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Objective: Central precocious puberty (CPP) is a rare condition that causes early sexual development in children. Although the cure is effective, the etiology of central precocious puberty is unclear., Methods: In total, 10 girls with central precocious puberty and same number of age-matched female controls were enrolled. Plasma samples were collected from each participant and subjected to untargeted metabolomics and lipidomics. Student's t -tests were employed to compare the mean of each metabolite and lipid. Furthermore, orthogonal partial least-squares discriminant analysis was conducted and the variable importance in the projection was calculated to identify differentially expressed metabolites or lipids. Subsequent bioinformatics was conducted to investigate the potential function of differentially expressed metabolites and lipids., Results: Fifty-nine differentially expressed metabolites were identified based on the criteria used (variable importance in the projection >1 and a P value < 0.05). Kyoto Encyclopedia Genes and Genome (KEGG) enrichment analysis showed that differentially expressed metabolites were enriched in four pathways: beta-alanine metabolism, histidine metabolism, bile secretion, and steroid hormone biosynthesis. As for the lipidomics, 41 differentially expressed lipids were observed and chain length analysis and lipid saturation analysis yielded similar results. Significant differences between the two groups were only observed in (O-acyl) ω-hydroxy fatty acids (OAHFA)., Conclusion: The present study showed that antibiotic overuse, increased meat consumption, and obesity may have potential roles in the development of central precocious puberty in girls. Several metabolites have diagnostic value but further research is required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhao, Zhang, Zhang, Li, Guo and Shi.)

Background: Air pollution induces neurotoxic reactions and may exert adverse effects on cognitive health. We aimed to investigate whether air pollutants accelerate cognitive decline and affect neurobiological signatures of Alzheimer's disease (AD)., Methods: We used a population-based cohort from the Chinese Longitudinal Healthy Longevity Survey with 31,573 participants and a 10-year follow-up (5878 cognitively unimpaired individuals in Chinese Longitudinal Healthy Longevity Survey followed for 5.95 ± 2.87 years), and biomarker-based data from the Chinese Alzheimer's Biomarker and Lifestyle study including 1131 participants who underwent cerebrospinal fluid measurements of AD-related amyloid-β (Aβ) and tau proteins. Cognitive impairment was determined by education-corrected performance on the China-Modified Mini-Mental State Examination. Annual exposures to fine particulate matter (PM 2.5 ), ground-level ozone (O 3 ), and nitrogen dioxide (NO 2 ) were estimated at areas of residence. Exposures were aggregated as 2-year averages preceding enrollments using Cox proportional hazards or linear models., Results: Long-term exposure to PM 2.5 (per 20 μg/m 3 ) increased the risk of cognitive impairment (hazard ratio, 1.100; 95% CI: 1.026-1.180), and similar associations were observed from separate cross-sectional analyses. Exposures to O 3 and NO 2 yielded elevated risk but with nonsignificant estimates. Individuals exposed to high PM 2.5 manifested increased amyloid burdens as reflected by cerebrospinal fluid-AD biomarkers. Moreover, PM 2.5 exposure-associated decline in global cognition was partly explained by amyloid pathology as measured by cerebrospinal fluid-Aβ 42 /Aβ 40 , P-tau/Aβ 42 , and T-tau/Aβ 42 , with mediation proportions ranging from 16.95% to 21.64%., Conclusions: Long-term exposure to PM 2.5 contributed to the development of cognitive decline, which may be partly explained by brain amyloid accumulation indicative of increased AD risk., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases., Methods: We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated., Results: Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimer's disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinson's disease. Among them, GPNMB was the most promising target for Parkinson's disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain., Conclusions: Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia., Methods: In this prospective cohort study, 354,313 participants ages 50-70 years were recruited from the UK Biobank between 2006 and 2010 and were followed until 2020, with a total of 4,212,929 person-years. We initially studied the effect of depression on dementia incidence across 4 subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with a diagnosis of depression were further categorized into treated and untreated groups. We compared the risk of dementia among different depression treatment groups in all participants who were depressed as well as 4 courses of depressive symptoms by performing survival analyses., Results: Depression was associated with a 51% higher risk of dementia, among which the increasing, chronically high, and chronically low courses were associated with increased dementia risk, while no association was found in the decreasing course. Compared to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% CI, 0.62-0.77). Among the 3 detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 32% and 28% lower risk of dementia, respectively, while the reduction effect for chronically high symptoms was insignificant., Conclusions: The negative association between depression treatment and incident dementia was significant in the increasing and chronically low courses, highlighting the necessity of timely interventional strategies before depression progresses to a chronically severe state., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

NK-lysin (NKL) is a positively charged antimicrobial peptide with broad-spectrum bactericidal activities. In this study, the cDNA sequence of NKL (TmNKL) from black scraper (Thamnaconus modestus) was cloned, which encodes a predicted polypeptide of 150 amino acids that contains a surfactant protein B domain with three disulfide bonds. Phylogenetically, TmNKL was most closely related to its teleost counterpart from tiger puffer (Takifugu rubripes). Expression analysis demonstrated that TmNKL transcripts were constitutively expressed in all tested tissues, with the highest expression levels in the gills. Its expression was significantly upregulated in the gills, head kidney, and spleen after infection with Vibrio parahaemolyticus. A linear peptide (TmNKLP40L) and a disulfide-type peptide (TmNKLP40O) were further synthesized and results showed that disulfide bonds are not essential for bactericidal activities of TmNKL, and that both forms of TmNKL exhibited potent bactericidal activities against 4 gram- negative bacteria, including V. parahaemolyticus, V. alginolyticus, Edwardsiella tarda, and V. harveyi. Observed antimicrobial activities are likely due to the effects of TmNKLP40L and TmNKLP40O treatment on disrupting the integrity of both inner and outer membrane of V. parahaemolyticus, resulting in hydrolysis of bacterial genomic DNA. Damaged cell membranes and leakage of intracellular contents were further confirmed using scanning and transmission microscopy. Moreover, administration of 1.0 μg/g TmNKLP40L or TmNKLP40O significantly decreased bacterial load in tissues and thus, pronouncedly enhanced the survival of V. parahaemolyticus-infected fish. Overall, our results demonstrated that TmNKL is a potent innate effector and provides protective effects against bacterial infection., Competing Interests: Declaration of competing interest The authors confirm they have no known conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Ganoderma sp. contains high amounts of diverse triterpenoids; however, few triterpenoid saponins could be isolated from the medicinal fungus. To produce novel Ganoderma triterpenoid saponins, biotransformation-guided purification (BGP) process was applied to a commercial Ganoderma extract. The commercial Ganoderma extract was partially separated into three fractions by preparative high-performance liquid chromatography, and the separated fractions were then directly biotransformed by a Bacillus glycosyltransferase (BsUGT489). One of the biotransformed products could be further purified and identified as a novel saponin: ganoderic acid C2 (GAC2)-3-O-β-glucoside by nucleic magnetic resonance (NMR) and mass spectral analyses. Based on the structure of the saponin, the predicted precursor should be the GAC2, which was confirmed to be biotransformed into four saponins, GAC2-3-O-β-glucoside, GAC2-3,15-O-β-diglucoside and two unknown GAC2 monoglucosides, revealed by NMR and mass spectral analyses. GAC2-3-O-β-glucoside and GAC2-3,15-O-β-diglucoside possessed 17-fold and 200-fold higher aqueous solubility than that of GAC2, respectively. In addition, GAC2-3-O-β-glucoside retained the most anti-α-glucosidase activity of GAC2 and was comparable with that of the anti-diabetes drug (acarbose). The present study showed that the BGP process is an efficient strategy to survey novel and bioactive molecules from crude extracts of natural products., (Copyright © 2023 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: Visual impairment and interventions to preserve vision may impact dementia risk. Thus, we aimed to explore the associations of cataract and cataract surgery with the risk of dementia., Methods: Prospective data from 300,823 individuals in the UK Biobank were used. We used multivariate Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals for associations, with healthy control subjects as a reference. The same method was used to explore the effects of surgery on dementia outcomes of patients with cataract. One-way analysis of variance was performed to examine the associations between cataract and brain morphometric measures., Results: After a mean follow-up of 8.4 years, 3226 individuals were diagnosed with dementia. The nonsurgical cataract group had increased risk of all-cause dementia (HR, 1.214; 95% CI, 1.012-1.456; p = .037) and Alzheimer's disease (HR, 1.479; 95% CI, 1.105-1.981; p = .009). However, there was no difference in dementia risk between the cataract surgery group and the healthy control group. Cataract surgery was associated with decreased risk of all-cause dementia (HR, 0.632; 95% CI, 0.421-0.947; p = .026) and Alzheimer's disease (HR, 0.399; 95% CI, 0.196-0.812; p = .011) compared with the nonsurgical group. Additionally, cataract was negatively associated with cortical volumes, aging-related subcortical volumes, and fractional anisotropy of white matter fibers., Conclusions: Cataract patients who did not receive surgical treatment had an increased risk of dementia. However, cataract surgery could reverse the risk of dementia. Our findings on brain structures and pathways in patients with cataract also provided evidence for the mechanism. Reversible visual impairment, such as cataract, is a promising modifiable risk factor for dementia., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD)., Methods: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators., Results: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aβ-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-β=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers., Conclusions: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022 the Alzheimer's Association.)

Background: Development of disease-modifying therapeutic trials of progressive supranuclear palsy (PSP) urges the need for sensitive fluid biomarkers., Objectives: The objectives of this study were to explore the utility of plasma biomarkers in the diagnosis, differential diagnosis, and assessment of disease severity, brain atrophy, and tau deposition in PSP., Methods: Plasma biomarkers were measured using a single-molecule array in a cohort composed of patients with PSP, Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P), and healthy controls (HCs)., Results: Plasma neurofilament light chain (NfL) outperformed other plasma makers (ie, glial fibrillary acidic protein [GFAP], phosphorylated-tau 181 [p-tau181], amyloid-β 1-40, amyloid-β 1-42) in identifying PSP from HC (area under the curve [AUC] = 0.904) and from MSA-P (AUC = 0.711). Plasma GFAP aided in distinguishing PSP from HC (AUC = 0.774) and from MSA-P (AUC = 0.832). It correlated with brainstem atrophy and higher regional tau accumulation. However, plasma p-tau181 neither helped in diagnosis nor was it associated with clinical or neuroimaging measures., Conclusions: Plasma NfL and GFAP showed different values in differentiating PSP from HC or controls with other forms of neurodegenerative parkinsonism and detecting disease severity, brain atrophy, or tau deposition in PSP. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Significantly decreased H3K4 methylation in oocytes from aged mice indicates the important roles of H3K4 methylation in female reproduction. However, how H3K4 methylation regulates oocyte development remains largely unexplored. In this study, it is demonstrated that oocyte-specific expression of dominant negative mutant H3.3-K4M led to a decrease of the level of H3K4 methylation in mouse oocytes, resulting in reduced transcriptional activity and increased DNA methylation in oocytes, disturbed oocyte developmental potency, and fertility of female mice. The impaired expression of genes regulating mitochondrial functions in H3.3-K4M oocytes, accompanied by mitochondrial abnormalities, is further noticed. Moreover, early embryos from H3.3-K4M oocytes show developmental arrest and reduced zygotic genome activation. Collectively, these results show that H3K4 methylation in oocytes is critical to orchestrating gene expression profile, driving the oocyte developmental program, and ensuring oocyte quality. This study also improves understanding of how histone modifications regulate organelle dynamics in oocytes., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown., Methods: We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders., Results: We identified 11 genetic loci (P < 8.3 × 10 -9 ) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories., Conclusions: Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders., Competing Interests: Declaration of Competing Interest Authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

There is a dire need for reliable biomarkers to solidify an early and accurate diagnosis of multiple system atrophy (MSA). We sought to compare the ability of emerging plasma markers in distinguishing MSA from its mimics and healthy controls in early disease stages, and to evaluate their performance in detecting disease severity and brain atrophy. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau181, amyloid-β (Aβ)42, and Aβ40 were measured using ultrasensitive Simoa in early-stage patients with MSA (n = 73), spinocerebellar ataxia (SCA, n = 29), Parkinson's disease (PD, n = 28), and healthy controls (n = 100). We observed that elevated NfL outperformed other biomarkers in distinguishing MSA and its subtypes (AUC = 0.9) versus controls. Intriguingly, when separating MSA from its mimics, increased GFAP (AUC = 0.717) in MSA-C and decreased Aβ40 (AUC = 0.807) in MSA-P best discriminated from SCA and PD respectively. Plasma levels were comparable between MSA-C and MSA-P and the differentiation by plasma index alone was poor. Combining plasma markers noticeably improved the discriminatory efficacy. Of note, among MSA patients, higher GFAP and NfL were correlated with the atrophy of brain regions vulnerable to MSA (e.g., cerebellum, pons, or putamen). They could also aggravate the severity of MSA, and this association was partially mediated by cerebral volumes. In contrast, no obvious associations of phosphorylated tau and Aβ with disease severity were observed. Collectively, plasma biomarkers, especially in combination, are useful to facilitate the discriminatory work-up of MSA at early stages. Moreover, NfL and GFAP may be promising biomarkers to monitor the disease severity of MSA., (© 2023. The Author(s).)

The critical dipole moment to bind an electron was empirically determined to be 2.5 debye, even though smaller values were predicted theoretically. Herein, we report the first observation of a polarization-assisted dipole-bound state (DBS) for a molecule with a dipole moment below 2.5 debye. Photoelectron and photodetachment spectroscopies are conducted for cryogenically cooled indolide anions, where the neutral indolyl radical has a dipole moment of 2.4 debye. The photodetachment experiment reveals a DBS only 6 cm -1 below the detachment threshold along with sharp vibrational Feshbach resonances. Rotational profiles are observed for all of the Feshbach resonances, which are found to have surprisingly narrow linewidths and long autodetachment lifetimes attributed to weak coupling between vibrational motions and the nearly free dipole-bound electron. Calculations suggest that the observed DBS has π-symmetry stabilized by the strong anisotropic polarizability of indolyl.

Objective: To translate the English version Child Food Neophobia Scale (CFNS) into the Chinese version and test its reliability and validity in preschool children., Methods: To create the Chinese version of the CFNS, it was translated, back-translated, and cross-culturally adapted. The use of the Chinese version of CFNS by 575 parents of preschool children in two kindergartens in Yangzhou City was investigated using cluster sampling to assess the reliability and validity of the scale., Results: The Chinese version of CFNS has nine items in total. The scale-level average content validity index (S-CVI/Ave) is 0.983. Exploratory factor analysis (EFA) extracted 2 common factors, and the cumulative variance contribution rate was 49.437%. Confirmatory factor analysis (CFA) showed that the 2-factor model was well fitted. The Cronbach'α coefficient of the scale was 0.759, the Cronbach'α coefficients of the two factors were 0.735 and 0.713, the split-half reliability was 0.788, and the test-retest reliability was 0.756., Conclusion: The Chinese version of the Child Food Neophobia Scale has good reliability and validity in preschool children and can be used as an assessment tool for food neophobia in preschool children in China., Practice Implications: This study has gone through a rigorous translation process, and the CFNS may support future exploration of food neophobia in preschool children. Food allergy factors in the results may be the next step in the research, and several studies are still needed to understand the relationship between food allergy and food neophobia., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests in this section., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms., Methods: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures., Findings: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10 -07 ; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10 -05 ; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10 -13 ). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function., Interpretation: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study explored the feasibility of a coupled system for antibiotic removal and biofuel production through microalgae cultivation. Initial, batch culture experiments demonstrated that sulfadiazine (SDZ) had an inhibitory effect on Chlorella sp. G-9, and 100.0 mg L-1 SDZ completely inhibited its growth. In order to improve SDZ removal efficiency by microalgae, three membrane photobioreactors (MPBRs) with different hydraulic retention times (HRTs) were established for continuous microalgae cultivation. The efficient coupling of SDZ removal and microalgal lipid production was achieved through the gradual increment of influent SDZ concentration from 0 to 100.0 mg L-1. The reduction in SDZ ranged between 57.8 and 89.7%, 54.7-91.7%, and 54.6-93.5% for the MPBRs with HRT of 4 d, 2 d, and 1 d, respectively. Chlorella sp. Was found to tolerate higher concentrations of SDZ in the MPBR system, and the resulting stress from high concentrations of SDZ effectively increased the lipid content of microalgae for potential biodiesel production. With the increase of influent SDZ concentration from 0 to 100.0 mg L-1, the lipid content of microalgae increased by 43.5%. Chlorophyll content, superoxide dismutase activity, and malondialdehyde content of microalgae were also evaluated to explore the mechanism of microalgae tolerance to SDZ stress in MPBR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Neuroendocrine neoplasms of the gallbladder (GB-NENs) are a rare group of histologically heterogeneous tumors, and surgical resection of the primary tumor is the mainstream treatment at the moment. The current study aimed to establish and validate novel nomograms for patients with GB-NENs undergoing primary tumor resection to predict the 6-, 12-, and 18-month overall survival (OS) and cancer-specific survival (CSS)., Methods: Clinicopathological information of patients with GB-NENs undergoing primary tumor resection between 2004 and 2018 was derived from the Surveillance, Epidemiology, and End Results (SEER) database. Candidate prognostic factors were selected by Cox regression analyses, and the nomograms were constructed. Finally, concordance index (C-index), calibration plot, area under the curve from the receiver operating characteristic curve (AUC), and decision curve analysis (DCA) were utilized to assess the effective performance of the nomograms., Results: A total of 221 patients with GB-NENs undergoing resection were enrolled in this retrospective study. Using the Cox regression analyses, age, pathological classification, tumor size, and SEER stage were identified as the independent prognostic factors of patients with GB-NENs undergoing resection, and nomograms were constructed. The C-indexes of OS and CSS in training dataset were 0.802 (95% CI: 0.757-0.848) and 0.846 (95% CI: 0.798-0.895), while those of internal validation dataset were 0.862 (95% CI: 0.802-0.922) and 0.879 (95% CI: 0.824-0.934), respectively., Conclusions: Taken together, the nomograms are accurate enough to predict the prognostic factors of GB-NEN patients undergoing resection, allowing for treatment decision-making and clinical monitoring for future clinical work.

Background: Failures in drug trials strengthen the necessity to further determine the neuropathological events during the development of Alzheimer's disease (AD). We sought to investigate the dynamic changes and performance of plasma biomarkers across the entire Alzheimer's continuum in the Chinese population., Methods: Plasma amyloid-β (Αβ)42, Aβ40, Aβ42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured utilizing the ultrasensitive single-molecule array technology across the AD continuum (n=206), wherein Aβ status was defined by the values of cerebrospinal fluid (CSF) Aβ42 or Aβ positron emission tomography (PET). Their trajectories were compared with those of putative CSF biomarkers., Results: Plasma GFAP and p-tau181 increased only in Aβ-positive individuals throughout aging, whereas NfL increased with aging regardless of Aβ status. Among the plasma biomarkers studied, GFAP was the one that changed first. It had a prominent elevation early in the cognitively unimpaired (CU) A+T- phase (CU A+T- phase: 97.10±41.29 pg/ml; CU A-T- phase: 49.18±14.39 pg/ml; p<0.001). From preclinical to symptomatic stages of AD, plasma GFAP started to rise sharply as soon as CSF Aβ became abnormal and continued to increase until reaching its highest level during the AD dementia phase. The greatest slope of change was seen in plasma GFAP. This is followed by CSF p-tau181 and total-tau, and, to a lesser extent, then plasma p-tau181. In contrast, the changes in plasma NfL, Aβ42/Aβ40, Aβ42, and Aβ40 were less pronounced. Of note, these plasma biomarkers exhibited smaller dynamic ranges than their CSF counterparts, except for GFAP which was the opposite. Plasma GFAP and p-tau181 were tightly associated with AD pathologies and amyloid tracer uptake in widespread brain areas. Plasma GFAP could accurately identify CSF Aβ42 (area under the curve (AUC)=0.911) and Aβ PET (AUC=0.971) positivity. Plasma p-tau181 also performed well in discriminating Aβ PET status (AUC=0.916), whereas the discriminative accuracy was relatively low for other plasma biomarkers., Conclusions: This study is the first to delineate the trajectories of plasma biomarkers throughout the Alzheimer's continuum in the Chinese population, providing important implications for future trials targeting plasma GFAP to facilitate AD prevention and treatment., (© 2023. The Author(s).)

Purpose: The aim of this study was to investigate the diagnostic efficacy of Acoustic Radiation Force Impulse (ARFI) for benign and malignant thyroid nodules in the presence and absence of non-papillary thyroid cancer (NPTC) and to determine the cut-off values of Shear Wave Velocity (SWV) for the highest diagnostic efficacy of Virtual Touch Quantification (VTQ) and Virtual Touch Tissue Imaging and Quantification (VTIQ)., Methods: The diagnostic accuracy of ARFI for benign and malignant thyroid nodules was assessed by pooling sensitivity, specificity and area under the curve (AUC) in each group in the presence and absence of both non-papillary thyroid glands, using histology and cytology as the gold standard. All included studies were divided into two groups according to VTQ and VTIQ, and each group was ranked according to the magnitude of the SWV cutoff value to determine the SWV cutoff interval with the highest diagnostic efficacy for VTQ and VTIQ., Results: A total of 57 studies were collected on the evaluation of ARFI for the diagnosis of benign and malignant thyroid nodules. The results showed that the presence of non-papillary thyroid carcinoma led to differences in the specificity of VTIQ for the identification of benign and malignant thyroid nodules, and the differences were statistically significant. In addition, the diagnostic efficacy of VTQ was best when the cutoff value of SWV was in the interval of 2.48-2.55 m/s, and the diagnostic efficacy of VTIQ was best when the cutoff value of SWV was in the interval of 3.01-3.15 m/s., Conclusion: VTQ and VTIQ have a high diagnostic value for benign and malignant thyroid nodules; however, when the malignant nodules in the study contain non-papillary thyroid carcinoma occupying the thyroid gland, the findings should be viewed in a comprehensive manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Zhang, Ren, Li, Zhu, Du, Ge, Chen and Cui.)

Background: Alzheimer's disease (AD) patients rank among the highest levels of comorbidities compared to persons with other diseases. However, it is unclear whether the conditions are caused by shared pathophysiology due to the genetic pleiotropy for AD risk genes., Objective: To figure out the genetic pleiotropy for AD risk genes in a wide range of diseases., Methods: We estimated the polygenic risk score (PRS) for AD and tested the association between PRS and 16 ICD10 main chapters, 136 ICD10 level-1 chapters, and 377 diseases with cases more than 1,000 in 312,305 individuals without AD diagnosis from the UK Biobank., Results: After correction for multiple testing, AD PRS was associated with two main ICD10 chapters: Chapter IV (endocrine, nutritional and metabolic diseases) and Chapter VII (eye and adnexa disorders). When narrowing the definition of the phenotypes, positive associations were observed between AD PRS and other types of dementia (OR = 1.39, 95% CI [1.34, 1.45], p = 1.96E-59) and other degenerative diseases of the nervous system (OR = 1.18, 95% CI [1.13, 1.24], p = 7.74E-10). In contrast, we detected negative associations between AD PRS and diabetes mellitus, obesity, chronic bronchitis, other retinal disorders, pancreas diseases, and cholecystitis without cholelithiasis (ORs range from 0.94 to 0.97, FDR < 0.05)., Conclusion: Our study confirms several associations reported previously and finds some novel results, which extends the knowledge of genetic pleiotropy for AD in a range of diseases. Further mechanistic studies are necessary to illustrate the molecular mechanisms behind these associations.

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.

Competing Interests: J-TY is the principal investigator for the China Healthy Aging and Dementia (HEAD) study (funded by Science and Technology Innovation 2030 Major Projects, 2022ZD0211600). All other authors declare no competing interests.

The identification of new psychoactive substances (NPS) is an active and cutting-edge topic in forensic science. With the emergence of a large number of NPS, their timely identification to prevent spread can pose a challenge to clinical and forensic toxicology laboratories. Three emerging NPS had been identified in recently seized materials, including two synthetic cannabinoids [N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobutyl)-1H-indazole-3-carboxamide (4F-AB-BUTINACA) and N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-phenethyl-1H-indazole-3-carboxamide (AB-PHETINACA)] and a ketamine-like substance [2-(2-fluorophenyl)-2-(ethylamino) cyclohexan-1-one(2F-NENDCK)]. The three compounds were first identified by Fourier transform infrared spectrometry (FT-IR), gas chromatography-mass spectrometry (GC-MS), ultrahigh-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UHPLC-QTOF-MS), and nuclear magnetic resonance (NMR). These data may assist forensic analysts in analyzing the same substances or their homologous compounds., (© 2022 John Wiley & Sons Ltd.)

In this study, a novel method of coupling phytohormones with saline wastewater was proposed to drive efficient microalgal lipid production. All the six phytohormones effectively promoted microalgae growth in saline wastewater, and further increased the microalgal lipid content based on salt stress, so as to achieve a large increase in microalgal lipid productivity. Among the phytohormones used, abscisic acid had the most significant promoting effect. Under the synergistic effect of 20 g/L salt and 20 mg/L abscisic acid, the microalgal lipid productivity reached 3.7 times that of the control. Transcriptome analysis showed that differentially expressed genes (DEGs) of microalgae in saline wastewater were mainly up-regulated under the effects of phytohormones except brassinolide. Common DEGs analysis showed that phytohormones all regulated the expression of genes related to DNA repair and substance synthesis. In conclusion, synergistic effect of salt stress and phytohormones can greatly improve the microalgal lipid production efficiency., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The strongest risk factor of neurodegenerative diseases (NDDs) is aging. Spontaneous asparaginyl deamidation leading to formation of isoaspartate (isoAsp) has been correlated with protein aggregation in NDDs., Methods: Two cohorts consisting of 140 subjects were studied. Cohort 1 contained patients with AD and healthy controls, while Cohort 2 recruited subjects with mild cognitive impairment (MCI), vascular dementia (VaD), frontotemporal dementia (FTD), Parkinson's disease (PD) and healthy controls. The levels of isoAsp in plasma human albumin (HSA), the most abundant protein in plasma, as well as the levels of immunoglobulin G (IgG) specific against deamidated HSA were measured. Apart from the memory tests, plasma biomarkers for NDDs reported in literature were also quantified, including amyloid beta (Aβ) peptides Aβ40 and Aβ42, neurofilament light protein (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated tau 181 (p-tau181) protein., Results: Deamidation products of blood albumin were significantly elevated in vascular dementia and frontotemporal dementia (P < 0.05), but less so in PD. Intriguingly, the deamidation levels were significantly (P < 0.01) associated with the memory test scores for all tested subjects. Deamidation biomarkers performed superiorly (accuracy up to 92%) compared with blood biomarkers Aß42/Aß40, NfL, GFAP and p-tau181 in separating mild cognitive impairment from healthy controls., Conclusion: We demonstrated the diagnostic capacity of deamidation-related biomarkers in predicting NDDs at the early stage of disease, and the biomarker levels significantly correlated with cognitive decline, strongly supporting the role of deamidation in triggering neurodegeneration and early stages of disease development. Prospective longitudinal studies with a longer observation period and larger cohorts should provide a more detailed picture of the deamidation role in NDD progression., (© 2022. The Author(s).)

The COP9 signalosome (CSN) is a highly conserved protein complex in eukaryotes, affecting various development and signaling processes. To date, the biological functions of the COP9 signalosome and its subunits have not been determined in Magnaporthe oryzae. In this study, we characterized the CSN in M. oryzae (which we named MoCsn6) and analyzed its biological functions. MoCsn6 is involved in fungal development, autophagy, and plant pathogenicity. Compared with the wild-type strain 70-15, Δ Mocsn6 mutants showed a significantly reduced growth rate, sporulation rate, and germ tube germination rate. Pathogenicity assays showed that the Δ Mocsn6 mutants did not cause or significantly reduced the number of disease spots on isolated barley leaves. After the MoCSN6 gene was complemented into the Δ Mocsn6 mutant, vegetative growth, sporulation, and pathogenicity were restored. The Osm1 and Pmk1 phosphorylation pathways were also disrupted in the Δ Mocsn6 mutants. Furthermore, we found that MoCsn6 participates in the autophagy pathway by interacting with the autophagy core protein MoAtg6 and regulating its ubiquitination level. Deletion of MoCSN6 resulted in rapid lipidation of MoAtg8 and degradation of the autophagic marker protein green fluorescent protein-tagged MoAtg8 under nutrient and starvation conditions, suggesting that MoCsn6 negatively regulates autophagic activity. Taken together, our results demonstrate that MoCsn6 plays a crucial role in regulating fungal development, pathogenicity, and autophagy in M. oryzae. IMPORTANCE Magnaporthe oryzae, a filamentous fungus, is the cause of many cereal diseases. Autophagy is involved in fungal development and pathogenicity. The COP9 signalosome (CSN) has been extensively studied in ubiquitin pathways, but its regulation of autophagy has rarely been reported in plant-pathogenic fungi. Investigations on the relationship between CSN and autophagy will deepen our understanding of the pathogenic mechanism of M. oryzae and provide new insights into the development of new drug targets to control fungal diseases. In this study, the important function of Csn6 in the autophagy regulation pathway and its impact on the pathogenicity of M. oryzae were determined. We showed that Csn6 manages autophagy by interacting with the autophagy core protein Atg6 and regulating its ubiquitination level. Furthermore, future investigations that explore the function of CSN will deepen our understanding of autophagy mechanisms in rice blast fungus.

The 2-furanyloxy radical is an important chemical reaction intermediate in the combustion of biofuels and aromatic compounds. We report an investigation of its electronic and vibrational structures using photoelectron and photodetachment spectroscopy and resonant photoelectron imaging (PEI) of cryogenically cooled 2-furanyloxide anion. The electron affinity of 2-furanyloxy is measured to be 1.7573(8) eV. Two excited electronic states are observed at excitation energies of 2.14 and 2.82 eV above the ground state. Photodetachment spectroscopy reveals a dipole-bound state 0.0143 eV below the detachment threshold and 25 vibrational Feshbach resonances for the 2-furanyloxide anion. The combination of photodetachment spectroscopy and resonant PEI yields frequencies for 18 out of a total of 21 vibrational modes for the 2-furanyloxy radical, including all six of its bending modes. The rich electronic and vibrational information will be valuable for further understanding the role of 2-furanyloxy as a key reaction intermediate of combustion and atmospheric interests.

Circadian rhythm disruption (CRD) is a shared characteristic of various brain disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and major depression disorder (MDD). Disruption of circadian rhythm might be a risk factor for brain disorder incidents. From 7-day accelerometry data of 72,242 participants in UK Biobank, we derived a circadian relative amplitude variable, which to some extent reflected the degree of circadian rhythm disruption. Records of brain disorder incidents were obtained from a wide range of health outcomes across self-report, primary care, hospital inpatient data, and death data. Using multivariate Cox proportional hazard ratio regression, we created two models adjusting for different covariates. Then, linear correlations between relative amplitude and several brain morphometric measures were examined in participants with brain MRI data. After a median follow-up of around 6.1 years, 72,242 participants were included in the current study (female 54.9%; mean age 62.1 years). Individuals with reduced relative amplitude had increasing risk of all-cause dementia (Hazard ratio 1.23 [95% CI 1.15 to 1.31]), PD (1.33 [1.25 to 1.41]), stroke (1.13 [1.06 to 1.22]), MDD (1.18 [1.13 to 1.23]), and anxiety disorder (1.14 [1.09 to 1.20]) in fully adjusted models. Additionally, significant correlations were found between several cortical regions and white matter tracts and relative amplitude that have been linked to dementia and psychiatric disorders. We confirm CRD to be a risk factor for various brain disorders. Interventions for regulating circadian rhythm may have clinical relevance to reducing the risk of various brain disorders., (© 2022. The Author(s).)

Based on risk profiles, several approaches for predicting dementia risk have been developed. Predicting the risk of dementia with accuracy is a significant clinical challenge. The goal was to create a modified dementia risk score (MDRS) based on a big sample size. A total of 239,745 participants from UK Biobank were studied (mean follow-up of 8.7 years). The score value of each risk factor was estimated according to the β coefficient in the logistic regression model. The total dementia risk score was the sum of each risk score. Kaplan Meier survival curves and Cox proportional hazards analyses were used to assess the associations between total score and dementia. Among all participants included, 3531 incident cases of all-cause dementia (ACD), 1729 cases of Alzheimer's disease (AD), and 925 cases of vascular dementia (VD) were identified. Several vascular risk factors (physical activity, current smoking status, and glycemic status) and depressive symptoms were found to be significantly related to dementia risk. The modified dementia risk scores predicted dementia well (model 1, area under curve 0.810; model 2, area under curve 0.832). In model 1, the cut-off value for high risk (HR) was 81 or higher, and in model 2 (including the APOE4), it was 98 or higher. According to Kaplan-Meier survival analyses, patients in the HR group had faster clinical progression (p < 0.0001) in either model 1 or 2. Cox regression analyses for HR versus low risk (LR) revealed that the Hazard radio for ACD was 7.541 (6.941 to 8.193) in model 1 and 8.348 (7.727 to 9.019) in model 2. MDRS is appropriate for dementia primary prevention, and may help quickly identify individuals with elevated risk of dementia., (© 2022. The Author(s).)

Objective: To provide information reference for resource allocation and decision-making in related fields, the cost-effectiveness of HIV input among men who have sex with men (MSM) in Ningbo. Different intervention coverages were compared. Methods: Taking MSM as the target population, data were collected and modeled by Optima HIV for the corresponding HIV health output and the budget under different intervention coverages. Results: According to the estimated size of the MSM population, which was 19 584 in Ningbo in 2020, if the coverage of 2020 baseline intervention is maintained in the next ten years, the number of HIV cases, new HIV infections, and HIV-related deaths among this population will show an upward trend. It is estimated that from 2021 to 2030, 7.9% of new infections and 1.7% of deaths can be avoided and the relevant funding investment comed to 2.4 time the baseline if the intervention coverage rate expanded to 3.0 times the 2020 baseline. After the coverage rate of intervention expanded to 3 times the baseline, it continued to grow, the health effect did not increase. Conclusions: At present, expanding the baseline coverage of HIV-related intervention projects among MSM in Ningbo and increasing capital investment will still reverse HIV-related death and reduce new infections. Moreover, there is a saturation point of the intervention effect. Researchers and policymakers must explore more effective interventions/combinations to obtain more significant health outcomes.

Multimorbidity (the presence of two or more long-term conditions [LTCs]) was suggested to exacerbate the neuronal injuries. The impact of multimorbidity on dementia has not been fully elucidated. We aimed to investigate the association between multimorbidity and dementia risk. We used the prospective data from 245,483 UK Biobank participants during a 9-year follow-up. Multimorbidity status was evaluated based on the LTC counts and multimorbidity patterns. Cox regression models adjusted for potential confounders were used to examine the associations of multimorbidity status with all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Participants with multimorbidity at baseline had higher risks of ACD and VD, and the risks were elevated with the increase of LTC counts (ACD: hazard ratios [HR] = 1.15, 95% confidence intervals [CI] = 1.01-1.31 with 2 LTCs; HR = 1.18, CI = 1.01-1.39 with 3 LTCs; HR = 1.65, CI = 1.44-1.88 with ≥4 LTCs; VD: HR = 1. 66, CI = 1.24-2.21 with 2 LTCs; HR = 2.10, CI = 1.53-2.88 with 3 LTCs; HR = 3.17, CI = 2.43-4.13 with ≥4 LTCs). Participants with ≥4 LTCs also had a higher risk of AD (HR = 1.34, CI = 1.08-1.66]. Participants with the cardio-cerebrovascular/respiratory/metabolic/musculoskeletal/depressive multimorbidity were 1.46, 1.28, and 2.50 times more likely to develop ACD (HR = 1.46, 95% CI = 1.28-1.67), AD (HR = 1.28, CI = 1.04-1.58), and VD (HR = 2.50, CI = 1.90-3.27), respectively. Those with tumor/genitourinary/digestive disorders had a 11% higher hazard of ACD (HR = 1.11, CI = 1.00-1.24) and a 73% elevated risk of VD (HR = 1.73, CI = 1.37-2.18). The prevention of LTC accumulation and the identification of specific multimorbidity patterns might be beneficial to the prevention of dementia and its subtypes, AD as well as VD., (© 2022. The Author(s).)

The related genetic variants of tau deposition, a seminal pathological hallmark of Alzheimer's disease, remain poorly understood. We sought to perform a genome-wide association study of brain tau load as measured by AV1451 positron emission tomography (PET). Among 543 non-demented European individuals, novel associations with higher tau were identified for rs56298435 (p = 8.35 × 10 -10 , β=0.31) within ZBTB20, and for rs150532 (p = 1.90 × 10 -8 , β=0.26) in the protein phosphorylation regulatory gene EYA4. The APOE association additionally reached genome-wide significant when APOE ε4 was not adjusted. Minor allele carriers of rs56298435 or rs150532 showed higher levels of tau PET load. As expected, phosphorylated-tau analyses in both plasma and cerebrospinal fluid also revealed the same direction of effect. Functionally, the effects of novel loci on cognitive decline could be mediated by tau pathology. In addition, we observed that the expression of VNN2 as regulated by rs150532, together with EYA4, displayed significant correlations with the tau-related gene MAPT in numerous brain regions. Our novel finding lends additional credence to heritable underpinnings of tau deposition., (Copyright © 2022. Published by Elsevier Inc.)

Wheat powdery mildew caused by Blumeria graminis f. sp. tritici ( Bgt ) is one of the most serious wheat diseases in the world. Biological control is considered an environmentally safe approach to control plant diseases. Here, to develop effective biocontrol agents for controlling wheat powdery mildew, antagonistic strain XZ16-1 was isolated and identified as Bacillus subtilis based on the morphological, biochemical, and physiological characteristics and 16S rDNA sequence. The culture filtrate of B. subtilis XZ16-1 and its extracts had a significant inhibitory effect on the spore germination of Bgt . Moreover, the therapeutic and prevention efficacy of the 100% culture filtrate on wheat powdery mildew reached 81.18 and 83.72%, respectively, which was better than that of chemical fungicide triadimefon. Further antimicrobial mechanism analysis showed that the XZ16-1 culture filtrate could inhibit the development of powdery mildew spores by disrupting the cell membrane integrity, causing reductions in the mitochondrial membrane potential, and inducing the accumulation of reactive oxygen species in the spores. Biochemical detection indicated that XZ16-1 could solubilize phosphate, fix nitrogen, and produce hydrolases, lipopeptides, siderophores, and indole-3-acetic acid. Defense-related enzymes activated in wheat seedlings treated with the culture filtrate indicated that disease resistance was induced in wheat to resist pathogens. Furthermore, a 10 6 CFU/ml suspension of XZ16-1 increased the height, root length, fresh weight, and dry weight of wheat seedlings by 77.13, 63.46, 76.73, and 19.16%, respectively, and showed good growth-promotion properties. This study investigates the antagonistic activity and reveals the action mechanism of XZ16-1, which can provide an effective microbial agent for controlling wheat powdery mildew.

Multiple emission metal-organic frameworks (MOFs) are superior materials for ratiometric fluorescence sensing and visible detection applications. The guest-encapsulation strategy is a simple method for the integration of the open structure of MOFs and the abundant choice of emissive guests. Herein, we reveal the factors that affect the performance of host-guest multi-emission MOFs based on the choice of ligands, metal nodes, and guest dyes. The size of organic dyes is often larger than 1 nm, which is incompatible with the small pores of traditional MOFs. Therefore, we selected a flexible ligand, i.e. , 1,3,5-tris(5-methoxy-1,3-benzene dicarboxylic acid)benzene (L), to enlarge the pore size of the MOF to 18 Å. Energy transfer may occur from the ligand and guest dye to the metal nodes; thus, we selected the Gd 3+ ion because of its high excited state level. L and Gd 3+ ions were used to form the Gd-L MOF with the pore size of 18 Å, as revealed by the single crystal result. Rhodamine B (RhB), as the guest dye with the size of 15.9 × 11.8 × 5.6 Å 3 , was encapsulated in Gd-L MOF, which was denoted as RhB@MOF. The matched size between RhB and the MOF pore and the breathing effect of the flexible MOF effectively prevented the leakage of RhB. Accordingly, dual emission was observed at 360 nm and 583 nm under the excitation of 290 nm from RhB@MOF. Alternatively, Cu 2+ quenched the emission at 360 nm due to the electron transfer process, while Fe 3+ interacted with both L and RhB, and thus quenched the two emissions simultaneously. However, other metal ions showed little effect on the two emissions. Consequently, the differentiation between Cu 2+ and Fe 3+ as well as them from other metal ions was realized with the dual-emission MOF. Thus, the guest-encapsulation strategy is simple and flexible ligands are efficient to encapsulate molecular dyes for dual-emission MOFs to improve their sensing performance, while flexible ligands are powerful to enhance the capacity and extend the applications of MOFs.

The never in mitosis gene A (NIMA)-related kinase 2 (NEK2) protein has been reported to be an oncoprotein that plays different oncogenic roles in multiple cancers. Here, we confirmed that NEK2 highly expressed in cervical cancer cells rather than in normal epithelial basal layer cells in cervical tissues and correlated with worse outcomes. We also demonstrated that NEK2 promoted the in vivo growth of subcutaneous xenograft tumors stemming from cervical cancer cells and the in vitro cell proliferation by decreasing Ser127-phosphorylation of the YAP protein retained in the cytoplasm while increasing the levels of active nucleus-associated YAP protein, which was followed by increases in the targeted proteins CTGF, CYR61 and GLI2. Furthermore, the Hippo signaling pathway was inactivated in manipulated NEK2-overexpressing cervical cancer cells by regulating the levels of MST1/2 dephosphorylation. Additionally, mass spectrometric sequencing and bilateral coimmunoprecipitation were employed suggested that NEK2 acted at an early upstream step to promote dephosphorylation of MST2 and inactivate the Hippo signaling cascade by cooperating with STRIPAK complexes. We conjecture that NEK2 may be a future target for cervical cancer therapy., Competing Interests: Declaration of competing interest All authors declare they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Peptidyl arginine deiminase 1 (PADI1) catalyzes protein citrullination and has a role in regulating immune responses. The tumor immune microenvironment has been reported to be important in colorectal cancer (CRC), which was correlated with the ability of CRC patients to benefit from immunotherapy. However, there is a lack of molecular markers for matching CRC immunotherapy. Previously, single-gene risk models have only considered the effect of individual genes on intrinsic tumor properties, ignoring the role of genes and their co-expressed genes as a whole. In this study, we analyzed the differential expression of PADI1 in colorectal cancer (CRC). We found that PADI1 was highly expressed in CRC. Subgroup survival analysis revealed a prognostic survival difference for PADI1 in CRC patients aged less than 65 years, male, T stage, N0, M0, and stage I-II ( p < 0.05). In addition, we analyzed the functions and signaling pathways associated with PADI1 in CRC and found that it was highly enriched in several immune-related functions and pathways. Then, a set of PADI1 co-expressed genes (PCGs) risk-prognosis scores was developed with PADI1 as the core, which could accurately predict the prognosis of CRC ( p < 0.05). PCGs risk score can be an independent prognostic factor for CRC. A new set of Norman plot models were developed for clinical characteristics with age, sex, and TNM stage, which can accurately predict CRC 1, 3, and 5 years survival, and calibration curves and decision curve analysis (DCA) validated the accuracy of the models. The risk score assessed the immune microenvironment of CRC and found that the immune score was higher in the low-risk group, and CD4+ T cells, helper T cells, and eosinophils were more infiltrated in the low-risk group ( p < 0.05). Immunotherapy efficacy was better in the low-risk group ( p < 0.05). The underlying mechanism may be that the high-risk group of PCGs was enriched in some pathways that promote immune escape and immune dysfunction. In conclusion, PCGs may better predict CRC prognosis and immunotherapeutic response., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yi-ran Zhang et al.)

Objective: To analyze the Prolyl 4-Hydroxylase subunit Alpha-2 (P4HA2) expression in Lung Adenocarcinoma (LAUD)., Methods: The authors assessed P4HA2 expression in the LUAD tumor ecosystem using single-cell analysis. The authors analyzed the relationship between P4HA2 expression and clinical features in LUAD and Brain Metastasis (BM) cases. The authors assessed the biological functions of P4HA2 using The Cancer Genome Atlas-LUAD dataset., Results: P4HA2 was more highly expressed in fibroblasts than in epithelial cells in normal lung and lung adenocarcinoma tissues (p < 0.001). P4HA2 was more highly expressed in malignant epithelial cells than in fibroblasts in the BM tissue (p = 0.002). P4HA2 expression was significantly higher in female cases than in male cases (p = 0.049) and was related to lymph node metastasis (p = 0.019) and a higher TNM stage (p = 0.020). High P4HA2 expression indicated a poor prognosis and served as an independent prognostic risk factor in lung cancer. P4HA2 was mainly enriched in the extracellular matrix organization, NADH regeneration, and canonical glycolysis. P4HA2 expression was negatively correlated with naive B cells, T-cells, CD8, and activated natural killer cells, but positively correlated with CD4 memory-activated T cells, regulatory T-cells, resting dendritic cells, and dendritic cell activation. P4HA2 messenger RNA expression was correlated with programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein 4., Conclusion: P4HA2 is highly expressed in LUAD tumor cells, especially for the BM subtype, and is a valuable prognostic indicator of LUAD. It may be involved in a biological activity of distant metastasis of LUAD tumor cells and serve as a potential treatment target., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population with unclear pathogenic mechanism. Herein, we detect downregulated circSPECC1 expression in retinal pigment epithelium (RPE) of AMD patients. In RPE cells, circSPECC1 insufficiency leads to oxidative stress-induced ferroptosis, depolarization, and irregular lipid metabolism. Consistently, in mice, circSPECC1 deficiency induces visual impairments and RPE anomalies and interrupts retinal homeostasis. Mechanically, nuclear export of circSPECC1 transcript depends on its N 6 -methyladenosine (m 6 A) level with YTHDC1 as the reader. CircSPECC1 directly sponges miR-145-5p to block its interaction with CDKN1A. Overexpressing miR-145-5p aggravates RPE dysfunctions, mimicking circSPECC1 silencing effects. Retinal phenotypes induced by circSPECC1 insufficiency are alleviated by miR-145-5p inhibition and are aggravated by miR-145-5p overexpression. Collectively, circSPECC1, mediated by m 6 A modification and sponging miR-145-5p, resists oxidative stress injuries and maintains lipid metabolism in RPE. Pharmacological supplementation of circSPECC1 is a promising therapeutic option for atrophic retinopathies like AMD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the current evidence of pregnancy outcomes among couples with recurrent pregnancy loss (RPL) with abnormal karyotypes vs. those with normal karyotypes and among couples with RPL and abnormal karyotypes after receiving expectant management vs. preimplantation genetic diagnosis (PGD)., Design: Systematic review and meta-analysis., Setting: Academic medical centers., Patient(s): Pregnancy outcomes in 6,301 couples with RPL who conceived without medical intervention in 11 studies were analyzed. However, only 2 studies addressed the outcomes of couples with RPL and abnormal karyotypes after expectant management (75 cases) vs. PGD (50 cases)., Intervention(s): None., Main Outcome Measure(s): The pregnancy outcomes in couples with RPL with abnormal and normal karyotypes across included studies were evaluated., Result(s): Compared with those with a normal karyotype, a significantly lower first pregnancy live birth rate (LBR) was found in couples with RPL with abnormal karyotypes (58.5% vs. 71.9%; odds ratio [OR], 0.55; 95% confidence interval [CI], 0.46-0.65; I 2 =27%). A markedly decreased first pregnancy LBR was found in couples with a translocation (52.9% vs. 72.4%; OR, 0.44; 95% CI, 0.31-0.61; I 2 =33%) but not in couples with an inversion. However, the differences in accumulated LBR (81.4% vs. 74.8%; OR, 0.96; 95% CI, 0.90-1.03; I 2 = 0) were nonsignificant, whereas the miscarriage rate was distinctly higher in couples with RPL and abnormal karyotypes (53.0% vs. 34.7%; OR, 2.21; 95% CI, 1.69-2.89; I 2 = 0). Compared with those who chose expectant management, differences in accumulated LBR were nonsignificant (60% vs. 68%; OR, 0.55; 95% CI, 0.11-2.62; I 2 =71%), whereas the miscarriage rate (24% vs. 65.3%; OR, 0.15; 95% CI, 0.04-0.51; I 2 = 45) was markedly low in couples with RPL and abnormal karyotypes who chose PGD., Conclusion(s): Couples with RPL and abnormal karyotypes had a higher miscarriage rate than couples with normal karyotypes but achieved a noninferior accumulated LBR through multiple conception attempts. In couples with RPL and abnormal karyotypes, PGD treatment did not increase the accumulated LBR but markedly reduced miscarriage rate compared with expectant management., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to evaluate recombinant human endostatin (rHE)-induced normalization of the tumor vasculature in colorectal cancer (CRC) and to evaluate the therapeutic effects of combined treatment with rHE and a programmed death ligand-1 (PD-L1) inhibitor., Methods: A mouse subcutaneous tumorigenesis model was established to evaluate the antitumor effects of endostatin combined with a PD-L1 inhibitor on CRC. Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DW MRI) was used to evaluate changes in the intratumor microcirculation in response to combined treatment with endostatin and a PD-L1 inhibitor. The infiltration density and function of CD8+ T cells in tumors were evaluated using flow cytometry. Finally, clinical specimens were used to evaluate the expression area of tumor vascular pericytes and CD8+ T cells in tumor tissues., Results: The antitumor effects of endostatin combined with a PD-L1 inhibitor were significantly greater than those of endostatin or a PD-L1 inhibitor alone. On the ninth day of intervention, the endostatin group showed significantly higher pseudo diffusion parameter (D*) and microvascular volume fraction (F) values in tumors than those in the control group or PD-L1 group. After 27 days of intervention, the endostatin groups showed significantly lower levels of vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β than those in the control group. Treatment of CD8+ T cells with endostatin for 24 h did not alter the expression levels of markers of reduced T-cell activity. However, endostatin reversed the VEGF-mediated inhibition of the secretion of interferon (IFN)-γ from T cells. The results in CRC clinical samples showed that treatment with endostatin induced significantly higher infiltration of CD8+ T cells compared with treatment that did not include endostatin. Furthermore, the expression area of pericytes was significantly positively related to the infiltration density of CD8+ T cells and overall survival time., Conclusion: Endostatin improved the antitumor effects of PD-L1 inhibitors on CRC, significantly increased the activity of CD8+ T cells, and synergistically improved the tumor treatment effect of the two inhibitors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chu, Bao, Lin, Chen, Zhang, Huang, He, Huangfu, Pan and Ding.)

Objective: To explore the effectiveness of formative evaluation in the mentoring of student nursing interns in an emergency department., Methods: A total of 144 intern nursing students in the emergency department of a tertiary care hospital in Fuzhou were selected as the study subjects from July 2020 to February 2021. Adopting quasi-experimental studies methods, the students were divided into the experiment group ( n = 74) and the control group ( n = 70), based on their practicing rotation times. Formative evaluation methods such as in-person interviews, clinical scenario simulations, and clinical operation skills exams were conducted in the experiment group, while traditional summative evaluation methods were adopted for the control group. At the end of the intern period, a unified examination paper on professional knowledge concerning the emergency department, a cardiopulmonary resuscitation skill assessment, and a self-rating scale of self-directed learning was employed to evaluate professional theory performance, clinical practice ability, self-directed learning ability, and academic satisfaction among the nursing students, respectively., Results: The professional theoretical performance, clinical practice ability assessment scores, academic satisfaction, and self-directed learning abilities of the nursing students were significantly higher in the experiment group compared with the control group ( P < 0.05)., Conclusion: The application of formative evaluation during the mentoring of student intern nurses in an emergency department improved their professional theoretical performance, clinical practice skills, academic satisfaction, and self-directed learning abilities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Hu, Liang, Chen, Wei, Xing and Fang.)

Operator spreading, often characterized by out-of-time-order correlators (OTOCs), is one of the central concepts in quantum many-body physics. However, measuring OTOCs is experimentally challenging due to the requirement of reversing the time evolution of systems. Here we apply Floquet engineering to investigate operator spreading in a superconducting 10-qubit chain. Floquet engineering provides an effective way to tune the coupling strength between nearby qubits, which is used to demonstrate quantum walks with tunable couplings, reversed time evolution, and the measurement of OTOCs. A clear light-cone-like operator propagation is observed in the system with multiple excitations, and has a nearly equal velocity as the single-particle quantum walk. For the butterfly operator that is nonlocal (local) under the Jordan-Wigner transformation, the OTOCs show distinct behaviors with (without) a signature of information scrambling in the near integrable system.

Microvascular dysfunction (MVD) has long plagued the medical field despite improvements in its prevention, diagnosis, and intervention. Microvascular lesions from MVD increase with age and further lead to impaired microcirculation, target organ dysfunction, and a mass of microvascular complications, thus contributing to a heavy medical burden and rising disability rates. An up-to-date understanding of molecular mechanisms underlying MVD will facilitate discoveries of more effective therapeutic strategies. Recent advances in epigenetics have revealed that RNA methylation, an epigenetic modification, has a pivotal role in vascular events. The N 6 -methylation of adenosine (m 6 A) modification is the most prevalent internal RNA modification in eukaryotic cells, which regulates vascular transcripts through splicing, degradation, translation, as well as translocation, thus maintaining microvascular homeostasis. Conversely, the disruption of the m 6 A regulatory network will lead to MVD. Herein, we provide a review discussing how m 6 A methylation interacts with MVD. We also focus on alterations of the m 6 A regulatory network under pathological conditions. Finally, we highlight the value of m 6 A regulators as prognostic biomarkers and novel therapeutic targets, which might be a promising addition to clinical medicine.

Background: Upper gastrointestinal endoscopy is critical for esophageal squamous cell carcinoma (ESCC) detection; however, endoscopists require long-term training to avoid missing superficial lesions., Aim: To develop a deep learning computer-assisted diagnosis (CAD) system for endoscopic detection of superficial ESCC and investigate its application value., Methods: We configured the CAD system for white-light and narrow-band imaging modes based on the YOLO v5 algorithm. A total of 4447 images from 837 patients and 1695 images from 323 patients were included in the training and testing datasets, respectively. Two experts and two non-expert endoscopists reviewed the testing dataset independently and with computer assistance. The diagnostic performance was evaluated in terms of the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity., Results: The area under the receiver operating characteristics curve, accuracy, sensitivity, and specificity of the CAD system were 0.982 [95% confidence interval (CI): 0.969-0.994], 92.9% (95%CI: 89.5%-95.2%), 91.9% (95%CI: 87.4%-94.9%), and 94.7% (95%CI: 89.0%-97.6%), respectively. The accuracy of CAD was significantly higher than that of non-expert endoscopists (78.3%, P < 0.001 compared with CAD) and comparable to that of expert endoscopists (91.0%, P = 0.129 compared with CAD). After referring to the CAD results, the accuracy of the non-expert endoscopists significantly improved (88.2% vs 78.3%, P < 0.001). Lesions with Paris classification type 0-IIb were more likely to be inaccurately identified by the CAD system., Conclusion: The diagnostic performance of the CAD system is promising and may assist in improving detectability, particularly for inexperienced endoscopists., Competing Interests: Conflict-of-interest statement: Dr. Wang reports grants from The Science and Technology Commission of Shanghai Municipality during the conduct of the study. Other authors report no relevant conflicts of interest for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Resting heart rate (RHR) has been linked with an increased risk of dementia. However, evidence characterizing the associations of RHR with different dementia subtypes and their underlying mechanisms remains scarce. This study aims to investigate the relationships of RHR with different dementia types, cognitive function, and brain structural abnormalities., Methods: Three hundred thirty-nine thousand nine hundred one participants with no prior diagnosis of dementia from the UK biobank were analyzed. Cox regression and restricted cubic spline models examined the associations between RHR with all-cause dementia (ACD) and its major subtypes-Alzheimer's disease (AD) and vascular dementia (VaD). Logistic regression models assessed the associations of RHR with cognitive function, and linear regression models estimated the associations with hippocampal subfield volume and white matter tract integrity indexed by magnetic resonance imaging data., Results: During an average of 3148 (± 941.08) days of follow-up, 4177 individuals were diagnosed with dementia, including 2354 AD and 989 VaD cases. RHR ≥ 80bpm was associated with ACD (HR: 1.18, 95% CI: 1.08-1.28, P < 0.001) and VaD (HR: 1.29, 95% CI: 1.08-1.54, P = 0.005) but not AD in multi-adjusted models. A 10-bpm increment of RHR demonstrated non-linear effects in VaD, consisting of J-shape relationships. Several heterogeneities were indicated in stratified analysis, in which RHR measures only showed associations with dementia incidents in relatively younger populations (age ≤ 65) and females. Apart from dementia analysis, elevated RHR was associated with worsening performance in fluid intelligence and reaction time of cognitive tasks, decreased hippocampal subfields volume, and poor white matter tract integrity., Conclusions: RHR is associated with increased risks of ACD and VaD but also presented with few heterogeneities across different sex and age groups. Elevated RHR also appears to have deleterious effects on cognitive function and is distinctively associated with volume reduction in hippocampal subfields and impaired white matter tract integrity., (© 2022. The Author(s).)