Keyword-Aware Relative Spatio-Temporal Graph Networks for Video Question Answering

The main challenge in video question answering (VideoQA) is to capture and understand the complex spatial and temporal relations between objects based on given questions. Existing graph-based methods for VideoQA usually ignore keywords in questions and employ a simple graph to aggregate features without considering relative relations between objects, which may lead to inferior performance. In this paper, we propose a Keyword-aware Relative Spatio-Temporal (KRST) graph network for VideoQA. First, to make question features aware of keywords, we employ an attention mechanism to assign high weights to keywords during question encoding. The keyword-aware question features are then used to guide video graph construction. Second, because relations are relative, we integrate the relative relation modeling to better capture the spatio-temporal dynamics among object nodes. Moreover, we disentangle the spatio-temporal reasoning into an object-level spatial graph and a frame-level temporal graph, which reduces the impact of spatial and temporal relation reasoning on each other. Extensive experiments on the TGIF-QA, MSVD-QA and MSRVTT-QA datasets demonstrate the superiority of our KRST over multiple state-of-the-art methods.Comment: under revie

Dietary UKMR-1 Roselle supplementation prevents nicotine-induced cardiac injury by inhibiting myocardial oxidative stress

UKMR-1, a local variant of mutant Roselle strain (Hibiscus sabdariffa) is enriched with free radical scavenging polyphenols such as anthocyanin, vitamin C and hydroxycitric acid. However, pharmacological actions of UKMR-1 are not fully known. This study was conducted to determine whether supplementation of aqueous UKMR-1 calyx extract was able to protect against nicotine-induced cardiac injury in rats. In this experimental study, healthy male albino rats were randomly allotted into three groups (n=7 per group): control, nicotine and UKMR-1+Nicotine groups. Nicotine (0.6 mg/kg, i.p.) was administered to both nicotine and UKMR-1+Nicotine groups for 28 consecutive days. UKMR-1+Nicotine group also received 100 mg/kg UKMR-1 extract orally via gavage 30 min prior to nicotine injection, daily. UKMR-1+Nicotine group had significantly (p<0.05) higher lactate dehydrogenase (LDH) activity, as well as lower malondialdehyde content in heart tissue homogenate than nicotine group, suggesting its cardio protective activity by inhibition of lipid peroxidation. UKMR-1 also lowered (p<0.05) the blood pressure in nicotine-administered rats. In addition, UKMR-1 significantly (p<0.05) restored activities of cytosolic superoxide dismutase, glutathione peroxidase and glutathione-S-transferase as well as redox balance ratio (GSH:GSSG). In conclusion, UKMR-1 was able to protect against myocardial injury in rat model of nicotine administration possibly by inhibiting oxidative stress

The vasorelaxant effect of Hibiscus sabdariffa linn. Polyphenol-rich extract (HPE) on rat’s isolated aorta

Hibiscus sabdariffa Linn. or also known as roselle which is rich in polyphenols, has been demonstrated to cause lowering of blood pressure in animal and clinical settings. However its exact mechanism of action particularly from polyphenolic compounds is not clearly understood. Therefore, we aimed to determine the effects of H. sabdariffa polyphenol extract (HPE) towards vascular reactivity and its mechanism of action. The HPE was studied on isolated thoracic aortic rings from normal Sprague-Dawley rats, suspended in a 15-ml organ chambers containing Krebs-Henseleit solution. The changes in tension were recorded by isometric transducer connected to data acquisition. HPE relaxed the contraction induced by phenylephrine (PE, 1 μM) in similar pattern for both endothelium-intact and endothelium denuded aortic rings in dose-dependent manner 0.1 ~ 0.9 mg/ml. The pretreatment with atropine (1 μM), a competitive muscarinic antagonist, and propranolol (1 μM), a non-selective beta- blocker did not alter HPE vasorelaxation response. In addition, HPE did not inhibit the contraction induced by extracellular Ca2+ precontracted by PE (1 μM) or KCl (60 mM), in Ca2+ -free solution, suggesting that the relaxation effect of HPE was not via inhibition of calcium channels. In conclusion, HPE demonstrated vasorelaxation effects on rat thoracic aorta although the underlying mechanism is still unknown. The vasorelaxation effect could be via angiotensin type 1 receptor inhibition in the vascular smooth muscle cells or the activation of hyperpolarizing K+ channel

Preparation of the Elusive [(por)Fe(NO)(O‐ligand)] Complex by Diffusion of Nitric Oxide into a Crystal of the Precursor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97283/1/anie_201208063_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/97283/2/3896_ftp.pd

Tabernacles of the Spirit

In the classic tradition of the exploratory essay, George Gammack examines the theme of community in this paper. He details varied aspects of the creation of community among those who are retired, taking as its focus the Men’s Sheds movement. The paper explores the relationship between persons and community in later years, looking in particular at how those with a lifetime’s worth of skills and knowledge can continue to contribute to the life of a community. Along the way we are introduced to the work of authors such as Charles Taylor, Richard Niebuhr, Primo Levi, Seamus Heaney and Richard Sennett on the subject of work and what comes after it.Publisher PD

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation

IntroductionA potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship.MethodsWe extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated.ResultsAfter adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ.DiscussionOur study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of t(9;22) chromosomal translocation that results in BCR-ABL fusion gene. ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, are currently the front-line treatment options for CML. Recently, natural killer (NK) cell activation and expansion have been shown to be associated with optimal treatment responses for CML. To investigate the effects and mechanisms of these TKIs on NK cells, here we characterized activating and inhibitory NK receptors in CD3−CD16+CD56dim NK cells isolated from CML patients in chronic phase (CP). The expressions of activating NK receptors, such as NKG2D, natural cytotoxicity receptor (NCR) and DNAM-1, rebounded after successful TKI treatments for CML. In contrast, among the three surveyed inhibitory receptors (NKG2A, KIR2DL1, and KIR3DL1), only the expression of NKG2A was reverted and suppressed to a very low level by dasatinib, and not by imatinib or nilotinib. CML patients treated with dasatinib indeed expressed fewer NKG2A+ NK cells, which send negative signals for induction of NK cytotoxicity. For these dasatinib-treated patients, the duration to reach major molecular response (MMR) was shorter, and significantly correlated with individual's NKG2A+ NK cell number. This clinical relevance to NKG2A was not observed in treatments with imatinib or nilotinib. In line with dasatinib-specific down-regulation of NKG2A, NK cytotoxicity evaluated by the killing assay was also significantly higher in patients treated with dasatinib than in those treated with imatinib or nilotinib. The lower NK cytotoxicity from imatinib or nilotinib treatments could be reverted by NKG2A blockade using anti-NKG2A antibody. Further in vitro experiments revealed mechanistically that dasatinib could inactivate p38 mitogen-activated protein kinase (MAPK), and consequently affect nuclear import of GATA-3 and GATA-3 transcriptional activities for NKG2A. Our results highlight the dual effects of dasatinib in direct inhibition of ABL kinase and in immunomodulation through NKG2A down-regulation, contributing to accelerated molecular responses (MR) in CML

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and strongly prompts development of TPL2 inhibitors for preclinical and clinical studies

Mutation and Lineage Analysis of DNMT3A in BCR-ABL1-negative Chronic Myeloproliferative Neoplasms

SummaryIn addition to the JAK2 V617F mutation, somatic mutation in DNMT3A has been described in BCL-ABL1-negative myeloproliferative neoplasms (MPNs). We have screened for DNMT3A exon 23 mutations in 130 adult Taiwanese patients with chronic phase myeloproliferative neoplasms. Only one somatic DNMT3A R882H mutation was identified in one JAK2 V617F mutation-positive essential thrombocythemia patient (1/91, 1%). Both mutations were detected in the CD34+-, CD19+-, peripheral blood mononuclear cell- and granulocyte-enriched fractions, but were not detected in the CD3+-enriched fraction by lineage analysis. Our findings suggest that DNMT3A mutation is not prevalent in MPNs, and further study is needed to clarify its role in the molecular pathogenesis of myeloproliferative neoplasms