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Background: Parkinson's disease (PD) is a prevalent disorder of the central nervous system, marked by the degeneration of dopamine (DA) neurons in the ventral midbrain. In the pathogenesis of PD, inflammation hypothesis has been concerned. This study aims to investigate clinical indicators of peripheral inflammation in PD patients and to explore the diagnostic value of neutrophil-to-lymphocyte ratio (NLR), albumin-to-fibrinogen ratio (AFR), and lymphocyte-to-monocyte ratio (LMR) in assessing PD risk., Methods: This study included 186 patients with PD and 201 matched healthy controls (HC) with baseline data. Firstly, the differences of hematological indicators between PD group and healthy participants were compared and analyzed. Univariate and multivariate regression analyses were then conducted. Smooth curve fitting was applied to further validate the relationships between NLR, LMR, AFR, and PD. Subsequently, subgroup analysis was conducted in PD group according to different duration of disease and Hoehn and Yahr (H&Y) stage, comparing differences in clinical indicators. Finally, the receiver operating characteristic (ROC) curve was employed to assess the diagnostic value of NLR, LMR, and AFR in PD., Results: Compared to the HC group, the PD group showed significantly higher levels of hypertension, diabetes, neutrophil count, monocyte count, CRP, homocysteine, fibrinogen, and NLR. Conversely, levels of LMR, AFR, lymphocyte count, HDL, LDL, TG, TC, uric acid, and albumin were significantly lower. The multivariate regression model indicated that NLR (OR = 1.79, 95% CI: 1.39-2.31, p  < 0.001), LMR (OR = 0.75, 95% CI: 0.66-0.85, p  < 0.001), and AFR (OR = 0.79, 95% CI: 0.73-0.85, p  < 0.001) were significant factors associated with PD. Smooth curve fitting revealed that NLR was positively linked to PD risk, whereas AFR and LMR were inversely associated with it. In ROC curve analysis, the AUC of AFR was 0.7290, the sensitivity was 63.98%, and the specificity was 76.00%. The AUC of NLR was 0.6200, the sensitivity was 50.54%, and the specificity was 71.50%. The AUC of LMR was 0.6253, the sensitivity was 48.39%, and the specificity was 73.00%. The AUC of the combination was 0.7498, the sensitivity was 74.19%, and the specificity was 64.00%., Conclusion: Our findings indicate that NLR, LMR, and AFR are significantly associated with Parkinson's disease and may serve as diagnostic markers., 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 © 2024 Li, Xu, Ren, Xu, Dai, Yang and Jin.)

Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers: reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.

Cluster headache (CH) is a common primary headache that severely impacts patients' quality of life, characterized by recurrent, severe, unilateral headaches often centered around the eyes, temples, or forehead. Distinguishing CH from other headache disorders is challenging, and its pathogenesis remains unclear. Notably, patients with CH often experience high levels of depression and suicidal tendencies, necessitating increased clinical attention. This comprehensive assessment combines various reports and the latest scientific literature to evaluate the current state of CH research. It covers epidemiology, population characteristics, predisposing factors, and treatment strategies. Additionally, we provide strategic insights into the holistic management of CH, which involves continuous, individualized care throughout the prevention, treatment, and rehabilitation stages. Recent advances in the field have revealed new insights into the pathophysiology of CH. While these findings are still evolving, they offer a more detailed understanding of the neurobiological mechanisms underlying this disorder. This growing body of knowledge, alongside ongoing research efforts, promises to lead to the development of more targeted and effective treatments in the future., 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 © 2024 Xu, Li, Ren, Xu, Dai, Jin and Yang.)

This study provided a systematic investigation of microplastics in Hong Kong's surface marine waters during the pandemic from 2019 to 2021. Microplastics (2.07 ± 4.00 particles/m 3 ) exhibited significant temporal variations with higher abundance in the wet season, without a consistent trend after the mandatory mask-wearing requirement was announced. The impact of pandemic restrictions on microplastic distribution was found to be relatively minor. However, significant correlations between microplastic abundances and rainfall highlighted the substantial contribution of local emissions through surface runoff. Notably, sites in closer proximity to the Pearl River Delta exhibited higher microplastic abundances, indicating their association with emission sources. The influence of rainfall and adverse weather on marine microplastic loads demonstrated different sensitivities among various locations but can generally last for one month. These results revealed the impact of seasonal rainfall on coastal microplastics and emphasized the need for efforts to reduce microplastic discharge from land-based sources., 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 © 2024 Elsevier Ltd. All rights reserved.)

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 μmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor., (© 2024. The Author(s).)

Key Message: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the effects of visualized precision electrophysiological diagnosis and transcutaneous low-frequency electrical stimulation (TES) on hypoxia-induced ED in high-altitude areas., Methods: This study included 152 ED patients from high-altitude hypoxic areas treated by TES based on the parameters obtained from visualized precision electrophysiological diagnosis. We followed up the patients for 1 to 3 months and compared their IIEF-5 scores, nocturnal penile tumescence and rigidity (NPTR) and infrared thermal metabolic technology (TMT)-based temperature of the whole body and diseased parts before and after treatment., Results: All the patients successfully completed 1 to 3 courses of TES. There were no statistically significant differences in the IIEF-5 scores (P<0.05) and penile tip optimal erection rigidity and duration (P<0.01) of the patients before and after treatment. TMT images indicated a temperature change of >1.5 ℃ in the penis and bilateral inguinal regions after treatment, suggesting the effectiveness of electrical stimulation. No recurrence was observed during the follow-up., Conclusion: TES based on the parameters obtained from visualized precision electrophysiological diagnosis has a definite effect on hypoxia-induced ED by enhancing oxygen supply to the penile corpus cavernosum and improving its function and structure.

Background: Studies on antiretroviral therapy (ART) in children living with HIV (CLHIV) are limited due to the small population and low accession rate of ART., Methods: All 0-14-year-old CLHIV admitted to the Ganzhou Center for Disease Control and Prevention from January 2006 to June 2023 were included retrospectively. The information of treatment regimens, disease progression, and laboratory tests of the patients under ART were used to explore the outcomes and impacts of long-term ART. The normality of all the data was tested by the Shapiro-Wilk test., Results: From 2006 to 2023, 18 CLHIV were reported in Ganzhou. Among them, 11 received ART and were followed up for 60.0 ± 48.4 months. After receiving ART, the median viral load of them decreased from 89,600 copies/ml to 22 copies/ml (P = 0.007), the median CD4 + T cell count increased from 380.7 cells/µL to 661.9 cells/µL (P = 0.028), and the median CD8 + T cell count decreased from 1065.8 cells/µL to 983.3 cells/µL (P = 0.584). The laboratory test results regarding liver function, renal function, blood cell count, and glucolipid metabolism tended to be within normal reference ranges, and the mean height-for-age z-score and weight-for-age z-score increased. However, all the three CLHIV who received cotrimoxazole developed pneumocystis carinii pneumonia, upper respiratory infection, skin lesions, bacterial pneumonia and/or thrush; the mean body-mass-index-for-age z-score decreased from 0.52 to -0.63., Conclusion: For CLHIV, ART could effectively inhibit the replication of HIV and improve the immune function of patients. More studies that focus on ART in CLHIV are urgently needed., (© 2024. The Author(s).)

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PP i ase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Olfactory systems in eusocial insects play a vital role in the discrimination of various chemical cues. Odorant receptors (ORs) are critical for odorant detection, and this family has undergone extensive expansion in ants. In this study, we re-annotated the OR genes from the most destructive invasive ant species Solenopsis invicta and 2 other Formicidae species, Ooceraea biroi and Monomorium pharaonis , with the aim of systematically comparing and analyzing the evolution and the functions of the ORs in ant species, identifying 356, 298, and 306 potential functional ORs , respectively. The evolutionary analysis of these ORs showed that ants had undergone chromosomal rearrangements and that tandem duplication may be the main contributor to the expansion of the OR gene family in S. invicta . Our further analysis revealed that 9-exon ORs had biased chromosome localization patterns in all three ant species and that a 9-exon OR cluster ( SinvOR4-8 ) in S. invicta was under strong positive selection (Ka/Ks = 1.32). Moreover, we identified 5 S. invicta OR genes, namely SinvOR89 , SinvOR102 , SinvOR352 , SinvOR327 , and SinvOR135 , with high sequence similarity (>70%) to the orthologs in O. biroi and M. pharaonis . An RT-PCR analysis was used to verify the antennal expression levels of these ORs , which showed caste-specific expression. The subsequent analysis of the antennal expression profiles of the ORs of the S. invicta workers from the polygyne and monogyne social forms indicated that SinvOR35 and SinvOR252 were expressed at much higher levels in the monogyne workers than in the polygyne workers and that SinvOR21 was expressed at higher levels in polygyne workers. Our study has contributed to the identification and analysis of the OR gene family in ants and expanded the understanding of the evolution and functions of the ORs in Formicidae species.

Background: COVID-19, the current global pandemic caused by SARS-CoV-2 infection, can damage the heart and lead to heart failure (HF) and even cardiac death. The 2',5'-oligoadenylate synthetase (OAS) gene family encode interferon (IFN)-induced antiviral proteins which is associated with the antiviral immune responses of COVID-19. While the potential association of OAS gene family with cardiac injury and failure in COVID-19 has not been determined., Methods: The expression levels and biological functions of OAS gene family in SARS-CoV-2 infected cardiomyocytes dataset (GSE150392) and HF dataset (GSE120852) were determined by comprehensive bioinformatic analysis and experimental validation. The associated microRNAs (miRNAs) were explored from Targetscan and GSE104150. The potential OAS gene family-regulatory chemicals or ingredients were predicted using Comparative Toxicogenomics Database (CTD) and SymMap database., Results: The OAS genes were highly expressed in both SARS-CoV-2 infected cardiomyocytes and failing hearts. The differentially expressed genes (DEGs) in the two datasets were enriched in both cardiovascular disease and COVID-19 related pathways. The miRNAs-target analysis indicated that 10 miRNAs could increase the expression of OAS genes. A variety of chemicals or ingredients were predicted regulating the expression of OAS gene family especially estradiol., Conclusion: OAS gene family is an important mediator of HF in COVID-19 and may serve as a potential therapeutic target for cardiac injury and HF in COVID-19., (© 2023. The Author(s).)

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL‑2‑dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Conclusions: Our analysis estimates BCD prevalence and revealed large differences among various populations. Moreover, it highlights advantages and limitations of the gnomAD database., Methods: CYP4V2 gnomAD data and reported mutations were used to calculate carrier frequency of each variant. An evolutionary-based sliding window analysis was used to detect conserved protein regions. Potential exonic splicing enhancers (ESEs) were identified using ESEfinder., Purpose: Bietti crystalline dystrophy (BCD) is a rare monogenic autosomal recessive (AR) chorioretinal degenerative disease caused by biallelic mutations in CYP4V2. The aim of the current study was to perform an in-depth calculation of worldwide carrier frequency and genetic prevalence of BCD using gnomAD data and comprehensive literature CYP4V2 analysis., Results: We identified 1171 CYP4V2 variants, 156 of which were considered pathogenic, including 108 reported in patients with BCD. Carrier frequency and genetic prevalence calculations confirmed that BCD is more common in the East Asian population, with ∼19 million healthy carriers and 52,000 individuals who carry biallelic CYP4V2 mutations and are expected to be affected. Additionally, we generated BCD prevalence estimates of other populations, including African, European, Finnish, Latino, and South Asian. Worldwide, the estimated overall carrier frequency of CYP4V2 mutation is 1:210, and therefore, ∼37 million individuals are expected to be healthy carriers of a CYP4V2 mutation. The estimated genetic prevalence of BCD is about 1:116,000, and we predict that ∼67,000 individuals are affected with BCD worldwide., Translational Relevance: This analysis is likely to have important implications for genetic counseling in each studied population and for developing clinical trials for potential BCD treatments.

300 million people live with at least one of 6,000 rare diseases worldwide. However, rare disease research is not always reviewed with scrutiny, making it susceptible to what the author refers to as nontransparent science. Nontransparent science can obscure animal model flaws, misguide medicine regulators and drug developers, delay or frustrate orphan drug development, or waste limited resources for rare disease research. Flawed animal models not only lack pharmacologic relevance, but also give rise to issue of clinical translatability. Sadly, these consequences and risks are grossly overlooked. Nontransparency in science can take many forms, such as premature publication of animal models without clinically significant data, not providing corrections when flaws to the model are discovered, lack of warning of critical study limitations, missing critical control data, questionable data quality, surprising results without a sound explanation, failure to rule out potential factors which may affect study conclusions, lack of sufficient detail for others to replicate the study, dubious authorship and study accountability. Science has no boarders, neither does nontransparent science. Nontransparent science can happen irrespective of the researcher's senority, institutional affiliation or country. As a patient-turned researcher suffering from Bietti crystalline dystrophy (BCD), I use BCD as an example to analyze various forms of nontransparent science in rare disease research. This article analyzes three papers published by different research groups on Cyp4v3 -/- , high-fat diet (HFD)-Cyp4v3 -/- , and Exon1-Cyp4v3 -/- mouse models of BCD. As the discussion probes various forms of nontransparent science, the flaws of these knockout mouse models are uncovered. These mouse models do not mimic BCD in humans nor do they address the lack of Cyp4v3 (murine ortholog of human CYP4V2) expression in wild type (WT) mouse retina which is markedly different from CYP4V2 expression in human retina. Further, this article discusses the impact of nontransparent science on drug development which can lead to significant delays ultimately affecting the patients. Lessons from BCD research can be helpful to all those suffering from rare diseases. As a patient, I call for transparent science in rare disease research., (© 2023. The Author(s).)

The WHO (2021) Classification classified a group of pediatric-type high-grade gliomas as IDH wildtype, H3 wildtype but as of currently, they are characterized only by negative molecular features of IDH and H3. We recruited 35 cases of pediatric IDH wildtype and H3 wildtype hemispheric glioblastomas. We evaluated them with genome-wide methylation profiling, targeted sequencing, RNAseq, TERT promoter sequencing, and FISH. The median survival of the cohort was 27.6 months. With Capper et al.'s 36 methylation groups as a map, the cases were found to be epigenetically heterogeneous and were clustered in proximity or overlay of methylation groups PXA-like (n = 8), LGG-like (n = 10), GBM&#95;MYCN (n = 9), GBM&#95;midline (n = 5), and GBM&#95;RTKIII (n = 3). Histology of the tumors in these groups was not different from regular glioblastomas. Methylation groups were not associated with OS. We were unable to identify groups specifically characterized by EGFR or PDGFRA amplification as proposed by other authors. EGFR, PDGFRA, and MYCN amplifications were not correlated with OS. 4/9 cases of the GBM&#95;MYCN cluster did not show MYCN amplification; the group was also enriched for EGFR amplification (4/9 cases) and the two biomarkers overlapped in two cases. Overall, PDGFRA amplification was found in only four cases and they were not restricted to any groups. Cases in proximity to GBM&#95;midline were all hemispheric and showed loss of H3K27me3 staining. Fusion genes ALK/NTRK/ROS1/MET characteristic of infantile glioblastomas were not identified in 17 cases successfully sequenced. BRAF V600E was only found in the PXA group but CDKN2A deletion could be found in other methylation groups. PXA-like cases did not show PXA histological features similar to findings by other authors. No case showed TERT promoter mutation. Mutations of mismatch repair (MMR) genes were poor prognosticators in single (p ≤ 0.001) but not in multivariate analyses (p = 0.229). MGMT had no survival significance in this cohort. Of the other common biomarkers, only TP53 and ATRX mutations were significant poor prognosticators and only TP53 mutation was significant after multivariate analyses (p = 0.024). We conclude that IDH wildtype, H3 wildtype pediatric hemispheric glioblastomas are molecularly heterogeneous and in routine practice, TP53, ATRX, and MMR status could profitably be screened for risk stratification in laboratories without ready access to methylation profiling., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Objective: To investigate the effects of a self-designed nutritional preparation on hypothalamic-pituitary-ovarian (HPO) axis function and energy metabolism in female SD rats exposed to intermittent cold. Methods: Female SD rats were divided into control group, cold exposure group and nutritional preparation group. The control group and cold exposure group were given distilled water by daily gavage, and the nutritional preparation group was given nutritional preparation intragastrically. After the treatment, the cold exposure group and nutritional preparation group were exposed to -10℃ in a cabin for 4 h every day. After being treated for 14 days, the serum, uterus and ovary of rats were collected. The serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and other hormone indicators were detected by enzyme-linked immunosorbent assay (ELISA) and colorimetry was used to detect ATPase and other energy metabolism related indicators. Results: Compared with the control group, cold exposure significantly up-regulated the protein expressions of FSHR and LHR, and notably enhanced the activity of Na + -K + -ATPase and Ca 2+ -Mg 2+ -ATPase in ovary and uterus (P<0.05). Nutritional preparation down-regulated the protein expressions of FSHR and LHR, and inhibited the activity of ATPase in ovary and uterus (P<0.05) compared with the cold exposure group. Conclusion: Nutritional preparations can effectively improve the expressions of HPO axis related receptors and abnormal energy metabolism in uterus and ovary caused by intermittent cold exposure.

The cell-type-specific recording and manipulation is instrumental to disentangle causal neural mechanisms in physiology and behavior and increasingly requires intersectional control; however, current approaches are largely limited by the number of intersectional features, incompatibility of common effectors and insufficient gene expression. Here, we utilized the protein-splicing technique mediated by intervening sequences (intein) and devised an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in multiple-feature defined cell types in mice. We validated the specificity and sufficiency of IBIST to control fluorophores, optogenetic opsins and Ca 2+ indicators in various intersectional conditions. The IBIST-based Ca 2+ imaging showed that the IBIST can intersect five features and that hippocampal neurons tune differently to distinct emotional stimuli depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and controls common effectors to effectively regulate gene expression, monitor and manipulate neural activities., (© 2022. The Author(s).)

Background: OAS gene family plays an important role in antiviral process, but its role in pancreatic cancer has not yet been studied., Methods: We analyzed the expression, prognostic value and biological function of the OAS gene family in human pancreatic cancer through comprehensive bioinformatic analysis and cellular level validation., Results: OAS family was highly expressed in pancreatic cancer, and this high expression significantly affected the clinical stage and prognosis of the tumor. OAS gene family was closely related to the immune infiltration of pancreatic cancer, especially neutrophils and dendritic cells, and many immune-related factors and pathways are enriched in the tumor, such as type I interferon signaling pathway and NOD-like receptor signaling pathway., Conclusion: Taken together, high expression of OAS family is closely related to poor prognosis of pancreatic cancer. OAS gene family may serve as the biomarker and even therapeutic target of pancreatic cancer., 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 Gao, Li, Yang, He, Yan, Cao and Cao.)

The 26S proteasome is the major engine of protein degradation in all eukaryotic cells. Adenosine triphosphatase (ATPase) regulatory subunits (Rpts) are constituents of the proteasome that are involved in the unfolding and translocation of substrate proteins into the core particle. In this study, by using the brown planthopper Nilaparvata lugens as a model insect, we report the biological importance of Rpts in female reproduction. We identified six homologous Rpt genes (Rpt1-6) in N. lugens. These genes were detected at high transcript levels in eggs and ovaries of females but at low transcript levels in males. RNA interference-mediated knockdown of N. lugens Rpt genes significantly decreased the proteolytic activity of the proteasome and impeded the transcription of triacylglycerol lipase and vitellogenin genes in the fat bodies and ovaries of adult females and reduced the triglyceride content in the ovaries. The decrease in the proteolytic activity of the proteasome via knockdown of Rpts also downregulated the transcription of the CYP307A2 gene encoding an important rate-limiting enzyme in the 20-hydroxyecdysone biosynthetic pathway in the ovaries, reduced 20E production in adult females and impaired ovarian development and oocyte maturation, leading to the failure of egg production and egg-laying. These novel findings indicate that Rpts are required for the proteolytic activity of the proteasome, which is important for female reproductive success in N. lugens., (© 2022 Royal Entomological Society.)

Cuticular hydrocarbons (CHCs) are important components in the integument of insects and are required for development and survival. Insect-specific CYP4G subfamily, of the P450 enzymes, catalyze the oxidative decarbonylation step in the biosynthesis of CHCs. Here, we characterized CYP380C10 gene function in a Hemiptera rice pest, Nilaparvata lugens. We used RNA interference-mediated expression silencing to reveal that NlCYP380C10 played a key role in waterproofing and water-retention in the integument of N. lugens. Knockdown of NlCYP380C10 significantly reduced body weight and caused mortality. Scanning electron microscopy showed the loss of the lipid layer on the surface of the abdominal cuticle of the dsNlCYP380C10-injected adults. Furthermore, CHC profile analysis revealed that NlCYP380C10 knockdown significantly decreased the amounts of CHCs in adult females. This suggested that NlCYP380C10 was involved in CHC biosynthesis. Reduction of CHC content caused the loss of the intact lipid layer of the cuticle, which resulted in loss of the waterproofing and water-retention functions. This led to failure of molting and eclosion. Our findings expanded the knowledge of CHC biosynthesis in the insect integument and led to a better understanding of the functional roles of CYP450 genes involved in waterproofing and water-retention in insects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Bioresorbable scaffolds (BRS) were considered to be beneficial for coronary bifurcation lesions regarding the avoidance of lateral branch opening incarceration after complete absorption. However, data is limited in this setting. The aim of this meta-analysis was to evaluate the short (6-month) and medium-term (1-year) outcomes of BRS in patients with coronary bifurcation lesions., Methods: PubMed, EMBASE, Web of Science, Cochrane library databases were searched to find the studies of BRS implantation in patients with coronary bifurcation lesions. The effective outcome was target lesion revascularization. The safety outcomes included major adverse cardiovascular events, target vessel revascularization, myocardial infarction, definite or probable scaffold thrombosis, and cardiac death., Results: A total of 1204 patients involved in 12 studies were included. The pooled estimate rate of target lesion revascularization as efficacy outcome was highly consistent between 6-month and 1-year follow-up, which was 4.74% (95% CI 2.36-9.54%, I² = 41.5%, p = 0.14) and 4.37% (95% CI 3.05-5.69%, I² = 4.6%, P = 0.39). The pooled estimated rate of major adverse cardiovascular events as safety outcome was 5.50% and 7.31% for both 6-month and 1-year follow-up. The pooled estimated rate of target vessel revascularization, myocardial infarction, definite or probable scaffold thrombosis, and cardiac death at 1-year follow-up was 5.92%, 2.52%, 1.69%, and 0.42%., Conclusions: The application of BRS for coronary bifurcation lesions is acceptable in efficacy outcome, but the high rate of scaffold thrombosis remains of concern (Registered by PROSPERO, CRD42019140341).

The myeloid differentiation factor 2 (MD-2)-related lipid-recognition protein is involved in immune responses through recognizing bacteria lipopolysaccharide in mammals, arthropods and plants. However, the physiological roles of MD-2 in other biological processes are largely unknown. Here, we identified three homologue MD-2 genes ( NlML1 , NlML2 and NlML3 ) by searching the genome and transcriptome databases of the brown planthopper Nilaparvata lugens , a hemipteran insect species. Temporospatial analysis showed that the NlML1 gene was highly expressed in the fat body but much less so in the other tissues, while the NlML2 and NlML3 genes were highly expressed in the testis or digestive tract. RNA interference-mediated depletion of the NlML1 gene significantly downregulated the transcription of numerous integument protein genes. The NlML1 knockdown led to moulting failure and mortality at the nymph-adult transition phase, impaired egg laying and hatching, and reduced 20-hydroxyecdysone (20E) production in the nymphs. 20E could rescue the deficient moulting phenotypes derived from ds NlML1 RNAi. These novel findings indicate that NlML1 is required for nymphal moulting and female reproductive success as it plays an important role in regulating 20E synthesis, lipid and chitin metabolisms in N. lugens , thus contributing to our understanding of developmental and reproductive mechanisms in insects.

Morphological degradation at the Li/solid-state electrolyte (SSE) interface is a prevalent issue causing performance fading of all-solid-state batteries (ASSBs). To maintain the interfacial integrity, most ASSBs are operated under low current density with considerable stack pressure, which significantly limits their widespread usage. Herein, a novel 3D-micropatterned SSE (3D-SSE) that can stabilize the morphology of the Li/SSE interface even under relatively high current density and limited stack pressure is reported. Under the pressure of 1.0 MPa, the Li symmetric cell using a garnet-type 3D-SSE fabricated by laser machining shows a high critical current density of 0.7 mA cm -2 and stable cycling over 500 h under 0.5 mA cm -2 . This excellent performance is attributed to the reduced local current density and amplified mechanical stress at the Li/3D-SSE interface. These two effects can benefit the flux balance between Li stripping and creep at the interface, thereby preventing interfacial degradation such as void formation and dendrite growth., (© 2021 Wiley-VCH GmbH.)

The diagnostic role of Isocitrate Dehydrogenase (IDH) mutation status in adult lower grade astrocytomas was first formally presented within the WHO Classification of Tumours of the Central Nervous System (2016). IDH-mutant astrocytomas are not as common as IDH-wildtype astrocytomas but are of better prognosis. Our previous study provided an evident that IDH-mutant lower grade astrocytomas is not a homogeneous group and could be further stratified by PDGFRA amplification, CDK4 amplification and CDKN2A deletion. In this study, we detected the expressions of DNA mismatch repair (MMR) proteins (PMS2, MLH1, MSH2, MSH6) and PD-L1 by immunohistochemistry in 147 IDH-mutant lower grade astrocytomas and explored their clinical relevance. The loss of was identified in 28.6%, 1.4%, 8.8% and 13.6%, respectively. PD-L1 expression was detected in 1.4% of this cohort. Survival analysis revealed that loss of PMS2 was correlated with shorter OS (p < 0.001) and PFS (p = 0.005). Loss of PMS2 or MLH1 was associated with shorter OS (p < 0.001) and PFS (p = 0.008). In IDH-mutant lower grade astrocytomas without CDKN2A deletion, loss of PMS2 was associated with poorer OS (p < 0.001) and PFS (p = 0.001). Furthermore, among IDH-mutant lower grade astrocytomas lacking the three biomarkers (PDGFRA, CDK4 and CDKN2A), loss of PMS2 was also associated with a poorer OS (p < 0.001) and PFS (p = 0.003). Our data illustrated the potential application of MMR genes in stratification of IDH-mutant lower grade astrocytomas without PDGFRA, CDK4 and CDKN2A copy number alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Dual antiplatelet therapy (DAPT) is the basis of preventing stent thrombosis and ischemic events after percutaneous coronary intervention (PCI), but prolonging the duration of DAPT will increase the risk of bleeding. The optimal duration of DAPT after PCI remains controversial at present. The purpose of this meta-analysis was to investigate the efficacy and safety of short-term DAPT in patients undergoing PCI. PubMed, Embase, Cochrane and Web of science from inception to September 2019 were systematically searched. Randomized controlled trials were included to compare short term (3 months or less) with a standard 12-months DAPT in patients undergoing PCI. Random effect model and fixed effect model wereused to calculate the risk ratio (RR) and 95% confidence interval (CI) of each endpoint. This meta-analysis included 38479 patients undergoing PCI from 8 randomized clinical trials. No difference was observed in the risk of all-cause death (RR 0.92, 95% CI 0.80-1.06, P = 0.25), cardiovascular death (RR 0.88, 0.69-1.12, P = 0.29), myocardial infarction (RR 1.05, 0.94-1.19, P = 0.38), definite or probable stent thrombosis (RR 1.05, 0.80-1.36, P = 0.73), and stroke (RR 1.02, 0.80-1.30, P = 0.89) between short term and standard DAPT. The short-term DAPT could reduce the risk of major bleeding (RR 0.67, 0.48-0.94, P = 0.02) and any bleeding (RR 0.63, 0.48-0.82, P = 0.0005) compared with 12 months of DAPT. In conclusion, the short-term DAPT can reduce the risk of bleeding compared with standard DAPT, without increasing the risk of death or ischemia (Registered by PROSPERO, CRD42020153881).

To explore the molecular epidemiological status of human immunodeficiency virus type 1 (HIV-1) in Yunnan, China, three HIV-1 near full-length genomes were amplified and sequenced from plasma samples that were collected from Burmese patients newly diagnosed with HIV-1 in Dehong Prefecture in Yunnan Province in 2017. Phylogenetic and bootscanning analyses revealed that all the sequences might be HIV-1 second-generation recombinant forms of circulating recombinant forms (CRF07&#95;BC and CRF83&#95;cpx) and unique recombinant forms. One of the sequences contained six CRF01&#95;AE fragments, five subtype C fragments, and two subtype B fragments, which were separated by 12 breakpoints. These results revealed that the second-generation recombination of HIV-1 within different strains is still ongoing in Dehong, China. Systematic surveys and immediate interventions are urgently needed to prevent the formation of increasingly complex HIV-1 recombinant forms.

Metastasis is the leading cause of cancer-related deaths, and obesity is associated with increased breast cancer (BC) metastasis. Preclinical studies have shown that obese adipose tissue induces lung neutrophilia associated with enhanced BC metastasis to this site. Here we show that obesity leads to neutrophil-dependent impairment of vascular integrity through loss of endothelial adhesions, enabling cancer cell extravasation into the lung. Mechanistically, neutrophil-produced reactive oxygen species in obese mice increase neutrophil extracellular DNA traps (NETs) and weaken endothelial junctions, facilitating the influx of tumor cells from the peripheral circulation. In vivo treatment with catalase, NET inhibitors or genetic deletion of Nos2 reversed this effect in preclinical models of obesity. Imaging mass cytometry of lung metastasis samples from patients with cancer revealed an enrichment in neutrophils with low catalase levels correlating with elevated body mass index. Our data provide insights into potentially targetable mechanisms that underlie the progression of BC in the obese population., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Non-ATPase regulatory subunits (Rpns) are components of the 26S proteasome involved in polyubiquitinated substrate recognition and deubiquitination in eukaryotes. Here, we identified 15 homologues sequences of Rpn and associated genes by searching the genome and transcriptome databases of the brown planthopper, Nilaparvata lugens , a hemipteran rice pest. Temporospatial analysis showed that NlRpn genes were significantly highly expressed in eggs and ovaries but were less-highly expressed in males. RNA interference-mediated depletion of NlRpn genes decreased the proteolytic activity of proteasome and impeded the transcription of lipase and vitellogenin genes in the fat bodies and ovaries in adult females, and reduced the triglyceride content in the ovaries. Decrease of the proteolytic activity of the proteasome via knockdown of NlRpn s also inhibited the transcription of halloween genes, including NlCYP307A2 , NlCYP306A2 and NlCYP314A1 , in the 20-hydroxyecdysone (20E) biosynthetic pathway in the ovaries, reduced 20E production in adult females, and impaired ovarian development and oocyte maturation, resulting in reduced fecundity. These novel findings indicate that the proteolytic activity of the proteasome is required for female reproductive processes in N. lugens , thus furthering our understanding of the reproductive and developmental strategies in insects.

This study tested the impact of single dose and two doses of endothelial progenitor cells (EPCs) and EPCs-derived condition medium (CM) on protecting the left-ventricular myocardium (LVM) from acute ischemia-reperfusion (IR) injury. In vitro study showed EPCs and CM had comparably higher capacity for enhancement of angiogenesis as compared with the controls (all P < .001). Adult-male SD rats ( n = 36) were equally categorized into groups 1 (sham-operated control), 2 (IR+vehicle), 3 [IR+EPCs/1.2 × 10 6 /intravenous administration at 3 h after IR procedure), 4 (IR+EPCs/1.2 × 10 6 /at 3 h/24 h after IR), 5 (IR+CM/3.0cc/intravenous administration at 3 h after IR), 6 (IR+EPCs/3.0cc/at 3h/24 h after IR), and euthanized by day 3 after IR. The left-ventricular-ejection-fraction, protein and cellular expressions of endothelial-cell markers (CD31/vWF), small vessel number and protein expression of mitochondrial (mitochondrial-cytochrome-C) integrity were highest in group 1, lowest in group 2, significantly higher in group 4 than in groups 3/5/6 and significantly higher in groups 3/6 than in group 5 but they showed no differences in groups3/6, whereas the protein expressions of apoptotic (cleaved-caspase 3/cleaved-PARP), fibrotic (Smad3/TGF-ß), mitochondrial-damaged (cytosolic-cytochrome-C), heart-failed/pressure-overload (BNP), oxidative-stress (p47phox/NOX-1/NOX-2/oxidized protein), and autophagic (LCB3-II/LCB3-I) biomarkers and fibrotic/collagen-deposition areas exhibited an opposite pattern to endothelial-cell markers (all P < .0001). The protein expressions of angiogenesis (VEGF/SDF-1α/CXCR4/HIF-1α) were lowest in group 1, highest in group 4, significantly higher in groups 3/6 than in groups 2/5, significantly higher in group 5 than in group 2, but they showed no difference between groups 3/6 (all P < .0001). These results demonstrate that two consecutive doses of EPC/CM were superior to just one at protecting LVM against IR injury.

Objective: To observe the differences in normal facial skin thickness and echo density by different ages and sites of healthy adults of the same sex using 50 MHz high-frequency ultrasound. Methods: From January to June 2019, 200 healthy adult volunteers with normal facial skin who were from Sichuan, Yunnan, Guizhou, and Chongqing and met the inclusion criteria were recruited by the Affiliated Hospital of Southwest Medical University with simple random sampling method, and then were included in this cross-sectional investigation study. Then 50 MHz high-frequency ultrasound was used to obtain skin ultrasonogram of volunteers' forehead, canthus, eyelid, and cheek. According to the ages, 100 female volunteers were divided into 20-29 years old (30 females), 30-39 years old (25 females), 40-49 years old (20 females), and 50-70 years old (25 females) groups; 100 male volunteers were divided into 20-29 years old (30 males), 30-39 years old (25 males), 40-49 years old (20 males), and 50-70 years old (25 males) groups. The thickness of full-skin, the upper dermal echo density, and the lower dermal echo density of the female and male volunteers'forehead, canthus, eyelid, and cheek were recorded respectively. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, least significant difference test, and Bonferroni correction. Results: (1) The thickness of full-thickness skin in forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old group were (1.86±0.26), (1.36±0.11), (1.24±0.25), and (1.90±0.21) mm, (2.45±0.37), (1.64±0.19), (1.44±0.16), and (2.53±0.26) mm, respectively, in 30-39 years old group were (1.98±0.24), (1.43±0.13), (1.15±0.15), and (2.12±0.13) mm, (2.34±0.27), (1.63±0.27), (1.50±0.38), and (2.43±0.40) mm, respectively, in 40-49 years old group were (1.90±0.21), (1.43±0.18), (1.24±0.27), and (1.98±0.12) mm, (2.14±0.24), (1.54±0.25), (1.28±0.14), and (2.39±0.36) mm, respectively, in 50-70 years old group were (1.64±0.25), (1.36±0.19), (1.16±0.12), and (1.89±0.29) mm, (2.28±0.27), (1.73±0.25), (1.58±0.18), and (2.38±0.32) mm, respectively. There were no statistically significant differences between female volunteers in the 4 groups and male volunteers in the 4 groups in thickness of full-thickness skin in canthus, eyelid, and cheek ( F =0.677, 0.666, 0.136, 0.697, 0.294, 0.888, P >0.05). The thickness of full-thickness skin in forehead and cheek of the female volunteers in the 4 groups and male volunteers in the 4 groups was similar ( P >0.05), and was significantly higher than that of canthus and eyelid ( P <0.05). The thickness of full-thickness skin in canthus and eyelid of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old group was similar ( P >0.05), while thickness of full-thickness skin in canthus and eyelid of male volunteers in the 4 groups was similar ( P >0.05). (2) The upper dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly lower than that in 20-29 years old and 30-39 years old groups ( P <0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly lower than that in 20-29 years old group ( P <0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old and 30-39 years old groups was similar ( P >0.05). The upper dermal echo density of forehead and cheek of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid ( P <0.05). The echo density of upper dermis of cheek of male volunteers in the 4 groups was significantly lower than that of canthus and eyelid ( P <0.05). The upper dermal echo density of canthus and eyelid of female volunteers in the 4 groups and male volunteers in the 4 groups was similar ( P >0.05), the upper dermal echo density of forehead and cheek was similar ( P >0.05). (3) The lower dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly higher than that in 20-29 years old and 30-39 years old groups ( P <0.05). The lower dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly higher than that in 20-29 years old group ( P <0.05). The echo density of the lower dermis of forehead, eyelid, and cheek of female and male volunteers in 20-29 years old, 30-39 years old, and 40-49 years old groups was similar ( P >0.05). The lower dermal echo density of forehead and cheek of female volunteers in the 4 groups was significantly lower than that of canthus and eyelid ( P <0.05). The lower dermal echo density of forehead and cheek of male volunteers in 30-39 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid ( P <0.05). The lower dermal echo density between canthus and eyelid and between forehead and check of female volunteers in the 4 groups and male volunteers in the 4 groups was similar ( P >0.05). Conclusions: The 50 MHz high-frequency ultrasonography shows that the thickness of full-thickness skin of canthus, eyelid, and cheek is similar in all age groups of female and male adult volunteers with normal facial skin. In the same age group, the thickness of full-thickness skin of forehead and cheek of male and female volunteers is significantly higher than that of canthus and eyelid. The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers shows a decreasing trend with age, while the lower dermal echo density shows an increasing trend with age. In addition, the echo density of upper and lower dermis of canthus and eyelid was significantly higher than that of cheek in all the four age groups.

The brown planthopper Nilaparvata lugens is a typical monophagous insect herbivore that feeds exclusively on rice sap. This insect pest causes serious damage to rice crops throughout East Asian countries. Chemical control remains the first choice for managing N. lugens populations; however, the use of insecticides has given rise to planthopper resurgence and additional environmental risks. Nilaparvata lugens is a model insect of Hemiptera because its whole genome sequence has been elucidated and is susceptible to RNA interference. In this study, our findings revealed that a superoxide-generating gene, NADPH oxidase 5 ( Nox5 ), is essential for molting and oviposition in a Hemipteran insect Nilaparvata lugens . Knockdown of Nox5 transcript levels by RNA interference in 2nd-5th-instar nymphs results in significantly lethal deficits in the molting transitions from nymph-nymph and nymph-adult. Nox5 knockdown leads to a reduction of hydrogen peroxide in female ovaries and failure of oviposition from the insect ovipositor into the rice leaf sheath. Here, we provide in vivo evidence demonstrating that Nox5 is a key enzyme for regulating molting and oviposition in this insect species.

Background and Objective: Intravascular ultrasound (IVUS) could take on a vital position when angiographic images are not clear enough to be precisely visualized or measured by computer-aided technology. This meta-analysis was designed to compare the benefits of IVUS-guided and angiography-guided percutaneous coronary intervention(PCI) strategies for improving clinical outcomes., Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched for articles published from inception to 13th October, 2019. A comparative study of IVUS-guided and angiography-guided PCI strategies for patients with coronary bifurcation lesions was retrieved. The early endpoint events (≤1 year) and the late endpoint events (>1 years) were determined according to the follow-up time. The former included cardiac death, target lesion or vessel revascularization, stent thrombus, and major adverse cardiac events, while the latter included cardiac death. Statistical software Review Manager Version 5.3 was performed for meta-analysis., Results: Five studies involving7,830 patients with coronary bifurcation lesions were included in this meta-analysis, the incidence of major adverse cardiac events for IVUS-guided strategy in patients with coronary bifurcation lesions were lower than those of patients with angiography-guided strategy at the early follow-up(OR = 0.55, 95% CI 0.42 - 0.70, P < .0001).Meanwhile, cardiac death, target vessel or target lesion revascularization, stent thrombosis were not statistically significant(OR = 0.68, 95% CI 0.34 - 1.35, P = .27; OR = 0.78, 95% CI 0.59 - 1.05, P = .10; OR = 0.36, 95% CI 0.12-1.04, P = .06).However, significant differences in cardiac death between IVUS-guided and angiographic-guided strategies were observed in the late follow - up (OR = 0.36, 95% CI 0.23 - 0.57, P < .00001)., Conclusion: The IVUS-guided PCI strategy was associated with more clinical benefits compared with angiography-guided PCI strategy in patients with coronary bifurcation lesions. These findings suggest that the IVUS-guided PCI strategy can be recommended as an optimization in this kind of patients.

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk., (© 2019 International Society of Neuropathology.)

Despite being innate, displays of aggression are influenced by cortical activities. Here, using Vglut1 as a marker for inputs from cortical structures, we identify a small population of excitatory neurons located in the posterior amygdala (PA) that project to the ventrolateral division of ventromedial nucleus of the hypothalamus (VMHvl), a region that critically regulates territorial aggression. Indeed, activities of PA Vglut1+ (PA Vglut1 ) neurons, as analyzed by post hoc c-Fos expression, differentiate trials in which attacks occur, or not, during resident-intruder assays. More importantly, chemogenetic activation of VMHvl-projecting PA Vglut1 neurons robustly promote aggression while inhibition of these neurons reduces attacks. Finally, a connectivity map places VMHvl-projecting PA Vglut1 neurons at the interface between emotion regulation and aggression as they receive broad inputs from limbic structures and project collaterally to the VMHvl and other targets. Taken together, these results point to VMHvl-projecting PA Vglut1 neurons as a potential site for cortical gating of territorial aggression., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the clinical effectiveness of super pulsed carbon dioxide fractional laser debridement surgery on the treatment of chronic wounds. Methods: From December 2018 to May 2019, 37 patients with chronic wounds who met the inclusion criteria were admitted to the Affiliated Hospital of Southwest Medical University for a prospective randomized controlled study. Using the random number table, the patients were divided into surgical debridement group (19 patients, 4 males and 15 females, aged (58±16) years, 25 wounds) and laser debridement group (18 patients, 9 males and 9 females, aged (58±10) years, 23 wounds). In patients of surgical debridement group, oedematous and aging granulation tissue was scraped from the wound by scalpel handle or curet, and the residual necrotic tissue was removed by sharp surgical instruments. In patients of laser debridement group, oedematous and aging granulation tissue and necrotic tissue was removed by super pulsed carbon dioxide fractional laser therapeutic machine, laser gasification debridement was performed repeatedly till fresh normal tissue layer observed. In patients of the two groups, according to the wound in the first 3 d after the first debridement, debridement dressing was performed twice at least as before, then wound debridement dressing was performed once every 1 to 4 days as before according to the wound conditions. The wound healing rates on 7, 14, 21, and 28 d after the first debridement were calculated. The positive rates of bacterial culture of wounds before and after the first debridement were calculated. The color and texture of the wound granulation tissue before the first debridement and on 7, 14, and 28 d after the first debridement were observed and scored. The pain scores before every debridement, during every debridement, and after every debridement dressing change were evaluated by visual analogue scale. The times of debridement dressing change were recorded. Data were statistically analyzed with two independent sample t test, analysis of variance for repeated measurement, Fisher's exact probability test, Mann-Whitney U test, and Bonferroni correction. Results: (1) On 7, 14, 21, and 28 d after the first debridement, the wound healing rates of patients in laser debridement group (29.5% (24.1%, 36.0%), 47.1% (42.7%, 62.4%), 71.4% (62.2%, 76.8%), and 88.6% (79.2%, 96.3%) were significantly higher than those of surgical debridement group (1.6% (1.0%, 12.8%), 12.7% (2.0%, 16.6%), 24.5% (8.9%, 45.5%), 43.9% (23.2%, 70.8%), Z =3.477, 3.553, 2.721, 2.193, P <0.05 or P <0.01). (2) Before the first debridement, the positive rates of bacterial culture of wounds in patients of laser debridement group and surgical debridement group were 92% (23/25) and 91% (21/23), respectively, which were similar ( P >0.05). After the first debridement, the positive rate of bacterial culture of wounds of patients in surgical debridement group was 64% (16/25), which was significantly higher than 13% (3/23) of laser debridement group ( P <0.01). (3) On 7, 14, and 28 d after the first debridement, the scores of color and texture of wound granulation tissue of patients in laser debridement group were significantly higher than those of surgical debridement group ( Z =3.420, 5.682, 6.142, 4.461, 5.337, 4.458, P <0.01). (4) The pain scores during every debridement and after every debridement dressing change in patients of laser debridement group were significantly lower than those of surgical debridement group ( t =2.847, 5.046, P <0.05 or P <0.01). (5) The time of debridement dressing change in laser debridement group was 8.0 (7.0, 10.0) times, which was significantly less than 10.0 (9.5, 12.5) times in surgical debridement group ( Z =2.261, P <0.05). Conclusions: Compared with traditional surgical debridement method, super pulsed carbon dioxide fractional laser debridement surgery is more effective in treating patients with chronic wounds. Laser debridement makes the wound healing more efficiently with reduced pain and better infection control; significantly reduces the number of dressing changes, and is especially suitable for the wound treatment in outpatients.

Giant cell glioblastoma (gcGBM) is a rare histological variant of GBM, accounting for about 1% of all GBM. The prognosis is poor generally though gcGBM does slightly better than the other IDH-wild-type GBM. Because of the rarity of the cases, there has been no comprehensive molecular analysis of gcGBM. Previously, single-gene study identified genetic changes in TP53, PTEN and TERT promoter mutation in gcGBM. In this report, we performed whole-exome sequencing (WES) to identify somatically acquired mutations and copy number variations (CNVs) in 10 gcGBM genomes. We also examined TERT promoter mutation and MGMT methylation in our cohort. On top of the reported mutations, WES revealed ATRX, PIK3R1, RB1 and SETD2 as the recurrent mutations in gcGBM. Notably, one tumor harbored a mutation in MutS homolog 6 (MSH6) that is a key mismatch repair (MMR) gene. This tumor demonstrated hypermutation phenotype and showed an increased number of somatic mutations. TERT promoter mutation and MGMT methylation were observed in 20% and 40% of our samples, respectively. In conclusion, we described relevant mutation profiling for developing future targeted therapies in gcGBM., (© 2019 International Society of Neuropathology.)

Background: IDH -mutant glioblastoma is classified by the 2016 CNS WHO as a group with good prognosis. However, the actual number of cases examined in the literature is relatively small. We hypothesize that IDH -mutant glioblastoma is not a uniform group and should be further stratified., Methods: We conducted methylation profiles and estimated copy number variations of 57 IDH- mutant glioblastomas., Results: Our results showed that 59.6% and 40.4% of tumors belonged to glioma-CpG island methylator phenotype (G-CIMP)-high and G-CIMP-low methylation subgroups, respectively. G-CIMP-low subgroup was associated with significantly worse overall survival (OS) as compared to G-CIMP-high ( P = .005). CDKN2A deletion (42.1%) was the most common gene copy number variation, and was significantly associated with G-CIMP-low subgroup ( P = .004). Other frequent copy number changes included mesenchymal-epithelial transition ( MET ) (5.3%), CCND2 (19.3%), PDGFRA (14.0%), CDK4 (12.3%), and EGFR (12.3%) amplification. Both CDKN2A deletion ( P = .036) and MET amplification ( P < .001) were associated with poor OS in IDH -mutant glioblastomas. Combined epigenetic signature and gene copy number variations separated IDH -mutant glioblastomas into Group 1 (G-CIMP-high), Group 2 (G-CIMP-low without CDKN2A nor MET alteration), and Group 3 (G-CIMP-low with CDKN2A and/or MET alteration). Survival analysis revealed Groups 1 and 2 exhibited a favorable OS (median survival: 619 d [20.6 mo] and 655 d [21.8 mo], respectively). Group 3 exhibited a significant shorter OS (median survival: 252 d [8.4 mo]). Multivariable analysis confirmed the independent prognostic significance of our Groups., Conclusions: IDH -mutant glioblastomas should be stratified for risk with combined epigenetic signature and CDKN2A/MET status and some cases have poor outcome., (© The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: To evaluate the effect of fluoride varnish Duraphat on preventing caries of primary teeth caries, and provide scientific basis for the establishment of oral health care., Methods: 1140 preschool children aged 3~4 years old were chosen from 25 public kindergartens in Xuhui district of Shanghai by cluster sampling method, they were divided into 2 groups on a voluntary basis with the informed consent of the child's parents. 762 preschool children in Fluoride Varnish group were taken oral examination and used fluoride varnishes every 6 months, 378 preschool children in the control group were without treatment. Oral health instruction was given to all the children. The data of caries prevalence, mean dmft, caries incidence and mean increments of dmft (decayed, missing and filled teeth) of 2 groups were compared. The results were analyzed using SAS 9.4 software package., Results: After 2 years, caries prevalence, mean dmft, caries incidence and mean increments of dmft of fluoride varnish groups were lower than those of control group and the difference was statistically significant (P＜0.05)., Conclusions: Fluoride varnish Duraphat is effective in decreasing caries incidence and mean dmft increments of primary teeth in preschool children and is worthy to be used widely in Xuhui district.

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.

Although oligodendrogliomas appear histologically similar in adult and pediatric patients, the latter have only been rarely studied and most of those studies did not have long follow-up. We examined 55 oligodendroglial tumors from pediatric and teenage patients for their biomarkers with formalin-fixed paraffin-embedded tissues and studied their survival status. None of the tumors harbored 1p/19q codeletion or IDH mutation. Mutations in TERTp (4%), BRAF (11%), FGFR1 (3%) and H3F3A (5%), fusions of BRAF (8%) and FGFR1 (8%) were found sparingly and almost all in a mutually exclusive manner. Molecular events were exclusively found in tumors with classic oligodendroglial histology. Survival analysis showed remarkably excellent prognosis compared to the adult counterparts. 5-year overall survival was 95% in our cohort with median follow-up of 8.1 years and in nine patients with follow-up more than 10 years, the 10-year overall survival was 100%. The 5-year and 10-year progression-free survivals of our cohort were 89 and 77%, respectively. FGFR1 fusion seemed to confer a poor prognosis in pediatric oligodendrogliomas. Patients receiving adjuvant chemotherapy (p = 0.046) or harboring Grade II histology (p < 0.001) had longer interval to recurrence. Our study demonstrated the distinct indolent clinical course of pediatric and teenage oligodendrogliomas compared to the adult tumors. Molecular markers commonly seen in adult oligodendrogliomas and other pediatric low-grade gliomas were only rarely seen. Since there is no clinical or molecular evidence suggesting that pediatric "oligodendrogliomas" are the same as adult oligodendrogliomas albeit histologic similarity, a case can be made for their separation from adult oligodendrogliomas in the next WHO classification.

Depression is a common psychiatric disorder with heavy economic and social burdens. Searching new agents with better antidepressant-like activities is of great significance for depression therapy. Tauroursodeoxycholic acid (TUDCA), a clinical drug for gallstone treatment, possesses neuroprotective effects in different brain disorders. However, whether it affects depression remains unclear. We addressed this issue by evaluating the effect of TUDCA on depression induced by chronic unpredictable stress (CUS). Results showed that TUDCA treatment at 200 but not 100 mg/kg prevented the 5 weeks of CUS-induced increases in the immobile time of C57BL6/J mice in the experiments of forced swimming test and tail suspension test as well as the CUS-induced decrease in sucrose intake and crossing numbers in the open-field test, and did not enhance the antidepressant-like effect of fluoxetine. Attenuation of neuroinflammation may be involved in the antidepressant-like effect of TUDCA, as TUDCA treatment (200 mg/kg) normalized the levels of tumor necrosis factor-α and interleukin-6 in both hippocampus and prefrontal cortex. The increases in inflammasome and microglial activation markers, including interleukin-β, nod-like receptor protein 3, and Iba-1, in CUS-treated mice were reduced by TUDCA treatment (200 mg/kg). TUDCA treatment (200 mg/kg) also normalized the changes in markers reflecting the oxidative-nitrosative and endoplasmic reticulum (ER) stress induced by CUS, such as nitric oxide, reduced glutathione, malondialdehyde, glucose-regulated protein 78, and C/EBP homologous protein. These results revealed that TUDCA improved the CUS-induced depression-like behaviors likely through attenuation of neuroinflammation, oxido-nitrosative, and ER stress., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Hong Kong's beach water quality classification scheme, used effectively for >25 years in protecting public health, was first established in local epidemiology studies during the late 1980s where Escherichia coli (E. coli) was identified as the most suitable faecal indicator bacteria. To review and further substantiate the scheme's robustness, a performance check was carried out to classify water quality of 37 major local beaches in Hong Kong during four bathing seasons (March-October) from 2010 to 2013. Given the enterococci and E. coli data collected, beach classification by the local scheme was found to be in line with the prominent international benchmarks recommended by the World Health Organization and the European Union. Local bacteriological studies over the last 15 years further confirmed that E. coli is the more suitable faecal indicator bacteria than enterococci in the local context., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Anion- and solvent-induced single-crystal-to-single-crystal transformation within an iron(II) triazole system has been generated from {[Fe(TPPT) 2 Cl 2 ]·CHCl 3 } n (1a) to [Fe(TPPT)(C 2 O 4 ) 0.5 Cl(H 2 O)] n (1b). Luminescence studies indicated that the resultant 1b can be considered as a promising luminescent probe for CrO 4 2- and cyano molecules.

Background: Z-guggulsterone, an active compound extracted from the gum resin of the tree Commiphora mukul, has been shown to improve animal memory deficits via activating the brain-derived neurotrophic factor signaling pathway. Here, we investigated the antidepressant-like effect of Z-guggulsterone in a chronic unpredictable stress mouse model of depression., Methods: The effects of Z-guggulsterone were assessed in mice with the tail suspension test and forced swimming test. Z-guggulsterone was also investigated in the chronic unpredictable stress model of depression with fluoxetine as the positive control. Changes in hippocampal neurogenesis as well as the brain-derived neurotrophic factor signaling pathway after chronic unpredictable stress/Z-guggulsterone treatment were investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressant-like mechanisms of Z-guggulsterone., Results: Z-guggulsterone (10, 30 mg/kg) administration protected the mice against the chronic unpredictable stress-induced increases in the immobile time in the tail suspension test and forced swimming test and also reversed the reduction in sucrose intake in sucrose preference experiment. Z-guggulsterone (10, 30 mg/kg) administration prevented the reductions in brain-derived neurotrophic factor protein expression levels as well as the phosphorylation levels of cAMP response element binding protein, extracellular signal-regulated kinase 1/2, and protein kinase B in the hippocampus and cortex induced by chronic unpredictable stress. Z-guggulsterone (10, 30 mg/kg) treatment also improved hippocampal neurogenesis in chronic unpredictable stress-treated mice. Blockade of the brain-derived neurotrophic factor signal, but not the monoaminergic system, attenuated the antidepressant-like effects of Z-guggulsterone., Conclusions: Z-guggulsterone exhibits antidepressant activity via activation of the brain-derived neurotrophic factor signaling pathway and upregulation of hippocampal neurogenesis., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Biopharmaceutics classification system of Chinese materia medica (CMMBCS) emphasizes characteristic of the multi-component environment based on the drug solubility and permeability. In this study, the in situ closed-loop method combined with LC-MS technique was utilized to study the intestinal absorption and metabolism of Puerariae Lobatae Radix decoction (PLRD), providing selection basis for intestinal permeability components in CMMBCS. A total of 36 components were identified from PLRD. Among them, 17 components could be detected in the plasma sample, indicating that 17 components could be absorbed into blood, so these 17 components could be used as intestinal permeability evaluation components in CMMBCS. The other 19 components were not detected in the plasma sample, suggesting that they may not be absorbed or metabolized by the gut wall enzymes., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Microglial cells are the pivotal immune cells of the central nervous system. Adult microglia cells under physiological conditions are in a ramification state with extensively branched processes. Upon disease stimulation, they retract their processes and become activated. Induction of ramification is an attracting strategy to terminate the excessive activation of microglia. Here, we investigated the influence of compound C (CC) on microglial shape. Results showed that CC reversibly induced a ramification of murine microglia in both basal and inflammatory conditions. These pro-ramification effects were independent of adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibition as both AMPKα1 and AMPKα2 silence failed to induce microglial ramification. The ramification state of microglia induced by CC was associated with a decrease in pro-inflammatory factors and an increase in brain-derived neurotrophic factors (BDNF) protein and phagocytic activity. Mechanistic studies confirmed that the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signal, extracellular signal-regulated kinase 1/2 (ERK1/2) or small RhoGTPase activation mediated the effect of CC on microglial shape change based on the following observations: (i) CC induced a significant activation of the small RhoGTPase Rac1 and Cdc42; (ii) CC promoted the phosphorylation of ERK1/2 and Akt; (iii) inhibition of Rac1, Cdc42, ERK1/2, or the PI3K-Akt signal abolished the effect of CC on microglial shape change. These signal mechanisms were also ascertained in primary microglia. Our results explore a potential agent that promotes microglial ramification, and provide an alternative explanation for the neuroprotective effects of CC in various disease models such as brain ischemia and subarachnoid hemorrhage., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the expression and role of autophagy in the progression of acute liver failure (ALF) using the mouse model of ALF induced by D-galactosamine/LPS (D-GalN/LPS). Methods: The C57BL/6 mice were used, and intraperitoneal injection of D-galactosamine (D-GalN) and lipopolysaccharide (LPS) was performed to establish the mouse model of ALF. The mice were divided into control group and 2-, 4-, and 6-hour D-GalN/LPS-induced ALF model groups. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured to assess liver function, and the pathological changes in liver tissue were observed to evaluate the status of liver injury. Quantitative real-time PCR was used to measure the expression of autophagy-related genes, Western blot was used to measure the expression of autophagy-related proteins in liver tissue, and a fluorescence microscope was used to observe the expression of autophagosome in the progression of liver failure. A one-way ANOVA was used for comparison of means of multiple samples between any two groups (LSD-t test for data with homogeneity of variance and Games-Howell method for data with heterogeneity of variance). P < 0.05 was considered statistically significant. Results: The ALF model groups showed gradual liver impairment over the time of D-GalN/LPS stimulation. There were significant increases in ALT and AST after 4 hours; the pathological injury of liver tissue gradually aggravated over the time of D-GalN/LPS stimulation and fulfilled the criteria for ALF at 6 hours. The mRNA and protein expression of autophagy-related genes (ATG-7, ATG-5, Beclin-1, Lamp-1, and LC3a) increased in the early and medium stages of ALF (2 and 4 hours) and decreased after ALF progressed to liver failure (6 hours). As was observed via the fluorescence microscope, the 4-hour D-GalN/LPS-induced ALF model group showed the highest expression of autophagosome. Conclusion: The expression of autophagy gradually increases in the early and medium stages of ALF and decreases when ALF progresses to liver failure. Therefore, autophagy plays an important role in the pathogenesis of ALF.