4-dihydroxybenzoyl)-5-( 3,4-dihydroxyphenyl)-6-methyl-5,6-dihydro-2 H-pyran-2-one( 1),hydroxysydonic acid( 2) and 11-hydroxysydonic acid( 3). Compound 1 is a new compound.

Pediatric low-grade gliomas can be molecularly stratified for risk.

Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.

Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats.

In hypertensive animals and patients, oxidative stress represents the primary risk factor for progression of renal disease. Recently, it has been demonstrated that hydrogen, as a novel antioxidant, can selectively reduce hydroxyl radicals and peroxynitrite anion to exert therapeutic antioxidant activity. Herein, we investigated the protective effect of hydrogen-rich water (HW) against renal injury in spontaneously hypertensive rats (SHR). The 8-week-old male SHR and age-matched Wistar-Kyoto rats were randomized into HW-treated (1.3 ± 0.2 mg/l for 3 months, drinking) and vehicle-treated group. Although treatment with HW had no significant effect on blood pressure, it significantly ameliorated renal injury in SHR. Treatment with HW lowered reactive oxygen species formation, upregulated the activities of superoxide dismutase, glutathione peroxidase, glutathione-S-epoxide transferase, and catalase, and suppressed NADPH oxidase activity. Treatment with HW in SHR depressed pro-inflammatory cytokines expression including TNF-α, IL-6, IL-1ß, and macrophage chemoattractant protein 1, which might be mediated by suppressing nuclear factor-κB activation. In addition, treatment with HW had protective effect on mitochondrial function including adenosine triphosphate formation and membrane integrity in SHR. In conclusion, consumption of HW is a promising strategy to alleviate renal injury as a supplement for anti-hypertensive therapy.

[Spatiotemporal Simulation and Prediction of Soil Organic Carbon Density in Gannan Grassland Under Future Climate Scenarios].

To study the temporal and spatial distribution characteristics of soil organic carbon density in grassland and explore the relationship between organic carbon density and influencing factors is of great significance to the management and maintenance of grassland ecosystems in Gannan Autonomous Prefecture, which is conducive to realizing the goal of "double carbon," promoting carbon sink, and mitigating climate change. Taking Gannan Tibetan Autonomous Prefecture of Gansu Province as the research object, based on data from two CMIP6 future climate scenarios (SSP126 and SSP585), the CENTURY model was used to simulate and predict the temporal and spatial changes in soil organic carbon density in grassland of Gannan during 2023-2100. The main conclusions were as follows:① From 2023 to 2100, total organic carbon density, slow organic carbon density, and inert organic carbon density all showed a downward trend, whereas active organic carbon density fluctuated first and then increased. Meanwhile, the total organic carbon density, active organic carbon density, slow organic carbon density, and inert organic carbon density under the SSP585 scenario were higher than those under the SSP126 scenario. ② Mann-Kendall mutation analysis showed that the abrupt change in the difference of soil total organic carbon density (Δsomtc) occurred in 2030. The abrupt change in the difference of soil active carbon density (Δsom1c) occurred in 2027. ③ During the study period, the average soil organic carbon density of Gannan grassland was 7 505.69 g·m-2 under the SSP126 scenario and 7 551.87 g·m-2 under the SSP585 scenario. Gannan grassland soil organic carbon density was higher in the west and lower in the east, and the coefficient of variation was relatively stable. ④ The results of partial correlation analysis showed that precipitation was positively correlated with soil organic carbon density, whereas temperature was significantly negatively correlated with soil organic carbon density under future climate scenarios. ⑤ The results of the Theil-Sen Median trend analysis and Mann-Kendall test showed that under the two climate scenarios, the soil organic carbon density in Gannan showed an overall downward trend, in which Luqu County showed the fastest downward trend and Dibe County showed the slowest.

[Occurrence Characteristic and Risk Assessment of Microplastics in Sishui River (Xingyang Section)].

Urban rivers are the main receptors and transporters of microplastic pollution. Understanding the occurrence and environmental risk of microplastics in urban rivers can provide theoretical basis for further control of microplastic pollution. The Sishui River, a tributary of the Yellow River, was selected as the research object. A total of nine water samples were collected from sewage outlets of the Sishui River (Xingyang section). The microplastics in the collected samples were characterized by their sizes, shapes, and colors using a microscope. It was found that microplastics were mostly in the form of transparent fibers and fragments in the water body of sewage outlets, of which the size below 500 µm was relatively high. In addition, PET and PE polymers were identified as the main types using a laser infrared imager. The correlation analysis showed that there was a significant correlation between the PET and PE, indicating that they were similar in origin. The results of the environmental risk assessment showed that the type of microplastics was the main factor affecting the assessment results, whereas the risk values of six sewage samples containing PVC were high. However, the value of pollution load index revealed a low risk level of pollutants in the study area.

Baseline Gut Microbiota Was Associated with Long-Term Immune Response at One Year Following Three Doses of BNT162b2.

BACKGROUND: This study explored neutralizing IgG antibody levels against COVID-19 decline over time post-vaccination. We conducted this prospective cohort study to investigate the function of gut microbiota in the host immune response following three doses of BNT162b2. METHODS: Subjects who received three doses of BNT162b2 were recruited from three centers in Hong Kong. Blood samples were obtained before the first dose and at the one-year timepoint for IgG ELISA to determine the level of neutralizing antibody (NAb). The primary outcome was a high immune response (NAb > 600 AU/mL). We performed shotgun DNA metagenomic sequencing on baseline fecal samples to identify bacterial species and metabolic pathways associated with high immune response using linear discriminant analysis effect size analysis. RESULTS: A total of 125 subjects were recruited (median age: 52 years [IQR: 46.2-59.0]; male: 43 [34.4%]), and 20 were regarded as low responders at the one-year timepoint. Streptococcus parasanguinis (log10LDA score = 2.38, p = 0.003; relative abundance of 2.97 × 10-5 vs. 0.03%, p = 0.001), Bacteroides stercoris (log10LDA score = 4.29, p = 0.024; relative abundance of 0.14% vs. 2.40%, p = 0.014) and Haemophilus parainfluenzae (log10LDA score = 2.15, p = 0.022; relative abundance of 0.01% vs. 0, p = 0.010) were enriched in low responders. Bifidobacterium pseudocatenulatum (log10LDA score = 2.99, p = 0.048; relative abundance of 0.09% vs. 0.36%, p = 0.049) and Clostridium leptum (log10LDA score = 2.38, p = 0.014; relative abundance of 1.2 × 10-5% vs. 0, p = 0.044) were enriched in high responders. S. parasanguinis was negatively correlated with the superpathway of pyrimidine ribonucleotides de novo biosynthesis (log10LDA score = 2.63), which contributes to inflammation and antibody production. H. parainfluenzae was positively correlated with pathways related to anti-inflammatory processes, including the superpathway of histidine, purine, and pyrimidine biosynthesis (log10LDA score = 2.14). CONCLUSION: Among three-dose BNT162b2 recipients, S. parasanguinis, B. stercoris and H. parainfluenzae were associated with poorer immunogenicity at one year, while B. pseudocatenulatum and C. leptum was associated with a better response.

Association between Gut Microbiota Composition and Long-Term Vaccine Immunogenicity following Three Doses of CoronaVac.

BACKGROUND: Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac. METHODS: This was a prospective cohort study recruiting three-dose CoronaVac recipients from two centers in Hong Kong. Blood samples were collected at baseline and one year post-first dose for virus microneutralization (vMN) assays to determine neutralization titers. The primary outcome was high immune response (defined as with vMN titer ≥ 40). Shotgun DNA metagenomic sequencing of baseline fecal samples identified potential bacterial species and metabolic pathways using Linear Discriminant Analysis Effect Size (LEfSe) analysis. Univariate and multivariable logistic regression models were used to identify high response predictors. RESULTS: In total, 36 subjects were recruited (median age: 52.7 years [IQR: 47.9-56.4]; male: 14 [38.9%]), and 18 had low immune response at one year post-first dose vaccination. Eubacterium rectale (log10LDA score = 4.15, p = 0.001; relative abundance of 1.4% vs. 0, p = 0.002), Collinsella aerofaciens (log10LDA score = 3.31, p = 0.037; 0.39% vs. 0.18%, p = 0.038), and Streptococcus salivarius (log10LDA score = 2.79, p = 0.021; 0.05% vs. 0.02%, p = 0.022) were enriched in low responders. The aOR of high immune response with E. rectale, C. aerofaciens, and S. salivarius was 0.03 (95% CI: 9.56 × 10-4-0.32), 0.03 (95% CI: 4.47 × 10-4-0.59), and 10.19 (95% CI: 0.81-323.88), respectively. S. salivarius had a positive correlation with pathways enriched in high responders like incomplete reductive TCA cycle (log10LDA score = 2.23). C. aerofaciens similarly correlated with amino acid biosynthesis-related pathways. These pathways all showed anti-inflammation functions. CONCLUSION: E. rectale,C. aerofaciens, and S. salivarius correlated with poorer long-term immunogenicity following three doses of CoronaVac.

Genomic and Metabolite Profiling Reveal a Novel Streptomyces Strain, QHH-9511, from the Qinghai-Tibet Plateau.

The prevalence of superbugs, represented by methicillin-resistant Staphylococcus aureus (MRSA), has become a serious clinical and public safety concern with rising incidence in hospitals. Polyketides with diverse chemical structures harbor many antimicrobial activities, including those of rifampin and rapamycin against MRSA. Streptomyces sp. QHH-9511 was isolated from a niche habitat in the Qinghai-Tibet Plateau and used to produce antibacterial metabolites. Herein, an integrated approach combining genome mining and metabolic analysis were employed to decipher the chemical origin of the antibacterial components with pigmented properties in strain QHH-9511, a novel Streptomyces species from a lichen symbiont on the Qinghai-Tibet Plateau. Genomic phylogeny assembled at the chromosome level revealed its unique evolutionary state. Further genome mining uncovered 36 candidate gene clusters, most of which were uncharacterized. Meanwhile, based on liquid chromatography coupled to diode array detection mass spectrometry, a series of granaticins, BSMs, chromones, phaeochromycins, and related molecules were discovered by using the Global Natural Product Social molecular networking platform. Subsequently, several pigment compounds were isolated and identified by high-resolution mass spectrometry and/or nuclear magnetic resonance, among which the structure-activity relationships of seven aromatic polyketides showed that the fused lactone ring of the C-2 carboxyl group could increase antibacterial activity. Genetic experiments indicated that all seven aromatic polyketides are a series of metabolic shunts produced by a single type II polyketide synthase (PKS) cluster. Comparative genomic analysis of granaticin producers showed that the granaticin gene cluster is widely distributed. This study provides an efficient method to combine genome mining and metabolic profiling techniques to uncover bioactive metabolites derived from specific habitats, while deepening our understanding of aromatic polyketide biosynthesis. IMPORTANCE Undescribed microorganisms from special habitats are being screened for anti-superbug drug molecules. In a project to screen actinomycetes for anti-MRSA activity, we isolated a Streptomyces strain from Qinghai Lake lichens. The phylogeny based on the genome assembled at the chromosome level revealed this strain's unique evolutionary state. The chemical origins of the antibacterial components with pigment properties in strain QHH-9511 were determined using an integrated approach combining genome mining and metabolic analysis. Further genome mining uncovered 36 secondary metabolite gene clusters, the majority of which were previously unknown. A series of aromatic compounds were discovered using molecular network analysis, separation, and extraction. Genetic experiments revealed that all seven aromatic polyketides are a series of metabolic shunts produced by a single cluster of type II PKSs. This study describes a method for identifying novel Streptomyces from specific habitats by combining genome mining with metabolic profiling techniques.

Poor Oral Health and Risk of Incident Dementia: A Prospective Cohort Study of 425,183 Participants.

BACKGROUND: The association between poor oral health and the risk of incident dementia remains unclear. OBJECTIVE: To investigate the associations of poor oral health with incident dementia, cognitive decline, and brain structure in a large population-based cohort study. METHODS: A total of 425,183 participants free of dementia at baseline were included from the UK Biobank study. The associations between oral health problems (mouth ulcers, painful gums, bleeding gums, loose teeth, toothaches, and dentures) and incident dementia were examined using Cox proportional hazards models. Mixed linear models were used to investigate whether oral health problems were associated with prospective cognitive decline. We examined the associations between oral health problems and regional cortical surface area using linear regression models. We further explored the potential mediating effects underlying the relationships between oral health problems and dementia. RESULTS: Painful gums (HR = 1.47, 95% CI [1.317-1.647], p < 0.001), toothaches (HR = 1.38, 95% CI [1.244-1.538], p < 0.001), and dentures (HR = 1.28, 95% CI [1.223-1.349], p < 0.001) were associated with increased risk of incident dementia. Dentures were associated with a faster decline in cognitive functions, including longer reaction time, worse numeric memory, and worse prospective memory. Participants with dentures had smaller surface areas of the inferior temporal cortex, inferior parietal cortex, and middle temporal cortex. Brain structural changes, smoking, alcohol drinking, and diabetes may mediate the associations between oral health problems and incident dementia. CONCLUSION: Poor oral health is associated with a higher risk of incident dementia. Dentures may predict accelerated cognitive decline and are associated with regional cortical surface area changes. Improvement of oral health care could be beneficial for the prevention of dementia.

Longitudinal associations of cardiovascular health and vascular events with incident dementia.

INTRODUCTION: Evidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is sought to: (1) determine the clinical validity of Framingham General Cardiovascular Risk Score (FGCRS) for dementia assessment and (2) examine the associations between cardiovascular diseases and the risk of dementia. METHODS: A total of 432 079 dementia-free individuals at baseline from UK Biobank were included. Multivariable Cox proportional hazard models were used to investigate the prospective associations for FGCRS and a series of cardiovascular diseases with all-cause dementia (ACD) and its major components, Alzheimer's disease (AD) and vascular dementia (VaD). RESULTS: During a median follow-up of 110.1 months, 4711 individuals were diagnosed with dementia. FGCRS was associated with increased risks across the dementia spectrum. In stratification analysis, high-risk groups have demonstrated the greatest dementia burdens, particularly to VaD. Over 74 traits, 9 adverse associations, such as chronic ischaemic heart disease (ACD: HR=1.354; AD: HR=1.269; VaD: HR=1.768), atrioventricular block (ACD: HR=1.562; AD: HR=1.556; VaD: HR=2.069), heart failure (ACD: HR=1.639; AD: HR=1.543; VaD: HR=2.141) and hypotension (ACD: HR=2.912; AD: HR=2.361; VaD: HR=3.315) were observed. Several distinctions were also found, with atrial fibrillation, cerebral infarction, and haemorrhage only associated with greater risks of ACD and VaD. DISCUSSION: By identifying distinctive associations between cardiovascular diseases and dementia, this study has established a comprehensive 'mapping' that may untangle the long-standing discrepancy. FGCRS has demonstrated its predictivity beyond cardiovascular diseases burdens, suggesting potential opportunities for implantation.

A weighted cranial diffusion-weighted imaging scale for Wilson's disease.

Objectives: Cranial magnetic resonance imaging (MRI) could be a crucial tool for the assessment for neurological symptoms in patients with Wilson's disease (WD). Diffusion-weighted imaging (DWI) hyperintensity reflects the acute brain injuries, which mainly occur in specific brain regions. Therefore, this study aimed to develop a weighted cranial DWI scale for patients with WD, with special focus on specific brain regions. Materials and methods: In total, 123 patients with WD were enrolled, 118 of whom underwent 1.5 T-MRI on admission. The imaging score was calculated as described previously and depended on the following sequences: one point was acquired when abnormal intensity occurred in the T1, T2, and fluid-attenuation inversion recovery sequences, and two points were acquired when DWI hyperintensity were found. Consensus weighting was conducted based on the symptoms and response to treatment. Results: Intra-rater agreement were good (r = 0.855 [0.798-0.897], p < 0.0001). DWI hyperintensity in the putamen was a high-risk factor for deterioration during de-copper therapy (OR = 8.656, p < 0.05). The high-risk factors for readmission for intravenous de-copper therapies were DWI hyperintensity in the midbrain (OR = 3.818, p < 0.05) and the corpus callosum (OR = 2.654, p < 0.05). Both scoring systems had positive correlation with UWDRS scale (original semi-quantitative scoring system, r = 0.35, p < 0.001; consensus semi-quantitative scoring system, r = 0.351, p < 0.001.). Compared to the original scoring system, the consensus scoring system had higher correlations with the occurrence of deterioration (OR = 1.052, 95%CI [1.003, 1.0103], p < 0.05) and readmission for intravenous de-copper therapy (OR = 1.043, 95%CI [1.001, 1.086], p < 0.05). Conclusion: The predictive performance of the consensus semi-quantitative scoring system for cranial MRI was improved to guide medication, healthcare management, and prognosis prediction in patients with WD. For every point increase in the neuroimaging score, the risk of exacerbations during treatment increased by 5.2%, and the risk of readmission to the hospital within 6 months increased by 4.3%.

Chromosome-Level Genome Sequences, Comparative Genomic Analyses, and Secondary-Metabolite Biosynthesis Evaluation of the Medicinal Edible Mushroom Laetiporus sulphureus.

Laetiporus sulphureus mushroom is a complementary and alternative medicine that has anticancer, antioxidation, and analgesic effects and immunomodulatory activity; it is used as a treatment for cough and rheumatism and is a functional food that can improve physical fitness. Even though L. sulphureus has garnered considerable biotechnological and pharmacological interest due to its excellent cellulose-degrading ability and diverse biological activities, its biosynthetic potential regarding polysaccharides and secondary metabolites has not been thoroughly examined. In this study, we sequenced and assembled the whole genome of a wild L. sulphureus isolate, NWAFU-1, from the Qinling Mountains in China. Comparative genomes analysis revealed genomic differences between subspecies, and phylogenomic analysis revealed evolutionary divergence as well as genome expansion and contraction of individual Polyporaceae family species. Bioinformatics investigation identified candidate genes associated with mating type, polysaccharide synthesis, carbohydrate-active enzymes, and secondary-metabolite biosynthesis, which included multiple terpenoids, nonribosomal peptides, and polyketides. The locations of biosynthetic core genes were mapped and displayed on chromosomes and contigs. Totals of 143 proteins from 126 coding genes were identified and divided into 14 cytochrome P450 families. Furthermore, the biosynthetic network of tetracyclic triterpenoid active components was postulated by genome mining of related genes combined with the molecular network of metabolites. The genome analysis of L. sulphureus in this study improves the understanding of the biosynthesis of active compounds, which will lay a theoretical foundation for subsequent research on active-compound biosynthesis and promote the application of Laetiporus in the field of drug research and functional-food creation. IMPORTANCE L. sulphureus is a parasitic basidiomycete fungus that causes brown rot. The fruiting bodies of L. sulphureus are used as ancient medicines in China and Europe to cure cancer, analgesia, cough, and rheumatism and are considered a functional food that regulates the body and improves health. L. sulphureus was inferred to be a tetrapolar system based on a high-quality genome, which will aid molecular breeding and artificial farming. Screening polysaccharide synthesis candidate genes and comparing carbohydrate-associated genes in brown-rot basidiomycetes help understand their growth. Identifying core genes for secondary-metabolite biosynthesis, gene cluster family analysis, and comparative cluster analysis will guide heterologous-biosynthesis investigations of these genes and help elucidate the biosynthetic pathways for L. sulphureus bioactive natural components. The biosynthesis network of tetracyclic triterpenes was mapped using metabolite profiling and genome scanning. This work explores the biosynthetic capacity of L. sulphureus-derived natural products and lays the foundation for biosynthetic studies of them.