Search

Background and aimsCurrent treatment guidelines recommend ursodeoxycholic acid (UDCA) as the first-line treatment for new-diagnosed primary biliary cholangitis (PBC) patients. However, up to 40% patients are insensitive to UDCA monotherapy, and evaluation of UDCA response at 12 months may result in long period of ineffective treatment. We aimed to develop a new criterion to reliably identify non-response patients much earlier.MethodsFive hundred sixty-nine patients with an average of 59 months (Median: 53; IQR:32-79) follow-up periods were randomly divided into either the training (70%) or the validation cohort (30%). The efficiency of different combinations of total bilirubin (TBIL), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) threshold values to predict outcomes was assessed at 1, 3 or 6 month after the initiation of UDCA therapy. The endpoints were defined as adverse outcomes, including liver-related death, liver transplantation and complications of cirrhosis. Adverse outcome-free survival was compared using various published criteria and a proposed new criterion.ResultsA new criterion of evaluating UDCA responses at 1 month was established as: ALP ≤ 2.5 × upper limit of normal (ULN) and AST ≤ 2 × ULN, and TBIL ≤ 1 × ULN (Xi'an criterion). The 5 year adverse outcome-free survival rate of UDCA responders, defined by Xi'an criterion, was 97%, which was significantly higher than that of those non-responders (64%). An accurate distinguishing high-risk patients' capacity of Xi'an criterion was confirmed in both early and late-stage PBC.ConclusionsXi'an criterion has a similar or even higher ability to distinguish high-risk PBC patients than other published criteria. Xi'an criterion can facilitate early identification of patients requiring new therapeutic approaches.

Clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology is a powerful tool to manipulate the genome with extraordinary simplicity and speed. To generate genetically modified animals, CRISPR/Cas9-mediated genome editing is typically accomplished by microinjection of a mixture of Cas9 DNA/mRNA and single-guide RNA (sgRNA) into zygotes. However, sgRNAs used for this approach require manipulation via molecular cloning as well as in vitro transcription. Beyond these complexities, most mutants obtained with this traditional approach are genetically mosaic, yielding several types of cells with different genetic mutations. Recently, a growing body of studies has utilized commercially available Cas9 protein together with sgRNA and a targeting construct to introduce desired mutations. Here, we report a cloning-free method to target the mouse genome by pronuclear injection of a commercial Cas9 protein:crRNA:tracrRNA:single-strand oligodeoxynucleotide (ssODN) complex into mouse zygotes. As illustration of this method, we report the successful generation of global gene-knockout, single-amino-acid-substituted, as well as floxed mice that can be used for conditional gene-targeting. These models were produced with high efficiency to generate non-mosaic mutant mice with a high germline transmission rate.

The optimization of job shop scheduling is pivotal for improving overall production efficiency within a workshop. In demand-driven personalized production modes, achieving a balance between workshop resources and the diverse demands of customers presents a challenge in scheduling. Additionally, considering the self-interested behaviors of agents, this study focuses on tackling the problem of multi-agent job shop scheduling with private information. Multiple consumer agents and one job shop agent are considered, all of which are self-interested and have private information. To address this problem, a two-stage decentralized algorithm rooted in the genetic algorithm is developed to achieve a consensus schedule. The algorithm allows agents to evolve independently and concurrently, aiming to satisfy individual requirements. To prevent becoming trapped in a local optimum, the search space is broadened through crossover between agents and agent-based block insertion. Non-dominated sorting and grey relational analysis are applied to generate the final solution with high social welfare. The proposed algorithm is compared using a centralized approach and two state-of-the-art decentralized approaches in computational experiments involving 734 problem instances. The results validate that the proposed algorithm generates non-dominated solutions with strong convergence and uniformity. Moreover, the final solution produced by the developed algorithm outperforms those of the decentralized approaches. These advantages are more pronounced in larger-scale problem instances with more agents. [ABSTRACT FROM AUTHOR]

BackgroundThe striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.Methods and resultsThe current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart.ConclusionsKindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.

BackgroundThe striated muscle Z-line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Cypher and its close homologue, Enigma homolog protein (ENH), are 2 Z-line proteins previously shown to be individually essential for maintenance of postnatal cardiac function and stability of the Z-line during muscle contraction, but dispensable for cardiac myofibrillogenesis and development.Methods and resultsThe current studies were designed to test whether Cypher and ENH play redundant roles during embryonic development. Here, we demonstrated that mice lacking both ENH and Cypher exhibited embryonic lethality and growth retardation. Lethality in double knockout embryos was associated with cardiac dilation and abnormal Z-line structure. In addition, when ENH was ablated in conjunction with selective ablation of either Cypher short isoforms (CypherS), or Cypher long isoforms (CypherL), only the latter resulted in embryonic lethality.ConclusionsCypher and ENH redundantly play an essential role in sustaining Z-line structure from the earliest stages of cardiac function, and are redundantly required to maintain normal embryonic heart function and embryonic viability.

Arrhythmogenic cardiomyopathy (AC) is associated with mutations in genes encoding intercalated disc proteins and ultimately results in sudden cardiac death. A subset of patients with AC have the autosomal recessive cardiocutaneous disorder Naxos disease, which is caused by a 2-base pair deletion in the plakoglobin-encoding gene JUP that results in a truncated protein with reduced expression. In mice, cardiomyocyte-specific plakoglobin deficiency recapitulates many aspects of human AC, and overexpression of the truncated Naxos-associated plakoglobin also results in an AC-like phenotype; therefore, it is unclear whether Naxos disease results from loss or gain of function consequent to the plakoglobin mutation. Here, we generated 2 knockin mouse models in which endogenous Jup was engineered to express the Naxos-associated form of plakoglobin. In one model, Naxos plakoglobin bypassed the nonsense-mediated mRNA decay pathway, resulting in normal levels of the truncated plakoglobin. Moreover, restoration of Naxos plakoglobin to WT levels resulted in normal heart function. Together, these data indicate that a gain of function in the truncated form of the protein does not underlie the clinical phenotype of patients with Naxos disease and instead suggest that insufficiency of the truncated Naxos plakoglobin accounts for disease manifestation. Moreover, these results suggest that increasing levels of truncated or WT plakoglobin has potential as a therapeutic approach to Naxos disease.

The purpose of this study was to compare the efficacy of nucleoside analogues (NAs) in the treatment of HBV-related liver failure. The data of patients with HBV-related liver failure treated with nucleoside analogues were used to conduct a network meta-analysis. A total of 1660 patients from 12 articles about the efficacy of lamivudine, entecavir, telbivudine and tenofovir for HBV-related liver failure treatment were recruited in the study. The highest two- and three-month survival rate was recorded for patients using tenofovir. The end-stage liver disease (MELD) score and mortality in patients undergoing tenofovir treatment were the lowest. Patients treated with telbivudine had the highest one-month survival rate. Patients receiving enticavir therapy showed the lowest HBV DNA level. Our results indicate that tenofovir may be the best therapy for the treatment of HBV-related liver failure compared to other nucleoside analogues (including lamivudine, entecavir and telbivudine) and non-NAs treatment.

In this paper, a novel tracking algorithm based on the cooperative operation of online appearance model and typical tracking in contiguous frames is proposed. First of all, to achieve satisfactory performances in challenging scenes, we focus on establishing a robust discriminative tracking model with linear Support Vector Machine (SVM) and use the particle filter for localization. Intended to fit the particle filter, the outputs of SVM classifier are mapped into probabilities with a sigmoid function so that the posterior of candidate samples is estimated. Then, the tracking loop starts with median flow method and the coordinated operation of the two trackers is mediated by the maximum a posteriori (MAP) estimate for the target probability of negative samples, which is defined during the sigmoid fit. Lastly, for the purpose of model update, we sum up the optimal SVM using a prototype set with the predefined budget, and the classifier is updated on both the prototype set and the updated data from the tracking results every few frames. A number of comparative experiments are conducted on real video sequences and both qualitative and quantitative evaluations demonstrate a robust and precise performance of our method.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.compeleceng.2008.09.006 Byline: Ying Zheng (a), Guangyao Li (a), Xiehua Sun (b), Xinmin Zhou (a) Keywords: Active contour; Squared local contrast; Color image segmentation; The GACV model Abstract: In this paper, a novel geometric active contour model for color image is presented. It combines squared local contrast based alignment term about directional information of edge location as part of driving force, together with the improved geodesic active contour model containing Bays error based two-region segmentation information. And all these measures are integrated as a unified framework. Finally, an unconditionally stable and simple numerical scheme, including the narrow band and fast marching methods, is introduced for efficiently implementing this novel model. Experimental results on color image segmentation show that it can extract the contour of color images precisely and its performance is shown much better than the geodesic-aided C-V (GACV) method when directional information about edge location is supplied. Author Affiliation: (a) College of Electronics and Information Engineering, Tongji University, Shanghai 201804, China (b) College of Information Engineering, China Liliang University, Hangzhou 310018, China Article History: Received 18 April 2008; Accepted 18 September 2008