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Abstract Background Hepatic dysfunction (HD) increases the morbidity and mortality rates after cardiac surgery. However, few studies have investigated the association between HD and acute DeBakey type I aortic dissection (ADIAD) surgery. This retrospective study aimed to identify risk factors for developing HD in patients who received acute type I aortic dissection repair and its consequences. Methods A total of 830 consecutive patients who received ADIAD surgery from January 2014 to December 2019 at our center were screened for this study. The End-Stage Liver Disease (MELD) score more than 14 was applied to identify postoperative HD. Logistic regression model was applied to identify risk factors for postoperative HD, Kaplan–Meier survival analysis and Cox proportional hazards regression assay were conducted to analyze the association between HD and postoperative long-term survival. Results Among 634 patients who eventually enrolled in this study, 401 (63.2%) experienced postoperative HD with a 30-Day mortality of 15.5%. Preoperative plasma fibrinogen level (PFL) [odds ratio (OR): 0.581, 95% confidence interval (CI): 0.362–0.933, P = 0.025], serum creatinine (sCr) on admission (OR: 1.050, 95% CI 1.022–1.079, P

Abstract Objective This study aimed to identify risk factors for 30-day mortality in patients who received DeBakey type I aortic dissection (AD) repair surgery. Methods A total of 830 consecutive patients who received acute DeBakey type I AD surgery between 2014 and 2019 were included in the study. The associations between 30-day mortality and perioperative parameters were examined in order to identify risk factors. Results Our data suggested that the overall 30-day mortality rate of all enrolled patients was 11.7%. Unsurprisingly, non-survivors were older and more frequently accompanied with histories of cardiovascular diseases. For intraoperative parameters, the prevalence of coronary artery bypass grafting and cardiopulmonary bypass times were increased in non-survivors. In addition, acute kidney injury (AKI), dialysis, stroke, and deep sternal wound infection were more commonly seen among non-survivors. The multivariate logistic regression analysis suggested that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery, and postoperative AKI were independent risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery. Conclusions Our study demonstrated that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery as well as postoperative AKI were risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery.

Abstract Congenital cataracts are the leading cause of childhood blindness. To date, surgical removal of cataracts is the only established treatment, but surgery is associated with multiple complications, which often lead to visual impairment. Therefore, mechanistic studies and drug-candidate screening have been intrigued by the aims of developing novel therapeutic strategies. However, these studies have been hampered by a lack of an appropriate human-disease model of congenital cataracts. Herein, we report the establishment of a human congenital cataract in vitro model through differentiation of patient-specific induced pluripotent stem cells (iPSCs) into regenerated lenses. The regenerated lenses derived from patient-specific iPSCs with known causative mutations of congenital cataracts (CRYBB2 [p. P24T] and CRYGD [p. Q155X]) showed obvious opacification that closely resembled that seen in patients’ cataracts in terms of opacification severity and disease course accordingly, as compared with lentoid bodies (LBs) derived from healthy individuals. Increased protein aggregation and decreased protein solubility corresponding to the patients’ cataract severity were observed in the patient-specific LBs and were attenuated by lanosterol treatment. Taken together, the in vitro model described herein, which recapitulates patient-specific clinical manifestations of congenital cataracts and protein aggregation in patient-specific LBs, provides a robust system for research on the pathological mechanisms of cataracts and screening of drug candidates for cataract treatment.

Background: Inflammation and oxidative stress are known to participate in the pathogenesis of hyperbilirubinemia. It has been known that acute type A aortic dissection (ATAAD) surgical repair often associates with complications which might affect the long-term prognosis. However, the clinical significance of postoperative hyperbilirubinemia (PH) has not been evaluated. Here in this study, we examined the incidence, risk factors, and prognosis of PH after ATAAD surgery.Methods: This retrospective study enrolled a total of 970 patients who received ATAAD surgical repair from January 2014 to December 2019. PH was defined as serum total bilirubin >3.0 mg/dl within the first week after the surgery. Propensity score matching was used to reduce selection bias and eliminate potential confounding factors. Kaplan–Meier survival and Cox proportional hazards regression analyses were conducted to explore the association between PH and postoperative long-term survival.Results: Development of PH (183 patients) was associated with a higher 30-Day mortality (20.8% vs. 9.0%, p < 0.001). Advanced age [odds ratio (OR) 1.538, p = 0.006], higher baseline total bilirubin level (OR 1.735, p = 0.026), preoperative pericardial tamponade (OR 3.192, p = 0.024), prolonged cardiopulmonary bypass (CPB) duration (OR 2.008, p = 0.005), and elevated postoperative central venous pressure (CVP) level (OR 2.183, p < 0.001) were associated with PH. The Kaplan-Meier analysis showed patients who developed PH were associated with poor long-term survival (p = 0.044). Cox analysis showed that the presence of PH (hazard ratio 2.006, p = 0.003) was an independent risk factor for increased mortality.Conclusion: PH is a common complication in patients undergoing ATAAD surgical repair that associates with worse short- and long-term prognosis. Our data indicated that age, preoperative total bilirubin level, pericardial tamponade, CPB duration, and postoperative CVP level were risk factors for the development of PH.

A wide plethora of intervention procedures, tissue plasminogen activators, mechanical thrombectomy, and several neuroprotective drugs were reported in stroke research over the last decennium. However, against this vivid background of newly emerging pieces of evidence, there is little to no advancement in the overall functional outcomes. With the advancement of epigenetic tools and technologies associated with intervention medicine, stroke research has entered a new fertile. The stroke involves an overabundance of inflammatory responses arising in part due to the body’s immune response to brain injury. Neuroinflammation contributes to significant neuronal cell death and the development of functional impairment and even death in stroke patients. Recent studies have demonstrated that epigenetics plays a key role in post-stroke conditions, leading to inflammatory responses and alteration of the microenvironment within the injured tissue. In this review, we summarize the progress of epigenetics which provides an overview of recent advancements on the emerging key role of secondary brain injury in stroke. We also discuss potential epigenetic therapies related to clinical practice.

The PLATZ (plant AT protein and zinc-binding protein) transcription factor family is involved in the regulation of plant growth and development and plant stress response. In this study, 24 SlPLATZs were identified from the cultivated tomato genome and classified into four groups based on the similarity of conserved patterns among members of the same subfamily. Fragment duplication was an important way to expand the SlPLATZ gene family in tomatoes, and the sequential order of tomato PLATZ genes in the evolution of monocotyledonous and dicotyledonous plants and the roles they played were hypothesized. Expression profiles based on quantitative real-time reverse transcription PCR showed that SlPLATZ was involved in the growth of different tissues in tomatoes. SlPLATZ21 acts mainly in the leaves. SlPLATZ9, SlPLATZ21, and SlPLATZ23 were primarily involved in the red ripening, expanding, and mature green periods of fruit, respectively. In addition, SlPLATZ1 was found to play an important role in salt stress. This study will lay the foundation for the analysis of the biological functions of SlPLATZ genes and will also provide a theoretical basis for the selection and breeding of new tomato varieties and germplasm innovation.

Purpose: Our previous study observed that human induced pluripotent stem cell (HiPSC)-derived lentoid bodies (LBs) became cloudy with extended culture time, partially mimicking the progress of human age-related cataracts (ARCs) in a dish. In the present study, lanosterol, a potential anticataract drug, was used to further verify the value of this model in drug screening for cataract treatment.Methods: Mature LBs on day 25, which were differentiated from HiPSCs using the “fried egg” method, were continually cultured and treated with either dimethyl sulfoxide (control) or lanosterol. The LBs’ shape and opacity alterations were examined using light microscopy and mean gray value evaluation. The soluble and insoluble proteins were examined through SDS-PAGE gel electrophoresis combined with Coomassie blue staining. The protein aggregations were examined with immunofluorescence.Results: The mature LBs became cloudy with an extended culture time, and the opacification of the LBs was partially prevented by lanosterol treatment. There was less increase in insoluble proteins in the lanosterol-treated LBs than in the control group. There were also fewer cells containing aggregated protein (αA‐crystallin and αB‐crystallin) puncta in the lanosterol-treated LBs than in the control LBs.Conclusion: It was found that the opacification of LBs could be delayed by lanosterol treatment, which could be achieved by reducing protein aggregation, suggesting a promising HiPSC-derived drug-screening model for Age-related cataract.

Citric acid is one of the most widely used organic acids in the world, with applications ranging from acidity regulation in food and beverages to metal chelation in hydrometallurgical processes. Most of its production is currently derived from fermentative processes, using plant-derived carbon feedstocks. While these are currently dominant, there is an increasing need to develop closed-loop production systems that reduce process carbon footprint. In this work, we demonstrate for the first time that an engineered marine cyanobacterium Synechococcus sp. PCC 7002 can be used as a sustainable chassis for the photosynthetic conversion of CO2 to citric acid. Decreased citric acid cycle flux, through the use of a theophylline-responsive riboswitch, was combined with improved flux through citrate synthase and enhanced citric acid excretion, resulting in a significant improvement to citric acid production. While allowing citrate production, this strategy induces a growth defect which can be overcome by glutamate supplementation or by fine-tuning aconitase levels, resulting in an increase in production relative to WT of over 100-fold. This work represents a first step toward sustainable production of a commodity organic acid from CO2.

The weedy rice (Oryza sativa f. spontanea) pericarp has diverse colors (e.g., purple, red, light-red, and white). However, research on pericarp colors has focused on red and purple, but not green. Unlike many other common weedy rice resources, LM8 has a green pericarp at maturity. In this study, the coloration of the LM8 pericarp was evaluated at the cellular and genetic levels. First, an examination of their ultrastructure indicated that LM8 chloroplasts were normal regarding plastid development and they contained many plastoglobules from the early immature stage to maturity. Analyses of transcriptome profiles and differentially expressed genes revealed that most chlorophyll (Chl) degradation-related genes in LM8 were expressed at lower levels than Chl a/b cycle-related genes in mature pericarps, suggesting that the green LM8 pericarp was associated with inhibited Chl degradation in intact chloroplasts. Second, the F2 generation derived from a cross between LM8 (green pericarp) and SLG (white pericarp) had a pericarp color segregation ratio of 9:3:4 (green:brown:white). The bulked segregant analysis of the F2 populations resulted in the identification of 12 known genes in the chromosome 3 and 4 hotspot regions as candidate genes related to Chl metabolism in the rice pericarp. The RNA-seq and sqRT-PCR assays indicated that the expression of the Chl a/b cycle-related structural gene DVR (encoding divinyl reductase) was sharply up-regulated. Moreover, genes encoding magnesium-chelatase subunit D and the light-harvesting Chl a/b-binding protein were transcriptionally active in the fully ripened dry pericarp. Regarding the ethylene signal transduction pathway, the CTR (encoding an ethylene-responsive protein kinase) and ERF (encoding an ethylene-responsive factor) genes expression profiles were determined. The findings of this study highlight the regulatory roles of Chl biosynthesis- and degradation-related genes influencing Chl accumulation during the maturation of the LM8 pericarp.

BackgroundIt has been well known that hyperlactatemia is an independent risk factor for postoperative mortality in patients who received acute type A aortic dissection (ATAAD) surgery. Some patients may require the assistance of continuous renal replacement therapy (CRRT) for acute postoperative renal deficiency and often associate with increased mortality rate. This study aimed to examine the association between the early dynamic change of lactate levels and postoperative CRRT in ATAAD patients who received surgical repairment.MethodsThis retrospective study included 503 patients who received ATAAD surgeries. Serum lactate levels were measured before operation and at 0, 1, 3, 6, 12, 24 h post intensive care unit (ICU) admission. We examined the association between dynamic changes of lactate and CRRT.ResultsAmong all patients, 19.9% (100 patients) required CRRT. Our data showed that the lactate levels were higher in the CRRT group at all timepoints compared to the non-CRRT group. In a multivariate model, lactate levels at 12 h post ICU admission [odds ratio (OR), 1.362; p = 0.007] was identified as an independent predictor for requiring CRRT. Unsurprisingly, 30-day mortality in the CRRT group (41%) was 8.2 times higher than in the non-CRRT group (5%). To better understand the associations between CRRT and lactate levels, patients in the CRRT group were further stratified into the non-survivor group (n = 41) and survivor group (n = 59) based on the 30-day mortality. Elevated lactate levels measured upon ICU admission (OR, 1.284; p = 0.001) and decreased 24 h lactate clearance (OR, 0.237; p = 0.039) were independent risk factors for 30-day mortality in patients who received CRRT. The area under the curve to predict requirement for CRRT at 6 and 12 h post CICU admission were 0.714 and 0.722, respectively, corresponding to lactate cut-off levels of 4.15 and 2.45 mmol/L.ConclusionThe CRRT is commonly required in patients who received ATAAD surgery and often associated with worse mortality. Early dynamic changes of lactate levels can be used to predict the requirement of postoperative CRRT.

Sodium-ion batteries with evident merits in resource abundance and expenditure are emerging as a more suitable alternative to lithium-ion batteries for fulfilling the voracious energy demand of human activities. As the integral component of the battery, the exploration of anode materials suited to the electrochemical system during the last few decades has been never suspended, and the sodium metal anode successfully stands out with its high theoretical capacity and low redox potential. However, a huge gap exists between the direct usage of the sodium metal anode and the large-scale applications, as the uncontrollable sodium dendritic growth during cycling brings about serious concerns (i.e. infinite volume change, unstable solid electrolyte interphase, and safety issues) on battery performance losses. Although a few review articles on high-performance sodium metal anode have been already published, new research on solving the aforementioned challenges is still in progress. Therefore, we herein summarize the recent progress on the high-energy sodium metal anode from four aspects (protective layers, electrolyte additives, three-dimensional framework current collectors, and alloy materials) together with the detailed discussion and analysis in this Perspective. Furthermore, the potential directions and prospects of future research on constructing high-performance sodium metal anodes are also proposed.

Cochlear nerve deficiency (CND) is often associated with variable outcomes of cochlear implantation (CI). We assessed previous investigations aiming to identify the main factors that determine CI outcomes, which would enable us to develop predictive models. Seventy patients with CND and normal cochlea who underwent CI surgery were retrospectively examined. First, using a data-driven approach, we collected demographic information, radiographic measurements, audiological findings, and audition and speech assessments. Next, CI outcomes were evaluated based on the scores obtained after 2 years of CI from the Categories of Auditory Performance index, Speech Intelligibility Rating, Infant/Toddler Meaningful Auditory Integration Scale or Meaningful Auditory Integration Scale, and Meaningful Use of Speech Scale. Then, we measured and averaged the audiological and radiographic characteristics of the patients to form feature vectors, adopting a multivariate feature selection method, called stability selection, to select the features that were consistent within a certain range of model parameters. Stability selection analysis identified two out of six characteristics, namely the vestibulocochlear nerve (VCN) area and the number of nerve bundles, which played an important role in predicting the hearing and speech rehabilitation results of CND patients. Finally, we used a parameter-optimized support vector machine (SVM) as a classifier to study the postoperative hearing and speech rehabilitation of the patients. For hearing rehabilitation, the accuracy rate was 71% for both the SVM classification and the area under the curve (AUC), whereas for speech rehabilitation, the accuracy rate for SVM classification and AUC was 93% and 94%, respectively. Our results identified that a greater number of nerve bundles and a larger VCN area were associated with better CI outcomes. The number of nerve bundles and VCN area can predict CI outcomes in patients with CND. These findings can help surgeons in selecting the side for CI and provide reasonable expectations for the outcomes of CI surgery.

Abstract Background Schistosoma japonicum is a parasitic flatworm that is the aetiological agent of human schistosomiasis, an important cause of hepatic fibrosis. Schistosomiasis-induced hepatic fibrosis is a consequence of the highly fibrogenic nature of egg-induced granulomatous lesions, which are the main pathogenic features of schistosomiasis. Although global awareness of the association between schistosomiasis-induced hepatic fibrosis and S. japonicum infection is increasing, little is known about the molecular differences associated with rapid progression to schistosomiasis in cirrhotic patients. Methods We systematically used data-independent acquisition (DIA)-based liquid chromatography-mass spectrometry to identify differentially expressed proteins in serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. Results Our analysis identified 1144 proteins, among which 66 were differentially expressed between the healthy control group and the group of patients with advanced S. japonicum-induced hepatic fibrosis stage F2 (SHF-F2) and 214 were differentially expressed between the SHF-F2 and SHF-F4 groups (up- or downregulation of at least 1.5-fold in serum samples). The results also indicated that two selected proteins (C1QA and CFD) are potential biomarkers for distinguishing between patients with SHF-F2 and those with SHF-F4 due to S. japonicum infection. Conclusions We provide here the first global proteomic profile of serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. The proteins C1QA and CFD are potential diagnostic markers for patients with SHF-F2 and SHF-F4 due to S. japonicum infection, although further large-scale studies are needed. Our DIA-based quantitative proteomic analysis revealed molecular differences among individuals at different stages of advanced S. japonicum-induced hepatic fibrosis and may provide fundamental information for further detailed investigations. Graphic Abstract

Abstract Wideband Absorbance Immittance (WAI) has been available for more than a decade, however its clinical use still faces the challenges of limited understanding and poor interpretation of WAI results. This study aimed to develop Machine Learning (ML) tools to identify the WAI absorbance characteristics across different frequency-pressure regions in the normal middle ear and ears with otitis media with effusion (OME) to enable diagnosis of middle ear conditions automatically. Data analysis included pre-processing of the WAI data, statistical analysis and classification model development, and key regions extraction from the 2D frequency-pressure WAI images. The experimental results show that ML tools appear to hold great potential for the automated diagnosis of middle ear diseases from WAI data. The identified key regions in the WAI provide guidance to practitioners to better understand and interpret WAI data and offer the prospect of quick and accurate diagnostic decisions.

Abstract Background Prevalence of neonatal microcephaly in populations without Zika-epidemics is sparse. The study aimed to report baseline prevalence of congenital microcephaly and its relationship with prenatal factors in an area at risk of Zika outbreak. Methods This study included singletons born after 24 gestational weeks in 2017–2018 at four hospitals in Guangzhou, China. Microcephaly was defined as a head circumference at birth >3SD below the mean for sex and gestational age. Prevalence of microcephaly was estimated by binomial exact method. Multivariable logistic regression was used to examine the associations of microcephaly with prenatal factors. The population attributable fraction (PAF) for associated risk factors was calculated. Results Of 46,610 live births included, 154 (3.3, 95% CI 2.8–3.9 per 1000 live births) microcephalies were identified. Maternal hepatitis B virus carriers (HBV, OR 1.80, 95% CI 1.05–3.10) and primipara (OR 2.68, 95% CI 1.89–3.81) had higher risk of having a microcephalic baby. Higher prevalence of microcephaly was observed in women who had premature labor (OR 1.98, 95% CI 1.17–3.34) and had a baby with fetal growth restriction (OR 16.38, 95% CI 11.81–22.71). Four identified factors (HBV, primiparity, preterm labor, and fetal growth restriction) contributed to 66.4% of the risk of microcephaly. Conclusions The prevalence of microcephaly in Guangzhou was higher than expected. This study identified four prenatal risk factors that, together, contributed to two-thirds of the increased risk of microcephaly. This is the first reported association between maternal HBV carrier status and microcephaly.

Functional groups on support membranes are important for the preparation of high-performance membrane adsorbers (MAs). In this work, the effects of different functional groups on support membranes on the adsorption performance of MAs were studied through surface modifications such as alkali treatment, oxidation treatment and polydopamine (PDA) deposition. Our experiment results indicate that chemical bonds are prone to form between C-F on PVDF membrane and amine groups on PEI, which serves to improve the protein adsorption capacity. Furthermore, PDA deposition has the potential to enhance protein adsorption capacity. Introducing a PDA layer on a support membrane with uniform pore size distribution shows potential to improve protein adsorption capacity.

Background: Cardiac surgical re-exploration for bleeding is associated with increased morbidity and mortality. Whether to perform these procedures in the operating room (OR) or the Cardiac Intensive Care Unit (CICU) in uncertain. We sought to determine if the location of the reoperation would affect postoperative outcomes when a reoperation for bleeding is required following cardiac surgery. Methods: Patients who underwent planned cardiac re-explorations for bleeding at our center from January 2019 to December 2021 were retrospectively enrolled in this study. Patient outcomes were compared and analyzed. Results: Due to hemorrhagic shock, 72 patients underwent planned cardiac re-explorations, including 21 operated in the CICU and 51 in the OR. Within 12 h of the primary operation, 65 re-explorations (90.3%) were performed. The peak Vasoactive-Inotropic Score was 47.0 ± 27.4, systolic blood pressure was 89.4 ± 9.6 mmHg, central venous pressure was 12.1 ± 4.4 cmH2O, and the serum lactate was 5.5 ± 4.1 mmol/L prior to the reoperation. Multivariate logistic analysis showed that a reoperation performed in the CICU was not an independent risk factor for the occurrence of major complications. There was no significant difference in mortality between the two groups. Conclusions: Planned re-exploration for bleeding following open cardiac surgery in the CICU is feasible and safe.

Landslides are one type of destructive and recurring natural calamities in the mountainous regions. The landslide occurrences often lead to immense damage to local infrastructure and loss of land, human lives and livestock. Data-driven risk assessment of landslide risk plays a crucial role in preventing the incoming landslide occurrences and recurrences. In this research, we developed a human-centric framework using information-granules to perform risk assessment of a group of landslides. First, the density-based spatial clustering of applications with noise (DBSCAN) has been selected as the backbone unsupervised learning method to subclusters for landslide risk indication. The clustering outcomes are visualized via t-distributed stochastic neighbor embedding (t-SNE) in the 2-D embedding space. Second, the prototype points within the subclusters produced by DBSCAN are computed for granular construction. Third, interval-based information-granules are constructed and measured via coverage, specificity and area under the coverage-specificity curve (AUC). Last, with the optimal information-granules constructed, two risk measures namely Value-at-Risk (VaR) and Conditional-Value-at-Risk (CVaR) are computed to interpret the rule-based information-granules with respect to the key attributes. Comparative experiments have also been performed against other benchmarking clustering approaches. Computational results indicate that the information-granules constructed from DBSCAN subclusters offered enhanced performance in reveal meaningful information-granules and provide promising results. The proposed approach can capture the main essence of landslide pattern with higher interpretability and help to reduce the computing overhead.

ObjectiveHigh-frequency repetitive transcranial magnetic stimulation (rTMS) induces analgesic effects in both experimental pain and clinical pain conditions. However, whether rTMS can modulate sensory and pain thresholds on sensory fibers is still unclear. Here, we compared the effects of three rTMS paradigms on sensory and pain thresholds conducted by different sensory fibers (Aβ, Aδ, and C fibers) with sham stimulation and investigate the potential brain activation using functional near-infrared spectroscopy (fNIRS).MethodsForty right-handed healthy subjects were randomly allocated into one of four groups. Each subject received one session rTMS [prolonged continuous theta-burst stimulation (pcTBS), intermittent theta-burst stimulation (iTBS), 10 Hz rTMS or sham]. Current perception threshold (CPT), pain tolerance threshold (PTT), and fNIRS were measured at baseline, immediately after stimulation, and 1 h after stimulation, respectively.ResultsSignificant differences between treatments were observed for changes for CPT 2,000 Hz between baseline and 1 h after rTMS (F = 6.551, P < 0.001): pcTBS versus sham (P = 0.004) and pcTBS versus 10 Hz rTMS (P = 0.007). There were significant difference in average HbO μm in the right frontopolar cortex (FPC) [channel 23: P = 0.030 (pcTBS versus sham: P = 0.036)], left dorsolateral prefrontal cortex (DLPFC) [channel 7: P = 0.006 (pcTBS versus sham: P = 0.004)], left FPC [channel 17: P = 0.014 (pcTBS versus sham: P = 0.046), channel 22: P = 0.004 (pcTBS versus sham: P = 0.004)] comparing four group in 1 h after stimulation in PTT 2000 Hz (Aβ-fiber).ConclusionProlonged continuous theta-burst stimulation can regulate sensitivity on Aβ fibers. In addition, single-session pcTBS placed on left M1 can increase the excitability of DLPFC and FPC, indicating the interaction between M1 and prefrontal cortex may be a potential mechanism of analgesic effect of rTMS. Studies in patients with central post-stroke pain are required to confirm the potential clinical applications of pcTBS.

This study was to explore the application of MRI based on artificial intelligence technology combined with neuropsychological assessment to the cognitive impairment of patients with neurological cerebrovascular diseases. A total of 176 patients were divided into a control group, a vascular cognitive impairment non-dementia (VCIND) group, a vascular dementia (VD) group, and an Alzheimer's disease (AD) group. All patients underwent MRI and neuropsychological evaluation and examination, and an improved fuzzy C-means (FCM) clustering algorithm was proposed for MRI processing. It was found that the segmentation accuracy (SA) and similarity (KI) data of the improved FCM algorithm used in this study were higher than those of the standard FCM algorithm, bias-corrected FCM (BCFCM) algorithm, and rough FCM (RFCM) algorithm (p < 0.05). In the activities of daily living (ADL), the values in the VCIND group (23.55 ± 6.12) and the VD group (28.56 ± 3.1) were higher than that in the control group (19.17 ± 3.67), so the hippocampal volume was negatively correlated with the ADL (r = −0.872, p < 0.01). In the VCIND group (52.4%), VD group (31%), and AD group (26.1%), the proportion of patients with the lacunar infarction distributed on both sides of the brain and the number of multiple cerebral infarction lesions (76.2, 71.4, and 71.7%, respectively) were significantly higher than those in the control group (23.9 and 50%). In short, the improved FCM algorithm showed a higher segmentation effect and SA for MRI of neurological cerebrovascular disease. In addition, the distribution, number, white matter lesions, and hippocampal volume of lacunar cerebral infarction were related to the cognitive impairment of patients with cerebrovascular diseases.

BackgroundAlzheimer's disease (AD) is a multifactorial neurological disease with neurofibrillary tangles and neuritic plaques as histopathological markers. Due to this, although AD is the leading cause of dementia worldwide, clinical AD dementia cannot be certainly diagnosed until neuropathological post-mortem evaluation. Coffee has been reported to have neurologically protective factors, particularly against AD, but coffee brand and type have not been taken into consideration in previous studies. We examined the discrepancies among popular commercial and instant coffees in limiting the development and progression through Aβ1-40 and Aβ1-42 production, and hypothesized that coffee consumption, regardless of brand or type, is beneficial for stalling the progression and development of Aβ-related AD.MethodsCoffee samples from four commercial coffee brands and four instant coffees were purchased or prepared following given instructions and filtered for the study. 5, 2.5, and 1.25% concentrations of each coffee were used to treat N2a/APPswe cell lines. MTT assay was used to assess cell viability for coffee concentrations, as well as pure caffeine concentrations. Sandwich ELISA assay was used to determine Aβ concentration for Aβ1-40 and Aβ1-42 peptides of coffee-treated cells.ResultsCaffeine concentrations were significantly varied among all coffees (DC vs. MDC, PC, SB, NIN, MIN p < 0.05). There was no correlation between caffeine concentration and cell toxicity among brands and types of coffee, with no toxicity at 0.5 mg/ml caffeine and lower. Most coffees were toxic to N2a/APPswe cells at 5% (p < 0.05), but not at 2.5%. Most coffees at a 2.5% concentration reduced Aβ1-40 and Aβ1-42 production, with comparable results between commercial and instant coffees.ConclusionAll coffees tested have beneficial health effects for AD through lowering Aβ1-40 and Aβ1-42 production, with Dunkin' Donuts® medium roast coffee demonstrating the most consistent and optimal cell survival rates and Aβ concentration. On the other hand, Starbucks® coffee exhibited the highest cell toxicity rates among the tested coffees.

ObjectTo investigate the long-term development of auditory and speech in patients with common cavity deformity (CCD) after cochlear implantation (CI) and its relationship to imaging characteristics.MethodsTwenty-three CCD patients and 59 age- and sex-matched CI children with normal inner ear structure were recruited. The auditory and speech development of these two groups were evaluated at 0, 1, 3, 6, 12, and 18 months after CI activation using four parent reports questionnaires [Categories of Auditory Performance (CAP), Speech Intelligibility Rating (SIR), Meaningful Auditory Integration Scale/Infant-Toddler Meaningful Auditory Integration Scale (MAIS/ITMAIS), and Meaningful Use of Speech Scale (MUSS)]. Computed tomography-based 3-dimensional reconstruction of the surgical side of 18 CCD children was performed, the volume and surface area were calculated. Correlation analysis was performed on the imaging performance and post-operative outcomes.ResultsThe percentages of MAIS/IT-MAIS scores and CAP scores at different evaluation time points are significantly different (p < 0.05). When comparing SIR results across time points, significant growth was observed in most of the comparisons. In addition, significant differences (p < 0.05) are observed among the percentages of MUSS scores at different time points except the comparison between 0 and 1 month after CI activation. Patients in the CCD group had poorer auditory and speech performances at different stages after CI compared with those in the control group. According to the reconstruction of CCD patients, the volume ranged from 12.21 to 291.96 mm3; the surface area ranged from 27.81 to 284.7 mm2. When the lumen surface area was

The study aimed to explore the risk factors of effects of patients with vascular mild cognitive impairment (VaMCI) through functional magnetic resonance imaging (fMRI). In this study, 62 patients were selected from the department of neurology, admitted to Changzhi People's Hospital from October 1, 2018 to February 1, 2020. Patients with VaMCI were defined as the VaMCI group according to Clinical Dementia Rating (CDR), and subjects with normal cognitive function were defined as the normal control (NC) group. All patients underwent fMRI to identify the amplitude low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values, and to analyze their association with VaMCI. The results showed that the VaMCI group had lower scores for Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and their subitems (visual space and execution, recall, attention and computation, and language ability) than NC group, with statistical differences (P < 0.05). In VaMCI group, the brain regions with increased ALFF values were the left temporal lobe, left parietal lobe, right temporal lobe, right parietal lobe, and posterior cingulate gyrus. Of them, the left parietal lobe and right temporal lobe were negatively correlated with the recall score on MMSE scale (r = −0.216, r = −0.132, P < 0.01). In VaMCI group, the brain regions with decreased ReHo values were the left temporal lobe, occipital lobe, and left middle temporal gyrus. Of them, the left temporal lobe and occipital lobe were positively correlated with MoCA score (r = 0.473, r = 0.848, P < 0.01). In conclusion, VaMCI patients have cognitive impairment and abnormally increased spontaneous brain activity, especially in the left parietal lobe and the right temporal lobe. At rest, VaMCI patients show decreased whole-brain ReHo in the left medial temporal lobe and occipital lobe. Hypertension is a high-risk factor for cognitive impairment in VaMCI patients. The study can provide a theoretical basis for early diagnosis of VaMCI.

Abstract Background Triazine coccidiostats are widely used in chickens and turkeys for coccidiosis control. Ethanamizuril is a novel triazine compound that exhibits anticoccidial activity in poultry. This study was designed to evaluate the subchronic toxicity of ethanamizuril in beagle dogs at doses of 12, 60 or 300 mg/kg/day in diet for 90 days. Results Ethanamizuril was well tolerated at low and middle dosages in beagle dogs, and no drug-related toxical effects were observaed in terms of survival, clinical observations, organs weight and damage in these dose groups. However, in high dose administration group, food consumption and histologic changes in kidneys were noticed in both sexes of beagle dog, although the renal lesions were finally resolved at the end of 4 weeks exposure of ethanamizuril. Conclusions No-observed-adverse-effect level (NOAEL) was considered for ethanamizuril at dose of 60 mg/kg/day in Beagle dog. This result added toxicity effects of ethanamizuril to the safety database, which might guide safely using of ethanamizuril as a novel coccidiostat.

Community search has been extensively studied in large networks, such as Protein-Protein Interaction (PPI) networks, citation graphs, and collaboration networks. However, in terms of widely existing multi-valued networks, where each node has d (d⩾1) numerical attributes, almost all existing algorithms either completely ignore the attributes of node at all or only consider one attribute. To solve this problem, the concept of skyline community was presented, based on the concepts of k-core and skyline recently. The skyline community is defined as a maximal k-core that satisfies some influence constraints, which is very useful in depicting the communities that are not dominated by other communities in multi-valued networks. However, the algorithms proposed on skyline community search can only work in the special case that the nodes have different values on each attribute, and the computation complexity degrades exponentially as the number of attributes increases. In this work, we turn our attention to the general scenario where multiple nodes may have the same attribute value. Specifically, we first present an algorithm, called MICS, which can find all skyline communities in a multi-valued network. To improve computation efficiency, we then propose a dimension reduction based algorithm, called P-MICS, using the maximum entropy method. Our algorithm can significantly reduce the skyline community searching time, while is still able to find almost all cohesive skyline communities. Extensive experiments on real-world datasets demonstrate the efficiency and effectiveness of our algorithms.

Wind speed forecasting is an essential procedure in electric grid dispatching. Short-term wind speed forecasting can be a great challenge and an intractable issue in increasing wind energy output and guaranteeing power safety. The current wind speed forecasting models are based on a single model, which is generally an artificial intelligence model or a statistical forecasting method. However, these models cannot perform well in all cases. An effective combined model is proposed in this paper, and this model includes four parts: weight coefficient optimization calculation based on the nonpositive constraint combination theory, singular-spectrum analysis, combined forecasting and discussion of results. The developed model can decrease the negative influences of the component models and maximize the advantages of each component model. To evaluate the forecasting accuracy of our proposed model, ten minutes of wind speed data from Shandong Peninsula, China, were used as test cases. It is clearly demonstrated that the developed combined strategy outperforms the individual forecasting methods in terms of forecast performance and stability.

Nowadays, industrial processes are fully equipped by redundant hardware sensors which can be interfered by random noises. Hence, it is of high importance to develop soft sensing solutions for key variables prediction and process monitoring. Various methods have been carried out to cope with different data characteristics among which auto-correlation and non-stable features have been considered as two challenging tasks. In this paper, a novel weighted autoregressive dynamic latent variable (WARDLV) model is constructed where a weighted log-likelihood function is created combined with high-order dynamic information extraction techniques. Different weights are designed for state transition and emission in latent space and original space, respectively. Compared with previous researches, global weights are completely redesigned and consisted of different window confidences and local weights. The efficiency of the proposed method is further demonstrated with a real industrial application.

Purpose: Owing to the characteristic anatomy, cochlear implantation (CI) for common cavity deformity (CCD) has resulted in varied outcomes and frequent facial and vestibular nerve stimulation. The current study analyzed the correlation among the distance between each electrode and cavity wall (abbreviation, D), programming parameters, and performances outcomes.Materials and Methods: The current, retrospective study included 25 patients (27 ears) with CCD underwent CI. The multiplanar volume reconstruction (MPVR) techniques were employed to reconstruct and evaluate the postoperative temporal bone CT. The D and maximum comfortable level (MCL) 6 months after CI, facial and vestibular nerve stimulation, and outcomes 1, 2, and 3 years after CI pertaining to the questionnaires were documented and analyzed.Results: The patients were divided into symptomatic (10, 37%) and asymptomatic (17, 63%) groups according to with or without facial and vestibular nerve stimulation. The MCL pertaining to the symptomatic group was significantly lower than asymptomatic group, but Categories of Auditory Performance (CAP) scores 1 year after surgery was better (p < 0.05). The subjects were divided into flat (12, 44.4%) and curved (15, 55.6%) groups based on the contour of MCL map. The MCL and D were lower and shorter in the curved group than the flat group, and CAP score 1 year after surgery and Speech Intelligibility Rating (SIR) 3 years after surgery were better (p < 0.05).Conclusion: Although abnormal reactions such as facial and vestibular nerve stimulation were observed to be more frequent, lower MCL and better outcomes were observed in relation to the shorter D.

Gastric cancer (GC) is an aggressive malignant tumor and causes a significant number of deaths every year. With the coming of the age of cancer immunotherapy, search for a new target in gastric cancer may benefit more advanced patients. Melanoma-associated antigen-A3 (MAGEA3), one of the members of the cancer-testis antigen (CTA) family, was considered an important part of cancer immunotherapy. We evaluate the potential role of MAGEA3 in GC through the TCGA database. The result revealed that MAGEA3 is upregulated in GC and linked to poor OS and lymph node metastasis. MAGEA3 was also correlated with immune checkpoints, TMB, and affected the tumor immune microenvironment and the prognosis of GC through CIBERSORT, TIMER, and Kaplan-Meier plotter database analysis. In addition, GSEA-identified MAGEA3 is involved in the immune regulation of GC. Moreover, the protein-protein interaction (PPI) networks of MAGEA3 were constructed through STRING database and MAGEA3-correlated miRNAs were screened based on the joint analysis of multiple databases. In terms of experimental verification, we constructed pET21a (+)/MAGEA3 restructuring plasmids and transformed to Escherichia coli Rosetta. MAGEA3 protein was used as an antigen after being expressed and purified and can effectively detect the specific IgG in 93 GC patients’ serum specimens with 44.08% sensitivity and 92.54% specificity. Through further analysis, the positive rate of MAGEA3 was related to the stage and transfer number of lymph nodes. These results indicated that MAGEA3 is a novel biomarker and correlated with lymph node metastasis and immune infiltrates in GC, which could be a new target for immunotherapy.

Prunus takasagomontana Sasaki 1931 is a deciduous flowering cherry endemic to Taiwan island, China. Here, we first report the complete chloroplast genome of P. takasagomontana. The complete chloroplast genome of P. takasagomontana is 157,946 bp in length, which is comprised of a pair of inverted repeat (IR) regions of 26,437 bp, a small single-copy (SSC) region of 19,145 bp, and a large single-copy (LSC) region of 85,927 bp. A total of 129 genes are annotated, including 84 protein-coding genes, 37 tRNA genes, and eight rRNA ribosomal genes. The phylogenetic analysis showed that P. takasagomontana is sister to P. serrulata var. spontanea.

Genes have been lost or weakened from cultivated rice during rice domestication and breeding. Weedy rice (Oryza sativa f. spontanea) is usually recognized as the progeny between cultivated rice and wild rice and is also known to harbor an gene pool for rice breeding. Therefore, identifying genes from weedy rice germplasms is an important way to break the bottleneck of rice breeding. To discover genes from weedy rice germplasms, we constructed a genetic map based on w-hole-genome sequencing of a F2 population derived from the cross between LM8 and a cultivated rice variety. We further identified 31 QTLs associated with 12 important agronomic traits and revealed that ORUFILM03g000095 gene may play an important role in grain length regulation and participate in grain formation. To clarify the genomic characteristics from weedy rice germplasms of LM8, we generated a high-quality genome assembly using single-molecule sequencing, Bionano optical mapping, and Hi-C technologies. The genome harbored a total size of 375.8 Mb, a scaffold N50 of 24.1 Mb, and originated approximately 0.32 million years ago (Mya) and was more closely related to Oryza sativa ssp. japonica. and contained 672 unique genes. It is related to the formation of grain shape, heading date and tillering. This study generated a high-quality reference genome of weedy rice and high-density genetic map that would benefit the analysis of genome evolution for related species and suggested an effective way to identify genes related to important agronomic traits for further rice breeding.

Summary: The importance of the G-protein βγ subunits in the regulation of cargo transport from the trans-Golgi network (TGN) to the plasma membrane (PM) is well accepted; however, the molecular mechanism underlying the G-protein activation at the TGN remains unclear. We show here that sphingosine 1-phosphate (S1P) receptors at the PM were trafficked to the TGN in response to a surface transport cargo, temperature-sensitive vesicular stomatitis virus glycoprotein tagged with green fluorescent protein accumulation in the Golgi. The receptor internalization occurred in an S1P-independent manner but required phosphorylation by G-protein receptor kinase 2 and β-arrestin association before internalization. Continuously activated S1P receptors in a manner dependent on S1P at the TGN kept transmitting G-protein signals including the βγ subunits supply necessary for transport carrier formation at the TGN destined for the PM.

Generally, cochlear implants (CIs) are effective in helping patients improve their hearing performance; however, some patients have poor hearing performance owing to facial nerve stimulation (FNS), which is often associated with cochlear anomalies. We report a case with a normal cochlea and severe and persistent FNS owing to cochlear–facial dehiscence (CFD) that affected the CI outcomes. Preoperatively, a careful review of the computed tomography images before CI surgery is necessary not only for patients with otosclerosis and inner ear malformations but also for patients with normal cochlear structures because facial nerve anomalies could be present.

An excessive high-fat/energy diet is a major cause of obesity and linked complications, such as non-alcoholic fatty liver disease (NAFLD). Betaine has been shown to effectively improve hepatic lipid metabolism. However, the mechanistic basis for this improvement is largely unknown. Herein, integration of mRNA sequencing and ribosome footprints profiling (Ribo-seq) was used to investigate the means by which betaine alleviates liver lipid metabolic disorders induced by a high-fat diet. For the transcriptome, gene set enrichment analysis demonstrated betaine to reduce liver steatosis by up-regulation of fatty acid beta oxidation, lipid oxidation, and fatty acid catabolic processes. For the translatome, 574 differentially expressed genes were identified, 17 of which were associated with the NAFLD pathway. By combined analysis of transcriptome and translatome, we found that betaine had the greater effect on NAFLD at the translational level. Further, betaine decreased translational efficiency (TE) for IDI1, CYP51A1, TM7SF2, and APOA4, which are related to lipid biosynthesis. In summary, this study demonstrated betaine alleviating lipid metabolic dysfunction at the translational level. The transcriptome and translatome data integration approach used herein provides for a new understanding of the means by which to treat NAFLD.

Arterial hypertension is considered the most prevalent risk factor for stroke. Both pathophysiologic and clinical data previously acquired suggest a strong correlation between the hemodynamic nature of arterial hypertension and an increase in the risk of ischemic insult to tissues. However, the knowledge of specific molecular interactions between hypertension and ischemic stroke (IS) is limited. In this study, we performed systematic bioinformatics analysis of stroke-prone spontaneous hypertensive brain tissue samples of rats (GSE41452), middle cerebral artery occlusion of brain tissue samples of rats (GSE97537), and peripheral blood array data of IS patients (GSE22255). We identified that Fos, an immediate-early gene (IEG) that responds to alterations in arterial blood pressure, has a strong correlation with the occurrence and prognosis of IS. To further evaluate the potential function of Fos, the oxygen–glucose deprivation model and RNA sequencing of HT22 neuronal cells were performed. Consistent with the sequencing results, real-time quantitative PCR and Western blot indicate that Fos was elevated at 3 h and returned to normal levels at 6 h after oxygen–glucose deprivation. Knock-down of Fos by lentivirus significantly increased the oxidative stress level, neuronal apoptosis, and inhibited the mitochondrial function. In conclusion, Fos acts as an important link between hypertension and IS. Furthermore, Fos can be used as a potential biomarker for target therapy in the prevention of stroke among hypertensive patients and also potential treatment targeting apoptosis and oxidative stress after its onset.

Eimeria species are intracellular parasites residing inside the intestinal epithelial cell, which cause poultry coccidiosis and result in significant financial losses in the poultry industry. Genome editing of Eimeria is of immense importance for the development of vaccines and drugs. CRISPR/Cas9 has been utilized for manipulating the genome of Eimeria tenella (E. tenella). Ectopic expression of Cas9, i.e., via plasmids, would introduce transgene, which substantially limits its application, especially for vaccine development. In this study, we initially optimized the condition of the transfection protocol. We demonstrated that with the optimized condition, the transfection of FnCas12a (also known as “FnCpf1”) protein and crRNA targeting EtHistone H4 triggered DNA double-strand breaks in vivo. We then used this strategy to knock-in a coding cassette for an enhanced yellow fluorescent protein (EYFP) and dihydrofolate reductase–thymidylate synthase gene (DHFR) as a selection marker to tag endogenous EtActin. The engineered E. tenella parasite possesses EYFP expression in its entire life cycle. Our results demonstrated that FnCas12a could trigger genome editing in E. tenella, which augments the applicability of the dissection of gene function and the development of anticoccidial drugs and vaccines for Eimeria species.

Inflammation and apoptosis of vascular endothelial cells play a key role in the occurrence and development of atherosclerosis (AS), and the AMPK/mTOR/Nrf2 signaling pathway plays an important role in alleviating the symptoms of AS. Geniposide combined with notoginsenoside R1 (GN combination) is a patented supplement for the prevention and treatment of AS. It has been proven to improve blood lipid levels and inhibit the formation of AS plaques; however, it is still unclear whether GN combination can inhibit inflammation and apoptosis in AS by regulating the AMPK/mTOR/Nrf2 signaling pathway and its downstream signals. Our results confirmed that the GN combination could improve blood lipid levels and plaque formation in ApoE−/− mice fed with a high-fat diet (HFD), inhibit the secretion of serum inflammatory factors and oxidative stress factors. It also decreased the expression of pyrin domain containing protein 3 (NLRP3) inflammasome-related protein and Bax/Bcl2/caspase-3 pathway-related proteins. At the same time, the GN combination could also inhibit the H2O2-induced inflammatory response and apoptosis of human umbilical vein endothelial cells (HUVECs), which is mainly related to the activation of the AMPK/mTOR pathway by GN combination, which in turn induces the activation of Nrf2/HO-1 signal. In addition, the above phenomenon could be significantly reversed by dorsomorphin. Therefore, our experiments proved for the first time that the GN combination can effectively inhibit AS inflammation and apoptosis by activating the AMPK/mTOR/Nrf2 signaling pathway to inhibit the NLRP3 inflammasome and Bax/Bcl2/caspase-3 pathway.

Abstract Background The exact pathogenesis of idiopathic choroidal neovascularization (ICNV) remains unclear. Cytokine-mediated inflammation has been thought to be involved in the pathophysiology of ICNV. The purpose of this study was to investigate serum cytokine profiles in patients with ICNV and to explore the relationship between serum cytokine levels and ICNV severity. Methods This case-control study was conducted in 32 ICNV patients and 30 healthy volunteers. Clinical and demographic information was obtained from the medical data platform and the serum was analysed with a multiplex assay to determine the levels of seven cytokines: interleukin (IL)-2, IL-10, IL-15, IL-17, basic fibroblast growth factor (basic FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF). Results Serum levels of IL-2, IL-10, IL-17, basic FGF, and VEGF were elevated in ICNV patients compared to controls. Serum GM-CSF levels were positively related to central retinal thickness, and serum IL-17 levels were positively related to CNV lesion area. Conclusion Serum inflammatory cytokines were significantly elevated in ICNV patients compared to controls. This suggests that systemic inflammation may play a critical role in the physiopathology of ICNV.

Precise wind speed prediction is increasingly practical for sustained and stable wind energy utilization considering the growing portion of wind energy in the global electric grid. Although plenty of wind speed forecasting approaches have been devoted to improving forecasting performance, the majority have neglected the utilization of error information, integrated the forecasting value of every component with simple ensemble approaches, and ignored forecasting stability, which may make the forecasting results poor. Considering the above drawbacks, a two-stage forecasting system is performed in our study based on the data preprocessing approach, improved multi-objective optimization algorithm, error correction and nonlinear ensemble strategy. The developed system effectively overcomes the shortcomings of previous models and observably prompts wind speed forecasting capacity. For investigating the prediction capacity of the developed system, six wind speed series obtained from China and Spain are applied as case sites. The forecasting consequences indicate that the developed system is more conducive to enhancing forecasting precision and stability than other involved models, which can provide beneficial assistance for wind speed forecasting.

Affibodies targeting intracellular proteins have a great potential to function as ideal therapeutic agents. However, little is known about how the affibodies enter target cells to interact with intracellular target proteins. We have previously developed the HPV16E7 affibody (ZHPV16E7384) for HPV16 positive cervical cancer treatment. Here, we explored the underlying mechanisms of ZHPV16E7384 and found that ZHPV16E7384 significantly inhibited the proliferation of target cells and induced a G1/S phase cell cycle arrest. Furthermore, ZHPV16E7384 treatment resulted in the upregulation of retinoblastoma protein (Rb) and downregulation of phosphorylated Rb (pRb), E2F1, cyclin D1, and CDK4 in the target cells. Moreover, treatment with dynamin or the caveolin-1 inhibitor not only significantly suppressed the internalization of ZHPV16E7384 into target cells but also reversed the regulation of cell cycle factors by ZHPV16E7384. Overall, these results indicate that ZHPV16E7384 was likely internalized specifically into target cells through dynamin- and caveolin-1 mediated endocytosis. ZHPV16E7384 induced the cell cycle arrest in the G1/S phase at least partially by interrupting HPV16E7 binding to and degrading Rb, subsequently leading to the downregulation of E2F1, cyclin D1, CDK4, and pRb, which ultimately inhibited target cell proliferation. These findings provide a rationale of using ZHPV16E7384 to conduct a clinical trial for target therapy in cervical cancer.

Despite prophylactic vaccination campaigns, high-risk human papillomavirus (HPV)-induced cervical cancer remains a significant health threat among women, especially in developing countries. The initial occurrence and consequent progression of this cancer type primarily rely on, E6 and E7, two key viral oncogenes expressed constitutively, inducing carcinogenesis. Thus, E6/E7 have been proposed as ideal targets for HPV-related cancer diagnosis and treatment. In this study, three novel HPV16 E6-binding affibody molecules (ZHPV16E61115, ZHPV16E61171, and ZHPV16E61235) were isolated from a randomized phage display library and cloned for bacterial production. These affibody molecules showed high binding affinity and specificity for recombinant and native HPV16 E6 as determined by surface plasmon resonance, indirect immunofluorescence, immunohistochemistry, and near-infrared small animal optical imaging in vitro and in vivo. Moreover, by binding to HPV16 E6 protein, ZHPV16E61235 blocked E6-mediated p53 degradation, which increased the expression of some key p53 target genes, including BAX, PUMA and p21, and thereby selectively reduced the viability and proliferation of HPV16-positive cells. Importantly, ZHPV16E61235 was applied in combination with HPV16 E7-binding affibody ZHPV16E7384 to simultaneously target the HPV16 E6/E7 oncoproteins, and this combination inhibited cell proliferation more potently than either modality alone. Mechanistic studies revealed that the synergistic antiproliferative activity depends primarily on the induction of cell apoptosis and senescence but not cell cycle arrest. Our findings provide strong evidence that three novel HPV16 E6-binding affibody molecules could form a novel basis for the development of rational strategies for molecular imaging and targeted therapy in HPV16-positive preneoplastic and neoplastic lesions.

Membranous nephropathy (MN), an autoimmune glomerular disease, is one of the most common causes of nephrotic syndrome in adults. In current clinical practice, the diagnosis is dependent on renal tissue biopsy. A new method for diagnosis and prognosis surveillance is urgently needed for patients. In the present study, we recruited 66 MN patients before any treatment and 11 healthy control (HC) and analyzed multiple aspects of the immunoglobulin heavy chain (IGH) repertoire of these samples using high-throughput sequencing. We found that the abnormalities of CDR-H3 length, hydrophobicity, somatic hypermutation (SHM), and germ line index were progressively more prominent in patients with MN, and the frequency of IGHV3-66 in post-therapy patients was significantly lower than that in pre-therapy patients. Moreover, we found that the IGHV3-38 gene was significantly related to PLA2R, which is the most commonly used biomarker. The most important discovery was that several IGHV, IGHD transcripts, CDR-H3 length, and SHM rate in pre-therapy patients had the potential to predict the therapeutic effect. Our study further demonstrated that the IGH repertoire could be a potential biomarker for prognosis prediction of MN. The landscape of circulating B-lymphocyte repertoires sheds new light on the detection and surveillance of MN.

Subarachnoid hemorrhage (SAH) is a devastating form of stroke, which poses a series of intractable challenges to clinical practice. Imbalance of mitochondrial homeostasis has been thought to be the crucial pathomechanism in early brain injury (EBI) cascade after SAH. Irisin, a protein related to metabolism and mitochondrial homeostasis, has been reported to play pivotal roles in post-stroke neuroprotection. However, whether this myokine can exert neuroprotection effects after SAH remains unknown. In the present study, we explored the protective effects of irisin and the underlying mechanisms related to mitochondrial biogenesis in a SAH animal model. Endovascular perforation was used to induce SAH, and recombinant irisin was administered intracerebroventricularly. Neurobehavioral assessments, TdT-UTP nick end labeling (TUNEL) staining, dihydroethidium (DHE) staining, immunofluorescence, western blot, and transmission electron microscopy (TEM) were performed for post-SAH assessments. We demonstrated that irisin treatment improved neurobehavioral scores, reduced neuronal apoptosis, and alleviated oxidative stress in EBI after SAH. More importantly, the administration of exogenous irisin conserved the mitochondrial morphology and promoted mitochondrial biogenesis. The protective effects of irisin were partially reversed by the mitochondrial uncoupling protein-2 (UCP-2) inhibitor. Taken together, irisin may have neuroprotective effects against SAH via improving the mitochondrial biogenesis, at least in part, through UCP-2 related targets.

Angiogenesis in the field of tissue engineering has attracted significant attention. Graphene oxide has become a promising nanomaterial in tissue engineering for its unique biochemical properties. Therefore, herein, a series of chitosan (CS)/graphene oxide (GO) hydrogel scaffolds were synthesized by crosslinking CS and GO at different concentrations (0.1, 0.5, and 1.0 wt.%) using genipin. Compared with the CS hydrogel scaffolds, the CS/GO hydrogel scaffolds have a better network structure and mechanical strength. Then, we used endothelial progenitor cells (EPCs) extracted from human umbilical cord blood and cocultured these EPCs with the as-prepared scaffolds. The scaffolds with 0.1 and 0.5 wt.%GO showed no considerable cytotoxicity, could promote the proliferation of EPCs and tube formation, and upregulated the expressions of CD34, VEGF, MMP9, and SDF-1 in EPCs compared to the case of the scaffold with 1.0 wt.%GO. This study shows that the addition of graphene oxide improves the structure of chitosan hydrogel and enhances the proliferation activity and angiogenic capacity of EPCs.

ObjectivesNon-communicable diseases (NCDs) have become the main cause of mortality in China. In 2009, the Chinese government introduced the Basic Public Health Service (BPHS) program to relieve the rising burden of NCDs through public health measures and delivery of essential medical care. The primary aim of this study was to evaluate the impact of the BPHS program on hypertension control.MethodsThe China National Health Development Research Center (CNHDRC) undertook a Cross-sectional Health Service Interview Survey (CHSIS) of 62,097 people from primary healthcare reform pilot areas across 17 provinces from eastern, central, and western parts of China in 2014. The current study is based on responses to the CHSIS survey from 7,867 participants, who had been diagnosed with hypertension. Multi-variable mixed logit regression analysis was used to estimate the association between BPHS management and uncontrolled hypertension. In a follow-up analysis, generalized structural equation modelling (GSEM) was used to test for mediation of the BPHS program effect through patient compliance with medication.FindingsThe estimated proportion of patients with uncontrolled hypertension was 30% lower (23.2% vs 31.5%) in those participants who were adequately managed under the BPHS program. Other predictors of hypertension control included compliance with medication, self-reported wellbeing, income, educational attainment and exercise; smoking was associated with reduced hypertension control. The significant inverse association between uncontrolled hypertension and age indicates poor outcomes for younger patients. Additional testing suggested that nearly 40% of the effect of BPHS management (95% CI: 28.2 to 51.7) could be mediated by improved compliance with medication; there was also an indication that the effect of management was 30% stronger in districts/counties with established digital information management systems (IMS).ConclusionHypertension control improved markedly following active management through the BPHS program. Some of that improvement could be explained by greater compliance with medication among program participants. This study also identified the need to tailor the BPHS program to the needs of younger patients to achieve higher levels of control in this population. Future investigations should explore ways in which existing healthcare management influences the success of the BPHS program.

Background. This meta-analysis was performed to compare the efficacy and safety of direct oral anticoagulants (DOACs) with vitamin K antagonists (VKAs) for stroke prevention in real-world patients with diabetes and nonvalvular atrial fibrillation (NVAF) through observational studies. Methods. PubMed, Embase, and Web of Science databases were searched up to August 2020 for eligible studies. Outputs were presented as risk ratios (RRs) and corresponding 95% confidence intervals (CIs) by using a random-effect model. Results. Seven observational studies involving 249,794 diabetic NVAF patients were selected. Compared with VKAs, the use of DOACs was associated with significantly reduced risks of stroke (RR=0.56, 95% CI 0.45-0.70; p

Free trial is a widely used business strategy that takes advantage of information asymmetry. However, evidence on what we can learn and how rapidly we can learn from a free trial of health care is limited. This study evaluates the effect of a free trial of eyeglasses on children’s 8 items of perception related to eyeglasses use. An evaluation was conducted alongside a cluster-randomized controlled trial involved 832 myopic children from northwest rural China. A total of 428 myopic children from 42 schools were randomized to receive free eyeglasses, and 404 myopic children from 42 schools were randomized as control group. We find that the perceived costs and benefits of eyeglasses use and the perceived timing of wearing eyeglasses at the appropriate time can be learned from a free trial of eyeglasses. Compared with the control group in the long run, 5.6 percentage points more children in treatment group agreed that wearing eyeglasses was attractive, 16.5 percentage points more children agreed that wearing eyeglasses is helpful to academic performance, and 7.9 percentage points more children agreed that children with vision problems should wear eyeglasses. Due to the effects of a free product and the time to learning from experience, the magnitude of the impact of a free trial changed over time. We also find that the indirect experience, such as a vision protection course, cannot change children’ perceptions about the cost or benefits of eyeglasses use. The findings imply that children can learn significantly from the experience of a free trial of eyeglasses. A free trial is an effective strategy to solve the information asymmetry problem for health care. The first pair of eyeglasses of children can be one-off subsidized to trigger demand for eyeglasses use.

Background: Non-invasive prenatal testing (NIPT) is a commonly employed clinical method to screen for fetal aneuploidy, while the Y chromosome-based NIPT method is regarded as the gold standard for the estimation of fetal fraction (FF) of male fetuses. However, when the fetus has a derivative Y chromosome thereby containing a partial Y chromosome, the Y chromosome-based NIPT method cannot accurately calculate FF. Therefore, alternative methods to precisely calculate FF are required.Methods: Two prenatal cases could not be detected effectively using the Y chromosome-based NIPT method because of low FF. According to the Y chromosome-based method, the FF of the fetuses were 1.730 ± 0.050% (average gestation week: 18+1) and 2.307 ± 0.191% (average gestation week: 20+0) for cases 1 and 2, respectively. Using various genetic diagnostic techniques, including the BoBs™ assay, karyotype analysis, improved nucleolus-organizing region (NOR)-banding analysis, Affymetrix CytoScan 750K Array, and fluorescence in situ hybridization (FISH) analysis, we determined the genetic defects of two fetuses with translocations of the SRY locus. Further, we reassessed the FF using FF-QuantSC and X chromosome-based methods. The distribution diagram of reads for chromosome Y was also analyzed.Results: The FF of the fetuses determined by FF-QuantSC were 10.330% (gestation week: 18+4) in case 1 and 9.470% (gestation week: 21+4) in case 2, while the FF of the fetuses determined using the X chromosome-based method were 8.889% (gestation week: 18+4) in case 1 and 2.296% (gestation week: 21+4) in case 2. Both the distribution diagrams of reads for chromosome Y of the two cases showed the deletion in the long arm of the Y chromosome.Conclusion: For repeatedly low FF samples detected using the Y chromosome-based NIPT method for a long gestational week, we believe that FF-QuantSC and distribution diagrams of reads could be used as a supplement to NIPT, especially for rare cases of sex reversal caused by SRY translocation.

Growing cultivated rice with a moderate heading date is the key to expanding its cultivation area and maintaining stable yields. The genes that regulate heading date are largely cloned; however, it remains unclear how genetic mutations and their combinations affect the heading date and adaptability of cultivated rice. Here, we report the analysis of genetic variation in eight long-day flowering suppressor genes (Hd1, DTH8, Ghd7, OsCOL4, DTH7, Hd6, Se5, and PhyB) and the phylogenetic relationship of eight genes. Genetic variations in DTH8, Ghd7, Hd1, DTH7, PhyB, and OsCOL4 are correlated with differences in heading date and the correlation between the genetic diversity of Hd6 and Se5 and rice heading data are weak. One group of haplotypes of DTH8, Ghd7, Hd1, DTH7, PhyB, and OsCOL4 are associated with earlier heading dates and appear to have accumulated during the northward expansion of rice cultivation. A minimum of four group A alleles of DTH8, Ghd7, Hd1, DTH7, PhyB, and OsCOL4 are required for the growth of cultivated rice at latitudes above 30°N. This study presents a preliminary investigation of the genetic patterns and adaptation mechanisms of long-day flowering suppressor genes and provides a useful reference for the molecular breeding of rice cultivars for various environments and farming systems.

Since the first reports that the novel coronavirus was showing human-to-human transmission characteristics and asymptomatic cases, the number of patients with associated pneumonia has continued to rise and the epidemic has grown. It now threatens the health and lives of people across the world. The governments of many countries have attached great importance to the prevention of SARS-CoV-2, via research into the etiology and epidemiology of this newly emerged disease. Clinical signs, treatment, and prevention characteristics of the novel coronavirus pneumonia have been receiving attention worldwide, especially from medical personnel. However, owing to the different experimental methods, sample sizes, sample sources, and research perspectives of various studies, results have been inconsistent, or relate to an isolated aspect of the virus or the disease it causes. Currently, systematic summary data on the novel coronavirus are limited. This review combines experimental and clinical evidence into a systematic analysis and summary of the current progress of research into SARS-CoV-2, from multiple perspectives, with the aim of gaining a better overall understanding of the disease. Our report provides important information for current clinicians, for the prevention and treatment of COVID-19 pneumonia.