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Abstract Female urethral caruncle is the most common urethral mass in postmenopausal women, yet there is a lack of studies on its imaging. The aim of this study was to provide a summary of the clinical and ultrasound features as well as the precise location of female urethral caruncle. This study reviewed the clinical and ultrasonographic records of 20 consecutive women with pathologically confirmed urethral caruncle. Data on patient demographics, symptoms, and transperineal and transrectal ultrasound imaging features, including location, shape, margin, size, blood flow, and inner echo of the caruncle, were extracted. Each patient presented with only one mass at the urethral meatus. Most caruncles were located on the posterior lip (75%) of the urethra, presenting as oval (80%), mixed-echoic (50%), or hypo-echoic (40%) nodules with abundant linear (40%) or dendritic (60%) blood flow. The average distance between the bladder neck and the cranial end of the masses was 28 mm. Hyper-echogenic spots, cystic echo areas, and macrocalcifications were detected in thirteen caruncles (70%). This study shows that transperineal combined with transrectal ultrasound can be used to assess female urethral caruncle, and its relative location to the urethra can be accurately described, which is helpful for surgeons making preoperative localization and conversations.

Abstract To explore the impacts of continuous Ganoderma lucidum cultivation on soil physicochemical factors, soil enzyme activity, and the metabolome of Ganoderma lucidum fruiting bodies, this study conducted two consecutive years of cultivation on the same plot of land. Soil physicochemical factors and enzyme activity were assessed, alongside non-targeted metabolomic analysis of the Ganoderma lucidum fruiting bodies under continuous cultivation. The findings unveiled that in the surface soil layer (0–15 cm), there was a declining trend in organic matter, ammonium nitrogen, available phosphorus, available potassium, pH, polyphenol oxidase, peroxidase, alkaline phosphatase, and sucrase, whereas nitrate nitrogen, electrical conductivity (EC), and salt content exhibited an upward trend. Conversely, in the deeper soil layer (15–30 cm), organic matter, ammonium nitrogen, available potassium, alkaline phosphatase, and sucrase demonstrated a decreasing trend, while nitrate nitrogen, available phosphorus, pH, EC, salt content, polyphenol oxidase, and soil peroxidase showed an increasing trend. Metabolomic analysis of Ganoderma lucidum fruiting bodies distinguished 64 significantly different metabolites between the GCK and GT groups, with 39 components having markedly higher relative contents in GCK and 25 components having significantly lower relative contents in GCK compared to GT. Moreover, among these metabolites, there were more types with higher contents in the fruiting bodies harvested in the first year (GCK) compared to those harvested in the second year (GT), with pronounced differences. KEGG pathway analysis revealed that GCK exhibited more complex metabolic pathways compared to GT. The metabolites of Ganoderma lucidum fruiting bodies were predominantly influenced by soil physicochemical factors and soil enzyme activity. In the surface soil layer (0–15 cm), the metabolome was significantly affected by soil pH, soil organic matter, available phosphorus, and soil alkaline phosphatase, while in the deeper soil layer (15–30 cm), differences in the Ganoderma lucidum metabolome were more influenced by soil alkaline phosphatase, soil catalase, pH, nitrate nitrogen, and soil sucrase.

Abstract Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation‐mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.

Abstract The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene expression by RNA-Seq in retina and choroid at the onset of unilateral experimental myopia in chick, isolating tissues every 4 h during a single 24-h period from myopic and contralateral control eyes. Occluded versus open eye gene expression differences varied considerably over the 24-h sampling period, with some occurring at multiple times of day but with others showing differences at only a single investigated timepoint. Some of the genes identified in retina or choroid of chick myopia were previously identified as candidate genes for common human myopia. Like differentially expressed genes, pathways identified by Gene Set Enrichment Analysis also varied dramatically by sampling time. Considered with other laboratory data, human genetic and epidemiology data, these findings further implicate circadian events in myopia pathogenesis. The present results emphasize a need to include time of day in mechanistic studies of myopia and to assess circadian biology directly in trying to understand better the origin of myopia and to develop more effective therapies.

Abstract Aim Aim The objective of this study was to understand the occupational protective behaviors of newly recruited nurses and explore the influencing factors. Methods A convenience sampling method was used to select newly recruited nurses in our hospital from July 2018 to November 2019. The survey was conducted using the general information questionnaire, work attitude scale (Wa), and occupational protective behavior scale. Results The total score of occupational protective behaviors of 150 newly enrolled nurses was 18.94 ± 3.59. There was a significant negative correlation between work attitude score and occupational protective behaviors (r = -0.324, p

Abstract Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis. Video Abstract

Introduction Pulmonary vein isolation (PVI) is the cornerstone of radiofrequency (RF) ablation for atrial fibrillation (AF). However, a single ablation strategy does not always achieve the desired therapeutic effect in all patients with persistent AF, and individualised strategies are required for different clinical characteristics.Methods and analysis This study aimed to determine the optimal catheter ablation strategy for persistent AF by comparing the efficacy of PVI and BCXL (BC: big circles encircling pulmonary vein isolation; XL: unfixed number of lines based on the left atrial substrate). The BCXL-AF study (clinical trial no. ChiCTR2200067081) was designed as a prospective, randomised, parallel-controlled, single-blinded clinical trial. Overall, 400 patients with persistent AF were randomised in a 1:1 ratio into PVI-only and BCXL-individualised ablation groups. Patients randomised to the individualised ablation group will be further categorised into risk strata according to their clinical condition using the actual ablation method determined by the strata. Seven postoperative visits were conducted from discharge to 24 months of age. The primary observation endpoint will be the incidence of atrial tachyarrhythmia (including AF, atrial flutter and atrial tachycardia with a duration of ≥30 s) without using antiarrhythmic drugs after a blank period of 3 months following a single ablation procedure. The BCXL-AF study will assess an optimal approach for persistent AF RF ablation and evaluate the effectiveness of individualised RF ablation strategies in reducing the recurrence rate of AF.Ethics and dissemination The study protocol was reviewed, and ethical approval was obtained from the Army Medical University Human Ethics Committee (approval number: 2022-484-01). All the participants provided written informed consent. This study was conducted according to the principles of the Declaration of Helsinki and its amendments. The results of this study will be disseminated through manuscript publication and conference presentations.Trial registration number ChiCTR2200067081.

BackgroundBletilla striata (Thunb.) Reichb.f. (B. striata) is a traditional Chinese medicinal herb. B. striata polysaccharides (BSP), stilbenes and 2-isobutyl malic acid glucosoxy-benzyl ester compounds are the main active ingredients in B. striata. However, there is limited report on the changes of medicinal components and their biosynthesis regulation mechanisms in the tubers of B. striata at different stages.MethodThe tubers of B. striata were collected during the flowering period, fruiting period, and harvest period to determine the total polysaccharide content using the phenol sulfuric acid method. The changes in secondary metabolites in the tubers at these stages were analyzed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS), and transcriptomics was conducted for further exploration of their biosynthetic pathways.ResultThe BSP content gradually increases from the flowering period to the fruiting period as the tubers develop, reaching its peak, but subsequently decreases at harvest time, which may be associated with the germination of B. striata buds in later stage. A total of 294 compounds were identified in this study. Among them, a majority of the compounds, such as 2-isobutyl malate gluconoxy-benzyl ester, exhibited high content during the fruit stage, while stilbenes like coelonin, 3'-O-methylbatatasin III, and blestriarene A accumulated during the harvesting period. The transcriptome data also revealed a substantial number of differentially expressed genes at various stages, providing a partial explanation for the complex changes in metabolites. We observed a correspondence between the expression pattern of GDP-Man biosynthesis-related enzyme genes and cumulative changes in BSP. And identified a positive correlation between 9 transcription factors and genes associated with polysaccharide biosynthesis, while 5 transcription factors were positively correlated with accumulation of 2-isobutyl malate gluconoxy-benzyl ester compounds and 5 transcription factors exhibited negative correlated with stilbene accumulation.ConclusionIt is imperative to determine the appropriate harvesting period based on the specific requirements of different active ingredients and the accumulation patterns of their metabolites. Considering the involvement of multiple transcription factors in the biosynthesis and accumulation of its active ingredients, a comprehensive investigation into the specific regulatory mechanisms that facilitate high-quality cultivation of B. striata is imperative.

AimsTo explore the causal relationship between ulcerative colitis (UC) and male infertility using Mendelian randomization method with single nucleotide polymorphism (SNP) as the instrumental variables.MethodsGenetic loci closely associated with UC were extracted as instrumental variables and male infertility was the outcome variable in pooled data from the gene-wide association study (GWAS),which was derived from European ethnic groups. The UC data(ebi-a-GCST003045) contained a total sample size of 27432 individuals and 110944 SNPs, and the male infertility data(finn-b-N14_MALEINFERT) contained a total sample size of 73479 individuals and 16377329 SNPs. The SNPs highly correlated with UC were screened from ebi-a-GCST003045(P0.8,replacing the missing SNPs with SNPs with high linkage, and deleting SNPs without substitution sites) were extracted. MR analysis was performed using MR-Egger regression, the weighted median and the inverse-variance weighted (IVW) respectively, and the causal relationship between UC and male infertility was evaluated by OR and 95% CI, and the Egger-intercept method was used to test for horizontal multiplicity, and the sensitivity analysis was performed using "leave-one-out method". Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study.ResultsA total of 86 SNPs were included as IVs, with OR and 95% CI of 1.095(0.820~1.462)、1.059(0.899~1.248)、1.125(1.002~1.264) for MR-Egger, the weighted median and IVW results respectively, and P value of less than 0.05 for IVW, indicating that a causal relationship between UC and male infertility was causally related. The results of MR analysis combined with BWMR analysis also showed positive genetic causal relationship between UC and male infertility.MR-Egger regression showed an intercept of -2.21×10-3 with a standard error of 0.006 and P = 0.751, there was no horizontal pleiotropy for the IVs of exposure factors. Heterogeneity tests showed no heterogeneity and the results of the "leave-one-out" sensitivity analysis were stable.ConclusionThere is a causal association between UC and male infertility, which increases the risk of developing male infertility.

The real-time monitoring on the risk status of the vehicle and its driver can provide the assistance for the early detection and blocking control of single-vehicle accidents. However, complex risk coupling relationship is one of the main features of single-vehicle accidents with high mortality rate. On the basis of investigating the coupling effect among multi-risk factors and establishing a safety management database throughout the life cycle of vehicles, single-vehicle driving risk network (SVDRN) with a three-level threshold was developed, and its topology features were analyzed to assessment the importance of nodes. To avoid the one-sidedness of single indicator, the multi-attribute comprehensive evaluation model was applied to measure the comprehensive effect of characteristic indicators for nodes importance. A algorithm for real-time monitoring of vehicle driving risk status was proposed to identify key risk chains. The result revealed that improper operation, speeding, loss of vehicle control and inefficient driver management were the sequence of top four risk factors in the comprehensive evaluation result of nodes importance (mean value = 0.185, SD = 0.119). There were minor differences of 0.017 in the node importance among environmental factors, among which non-standard road alignment had the larger value. The improper operation and non-standard road alignment were the highest combination correlation of factors affecting road safety, with the support of 51.81% and the confidence of 69.35%. This identification algorithm of key risk chains that combines node importance and its risk state threshold can effectively determine the high-frequency risk transmission paths and risk factors through multi-vehicle test, providing a basis for centralization management of transport enterprises.

Abstract Background In colorectal cancer (CRC), the normal tissue adjacent to tumor (NAT) communicates actively with the tumor. Adult stem cells from the colon play a crucial role in the development of the colonic epithelium. In the tumor microenvironment, however, it is unclear what changes have occurred in colonic stem cells derived from NAT. Methods Using an intestinal stem cell culture system, we cultured colonic cells from NAT and paired CRC tissue, as well as cells from healthy tissue (HLT). Clonogenicity and differentiation ability were used to compare the function of clones from NAT, HLT and CRC tissues. RNA high-throughput sequencing of these clones was used to identify the molecular characteristics of NAT-derived clones. Coculture of clones from HLT and CRC was used to assess molecular changes. Results We found that the morphological characteristics, clonogenic ability, and differentiation ability of NAT-derived clones were consistent with those of HLT-derived clones. However, NAT-derived clones changed at the molecular level. A number of genes were specifically activated in NAT. NAT-derived clones enriched pathways related to inflammation and fibrosis, including epithelial mesenchymal transition (EMT) pathway and TGF-beta signaling pathway. Our results also confirmed that NAT-derived clones could recruit fibroblasts in mice. In addition, HLT-derived clones showed high expression of FOSB when cocultured with tumor cells. Conclusions Our results demonstrate that colonic stem cells from NAT in the tumor microenvironment undergo changes at the molecular level, and these molecular characteristics can be maintained in vitro, which can induce fibrosis and an inflammatory response. Video Abstract

Abstract Background Previous studies have shown inconsistent findings regarding the association of light to moderate alcohol consumption with cause-specific mortality. Therefore, this study sought to examine the prospective association of alcohol consumption with all-cause and cause-specific mortality in the US population. Methods This was a population-based cohort study of adults aged 18 years or older in the National Health Interview Survey (1997 to 2014) with linkage to the National Death Index records through December 31, 2019. Self-reported alcohol consumption was categorized into seven groups (lifetime abstainers; former infrequent or regular drinkers; and current infrequent, light, moderate, or heavy drinkers). The main outcome was all-cause and cause-specific mortality. Results During an average follow-up of 12.65 years, among the 918,529 participants (mean age 46.1 years; 48.0% male), 141,512 adults died from all causes, 43,979 from cardiovascular disease (CVD), 33,222 from cancer, 8246 from chronic lower respiratory tract diseases, 5572 from accidents (unintentional injuries), 4776 from Alzheimer’s disease, 4845 from diabetes mellitus, 2815 from influenza and pneumonia, and 2692 from nephritis, nephrotic syndrome, or nephrosis. Compared with lifetime abstainers, current infrequent, light, or moderate drinkers were at a lower risk of mortality from all causes [infrequent—hazard ratio: 0.87; 95% confidence interval: 0.84 to 0.90; light: 0.77; 0.75 to 0.79; moderate 0.82; 0.80 to 0.85], CVD, chronic lower respiratory tract diseases, Alzheimer’s disease, and influenza and pneumonia. Also, light or moderate drinkers were associated with lower risk of mortality from diabetes mellitus and nephritis, nephrotic syndrome, or nephrosis. In contrast, heavy drinkers had a significantly higher risk of mortality from all causes, cancer, and accidents (unintentional injuries). Furthermore, binge drinking ≥ 1 day/week was associated with a higher risk of mortality from all causes (1.15; 1.09 to 1.22), cancer (1.22; 1.10 to 1.35), and accidents (unintentional injuries) (1.39; 1.11 to 1.74). Conclusions Infrequent, light, and moderate alcohol consumption were inversely associated with mortality from all causes, CVD, chronic lower respiratory tract diseases, Alzheimer’s disease, and influenza and pneumonia. Light or moderate alcohol consumption might also have a beneficial effect on mortality from diabetes mellitus and nephritis, nephrotic syndrome, or nephrosis. However, heavy or binge had a higher risk of all-cause, cancer, and accidents (unintentional injuries) mortality.

IntroductionThe role of systolic blood pressure (SBP) variability in the pathogenesis of cerebral amyloid angiopathy (CAA) as an underlying cause of intracerebral hemorrhage (ICH) is unknown. We studied SBP variability before ICH according to CAA severity at autopsy.MethodsWe collected office (primary care or hospital clinic) BP readings during 10 years before first-ever ICH onset in adults who died and had brain research autopsy in the Lothian IntraCerebral Hemorrhage, Pathology, Imaging, and Neurological Outcome (LINCHPIN), prospective, population-based, inception cohort study. A neuropathologist assessed CAA severity using a histopathological rating scale, masked to BP readings. Functional principal component analysis was used to model SBP levels by time before ICH, and logistic regression models assessed associations of SBP variability indices with CAA severity (moderate-severe vs. absent-mild) adjusted for age, gender, and mean SBP.ResultsAmong 72 adults (median age 81 [interquartile range 76–86], 56% female, median number of SBP readings 11 [3–19]), patients with moderate-severe CAA had similar mean SBP (143 vs. 145 mmHg, P = 0.588) but lower SBP variability (SBP standard deviation [SD] 14 vs. 17 mmHg, P = 0.033) compared with patients with absent-mild CAA, and their SBP trajectories seemed to differ over 10 years before ICH. The odds of moderate-severe CAA were higher with lower maximum SBP (adjusted OR per 10 mmHg lower: 1.53, 95% confidence interval [CI] 1.09–2.15; P = 0.015) and lower SBP range (1.29 [1.03–1.61]; P = 0.028), but not SBP SD (1.95 [0.87–4.38]; P = 0.11).DiscussionCompared with absent-mild autopsy-verified CAA, moderate-severe CAA is associated with lower maximum and range of pre-morbid SBP.

Biotechnology is a rapidly evolving field that has the potential to transform the way we diagnose and treat diseases and is changing the landscape of healthcare. Great endeavors have been devoted to the field of healthcare biotechnology, and our knowledge of the subject has remarkably improved. By leveraging the latest advancements in molecular biology and genetics, new biotech paradigms are emerging, sparking new searches for novel solutions for human health and well-being. However, the clinical translational development of breakthrough biotechnology discoveries remains an intriguing challenge. Only a few biotech innovations have progressed to new transformative healthcare tools and therapies. In this review, we will outline the clinical translational development landscape of biotechnology in healthcare. Notable discoveries and translational developments in healthcare biotechnology, including classical discoveries and new paradigms, are thoroughly discussed. Even though great challenges remain in the bench-to-bedside translational development process, more groundbreaking biotech ideas are about to be translated into commercial products to bring positive health gains, with a tight multitude of collaboration among research institutes, healthcare providers, and industry partners.

Objective To analyze the status of HBV infection in blood donors reactive to jointed NAT but non-reactive to primary discriminatory tests (NRR), so as to provide suggestions and data support for subsequent studies on NRR samples. Methods HCV RNA and HIV RNA repeat differential detection, HBV DNA viral load detection and HBV pgRNA copy volume detection were performed in the plasma of 60 blood donors with negative ELISA results in routine blood screening and NRR in NAT. HBsAg, HBsAb, HBcAb, HBeAg and HBeAb serological tests were performed on the NRR samples with positivity in HBV DNA viral load and HBV pgRNA virus copy detection, so as to analyze the serological infection status and occult hepatitis B (OBI) infection. Results The HCV RNA and HIV RNA repeat discrimination results of 60 NRR samples were negative. The quantitative detection results of HBV DNA in 60 NRR samples were positive in 9 cases (15%), and the HBV DNA concentration was less than 10IU/mL. Nine cases (15%) were positive for HBV pgRNA quantitative detection, and the virus copy volume x-±SD was (289±58.25) copies/mL. Two NRR samples (3.33%) were HBV DNA positive and HBV pgRNA positive. Among the 9 HBV-DNA positive samples, the highest positive rate of HBcAb was 66.67%, and 7 (77.78%) of them were confirmed to be seropositive for OBI. Among the 9 HBV pgRNA positive samples, the copy amount of pgRNA in HBcAb positive samples was slightly higher than that in negative samples, while the copy amount of pgRNA in HBsAb and HBeAb positive samples was lower than that in corresponding negative samples. In recent 6 years, the proportion of NRR samples in the single NAT system of the center fluctuated from 0.09% to 0.13%. Conclusion HBV DNA and HBV pgRNA exist in NRR samples. HBV DNA and/or HBV pgRNA positive samples can be detected in the relevant serological infectious markers. NRR samples have a certain potential risk of OBI infection. HBV DNA detection plus HBV pgRNA can better confirm the status of virus infection in NRR and improve the safety of blood transfusion.

Abstract Monitoring the ecological environment quality is an important task that is often connected to achieving sustainable development. Timely and accurate monitoring can provide a scientific basis for regional land use planning and environmental protection. Based on the Google Earth Engine platform coupled with the greenness, humidity, heat, and dryness identified in remote sensing imagery, this paper constructed a remote sensing ecological index (RSEI) covering northern Anhui and quantitatively analyzed the characteristics of the spatiotemporal changes in the ecological environment quality from 2001 to 2020. Geodetector software was used to explore the mechanism driving the characteristics of spatial differentiation in the ecological environment quality. The main conclusions were as follows. First, the ecological environment quality in northern Anhui declined rapidly from 2001 to 2005, but the rate of decline slowed from 2005 to 2020 and a trend of improvement gradually emerged. The ecological environment quality of Huainan from 2001 to 2020 was better and more stable compared with other regional cities. Bengbu and Suzhou showed a trend of initially declining and then improving. Huaibei, Fuyang, and Bozhou demonstrated a trend of a fluctuating decline over time. Second, vegetation coverage was the main influencing factor of the RSEI, while rainfall was a secondary factor in northern Anhui from 2001 to 2020. Finally, interactions were observed between the factors, and the explanatory power of these factors increased significantly after the interaction. The most apparent interaction was between vegetation coverage and rainfall (q = 0.404). In addition, we found that vegetation abundance had a positive impact on ecological environment quality, while population density and urbanization had negative impacts, and the ecological environment quality of wetlands was the highest. Our research will provide a theoretical basis for environmental protection and support the high-quality development of northern Anhui.

Abstract Upper airway collapsibility after anaesthesia induction may be associated with unpredictable difficult airway. However, most works on airway anatomy are tended to morphological description before anaesthesia. This study aimed to evaluate the changes of upper airway after anaesthesia induction and using pre-anesthetic ultrasound measurements to predict Difficult Laryngoscopy (DL). We included 104 eligible subjects with complete data, who were performed tracheal intubations under general anaesthesia in the study. The upper airway changes before and after anaesthesia induction were determined by seven neck ultrasound measurements, included as follow: (1) Distance from skin to under surface of Tongue (DT), (2) Thickness of the thickest part of Tongue body (TT), (3) Hyoid Mental Distance (HMD), (4) Depth of Hyoid (DH), (5) Width of Hyoid (WH), (6) Distance from Skin to Epiglottis (DSE), (7) Depth of the anterior combination of the Vocal Cords (DVC). DL was evaluated with Cormack–Lehane (CL). Data regarding HMD [from 45.3 (42.4–48.5) to 41.1 (38.5–44.9) mm], DH [from 8.7 (6.6–10.9) to 7.0 (5.3–9.1) mm], DSE [from 20.1 (16.6–22.5) to 19.5 (16.5–21.6) mm] and the DVC [from 7.1 (5.7–8.3) to 6.8 (5.7–7.9) mm] were decreased (P 0.05) after anaesthesia induction. Additionally, when cut-off value of DSE was 21.25 mm before anaesthesia, it may be better predicted to DL [sensitivity 80.0% (95% CI: 60.7–91.6%) and specificity 83.8% (95% CI: 73.0–91.0%)]. The upper airway after induction showed the propensity of collapsibility by ultrasound measurements. Compared with other indicators, the DSE assessed by ultrasound might be considered to a valuable predictor of DL. Trial registration: The study was registered in ClinicalTrials.gov on 23th Jan 2019, ChiCTR1900021123.

We study the nonlinear localized modes in two-component Bose-Einstein condensates with parity-time-symmetric Scarf-II potential, which can be described by the coupled Gross-Pitaevskii equations. Firstly, we investigate the linear stability of the nonlinear modes in the focusing and defocusing cases, and get the stable and unstable domains of nonlinear localized modes. Then we validate the results by evolving them with 5% perturbations as an initial condition. Finally, we get stable solitons by considering excitations of the soliton via adiabatical change of system parameters. These findings of nonlinear modes can be potentially applied to physical experiments of matter waves in Bose-Einstein condensates.

The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. In this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives the transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung-infiltrating tumor cells in xenograft models and predicted poor prognosis of patients with lung cancer. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured the chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this led to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of patients with GFI1-positive lung cancer.

Abstract Decompressive hemicraniectomy (DHC) can improve outcomes for patients with severe forms of acute ischemic stroke (AIS), but the evidence is mainly derived from non-thrombolyzed patients. We aimed to determine the characteristics and outcomes of early DHC in thrombolyzed AIS participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Post-hoc analyses of ENCHANTED, an international, partial-factorial, open, blinded outcome-assessed, controlled trial in 4557 thrombolysis-eligible AIS patients randomized to low- versus standard-dose intravenous alteplase (Arm A, n = 2350), intensive versus guideline-recommended blood pressure control (Arm B, n = 1280), or both (Arms A + B, n = 947). Logistic regression models were used to identify baseline variables associated with DHC, with inverse probability of treatment weights employed to eliminate baseline imbalances between those with and without DHC. Logistic regression was also used to determine associations of DHC and clinical outcomes of death/disability, major disability, and death (defined by scores 2–6, 3–5, and 6, respectively, on the modified Rankin scale) at 90 days post-randomization. There were 95 (2.1%) thrombolyzed AIS patients who underwent DHC, who were significantly younger, of non-Asian ethnicity, and more likely to have had prior lipid-lowering treatment and severe neurological impairment from large vessel occlusion than other patients. DHC patients were more likely to receive other management interventions and have poor functional outcomes than non-DHC patients, with no relation to different doses of intravenous alteplase. Compared to other thrombolyzed AIS patients, those who received DHC had a poor prognosis from more severe disease despite intensive in-hospital management.

Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and a GFP BM chimeric approach, we found neuroprotection and a lack of significant motor deficits marked by reduced monocyte/macrophage cortical infiltration and an increased number of arginase-1+ cells in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to antiinflammatory that included increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocytes/macrophages. In Epha4-BM–deficient mice, cortical-isolated GFP+ monocytes/macrophages displayed a phenotypic shift from a classical to an intermediate subtype, which displayed reduced Ly6chi concomitant with increased Ly6clo- and Tie2-expressing populations. Furthermore, clodronate liposome–mediated monocyte depletion mimicked these effects in WT mice but resulted in attenuation of phenotype in Epha4-BM–deficient mice. This demonstrates that monocyte polarization not overall recruitment dictates neural tissue damage. Thus, coordination of monocyte proinflammatory phenotypic state by Epha4 is a key regulatory step mediating brain injury.

Summary: Background: Exercise training protects the heart against pathological cardiac remodeling and confers cardioprotection from heart failure. However, the underlying mechanism is still elusive. Methods: An integrative analysis of multi-omics data of the skeletal muscle in response to exercise is performed to search for potential exerkine. Then, CCDC80tide is examined in humans after acute exercise. The role of CCDC80tide is assessed in a mouse model of hypertensive cardiac remodeling and in hypertension-mediated cell injury models. The transcriptomic analysis and immunoprecipitation assay are conducted to explore the mechanism. Findings: The coiled-coil domain-containing protein 80 (CCDC80) is found strongly positively associated with exercise. Interestingly, exercise stimuli induce the secretion of C-terminal CCDC80 (referred as CCDC80tide hereafter) via EVs-encapsulated CCDC80tide into the circulation. Importantly, cardiac-specific expression of CCDC80tide protects against angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in mice. In in vitro studies, the expression of CCDC80tide reduces Ang II-induced cardiomyocyte hypertrophy, cardiac microvascular endothelial cell (CMEC) inflammation, and mitigated vascular smooth muscle cell (VSMC) proliferation and collagen formation. To understand the cardioprotective effect of CCDC80tide, a transcriptomic analysis reveals a dramatic inhibition of the STAT3 (Signal transducer and activator of transcription 3) signaling pathway in CCDC80tide overexpressing cells. Mechanistically, CCDC80tide selectively interacts with the kinase-active form of JAK2 (Janus kinase 2) and consequently inhibits its kinase activity to phosphorylate and activate STAT3. Interpretation: The results provide new insights into exercise-afforded cardioprotection in pathological cardiac remodeling and highlight the therapeutic potential of CCDC80tide in heart failure treatment. Funding: This work was supported by the National Natural Science Foundation of China [Grant/Award Numbers: 81770428, 81830010, 82130012, 81900438, 82100447); Shanghai Science and Technology Committee [Grant/Award Numbers: 21S11903000, 19JC1415702]; Emerging and Advanced Technology Programs of Hospital Development Center of Shanghai [Grant/Award Number: SHDC12018129]; China Postdoctoral Science Foundation [2021M692108]; and China National Postdoctoral Program for Innovative Talents [BX20200211].

Abstract. Background:. Normal tension glaucoma (NTG) is a less pressure-dependent type of glaucoma with characteristic optic neuropathy. Recently, the biomechanical mechanism has been thought to account for glaucomatous optic neuropathy to some degree. We intended to compare dynamic corneal response parameters (DCRs) among patients with primary open-angle glaucoma with normal tension or hypertension and controls. The correlations between DCRs and known risk factors for glaucoma were also analyzed. Methods:. In this cross-sectional study, 49 NTG subjects, 45 hypertension glaucoma (HTG) subjects, and 50 control subjects were enrolled. We compared the differences in DCRs using corneal visualization Scheimpflug technology among the NTG, HTG, and control groups. We also analyzed the correlations between DCRs and known risk factors for glaucoma (eg, central corneal thickness [CCT], intraocular pressure [IOP], etc). Results:. The maximum inverse concave radius (NTG: 0.18 [0.17, 0.20] mm−1; control: 0.17 [0.16, 0.18] mm−1; P = 0.033), deformation amplitude ratio of 2 mm (DAR 2 mm, NTG: 4.87 [4.33, 5.39]; control: 4.37 [4.07, 4.88]; P 0.05). In the univariate and multivariate analyses, some of the DCRs, such as IR, were negatively correlated with CCT and IOP, whereas SP-A1 was positively correlated with CCT and IOP. Conclusions:. The cornea was more deformable in NTG than in HTG or controls. There were no significant differences in corneal deformability between HTG and controls. The cornea was more deformable with the thinner cornea and lower IOP.

Abstract At present, there are still ambiguous reports about the perinatal infection of infants born to mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The dynamic characteristics of infantile serum antibodies born to mother with SARS-CoV-2 has not been well described. In this study, we analyzed the seroconversion of 27 newborns born to 26 pregnant women infected with SARS-CoV-2. The SARS-CoV-2 IgG positive rate of parturient was 80.8%, and half of their infants obtained maternal IgG. IgG transfer rates were 18.8% and 81.8% in those infants whose mother infected less and more than 2 weeks before delivery. In the first two months of life, the IgG level of infants dropped sharply to one tenth of that at birth. These results suggest that maternal SARS-CoV-2 IgG provides limited protection for infants.

Despite the global health burden, treatment of spontaneous intracerebral haemorrhage (ICH) is largely supportive, and translation of specific medical therapies has not been successful. Zebrafish larvae offer a unique platform for drug screening to rapidly identify neuroprotective compounds following ICH. We applied the Spectrum Collection library compounds to zebrafish larvae acutely after ICH to screen for decreased brain cell death and identified 150 successful drugs. Candidates were then evaluated for possible indications with other cardiovascular diseases. Six compounds were identified, including two angiotensin-converting enzyme inhibitors (ACE-Is). Ramipril and quinapril were further assessed to confirm a significant 55% reduction in brain cell death. Proteomic analysis revealed potential mechanisms of neuroprotection. Using the INTERACT2 clinical trial dataset, we demonstrated a significant reduction in the adjusted odds of an unfavourable shift in the modified Rankin scale at 90 days for patients receiving an ACE-I after ICH (versus no ACE-I; odds ratio, 0.80; 95% confidence interval, 0.68-0.95; P=0.009). The zebrafish larval model of spontaneous ICH can be used as a reliable drug screening platform and has identified therapeutics that may offer neuroprotection. This article has an associated First Person interview with the first author of the paper.

Abstract Our aim was to detect type 2 innate lymphoid cells (ILC2s)-related cytokines of infants with bronchiolitis by using Elisa, Liquidchip technology and RT-PCR and investigated its correlation with bronchiolitis. We recruited 26 infants with bronchiolitis and 20 healthy infants as control from Xiangya Hospital. Compared to the control group, the serum levels of interleukin-5 (IL-5) [41.99 (21.11) vs 25.70 (19.64)], IL-9 [27.04 (37.51) vs 8.30 (0.54)], IL-13 [184.05 (132.81) vs 121.75 (176.13)], IL-33 [83.70 (46.69) vs 11.23 (55.31)] and thymic stromal lymphopoietin (TSLP) [31.42 (5.41) vs 28.76 (2.56)] were significantly increased in infants with bronchiolitis (P 0.05]. The mRNA expression of IL-17RB (9.83 ± 0.35 vs 9.19 ± 0.58), TSLP (16.98 ± 2.12 vs 15.07 ± 2.25), retinoid acid receptor related orphan receptor α (7.18 ± 0.71 vs 5.46 ± 1.09) and trans-acting T-cell-specific transcription factor 3 (4.86 ± 0.66 vs 4.19 ± 0.90) were significantly increased in infants with bronchiolitis versus the control group (P 0.05). Our findings suggested that ILC2s possibly play a specific role in immunopathology of bronchiolitis.

Aim: To study the associations between baseline blood glucose levels (BGL), glycemic variability and clinical outcomes in patients with severe acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). Methods: We performed a secondary analysis of the Randomized Evaluation of Normal versus Augmented Level of RRT (RENAL) study. A multivariate Cox regression model was used to assess the association between baseline BGL, glycemic variability and clinical outcomes. The primary outcome was all-cause mortality, and secondary outcomes were duration of hospital and intensive care unit (ICU) stay. Results: Baseline BGL data were available in 1404 out of 1508 patients from the RENAL study. Among them, 627 patients died within 90 days of randomization. Compared to patients in the second quartile (BGL 5.8–7.2 mmol/L), patients in the first quartile (BGL < 5.8 mmol/L) had increased mortality rate (90-day HR 1.48; p = 0.001; 28-day HR 1.47; p = 0.042). However, there were no significant differences in ICU and hospital length of stay (LOS) (p = 0.82 and p = 0.33, respectively). Glycemic variability data were from 1345 out of 1404 patients who had data for BG values within 28 days. Higher coefficient of variation (CV) (HR 1.02; P trend = 0.002) and standard deviation value (SD) (HR 1.29; P trend = 0.027) were associated with higher risk of death at day 90. Conclusions: We identified a low BGL within the normal physiological range at baseline and greater CV and SD values as significant modifiable risk factors for mortality in severe AKI patients in ICU, which may be a target for intervention.

Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells from 3 left-sided and 3 right-sided CRC patients were profiled by single-cell RNA-Seq (scRNA-Seq). Right-sided CRC harbors a significant proportion of exhausted CD8+ T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of preexhausted/exhausted T cells were favorable prognostic markers. Notably, we identified a potentially novel RBP4+NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.

Introduction Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months.Methods and analysis The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat.Ethics and dissemination This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications.Trial registration numbers Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

To date, utilization of feed grains is increasing, which competes for human food. It is imperative to develop and utilize unconventional feed materials. Broussonetia papyrifera L. (B. papyrifera) is a good feeding material with high crude protein, crude fat, and low crude fiber, which is widely distributed in China. In this study, 12 Dorper ♂×Hu ♀ crossbred weaned male lambs were seleted into four groups based on the feed that ratio of the B. papyrifera fermented feed in the total mixed diet (0%, 6%, 18%, and 100%), to character the lambs’ longissimus dorsi (LD) fatty acids, morphology and transcriptome. Results showed that the muscle fiber’s diameter and area were the smallest in the 100% group. The highest content of beneficial fatty acids and the lowest content of harmful fatty acids in group 18%. RNA-seq identified 443 differentially expressed genes (DEGs) in the LD of lambs from 4 groups. Among these genes, 169 (38.1%) were up-regulated and 274 (61.9%) were down-regulated. The DEGs were mostly enriched in in fatty acid metabolism, arginine and proline metabolism, and PPAR signaling pathways. Our results provide knowledge to understand effect of different ratios of B. papyrifera fermented feed on sheep meat quality traits, also a basis for understanding of the molecular regulation mechanism of B. papyrifera fermented feed affecting on sheep meat quality.

Abstract Background Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have only recently emerged as routine clinical diagnostic tests. To date, few systematic analyses of mosaic variants detected by diagnostic exome sequencing for diverse clinical indications have been performed. Methods To investigate the frequency, type, allelic fraction, and phenotypic consequences of clinically relevant somatic mosaic single nucleotide variants (SNVs) and characteristics of the corresponding genes, we retrospectively queried reported mosaic variants from a cohort of ~ 12,000 samples submitted for clinical exome sequencing (ES) at Baylor Genetics. Results We found 120 mosaic variants involving 107 genes, including 80 mosaic SNVs in proband samples and 40 in parental/grandparental samples. Average mosaic alternate allele fraction (AAF) detected in autosomes and in X-linked disease genes in females was 18.2% compared with 34.8% in X-linked disease genes in males. Of these mosaic variants, 74 variants (61.7%) were classified as pathogenic or likely pathogenic and 46 (38.3%) as variants of uncertain significance. Mosaic variants occurred in disease genes associated with autosomal dominant (AD) or AD/autosomal recessive (AR) (67/120, 55.8%), X-linked (33/120, 27.5%), AD/somatic (10/120, 8.3%), and AR (8/120, 6.7%) inheritance. Of note, 1.7% (2/120) of variants were found in genes in which only somatic events have been described. Nine genes had recurrent mosaic events in unrelated individuals which accounted for 18.3% (22/120) of all detected mosaic variants in this study. The proband group was enriched for mosaicism affecting Ras signaling pathway genes. Conclusions In sum, an estimated 1.5% of all molecular diagnoses made in this cohort could be attributed to a mosaic variant detected in the proband, while parental mosaicism was identified in 0.3% of families analyzed. As ES design favors breadth over depth of coverage, this estimate of the prevalence of mosaic variants likely represents an underestimate of the total number of clinically relevant mosaic variants in our cohort.

Abstract Background Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES. Methods In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array. Results The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities. Conclusions Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

The present investigation evaluates the protective effect of Ginkgetin aglycone (GA) against ischemic stroke-induced neuronal injury. Ischemic stroke was produced by the middle cerebral artery occlusion (MCAO) model and animals were a group that received GA 100 and 200 mg/kg, i.p. five days before the induction of MCAO. The effect of GA against stroke was determined by estimating the neurological deficit score and brain water content was also observed. Moreover terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay was done for determining the neuronal apoptosis and Western blot assay also performed for estimating the expression of several proteins. Results of the study suggest that the neurological deficit score and brain water content was found to be lower in the GA treated group than the ischemia/reperfusion (I/R) group of rats. Moreover the number of TUNEL positive cells was found to be lower in the GA treated group than in the I/R group of rats. There was a significant (p < 0.01) decrease in the oxidative stress parameters and cytokine in the tissue homogenate of the GA treated group compared to the I/R group of rats. Further treatment with GA attenuates altered expression of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein kinase B (Akt), B-cell lymphoma 2 (Bcl-2), signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa light chain enhancer of activated B cells (NF-B), toll-like receptor 4 (TLR-4), Janus kinase 2 (JAK-2) and sirtuin-1 (SIRT-1) protein in the brain tissues of stroke rats. In conclusion, data of the report reveal that treatment with Ginkgetin aglycone protects the neuronal injury against stroke in rats by reducing oxidative stress and inflammation.

Abstract Background Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting. Methods We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive “fetal exomes” performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher’s exact test. Results Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families. Conclusion Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.

Introduction Postsurgical rehabilitation is critical for optimal recovery in people undergoing orthopaedic surgery. Currently, knee and lumbar spine postsurgical care is not standardised, economically sustainable, nor based on quality evidence, contributing to substantial clinical variation, poor outcomes and increasing healthcare costs. This protocol describes the design of a randomised controlled trial aiming to evaluate the effectiveness and cost-effectiveness of a postsurgical clinical pathway augmented by disruptive technology and compared with standardised rehabilitation alone, in decreasing pain and improving function after total knee replacement (TKR) or lumbar laminectomy (with or without fusion).Methods An assessor-blinded, parallel group, randomised controlled trial will be conducted to recruit 204 consenting participants (102 per arm) of whom 50% are undergoing TKR and 50% lumbar surgery. The intervention group will receive a 6-month technology-enabled rehabilitation package in addition to usual postsurgical care. The package includes (1) an exercise program delivered via the Physitrack app on the iPad, (2) a health-coaching program delivered via video calls and motivational messages, (3) use of physical activity tracker with goal setting and motivational reminders (Fitbit). For those undergoing TKR, the intervention will also include knee joint range of motion self-monitoring via the Goniometer app. The control group will receive usual postsurgical care. Participants will be followed up at 3, 6 and 12 months from the enrolment date. The primary outcome is pain measured with the Numerical Rating Scale at 3 months. Secondary outcomes include pain-related disability, quality of life, computer self-efficacy, physical activity participation and sedentary behaviour. Data analysis will be blinded and by intention-to-treat. A trial-based cost-effectiveness analysis will determine the potential incremental cost per quality-adjusted life-year gained.Ethics and dissemination This protocol is approved by the human research ethics committee of the University of Sydney. Dissemination will occur through lay summary, infographics, conferences and journal publications.Trial registration number ACTRN12618001448235.

Quercetin (QN) is a naturally occurring phenolic compound found largely in vegetables and fruits. Lycopene (LY) is yet another natural phytocompound, found abundantly in red-colored fruits and vegetables. Both have been reported to have beneficial activities in humans. In this study, we document in vivo experimental model for isoproterenol (ISO) cardiac injury toxicity in Sprague-Dawley (SD) rats and treatment with a combined optimized concentration of quercetin and lycopene (QL). Male SD rats of different groups were treated with QL (80 mg/kg QN and 3 mg/kg LY together p.o.) for 10 days with ISO administration (100 mg/kg i.p.) on days 7 and 8. After experimental period, CK-MB, TROP, AST, ALT, LDH, GST, GPx, CAT, SOD, Vit.E, Vit. C, GSH, GSSG and MDA were estimated. SD rats administered with ISO showed an obvious rise in the serum marker enzyme levels and tissue oxidative stress markers (MDA and GSSG). Furthermore, marked reductions in the body weight and increases enzymic and non-enzymic antioxidant levels were noticed. Histological features of the heart also indicated a disruption in the cardiac myofibrils structure of ISO-intoxicated rats. Also, quantitative PCR analysis revealed an involvement of antioxidant and related pathway genes such as Nrf2, HO-1, NQO1, GSTµ, SOD1, SOD2, CAT and BCl-2 genes. QL pretreatment prevented all these adverse effects of ISO cardiotoxicity and significantly reduced the myocardial damage. Decrease in oxidative stress was observed, possibly through alterations in the expression levels of enzymic antioxidant genes (GSTµ, SOD1, SOD2 and CAT). In general, QL exert a strong protective effect through the modulations in enzymic antioxidant activity and associated molecular pathways-regulating effect in cardiovascular disease.

Introduction The Systemic Lupus Erythematosus (SLE) Prospective Observational Cohort Study (SPOCS) aims to describe the disease course of SLE and its association with type I interferon gene signature (IFNGS) status.Methods and analysis SPOCS is an international, multicentre, prospective, observational cohort study designed to follow patients through biannual study visits during a 3-year observation period. Patients ≥18 years old with a physician diagnosis that meets the American College of Rheumatology or Systemic Lupus International Collaborating Clinics SLE classification criteria will be included. SPOCS will comprehensively analyse clinical features, disease progression and treatment, SLE outcomes, health status assessments and quality of life, and healthcare resource utilisation of patients with moderate to severe SLE. A four-gene test will be used to measure IFNGS status; scores will be compared with a pre-established cut-off. Patients will be stratified by low or high IFNGS expression levels. Enrolment began in June 2017, and study completion is expected in 2022. The total number of anticipated patients was initially planned for 1500 patients and was amended to 900 patients owing to slow accrual of eligible patients.Ethics and dissemination The ethics committee/institutional review board/independent ethics committee at each study site approved the SPOCS protocol prior to study initiation (protocol number: D3461R00001, version 3.0, 26 June 2019). Study findings will be disseminated through peer-reviewed publications and presentations at scientific meetings.Trial registration number NCT03189875.

Objective At least half of patients with systemic lupus erythematosus (SLE) develop organ damage as a consequence of autoimmune disease or long-term therapeutic steroid use. This study synthesised evidence on the association between organ damage and mortality in patients with SLE.Design Systematic review and meta-analysis.Methods Electronic searches were performed in PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Sciences Literature for observational (cohort, case-control and cross-sectional) studies published between January 2000 and February 2017. Included studies reported HRs or ORs on the association between organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score) and mortality. Study quality was assessed using the modified Newcastle-Ottawa assessment. Pooled HRs were obtained using the DerSimonian and Laird random-effects model. Heterogeneity was assessed using the Cochrane Q (Q) and I2 statistics.Results The search yielded 10 420 articles, from which 21 longitudinal studies were selected. Most studies (85%) were of high quality. For 10 studies evaluating organ damage (SDI) as a continuous variable and reporting HR as a measure of association, a 1-unit increase in SDI was associated with increased mortality; pooled HR was 1.34 (95% CI: 1.24 to 1.44, p

Selecting optimal revegetation patterns, i.e., patterns that are more effective for soil organic carbon (SOC) and total nitrogen (TN) accumulation, is particularly important for mine land reclamation. However, there have been few evaluations of the effects of different revegetation patterns on the SOC and TN in reclaimed mine soils on the Loess Plateau, China. In this study, the SOC and TN stocks were investigated at reclaimed mine sites (RMSs), including artificially revegetated sites (ARSs) (arbors (Ar), bushes (Bu), arbor-bush mixtures (AB), and grasslands (Gr)) and a natural recovery site (NRS), as well as at undisturbed native sites (UNSs). Overall, the SOC and TN stocks in the RMSs were lower than those in the UNSs over 10–13 years after reclamation. The SOC stocks in the RMSs and UNSs only differed in the top 0–20 cm of the soil (p AB (2.88 kg m−2) ≥ Bu (2.72 kg m−2), and the TN stocks exhibited a similar trend. These results suggest that grasslands were more favorable than woodlands for SOC and TN accumulation in this arid area. Thus, in terms of the accumulation of SOC and TN, grassland planting is recommended as a revegetation pattern for areas with reclaimed mine soils.

The number, intensity and order of emergence of HIV-1 specific antibodies in serum or plasma were associated with the stage of HIV-1 infection. In this study, we retrospectively analyzed the HIV-1 confirmatory results tested by western blot (WB) or recombination immunoblot assay (RIBA) in Wuhan, 2012-2018, to access the profiles of HIV-1 specific antibodies. A total of 14432 HIV-suspected serum or plasma samples collected from local hospitals and other HIV screening laboratories were further screened by two 4th generation enzyme-linked immunosorbent assay (ELISA) kits in our laboratory, of which 11068 specimens (76.69%) had at least one positive ELISA result and thereby were finally confirmed with WB or RIBA. RIBA had identified 652 (81.09%) positive and 13 (1.62%) indeterminate cases from July 1, 2014 to January 7, 2015, while WB had identified 8358 (81.43%) positive and 643 (6.26%) indeterminate cases in the other times during 2012-2018. The indeterminate rate of WB was significant higher than that of RIBA (p

Pennisetum setaceum 'Rubrum' is an ornamental grass plant that produces purple leaves in high-light environments and light purple or green leaves in low-light environments, the latter of which greatly reduces its aesthetic appeal. Therefore, we aimed to identify the key genes associated with leaf coloration and elucidate the molecular mechanisms involved in the color changes in P. setaceum 'Rubrum' leaves. We performed transcriptome sequencing of P. setaceum 'Rubrum' leaves before and after shading. A total of 19,043 differentially expressed genes were identified, and the numbers of upregulated and downregulated genes at T1 stage, when compared with their expression at the T0 stage, were 10,761 and 8,642, respectively. The possible pathways that determine P. setaceum 'Rubrum' leaf color included flavonoid biosynthesis, flavone and flavonol biosynthesis, and carotenoid biosynthesis. There were 31 differentially expressed genes related to chlorophyll metabolism, of which 21 were related to chlorophyll biosynthesis and 10 to chlorophyll degradation, as well as three transcription factors that may be involved in the regulation of chlorophyll degradation. There were 31 key enzyme genes involved in anthocyanin synthesis and accumulation in P. setaceum 'Rubrum' leaves, with four transcription factors that may be involved in the regulation of anthocyanin metabolism. The transcriptome data were verified and confirmed reliable by real-time fluorescence quantitative PCR analysis. These findings provide a genetic basis for improving leaf color in P. setaceum 'Rubrum.'

Annual ryegrass (Lolium multiflorum) is a widely used cool-season turf and forage grass with high productivity and ornamental characteristics. However, the abundant intra-cultivar genetic variability usually hampers the application of conventional techniques for cultivar identification. The objectives of this study were to: (1) describe an efficient strategy for identification of six tetraploid annual ryegrass cultivars and (2) investigate the genetic diversity based on SSR markers. A total of 242 reliable bands were obtained from 29 SSR primer pairs with an average of 8.3 bands for each primer pair and the average value of polymorphic information content (PIC) was 0.304. The result of analysis of molecular variance (AMOVA) revealed that 81.99% of the genetic variation occurred in within-cultivars and 18.01% among-cultivars. The principal coordinate analysis (PCoA) showed that the first two principal axes explain 8.57% (PC1) and 6.05% (PC2) of total variation, respectively. By using multi-bulk strategy based on different filtering thresholds, the results suggested that bands frequency of 40% could be used as a reliable standard for cultivar identification in annual ryegrass. Under this threshold, 12 SSR primer pairs (00-04A, 02-06G, 02-08C, 03-05A, 04-05B, 10-09E, 12-01A, 13-02H, 13-12D, 14-06F, 15-01C and 17-10D) were detected for direct identification of six tetraploid annual ryegrass cultivars, which could be incorporated into conservation schemes to protect the intellectual property of breeders, ensure purity for consumers, as well as guarantee effective use of cultivars in future.

Abstract It is a grand attraction for contemporary biochemists to computationally design enzymes for novel chemical transformation or improved catalytic efficiency. Rosetta by Baker et al. is no doubt the leading software in the protein design society. Generally, optimization of the transition state (TS) is part of the Rosetta’s protocol to enhance the catalytic efficiency of target enzymes, since TS stabilization is the determining factor for catalytic efficiency based on the TS theory (TST). However, it is confusing that optimization of the reactant state (RS) also results in significant improvement of catalytic efficiency in some cases, such as design of gluten hydrolase (Kuma030). Therefore, it is interesting to uncover underlying reason why a better binding in the RS leading to an increased k cat . In this study, the combined quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy (PMF) simulations, pK a calculation, and the statistical analysis such as the ANOVA test were carried out to shed light on the interesting but elusive question. By integration of our computational results and general acid/base theory, we answered the question why optimization of RS stabilization leads to a better TS stabilization in the general acid/base catalysis. In addition, a new and simplified protein-design strategy is proposed for the general acid/base catalysis. The idea, that application of traditional well-defined enzyme mechanism to protein design strategy, would be a great help for methodology development of protein design.

Abstract Background Urinary miRNAs may potentially serve as noninvasive biomarkers in various kidney diseases to reflect disease activity, severity and progression, especially those correlated with the pathogenesis of kidney diseases. This study demonstrates that urinary miR-196a, a kidney-enriched miRNA, can predict progression of chronic kidney disease (CKD). Methods Focal segmental glomerulosclerosis (FSGS) cohorts were used as the representative example of CKD. First, correlation of miR-196a with disease activity was analyzed using paired urine and plasma samples from FSGS patients with nephrotic-range proteinuria (FSGS-A), complete remission (FSGS-CR) and normal controls (NCs). Then, the value of urinary miR-196a in predicting disease progression was validated using another cohort of 231 FSGS patients who were followed-up until over 36 months or reaching end-stage renal disease (ESRD). MiR-196a levels were analyzed by quantitative reverse transcription-polymerase chain reaction. Results The results showed that urinary miR-196a significantly increased in FSGS-A compared with FSGS-CR and NCs, clearly distinguishing FSGS-A from FSGS-CR and NCs, whereas plasma miR-196a showed no difference among these groups. Moreover, urinary miR-196a, which was associated with proteinuria, estimated glomerular filtration rate (eGFR), interstitial fibrosis and tubular atrophy, significantly increased in patients progressed to ESRD compared to those not. Furthermore, patients with higher urinary miR-196a displayed poorer renal survival than those with lower urinary miR-196a. Multivariate Cox analysis confirmed urinary miR-196a as an independent risk factor for FSGS progression after adjusting for age, sex, proteinuria and eGFR. Prediction accuracy of ESRD was significantly improved by combining urinary miR-196a with other indicators including eGFR and proteinuria. Conclusion Urinary miR-196a may serve as a biomarker for predicting CKD progression

Abstract Door-to-needle time (DNT) is a key performance indicator for efficient use of intravenous thrombolysis in acute ischemic stroke (AIS). We aimed to determine whether DNT improved over time in the Enhanced Control of Hypertension and Acute Stroke Study (ENCHANTED) and the clinical predictors of DNT. Temporal trends in DNT were assessed across fourths of time since activation of study centers using generalized linear model. Predictors of long DNT (>60 min) were determined in logistic regression models. Overall mean DNT (min) was 71.8 (95% confidence interval [CI] 70.4–73.2), but decreased significantly over time (fourths): 77.9 (74.9–80.9), 69.3 (66.7–72.0), 69.1 (66.5–71.8) and 71.4 (68.7–74.2) (P for trend, 0.003). The reduction in DNT was particularly marked in China (P for trend, 0.001), but was not significant across the other participating countries (P for trend, 0.065). Independent predictors of long DNT were recruitment from China, short onset-to-door time, lower numbers of patients treated per center, higher diastolic blood pressure, off-hour admission, and absence of proximal clot occlusion. DNT in ENCHANTED declined progressively during the trial, especially in China. However, DNT in China is still longer than the key performance parameter of ≤60 minutes recommended in guidelines. Effective national programs are needed to improve DNT in China.

Abstract Background De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

Abstract Traditional Chinese medicines (TCMs) have important therapeutic value in long-term clinical practice. However, because TCMs contain diverse ingredients and have complex effects on the human body, the molecular mechanisms of TCMs are poorly understood. In this work, we determined the gene expression profiles of cells in response to TCM components to investigate TCM activities at the molecular and cellular levels. MCF7 cells were separately treated with 102 different molecules from TCMs, and their gene expression profiles were compared with the Connectivity Map (CMAP). To demonstrate the reliability and utility of our approach, we used nitidine chloride (NC) from the root of Zanthoxylum nitidum, a topoisomerase I/II inhibitor and α-adrenoreceptor antagonist, as an example to study the molecular function of TCMs using CMAP data as references. We successfully applied this approach to the four ingredients in Danshen and analyzed the synergistic mechanism of TCM components. The results demonstrate that our newly generated TCM data and related methods are valuable in the analysis and discovery of the molecular actions of TCM components. This is the first work to establish gene expression profiles for the study of TCM components and serves as a template for general TCM research.

Abstract Background Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease. Methods Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human. Results Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients’ missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria. Conclusions Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

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Objective: To understand whether reduced pregnancy and live birth rates for Asian patients undergoing in vitro fertilization (IVF) could be explained by discrepant rates of aneuploid embryos. Methods: A retrospective cohort study of all autologous and donor IVF cycles utilizing pre-implantation genetic screening (PGS) at a single infertility clinic from January 2012 to December 2013. Results: After controlling for maternal age, there was no difference in aneuploidy rates of Caucasian patients compared to Asian patients'. A trend was discerned that embryos of Caucasians form blastocysts more frequently than those of Asian patients, reaching significance for patients aged 25 to 30 and 40 to 45, but there was no difference in the likelihood of having at least one euploid blastocyst to transfer in any age group. Conclusion: While there may be a slight difference in blastocyst formation rates, there is no difference in aneuploidy or euploid blastocyst transfer rates between Asian and Caucasian patients that would explain the discrepancy in IVF outcomes observed between these patient populations. Possible ethnicity specific differences in non-ploidy related embryo viability and endometrial receptivity should be investigated as potential etiologies for this observation.