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Aims: The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood–brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL‐10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood. Methods: Recombinant IL‐10 was administered to ICH model mice via caudal vein injection, an IL‐10‐inhibiting adeno‐associated virus and an IL‐10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated. Results: Our study demonstrated that the peripheral cytokine IL‐10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL‐10 deficiency reversed these effects, likely through the IL‐10R/JAK1/STAT3 signaling pathway. Conclusions: Peripheral IL‐10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis. [ABSTRACT FROM AUTHOR]

Objective: To compare the outcomes of postacute care between home health (HH) and skilled nursing facilities (SNFs) following hospitalization among Medicare beneficiaries with a diagnosis of dementia. Data Sources: 100% MedPAR data, Minimum Data Set, and Outcome and Assessment Information Set assessment data from January 1, 2015 to December 31, 2016. Study Design: Retrospective cohort analysis using an instrumental variable design to compare outcomes (30‐day readmission and mortality, 100‐day mortality) of HH versus SNF following acute hospitalization. We used the differential distance between patients' home and the closest HH agency and SNF to instrument for nonrandom allocation of patients. Data Collection/Extraction Methods: We identified hospital discharges followed by SNF and HH stays for Medicare fee‐for‐service beneficiaries with dementia. We excluded beneficiaries younger than age 65, admitted to the hospital from a nursing home, or enrolled in hospice. We identified dementia using validated diagnostic codes with a 3‐year look‐back. Principal Findings: Our sample included 977,946 beneficiaries with a diagnosis of dementia; 297,732 (30.4%) received HH, while 680,214 (69.6%) went to SNF. Overall, 16.8% were readmitted to the hospital and 6.1% died within 30 days, while 15.4% died within 100 days of hospital discharge. In the instrumental variable analysis, there were no differences in any outcome between the two postacute care settings. Conclusions: Medicare beneficiaries with a diagnosis of dementia receiving postacute care in HH or SNF experienced similar rates of readmission and mortality across settings. This finding raises important questions about current postacute care referral patterns, given 7 in 10 patients with a diagnosis of dementia in our sample were discharged to SNF. [ABSTRACT FROM AUTHOR]

With the development of smart grids, appliance‐level data information plays a vital role in smart power consumption. Nowadays, appliance signatures detected by non‐intrusive load monitoring (NILM) can be used for anomaly detection, demand response, and electricity management. These applications increase the requirements for the accuracy of appliance identification in NILM. And it has been proved that the voltage–current (V–I) trajectory can be applied as an effective load signature to represent the electrical characteristics of appliances with different statuses in previous researches. In this paper, a V–I trajectory enabled asymmetric deep supervised hashing (ADSH) method has been proposed for NILM. ADSH method converts load identification into the large‐scale approximate nearest neighbour search. Different from the existing methods, ADSH treats the query images and database images in an asymmetric way in order to improve accuracy. More specifically, ADSH learns a deep hash function only for query images, while the hash codes for database images are directly learned. The experimental results on REDD and PLAID datasets show that the proposed method significantly improves the accuracy of load identification compared with state‐of‐art methods. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the role of farnesoid X receptor (FXR), a ligand‐dependent transcription factor, in renal ischaemia‐reperfusion (I/R) injury. Materials and Methods: We performed unilateral renal I/R model in FXR knockout (Fxr−/−) and wild‐type (WT) mice in vivo and a hypoxia‐reoxygenation (H/R) model in vitro. The pathways by which FXR induces apoptosis were detected using a proteome profiler array. The effects of FXR on apoptosis were evaluated using immunoblotting, TUNEL assays and flow cytometry. Results: Compared with WT mice, Fxr−/− mice showed improved renal function and reduced tubular injury scores and apoptosis. Consistent with the in vivo results, the silencing of FXR decreased the number of apoptotic HK‐2 cells after H/R, while FXR overexpression aggravated apoptosis. Notably, bone marrow transplantation (BMT) and immunohistochemistry experiments revealed the involvement of FXR in the tubular epithelium rather than in inflammatory cells. Furthermore, in vivo and in vitro studies demonstrated that FXR deficiency increased phosphorylated Bcl‐2 agonist of cell death (p‐Bad) expression levels and the ratio of Bcl‐2/Bcl‐xL to Bax expression in the kidney. Treatment with wortmannin, which reduced p‐Bad expression, inhibited the effects of FXR deficiency and eliminated the tolerance of Fxr−/− mouse kidneys to I/R injury. Conclusions: These results established the pivotal importance of FXR inactivation in tubular epithelial cells after I/R injury. FXR may promote the apoptosis of renal tubular epithelial cells by inhibiting PI3k/Akt‐mediated Bad phosphorylation to cause renal I/R damage. [ABSTRACT FROM AUTHOR]

Background: Major perioperative complications of stent‐assisted embolization treated for aneurysmal subarachnoid hemorrhage patients include the formation of thromboembolic events (TEs) and hemorrhagic events (HEs), for which antiplatelet protocols play a key role. Methods: We conducted a single‐center retrospective analysis to compare the differences between arteriovenous tirofiban administration with traditional oral dual antiplatelet therapy (DAPT). A total of 417 consecutive patients were enrolled. General clinical characteristics, as well as the perioperative ischemic and hemorrhagic events, were retracted in digital documents. Logistic regression was conducted to identify both risk and protective factors of perioperative TEs and HEs. Results: Perioperative TEs occurred in 21 patients, with an overall perioperative TEs rate of approximately 5.04%; among these patients, the incidence of perioperative TEs in the tirofiban group was less than that in the DAPT group. Additionally, 66 patients developed perioperative HEs, with an incidence of approximately 15.83%; among these patients, the incidence of perioperative HEs was less than that in the DAPT group. No significant differences were seen between the two groups in terms of the mRS score at the time of discharge. Conclusion: This study indicated that an improved perioperative antiplatelet drug tirofiban was an independent protective factor for perioperative TEs in stent‐assisted embolization of ruptured intracranial aneurysms, but it did not impart an elevated risk of perioperative HEs and had no significant effects on the near‐term prognosis of the patients. [ABSTRACT FROM AUTHOR]

Early embryonic arrest is one of the major causes of recurrent assisted reproduction failure. It is characterized by delayed embryonic development and failure to form viable eight‐cell stage embryos on day 3 of an assisted reproduction cycle. A recent study reported that biallelic mutations in NLRP5 can cause early embryonic arrest. NLRP5 is a member of subcortical maternal complex, which plays a significant role in embryogenesis. In this study, we described a female in a consanguineous Chinese family who displayed clinical features of early embryonic arrest and identified a novel homozygous variant c.1061C>T (p.Pro354Leu) in NLRP5. This is the second report of the biallelic NLRP5 variant that associates with early embryonic arrest in humans, further confirming the role of NLRP5 variants in early embryonic arrest and expanding the spectrum of known pathogenic variants in NLRP5. [ABSTRACT FROM AUTHOR]

Motivated by Markovian regime‐switching diffusion (MRSD), time‐varying delays and non‐linear coupling forms, this study is concerned with stabilisation of coupled regime‐switching diffusion with time‐varying delays (CRSDTD) under periodically intermittent control. Compared with most papers investigating MRSD, a striking feature of regime‐switching diffusion is that in the two‐component process (x(t),α(t)), switching process α(t) depends on the diffusion x(t), which can be regarded as the x ‐dependent process briefly. It is worth mentioning that time‐varying delays and non‐linear coupling forms are taken into consideration when modelling, which makes their work more realistic. Moreover, a periodically intermittent controller is adopted to guarantee that CRSDTD can achieve the p th moment exponential stability and some sufficient conditions are derived by using the Lyapunov method and Kirchhoff's matrix tree theorem. Furthermore, to illustrate the applicability of their theoretical results, an application to regime‐switching coupled oscillators with time‐varying delays (RSCOTD) is presented and a stability criterion is given. Conclusively, numerical simulations on RSCOTD are presented to illustrate the effectiveness of the theoretical results. [ABSTRACT FROM AUTHOR]

Research Objective: To compare the outcomes of post‐acute care between home health (HH) and skilled nursing facilities (SNFs) following hospitalization among Medicare beneficiaries with dementia. Despite the fact that both post‐acute care use and dementia are highly prevalent in the Medicare population, very few studies have compared the outcomes of different post‐acute care settings for patients with dementia, leaving patients, caregivers, and clinicians uncertain how to make optimal decisions around hospital discharge. Study Design: Retrospective analysis of secondary data using an instrumental variable design to compare outcomes of HH versus SNF following an acute hospitalization. We used a 100% sample of Medicare inpatient, outpatient, and post‐acute care claims and assessment data from January 1, 2015 to December 31, 2016 and used differential distance between home health and SNF as the instrumental variable to account for nonrandom allocation of patients (F‐statistic: 26.5). Outcomes included unplanned 30‐day readmission, 30‐ and 100‐day mortality, and a composite measure of readmission and mortality to address competing risks. Our analysis adjusted for beneficiary characteristics and year of analysis, included fixed effects for hospital and year, and adjusted for clustering at the hospital level. Population Studied: We used MedPAR to identify hospitalizations and Minimum Data Set and Outcome and Assessment Information Set assessments to identify SNF and HH stays following hospital discharge. We excluded beneficiaries younger than age 65, admitted to the hospital from a nursing home, or were enrolled in hospice. We identified dementia using validated diagnostic codes with a three‐year look‐back. We also measured demographics, comorbidities, characteristics of the index hospital stay, prior health care utilization, and both cognitive and physical function on admission to post‐acute care. Principal Findings: Our sample included 1,369,192 beneficiaries with a diagnosis of dementia; 404,539 (29.5%) received HH, while 964,653 (70.5%) went to SNF. The cohort was older (mean age 83), approximately 70% were cognitively impaired on SNF admission, and only 30.4% of patients were independent in Activities of Daily Living. Overall, 16.1% were readmitted to the hospital and 5.9% died within 30 days, while 19.5% died within 100 days of hospital discharge. In the instrumental variable analysis, there were no differences in any outcome between the two post‐acute care settings. These findings were similar when the analysis was stratified by degree of cognitive impairment. Conclusions: In a sample of more than 1.6 million Medicare beneficiaries discharged to post‐acute care following hospitalization, use of home health services and SNF were equivalent in terms of unplanned readmissions and 30‐ and 100‐day mortality. These are important findings given more than 7 in 10 Medicare beneficiaries with dementia are currently discharged to SNF for post‐acute care at much higher cost than HH, and the prevalence of both dementia and post‐acute care use are increasing in the United States. Implications for Policy or Practice: Our findings suggest HH may provide similar outcomes at lower cost following hospitalization for Medicare beneficiaries with a diagnosis of dementia, and that home‐based models of care may provide increased post‐acute care value. Primary Funding Source: University of Pennsylvania Institute on Aging. [ABSTRACT FROM AUTHOR]

Research Objective: To compare the outcomes of post‐acute care between home health (HH) and skilled nursing facilities (SNFs) following hospitalization among Medicare beneficiaries with dementia. Despite the fact that both post‐acute care use and dementia are highly prevalent in the Medicare population, very few studies have compared the outcomes of different post‐acute care settings for patients with dementia, leaving patients, caregivers, and clinicians uncertain how to make optimal decisions around hospital discharge. Study Design: Retrospective analysis of secondary data using an instrumental variable design to compare outcomes of HH versus SNF following an acute hospitalization. We used a 100% sample of Medicare inpatient, outpatient, and post‐acute care claims and assessment data from January 1, 2015 to December 31, 2016 and used differential distance between home health and SNF as the instrumental variable to account for nonrandom allocation of patients (F‐statistic: 26.5). Outcomes included unplanned 30‐day readmission, 30‐ and 100‐day mortality, and a composite measure of readmission and mortality to address competing risks. Our analysis adjusted for beneficiary characteristics and year of analysis, included fixed effects for hospital and year, and adjusted for clustering at the hospital level. Population Studied: We used MedPAR to identify hospitalizations and Minimum Data Set and Outcome and Assessment Information Set assessments to identify SNF and HH stays following hospital discharge. We excluded beneficiaries younger than age 65, admitted to the hospital from a nursing home, or were enrolled in hospice. We identified dementia using validated diagnostic codes with a three‐year look‐back. We also measured demographics, comorbidities, characteristics of the index hospital stay, prior health care utilization, and both cognitive and physical function on admission to post‐acute care. Principal Findings: Our sample included 1,369,192 beneficiaries with a diagnosis of dementia; 404,539 (29.5%) received HH, while 964,653 (70.5%) went to SNF. The cohort was older (mean age 83), approximately 70% were cognitively impaired on SNF admission, and only 30.4% of patients were independent in Activities of Daily Living. Overall, 16.1% were readmitted to the hospital and 5.9% died within 30 days, while 19.5% died within 100 days of hospital discharge. In the instrumental variable analysis, there were no differences in any outcome between the two post‐acute care settings. These findings were similar when the analysis was stratified by degree of cognitive impairment. Conclusions: In a sample of more than 1.6 million Medicare beneficiaries discharged to post‐acute care following hospitalization, use of home health services and SNF were equivalent in terms of unplanned readmissions and 30‐ and 100‐day mortality. These are important findings given more than 7 in 10 Medicare beneficiaries with dementia are currently discharged to SNF for post‐acute care at much higher cost than HH, and the prevalence of both dementia and post‐acute care use are increasing in the United States. Implications for Policy or Practice: Our findings suggest HH may provide similar outcomes at lower cost following hospitalization for Medicare beneficiaries with a diagnosis of dementia, and that home‐based models of care may provide increased post‐acute care value. Primary Funding Source: University of Pennsylvania Institute on Aging. [ABSTRACT FROM AUTHOR]

An enhancement of the cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation in renovascular hypertension. Angiotensin II in the paraventricular nucleus (PVN) augments the CSAR and increases sympathetic outflow and blood pressure. The present study aimed to determine whether endogenous hydrogen peroxide in the PVN mediated the enhanced CSAR, sympathetic activity and the effects of angiotensin II in the PVN in renovascular hypertension induced by the two-kidney, one-clip method (2K1C) in rats. At the end of the fourth week, the rats underwent sino-aortic and vagal denervation under general anaesthesia with urethane and α-chloralose. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. The CSAR was evaluated by the RSNA response to epicardial application of bradykinin. Microinjection of polyethylene glycol-catalase (PEG-CAT), an analogue of endogenous catalase, into the PVN decreased the RSNA and MAP and abolished the CSAR in both sham-operated and 2K1C rats. Microinjection into the PVN of the catalase inhibitor, aminotriazole, increased the RSNA and MAP and enhanced the CSAR. The effects of PEG-CAT or aminotriazole were greater in 2K1C rats than in sham-operated animals. The effects of angiotensin II in the PVN were abolished by pretreatment with PEG-CAT in both sham-operated and 2K1C rats; however, aminotriazole failed to potentiate the effects of angiotensin II. The catalase activity was decreased but the H2O2 levels were increased in the PVN of 2K1C rats. These results indicate that endogenous H2O2 in the PVN not only mediates the enhanced sympathetic activity and CSAR, but also the effects of angiotensin II in the PVN in renovascular hypertensive rats. [ABSTRACT FROM AUTHOR]

The cyanobacterial gene cluster kaiABC encodes three essential circadian clock proteins: KaiA, KaiB and KaiC. The KaiB and KaiC protein levels are robustly rhythmical, whereas the KaiA protein abundance undergoes little if any circadian oscillation in constant light. The level of the KaiC protein is crucial for correct functioning of the clock because induction of the protein at phases when the protein level is normally low elicits phase resetting. Titration of the effects of the inducer upon phase resetting versus KaiC level shows a direct correlation between induction of the KaiC protein within the physiological range and significant phase shifting. The protein synthesis inhibitor chloramphenicol prevents the induction of KaiC and blocks phase shifting. When the metabolism is repressed by either translational inhibition or constant darkness, the rhythm of KaiC abundance persists; therefore, clock protein expression has a preferred status under a variety of conditions. These data indicate that rhythmic expression of KaiC appears to be a crucial component of clock precession in cyanobacteria. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine the survival rate of patients with different bone sarcomas and to investigate homogenous and heterogenous prognostic factors for different types of bone sarcomas. Methods: This is a retrospective analysis of records from the Surveillance, Epidemiology, and End Result (SEER) database. Clear information on the distant metastasis of cancer is provided in the SEER database for patients diagnosed between January 2010 and December 2016. Data for the four types of malignant bone sarcomas were extracted, including osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. Patients with bone sarcomas originated from other sites, diagnosed at autopsy, or indicated in death certification were excluded. The overall survival was calculated for the entire cohort and across different bone sarcomas using the Kaplan–Meier method. A subgroup analysis of the different survival rates of four types of bone sarcomas in various levels of each variable was conducted and the differences were tested with the log‐rank test. Cox proportional hazard regression analysis was performed to determine the prognostic factors. Variables with P < 0.05 in the univariate Cox regression analysis were further analyzed using a multivariate Cox regression analysis. The prognostic factors in four groups of bone sarcomas were compared to determine the homogenous and heterogenous factors. Results: A total of 4732 patients were included with a follow up of 25 (0–83) months. The mean age of patients was 39.7 ± 24.1 years. The 1‐year, 3‐year, and 5‐year overall survival rate for the entire cohort was 86.2% (95% confidence interval [CI]: 85.2%–87.2%), 70.5% (95% CI: 68.9%–72.1%), and 63.0% (95% CI: 61.2%–64.8%), respectively. Factors including age older than 40 years, higher grade, regional and distant stage, tumor in the extremities, T2 stage, bone and lung metastases, and non‐surgery were significantly associated with the poor survival of the entire cohort. The mean overall survival duration of patients with chordoma, chondrosarcoma, Ewing sarcoma, and osteosarcoma was 66.86 (95% CI: 64.06–69.66), 63.53 (95% CI: 61.81–65.25), 58.06 (95% CI: 55.49–60.62) and 54.91 (95% CI: 53.14–56.69) months, respectively. Compared with chordoma, the hazard ratio (HR) and 95% CI for patients with chondrosarcoma, Ewing sarcoma, and osteosarcoma were 1.30 (95% CI: 1.04–1.62; P = 0.023), 1.69 (95% CI: 1.33–2.14; P < 0.001), and 2.00 (95% CI: 1.61–2.48; P <0.001), respectively. Different bone sarcomas showed homogenous and heterogenous prognostic factors. Conclusion: Different clinicopathological characteristics and prognoses were revealed in patients with osteosarcoma, chondrosarcoma, Ewing sarcoma, and chordoma. The risk factors can potentially guide prognostic prediction and sarcoma‐specific treatment. [ABSTRACT FROM AUTHOR]

To avoid dramatic economic losses and unrecoverable failures in offshore wind farms, it is necessary to accurately detect faults at the early stage of doubly-fed induction generators. The new extended Park's vector method is proposed in the study. The amplitude of the twice fundamental frequency component of the square of the Park's vector module is selected as the new fault feature to realise the early fault detection. The relationship between the extended Park's vector method and negative sequence current of the stator is also analysed in the study. The Fryze–Buchholz–Dpenbrock algorithm and the non-linear least squares method are applied to estimate the mathematic relationship among unbalanced stator voltage, load change and the negative sequence current of the stator. The experiments were conducted and the results showed that the proposed method is robust to the effects of the unbalanced stator voltage and load change. Therefore, the proposed method can accurately detect faults at the early stage with high sensitivity and reliability. [ABSTRACT FROM AUTHOR]

To avoid dramatic economic losses and unrecoverable failures in offshore wind farms, it is necessary to accurately detect faults at the early stage of doubly‐fed induction generators. The new extended Park's vector method is proposed in the study. The amplitude of the twice fundamental frequency component of the square of the Park's vector module is selected as the new fault feature to realise the early fault detection. The relationship between the extended Park's vector method and negative sequence current of the stator is also analysed in the study. The Fryze–Buchholz–Dpenbrock algorithm and the non‐linear least squares method are applied to estimate the mathematic relationship among unbalanced stator voltage, load change and the negative sequence current of the stator. The experiments were conducted and the results showed that the proposed method is robust to the effects of the unbalanced stator voltage and load change. Therefore, the proposed method can accurately detect faults at the early stage with high sensitivity and reliability. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non-alcoholic hepatic fatty liver disease (NAFLD) is a manifestation of the metabolic syndrome in the liver and non-alcoholic steatohepatitis (NASH) represents its advanced stage. R17 derived from bouchardatine, shows benefits in the metabolic syndrome, but has not been tested in the liver. The present study examined the pharmacological effects of R17 in a model of NAFLD/NASH and its mode of action.Experimental Approach: The effects of R17 were examined in mice fed a high-fat (HF) diet to induce the pathological characteristics of NAFLD/NASH and in cultures of HuH7 cells. We used histological and immunohistochemical techniques along with western blotting and siRNA. Generation of ROS and apoptosis were measured.Key Results: Administration of R17 (20 mg·kg-1 , i.p. every other day) for 5 weeks reversed HF-induced hepatic triglyceride content, inflammation (inflammatory cytokines and macrophage numbers), injury (hepatocyte ballooning and apoptosis, plasma levels of alanine aminotransferase and aspartate aminotransferase), and fibrogenesis (collagen deposition and mRNA expression of fibrosis markers). In cultured cells, R17 reduced cell steatosis from both lipogenesis and fatty acid influx. The attenuated inflammation and cell injury were associated with inhibition of both endoplasmic reticulum (ER) stress and oxidative stress. Notably, R17 activated the liver kinase B1-AMP-activated protein kinase (AMPK) pathway by inhibiting activity of ATP synthase, rather than direct stimulation of AMPK.Conclusion and Implications: R17 has therapeutic potential for NAFLD/NASH. Its mode of action involves the elimination of ER and oxidative stresses, possibly via activating the LKB1-AMPK axis by inhibiting the activity of ATP synthase. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to characterize the topological alterations and classification performance of high‐order functional connectivity (HOFC) networks in cognitively preserved patients with Parkinson's disease (PD), relative to low‐order FC (LOFC) networks. Methods: The topological metrics of the constructed networks (LOFC and HOFC) obtained from fifty‐one cognitively normal patients with PD and 60 matched healthy control subjects were analyzed. The discriminative abilities were evaluated using machine learning approach. Results: The HOFC networks in the PD group showed decreased segregation and integration. The normalized clustering coefficient and small‐worldness in the HOFC networks were correlated to motor performance. The altered nodal centralities (distributed in the precuneus, putamen, lingual gyrus, supramarginal gyrus, motor area, postcentral gyrus and inferior occipital gyrus) and intermodular FC (frontoparietal and visual networks, sensorimotor and subcortical networks) were specific to HOFC networks. Several highly connected nodes (thalamus, paracentral lobule, calcarine fissure and precuneus) and improved classification performance were found based on HOFC profiles. Conclusion: This study identified disrupted topology of functional interactions at a high level with extensive alterations in topological properties and improved differentiation ability in patients with PD prior to clinical symptoms of cognitive impairment, providing complementary insights into complex neurodegeneration in PD. [ABSTRACT FROM AUTHOR]

Efferocytosis is defined as the clearance of apoptotic cells (ACs) in physiological and pathological states and is performed by efferocytes, such as macrophages. Efferocytosis can lead to the resolution of inflammation and restore tissue homoeostasis; however, the mechanisms of efferocytosis in determining inflammation resolution are still not completely understood, and the effects of efferocytosis on other proresolving properties need to be explored and explained. In this review, the process of efferocytosis will be summarized briefly, and then these mechanisms and effects will be thoroughly discussed. In addition, the association between mechanisms of efferocytosis in determining resolution of inflammation and cardiovascular diseases will also be reviewed, as an understanding of this association may provide information on novel treatment targets. [ABSTRACT FROM AUTHOR]

Background and Purpose: Non‐alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH. Experimental Approach The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin‐immunoprecipitation sequencing. The effects and mechanisms of SYSU‐3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high‐fat and high‐cholesterol diet and the methionine‐choline deficient diet‐fed mice). The actions of SYSU‐3d in vivo were evaluated. Key Results: HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU‐3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPARγ coactivator‐1α (PGC‐1α) to induce mitochondrial biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC‐1α or recovery of HSF1 in HSF1‐deficiency cells showed the HSF1/PGC‐1α pathway was mainly responsible for the anti‐NASH effects of SYSU‐3d independent of AMP‐activated protein kinase (AMPK). Conclusion and Implications: Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC‐1α/mitochondrial pathway and SYSU‐3d can be considered as a potential candidate for the treatment of NASH. [ABSTRACT FROM AUTHOR]

Objective: Based on a large public cohort, we aimed to investigate the prevalence of distant metastases in patients with osteosarcoma, to evaluate the survival of patients with different metastases and to reveal the related risk and prognostic factors for distant metastases. Methods: The information of osteosarcoma patients with or without distant metastases was retrospectively extracted from the Surveillance, Epidemiology, and End Result database from January 2010 to December 2015. Patients were excluded if they were diagnosed at autopsy or via death certification. The Kaplan–Meier method was used to calculate the overall survival in the entire cohort and across patients with metastases to different organs. The related prognostic factors were investigated by univariate and multivariate Cox proportional hazard regression analysis. The logistic regression method was used to reveal the risk factors for the development of different metastases. The effects of different variables on the survival and prevalence of distant metastases were compared using subgroup analysis. Variables with P < 0.05 in the univariate regression analysis were further examined using multivariate regression analysis. Results: In total, 1470 osteosarcoma patients (mean age 30 ± 22 years) were included, among which 278 patients (18.9%) were initially diagnosed with distant metastasis. The median follow‐up duration was 33.0 (30.2–35.8) months. The lung was the most common metastatic site (83.8%), followed by the bone (21.9%), liver (2.9%), and brain (2.2%). A total of 232 patients (83.5%) presented only one distant metastatic site, while the other 46 patients showed two or more metastatic sites. A lower proportion of metastasis was observed in patients aged from 25 to 59 years [odds ratio (OR) = 0.59; 95% confidence interval (CI): 0.37–0.95]. More metastases were noted in patients with T2/T1 (OR = 1.91; 95% CI: 1.28–2.84), T3/T1 (OR = 4.48; 95% CI: 1.78–11.30) and N1/N0 stages (OR = 6.66; 95% CI: 2.68–16.56). The 1‐, 3‐, and 5‐year overall survival rates for metastatic patients were 57.3% (95% CI: 50.8%–63.8%), 25.3% (95% CI: 18.8%–31.9%), and 18.1% (95% CI: 10.2%–26.0%), respectively. Metastatic patients older than 25 years were prone to have poor survival and a relatively better prognosis (hazard ratio = 0.41; 95% CI: 0.25–0.69) was noticed among those who underwent surgery on the primary site. Different metastatic organs have homogeneous and heterogeneous risk and prognostic factors. Conclusion: The high incidence of initial distant metastasis in osteosarcoma and the inconsistent predictive factors should be given more attention in the clinical management of patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

Protein regulator of cytokinesis 1 (PRC1) is a microtubule bundling protein that is involved in the regulation of the central spindle bundle and spindle orientation during mitosis. However, the functions of PRC1 during meiosis have rarely been studied. In this study, we explored the roles of PRC1 during meiosis using an oocyte model. Our results found that PRC1 was expressed at all stages of mouse oocyte meiosis, and PRC1 accumulated in the midzone/midbody during anaphase/telophase I. Moreover, depleting PRC1 caused defects in polar body extrusion during mouse oocyte maturation. Further analysis found that PRC1 knockdown did not affect meiotic spindle formation or chromosome segregation; however, deleting PRC1 prevented formation of the midzone and midbody at the anaphase/telophase stage of meiosis I, which caused cytokinesis defects and further induced the formation of two spindles in the oocytes. PRC1 knockdown increased the level of tubulin acetylation, indicating that microtubule stability was affected. Furthermore, KIF4A and PRC1 showed similar localization in the midzone/midbody of oocytes at anaphase/telophase I, while the depletion of KIF4A affected the expression and localization of PRC1. The PRC1 mRNA injection rescued the defects caused by PRC1 knockdown in oocytes. In summary, our results suggest that PRC1 is critical for midzone/midbody formation and cytokinesis under regulation of KIF4A in mouse oocytes. [ABSTRACT FROM AUTHOR]

Objectives: DNA damage and errors of accurate chromosome segregation lead to aneuploidy and foetal defects. DNA repair and the spindle assembly checkpoint (SAC) are the mechanisms developed to protect from these defects. Checkpoint kinase 1 (CHK1) is reported to be an important DNA damage response protein in multiple models, but its functions remain unclear in early mouse embryos. Materials and Methods: Immunofluorescence staining, immunoblotting and real‐time reverse transcription polymerase chain reaction were used to perform the analyses. Reactive oxygen species levels and Annexin‐V were also detected. Results: Loss of CHK1 activity accelerated progress of the cell cycle at the first cleavage; however, it disturbed the development of early embryos to the morula/blastocyst stages. Further analysis indicated that CHK1 participated in spindle assembly and chromosome alignment, possibly due to its regulation of kinetochore‐microtubule attachment and recruitment of BubR1 and p‐Aurora B to the kinetochores, indicating its role in SAC activity. Loss of CHK1 activity led to embryonic DNA damage and oxidative stress, which further induced early apoptosis and autophagy, indicating that CHK1 is responsible for interphase DNA damage repair. Conclusions: Our results indicate that CHK1 is a key regulator of the SAC and DNA damage repair during early embryonic development in mice. [ABSTRACT FROM AUTHOR]

Intellectual disability (ID) describes a wide range of serious human diseases caused by defects in central nervous system development and function. Some mutant genes have been found to be associated with these diseases, but not all cases can be explained, thus suggesting that other disease‐causing genes have not yet been discovered. Sialic acid is involved in a number of key biological processes, including embryo formation, nerve cell growth, and cancer cell metastasis, and very recently it has been suggested that N‐acetylneuraminic acid synthase‐mediated synthesis of sialic acid is required for brain and skeletal development. CMP‐sialic acid synthetase (CMAS) is one of four enzymes involved in NeuNAc metabolism, as it catalyzes the formation of CMP‐NeuNAc. Before the present study, no links between mutations in CMAS and incidences of human ID had been reported. In the current study, we recruited a recessive nonsyndromic ID pedigree with consanguineous marriage in which all patients have typical clinical manifestations of ID. We identified the NM_018686.3:c.563G > A (p.Arg188His) substitution in CMAS as being responsible for the disease in this family. Conservation analysis, structural prediction, and enzyme activity experiments demonstrated that (p.Arg188His) influences protein dimerization and alters CMAS enzyme activity. Our results offer a new orientation for future research and clinical diagnosis. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to present the surgical technique and clinical results of percutaneous compression plate ( PCCP) for the treatment of femoral neck fractures. Methods Between December 2010 and April 2013, 74 consecutive patients with 74 femoral neck fractures were treated by closed reduction and PCCP implants in our university hospital. Their mean age was 51.3 years (range, 15-83 years); 38 (51.4%) were male and 46 (62.2%) of the fractures were on the left. The patients' clinical and radiographic data were analyzed retrospectively. Results There were 45 undisplaced (60.8%) and 29 displaced fractures (39.2%). Eight patients (10.8%) were lost to follow-up. The mean duration of follow-up was 18.8 months for the remaining 66 patients. At the last follow-up, mean Harris hip score was 92.9 (range, 75-100), and 65 patients (98.5%) had excellent and good outcomes. Sixty-five patients (98.5%) were able to walk independently and one (1.5%) with walking-sticks. The mean time to clinical fracture healing was 3.9 months. There were no cases of nonunion. Two patients (3.0%) had delayed union and two (3.0%) developed avascular necrosis, one of 29 (3.7%) with a displaced fracture and one of 45 (2.6%) with an undisplaced fracture. There were no other complications or prosthetic replacement. Conclusions PCCP is a stable internal fixation device that resists axial and rotational stresses. Our PCCP procedure has a low incidence of nonunion and avascular necrosis. [ABSTRACT FROM AUTHOR]

Sodium carbonate (Na2CO3) presents a huge challenge to plants by the combined damaging effects of Na+, high pH, and CO32-. Little is known about the cellular responses to Na2CO3 stress. In this study, the transcriptome of maize ( Zea mays L. cv. B73) roots exposed to Na2CO3 stress for 5 h was compared with those of NaCl and NaOH stresses. The expression of 8,319 genes, representing over a quarter of the total number of genes in the maize genome, was altered by Na2CO3 stress, and the downregulated genes (5,232) outnumbered the upregulated genes (3,087). The effects of Na2CO3 differed from those of NaCl and NaOH, primarily by downregulating different categories of genes. Pathways commonly altered by Na2CO3, NaCl, and NaOH were enriched in phenylpropanoid biosynthesis, oxidation of unsaturated fatty acids, ATP-binding cassette (ABC) transporters, as well as the metabolism of secondary metabolites. Genes for brassinosteroid biosynthesis were specifically upregulated by Na2CO3, while genes involved in ascorbate and aldarate metabolism, protein processing in the endoplasmic reticulum and by N-glycosylation, fatty acid biosynthesis, and the circadian rhythm were downregulated. This work provides the first holistic picture of early transcriptomic adaptation to Na2CO3 stress, and highlights potential molecular pathways that could be manipulated to improve tolerance in maize. [ABSTRACT FROM AUTHOR]