Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing. During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine. Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis. Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferator-activated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism. In addition, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis. The treatment includes lifestyle modification, pharmacological therapy, and non-pharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have also been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis

An Outbreak of Coxsackievirus A16 Infection: Comparison With Other Enteroviruses in a Preschool in Taipei

Background/PurposeThe transmission rate of enteroviruses in young children remains unclear. Therefore, we carried out active surveillance in preschool children to investigate the transmission rate and clinical manifestation of enteroviruses.MethodsFrom September 2006 to December 2008, we monitored infectious diseases in children 2(–3 years of age) in a preschool in Taipei. If any child had a febrile illness or symptoms/signs of enteroviral infection [e.g. herpangina or hand-foot-and-mouth disease (HFMD)], we performed viral isolation and enterovirus polymerase chain reaction. VP1 sequencing was performed to define their serotypes. We also collected clinical data and analyzed transmission rates.ResultsThere were eight episodes of enterovirus infection during the study period. The serotypes included coxsackievirus A4 (CA4), CA2 and CA16. The transmission rates of CA4 and CA2 among children in same class were 26% and 35%, respectively. Between November 28 and December 12, 2008, 13/21 (61.9%) children contracted herpangina and/or HFMD. The average age was 2.82 (range, 2.43–3.39) years. CA16 was detected in 10/13 (76.9%) of the throat swabs by polymerase chain reaction VP1 genotyping. Compared with previous CA2 and CA4 outbreaks, CA16 had a significantly higher transmission rate (p = 0.035) and resulted in more cases of HFMD (p < 0.001). The transmission duration of coxsackie A viruses within the same class ranged from 12 to 40 days.ConclusionCompared with CA2 and CA4, CA16 infections resulted in more cases of HFMD and had significantly higher transmission rates in preschoolers

Location-based Data Analysis of Visitor Structure for Recreational Area Management

This work presents a location-based data analysis framework for profiling visitors structures. In terms of recreational area management, understanding visitors’ structure and popularity is important. Traditionally, visitors monitoring with automatic counting devices has drawbacks of inaccurate visitors counting. In this work, compared to automatic counting devices, we use Wi-Fi tracking as the main method to count visitors, which provides a fairly precise picture of visitor structures. Moreover, we deliver rich analytic functions in this framework and we present the functionality with visitor data collected from Guanyinshan Visitor Center. This framework not only standardizes visitor counting process but also facilitates a profound analysis of visitor structures. Key Words: Guanyinshan Visitor Center, Wi-Fi trackin

Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan.

Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offsprings psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy &gt;98%) in Taiwans single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997-2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offsprings MDD, ED, SUD, and anxiety. A very young maternal age (&lt;20 years) was associated with markedly higher risk in offsprings SUD, MR, and suicide. Older paternal age (&gt;25 years) was linearly associated with offsprings schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offsprings schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offsprings ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offsprings OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity

Ser-634 and Ser-636 of Kaposi’s Sarcoma-Associated Herpesvirus RTA are Involved in Transactivation and are Potential Cdk9 Phosphorylation Sites

The replication and transcription activator (RTA) of Kaposi’s sarcoma-associated herpesvirus (KSHV), K-RTA, is a lytic switch protein that moderates the reactivation process of KSHV latency. By mass spectrometric analysis of affinity purified K-RTA, we showed that Thr-513 or Thr-514 was the primary in vivo phosphorylation site. Thr-513 and Thr-514 are proximal to the nuclear localization signal (527KKRK530) and were previously hypothesized to be target sites of Ser/Thr kinase hKFC. However, substitutions of Thr with Ala at 513 and 514 had no effect on K-RTA subcellular localization or transactivation activity. By contrast, replacement of Ser with Ala at Ser-634 and Ser-636 located in a Ser/Pro-rich region of K-RTA, designated as S634A/S636A, produced a polypeptide with ∼10 kDa shorter in molecular weight and reduced transactivation in a luciferase reporter assay relative to the wild type. In contrast to prediction, the decrease in molecular weight was not due to lack of phosphorylation because the overall Ser and Thr phosphorylation state in K-RTA and S634A/S636A were similar, excluding that Ser-634 or Ser-636 motif served as docking sites for consecutive phosphorylation. Interestingly, S634A/S636A lost ∼30% immuno-reactivity to MPM2, an antibody specific to pSer/pThr-Pro motif, indicating that 634SPSP637 motif was in vivo phosphorylated. By in vitro kinase assay, we showed that K-RTA is a substrate of CDK9, a Pro-directed Ser/Thr kinase central to transcriptional regulation. Importantly, the capability of K-RTA in associating with endogenous CDK9 was reduced in S634A/S636A, which suggested that Ser-634 and Ser-636 may be involved in CDK9 recruitment. In agreement, S634A/S636A mutant exhibited ∼25% reduction in KSHV lytic cycle reactivation relative to that by the wild type K-RTA. Taken together, our data propose that Ser-634 and Ser-636 of K-RTA are phosphorylated by host transcriptional kinase CDK9 and such a process contributes to a full transcriptional potency of K-RTA

Image-Text Co-Decomposition for Text-Supervised Semantic Segmentation

This paper addresses text-supervised semantic segmentation, aiming to learn a model capable of segmenting arbitrary visual concepts within images by using only image-text pairs without dense annotations. Existing methods have demonstrated that contrastive learning on image-text pairs effectively aligns visual segments with the meanings of texts. We notice that there is a discrepancy between text alignment and semantic segmentation: A text often consists of multiple semantic concepts, whereas semantic segmentation strives to create semantically homogeneous segments. To address this issue, we propose a novel framework, Image-Text Co-Decomposition (CoDe), where the paired image and text are jointly decomposed into a set of image regions and a set of word segments, respectively, and contrastive learning is developed to enforce region-word alignment. To work with a vision-language model, we present a prompt learning mechanism that derives an extra representation to highlight an image segment or a word segment of interest, with which more effective features can be extracted from that segment. Comprehensive experimental results demonstrate that our method performs favorably against existing text-supervised semantic segmentation methods on six benchmark datasets.Comment: CVPR 202

The nucleolar protein NIFK promotes cancer progression via CK1α/β-catenin in metastasis and Ki-67-dependent cell proliferation.

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation

The potential impact of primary headache disorders on stroke risk

Distribution of PHDs. (DOC 55 kb

KCNN2 polymorphisms and cardiac tachyarrhythmias

Potassium calcium-activated channel subfamily N member 2 (KCNN2) encodes an integral membrane protein that forms small-conductance calcium-activated potassium (SK) channels. Recent studies in animal models show that SK channels are important in atrial and ventricular repolarization and arrhythmogenesis. However, the importance of SK channels in human arrhythmia remains unclear. The purpose of the present study was to test the association between genetic polymorphism of the SK2 channel and the occurrence of cardiac tachyarrhythmias in humans. We enrolled 327 Han Chinese, including 72 with clinically significant ventricular tachyarrhythmias (VTa) who had a history of aborted sudden cardiac death (SCD) or unexplained syncope, 98 with a history of atrial fibrillation (AF), and 144 normal controls. We genotyped 12 representative tag single nucleotide polymorphisms (SNPs) across a 141-kb genetic region containing the KCNN2 gene; these captured the full haplotype information. The rs13184658 and rs10076582 variants of KCNN2 were associated with VTa in both the additive and dominant models (odds ratio [OR] 2.89, 95% confidence interval [CI] = 1.505-5.545, P = 0.001; and OR 2.55, 95% CI = 1.428-4.566, P = 0.002, respectively). After adjustment for potential risk factors, the association remained significant. The population attributable risks of these 2 variants of VTa were 17.3% and 10.6%, respectively. One variant (rs13184658) showed weak but significant association with AF in a dominant model (OR 1.91, CI = 1.025-3.570], P = 0.042). There was a significant association between the KCNN2 variants and clinically significant VTa. These findings suggest an association between KCNN2 and VTa; it also appears that KCNN2 variants may be adjunctive markers for risk stratification in patients susceptible to SCD