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Background: Atrial fibrillation (AF) represents the most common clinical cardiac arrhythmia and substantially increases the risk of cerebral stroke, heart failure, and death. Although causative genes for AF have been identified, the genetic determinants for AF remain largely unclear.Objective: This study aimed to investigate the molecular basis of AF in a Chinese kindred.Methods: A 4-generation family with autosomal-dominant AF and other arrhythmias (atrioventricular block, sinus bradycardia, and premature ventricular contractions) was recruited. Genome-wide scan with microsatellite markers and linkage analysis as well as whole-exome sequencing analysis were performed. Electrophysiological characteristics and subcellular localization of the AF-linked mutant were analyzed using dual whole-cell patch clamps and confocal microscopy, respectively.Results: A novel genetic locus for AF was mapped to chromosome 17q21.3, a 3.23-cM interval between markers D17S951 and D17S931, with a maximum 2-point logarithm of odds score of 4.2144 at marker D17S1868. Sequencing analysis revealed a heterozygous mutation in the mapping region, NM_005497.4:c.703A>T;p.(M235L), in the GJC1 gene encoding connexin45 (Cx45). The mutation cosegregated with AF in the family and was absent in 632 control individuals. The mutation decreased the coupling conductance in cell pairs (M235L/M235L, M235L/Cx45, M235L/Cx43, and M235L/Cx40), likely because of impaired subcellular localization.Conclusion: This study defines a novel genetic locus for AF on chromosome 17q21.3 and reveals a loss-of-function mutation in GJC1 (Cx45) contributing to AF and other cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

Congenital bicuspid aortic valve (BAV), the most common form of birth defect in humans, is associated with substantial morbidity and mortality. Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of BAV. However, BAV is a genetically heterogeneous disease and the genetic determinants underpinning BAV in an overwhelming majority of patients remain unknown. In the present study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc-finger transcription factor essential for the normal development of the aortic valves, were sequenced in 152 unrelated patients with congenital BAV. The available relatives of a proband harboring an identified GATA6 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA6 . The functional characteristics of the mutation were analyzed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.E386X, was identified in a family with BAV transmitted in an autosomal dominant mode. The nonsense mutation was absent in 400 control chromosomes. Biological assays revealed that the mutant GATA6 protein had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA6 and GATA4, another transcription factor causally linked to BAV. In conclusion, this study firstly associates GATA6 loss-of-function mutation with enhanced susceptibility to familial BAV, which provides novel insight into the molecular mechanism of BAV, implying potential implications for genetic counseling and personalized management of BAV patients. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) represents the most frequent developmental deformity in human beings and accounts for substantial morbidity and mortality worldwide. Accumulating investigations underscore the strong inherited basis of CHD, and pathogenic variations in >100 genes have been related to CHD. Nevertheless, the heritable defects underpinning CHD remain elusive in most cases, mainly because of the pronounced genetic heterogeneity. In this investigation, a four-generation family with CHD was recruited and clinically investigated. Via whole-exome sequencing and Sanger sequencing assays in selected family members, a heterozygous variation in the SMAD4 gene (coding for a transcription factor essential for cardiovascular morphogenesis), NM_005359.6: c.285T > A; p.(Tyr95*), was identified to be in co-segregation with autosomal-dominant CHD in the entire family. The truncating variation was not observed in 460 unrelated non-CHD volunteers employed as control subjects. Functional exploration by dual-reporter gene analysis demonstrated that Tyr95*-mutant SMAD4 lost transactivation of its two key downstream target genes NKX2.5 and ID2 , which were both implicated with CHD. Additionally, the variation nullified the synergistic transcriptional activation between SMAD4 and GATA4, another transcription factor involved in CHD. These data strongly indicate SMAD4 may be associated with CHD and shed more light on the molecular pathogenesis underlying CHD, implying potential implications for antenatal precise prevention and prognostic risk stratification of the patients affected with CHD. [ABSTRACT FROM AUTHOR]

Langkawi lies within the North-western Domain of Western Belt of Peninsular Malaysia which belongs to Sundaland and is composed of Palaeozoic sedimentary rocks, varying from the Cambrian to the Permian in age; Machinchang, Setul, Singa, and Chuping formations. Understanding the sediment depositional setting is a fundamental process in providing necessary information regarding the area's geologic history. The study's significance is to emphasize that the sedimentology, stratigraphy, and depositional environment must become the focal point of the inter-disciplinary research necessary to advance our understanding of the complex behaviors of the Earth. Updating and improving the sedimentary facies is vital to establishing a precise chronology of past events by completing the sedimentary sequences. The study involved the analysis of three sedimentary logs recorded within exposed rock sections of the Machinchang Formation in Langkawi. All sedimentary logs were then correlated to getting a composite log representing the entire succession sequence. The facies analysis belonging to Machinchang Formation shows the presence of nine facies types (F1 to F9) for this succession which can be assigned to four facies associations; tidal flat (FA1) represented by F1, F2, F3 and F4, upper shoreface (FA2) represents by F1 and F6, lower shoreface (FA3) represented by F1, F2 and F5 and foreshore (FA4) are represented by F1, F2, F7, F8 and F9. These sediments represent clastic types deposited in a shallow marine environment during a relatively short regression period. • Machinchang Formation is perhaps the best described Cambrian formation in Malaysia. • Machinchang Formation consists of three members; Hulor, Chinchin, and Tengkorak. • Update the sedimentary facies is vital to create a precise chronology of past events. • Sedimentology must become the focus to understand the complex process of the Earth. [ABSTRACT FROM AUTHOR]

Due to limited information, this paper aims to present a detailed facies analysis and depositional environment of the Carboniferous age, Singa Formation at Pulau Ular, Langkawi, Kedah. One exposed outcrop at Hill C was examined in detail, and one sedimentary log was created. The log is categorized bed by bed into several facies according to lithology and sedimentary structures. The focus was to identify the facies succession and to analyze the depositional environment as Singa Formation. This study is vital to reconstructing the pattern of past glacial as it will provide the crucial link between glacial processes and history, ice masses, and a more comprehensive Earth system. The Singa Formation is concluded into coarsening upward facies successions based on the facies succession grades upward from offshore facies. The depositional environment of Pulau Ular is interpreted as a coastal and a glacier depositional environment. Eight facies have been recognized; shale (FC1), shale with burrows (FC2), siltstone (FC3), shale with burrows, clay to silt (FC4), laminated shale with dropstone (FC5), sandstone that consists of dropstone (FC6), shale consists of dropstone (FC7) and sandstone with diamictite rock (FC8). Facies shale, sandstone, and siltstone proved that the study area is a coastal depositional environment, while facies consisting of dropstones and diamictite show that the study area is a glacier depositional environment. • To give a detailed facies analysis and depositional setting of the Singa Formation. • The Singa Formation is best seen in the exposed rock of Langkawi and north Perlis. • The Singa Formation consists of four members: Rebak, Kentut, Ular and Selang. • The facies of Pulau Ular indicate a coastal environment and glacial marine deposits. [ABSTRACT FROM AUTHOR]

An UHPLC–QTOF-MS/MS based metabolomics and chemical profiling approach was developed to identify the characteristic chemical markers for inspecting sulfur-fumigated Radix Angelicae Sinensis (S-RAS). Two sulfur-containing compounds in S-RAS were discovered and deduced to be (3 Z )-6-sulfite-ligustilide and (3 E )-6-sulfite-ligustilide. Furthermore, utilizing extraction ion method with the typical ion ( m/z 271.06) of (3 Z )-6-sulfite-ligustilide/(3 E )-6-sulfite-ligustilide as the diagnostic ion, another six sulfur-containing components were determined in S-RAS, and identified as 6, 8-disulfite-ligustilide and 8-sulfite-ligustilide or their isomers. The generation mechanisms of these compounds were proposed as the addition reaction of sulfurous acid with ( Z )-ligustilide and/or ( E )-ligustilide, two major naturally occurring components in RAS, at the double bonds of C6 C7 and C3 C8 positions. Using (3 Z )-6-sulfite-ligustilide and (3 E )-6-sulfite-ligustilide as the chemical markers, fourteen of sixteen batches of commercial RAS samples were inspected to be S-RAS, suggesting that the newly generated sulfur-containing compounds could be used as characteristic chemical markers for inspecting S-RAS among commercial RAS samples. [ABSTRACT FROM AUTHOR]

In the present paper, we are concerned with the existence of Q 0 -rotating periodic solutions on a class of perturbed systems in R 2 n. This type of rotating periodic solutions has the form of X (t + T) = Q 0 X (t) , ∀ t ∈ R with T > 0 and Q 0 an orthogonal matrix. The systems under consideration are linear but completely degenerate, in another word, completely resonant. In general it is quite difficult to the situation. We establish a persistence result about Q 0 -rotating periodic solutions undergoing small perturbations. Our transversality condition is based on the topological degree, but easily verifiable in applications. [ABSTRACT FROM AUTHOR]

Highlights: [•] We propose a new approach for mobile users’ movement behavior mining and prediction and items recommendation. [•] We employ the notion of semantic trajectory similarity to cluster similar users together. [•] Based on the trajectory patterns and high utility itemsets, we propose a novel location-based recommendation strategy. [ABSTRACT FROM AUTHOR]

Microplastic (MP) pollution is widespread in various ecosystems and is colonized by microbes that form biofilms with compositions and functions. However, compared with aquatic environments, the soil environment has been poorly studied in terms of the taxonomic composition of microbial communities and the factors influencing the community structure of microbes in the plastisphere. In the present study, a microcosm experiment was conducted to investigate the plastisphere bacterial communities of MP (polyvinyl chloride, PVC) in soils with different pH (4.62, 6.5, and 7.46) and arsenic (As) contents (13 and 74 mg kg−1). Bacterial communities in the plastisphere were dominated by Proteobacteria and Firmicutes, with distinct compositions and structures compared with soil bacterial communities. Soil pH and As content significantly affected the plastisphere bacterial communities. Constrained analysis of principal coordinates and a structural equation model demonstrated that soil pH had a stronger influence on the dissimilarity and diversity of bacterial communities than did soil As content. Soil pH affected As speciation in soil and on MP. The concentration of dimethylarsinic acid (DMA) was significantly higher on MP than that in soil, indicating that As methylation occurred on MP. These results suggest that environmental fluctuations govern plastisphere bacterial communities with cascading effects on biogeochemical cycling of As in the soil ecosystems. [Display omitted] • Plastisphere bacterial communities were significantly different from soil communities. • Soil pH and arsenic content significantly affected plastisphere bacterial communities. • Soil pH had a stronger influence on the dissimilarity and diversity of bacterial community than arsenic content. • Dimethylarsinic acid (DMA) concentration in MPs was significantly higher than that in soil. [ABSTRACT FROM AUTHOR]

Abstract: The sarcoplasmic reticulum Ca2+ ATPase (SERCA) is redox-regulated by posttranslational thiol modifications of cysteine-674 to regulate smooth muscle relaxation and migration. To detect oxidation of cysteine-674 that irreversibly prevents redox regulation, a polyclonal, sequence-specific antibody was developed toward a peptide containing cysteine-674 sulfonic acid. The antibody stained intact 110-kDa SERCA in pig cardiac SR that was oxidized in vitro by peroxynitrite in a sequence-specific manner, and histochemically stained atherosclerotic pig and rabbit aorta. Surprisingly, immunoblots of the pig aorta failed to stain intact 110-kDa SERCA protein, but rather, higher molecular mass aggregates and lower molecular mass bands. Of the latter bands at 70 and 60 kDa, the largest were observed in diabetic, hyperlipidemic pigs, and coincided with the most positive histochemical staining. The 70- and 60-kDa molecular mass bands also coincided with the majority of the protein detected by a monoclonal total anti-SERCA antibody, which detected the intact 110-kDa protein in normal pigs. Mass spectrometry identified SERCA in all the major bands detected by the sulfonic acid antibody as well as the oxidation of cysteine-674 in the 70-kDa band. These studies demonstrate a sequence-specific antibody that detects partial degradation products of SERCA, which represent the majority of the protein in some diabetic hypercholesterolemic pig aortae. In addition, the results suggest an association between irreversible oxidation of SERCA and its degradation, and that an important portion of the oxidized protein in tissue samples may be partially degraded. [Copyright &y& Elsevier]

Abstract: Cysteine thiol modifications are increasingly recognized to occur under both physiological and pathophysiological conditions, making their accurate detection, identification, and quantification of growing importance. Among free cysteines, the bulk of modifications occurs on a subset of cysteines that are more reactive. These exist as thiolate anions at physiological pH because of their surrounding electrostatic environment. Reagents with iodoacetamide-active groups can be used to selectively label these reactive thiols with a high degree of selectivity. Thiol adducts can be detected by the failure to label with iodoacetamide or other reagents; restoration of labeling by specific reducing agents (e.g., ascorbate or glutaredoxin) can be used to detect reversible S-nitroso and S-glutathione adducts. These adducts also may be detected with radiolabels and antibodies. S-Glutathiolation in response to physiological stimuli may be detected in cells and tissues with glutathione ester labeled with biotin. Mass spectrometry can identify thiol modifications with precision, and with isotope-coded affinity tags, used to quantify modification of specific thiols. Combinations of these methods increase sensitivity and specificity, and enable quantification and precise identification of thiol modifications that occur under physiological and pathological conditions. [Copyright &y& Elsevier]

Objective: This study aimed to investigate the role of computed tomography angiography (CTA) and three-dimensional (3D) reconstruction of renal arteries in the evaluation of bleeding after mini- percutaneous nephrolithotomy (PCNL).Methods: Thirty-one consecutive patients with continuous renal hemorrhage after mini-PCNL were enrolled from January 2015 to January 2022. Demographic and clinical data were retrospectively recorded and analyzed. All patients had received CTA evaluation and subsequently digital subtraction angiography (DSA) embolization to manage renal bleeding. CTA and 3D reconstruction of renal arteries were performed using the 320 multi-detector computed tomography technique and the images were evaluated by experienced radiologists. DSA embolization were performed by an interventional radiologist with more than 10 years of experiences.Results: CTA and 3D construction of renal arteries showed 28 cases of vascular lesions (28/31, 90.3%), including 15 cases of pseudoaneurysm (15/28, 53.6%), 9 cases of arteriovenous fistula (9/28, 32.1%), and 4 cases of suspicious bleeding spot (4/28, 14.3%). While DSA revealed 31 cases of vascular lesions (100%), including 15 cases of pseudoaneurysm (15/31, 48.4%), 10 cases of arteriovenous fistula (10/31, 32.3%), 6 cases of bleeding spot and (6/31, 19.4%). The serum creatinine level was elevated slightly before mini-PCNL and after DSA embolization (73.1±18.1 vs 92.1±33.6, P <.01). 15 patients (15/31, 48.4%) required blood transfusion, with mean blood transfusion volume of 700 ml ±660 ml (range, 400 ml-1800 ml). The bleeding was controlled without any further severe complications.Conclusion: CTA and 3D reconstruction of renal arteries were safe and effective in diagnosing renal arterial bleedings after mini-PCNL, with a sensitivity of 90.3% and a specificity of 100%. [ABSTRACT FROM AUTHOR]

• Para- and mid-sagittal gestures in /l/ examined with electromagnetic articulography (3D EMA). • Lateral channel formation involves parasagittal asymmetries in tongue blade movements. • Tongue lateralization is under task-directed control during /l/ production. Research on the temporal dynamics of /l/ production has focused primarily on mid-sagittal tongue movements. This study reports how known variations in the timing of mid-sagittal gestures are related to para-sagittal dynamics in /l/ formation in Australian English (AusE), using three-dimensional electromagnetic articulography (3D EMA). The articulatory analyses show (1) consistent with past work, the temporal lag between tongue tip and tongue body gestures identified in the mid-sagittal plane changes across different syllable positions and vowel contexts; (2) the lateral channel is largely formed by tilting the tongue to the left/right side of the oral cavity as opposed to curving the tongue within the coronal plane; and, (3) the timing of lateral channel formation relative to the tongue body gesture is consistent across syllable positions and vowel contexts, even as the temporal lag between tongue tip and tongue body gestures varies. This last result is particularly informative with respect to theoretical hypotheses regarding gestural control for /l/s, as it suggests that lateral channel formation is actively controlled as opposed to resulting as a passive consequence of tongue stretching. These results are interpreted as evidence that the formation of the lateral channel is a primary articulatory goal of /l/ production in AusE. [ABSTRACT FROM AUTHOR]

We aimed to (1) evaluate the effectiveness of virtual reality (VR) training in improving knowledge among nursing students and (2) identify the essential features of training. This systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Randomised controlled trials (RCTs) were obtained from PubMed, EMBASE, Cochrane Library, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, ProQuest and Scopus databases from inception up until 15 October 2019. Meta-analysis and random-effects meta-regression was performed using the Comprehensive Meta-analysis 3.0 software. The overall effect was measured using Hedges' g and determined using Z -statistics at the significance level of p < 0.05. Heterogeneity was assessed using χ 2 and I 2 statistics. The risk of bias tool and the Grading of the Recommendation, Assessment, Development and Evaluation (GRADE) system were employed to assess individual and overall quality of evidence, respectively. Among the 1993 records identified, 14 trials were included. Meta-analysis demonstrated a significant improvement in knowledge, with a small-to-medium effect (g = 0.47) in the VR group compared to the control group (Z = 2.66, p = 0.01). Subgroup analyses highlighted that VR training was more efficacious in delivering procedural knowledge to undergraduate nursing students when conducted in multiple, self-guided, short sessions within 30 min and by using low–moderate level of immersion. Meta-regression did not detect significant covariates that influenced knowledge scores. Virtual reality may be a viable teaching strategy to improve knowledge acquisition, but it is presently suitable for supplementing conventional teaching methods. Nonetheless, VR could complement current pedagogy to address challenges associated with decreased clinical placement opportunities. Larger, well-designed RCTs are required to strengthen the evidence about the effectiveness of VR training. • Virtual reality training significantly improved knowledge acquisition. • The training effectively delivered procedural content to undergraduate students. • The training regime should use multiple, self-guided and short sessions. • Low–moderate level of immersion is recommended for training. [ABSTRACT FROM AUTHOR]

We propose a remote state preparation scheme working in noisy environment via one intermediate node. Firstly, we report the remote preparation of an arbitrary single-qubit state with one intermediate node in ideal environment. Afterwards, we investigate the influence of four kinds of representative noises that are commonly encountered in practical applications of quantum communication protocols. Detailed analysis indicates that the fidelities of the output state rely on the coefficients of the prepared state and the decoherence rate. The turning point is λ = 0.5 in both the bit-flip and phase-flip noisy channels. The fidelity in the depolarizing channel is related with the decoherence rate, and independent with the phase parameters. • Deterministic joint remote preparation of arbitrary single-qubit state with one intermediate node is proposed. • Four types of noises (bit-flip, phase-flip, amplitude-damping and depolarizing noises) are considered. • The fidelities of the output state rely on the coefficients of the prepared states and the decoherence rates. • The turning point is λ = 0.5 in both the bit-flip and phase-flip noisy channels and F D E is independent of α and θ. [ABSTRACT FROM AUTHOR]

A novel silicon(IV) phthalocyanine (SiPc) axially di-substituted with Arg-Arg-Arg oligopeptides (compound 4) has been synthesized and characterized. Meanwhile, two analogues have been used as controls. The effect of arginine number on the spectral properties, photosensitizing activities, partition coefficient, cellular uptake, and photodynamic antimicrobial activities have been investigated. The novel SiPc 4 containing tri-arginine oligopeptides exhibits an extremely high in vitro photodynamic activity not only against Gram-positive/negative bacteria but also against fungus, which is obviously superior to its analogues containing mono-arginine (compound 2) and di-arginine oligopeptides (compound 3). In addition, 4 shows a higher photodynamic inactivation against S.aureus , E.coli and C. albicans cells than methylene blue (MB), a known antimicrobial photosensitizer. The IC 90 values against C. albicans for 4 is ca. 179-fold lower than that for MB. Moreover, the potent photodynamic effect of 4 has been further confirmed by in vivo animal model. These results indicate that the tri-arginine-modified SiPc is a highly promising photosensitizer for photodynamic antimicrobial therapy. Image 1 • A novel SiPc (4) di-substituted with tri-arginine oligopeptides has been prepared. • The effect of arginine number between 4 and its analogues have been investigated. • 4 exhibited a high in vitro photodynamic activity toward both bacteria and fungus cells. • 4 showed a highly efficient antimicrobial PDT effect on the in vivo animal model. • 4 is a highly promising photosensitizer for photodynamic antimicrobial therapy. [ABSTRACT FROM AUTHOR]

As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, t he coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM. [ABSTRACT FROM AUTHOR]

Polysaccharide from Ganoderma lucidum is one of the best metal-ion chelating agents because of its structural characteristics and excellent functional activities. In this study, we synthesized and characterized a novel G. lucidum polysaccharide‑chromium (III) [GLP-Cr(III)] complex. Response surface methodology (RSM) was used to optimize the reaction conditions for the maximum chelation rate of GLP-Cr(III) complex. The optimal reaction conditions obtained from RSM were as follows: concentration of CrCl 3 5.71 mg/mL, pH 6.36, temperature 66.4 °C and time 2.0 h, respectively. The pH was the most significant factor, followed by reaction temperature and CrCl 3 concentration. Under the optimal conditions, the experimental chelation rate was 94.17 ± 1.0% for GLP-Cr(III) complex, which agreed closely with the predicted value (94.60%). Fourier transform infrared (FT-IR) spectroscopy revealed that the primary sites of chromium (III)-binding in G. lucidum polysaccharide were O H and C O groups, which induce the morphology change from flat sheet to rough surface. Meanwhile, according to the result of X-ray diffraction (XRD), the crystal degree of GLP was disappeared after chelation with Cr(III). The presence of a "blind zone" in the 1H NMR spectrum obviously indicated the binding of Cr(III) to GLP. Additionally, the effects of GLP-Cr(III) complex on hyperglycemia and hyperlipidemia in high fructose and fat diet-induced pre-diabetic mice were also investigated. Results showed that the serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting blood glucose levels and glucose tolerance in mice supplemented with GLP-Cr(III) complex (50 mg/kg day) were significantly lower than the model group (P < 0.01). More importantly, the GLP-Cr(III) complex had no significant adverse effects on the physiological metabolism, organ index, and liver tissue morphology of mice fed a normal diet. These results suggest that GLP-Cr(III) complex could be used as potential functional food ingredients for the prevention or treatment of hyperglycemia and hyperlipidemia. Unlabelled Image • A novel Ganoderma lucidum polysaccharide-chromium (III)complex was synthesized and characterized. • Optimal synthesis condition of GLP-Cr(III) complex was obtained through response surface methodology. • GLP-Cr(III) complex showed significant hypoglycemic and hypolipidemic effects on pre-diabetic mice. • Cr(III) modification significantly enhanced the hypoglycemic and hypolipidemic activities of GLP. [ABSTRACT FROM AUTHOR]

The residual content of sulfur dioxide is frequently regarded as the exclusive indicator in the safety evaluation of sulfur-fumigated edible herbs. To examine the feasibility of such assessment criteria, here the variations in residual sulfur dioxide content during sulfur-fumigation and the potential mechanisms involved were investigated, using Angelicae Sinensis Radix (ASR) as a model herb. The residual sulfur dioxide content and ten major bioactive components in sulfur-fumigated ASR samples were dynamically examined at 13 successive time points within 72 h sulfur-fumigation. The relationship between the content variation tendency of sulfur dioxide and the ten chemicals was discussed. The results suggested that sulfur dioxide-involved chemical transformation of the original components in ASR might cause large consumption of residual sulfur dioxide during sulfur-fumigation. It implies that without considering the induced chemical transformation of bioactive components, the residual sulfur dioxide content alone might be inadequate to comprehensively evaluate the safety of sulfur-fumigated herbs. [ABSTRACT FROM AUTHOR]

Objective Most publications describe cathepsin B and L as tumor and metastasis factors. These proteases also play a very important role in aging process. The aim of this study was to evaluate the serum level of cathepsin B and L with aging and their association with matrix metalloproteinase 2 (MMP2), which was reported to associate with age-related diseases. Methods This research was conducted using blood samples provided by healthy people ( n = 90, 63 men and 27 women). Subjects were subdivided into groups with respect to age: young (about 18–30 years old, n = 30), middle age (about 36–50 years old, n = 30), and aged (above 56 years old, n = 30). Altered serum level of cathepsin B, cathepsin L, and MMP2 with aging was studied by enzyme-linked immunosorbent assay (ELISA) and Western blotting using discriminative antibodies specific for each factor. Results ELISA and Western blotting revealed that the serum level of cathepsin L and MMP2, but not cathepsin B significantly decreased in aged group compared with young group. Cathepsin L positively correlates with MMP2 among the whole healthy people ( r 2 = 0.869, p < 0.0001). Conclusion The serum level of cathepsin L decreased with age, while cathepsin B remained no significant difference between young and aged individuals. In addition, cathepsin L positively correlates with MMP2. Practice The cathepsin L may be used as a monitoring index in age-related diseases. Implications In addition to cathepsin B, cathepsin L may be also involved in the aging process. [ABSTRACT FROM AUTHOR]

Abstract: Automatic Chinese text classification is an important and a well-known technology in the field of machine learning. The first step for solving Chinese text categorization problems is to tokenize the Chinese words from a sequence of non-segmented sentences. However, previous literatures often employ a Chinese word tokenizer that was trained with different sources and then perform the conventional text classification approaches. However, these taggers are not perfect and often provide incorrect word boundary information. In this paper, we propose an N-gram-based language model which takes word relations into account for Chinese text categorization without Chinese word tokenizer. To prevent from out-of-vocabulary, we also propose a novel smoothing approach based on logistic regression to improve accuracy. The experimental result shows that our approach outperforms traditional methods at least 11% on micro-average F-measure. [Copyright &y& Elsevier]

Abstract: Purpose: This study compares the radiation dose-volume of the cervical esophagus during head and neck radiotherapy using three different techniques. Methods: Treatment plans of 58 patients from 3/04 to 1/06 treated with bilateral head and neck radiotherapy were analyzed retrospectively. A comparison of the cervical esophagus dose with three-field 3D conformal RT (3DRT, n =34), whole-field IMRT (WF-IMRT, n =12), and half-beam IMRT (HB-IMRT, n =12) was performed. The volumes of esophagus receiving ⩾50Gy (V50), ⩾54Gy (V54) and ⩾60Gy (V60) and lengths receiving circumferential dose ⩾50Gy (L50) and ⩾54Gy (L54) were evaluated. Results: Maximum dose, V54 and L54 were greater for the first 2cm and entire cervical esophagus with WF-IMRT than HB-IMRT or 3DRT. In patients requiring a high match, WF-IMRT was associated with a greater maximum dose, V54 and L54 than HB-IMRT and 3DRT (p <0.05). In the low match group, WF-IMRT was associated with a greater V54 and L54 (p <0.05). Low neck disease, low primary site, and definitive radiotherapy were associated with increased irradiation of the esophagus. Conclusion: Treatment of the lower neck with IMRT is associated with increased irradiation to the cervical esophagus, and dose constraints should be included to reduce toxicity. [Copyright &y& Elsevier]

This paper establishes a two-dimensional mathematical model of a continuous floating bridge with heave plates under linear monochromatic waves. Based on linear potential flow theory, the fluid domain is divided into two regions. The analytical equations for the rigid floating bridge considering the heave plate effect are derived from the boundary conditions. The wave force, added mass and damping coefficient, and response amplitude operator (RAO) are calculated via the matched eigenfunction expansion method (MEEM). The influence of the number and size of heave plates on bridge hydrodynamic performance is analyzed, and the New Lacey V. Murrow Memorial Bridge is taken as an example for optimization. The results show that heave plates have a significant impact on the hydrodynamic performance of the floating structure. An increase in the number and length of heave plates makes the roll and roll resonance frequency approach the high-frequency area, while the heave is opposite. Compared with increasing the number of heave plates, the heave response can be maintained at a relatively low level over a wider wavelength range by increasing heave plate length. Heave plate length is a more sensitive parameter during optimization. [ABSTRACT FROM AUTHOR]

• It was the first study to evaluate twice-weekly docetaxel and nedaplatin as radiosensitizers in inoperable ESCC. • The MTD was 5 mg/m2, and the DLTs were esophagitis and increased liver enzymes. • The regimen showed promising radiosentizing effect on in-filed disease control and good tolerability. This phase I trial aimed to determine the maximal tolerated dose (MTD) of incorporating a twice-weekly docetaxel and nedaplatin regimen into definitive concurrent chemoradiotherapy (CCRT) as radiosensitizers in patients with inoperable esophageal squamous cell carcinoma (ESCC). The CCRT regimen included docetaxel (5 mg/m2, 10 mg/m2, or 15 mg/m2) and nedaplatin (5 mg/m2, 10 mg/m2, or 15 mg/m2) twice-weekly based on the traditional 3 + 3 dose escalation strategy, and radiotherapy (64 Gy in 32 fractions). The primary goals were to determine the MTD of concurrent chemotherapy and the dose limiting toxicities (DLTs). In-field objective response rate (ORR) was investigated. Fifteen patients had been recruited and analyzed. DLT involving persistent grade 3 esophagitis over 1 week was observed in all three patients (3/3) at dose level 3 (15 mg/m2), and two patients (2/6) experienced DLTs in the dose level 2 (10 mg/m2) due to esophageal fistula and persistent grade 3 esophagitis over 1 week, while one patient (1/6) treated at dose level 1 (5 mg/m2) exhibited DLT owing to Grade 3 increased liver enzymes, suggesting a MTD of 5 mg/m2. The in-filed ORR was both 100% in all patients and those receiving MTD. The 1-year loco-regional recurrence-free survival rate was 83.3%, 83.3% and 66.7% in dose level 1, 2, and 3, respectively. The MTD of twice-weekly docetaxel and nedaplatin regimen was 5 mg/m2 in inoperable ESCC patients treated with definitive CCRT. Low dose concurrent docetaxel and nedaplatin showed promising radiosensitizing effect on in-filed disease control and good tolerability. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far from completely understood. Here, whole-exome sequencing and bioinformatics analyses of a three-generation family with AF were performed, and after filtering variants by multiple metrics, we identified a heterozygous variant in the ISL1 gene (encoding a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling), NM_002202.2: c.481G > T; p.(Glu161*), which was validated by Sanger sequencing and segregated with autosome-dominant AF in the family with complete penetrance. The nonsense variant was absent from 284 unrelated healthy individuals used as controls. Functional assays with a dual-luciferase reporter assay system revealed that the truncating ISL1 protein lost transcriptional activation on the verified target genes MEF2C and NKX2-5. Additionally, the variant nullified the synergistic transactivation between ISL1 and TBX5 as well as GATA4, two other transcription factors that have been implicated in AF. The findings suggest ISL1 as a novel gene contributing to AF, which adds new insight to the genetic mechanisms underpinning AF, implying potential implications for genetic testing and risk stratification of the AF family members. [ABSTRACT FROM AUTHOR]

Congenital heart defect (CHD) is the most common type of birth defect in humans and a leading cause of infant morbidity and mortality. Previous studies have demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, the genetic basis of CHD remains poorly understood due to substantial genetic heterogeneity. In this study, the coding exons and splicing boundaries of the NR2F2 gene, which encodes a pleiotropic transcription factor required for normal cardiovascular development, were sequenced in 168 unrelated patients with CHD, and a novel mutation (c.247G > T, equivalent to p.G83X) was detected in a patient with double outlet right ventricle as well as ventricular septal defect. Genetic scanning of the mutation carrier's relatives available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the index patient's pedigree displayed that the mutation co-segregated with CHD, which was transmitted as an autosomal dominant trait with complete penetrance. The nonsense mutation was absent in 230 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system revealed that the mutant NR2F2 protein had no transcriptional activity as compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD. This study firstly associates NR2F2 loss-of-function mutation with an increased susceptibility to double outlet right ventricle in humans, which provides further significant insight into the molecular mechanisms underpinning CHD, suggesting potential implications for genetic counseling of CHD families and personalized treatment of CHD patients. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death. Aggregating evidence highlights the underlying genetic basis of DCM, and mutations in over 100 genes have been causally linked to DCM. Nevertheless, due to pronounced genetic heterogeneity, the genetic defects underpinning DCM in most cases remain obscure. Hence, this study was sought to identify novel genetic determinants of DCM. In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM, and a novel heterozygous mutation in the VEZF1 gene (coding for a zinc finger-containing transcription factor critical for cardiovascular development and structural remodeling), NM_007146.3: c.490A > T; p.(Lys164*), was identified. The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance. The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database. Biological analyses by utilizing a dual-luciferase reporter assay system revealed that the mutant VEZF1 protein failed to transactivate the promoters of MYH7 and ET1 , two genes that have been associated with DCM. The findings indicate VEZF1 as a new gene responsible for DCM, which provides novel insight into the molecular pathogenesis of DCM, implying potential implications for personalized precisive medical management of the patients affected with DCM. [ABSTRACT FROM AUTHOR]

Antibacterial peptide CM4 (ABP-CM4) is a natural product isolated from the silkworm Bombyx mori . It is a small cationic peptide with broad-spectrum activities against harmful microorganisms and may be used as a novel food preservative. However, ABP-CM4 lacks tertiary structure in water-like solutions, which makes it more susceptible to proteases and labile when exposed to air. In this study, β-cyclodextrin (β-CD) was chosen to form an inclusion complex with ABP-CM4, which enhanced the physical and chemical properties of ABP-CM4 but did not decrease its antibacterial activity. The storage stability and susceptibility to proteinases of ABP-CM4 were apparently improved under the protection of β-CD. This technology could also be widely applied to other AMPs as an antimicrobial system to be used in the food industry. [ABSTRACT FROM AUTHOR]

As the most common form of birth defect in humans, congenital heart disease (CHD) is associated with substantial morbidity and mortality in both children and adults. Increasing evidence demonstrates that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is of great heterogeneity, and in an overwhelming majority of cases, the genetic determinants underpinning CHD remain elusive. In the present investigation, the coding exons and flanking introns of the CASZ1 gene, which codes for a zinc finger transcription factor essential for the cardiovascular morphogenesis, were sequenced in 172 unrelated patients with CHD. As a result, a novel heterozygous CASZ1 mutation, p.L38P, was identified in an index patient with congenital ventricular septal defect (VSD). Genetic scanning of the mutation carrier's available family members revealed that the mutation was present in all affected patients but absent in unaffected individuals. Analysis of the proband's pedigree showed that the mutation co-segregated with VSD, which was transmitted as an autosomal dominant trait with complete penetrance. The missense mutation, which altered the amino acid that was highly conserved evolutionarily, was absent in 200 unrelated, ethnically-matched healthy subjects used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant CASZ1 had significantly reduced transcriptional activity as compared with its wild-type counterpart. To the best of our knowledge, the current study firstly identifies CASZ1 as a new gene predisposing to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD and a potential therapeutic target for CASZ1-associated CHD, suggesting potential implications for personalized prophylaxis and therapy of CHD. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2 . The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the mutation co-segregated with TOF. The mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 loss-of-function mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV) is the most common form of congenital cardiovascular defect in humans and is associated with substantial morbidity and mortality. Emerging evidence demonstrates that genetic risk factors play an important role in the pathogenesis of BAV. However, BAV is a genetically heterogenous disorder, and the genetic defects underpinning BAV in most patients remain to be identified. In the present study, the coding exons and flanking introns of the NKX2.5 gene, which encodes a homeodomain-containing transcrip-tion factor essential for the normal development of the aortic valve, were sequenced in 142 unrelated patients with BAV. The available relatives of the mutation carrier and 200 unre-lated healthy subjects used as controls were also genotyped for NKX2.5. The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2.5 mutation, p.K192X, was identified in a family with BAV transmitted in an autosomal dominant pattern. The nonsense mutation was absent in 400 control chromosomes. Functional analyses revealed that the mutant NKX2.5 had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation abolished the synergistic transcriptional activation between NKX2.5 and GATA5, another transcription factor crucial for the aortic valvular morphogenesis. In conclusion, this study is the first to link an NKX2.5 loss-of-function mutation to enhanced susceptibility to human BAV, providing novel insight into the molecular mechanism of BAV and suggesting potential implications for genetic counseling and clinical care of families presenting with BAV. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most common form of birth defect and is the most prevalent non-infectious cause of infant death. A growing body of evidence documents that genetic defects are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remain unclear. In this study, the coding exons and flanking introns of the Nkx2.6 gene, which codes for a homeodomain-containing transcription factor important for normal cardiovascular development, were sequenced in 320 unrelated patients with CHD, and two novel heterozygous Nkx2.6 mutations, p.V176M and p.K177X, were identified in two unrelated patients with CHD, respectively, including a patient with tetralogy of Fallot and a patient with double outlet of right ventricle and ventricular septal defect. The mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Due to unknown transcriptional targets of Nkx2.6, the functional consequences of the identified mutations at transcriptional activity were evaluated by using Nkx2.5 as a surrogate. Alignment between human Nkx2.6 and Nkx2.5 proteins showed that V176M-mutant Nkx2.6 was equivalent to V182M-mutant Nkx2.5 and K177X-mutant Nkx2.6 was equal to K183X-mutant Nkx2.5, and introduction of V182M or K183X into Nkx2.5 significantly diminished its transcriptional activating function when compared with its wild-type counterpart. To our knowledge, this is the first report on the association of Nkx2.6 loss-of-function mutation with increased susceptibility to tetralogy of Fallot or double outlet of right ventricle and ventricular septal defect, providing novel insight into the molecular mechanism of CHD. [ABSTRACT FROM AUTHOR]

Semen Ziziphi Spinosae (SZS) has been used as a hypnotic-sedative medicine for thousands of years. Recently, SZS has also shown notable neuroprotective activities via anti-oxidative and anti-inflammatory effects in dementia animals. Jujuboside A (JuA), isolated from SZS, has been proved to be a major hypnotic-sedative component of SZS. In the present study, we firstly evaluated the effects of intracerebroventricular (ICV) injection of JuA (0.02 and 0.2 mg/kg) for five consecutive days on cognitive impairment induced by ICV injection of Aβ1-42. The results showed that ICV treatment with JuA significantly mitigated learning and memory impairment in mice induced by Aβ1-42 as measured by the Y-maze, active avoidance and Morris water maze. Furthermore, ICV treatment with JuA reduced the level of Aβ1-42 in hippocampus, significantly inhibited the activities of acetylcholinesterase (AChE) and NO, and decreased the amount of the increased malondialdehyde (MDA) in the hippocampus and cerebral cortex of mice treated with ICV injection of Aβ1-42. Shrinkage of nuclei, swollen and eccentrically dispersed neuronal bodies were observed in hippocampus of AD mice induced by Aβ1-42, however, JuA noticeably improved the histopathological damage. Cumulatively, the present study indicates that JuA may serve as a potential therapeutic agent for the treatment of Alzheimer׳s disease. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Nephrotic syndrome (NS) is a clinical syndrome with a variety of causes, mainly characterized by heavy proteinuria. Podocyte injury plays a key role in proteinuria, one of the principal means for the control of NS is to prevent podocyte injury. Qi-Dan Fang consists of two of the most extensively applied herbal remedies among Traditional Chinese Medicine (TCM) (Radix Astragali Mongolici and Radix Salviae Miltiorrhizae, with a weight ratio of 5:1) which are specifically used for the treatment of various kidney diseases. In previous studies, we found that Qi-Dan Fang provides improvement to patients with adriamycin-induced nephrotic syndrome by alleviating proteinuria and serum lipid. The aim of this study is to study the efficiency of Qi-Dan Fang on NS model rat with renal dysfunction and podocyte injury, something which has not been carried out yet. Materials and methods: The rats were divided into Normal, Model, Jin Gui Shen Qi Pill (4.12g/kg), Qi-Dan Fang (3.09, 6.17 and 12.34g/kg/d) groups, they were each given a single tail intravenous injection of Adriamycin (6.0mg/kg) except for the Normal group and were orally administered dosages of Qi-Dian Fang and Jin Gui Shen Qi pills once daily for 7 weeks. Following the treatment, the content of cystation C (CysC), blood urea nitrogen (BUN), serum creatinine (Scr) were measured with an autobiochemical analyser. The pathomorphological changes to the glomeruli, the mRNA expressions of nephrin, podocin, CD2AP genes and p53, bax, bcl-2 proteins expressions were also carried out to probe the effects of Qi-Dan Fang. Results: (1) Qi-Dan Fang treatment raised the level of CysC in blood serum while lowering the content of BUN and Scr in the adriamycin-induced nephrotic syndrome rat model; (2) Long-term administration of Qi-Dan Fang was able to ameliorate pathomorphological change of glomeruli and repair the organization structure of Glomerulus; (3) Qi-Dan Fang could increase the mRNA expression of nephrin, podocin and CD2AP genes, down-regulate the expression of p53, bax proteins, while increased bcl-2 protein to protect the podocyte and restore Glomerular selective filtration function. Conclusions: Results of our present studies reveal that Qi-Dan Fang is able to enhance renal function, inhibit podocyte injury to provide improvements to the Adriamycin-induced nephrotic syndrome. [Copyright &y& Elsevier]

Abstract: Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia and is associated with substantial morbidity and mortality. Increasing evidence demonstrates that hereditary defects are involved in the pathogenesis of AF. However, AF is of remarkable genetic heterogeneity, and the heritable components responsible for AF in the majority of patients remain unclear. In this study, the entire coding region of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, was sequenced in 138 unrelated patients with lone AF, and a novel heterozygous GATA6 mutation, c.704A > C equivalent to p.Y235S, was identified in a patient. The detected substitution, which altered the amino acid highly conserved evolutionarily across species, was absent in 200 unrelated ethnically matched healthy individuals, and was predicted to be disease-causing by MutationTaster. Genetic analysis of the available relatives of the mutation carrier showed that in the family the variation co-segregated with the disease transmitted as an autosomal dominant trait, with complete penetrance. The functional analysis performed using a luciferase reporter assay system revealed that the mutant GATA6 protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. These findings provide novel insight into the molecular pathophysiology implicated in AF, suggesting the potential implications in the prophylactic strategy and effective therapy for this common arrhythmia. [Copyright &y& Elsevier]

Abstract: Nuclear factor-κB (NF-κB) and Akt are two major cell survival pathways that are often constitutively activated and can be further stimulated by chemotherpeutics in cancer cells. Although individually targeting the NF-κB or Akt has been reported to sensitize caner therapy, the effectiveness of concurrent blocking these two pathways for chemosensitizing of cancer cells to genotoxic therapeutics has not been investigated. In the present study, we investigate the activation of the NF-κB and Akt pathways by two frontline anticancer drugs cisplatin and etopside in a variety of cancer cell lines. The effects of blocking these two survival pathways individually or concurrently on cisplatin- or etopside-induced cytotoxicity were detected. The results show that cisplatin and etopside activate both NF-κB and Akt in cancer cells. Blockade of either of these pathways with chemical inhibitors or siRNA moderately sensitized cancer cells to cisplatin- or etopside-induced cytotoxicity. Strikingly, much more effective potentiation of cytotoxicity to these anticancer drugs was achieved when NF-κB and Akt were concurrently blocked. These data suggest that NF-κB and Akt cooperatively attenuate therapeutic-induced cytotoxicity and concurrently blocking these pathways is an effective strategy for improving the anticancer efficacy of therapeutics. [Copyright &y& Elsevier]