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Although neuropsychiatric manifestations are common in survivors of coronavirus disease 2019 (COVID-19), the pathophysiology is not yet elucidated. Here we describe the case of a geriatric inpatient who developed post-COVID depression with psychomotor retardation, anxiety, hopelessness, executive function problems, and suicidal ideations. The language problems and cognitive impairments coemerged with the motor problems. We propose a mechanism associated with problems in energy prediction and regulation in which the coronavirus infection, which causes neuroinflammation and viral activity in the nervous system, interferes with the reward pathway and sensory prediction process. Sigma-1 receptor agonists such as sertraline may regulate energy expenditure and, thus, be beneficial to the process. The treatment improvements in our patient included those in the autonomic nervous system, activity, and circadian rhythm.

Abstract Activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) is a plasma-based global haemostatic assay. Elevated CWA parameters have been associated with hypercoagulability in venous thromboembolism, but its role in arterial thrombotic disease is uncertain. This study aims to explore the relationship between aPTT-based CWA and acute myocardial infarction (AMI) and its complications. In a retrospective cohort study of patients with AMI who underwent emergency cardiac catheterisation, pre-procedural aPTT and CWA parameters—min1, min2 and max2 were measured. These were compared against a control group of patients, consisting of patients who underwent elective orthopaedic and urological procedures. Within the AMI cohort, we also compared aPTT and CWA parameters of those with and without clinical complications of AMI. Results: Compared to controls (N = 109), patients with AMI (N = 214) had shorter aPTT (26.7 ± 3.3 s vs 27.9 ± 1.7 s, P

Abstract Traditional chemotherapy drugs for cervical cancer often cause significant toxic side effects and drug resistance problems, highlighting the urgent need for more innovative and effective treatment strategies. Magnesium alloy is known to be degradable and biocompatible. The release of degradation products Mg2+, OH−, and H2 from magnesium alloy can alter the tumor microenvironment, providing potential anti-tumor properties. We explored the innovative use of magnesium alloy biomaterials in the treatment of cervical cancer, investigating how various concentrations of Mg2+ on the proliferation and cell death of cervical cancer cells. The results revealed that varying concentrations of Mg2+ significantly inhibited cervical cancer by arresting the cell cycle in the G0/G1 phase and inducing apoptosis in SiHa cells, effectively reducing tumor cell proliferation. In vivo experiments demonstrated that 20 mM Mg2+ group had the smallest tumor volume, exhibiting a potent inhibitory effect on the biological characteristics of cervical cancer. This enhances the therapeutic potential of this biomaterial as a local anti-tumor therapy and lays a theoretical foundation for the potential application of magnesium in the treatment of cervical cancer.

Background: The abnormal expression of circRNA may contribute to the progression of cervical cancer by influencing the biological processes. Aim: This study aimed to identify the differentially expressed circRNAs in cervical cancer and validate the circ_0008193 ceRNA network in cervical cancer cells. Methods: Using the absolute log2 value of fold change >1 and p-value of

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and belongs to the category of malignant tumors of the thyroid gland. Autophagy plays an important role in PTC. The purpose of this study is to develop a novel diagnostic model using autophagy-related genes (ARGs) in patients. In this study, RNA sequencing data of PTC samples and normal samples were obtained from GSE33630 and GSE29265. Then, we analyzed GSE33630 datasets and identified 127 DE-ARGs. Functional enrichment analysis suggested that 127 DE-ARGs were mainly enriched in pathways in cancer, protein processing in endoplasmic reticulum, toll-like receptor pathway, MAPK pathway, apoptosis, neurotrophin signaling pathway, and regulation of autophagy. Subsequently, CALCOCO2, DAPK1, and RAC1 among the 127 DE-ARGs were identified as diagnostic genes by support vector machine recursive feature elimination and least absolute shrinkage and selection operator algorithms. Then, we developed a novel diagnostic model using CALCOCO2, DAPK1, and RAC1 and its diagnostic value was confirmed in GSE29265 and our cohorts. Importantly, CALCOCO2 may be a critical regulator involved in immune microenvironment because its expression was related to many types of immune cells. Overall, we developed a novel diagnostic model using CALCOCO2, DAPK1, and RAC1 which can be used as diagnostic markers of PTC.

Abstract Cockroaches are considered mechanical transmitters of infectious diseases, posing a threat to human health. This study assessed the potential of cockroaches in food-related environments to mechanically transmit intestinal pathogens. Cockroaches captured with traps were placed together into a low temperature refrigerator at − 80° for 2 h. Standard taxonomic keys and Fluorescent quantitative PCR techniques were applied for species identification and digestive tract etiological examination. A total of 360 cockroach traps were placed, with a positive rate of 20.8%, and 266 cockroaches were captured. In general, compared with other places and areas, the degree of infestation of cockroaches was more serious in catering places and kitchens. Blattella germanica were most found in catering places (40.2%), followed by Periplaneta fuliginosa in schools (22.2%). According to the life stage, among the 128 cockroach samples, 23 were positive for nymphs and 13 were positive for adults. There were statistically significant differences in the intestinal pathogen detection rates between nymphs and adults (P

Abstract Several studies have demonstrated that exosomes (Exos) are involved in the regulation of macrophage polarization and osteoclast differentiation. However, the characteristics as well as roles of exosomes from human periodontal ligament cells (hPDLCs-Exos) in M1/M2 macrophage polarization and osteoclast differentiation remain unclear. Here, periodontal ligament cells were successfully extracted by method of improved Type-I collagen enzyme digestion. hPDLCs-Exos were extracted by ultracentrifugation. hPDLCs-Exos were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blotting (WB). Osteoclast differentiation was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR), WB and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization were evaluated by RT-qPCR and WB. The results showed hPDLCs-Exos promoted osteoclast differentiation and M2 macrophage polarization, but inhibited M1 macrophage polarization. Moreover, M1 macrophages inhibited osteoclast differentiation, whereas M2 macrophages promoted osteoclast differentiation. It has shown that hPDLCs-Exos promoted osteoclast differentiation by inhibiting M1 and promoting M2 macrophage polarization.

Abstract Heart rhythm complexity (HRC), a subtype of heart rate variability (HRV), is an important tool to investigate cardiovascular disease. In this study, we aimed to analyze serial changes in HRV and HRC metrics in patients with inferior ST-elevation myocardial infarction (STEMI) within 1 year postinfarct and explore the association between HRC and postinfarct left ventricular (LV) systolic impairment. We prospectively enrolled 33 inferior STEMI patients and 74 control subjects and analyzed traditional linear HRV and HRC metrics in both groups, including detrended fluctuation analysis (DFA) and multiscale entropy (MSE). We also analyzed follow-up postinfarct echocardiography for 1 year. The STEMI group had significantly lower standard deviation of RR interval (SDNN), and DFAα2 within 7 days postinfarct (acute stage) comparing to control subjects. LF power was consistently higher in STEMI group during follow up. The MSE scale 5 was higher at acute stage comparing to control subjects and had a trend of decrease during 1-year postinfarct. The MSE area under scale 1–5 showed persistently lower than control subjects and progressively decreased during 1-year postinfarct. To predict long-term postinfarct LV systolic impairment, the slope between MSE scale 1 to 5 (slope 1–5) had the best predictive value. MSE slope 1–5 also increased the predictive ability of the linear HRV metrics in both the net reclassification index and integrated discrimination index models. In conclusion, HRC and LV contractility decreased 1 year postinfarct in inferior STEMI patients, and MSE slope 1–5 was a good predictor of postinfarct LV systolic impairment.

Abstract From an initial pool of 2303 studies, ten eligible and potential studies were selected through rigor inclusion and exclusion criteria for this systematic review to examine music therapy's effect on dementia. The review included 967 participants, with the majority being female. A significant number of studies were conducted in Taiwan. Although several cognitive ability assessment methods were employed in the selected studies, the Mini-Mental State Examination (MMSE) was the most commonly used tool for evaluating the effects of music therapy on dementia. Overall, the current review demonstrates that music therapy can be a valuable strategy for treating patients with dementia, with its outcomes including improved cognitive function and potentially slowing the progression of the disease's severity. Therefore, this study can significantly contribute to future studies and practices aimed at using music therapy to treat dementia.

Abstract Head and neck squamous carcinoma (HNSCC) is the seventh most common cancer worldwide. Targeted therapeutic drugs for HNSCC are still being explored. Among them, (S)-10-hydroxycamptothecin (10-HCPT), a specific inhibitor of TOP1, functions by DNA double-strand breaks that can inhibit DNA replication and trigger apoptotic cell death subsequently. Previous studies have reported that MLN4924 exerts potent anti-tumor effects by inhibiting cullin–RING ligases and causing substrate accumulation in a variety of cancers. Here, we show that MLN4924 effectively causes dose-dependent accumulation of topoisomerase I (TOP1) and blocks TOP1 ubiquitination. Importantly, neddylation inhibition with MLN4924 acts synergistically with 10-HCPT to suppress cell growth, migration and apoptosis in HNSCC cells. Mechanistically, transcriptome sequencing shows that the cytotoxic effects of the combination of MLN4924 and 10-HCPT may involve activation of the NFKB1 pathway. Taken together, our results suggest that combined treatment with MLN4924 and 10-HCPT may be an effective strategy in HNSCC.

Septic Cardiomyopathy (SCM) is a syndrome of acute cardiac dysfunction in septic patients, unrelated to cardiac ischemia. Multiomics studies including transcriptomics and proteomics have provided new insights into the mechanisms of SCM. In here, a rat model of SCM was established by intraperitoneal injection of lipopolysaccharide (LPS). Biomarkers of SCM were characterized via a multi-omics analysis. The differentially expressed (DE) mRNAs predominantly appeared in pathways linked to the immune response, inflammatory response, and the complement and coagulation cascades, while DE proteins were mainly enriched in pathways associated with the complement and coagulation cascades. On this basis, the integrated analysis was performed between transcriptome and proteome. The potential biomarkers were further verified by RT-qPCR and WB. The current proteotranscriptomic research has furnished a valuable dataset and fresh perspectives that will enhance our comprehension of the development of SCM. This, in turn, is expected to expedite the formulation of novel approaches for the prevention and management of SCM in patients.

Objective To investigate the feasibility of epidural catheters in parotid gland duct anastomosis and the function of the affected side gland after parotid gland duct anastomosis. Methods Thirteen patients who were treated in the Department of Oral and Maxillofacial Surgery of Xuzhou Central Hospital using an epidural catheter as the scaffold for parotid gland catheter anastomosis were enrolled from Jan. 2019 to June 2021. The swelling, salivary fistula and catheter patency in the parotid gland area were evaluated two weeks after the operation. 99mTcO4- single photon emission computed tomography (SPECT) was used for quantitative detection of salivary gland secretion function. Results Thirteen patients had no swelling or salivary fistula in the parotid gland area of the affected side two weeks after the operation, and the catheter secretion was unobstructed. There was no significant difference in the uptake rate between the parotid gland on the affected side and the parotid gland on the healthy side (t = -0.859, P = 0.399), and there was no significant difference in the excretion rate between the parotid gland on the affected side and the parotid gland on the healthy side (t = 0.693, P = 0.495). The parotid gland excretion function of the affected side was excellent three months after the operation. Conclusion Parotid duct anastomosis with an epidural catheter as the stent has good feasibility, and parotid gland secretion function recovers well after the operation, which is worthy of clinical application.

Objective To discuss the treatment of pneumoparotid and to provide a reference for clinical practice. Methods A case of refractory pneumoparotid was reported, and the diagnosis and treatment of parotid emphysema were reviewed and analyzed in combination with the literature. Results This child had parotid gland enlargement without any obvious cause for more than 1 month. Conservative treatment, such as anti-inflammatory agents, psychological interventions and physical compression were ineffective. The patient had a history of cerebral palsy with epilepsy and involuntary cheek bulging behavior. Therefore, we considered it a refractory case. It was cured after parotid duct ligation and partial parotidectomy of the superficial lobe. A literature review showed that a pneumoparotid is a rare parotid enlargement. Most of the clinical cases were considered to be caused by the return of air into the parotid gland through the parotid duct due to an increase in oral pressure. The diagnosis of pneumoparotid mainly depends on intermittent parotid gland swelling and other clinical manifestations and imaging examination methods, such as ultrasound, CT, MRI and angiography. Its treatment mainly includes conservative anti-inflammatory treatment, physical therapy and psychological intervention. Surgical treatment is indicated for refractory parotid emphysema. Conclusion Pneumoparotid cases may further develop into parotid inflammation, which is generally treated conservatively. For some severe, recurrent and poor compliance cases, surgical treatment is sometimes needed.

With the rapid development of life science, laboratory animals play an important role in many fields, such as biomedicine. In recent years, the national reforms “to delegate power, streamline administration and optimize government services” continues deepen, the laboratory animals administrative departments have paid more attention to interim and post-event supervision, in which the safety management of laboratory animals is the key and challenging point in the supervision process. In this paper, the information regarding licenses for laboratory animals in Jiangsu, facility areas, animal production and usage, employees, and other information the past three years were introduced. Combined with legal administrative management in recent years, the potential safety risks in the production and use of laboratory animals were analyzed, such as risks in management systems, employees, facility operation, animal quality control, accidental injury and zoonosis, animal transportation, and waste disposal. Additionally, the current construction, daily management services, and the list of interim and post-event supervision of the laboratory animal safety management system were introduced. Based on this discussion, we proposed relevant safety management countermeasures and suggestions and provided support for further improvements to laboratory animal safety management.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus behind the coronavirus disease 2019 (COVID-19) pandemic, is a type of RNA virus that is nonsegmented. Cardiovascular diseases (CVDs) increase the mortality risk of patients. In this review article, we overview the existing evidence regarding the potential mechanisms of myocardial damage in coronavirus disease 2019 (COVID-19) patients. Having a comprehensive knowledge of the cardiovascular damage caused by SARS-CoV-2 and its underlying mechanisms is essential for providing prompt and efficient treatment, ultimately leading to a reduction in mortality rates. Severe COVID-19 causes acute respiratory distress syndrome and shock in patients. In addition, awareness regarding COVID-19 cardiovascular manifestations has increased, including the adverse impact on prognosis with cardiovascular involvement. Angiotensin-converting enzyme 2 receptor may play a role in acute myocardial injury caused by SARS-CoV-2 infection. COVID-19 patients experiencing heart failure may have their condition exacerbated by various contributing factors and mechanisms. Increased oxygen demand, myocarditis, stress cardiomyopathy, elevated pulmonary pressures, and venous thrombosis are potential health issues. The combination of these factors may lead to COVID-19-related cardiogenic shock, resulting in acute systolic heart failure. Extracorporeal membrane oxygenation (ECMO) and left ventricular assist devices (LVADs) are treatment options when inotropic support fails for effective circulatory support. To ensure effective COVID-19-related cardiovascular disease (CVD) surveillance, it is crucial to closely monitor the future host adaptation, viral evolution, and transmissibility of SARS-CoV-2, given the virus's pandemic potential.

Abstract In breast conserving surgery (BCS), specimen mammography is one of the most widely used intraoperative methods of assessing margin status. We performed a meta-analysis to evaluate the diagnostic accuracy of specimen mammography. Literature databases including PubMed, Cochrane Library, Web of Science, and EMBASE were searched prior to Jun 2022. A total of 1967 patients were included from 20 studies. A pooled analysis, heterogeneity testing, threshold effect testing, publication bias analysis, and subgroup analyses were performed from extracted data. The pooled weighted values were a sensitivity of 0.55 (95% confidence interval [CI], 0.47–0.63), a specificity of 0.85 (95% CI, 0.78–0.90), a diagnostic odds ratio of 7 (95% CI, 4–12), and a pooled positive likelihood ratio of 3.7 (95% CI 2.6–5.5). The area under the receiver operator characteristic curve was 0.75 (95% CI 0.71–0.78). In the subgroup analysis, the pooled specificity in the positive margin defined as tumor at margin subgroup was lower than the other positive margin definition subgroup (0.82 [95% CI: 0.71, 0.92] vs. 0.87 [95% CI: 0.80, 0.94], p = 0.01). Our findings indicated that specimen mammography was an accurate intraoperative imaging technique for margin assessment in BCS.

Abstract Primary hyperparathyroidism (PHPT) is mainly caused by parathyroid adenoma, which produces excess parathyroid hormones. Its pathogenic mechanisms have not yet been fully understood. To investigate the mechanism in the pathogenesis of PHPT, the transcriptome and genome-wide DNA methylation profiles of parathyroid adenoma were analyzed. The candidate genes that may be involved in the PHPT were verified via qRT-PCR, immunohistochemistry, western blot, and methylation-specific PCR. A total of 1650 differentially expressed genes and 2373 differentially methylated regions were identified. After the integration of its transcriptome and DNA methylation data, IL6, SYP, GNA01, and pro-opiomelanocortin (POMC) were the candidate genes that demonstrated a similar pattern between their mRNA expression and DNA methylation status. Of the 4 candidate genes, POMC, a pro-peptide which is processed to a range of bioactive peptide products like ACTH, was further confirmed to be expressed at low levels at both the mRNA and protein levels, which may be due to POMC promoter hypermethylation. Hypermethylation of the POMC promoter may contribute to its low expression, which may be involved in the pathogenesis of PHPT.

Localized peripheral neuropathy amyloidosis is a rare disease that mainly occurred in elder people who present with focal neurological symptoms. AL is the main type of amyloid protein. Biopsy is the golden standard for diagnosis. Mass spectrometry and immunohistochemical analysis help to confirm the type of amyloid protein. This paper retrospectively analyzes the clinical and imaging data, auxiliary examinations, histological, and immunohistochemical markers. The patient, a 34-year-old woman, presented with a right neck mass and weakness of the right arm. Brachial plexus magnetic resonance imaging (MRI) showed a tumor-like lesion in the nerve root at C5 and C6 and in upper trunk. Electrophysiological studies revealed damage in the upper trunk of the brachial plexus. Positive staining with Congo red was found in brachial plexus biopsy. Mass spectrometry showed that the type of amyloid protein was AHL(G-λ). The patient underwent nerve graft for treatment. Meanwhile, literature review revealed that the average onset age of localized spinal nerve amyloidosis was 62.4 years old.The radial nerve was the most susceptible, followed by the lumbosacral plexus. Fifty percent of the type of amyloid protein is AL.Until now, no consolidated treatment is available. Here, we summarize the clinical characteristics of localized peripheral neuropathy amyloidosis in order to raise the awareness of the disease.

BackgroundReal-time air pollution monitoring is a valuable tool for public health and environmental surveillance. In recent years, there has been a dramatic increase in air pollution forecasting and monitoring research using artificial neural networks. Most prior work relied on modeling pollutant concentrations collected from ground-based monitors and meteorological data for long-term forecasting of outdoor ozone (O3), oxides of nitrogen, and fine particulate matter (PM2.5). Given that traditional, highly sophisticated air quality monitors are expensive and not universally available, these models cannot adequately serve those not living near pollutant monitoring sites. Furthermore, because prior models were built based on physical measurement data collected from sensors, they may not be suitable for predicting the public health effects of pollution exposure. ObjectiveThis study aimed to develop and validate models to nowcast the observed pollution levels using web search data, which are publicly available in near real time from major search engines. MethodsWe developed novel machine learning–based models using both traditional supervised classification methods and state-of-the-art deep learning methods to detect elevated air pollution levels at the US city level by using generally available meteorological data and aggregate web-based search volume data derived from Google Trends. We validated the performance of these methods by predicting 3 critical air pollutants (O3, nitrogen dioxide, and PM2.5) across 10 major US metropolitan statistical areas in 2017 and 2018. We also explore different variations of the long short-term memory model and propose a novel search term dictionary learner-long short-term memory model to learn sequential patterns across multiple search terms for prediction. ResultsThe top-performing model was a deep neural sequence model long short-term memory, using meteorological and web search data, and reached an accuracy of 0.82 (F1-score 0.51) for O3, 0.74 (F1-score 0.41) for nitrogen dioxide, and 0.85 (F1-score 0.27) for PM2.5, when used for detecting elevated pollution levels. Compared with using only meteorological data, the proposed method achieved superior accuracy by incorporating web search data. ConclusionsThe results show that incorporating web search data with meteorological data improves the nowcasting performance for all 3 pollutants and suggest promising novel applications for tracking global physical phenomena using web search data.

ObjectiveTo explore an improved method for constructing a mouse model of aortic dissection (AD).MethodsAD was induced by the simultaneous administration of β-aminopropionitrile (BAPN) with angiotensin Ⅱ (Ang-Ⅱ) for 16 days in mice. One hundred 6-week-old male C57B1/6J mice were randomly divided into BAPN (BAPN 0.1 g•kg-1•d-1 + 0.9% saline), BAPN+Ang-Ⅱ (BAPN 0.1 g•kg-1•d-1 + Ang-Ⅱ), and control groups. BAPN (0.1 g•kg-1•d-1), freshly prepared and dissolved in drinking water, was administered to all mice in the BAPN and BAPN + Ang-Ⅱ groups for 16 days. Mice in the BAPN+Ang-Ⅱ group were treated with an additional subcutaneous injection of Ang-Ⅱ for 16 days. The concentration of Ang-Ⅱ was halved from 1.5 mg•kg-1•d-1 every week until it was set at 0.375 mg•kg-1•d-1 on day 15, and then maintained. The daily water intake and body weight were recorded from the beginning until the end of the study. If a mouse died during the experiment, an autopsy was performed to analyze the cause of death. On day 17, the mice were sacrificed, and each aorta was harvested. The formation of the aortic false lumen was observed pathologically using hematoxylin and eosin (HE) staining.ResultsCompared with the control group, the amount of water consumed and body weight in the BAPN+Ang-Ⅱ and BAPN groups were significantly reduced (P < 0.05). In the control group, the incidence of dissection and mortality was 0.0%. In the BAPN group, the incidence of AD and the mortality was 7.5% and 2.5%, respectively. In the BAPN+Ang-Ⅱ group, the incidence of AD and the mortality was 80.0% and 30.0%, respectively. Interestingly, the deaths in the BAPN+Ang-Ⅱ group occurred frequently at 1-3 days after dose adjustment, and 83.3% of the mice died a few minutes after the operation.ConclusionThis modified method for constructing an AD mouse model induced by BAPN drinking combined with Ang-Ⅱ subcutaneous injection was replicable, regular, effective, cheap, and quick.

This article investigates the administrative licensing data of laboratory animals in Jiangsu Province, summarizes the administrative licenses for laboratory animals in recent years, analyzes the status of the administrative management of laboratory animals in Jiangsu Province, and proposes corresponding countermeasures to provide a reference for the administration of laboratory animal industry in Jiangsu Province and other regions.

Abstract As a highly prevalent disease among women worldwide, breast cancer remains in urgent need of further elucidation its molecular mechanisms to improve the patient outcomes. Identifying hub genes involved in the pathogenesis and progression of breast cancer can potentially help to unveil mechanism and also provide novel diagnostic and prognostic markers. In this study, we integrated multiple bioinformatic methods and RNA in situ detection technology to identify and validate hub genes. EZH2 was recognized as a key gene by PPI network analysis. CENPL, ISG20L2, LSM4, MRPL3 were identified as four novel hub genes through the WGCNA analysis and literate search. Among these, many studies on EZH2 in breast cancer have been reported, but no studies are related to the roles of CENPL, ISG20L2, MRPL3 and LSM4 in breast cancer. These four novel hub genes were up-regulated in tumor tissues and associated with cancer progression. The receiver operating characteristic analysis and Kaplan–Meier survival analysis indicated that these four hub genes are promising candidate genes that can serve as diagnostic and prognostic biomarkers for breast cancer. Moreover, these four newly identified hub genes as aberrant molecules in the maintenance of breast cancer development, their exact functional mechanisms deserve further in-depth study.

Apert syndrome (AS) is characterized by synostosis of coronal sutures, midfacial hypoplasia,abnormity of brain, syndactyly of hands and feet. Majority of AS is caused by gain-of-function mutation of fibro‐blast growth factor receptor 2 (FGFR2). To date, the treatment of AS is surgical correction for the deformed skull.The reconstruction of sutures is often executed several times, because of constant premature of sutures. Some dis‐eased tissues, such as brain, are difficult to treat with surgery. CRISPR/Cas9 gene editing technology exhibits pow‐erful prospect in the treatment of human genetic diseases. In this study, small guiding RNA (gRNA) specificallytargeting the Fgfr2 gene was screened and lentivirus mediated Cas9/gRNA was employed to treat mice (Fg‐fr2+/P253R) that mimicking human Apert syndrome in primary calvarial cells, calvarial explants or calvarial bone. Incultured primary calvarial cells, Cas9/gRNA reduced the phosphorylation of ERK1/2 and P38, and resultantly inhibited osteoblastic differentiation and matrix mineralization. Besides, Cas9/gRNA attenuated the premature closure ofcoronal suture and the decreased calvarial bone volume calvarial explants and AS mice. This study provides exper‐imental basis of gene therapy for Apert syndrome, and is prospective to provide new strategies for the treatment ofskeletal genetic diseases.

Abstract Erectile dysfunction (ED) is mostly due to the lack of blood flow into the penis. In the past 20 years, near-infrared spectroscopy (NIRS) was used in measuring the concentrations and temporal dynamics of different hemoglobin types. However, the dynamics of the light absorption (photoplethysmography; PPG) have not been applied to survey penile hemodynamics and erection quality. This paper compared the use of photoplethysmography (PPG) to study vascular ED with standard penile Doppler ultrasonography. Men diagnosed with vascular ED for at least 6 months and nominated for penile ultrasonography were included. PPG signals were collected during the ultrasound examination. All beat-to-beat PPG waveforms were aligned with the peak and averaged to one representative template waveform for feature analysis, including amplitude differences (APD) index, reflection time index (RTI), augmentation index (AI), and perfusion index (PI). An inverse correlation was found between end-erection amplitude and both erection hardness score (EHS) and resistive index (RI). APD index and EHS as well as the international index of erectile function-5 (IIEF) and RI were positively correlated. RTI and AI were inversely correlated to IIEF and RI. PI was positively correlated to RI. PPG may therefore be useful as a noninvasive, convenient, technique for sexual function evaluation.

Abstract Due to unique photovoltaic properties, the nanostructured morphologies of TiO2 on flexible substrate have been studied extensively in the recent years for applications in dye sensitized solar cells (DSSCs). Microstructured electrode materials with high surface area can facilitate rapid charge transport and thus improve the light-to-current conversion efficiency. Herein we present an improved photoanode with forest like photoactive TiO2 hierarchical microstructure using a simple and facile hydrothermal route. To utilize the surface plasmon resonance (SPR) and hence increase the photon conversion efficiency, a plasmonic nanoparticle Ag has also been deposited using a very feasible photoreduction method. The branched structure of the photoanode increases the dye loading by filling the space between the nanowires, whereas Ag nanoparticles play the multiple roles of dye absorption and light scattering to increase the light-to-current conversion efficiency of the device. The branched structure provides a suitable matrix for the subsequent Ag deposition. They improve the charge collection efficiency by providing the preferential electron pathways. The high-density Ag nanoparticles deposited on the forest like structure also decrease the charge recombination and therefore improve the photovoltaic efficiency of the cells. As a result, the DSSC based on this novel photoanode shows remarkably higher photon conversion efficiency (ηmax = 4.0% and ηopt = 3.15%) compared to the device based on pristine nanowire or forest-like TiO2 structure. The flexibility of the device showed sustainable and efficient performance of the microcells.

Abstract Glaucoma is a leading cause of blindness characterized by progressive degeneration of retinal ganglion cells (RGCs). A well-established risk factor for the development and progression of glaucoma is elevation of intraocular pressure (IOP). However, how elevated IOP leads to RGC degeneration remains poorly understood. Here, we fabricate a facile, tunable hydrostatic pressure platform to study the effect of increased hydrostatic pressure on RGC axon and total neurite length, cell body area, dendritic branching, and cell survival. The hydrostatic pressure can be adjusted by varying the height of a liquid reservoir attached to a three-dimensional (3D)-printed adapter. The proposed platform enables long-term monitoring of primary RGCs in response to various pressure levels. Our results showed pressure-dependent changes in the axon length, and the total neurite length. The proportion of RGCs with neurite extensions significantly decreased by an average of 38 ± 2% (mean ± SEM) at pressures 30 mmHg and above (p

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Ulocladium was thought to be a strictly asexual genus of filamentous fungi. However, Ulocladium strains were shown to possess both MAT1-1-1 and MAT1-2-1 genes as observed in homothallic filamentous Ascomycetes. Here, we demonstrate that the U. botrytis MAT genes play essential roles for controlling asexual traits (conidial size and number). Using reciprocal genetic transformation, we demonstrate that MAT genes from the related heterothallic species Cochliobolus heterostrophus can also influence U. botrytis colony growth, conidial number and size, and have a strong effect on the range of the number of septa/conidium. Moreover, U. botrytis MAT genes can also affect similar aspects of asexual reproduction when expressed in C. heterostrophus. Heterologous complementation using C. heterostrophus MAT genes shows that they have lost the ability to regulate sexual reproduction in U. botrytis, under the conditions we employed, while the reciprocal heterologous complementation demonstrates that U. botrytis MAT genes have the ability to partially induce sexual reproduction in C. heterostrophus. Thus, the genetic backgrounds of C. heterostrophus and U. botrytis play significant roles in determining the function of MAT genes on sexual reproduction in these two fungi species. These data further support the role of MAT genes in controlling asexual growth in filamentous Ascomycetes but also confirm that heterothallic and homothallic Dothideomycete fungi can be interconverted by the exchange of MAT genes.

HIV-1 Gag is a large multidomain poly-protein with flexible unstructured linkers connecting its globular subdomains. It is compact when in solution but assumes an extended conformation when assembled within the immature HIV-1 virion. Here, we use molecular dynamics (MD) simulations to quantitatively characterize the intra-domain interactions of HIV-1 Gag. We find that the matrix (MA) domain and the C-terminal subdomain CActd of the CA capsid domain can form a bound state. The bound state, which is held together primarily by interactions between complementary charged and polar residues, stabilizes the compact state of HIV-1 Gag. We calculate the depth of the attractive free energy potential between the MA/ CActd sites and find it to be about three times larger than the dimerization interaction between the CActd domains. Sequence analysis shows high conservation within the newly-found intra-Gag MA/CActd binding site, as well as its spatial proximity to other well known elements of Gag -such as CActd's SP1 helix region, its inositol hexaphosphate (IP6) binding site and major homology region (MHR), as well as the MA trimerization site. Our results point to a high, but yet undetermined, functional significance of the intra-Gag binding site. Recent biophysical experiments that address the binding specificity of Gag are interpreted in the context of the MA/CActd bound state, suggesting an important role in selective packaging of genomic RNA by Gag.

Objective To study the correlation between the movement distance of small intestinal contents and survival time in female SD rat models after one-time satiation, and to evaluate its application value for postmortem interval estimation. Methods Adult female SD rats were randomly divided into postprandial groups （1, 2, 3, 4 and 5 h after feeding） and control group. The postprandial groups were fed for 1 h, meanwhile control group was kept fasting. All rats were sacrificed at the given time. The contents in stomach and small intestine were observed, described, compared and photographed, and the movement distance of small intestinal contents was measured. The data of postprandial groups were analysed by one-way analysis of variance. Results The stomach and duodenum of control group were empty with a little thin and yellow small intestinal liquid. The gastral cavities of 1 h postprandial group were full of undigested food. The evolutionary changes of character, colour and content were observed in the gastric and small intestinal contents of other postprandial groups. The movement distance of intestinal contents increased while the empty part decreased gradually. The differences among the postprandial groups were statistically significant （P

Antimicrobial peptides from amphibian skin secretion display remarkable broad-spectrum antimicrobial activity and are thus promising for the discovery of new antibiotics. In this study, we report a novel peptide belonging to the phylloseptin family of antimicrobial peptides, from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea, which was named Phylloseptin-PBa. Degenerate primers complementary to putative signal peptide sites of frog skin peptide precursor-encoding cDNAs were designed to interrogate a skin secretion-derived cDNA library from this frog. Subsequently, the peptide was isolated and identified using reverse phase HPLC and MS/MS fragmentation. The synthetic replicate was demonstrated to have activity against S. aureus, E. coli and C. albicans at concentrations of 8, 128 and 8 mg/L, respectively. In addition, it exhibited anti-proliferative activity against the human cancer cell lines, H460, PC3 and U251MG, but was less active against a normal human cell line (HMEC). Furthermore, a haemolysis assay was performed to assess mammalian cell cytotoxicity of Phylloseptin-PBa. This peptide contained a large proportion of α-helical domain, which may explain its antimicrobial and anticancer activities.

Background: To evaluate the feasibility of a new surgeon-modified iliac branch device (IBD) technique to maintain pelvic perfusion in the management of common iliac artery (CIA) aneurysm during endovascular aneurysm repair (EVAR). Methods: From January 2011 to December 2013, a new surgeon-modified IBD technique was performed in department of vascular surgery of Peking Union Medical College Hospital in five patients treated for CIA aneurysm with or without abdominal aortic aneurysm. A stent-graft limb was initially deployed in vitro, anastomosed with vascular graft, creating a modified IBD reloaded into a larger sheath, with or without a guidewire preloaded into the side branch. The reloaded IBD was then placed in the iliac artery, with a covered stent bridging internal iliac artery and the branch. Finally, a bifurcated stent-graft was deployed, and a limb device was used to connect the main body and IBD. Results: Technical successes were obtained in all patients. The mean follow-up length was 24 months (range: 6-38 months). All grafts remained patent without any sign of endoleaks. There were no aneurysm ruptures, deaths, or other complications related to pelvic flow. Conclusions: Using the surgeon-modified IBD to preserve pelvic flow is a feasible endovascular technique and an appealing solution for personalized treatment of CIA aneurysm during EVAR.

BACKGROUND:This study investigated the feasibility of using the precordial surface ECG lead interlead QRS dispersion (IQRSD) in the identification of abnormal ventricular substrate in arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS:Seventy-one consecutive patients were enrolled and reclassified into 4 groups: definite ARVC with epicardial ablation (Group 1), ARVC with ventricular tachycardia (VT, Group 2), idiopathic right ventricular outflow tract VT without ARVC (Group 3), and controls without VT (Group 4). IQRSD was quantified by the angular difference between the reconstruction vectors obtained from the QRS-loop decomposition, based on a principal component analysis (PCA). Electroanatomic mapping and simulated ECGs were used to investigate the relationship between QRS dispersion and abnormal substrate. RESULTS:The percentage of the QRS loop area in the Group 1-2 was smaller than the controls (P = 0.01). The IQRSD between V1-V2 could differentiate all VTs from control (P

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1-2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.

INTRODUCTION:The signal characteristics of intracardiac bipolar electrograms at the origin of idiopathic RVOT-VT during sinus rhythm remain unclear. OBJECTIVE:The study sought to develop a novel real-time/online technique, simultaneous amplitude frequency electrogram transformation (SAFE-T), to quantify and localize the diseased ventricular substrate in idiopathic RVOT-VT. METHODS:We retrospectively investigated the intracardiac bipolar recordings in 70 consecutive patients (26% male, mean age 42±12 years) who underwent successful radiofrequency catheter ablation of idiopathic RVOT-VT. We quantified the extent of the frequency fraction of ventricular potentials during sinus rhythm or ventricular pacing using a novel formula, the product of instantaneous amplitude and frequency, and showed that in a 3D geometry as an online SAFE-T map. RESULTS:The characteristics of the HHT spectra of electrograms derived from VT origins demonstrated high frequency components (>70 Hz), which were independent of the rhythm. The density of the abnormal potentials at the VT origins were higher (VT origins, 7.5±2.3 sites/cm2 vs. surrounding myocardium, 1.5±1.3 sites/cm2, p3.0 Hz·mV. CONCLUSION:The online SAFE-T map was feasible for quantifying the diseased ventricular substrate, irrespective of the rhythm of activation, and can be used to identify the optimal ablation targets for idiopathic RVOT-VT. We found a limited region of abnormal potentials where the RVOT-VT origins were successfully ablated.

PURPOSE:The aim of this study was to evaluate the therapeutic efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of patients with knee osteoarthritis (OA). MATERIALS:We performed a meta-analysis of relevant published clinical studies. An electronic search was conducted for randomized controlled trials (RCTs) of MSC-based therapy in knee OA. The visual analogue scale (VAS), International Knee Documentation Committee (IKDC) form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), Tegner activity scale (Tegner) and adverse events (AEs) were evaluated. RESULTS:Eleven eligible trials with 582 knee OA patients were included in the present meta-analysis. We demonstrated that MSC treatment could significantly decrease VAS and increase IKDC scoresafter a 24-month follow-up compared with controls (P

Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells.By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway.In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway.

Anaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Tissue microarray (TMA) was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC) cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC) assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (qRT-PCR), target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.Among the tested cases, 2 (0.44%) CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1). One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

Nedaplatin, a cisplatin analog, was developed to reduce the toxicity of cisplatin, whereas it can be cross-resistant with cisplatin in some circumstances. This study aimed to investigate the role of autophagy in nedaplatin induced cell death in cisplatin-resistant nasopharyngeal carcinoma cells. Here, we showed that HNE1/DDP and CNE2/DDP cells were resistant to nedaplatin-induced cell death with reduced apoptotic activity. Nedaplatin treatment resulted in autophagosome accumulation and increased expression of LC3-II, indicating the induction of autophagy by nedaplatin in HNE1/DDP and CNE2/DDP cells. Inhibition of autophagy by Bafilomycin A1 (Baf A1) and 3-Methyladenine (3-MA) remarkably enhanced the antitumor efficacy of nedaplatin in HNE1/DDP and CNE2/DDP cells, suggesting that the resistance to nedaplatin-induced cell death was caused by enhanced autophagy in nedaplatin-resistant NPC cells. Additionally, Baf A1 enhanced reactive oxygen species (ROS) generation and apoptosis induced by nedaplatin in HNE1/DDP cells. Mechanistically, nedaplatin treatment caused activation of ERK1/2 and suppression of Akt/mTOR signaling pathways. While inhibition of ERK1/2 by MEK1/2 inhibitor, U0126, could reduce the expression of LC3-II in nedaplatin-resistant NPC cells. Furthermore, suppression of ROS could inhibit nedaplatin-induced ERK activation in HNE1/DDP cells, indicating that ROS and ERK were involved in nedaplatin-induced autophagy. Together, these findings suggested that autophagy played a cytoprotective role in nedaplatin-induced cytotoxicity of HNE1/DDP and CNE2/DDP cells. Furthermore, our results highlighted a potential approach to restore the sensitivity of cisplatin-resistant nasopharyngeal cancer cells to nedaplatin in combination with autophagy inhibitors.

Monitoring of fetal heart rate (FHR) is important during labor since it is a sensitive marker to obtain significant information about fetal condition. To take immediate response during cesarean section (CS), we noninvasively derive FHR from maternal abdominal ECG.We recruited 17 pregnant women delivered by elective cesarean section, with abdominal ECG obtained before and during the entire CS. First, a QRS-template is created by averaging all the maternal ECG heart beats. Then, Hilbert transform was applied to QRS-template to generate the other basis which is orthogonal to the QRS-template. Second, maternal QRS, P and T waves were adaptively subtracted from the composited ECG. Third, Gabor transformation was applied to obtain time-frequency spectrogram of FHR. Heart rate variability (HRV) parameters including standard deviation of normal-to-normal intervals (SDNN), 0V, 1V, 2V derived from symbolic dynamics of HRV and SD1, SD2 derived from Poincareé plot. Three emphasized stages includes: (1) before anesthesia, (2) 5 minutes after anesthesia and (3) 5 minutes before CS delivery.FHRs were successfully derived from all maternal abdominal ECGs. FHR increased 5 minutes after anesthesia and 5 minutes before delivery. As for HRV parameters, SDNN increased both 5 minutes after anesthesia and 5 minutes before delivery (21.30±9.05 vs. 13.01±6.89, P < 0.001 and 22.88±12.01 vs. 13.01±6.89, P < 0.05). SD1 did not change during anesthesia, while SD2 increased significantly 5 minutes after anesthesia (27.92±12.28 vs. 16.18±10.01, P < 0.001) and both SD2 and 0V percentage increased significantly 5 minutes before delivery (30.54±15.88 vs. 16.18±10.01, P < 0.05; 0.39±0.14 vs. 0.30±0.13, P < 0.05).We developed a novel method to automatically derive FHR from maternal abdominal ECGs and proved that it is feasible during CS.

The heart begins to beat before the brain is formed. Whether conventional hierarchical central commands sent by the brain to the heart alone explain all the interplay between these two organs should be reconsidered. Here, we demonstrate correlations between the signal complexity of brain and cardiac activity. Eighty-seven geriatric outpatients with healthy hearts and varied cognitive abilities each provided a 24-hour electrocardiography (ECG) and a 19-channel eye-closed routine electroencephalography (EEG). Multiscale entropy (MSE) analysis was applied to three epochs (resting-awake state, photic stimulation of fast frequencies (fast-PS), and photic stimulation of slow frequencies (slow-PS)) of EEG in the 1-58 Hz frequency range, and three RR interval (RRI) time series (awake-state, sleep and that concomitant with the EEG) for each subject. The low-to-high frequency power (LF/HF) ratio of RRI was calculated to represent sympatho-vagal balance. With statistics after Bonferroni corrections, we found that: (a) the summed MSE value on coarse scales of the awake RRI (scales 11-20, RRI-MSE-coarse) were inversely correlated with the summed MSE value on coarse scales of the resting-awake EEG (scales 6-20, EEG-MSE-coarse) at Fp2, C4, T6 and T4; (b) the awake RRI-MSE-coarse was inversely correlated with the fast-PS EEG-MSE-coarse at O1, O2 and C4; (c) the sleep RRI-MSE-coarse was inversely correlated with the slow-PS EEG-MSE-coarse at Fp2; (d) the RRI-MSE-coarse and LF/HF ratio of the awake RRI were correlated positively to each other; (e) the EEG-MSE-coarse at F8 was proportional to the cognitive test score; (f) the results conform to the cholinergic hypothesis which states that cognitive impairment causes reduction in vagal cardiac modulation; (g) fast-PS significantly lowered the EEG-MSE-coarse globally. Whether these heart-brain correlations could be fully explained by the central autonomic network is unknown and needs further exploration.

Vestibular disorder is the cause of approximately 50% of dizziness in older people. The vestibular system is a critical postural control mechanism, and posturography analysis is helpful for diagnosing vestibular disorder. In clinical practice, the sensory organization test (SOT) is used to quantify postural control in an upright stance under different test conditions. However, both aging and vestibular disorder cause declines of postural control mechanisms. The aim of this study was to enhance the performance of the SOT using a nonlinear algorithm of empirical mode decomposition (EMD) and to verify the differences of effects caused by aging and/or illnesses benefits to clinical diagnosis. A total of 51 subjects belonging to 3 groups--healthy-young, healthy-elderly and dizzy--were recruited for this study. New dynamic parameters of the SOT were derived from the center of pressure (COP) signals. EMD served as an adaptive filter bank to derive the low- and high-frequency components of the COP. The effects on four ratios of sensory analysis caused by aging and vestibular disorder can be investigated for the specific frequency bands. According to our findings, new SOT parameters derived from the component with the specific frequency band more sensitively reflect the functional condition of vestibular dysfunction. Furthermore, both aging and vestibular dysfunction caused an increase in magnitude for the low-frequency component of the AP-direction COP time series. In summary, the low-frequency fluctuation reflects the stability of postural control, while the high-frequency fluctuation is sensitive to the functional condition of the sensory system. EMD successfully improved the accuracy of SOT measurements in this investigation.

The principal event underlying the development of prion disease is the conversion of soluble cellular prion protein (PrP(C)) into its disease-causing isoform, PrP(Sc). This conversion is associated with a marked change in secondary structure from predominantly α-helical to a high β-sheet content, ultimately leading to the formation of aggregates consisting of ordered fibrillar assemblies referred to as amyloid. In vitro, recombinant prion proteins and short prion peptides from various species have been shown to form amyloid under various conditions and it has been proposed that, theoretically, any protein and peptide could form amyloid under appropriate conditions. To identify the peptide segment involved in the amyloid core formed from recombinant full-length mouse prion protein mPrP(23-230), we carried out seed-induced amyloid formation from recombinant prion protein in the presence of seeds generated from the short prion peptides mPrP(107-143), mPrP(107-126), and mPrP(127-143). Our results showed that the amyloid fibrils formed from mPrP(107-143) and mPrP(127-143), but not those formed from mPrP(107-126), were able to seed the amyloidogenesis of mPrP(23-230), showing that the segment residing in sequence 127-143 was used to form the amyloid core in the fibrillization of mPrP(23-230).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular atherosclerosis independent of classical risk factors. This study investigated the influence of NAFLD on autonomic changes, which is currently unknown. METHODS: Subjects without an overt history of cardiovascular disease were enrolled during health checkups. The subjects diagnosed for NAFLD using ultrasonography underwent 5-min heart rate variability (HRV) measurements that was analyzed using the following indices: (1) the time domain with the standard deviation of N-N (SDNN) intervals and root mean square of successive differences between adjacent N-N intervals (rMSSD); (2) the frequency domain with low frequency (LF) and high frequency (HF) components; and (3) symbolic dynamics analysis. Routine blood biochemistry data and serum leptin levels were analyzed. Homeostasis model assessment of insulin resistance (HOMA-IR) was measured. RESULTS: Of the 497 subjects (mean age, 46.2 years), 176 (35.4%) had NAFLD. The HRV indices (Ln SDNN, Ln rMSSD, Ln LF, and Ln HF) were significantly decreased in the NAFLD group (3.51 vs 3.62 ms, 3.06 vs 3.22 ms, 5.26 vs 5.49 ms(2), 4.49 vs 5.21 ms(2), respectively, all P

In addition to the ubiquitous apical-basal polarity, epithelial cells are often polarized within the plane of the tissue--the phenomenon known as planar cell polarity (PCP). In Drosophila, manifestations of PCP are visible in the eye, wing, and cuticle. Several components of the PCP signaling have been characterized in flies and vertebrates, including the heterotrimeric Go protein. However, Go signaling partners in PCP remain largely unknown. Using a genetic screen we uncover Kermit, previously implicated in G protein and PCP signaling, as a novel binding partner of Go. Through pull-down and genetic interaction studies, we find that Kermit interacts with Go and another PCP component Vang, known to undergo intracellular relocalization during PCP establishment. We further demonstrate that the activity of Kermit in PCP differentially relies on the motor proteins: the microtubule-based dynein and kinesin motors and the actin-based myosin VI. Our results place Kermit as a potential transducer of Go, linking Vang with motor proteins for its delivery to dedicated cellular compartments during PCP establishment.

We aimed to mine the data in the Electronic Medical Record to automatically discover patients' Rheumatoid Arthritis disease activity at discrete rheumatology clinic visits. We cast the problem as a document classification task where the feature space includes concepts from the clinical narrative and lab values as stored in the Electronic Medical Record.The Training Set consisted of 2792 clinical notes and associated lab values. Test Set 1 included 1749 clinical notes and associated lab values. Test Set 2 included 344 clinical notes for which there were no associated lab values. The Apache clinical Text Analysis and Knowledge Extraction System was used to analyze the text and transform it into informative features to be combined with relevant lab values.Experiments over a range of machine learning algorithms and features were conducted. The best performing combination was linear kernel Support Vector Machines with Unified Medical Language System Concept Unique Identifier features with feature selection and lab values. The Area Under the Receiver Operating Characteristic Curve (AUC) is 0.831 (σ = 0.0317), statistically significant as compared to two baselines (AUC = 0.758, σ = 0.0291). Algorithms demonstrated superior performance on cases clinically defined as extreme categories of disease activity (Remission and High) compared to those defined as intermediate categories (Moderate and Low) and included laboratory data on inflammatory markers.Automatic Rheumatoid Arthritis disease activity discovery from Electronic Medical Record data is a learnable task approximating human performance. As a result, this approach might have several research applications, such as the identification of patients for genome-wide pharmacogenetic studies that require large sample sizes with precise definitions of disease activity and response to therapies.

The analysis of biological information from protein sequences is important for the study of cellular functions and interactions, and protein fold recognition plays a key role in the prediction of protein structures. Unfortunately, the prediction of protein fold patterns is challenging due to the existence of compound protein structures. Here, we processed the latest release of the Structural Classification of Proteins (SCOP, version 1.75) database and exploited novel techniques to impressively increase the accuracy of protein fold classification. The techniques proposed in this paper include ensemble classifying and a hierarchical framework, in the first layer of which similar or redundant sequences were deleted in two manners; a set of base classifiers, fused by various selection strategies, divides the input into seven classes; in the second layer of which, an analogous ensemble method is adopted to predict all protein folds. To our knowledge, it is the first time all protein folds can be intelligently detected hierarchically. Compared with prior studies, our experimental results demonstrated the efficiency and effectiveness of our proposed method, which achieved a success rate of 74.21%, which is much higher than results obtained with previous methods (ranging from 45.6% to 70.5%). When applied to the second layer of classification, the prediction accuracy was in the range between 23.13% and 46.05%. This value, which may not be remarkably high, is scientifically admirable and encouraging as compared to the relatively low counts of proteins from most fold recognition programs. The web server Hierarchical Protein Fold Prediction (HPFP) is available at http://datamining.xmu.edu.cn/software/hpfp.

The defensive skin secretions of amphibians are a rich resource for the discovery of novel, bioactive peptides. Here we report the identification of a novel vascular smooth muscle-relaxing peptide, named vasorelaxin, from the skin secretion of the Chinese piebald odorous frog, Odorrana schmackeri. Vasorelaxin consists of 20 amino acid residues, SRVVKCSGFRPGSPDSREFC, with a disulfide-bridge between Cys-6 and Cys-20. The structure of its biosynthetic precursor was deduced from cloned skin cDNA and consists of 67 amino acid residues encoding a single copy of vasorelaxin (vasorelaxin, accession number: HE860494). Synthetic vasorelaxin caused a profound relaxation of rat arterial smooth muscle with an EC(50) of 6.76 nM.

BACKGROUND: Angiogenesis plays an important role in many physiological and pathological processes. Identification of small molecules that block angiogenesis and are safe and affordable has been a challenge in drug development. Hypericum attenuatum Choisy is a Chinese herb medicine commonly used for treating hemorrhagic diseases. The present study investigates the anti-angiogenic effects of quercetin-4'-O-β-D-glucopyranoside (QODG), a flavonoid isolated from Hypericum attenuatum Choisy, in vivo and in vitro, and clarifies the underlying mechanism of the activity. METHODOLOGY/PRINCIPAL FINDINGS: Tg(fli1:EGFP) transgenic zebrafish embryos were treated with different concentrations of quercetin-4'-O-β-D-glucopyranoside (QODG) (20, 60, 180 µM) from 6 hours post fertilisation (hpf) to 72 hpf, and adult zebrafish were allowed to recover in different concentrations of QODG (20, 60, 180 µM) for 7 days post amputation (dpa) prior morphological observation and angiogenesis phenotypes assessment. Human umbilical vein endothelial cells (HUVECs) were treated with or without VEGF and different concentrations of QODG (5, 20, 60, 180 µM), then tested for cell viability, cell migration, tube formation and apoptosis. The role of VEGFR2-mediated signaling pathway in QODG-inhibited angiogenesis was evaluated using quantitative real-time PCR (qRT-PCR) and Western blotting. CONCLUSION/SIGNIFICANCE: Quercetin-4'-O-β-D-glucopyranoside (QODG) was shown to inhibit angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish in vivo via suppressing VEGF-induced phosphorylation of VEGFR2. Our results further indicate that QODG inhibits angiogenesis via inhibition of VEGFR2-mediated signaling with the involvement of some key kinases such as c-Src, FAK, ERK, AKT, mTOR and S6K and induction of apoptosis. Together, this study reveals, for the first time, that QODG acts as a potent VEGFR2 kinase inhibitor, and exerts the anti-angiogenic activity at least in part through VEGFR2-mediated signaling pathway.