To understand the role of the type 2A-like protein phosphatase in the cell division cycle, we investigated the mutant phenotypes obtained when the fission yeast ppa1+ and ppa2+ phosphatase genes ...(which encode polypeptides with approximately 80% identity to mammalian type 2A phosphatases) were either deleted or overexpressed. We also investigated the in vivo effect of okadaic acid, an inhibitor of protein serine/threonine phosphatases, on cell division. We show that ppa2+ interacts genetically with the cell cell regulators cdc25+ and wee1+, as a ppa2 deletion is lethal when combined with wee1-50 but partially suppresses the conditional lethality of cdc25-22 mutation. Evidence that ppa2+ negatively controls the entry into mitosis, possibly through the regulation of cdc2 tyrosine phosphorylation, is presented. ppa2 phosphatase is abundant in the cytoplasm, in contrast to the type 1-like phosphatase dis2, which is enriched in the nucleus. Overproduced ppa1 or ppa2 proteins accumulate in the cytoplasm near the nuclear periphery, and cells arrest in interphase. Okadaic acid-treated cells, like a ppa2 deletion, are short in length and display protein hyperphosphorylation. Cytokinesis is also inhibited, producing binucleated cells. We show that ppa2 is the genetic locus controlling okadaic acid sensitivity. The ppa2 deletion reveals the same hyperphosphorylated proteins as okadaic acid. When a strain deleted for ppa2 is treated with okadaic acid, cell size is reduced further to that of wee1-50 mutant strain or overexpressing the cdc25+ gene product, suggesting functional relationship of ppa2 with the cdc25 tyrosine phosphatase and/or the wee1 kinase in cell cycle control.
Impaired proteasome activity due to genetic variants of certain subunits might lead to proteasome-associated autoinflammatory syndromes (PRAAS). Here we report a de novo heterozygous missense variant ...of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i. In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms. The missense variant results in impaired immunoproteasome maturation and activity, yet ubiquitin accumulation is hardly detectable in the patients. A mouse model of the heterozygous human genetic variant (Psmb9
) recapitulates the proteasome defects and the immunodeficiency phenotype of patients. Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation. We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study.
Background
Large clinical trials are lack of data on non-vitamin K antagonist oral anticoagulants for acute stroke patients.
Aim
To evaluate the choice of oral anticoagulants at acute hospital ...discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry (ClinicalTrials.gov NCT01581502).
Method
The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23-day stay) was assessed.
Results
Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10-month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS2, CHA2DS2-VASc, and HAS-BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four-days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20-day or shorter hospitalization (OR 2·46, 95% CI 1·87–3·24).
Conclusions
Warfarin use at acute hospital discharge was still common in the initial years after approval of nonvitamin K antagonist oral anticoagulants, although nonvitamin K antagonist oral anticoagulant users increased gradually. The index stroke was milder and ischemia-risk indices were lower in nonvitamin K antagonist oral anticoagulant users than in warfarin users. Early initiation of nonvitamin K antagonist oral anticoagulants seemed safe.
The applicability of bio-chemical grouting as the environmentally friendly and economically method for liquefaction remediation was evaluated. Several combinations of organic and in-organic ...precipitations methods were conducted to obtain the optimum grouting solution. Organic precipitation method employs a bio-agent of urease enzyme to dissociate urea into ammonium and carbonate ions. The produced carbonate ions are precipitated as calcite crystals in the presence of calcium ions. Meanwhile, the in-organic methods were performed using chemical compounds only, without the bio-agent. Unconfined compressive strength (UCS) tests were performed to evaluate the applicability of the grouting solutions for improving the soil strength. Grouting solution is injected into the prepared sand samples. The sand samples with a relative density of 50% were treated with one and two PV for 3-day curing times. The experimental results showed that the organic precipitation method produced the high precipitated amount and resulted in the significant improvement in the strength of the treated sand. The presence of the precipitated materials within the grains of soil generated the strength of 272 kPa. The results of this study have elucidated that the organic precipitation method composed of calcium chloride, magnesium sulfate, urea and enzyme of urease may be an alternative soil-improvement technique to prevent the liquefaction susceptibility.
We have previously reported that YO-2, a selective plasmin inhibitor, induces thymocyte apoptosis. To elucidate the mechanism of YO-2-induced apoptosis, other YO compounds with different plasmin ...inhibitory action were tested for the pro-apoptotic activity in this study. The treatment of rat thymocytes with the YO compounds which had the hydrophobic but not the hydrophilic moiety at the C-terminal increased DNA fragmentation, the number of condensed nuclei and caspase-3-like activity. All pro-apoptotic YO compounds not only were potent plasmin inhibitors but also had the hydrophobic C-terminal as the common structure. Therefore, the target molecule of the YO compounds may be located not on the cell surface but rather inside the cells.
A novel 16-membered lactone antibiotic named tubelactomicin A was isolated from the culture broth of an actinomycete strain. The producing organism, designated MK703-102F1, was identified as a member ...of Nocardia. Tubelactomicin A was isolated from the culture broth by Diaion HP20 absorption, ethyl acetate extraction, silica gel and Sephadex LH-20 column chromatographies and centrifugal liquid-liquid partition chromatography (CPC). Tubelactomicin A showed strong activity against acid-fast bacteria including the drug-resistant strains.
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