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AbstractAdult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials. [ABSTRACT FROM AUTHOR]

Escaping from danger is one of the most fundamental survival behaviors for animals. Most freshwater fishes display olfactory alarm reactions in which an injured fish releases putative alarm substances from the skin to notify its shoaling company about the presence of danger. Here, we identified two small compounds in zebrafish skin extract, designated as ostariopterin and daniol sulfate. Ostariopterin is a pterin derivative commonly produced in many freshwater fishes belonging to the Ostariophysi superorder. Daniol sulfate is a novel sulfated bile alcohol specifically present in the Danio species, including zebrafish. Ostariopterin and daniol sulfate activate distinct glomeruli in the olfactory bulb. Zebrafish display robust alarm reactions, composed of darting, freezing, and bottom dwelling, only when they are concomitantly stimulated with ostariopterin and daniol sulfate. These results demonstrate that the fish alarm reaction is driven through a coincidence detection mechanism of the two compounds along the olfactory neural circuitry. [Display omitted] • Ostariopterin is a "danger signal" commonly present in many freshwater fishes • Daniol sulfate is a "conspecific signal" specifically present in Danio fish species • Ostariopterin and daniol sulfate activate distinct olfactory circuits in zebrafish • Coincidence detection of these two molecules triggers robust alarm reaction In 1938, Karl von Frisch postulated the existence of olfactory alarm substances (Schreckstoff) in fish. Masuda et al. identify two compounds in zebrafish skin extract, ostariopterin and daniol sulfate, which act as "danger" and "conspecific" signals, respectively. Only when they are concomitantly applied do zebrafish display a robust alarm reaction. [ABSTRACT FROM AUTHOR]

Although the standard falls prevention strategy is to identify and respond to patients with high-risk conditions, it remains unclear whether falls in patients with high fall risk account for most observed falls. In this study, fall risk and number of falls were calculated based on patients' motor and cognitive abilities, and the relationship between the two was examined. We conducted a retrospective cohort study. We included 2518 consecutive patients with stroke who were admitted to a rehabilitation hospital. Data on falls during hospitalization and biweekly assessed Functional Independence Measure scores were retrieved from the medical records. The average Functional Independence Measure scores for the motor and cognitive items were obtained and categorized as complete dependence, modified dependence, and independence. The fall rate (falls/1000 person-days) and number of observed falls in each combined condition were investigated. Modified dependence on motor ability and complete dependence on cognitive ability had the highest risk of falls, with a fall rate of 10.8/1000 person-days and 51 fall observations, which accounted for 4.3% of all falls. Independent motor and cognitive ability had the lowest risk of falls, a fall rate of 2.6/1000 person-days and 146 observed falls, accounting for 12.4% of all falls, which was 2.8 times higher than the number of falls observed in the highest risk of falls condition. The combined motor-cognitive ability with the highest risk of falls in stroke inpatients did not have the highest number of observed falls. Rather, the combined motor-cognitive ability with the lowest risk of falls tended to have a high number of observed falls. A different strategy is needed to reduce the total number of falls. [ABSTRACT FROM AUTHOR]

We developed an oxidative synthetic method for α‐nitroketones from α‐substituted malononitriles and nitromethane under molecular oxygen. Only base and molecular oxygen are necessary without condensation reagents; this is an environmentally benign synthesis. [ABSTRACT FROM AUTHOR]

Volicitin [N-(17-hydroxylinolenoyl)-L-glutamine] and N-linolenoyl-L-glutamine were originally identified in the regurgitant of Spodoptera exigua larvae. These fatty acid amino acid conjugates (FACs) are known to be elicitors that induce plants to release volatile compounds which in turn attract natural enemies of the larvae such as parasitic wasps. FAC concentrations are regulated by enzymatic biosynthesis and hydrolysis in the intestine of Lepidoptera larvae. It has been proposed that FAC metabolism activates glutamine synthetase and plays an important role in nitrogen metabolism in larvae. In this study, we identified candidate genes encoding a FACs hydrolase in Spodoptera litura using genomic information of various related lepidopteran species in which FACs hydrolases have been reported. We analyzed the importance of FAC hydrolysis on caterpillar performance with CRISPR/Cas9 knock outs. Larvae of strains with an inactive FACs hydrolase excreted FACs in their feces. They absorbed 30% less nitrogen from the diet compared to WT caterpillars resulting in a reduction of their body weight of up to 40% compared to wild type caterpillars. These results suggest that the hydrolysis of FACs is an important metabolism for insects and that FACs are important for larval growth. [ABSTRACT FROM AUTHOR]