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BackgroundSubstance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation.MethodUsing results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia).ResultsTwo correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods.ConclusionsGenetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.

Acinetobacter baumannii has become a major healthcare threat that causes nosocomial infections, especially in critically ill patients. The spread of carbapenem-resistant A. baumannii (CRAB) strains has long been a clinical concern. It is important to study the epidemiology and virulence characteristics of different CRAB isolates in order to tailor infection prevention and antibiotic prescribing. In this study, a total of 71 CRAB isolates were collected in the hospital, and clinical characteristics of infections were analyzed. The genomic characteristics and phylogenetic relationships were elucidated based on genome sequencing and analysis. The isolates were assigned to three sequence types (STs, Pasteur) and nine capsular polysaccharide (KL) types, among which ST2/KL22 was the most prevalent CRAB in the hospital. Even though all the ST2/KL22 isolates contained the same reported virulence genes, one specific clade of ST2/KL22 showed more pathogenic in mouse infection model. Complete genomic analysis revealed differences at the oprD locus between the low- and high-virulent isolates. More specifically, a premature stop codon in the low-virulence strains resulted in truncated OprD expression. By evaluating pathogenicity in C57BL/6 J mice, knock-out of oprD in high-virulent isolate resulted in virulence attenuation, and complementing the avirulent strain with full-length oprD from high-virulent isolate enhanced virulence of the former. The oprD gene may be associated with the enhanced virulence of the specific ST2/KL22 clone, which provides a potential molecular marker for screening the hypervirulent A. baumannii strains.

The analysis of cancer omics data is a "classic" problem, however, still remains challenging. Advancing from early studies that are mostly focused on a single type of cancer, some recent studies have analyzed data on multiple "related" cancer types/subtypes, examined their commonality and difference, and led to insightful findings. In this article, we consider the analysis of multiple omics datasets, with each dataset on one type/subtype of "related" cancers. A Community Fusion (CoFu) approach is developed, which conducts marker selection and model building using a novel penalization technique, informatively accommodates the network community structure of omics measurements, and automatically identifies the commonality and difference of cancer omics markers. Simulation demonstrates its superiority over direct competitors. The analysis of TCGA lung cancer and melanoma data leads to interesting findings, 33 pages, 11 figures

In cancer research, high-throughput profiling has been extensively conducted. In recent studies, the integrative analysis of data on multiple cancer patient groups/subgroups has been conducted. Such analysis has the potential to reveal the genomic commonality as well as difference across groups/subgroups. However, in the existing literature, methods with a special attention to the genomic commonality and difference are very limited. In this study, a novel estimation and marker selection method based on the sparse boosting technique is developed to address the commonality/difference problem. In terms of technical innovation, a new penalty and computation of increments are introduced. The proposed method can also effectively accommodate the grouping structure of covariates. Simulation shows that it can outperform direct competitors under a wide spectrum of settings. The analysis of two TCGA (The Cancer Genome Atlas) datasets is conducted, showing that the proposed analysis can identify markers with important biological implications and have satisfactory prediction and stability., 13 pages

BackgroundThe effective implementation of government policies and measures for controlling the coronavirus disease 2019 (COVID-19) pandemic requires compliance from the public. This study aimed to examine cross-sectional and longitudinal associations of trust in government regarding COVID-19 control with the adoption of recommended health behaviours and prosocial behaviours, and potential determinants of trust in government during the pandemic.MethodsThis study analysed data from the PsyCorona Survey, an international project on COVID-19 that included 23 733 participants from 23 countries (representative in age and gender distributions by country) at baseline survey and 7785 participants who also completed follow-up surveys. Specification curve analysis was used to examine concurrent associations between trust in government and self-reported behaviours. We further used structural equation model to explore potential determinants of trust in government. Multilevel linear regressions were used to examine associations between baseline trust and longitudinal behavioural changes.ResultsHigher trust in government regarding COVID-19 control was significantly associated with higher adoption of health behaviours (handwashing, avoiding crowded space, self-quarantine) and prosocial behaviours in specification curve analyses (median standardised β = 0.173 and 0.229, p < 0.001). Government perceived as well organised, disseminating clear messages and knowledge on COVID-19, and perceived fairness were positively associated with trust in government (standardised β = 0.358, 0.230, 0.056, and 0.249, p < 0.01). Higher trust at baseline survey was significantly associated with lower rate of decline in health behaviours over time (p for interaction = 0.001).ConclusionsThese results highlighted the importance of trust in government in the control of COVID-19.

Background The serum surfactant protein D (SP-D) level is suggested to be a useful biomarker for acute lung injuries and acute respiratory distress syndrome. Whether the serum SP-D level could identify the severity of coronavirus disease 2019 (COVID-19) in the early stage has not been elucidated. Methods We performed an observational study on 39 laboratory-confirmed COVID-19 patients from The Fourth People’s Hospital of Yiyang, Hunan, China. Receiver operating characteristic (ROC) curve analysis, correlation analysis, and multivariate logistic regression model analysis were performed. Results In the acute phase, the serum levels of SP-D were elevated significantly in severe COVID-19 patients than in mild cases (mean value ± standard deviation (SD), 449.7 ± 125.8 vs 245.9 ± 90.0 ng/mL, PPP = 0.011), while markedly lower in the recovery period than those in the acute phase (median value, 2.0 vs 9.0, PP = 0.047), while positively correlated with CRP (r = 0.658, PP = 0.002), the duration of nucleic acid of throat swab turning negative (r = 0.668, PPP = 0.008). Multivariate logistic regression model analysis showed that age (P = 0.041, OR = 1.093) and SP-D (P = 0.008, OR = 1.018) were risk factors for severe COVID-19. Conclusions Elevated serum SP-D level was a potential biomarker for the severity of COVID-19; this may be useful in identifying patients whose condition worsens at an early stage.

PURPOSE: To assess anatomic changes after laser peripheral iridotomy (LPI) and predictors of angle widening based on anterior segment (AS) OCT and angle opening based on gonioscopy. DESIGN: Prospective observational study. PARTICIPANTS: Primary angle-closure suspects (PACSs) 50 to 70 years of age. METHODS: Participants of the Zhongshan Angle Closure Prevention (ZAP) Trial underwent gonioscopy and AS-OCT imaging at baseline and 2 weeks after LPI. Primary angle-closure suspect was defined as the inability to visualize pigmented trabecular meshwork in 2 or more quadrants on static gonioscopy. Laser peripheral iridotomy was performed on 1 eye per patient in superior (between 11 and 1 o'clock) or temporal or nasal locations (at or below 10:30 or 1:30 o'clock). Biometric parameters in horizontal and vertical AS-OCT scans were measured and averaged. Linear and logistic regression modeling were performed to determine predictors of angle widening, defined as change in mean angle opening distance measured at 750 μm from the scleral spur (AOD750); poor angle widening, defined as the lowest quintile of change in mean AOD750; and poor angle opening, defined as residual PACS after LPI based on gonioscopy. MAIN OUTCOME MEASURES: Anatomic changes and predictors of angle widening and opening after LPI. RESULTS: Four hundred fifty-four patients were included in the analysis. Two hundred nineteen underwent superior LPI and 235 underwent temporal or nasal LPI. Significant changes were found among most biometric parameters (P < 0.006) after LPI, including greater AOD750 (P < 0.001). One hundred twenty eyes (26.4%) showed residual PACS after LPI. In multivariate regression analysis, superior LPI location (P = 0.004), smaller AOD750 (P < 0.001), and greater iris curvature (P < 0.001), were predictive of greater angle widening. Temporal or nasal LPI locations (odds ratio [OR], 2.60, P < 0.001) was predictive of poor angle widening. Smaller mean gonioscopy grade (OR, 0.34, 1-grade increment) was predictive of poor angle opening. CONCLUSIONS: Superior LPI location results in significantly greater angle widening compared with temporal or nasal locations in a Chinese population with PACS. This supports consideration of superior LPI locations to optimize anatomic changes after LPI.

Germplasm preservation of livestock or endangered animals and expansion of germline stem cells are important. The purpose of this study is to investigate whether supplementation of trehalose to the freezing medium (FM) reduces tissular damage and improves the quality of testicular cells in the cryopreserved bovine testicular tissues. We herein established an optimized protocol for the cryopreservation of bovine testicular tissues, and the isolation as well as culture of bovine germ cells containing spermatogonial stem cells (SSCs) from these tissues. The results showed that FM containing 10% dimethyl sulfoxide (Me2SO/DMSO), 10% knockout serum replacement (KSR) and 20% trehalose (FM5) combined with the uncontrolled slow freezing (USF) procedures has the optimized cryoprotective effect on bovine testicular tissues. The FM5 + USF protocol reduced the cell apoptosis, maintained high cell viability, supported the structural integrity and seminiferous epithelial cohesion similar to that in the fresh tissues. Viable germ cells containing SSCs were effectively isolated from these tissues and they maintained germline marker expressions in the co-testicular cells and co-mouse embryonic fibroblasts (MEF) feeder culture systems respectively, during the short-term culture. Additionally, upregulated transcriptions of spermatogenic differentiation marker C-KIT and meiotic marker SYCP3 were detected in these cells after retinoic acid-induced differentiation. Together, FM5 + USF is suitable for the cryopreservation of bovine testicular tissues, with benefits of reducing the apoptosis, maintaining the cell viability, supporting the testicular structure integrity, and sustaining the survival and differentiation potential of bovine germ cells containing SSCs.

Melatonin mediates multiple physiological processes in plants and is involved in many reactions related to the protection of plants from abiotic stress. In this paper, the effect of melatonin on the antioxidant capacity of rice under salt stress was studied. Melatonin alleviated the inhibition of salt stress on the growth of rice seedlings, mainly by increasing the dry weight and fresh weight of shoots and roots. Melatonin alleviated the membrane damage caused by salt stress, which was mainly manifested by the decrease of TBARS content and the decrease of leaf and root damage. During the whole salt stress period, rice after melatonin pretreatment showed lower ROS (H2O2, O2•−,OH−) accumulation. In the early stage (1–3 d) of stress, the rice after melatonin pretreatment showed a strong increase in antioxidant enzyme activity, while in the later stage (5,7 d), it showed a strong increase in antioxidant content. During the whole period of salt stress, melatonin had a weak regulatory effect on AsA-GSH cycle. Through the above regulation process, the decreasing effect of melatonin on ROS content of rice under salt stress did not decrease with prolonged stress time in a short time (1-7 d). In conclusion, melatonin improved the antioxidant capacity of rice under continuous salt stress, and rice showed variable antioxidant strategies after melatonin pretreatment.

Purpose Numerous studies have applied a variety of methods to assess paraspinal muscle degeneration. However, the methodological differences in imaging evaluation may lead to imprecise or inconsistent results. This article aimed to provide a pragmatic summary review of the current imaging modalities, measurement protocols, and imaging parameters in the evaluation of paraspinal muscle fat infiltration (FI) in MRI studies. Methods Web of Science, EMBASE, and PubMed were searched from January 2005 to March 2020 to identify studies that examined the FI of paraspinal muscles on MRI among patients with lumbar degenerative diseases. Results Intramyocellular lipids measured by magnetic resonance spectroscopy and FI measured by chemical‐shift MRI were both correlated to low back pain and several degenerative lumbar diseases, whereas results on the relationship between FI and degenerative lumbar pathologies using conventional MRI were conflicting. Multi‐segment measurement of FI at the lesion segment and adjacent segments could be a prognostic indicator for lumbar surgery. Most studies adopted the center of the intervertebral disc or endplate as the level of slice to evaluate the FI. Compared with visual semiquantitative assessment, quantitative parameters appeared to be precise for eliminating individual or modality differences. It has been demonstrated that fat CSA/total CSA (based on area) and muscle–fat index (based on signal intensity) as quantitative FI parameters are associated with multiple lumbar diseases and clinical outcomes after surgery. Conclusion Having a good command of the methodology of paraspinal muscle FI on MRI was effective for diagnosis and prognosis in clinical practice., Heterogeneity in assessing the paraspinal muscle fat infiltration exists in imaging modalities, measurement protocols (including measured level and slices, region of interest definition, and fat detection methods), and imaging parameters (semiquantitative and quantitative parameters).

Background COVID-19 can lead to increased psychological symptoms such as post-traumatic stress disorder (PTSD), depression, and anxiety among patients with COVID-19. Based on the previous mindfulness-based interventions proved to be effective, this protocol reports a design of a randomized controlled trial aiming to explore the efficacy and possible mechanism of a mindful living with challenge (MLWC) intervention developed for COVID-19 survivors in alleviating their psychological problems caused by both the disease and the pandemic. Methods In April 2021, more than 1600 eligible participants from Hubei Province of China will be assigned 1:1 to an online MLWC intervention group or a waitlist control group. All participants will be asked to complete online questionnaires at baseline, post-program, and 3-month follow-up. The differences of mental health status (e.g. PTSD) and physical symptoms including fatigue and sleeplessness between the COVID-19 survivors who receiving the online MLWC intervention and the control group will be assessed. In addition, the possible mediators and moderators of the link between the MLWC intervention and target outcomes will be evaluated by related verified scales, such as the Five Facets Mindfulness Questionnaire. Data will be analyzed based on an intention-to-treat approach, and SPSS software will be used to perform statistical analysis. Discussion The efficacy and potential mechanism of MLWC intervention in improving the quality of life and psychological status of COVID-19 survivors in China are expected to be reported. Findings from this study will shed light on a novel and feasible model in improving the psychological well-being of people during such public health emergencies. Trial registration Chinese Clinical Trial Registry (ChiCTR), ChiCTR2000037524; Registered on August 29, 2020, http://www.chictr.org.cn/showproj.aspx?proj=60034.

The transcription factor nuclear factor erythroid-derived 2-like 2 (NRF2) participates in the activation of the antioxidant cytoprotective pathway and other important physiological processes to maintain cellular homeostasis. The dysregulation of NRF2 activity plays a role in various diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Thus, NRF2 activity is tightly regulated through multiple mechanisms, among which phosphorylation by kinases is critical in the posttranslational regulation of NRF2. For instance, PKC, casein kinase 2, and AMP-activated kinase positively, while GSK-3 negatively regulates NRF2 activity through phosphorylation of different sites. Here, we provide an overview of the phosphorylation regulation pattern of NRF2 and discuss the therapeutic potential of interventions targeting NRF2 phosphorylation.

Hepatocellular carcinoma (HCC) is a common malignancy, and the hepatitis B virus (HBV) is its major pathogenic factor. Over the past decades, it has been confirmed that HBV infection could promote disease progression through a variety of mechanisms, ultimately leading to the malignant transformation of liver cells. Many factors have been identified in the pathogenesis of HBV-associated HCC (HBV-HCC), including HBV gene integration, genomic instability caused by mutation, and activation of cancer-promoting signaling pathways. As research in the progression of HBV-HCC progresses, the role of many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immune suppression, is also being continuously explored. The occurrence of HBV-HCC is a complex process caused by interactions across multiple genes and multiple steps, where the synergistic effects of various cancer-promoting mechanisms accelerate the process of disease evolution from inflammation to tumorigenesis. In this review, we aim to provide a brief overview of the mechanisms involved in the occurrence and development of HBV-HCC, which may contribute to a better understanding of the role of HBV in the occurrence and development of HCC.

Depression associated with structural brain abnormalities is hypothesized to be related with accelerated brain aging. However, there is far from a unified conclusion because of clinical variations such as medication status, cumulative illness burden. To explore whether brain age is accelerated in never‐treated first‐episode patients with depression and its association with clinical characteristics, we constructed a prediction model where gray matter volumes measured by voxel‐based morphometry derived from T1‐weighted MRI scans were treated as features. The prediction model was first validated using healthy controls (HCs) in two Chinese Han datasets (Dataset 1, N = 130 for HCs and N = 195 for patients with depression; Dataset 2, N = 270 for HCs) separately or jointly, then the trained prediction model using HCs (N = 400) was applied to never‐treated first‐episode patients with depression (N = 195). The brain‐predicted age difference (brain‐PAD) scores defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with age‐, gender‐, educational level‐matched HCs in Dataset 1. Overall, patients presented higher brain‐PAD scores suggesting patients with depression having an “older” brain than expected. More specially, this difference occurred at illness onset (illness duration 2 years) in patients. This phenomenon was verified by another data‐driven method and significant correlation between brain‐PAD scores and illness duration in patients. Our results reveal that accelerated brain aging occurs at illness onset and suggest it is a stage‐dependent phenomenon in depression., With the help of prediction model built with two independent datasets, we found stage‐specially accelerated brain aging in patients with depression according to illness duration. Our results reveal that accelerated brain aging occurs at illness onset and suggest it is a stage‐dependent phenomenon in depression.

This study evaluated the gel and microstructure properties of scallop (Patinopecten yessoensis) male gonads hydrolysates (SMGHs) combined with xanthan gum (XG). SMGHs/XG hydrogel matrix properties and structures were elucidated via different analysis tools such as rheometry, LF-NMR, FTIR, AFM, and Cryo-SEM. The addition of XG significantly improved the rheological properties of SMGHs, as indicated by 3.1-fold G' and 1.3-fold melting temperature with increasing the XG dose to 5.6 mg/ml. The corresponding decrease in the T23 relaxation time from 450.3 to 365.6 ms also signified the strong binding between SMGHs and XG. SMGHs/XG also had a higher proton density (T1 and T2 weighted images) due to the higher bound and free water content of the hybrid gel systems, respectively. Additionally, the blueshift in the amide I and II bands in SMGHs/XG further indicated stronger electrostatic interactions between SMGHs and XG. Such scenarios resulted in a well-distributed and compact network with a rougher surface of SMGHs/XG in comparison to pure SMGHs and XG, as assessed by AFM and SEM. These results suggest that SMGHs/XG gel could be a potential hybrid gel applied in the food industry. PRACTICAL APPLICATION: Scallop (Patinopecten yessoensis) male gonads are edible, but are usually discarded during processing of scallop adductor. Because of its rich nutrition and gelation properties, scallop male gonads have a potential role in developing marine source-protein as a functional food base. The SMGHs/XG binary gel would be potentially applied in delivery system in food and biological fields. Further study is undergoing to apply SMGHs/XG binary gel to embed bioactive compounds, such as curcumin and β-carotene.

Background Preweaned rumen development is vital for animal health and efficient fermentation. In this study, we integrated ruminal transcriptomic and metagenomic data to explore the dynamics of rumen functions, microbial colonization, and their functional interactions during the first 8 weeks of life in goats. Results The dynamic rumen transcriptomic and microbial profiles both exhibited two distinct phases during early rumen development. The differentially expressed genes of the rumen transcriptome between the two phases showed that the immune-related response was enriched in the first phase and nutrient-related metabolism was enriched in the second phase, whereas the differentially expressed genes of the rumen microbiome were enriched in bacteriocin biosynthesis and glycolysis/gluconeogenesis activities. The developmental shift in the rumen transcriptome (at d 21) was earlier than the feed stimulus (at d 25) and the shift in the rumen microbiome (at d 42). Additionally, 15 temporal dynamic rumen gene modules and 20 microbial modules were revealed by coexpression network analysis. Functional correlations between the rumen and its microbiome were primarily involved in rumen pH homeostasis, nitrogen metabolism and the immune response. Rumen gene modules associated with the microbial alpha diversity index were also enriched in the immune response process. Conclusions The present study touched the critical developmental process of rumen functions, microbial colonization and their functional interactions during preweaned development. Taken together, these results demonstrated that rumen development at the first phase is more likely a programmed process rather than stimulation from feed and the microbiome, while the shift of rumen metagenomes was likely regulated by both the diet and host. The intensive functional correlations between rumen genes and the microbiome demonstrated that synergistic processes occurred between them during early rumen development.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare, benign neoplasm with a predilection for children that predominantly involves the craniofacial region. Here we report 2 cases of MNTI involving epididymis, placing emphasis on the sonographic features. Both appeared to be hypoechoic, regular shaped masses with abundant blood supplies. The unique sonographic features and age of predilection make it possible to diagnose MNTI within the scrotum by ultrasonography.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [(14)C]-uric acid in URAT1-expressing HEK293 cells with an IC(50) value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC(50) value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC(50) value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg(−1) · d(−1)) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg(−1) · d(−1)) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.

Dysregulations in transcription factors (TFs) and their genetic products play important roles in tumorigenesis, tumor progression and metastasis. However, prognostic value of the transcriptional regulatory networks in different cancers has not been investigated in depth. The purpose of our study was to identify and validate a potential predictive signature that combines TFs and their regulatory products in eight solid tumors. We used bioinformatics analysis to identify MET Transcriptional Regulator (MACC1) and Serine Peptidase Inhibitor Kunitz Type 1 (SPINT1) as candidate TFs with the respective downstream regulatory proteins for patient prognosis in pan‐cancer. Subsequent molecular analysis of clinical gastric cancer tissue samples further verified the negative correlation between MACC1 and SPINT1. Further, we showed that mechanistically, MACC1/SPINT1 mediated the pro‐HGF proteolysis and c‐Met phosphorylation in HGF/c‐MET signaling pathway. Kaplan‐Meier plots and receiver operating characteristics analysis revealed that the two‐gene signature combining MACC1 with SPINT1 was effective in predicting survival in all eight cancer cohorts tested. In conclusion, our study clarified the regulatory relationship between MACC1 and SPINT1 in the context of the HGF/c‐MET signaling pathway and determined MACC1/SPINT1 panel as a valuable signature for the prediction of prognosis in patients for multiple solid cancer types., The manuscript addressed on the regulatory relationship and tumor prognostic value of transcription factors (TFs) MACC1 and transmembrane protein SPINT1. Through bioinformatics analysis and molecular experiments, we verified the transcriptional regulatory relationship and biological functions of MACC1 and SPINT1 in HGF/c‐Met signaling axis. Besides, MACC1/SPINT1 panel was established to effectively predict survival in eight cancers.

The clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (Cas9)-based genome editing tool pCas/pTargetF system that we established previously has been widely used in Escherichia coli MG1655. However, this system failed to manipulate the genome of E. coli BL21(DE3), owing to the potential higher leaky transcription of the gRNA-pMB1 specific to pTargetF in this strain. In this study, we modified the pCas/pTargetF system by replacing the promoter of gRNA-pMB1 with a tightly regulated promoter PrhaB, changing the replicon of pCas to a nontemperature-sensitive replicon, adding the sacB gene into pCas, and replacing the original N20-specific sequence of pTargetF with ccdB gene. We call this updated system as pEcCas/pEcgRNA. We found that gRNA-pMB1 indeed showed a slightly higher leaky expression in the pCas/pTargetF system compared with pEcCas/pEcgRNA. We also confirmed that genome editing can successfully be performed in BL21(DE3) by pEcCas/pEcgRNA with high efficiency. The application of pEcCas/pEcgRNA was then expanded to the E. coli B strain BL21 StarTM (DE3), K-12 strains MG1655, DH5α, CGMCC3705, Nissle1917, W strain ATCC9637, and also another species of Enterobacteriaceae, Tatumella citrea DSM13699, without any specific modifications. Finally, the plasmid curing process was optimized to shorten the time from $\sim$60 h to $\sim$32 h. The entire protocol (including plasmid construction, editing, electroporation and mutant verification, and plasmid elimination) took only $\sim$5.5 days per round in the pEcCas/pEcgRNA system, whereas it took $\sim$7.5 days in the pCas/pTargetF system. This study established a faster-acting genome editing tool that can be used in a wider range of E. coli strains and will also be useful for other Enterobacteriaceae species.

Current studies on circulating cell-free DNA (cfDNA) have been focusing on its potential as biomarkers in liquid biopsy by detecting its content or genetic and epigenetic changes for the evaluation of tumor burden and therapeutic efficacy. However, the regulatory mechanism of cfDNA release remains unclear. Stat3 has been documented as an oncogene for the development and metastasis of breast cancer cells. In this study, we investigated whether Stat3 affects the release of cfDNA into blood and its association with the number of circulating tumor cells (CTCs). The cfDNA level in plasma of patients with breast cancer and healthy volunteers were determined by quantitative real-time PCR. Three mouse breast cancer models with different Stat3 expression were generated and used to established three breast cancer orthotopic animal models to examine the effect of Stat3 on cfDNA release in vivo. Stat3 mediated Epithelial-mesenchymal phenotype transition of CTCs was determined by immunofluorescence assay and Western blot assay. The data showed that Stat3 increased circulating cfDNA, which is correlated with the increased volume of primary tumors and number of CTCs, accompanied with the dynamic EMT changes regulated by Snail induction. Furthermore, the high level of total circulating cfDNA and Stat3-cfDNA in patients with breast cancer were detected by quantitative real-time PCR using GAPDH and Stat3 primers. Our results suggested that Stat3 increases the circulating cfDNA and CTCs in breast cancer.

Intracrine androgen synthesis plays a critical role in the development of castration-resistant prostate cancer (CRPC). Aldo-keto reductase family 1 member C3 (AKR1C3) is a vital enzyme in the intracrine androgen synthesis pathway. In this study, mesoporous silica nanoparticles (MSNs) were employed to deliver small interfering RNA targeting AKR1C3 (siAKR1C3) to downregulate AKR1C3 expression in CPRC cells. The optimal weight ratio of MSNs/siAKR1C3 was determined by a gel retardation assay. Prostate cancer cells such as VCaP cells, which intracrinally express AKR1C3, and LNCaP-AKR1C3 cells stably transfected with AKR1C3 were used to investigate the antitumour effect of MSNs-siAKR1C3. Fluorescence detection and Western blot analyses were applied to confirm the entrance of MSNs-siAKR1C3 into the cells. A SRB (Sulforhodamine B) assay was employed to assess the cell viability, and a radioimmunoassay was used to measure the androgen concentration. Moreover, real-time PCR (RT-PCR), Western blot analysis and ELISA were used to determine the transcription and expression of prostate-specific antigen (PSA), AKR1C3 and androgen receptor (AR). Meanwhile, a reporter gene assay was performed to determine the AR activity. Additionally, a castrated nude mouse xenograft tumour model was produced to verify the inhibitory effect of MSNs-siAKR1C3 in vivo. The results showed that the optimal weight ratio of MSNs/siAKR1C3 was 140:1, and the complex could effectively enter cells, downregulate AKR1C3 expression, reduce the androgen concentration, inhibit AR activation, and inhibit CRPC development both in vitro and in vivo. These results indicate that decreasing intracrine androgen synthesis and inactivating AR signals by MSNs-siAKR1C3 may be a potential effective method for CRPC treatment.

The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside (AICAR) or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that, consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy and improves hepatic insulin sensitivity in high-fat-diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.

The current evidence regarding the prevalence of subclinical carotid atherosclerosis (SCA) for people living with HIV(PLWH) is inconsistent. In this study, we aimed to synthesize data on the prevalence and association of SCA patients with HIV infection. We searched PubMed, EMBASE, Web of Science, Medline, SinoMed, and CNKI from inception to March 2, 2020. The pooled proportion, odds ratio (OR) with 95% confidence intervals (CIs) were calculated. For inclusion, SCA was measured by carotid intima-media thickness (CIMT), with a B-mode ultrasound machine. Twenty-six studies consisting of 6590 participants were identified. The overall prevalence of SCA was 31.6% (95% CI 13.4‐53.3; I2 = 99%; 4 studies) according to CIMT ≥ 0.78 mm criteria, and 32.3% (19.6‐46.4; 97%; 10 studies) according to CIMT ≥ 0.90 mm criteria. SCA prevalence was higher in Europe, over 40 years old and male. What’s more, PLWH have a higher likelihood of developing SCA comorbidity than HIV-negative controls (pooled OR 2.66, 95% CI 1.57‐4.50, I2 = 74%; 9 studies), even after sensitivity analysis (pooled OR 2.58, 1.54‐4.31, 73%). This study suggests a high prevalence and risk of SCA in the global population with HIV. As a result, subclinical carotid atherosclerosis deserves more attention from policymakers, HIV health-care providers, researchers, and stakeholders.

PurposeTo investigate the associations between body mass index (BMI) with diabetes mellitus (DM) and vision-threatening diabetic retinopathy (VTDR).MethodsThis was a longitudinal study which included DM-free participants aged ≥40 years from the Lingtou Eye Cohort Study at baseline (2008–2010). Physical and ocular examinations were performed at baseline and annual follow-ups under standardised protocol. Two 45° non-mydriatic colour digital retinal photographs were obtained for each eye at all study visits, and presence of VTDR at the 2016 follow-up was graded by a deep-learning algorithm (LableMe) with proved high accuracy for detection of VTDR.ResultsA total of 2934 participants were included with a mean (SD) age of 59.5 (7.3) years (58.3% men). Participants with incident DM (441/2934, 15%) were significantly older (pConclusionsHigher baseline BMI increased the risk of incident DM, but was not related to the risk of VTDR in this adult Chinese population.

Copy number variation (CNV) is the most prevalent type of genetic structural variation that has been recognized as an important source of phenotypic variation in humans, animals and plants. However, the mechanisms underlying the evolution of CNVs and their function in natural or artificial selection remain unknown. Here, we generated CNV region (CNVR) datasets which were diverged or shared among cattle, goat, and sheep, including 886 individuals from 171 diverse populations. Using 9 environmental factors for genome-wide association study (GWAS), we identified a series of candidate CNVRs, including genes relating to immunity, tick resistance, multi-drug resistance, and muscle development. The number of CNVRs shared between species is significantly higher than expected (P

Objective: The aim of this study was to observe the liver function recovery of COVID-19 patients after discharge. Patients and Methods: A total of 253 discharged COVID-19 patients in Shenzhen city, China were selected. The clinical characteristics of these patients were assessed. A 2-month follow-up and laboratory hematology test were performed to examine the status of patients' liver function. Results: Patients combined with liver diseases, especially fatty liver, are more likely to progress to severe condition (P

Background: Berberine, as an alkaloid, has a significant antitumor effect, but its mechanism in tumor metabolism, especially the Warburg effect has not been elucidated. Objectives: To study the molecular mechanism of berberine regulating the Warburg effect in ovarian cancer cells. Methods: Treatment by berberine in SKOV3 and 3AO cells or inhibited by miR-145 inhibitor transfection in berberine-treated cells to examine the changes in HK2 expression, glucose consumption and lactate production. The methylation status in the promoter region of pre-miR-145 gene was examined by bisulfite sequencing. Dual-luciferase reporter assay was conducted to verify the direct binding of miR-145 to HK2. Finally, the expression of TET3 in ovarian cancer was investigated by quantitative real-time PCR and immunohistochemistry. Results: We found berberine inhibited the Warburg effect by up-regulating miR-145, miR-145 targeted HK2 directly. Berberine increased the expression of miR-145 by promoting the expression of TET3 and reducing the methylation level of the promoter region of miR-145 precursor gene. We further found that TET3 expression was negatively correlated with clinical stage and pathological grade. Conclusions: Our results revealed berberine increased the TET3-mediated demethylation and promoted the suppression of miR-145 on HK2 to antagonize the Warburg effect of ovarian cancer cells.

Ovarian cancer is the first leading cause of death in gynecological cancers. The continuous survival and metastasis of cancer cells are the main causes of death and poor prognosis in patients with ovarian cancer. Berberine is an effective component extracted from the rhizomes of coptis chinensis and phellodendron chinensis. In our study, we aim to explore the molecular mechanism underlying the regulation of proliferation, migration and invasion by berberine in ovarian cancer cells. CCK8 assay was used for detection of proliferative capacity of SKOV3 and 3AO cells. Wound healing assay was used to estimate cell migration and transwell assay was used to assess cell invasion. The mRNA expression of miR-145 and MMP16 were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein level of MMP16 was detected by western blot analysis. In addition, luciferase reporter assays were used to demonstrate MMP16 was a target of miR-145. The results demonstrated berberine inhibited proliferation, migration and invasion, promoted miR-145 expression, and decreased MMP16 expression in SKOV3 and 3AO cells. MMP16 was a target of miR-145. Moreover, downregulation of MMP16 contributed to the inhibition of proliferation, migration and invasion by berberine. Together, our results revealed that berberine inhibited proliferation, migration and invasion through miR-145/MMP16 in SKOV3 and 3AO cells, highlighting the potentiality of berberine to be used as a therapeutic agent for ovarian cancer.

Treatment options for unresectable local recurrence or metastatic well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS) remain limited. Different liposarcoma subtypes have varying clinical features and sensitivities to treatment regimens. The multitarget tyrosine kinase inhibitors (TKIs), such as pazopanib and regorafenib, have been approved for use in nonadipocytic soft tissue sarcomas (STS). Anlotinib, another TKI, has been approved in China for treating metastatic STS that has progressed after the use of anthracycline-based regimens. In this study, we aimed to evaluate the role of anlotinib in the treatment of local recurrence or metastatic WDLS/DDLS. From August 2018 to June 2020, 17 patients with unresectable local recurrence or metastatic WDLS/DDLS treated with anlotinib in our center were included. The follow-up cutoff time was set as 20 October 2020. Baseline and observation indicators were collected and analyzed. Estimated median progression-free survival (PFS) was 27.9 weeks, the PFS rate at 24 weeks was 58.8%, overall survival (OS) was 56.6 weeks, the disease control rate was 64.7% and no complete response or partial response was detected. Grade 3/4 adverse events occurred in four cases and could be managed. Anlotinib is a potential treatment option for unresectable local recurrence or metastatic WDLS/DDLS.

Abstract N-butanol is an important chemical and can be naturally synthesized by Clostridium species; however, the poor n-butanol tolerance of Clostridium impedes the further improvement in titer. In this study, Lactobacillus brevis, which possesses a higher butanol tolerance, was selected as host for heterologous butanol production. The Clostridium acetobutylicum genes thl, hbd, and crt which encode thiolase, β-hydroxybutyryl-CoA dehydrogenase, and crotonase, and the Treponema denticola gene ter, which encodes trans-enoyl-CoA reductase were cloned into a single plasmid to express the butanol synthesis pathway in L. brevis. A titer of 40 mg/L n-butanol was initially achieved with plasmid pLY15-opt, in which all pathway genes are codon-optimized. A titer of 450 mg/L of n-butanol was then synthesized when ter was further overexpressed in this pathway. The role of metabolic flux was reinforced with pLY15, in which only the ter gene was codon-optimized, which greatly increased the n-butanol titer to 817 mg/L. Our strategy significantly improved n-butanol synthesis in L. brevis and the final titer is the highest achieved amongst butanol-tolerant lactic acid bacteria. Graphic abstract

Alzheimer's disease (AD) is a complex pathological neurodegenerative disease that seriously threatens human health. Therefore, how to effectively improve and treat AD is an urgent problem. In this study, a novel multitarget derivative based on tacrine (named 9i), which could work simultaneously on more than one pathological target, was used to treat AD model APP/PS1 transgenic mice. After 4 weeks of intragastric administration, cognitive function and synaptic plasticity were significantly improved and β-amyloid (Aβ) plaques that are main pathological hallmarks of AD were decreased in the APP/PS1 mice. On the one hand, 9i inhibited the excessive activation of the Raf/MEK/ERK signaling pathway to alleviate the loss of neurons, which provides a foundation for structural integrity. On the other hand, synaptic associated proteins and the density of synaptic spines were increased in APP/PS1 mice treated with 9i, which provides the basis for the improvement of synaptic plasticity and cognitive impairment. Interestingly, 9i also reduced Aβ plaques in the DG region, which is consistent with previous in vitro experiments showing that 9i inhibited the self-assembly of Aβ fibers, thus protecting neurons from Aβ plaque neurotoxicity. Our results suggest that 9i as a novel compound can effectively improve the cognitive function and the pathological changes of AD in APP/PS1 transgenic mice.

OBJECTIVE: To investigate the differences of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and galectin-3 concentrations in lobar pneumonia and bronchopneumonia induced by mycoplasma pneumoniae (MP) in children and to explore these related factors predicting the severity of MP. METHODS: A total of 148 children with mycoplasma pneumoniae pneumonia (MPP) and 32 healthy controls were analyzed from March 2017 to August 2018 in our province. Clinical information was collected from the hospitalized MP patients. The 148 patients with MPP were divided into two groups: lobar pneumonia group and bronchial pneumonia group. The 32 healthy children were considered the control group. The concentrations of TNF-α, IL-6 and Gal-3 were examined in the serum of 148 children patients with MPP and 32 healthy children by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The TNF-α, IL-6 and Gal-3 levels were obviously higher in both the lobar pneumonia and bronchial pneumonia groups, compared to those in the control group. Furthermore, these levels were significantly higher in the lobar pneumonia group, compared to the bronchial pneumonia group. After treatment, the levels of TNF-α, IL-6 and Gal-3 totally descended during the recovery period. CONCLUSION: There are differences in serum TNF-α, IL-6 and Gal-3 concentrations in lobar pneumonia and bronchial pneumonia caused by MP in children. In general, the TNF-α, IL-6 and Gal-3 levels were significantly higher in the lobar pneumonia group, when compared to the bronchial pneumonia group. This was because most lobar pneumonia cases are much more serious than bronchial pneumonia. Moreover, it has been proven that TNF-α, IL-6 and Gal-3 may play an important role in the pathogenesis development of MPP. At the same time, these are important issues in diagnosing MPP.

Background: Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer’s disease (AD). Objective: To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. Methods: We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson’s correlation analysis followed by multiple linear regression separately in the original population and matched participants. Results: After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r = 0.222, p = 0.008) but not in patients with AD (r = 0.137, p = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β= 7.347, p = 0.014) but not in the AD group (β= 10.409, p = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. Conclusion: The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

Microsporidia are a group of obligate intracellular parasites causing significant disease in human beings and economically important animals. Though a few spore wall proteins (SWPs) have now been identified in these intriguing species, the information on SWPs remains too little to elucidate the spore wall formation mechanisms of microsporidia. It has been well described that numerous proteins with tandem repeats tend to be localized on the cell wall of fungi and parasites. Previously, by scanning the proteins with tandem repeats in microsporidian Nosema bombycis, we obtained 83 candidate SWPs based on whether those proteins possess a signal peptide and/or transmembrane domain. Here, we further characterized a candidate protein (EOB13250) with three tandem repeats in the N-terminal region and a transmembrane domain in C-terminus of N. bombycis. Sequence analysis showed that the tandem repeat domain of EOB13250 was species-specific for this parasite. RT-PCR indicated that the expression of the gene encoding this protein started on the fourth day postinfection. After cloned and expressed in Escherichia coli, a polyclone antibody against the recombinant EOB13250 protein was prepared. Western blotting demonstrated this protein exist in N. bombycis. Immunofluorescence analysis (IFA) and immunoelectron microscopy analysis (IEM) further provided evidence that EOB13250 was an endospore wall protein. These results together suggested that EOB13250 was a novel spore wall protein of N. bombycis. This study provides a further enrichment of the number of identified spore wall proteins in microsporidia and advances our understanding of the spore wall formation mechanism in these obligate unicellular parasites.

Background The Tibetan population is minority in southwest China, and data on the psychological states of Tibetan cancer inpatients are not available. The study participants included Tibetan and Han cancer inpatients, and their depression and anxiety were investigated and analyzed to understand the psychological states of Tibetan cancer patients. The aim of the present study was to understand the incidence of depression and anxiety among Tibetan cancer inpatients, and the factors affecting their depression and anxiety. Methods We used questionnaires to investigate the anxiety and depression of Tibetan and Han cancer inpatients. The questionnaires included the Zung Self-Rating Anxiety Scale, Zung Self-Rating Depression Scale, and a general information questionnaire. Results The results showed that there were 61 cases (53%) of depression and 43 (37.4%) of anxiety among Tibetan cancer inpatients, and 27 cases (23.5%) and 16 (13.9%) among Han cancer patients. The major factors affecting depression among Tibetan cancer patients were permanent address and type and stage of cancer; the major factors affecting anxiety among Tibetan cancer patients were education level and type and stage of cancer. Conclusions The incidence of depression and anxiety among Tibetan cancer inpatients was significantly greater than that of Han cancer inpatients. The major factors affecting the incidence of depression and anxiety were permanent address, education level, and type and stage of cancer. We suggest that further research should be directed at mental health problems among Tibetan cancer patients in order to determine the best possible psychological interventions.

The association between polycystic ovary syndrome (PCOS) and breast cancer remains inconclusive. Conventional observational studies are susceptible to inverse causality and potential confounders. With a Mendelian randomization (MR) approach, we aimed to investigate the causal relationship between genetically predicted PCOS and breast cancer risk. Our study included 11 PCOS-associated single nucleotide polymorphisms as instrumental variables identified by the latest genome-wide association study. Individual-level genetic summary data of participants were obtained from the Breast Cancer Association Consortium, with a total of 122,977 cases and 105,974 controls. The inverse-variance weighted method was applied to estimate the causality between genetically predicted PCOS and breast cancer risk. To further evaluate the pleiotropy, the weighted median and MR-Egger regression methods were implemented as well. Our study demonstrated that genetically predicted PCOS was causally associated with an increased risk of overall breast cancer (odds ratio (OR) = 1.07; 95% confidence interval (CI) 1.02–1.12, p = 0.005). The subgroup analyses according to immunohistochemical type further illustrated that genetically predicted PCOS was associated with an increased risk of estrogen receptor (ER)-positive breast cancer (OR = 1.09; 95% CI 1.03–1.15, p = 0.002), while no causality was observed for ER-negative breast cancer (OR = 1.02; 95% CI 0.96–1.09, p = 0.463). In addition, no pleiotropy was found in our study. Our findings indicated that PCOS was likely to be a causal factor in the development of ER-positive breast cancer, providing a better understanding for the etiology of breast cancer and the prevention of breast cancer.

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein–protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision., Graphical abstract This review summarizes the current states on modulation of molecular chaperone by small molecules, focusing on the protein fate decision by comprehensive strategies and different mechanisms.Image 1

B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy. Recently, an increasing number of Mcl-1-selective small-molecule inhibitors have entered preclinical studies and advanced into clinical trials. In this review, we briefly introduce the role of Mcl-1 in apoptosis and highlight the recent development of Mcl-1 small-molecule inhibitors.

Having great medicinal values, Dendrobium species of “Fengdou” (DSFs) are a taxonomically complex group in Dendrobium genus including many closely related and recently diverged species. Traditionally used DNA markers have been proved to be insufficient in authenticating many species of this group. Here, we investigated 101 complete plastomes from 23 DSFs, comprising 72 newly sequenced and 29 documented, which all exhibited well-conserved genomic organization and gene order. Plastome-wide comparison showed the co-occurrence of single nucleotide polymorphisms (SNPs) and insertions/deletions (indels), which can be explained by both the repeat-associated and indel-associated mutation hypotheses. Moreover, guanine-cytosine (GC) content was found to be negatively correlated with the three divergence variables (SNPs, indels and repeats), indicating that GC content may reflect the level of the local sequence divergence. Our species authentication analyses revealed that the relaxed filtering strategies of sequence alignment had no negative impact on species identification. By assessing the maximum likelihood (ML) trees inferred from different datasets, we found that the complete plastome and large single-copy (LSC) datasets both successfully identified all 23 DSFs with the maximum bootstrap values. However, owing to the high efficiency of LSC in species identification, we recommend using LSC for accurate authentication of DSFs., Graphical abstract Compared with other datasets, the large single-copy (LSC) and complete plastome datasets both exhibited the highest discriminatory power of 100% for Dendrobium species of “Fengdou” (DSFs). Considering the potential advantages of LSC in the efficiency and cost of authentication, we recommend using the LSC for accurate authentication of DSFs.Image 1

Heterogeneity is a hallmark of many complex diseases. There are multiple ways of defining heterogeneity, among which the heterogeneity in genetic regulations, for example GEs (gene expressions) by CNVs (copy number variations) and methylation, has been suggested but little investigated. Heterogeneity in genetic regulations can be linked with disease severity, progression, and other traits and is biologically important. However, the analysis can be very challenging with the high dimensionality of both sides of regulation as well as sparse and weak signals. In this article, we consider the scenario where subjects form unknown subgroups, and each subgroup has unique genetic regulation relationships. Further, such heterogeneity is "guided" by a known biomarker. We develop an MSF (Multivariate Sparse Fusion) approach, which innovatively applies the penalized fusion technique to simultaneously determine the number and structure of subgroups and regulation relationships within each subgroup. An effective computational algorithm is developed, and extensive simulations are conducted. The analysis of heterogeneity in the GE-CNV regulations in melanoma and GE-methylation regulations in stomach cancer using the TCGA data leads to interesting findings., Comment: 24 pages, 8 figures

The Y chromosome plays key roles in male fertility and reflects the evolutionary history of paternal lineages. Here, we present a de novo genome assembly of the Hu sheep with the first draft assembly of ovine Y chromosome (oMSY), using nanopore sequencing and Hi-C technologies. The oMSY that we generated spans 10.6 Mb from which 775 Y-SNPs were identified by applying a large panel of whole genome sequences from worldwide sheep and wild Iranian mouflons. Three major paternal lineages (HY1a, HY1b and HY2) were defined across domestic sheep, of which HY2 was newly detected. Surprisingly, HY2 forms a monophyletic clade with the Iranian mouflons and is highly divergent from both HY1a and HY1b. Demographic analysis of Y chromosomes, mitochondrial and nuclear genomes confirmed that HY2 and the maternal counterpart of lineage C represented a distinct wild mouflon population in Iran that diverge from the direct ancestor of domestic sheep, the wild mouflons in Southeastern Anatolia. Our results suggest that wild Iranian mouflons had introgressed into domestic sheep and thereby introduced this Iranian mouflon specific lineage carrying HY2 to both East Asian and Africa sheep populations.

We aimed to elucidate the associations between aspirin use with risk of lung cancer, by conducting a meta-analysis and Mendelian randomization (MR) analyses from published Genome-Wide Association Studies (GWAS). Cohort studies, nested case–control studies, and randomized controlled trials (RCTs) investigating the impact of aspirin exposure and lung cancer incidence were included. Relative risk (RR) and its 95% confidence interval (CI) were evaluated in eligible studies. Subgroup analyses regarding gender, pathologic subtypes and smoking status were also executed. MR analyses were conducted using summary statistics obtained from two large consortia [Neale Lab and International Lung Cancer Consortium (ILCCO)] to assess the possible causal relationship of aspirin on lung cancer incidence. Sixteen eligible studies involving 1,522,687 patients were included. The combined RR of aspirin use for the incidence of lung cancer was 0.95 (95% confidence interval (CI) 0.91–0.98). In subgroup meta-analyses, a significant protective effect was observed in squamous cell lung cancer (RR = 0.80; 95% CI 0.65–0.98). In terms of gender, the chemopreventive value was only observed among men (RR = 0.87; 95% CI 0.77–0.97). The MR risk analysis suggested a causal effect of aspirin on lung cancer incidence, with evidence of a decreased risk for overall lung cancer (OR = 0.042; 95% CI 0.003–0.564) and squamous cell lung cancer (OR = 0.002; 95% CI 1.21 × 10–5–0.301). Our study provided evidence for a causal protective effect of aspirin on the risk of lung cancer incidence among men, particularly on the squamous cell lung cancer risk.

The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified 19a as the most potent inhibitor in this series, with an IC50 of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of 19a. Compound 19a dose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.

Aberrant inflammasome activation contributes to the pathogenesis of various human diseases, including atherosclerosis, gout, and metabolic disorders. Elucidation of the underlying mechanism involved in the negative regulation of the inflammasome is important for developing new therapeutic targets for these diseases. Here, we showed that Raf kinase inhibitor protein (RKIP) negatively regulates the activation of the NLRP1, NLRP3, and NLRC4 inflammasomes. RKIP deficiency enhanced caspase-1 activation and IL-1β secretion via NLRP1, NLRP3, and NLRC4 inflammasome activation in primary macrophages. The overexpression of RKIP in THP-1 cells inhibited NLRP1, NLRP3, and NLRC4 inflammasome activation. RKIP-deficient mice showed increased sensitivity to Alum-induced peritonitis and Salmonella typhimurium-induced inflammation, indicating that RKIP inhibits NLRP3 and NLRC4 inflammasome activation in vivo. Mechanistically, RKIP directly binds to apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and competes with NLRP1, NLRP3, or NLRC4 to interact with ASC, thus interrupting inflammasome assembly and activation. The depletion of RKIP aggravated inflammasome-related diseases such as monosodium urate (MSU)-induced gouty arthritis and high-fat diet (HFD)-induced metabolic disorders. Furthermore, the expression of RKIP was substantially downregulated in patients with gouty arthritis or type 2 diabetes (T2D) compared to healthy controls. Collectively, our findings suggest that RKIP negatively regulates NLRP1, NLRP3, and NLRC4 inflammasome activation and is a potential therapeutic target for the treatment of inflammasome-related diseases.

Background Peroxiredoxin 1 (PRDX1) has been identified as a dual regulator of tumorigenesis. However, its expression, clinical significance, and biological function in nasopharyngeal carcinoma (NPC) remain unknown. This study aimed to explore the role and underlying mechanisms of PRDX1 in NPC. Materials and methods The expression of PRDX1 in NPC tissues was evaluated by immunohistochemistry, and the relationships between the expression of PRDX1 and clinical features and prognosis of NPC patients were analyzed. The effects of PRDX1 on NPC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) were examined. A tumor-bearing model of nude mouse was established to verify the function of PRDX1 in vivo. Results PRDX1 expression level was negatively associated with recurrence and metastasis of NPC. PRDX1 knockdown promoted NPC cell proliferation, migration, invasion and EMT in vitro, and enhanced tumor growth in vivo, while PRDX1 overexpression had opposite effects. Furthermore, transcriptome analysis showed that PRDX1 inhibited the activation of PI3K/AKT/TRAF1 signaling in NPC cells. Conclusion PRDX1 inhibits NPC by inhibiting the activation of PI3K/AKT/TRAF1 signaling. PRDX1 is a tumor suppressor in human NPC and may be a prognostic biomarker for NPC patients.

Highlights • Epidemic dynamics of COVID-19 by age and gender groups in South Korea are different. • The epidemic process of COVID-19 was driven by young people aged 20-39, with two peaks from Feb 19 to May 2, 2020. • The epidemic in the elderly people had been declining steadily after Mar. 15, 2020, despite large fluctuations in daily new cases among young people. • Elderly people can be effectively protected during the COVID-19 pandemic., Objectives Elderly people had suffered disproportional burden of COVID-19. We hypothesized that males and females in different age groups might have different epidemic trajectories. Methods Using publicly available data from South Korea, daily new COVID-19 cases were fitted with generalized additive models, assuming Poisson and negative binomial distributions. Epidemic dynamics by age and gender groups were explored with interactions between smoothed time terms and age and gender. Results A negative binomial distribution fitted the daily case counts best. Interaction between the dynamic patterns of daily new cases and age groups was statistically significant (p

The objective of this study is to report a case of deep endometriosis of the paralumbar muscles (psoas, multifidus, and erector spinae) and review existing literature on its management. A 34-year-old female with a history of endometriosis was seen for infertility. Paralumbar muscle masses seen on computed tomography (CT) scan were sampled, confirming endometriosis. Gonadotropin-releasing hormone agonist was given for 2 months. The patient was primed for assisted reproduction. A literature review was conducted to provide an understanding of paralumbar muscle endometriosis. To our knowledge, this is the first reported case of multifidus and erector spinae muscle endometriosis and fifth case of psoas muscle endometriosis. Because the available information is scarce, data from the existing literature on deep endometriosis may aid in the diagnosis and management. Magnetic resonance imaging and CT scan are essential imaging techniques to map lesions. Excision seems prudent, but the approach should be individualized depending on the patient's presentation and her preferences.

As the computer processing technique and display technology evolved dramatically, the surgical approach to early-stage non-small cell lung cancer (NSCLC) has made a rapid progress within the past few years. Currently, the gold standard for NSCLC is lobectomy. After the introduction of video-assisted thoracoscopic surgery (VATS), lung resection can now be conducted mini-invasively, enabling better prognosis for patients and better operation condition for surgeons. At the very beginning, the conventional two-dimensional (2D) system enabled operators to have a closer, magnified and illuminated view inside the body cavity than open thoracotomy. With the introduction of the glasses-assisted three-dimensional (3D) and glasses-free 3D display system, multiple viewing angles were further enhanced, thus a more stable, easier to master and less invasive video-assisted thoracoscopic surgery (VATS) appeared. However, given that the standard VATS is associated with limited maneuverability and stereoscopy, it restricts the availability in more advanced cases. Hopefully, most of the limitations of standard VATS can be overcome with the robotic-assisted thoracic surgery (RATS). The RATS system consists of a remote console and a robotic unit with 3 or 4 arms that can duplicate surgeons’ movements. Also, it provides a magnified, 3D and high definition (HD) operation field to surgeons, allowing them to perform more complicated procedures. Apart from these, some new technologies are also invented in combination with the existing surgery system to solve difficult problems. It is hoped that the higher costs of innovative surgical technique can be offset by the better patient outcomes and improved benefits in cost-effectiveness.

The JAK family (JAK1, JAK2, JAK3, and TYK2) have recently emerged as a potential therapeutic management in controlling severe and refractory dermatomyositis. Meanwhile, the progress in the discovery of JAK blockers is significant, with an increasing number of selective JAK inhibitors reported and some are in or prepare for clinical trials. However, the importance of each JAK in dermatomyositis is unclear, which is critical for a comprehensive understanding of dermatomyositis and significant for forming mechanism-based strategy. Here, we presented a case with clinically amyopathic dermatomyositis and essential thrombocytosis with a somatic constitutive active mutation of JAK2(V617F). The coexistence of these two uncommon diseases attracted us to investigate their underlying relationship. To this end, we characterized the clinical course and laboratory findings of this patient. Particularly, we correlated JAK2(V617F) mutation burden in affected peripheral blood subset with clinical activity score of dermatomyositis. Based on our observation, we concluded that these two diseases are independent disorders, and JAK2(V617F) mutation burden is irrelevant to the severity of dermatomyositis. Finally, we reviewed the literature and summarized them with a thorough discussion.