In the ubiquitin-proteasome system, E3 ubiquitin ligase (E3s for short) selectively recognize and bind specific regions of their substrate proteins. Sequence motifs whose sites are bound by E3 ...ubiquitin ligases are called degrons. Because much remains unclear about the relationship between substrate proteins of E3s and their binding sites, there is a need to computationally identify such binding sites from the substrate proteins. For this motif identification problem, in our previous works, we have proposed a series of collapsed Gibbs sampling algorithms, called DegSampler1 and DegSampler2, both of which use position-specific prior information. In this work, we propose a new collapsed Gibbs sampling algorithm, called DegSampler3, by integrating intra-motif pair-wise dependency model into the posterior probability distribution of DegSampler2. In our preliminary experiments, we found that DegSampler3 has the ability of finding more various degron sites than DegSampler2 while keeping the prediction accuracy almost the same as that of the previous method, DegSampler2.
In this paper, we address the problem of finding sequence motifs in substrate proteins specific to E3 ubiquitin ligases (E3s). We formulated a posterior probability distribution of sites by designing ...a likelihood function based on amino acid indexing and a prior distribution based on the disorderness of protein sequences. These designs are derived from known characteristics of E3 binding sites in substrate proteins. Then, we devise a collapsed Gibbs sampling algorithm for the posterior probability distribution called DegSampler. We performed computational experiments using 36 sets of substrate proteins specific to E3s and compared the performance of DegSampler with those of popular motif finders, MEME and GLAM2. The results showed that DegSampler was superior to the others in finding E3 binding motifs. Thus, DegSampler is a promising tool for finding E3 motifs in substrate proteins.
When using administrative data, validation is essential since these data are not collected for research purposes and misclassification can occur. Thus, this study aimed to develop algorithms ...identifying pregnancy and to evaluate the validity of administrative claims data in Japan.
All females who visited the Tohoku University Hospital Department of Obstetrics in 2018 were included. The diagnosis, medical procedure, medication, and medical service addition fee data were utilized to identify pregnancy, with the electronic medical records set as the gold standard. Combination algorithms were developed using predefined pregnancy-related claims data with a positive predictive value (PPV) ≥80%. Sensitivity (SE), specificity (SP), PPV, and negative predictive value (NPV) with their corresponding 95% confidence intervals (CIs) were calculated for these combination algorithms.
This study included 1757 females with a mean age of 32.8 (standard deviation: 5.9) years. In general, the individual claims data were able to identify pregnancy with a PPV ≥80%; however, the number of pregnancies identified using a single claims data was limited. Based on the combination algorithm with all of the categories, including diagnosis, medical procedure, medication, and medical service addition, the calculated SE, SP, PPV, and NPV were 73.4% (95% CI: 71.2%-75.4%), 96.9% (95% CI: 89.3%-99.6%), 99.8%,(95% CI: 99.4%-100.0%), and 12.3% (95% CI: 9.6%-15.4%), respectively.
The combination algorithm to identify pregnancy demonstrated a high PPV and moderate SE. The algorithm validated in this study is expected to accelerate future studies that aim to identify pregnancies and evaluate pregnancy outcome.
Blood and lymphatic vessels structurally bear a strong resemblance but never share a lumen, thus maintaining their distinct functions. Although lymphatic vessels initially arise from embryonic veins, ...the molecular mechanism that maintains separation of these two systems has not been elucidated. Here, we show that genetic deficiency of Folliculin, a tumor suppressor, leads to misconnection of blood and lymphatic vessels in mice and humans. Absence of Folliculin results in the appearance of lymphatic-biased venous endothelial cells caused by ectopic expression of Prox1, a master transcription factor for lymphatic specification. Mechanistically, this phenotype is ascribed to nuclear translocation of the basic helix-loop-helix transcription factor Transcription Factor E3 (TFE3), binding to a regulatory element of Prox1, thereby enhancing its venous expression. Overall, these data demonstrate that Folliculin acts as a gatekeeper that maintains separation of blood and lymphatic vessels by limiting the plasticity of committed endothelial cells.
Zhenxuanyin symbol: see text is composed of pure Chinese medicinal herbs, such as gastrodia tuber, poria cocos, ligusticum wallichii etc. 4-verssel occlusion (4VO) model rats were reperfused after 30 ...minutes' complete occlusion, and Zhenxuanyin was administered 3 times a day. 24 hours later, 123I-IMP uptake in the brain was evaluated as an index of cerebral blood flow (CBF). The results show that Zhenxuanyin (0.03 g/kg, 0.3 g/kg, 1 g/kg, or 3 g/kg a day) can greatly improve the blood flow in the main cerebral regions, and 0.3 g/kg can increase cerebral blood flow (CBF) to the normal level.
Abstract The prevalence of Panton-Valentine leukocidin gene ( pvl )-positive community-acquired methicillin-resistant Staphylococcus aureus USA300 clone, which is designated as the ST8-staphylococcal ...cassette chromosome (SCC) mec type IV (ST8-IV) lineage, is a major public health concern worldwide. Thus, to elucidate the prevalence and characteristics of pvl -positive community-onset MRSA in Japan, we conducted a molecular epidemiological analysis for 854 S. aureus isolates obtained from outpatients with skin infections during 2013 and 2014. The isolation rate of MRSA was 25.6% (219 isolates), and the ratio of pvl -positive MRSA was 13.2% (29 isolates). Notably, the proportion (93.8%) of pvl -positive isolates was particularly high among MRSA isolates from Ishigaki island in Okinawa. Pulsed-field gel electrophoresis and multilocus sequence typing showed that the pulsotype C isolates (11 isolates) were typical USA300 clones with arginine catabolic mobile element (ACME) type I-CC8-IV lineages and prevalent on the main island of Japan (Honshu). Pulsotypes A (11 isolates) and B (four isolates) consisted of ACME-negative CC8-IV clones and were specific for Ishigaki island. Both USA300 and Okinawa-Ishigaki specific clones were associated with deep-seated skin infections, such as furuncle and cellulitis. Pulsotypes D (two isolates) and E (one isolate) were ACME-negative clonal complex (CC) 59-IV clones and were related to superficial skin infections, such as impetigo. Our findings revealed that pvl -positive MRSA associated with deep-seated skin infections are spreading in Japanese communities, particularly in Ishigaki, Okinawa.
The USA300 clone, which produces Panton–Valentine leukocidin (PVL), is a major pathogenic community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA) clone that causes intractable skin ...infections. Recently, PVL‐positive CA‐MRSA, including USA300 clones, have emerged in both communities and hospitals in Japan. To prevent an outbreak of PVL‐positive MRSA, infected patients should be treated with effective antimicrobial agents at community clinics. Herein, we investigate molecular epidemiological characteristics of PVL‐positive MRSA isolated from outpatients with skin and soft tissue infections (SSTI), which are common community‐onset infectious diseases. The detection rate of MRSA was 24.9% (362 strains) out of 1455 S. aureus strains isolated between 2013 and 2017. Among the MRSA strains, 15.5% (56 strains) were PVL‐positive strains and associated with deep‐seated skin infections. Molecular epidemiological analyses of PVL‐positive MRSA showed that USA300 was the predominant clone (53.6%, 30 strains) and was identified in Kanto (18 strains), Kagawa (nine strains), Tohoku (two strains) and Hokkaido (one strain). Notably, minocycline and fusidic acid were effective against all PVL‐positive MRSA strains. Hence, our data reveals the current status of PVL‐positive MRSA isolated from patients with SSTI in Japan. Continuous surveillance of CA‐MRSA is necessary to monitor latest prevalence rates and identify effective antimicrobial agents for PVL‐positive MRSA strains.
Phosphatidylserine (PS)―normally present on the inner leaflet of the plasma membrane―translocates to the outer leaflet at an early stage of apoptosis. PS-containing liposomes (PSLs) can mimic the ...effect of apoptotic cells in inducing the secretion of prostaglandin E2 from phagocytes and inhibiting the maturation of dendritic cells and osteoclast precursors. The present study attempted to evaluate the effect of calcium phosphate (in the form of hydroxyapatite HAP) in the presence or absence of PSLs for repair of rat calvarial bone defects. The defects, each 5 mm in diameter, were created in the calvaria parietal bone of 8-week-old Wistar rats and subjected to one of the following treatments: no augmentation (Sham), HAP alone, or a mixture of HAP and PSL (HAP+PSL). Micro-computed tomography data showed that the HAP+PSL complexes promoted greater bone regeneration in comparison with either the Sham procedure or HAP alone at 4 and 8 weeks after implantation. The regeneration of calvarial bone defects induced by PSLs was mediated partly through upregulation of the osteogenic marker Alkaline Phosphatase, Type I collagen, osteocalcin, Runx2, and Osterix mRNAs. These data are the first to show that PSLs can influence bone regeneration by regulating osteoblast differentiation.
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