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Centromere‐associated protein E (CENP‐E) is a kinesin motor protein essential for mitosis and a new target for anticancer agents with less side effects. To rationally design anticancer drug candidates based on structure, it is important to determine the three‐dimensional structure of the CENP‐E motor domain bound to its inhibitor. Here, we report the first crystal structure of the CENP‐E motor domain in complex with a non‐hydrolysable ATP analogue, adenylyl‐imidodiphosphate (AMPPNP). Furthermore, the structure is compared with the ADP‐bound form of the CENP‐E motor domain as well as the AMPPNP‐bound forms of other kinesins. This study indicates that helix α4 of CENP‐E participates in the slow binding of CENP‐E to microtubules. These results will contribute to the development of anticancer drugs targeting CENP‐E. [ABSTRACT FROM AUTHOR]

Phase-I analysis of historical data from a statistical process is a strategic problem in Statistical Process Monitoring and control. Before the establishment of process stability, it is challenging to model historical data. Consequently, a distribution-free approach is a natural choice in Phase-I monitoring. Existing distribution-free Phase-I control charts are suitable for detecting instability in location and scale parameters only and are often insensitive in complex processes involving skewness or shape parameters. A new Phase-I control chart is proposed to identify more general shifts, including location, scale and skewness. The proposed Phase-I scheme is efficient in such a situation. The proposed Phase-I scheme uses subsamples, and the plotting statistic is based on the omnibus multi-sample linear rank statistic corresponding to the location, scale and skewness shifts. The new scheme can identify subsamples that are not in control, and it can also indicate one or more process parameters where a deviation has occurred. The encouraging performance of the proposed scheme is established with a large-scale numerical study based on Monte-Carlo in detecting shifts of various nature in a comprehensive class of situations. An illustration based on monitoring the waiting time data from a customer service centre is given. Some concluding remarks and some future research problems are also offered. [ABSTRACT FROM AUTHOR]

Highlights • Over 38% of adult community-acquired pneumonia (CAP) patients were <50 years old. • The detection rate was higher for bacteria (40%) than viruses (13%). • The proportion of Mycobacterium tuberculosis infections was higher in young CAP patients. • The case fatality rate was 14% among hospitalized adult CAP patients. • Drowsiness on admission and SpO 2 <90% were independent risk factors for mortality. Abstract Background Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality among adults worldwide. However, the distribution of the etiology of CAP varies from one country to another, with limited data from rural areas. Methods A prospective hospital-based study on adult CAP was conducted in Leyte, Central Philippines from May 2010 to May 2012. Blood, sputum, and nasopharyngeal samples obtained from patients were used to identify pathogens using standard microbiological culture methods and PCR. Results Of the 535 patients enrolled, 38% were younger than 50 years old. More than half of the patients had an underlying disease, including pulmonary tuberculosis (22%). The detection rate was higher for bacteria (40%) than viruses (13%). Haemophilus influenzae (12%) was the most commonly detected bacterium and influenza virus (5%) was the most commonly detected virus. The proportion of CAP patients with Mycobacterium tuberculosis infection was higher in the younger age group than in the older age group. Among CAP patients, 14% died during hospitalization, and drowsiness on admission and SpO 2 <90% were independent risk factors for mortality. Conclusions Bacterial infections contribute substantially to the number of hospitalizations among CAP patients in rural Philippines. This study also highlights the importance of treatment of tuberculosis in reducing the burden of adult CAP in the country. [ABSTRACT FROM AUTHOR]

The effects of NH4Cl concentration (0.1-1600 mM), temperature (5.0-35.0°C), pH (3.0-11.0), conidial density (2.5 × 105-1.0 × 107 conidia/ml), and conidial maturation (0-21 days) on the conidial germination of the early phase (EP) ammonia fungus Amblyosporium botrytis were investigated. The optimum NH4Cl concentration for conidial germination was 300 mM. No germination was observed above 1000 mM NH4Cl, while low NH4Cl concentration (0.1-30 mM) retarded the conidial germination. The conidia did not germinate in distilled water. The effective pH ranges for the conidial germination were from 5.0 to 9.0 with optimum at 8.0. Germination was possible from 5.0°C to 35°C with the optimum at 15°C. These results demonstrate that ammonium-nitrogen concentration and pH are principal factors in the conidial germination of A. botrytis. It is expected that the obtained physiological characteristics of A. botrytis are suitable to colonize in nitrogen-enriched soil as the EP ammonia fungus. [ABSTRACT FROM AUTHOR]

The confinement of water in organic self-assemblies with nanometer-sized pores is ubiquitous in nature. Water pools in sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelles have been intensively studied as a representative model of such confined water. However, the freezing and melting behavior of such water pools is poorly understood owing to their poor structural stability under phase transition. In the present work, the melting of iced water pools accompanied by a reconstruction of AOT reverse micelles was studied with infrared spectroscopy. For all AOT reverse micelles tested ( R w : 1.2–4.4 nm), a characteristic ice–water coexistence phase was observed during melting. The results provide experimental evidence of the previously proposed core–shell structure of the water pool. For larger frozen reverse micelles ( R w > 2.3 nm), shifts of the υ (OH) bands were observed. The spectra of the shifted υ (OH) bands were similar to those for the melted water pools in the smaller micelles. The mechanism of the reconstruction of AOT reverse micelles from their frozen states and the corresponding transient changes in the local environments were also discussed. [ABSTRACT FROM AUTHOR]

Enterovirus 68 ( EV68) infection occasionally manifests with fatal outcomes. However, detection of EV68 in serum and its clinical outcomes are yet to be determined. In this study, we retrospectively tested stored serum samples collected from pediatric pneumonia patients whose nasopharyngeal specimens were positive for EV68. Of total 28 nasopharyngeal sample-positive patients, EV68 was detected in serum samples among 12 (43%) patients aged between 1 and 4 years. Our results suggest that EV68 can cause viremia by which the virus may exhibit systemic manifestations. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we consider a logic circuit (i.e., a combinatorial circuit consisting of gates, each of which computes a Boolean function) computing a symmetric Boolean function , and investigate a relationship between two complexity measures, energy and fan-in of , where the energy is the maximum number of gates outputting “1” over all inputs to , and the fan-in is the maximum number of inputs of every gate in . We first prove that any symmetric Boolean function of variables can be computed by a logic circuit of energy and fan-in , and then provide an almost tight lower bound where is the maximum numbers of consecutive “0”s or “1”s in the value vector of . Our results imply that there exists a tradeoff between the energy and fan-in of logic circuits computing a symmetric Boolean function. [Copyright &y& Elsevier]

Background: Detection of Enterovirus 68 (EV68) has recently been increased. However, underlying evolutionary mechanism of this increasing trend is not fully understood. Methods: Nasopharyngeal swabs were collected from 5,240 patients with acute respiratory infections in the Philippines from June 2009 to December 2011. EV68 was detected by polymerase chain reaction (PCR) targeting for 5′ untranslated region (5′UTR), viral protein 1 (VP1), and VP4/VP2. Phylogenetic trees were generated using the obtained sequences. Results: Of the 5,240 tested samples, 12 EV68 positive cases were detected between August and December in 2011 (detection rate, 0.23%). The detection rate was higher among inpatients than outpatients (p<0.0001). Among VP1 sequences detected from 7 patients in 2011, 5 in lineage 2 were diverged from those detected in the Philippines in 2008, however, 2 in lineage 3 were not diverged from strains detected in the Philippines in 2008 but closely associated with strains detected in the United States. Combined with our previous report, EV68 occurrences were observed twice in the Philippines within the last four years. Conclusions: EV68 detections might be occurring in cyclic patterns, and viruses might have been maintained in the community while some strains might have been newly introduced. [ABSTRACT FROM AUTHOR]

Four early-phase (EP) and one late-phase (LP) ammonia fungi were co-cultured with three non-ammonia fungi on urea, ammonium, nitrite and nitrate agar media at different pH values (5.5, 7.0 and 9.0). The early stage EP species Amblyosporium botrytis and Ascobolus denudatus showed deadlock competition with the non-ammonia fungi Aspergillus niger and Penicillium citrinum on urea agar medium, and neutral intermingling or weak competing deadlock on ammonium, nitrite and nitrate agar media in all pH conditions. The late stage EP species, Coprinopsis phlyctidospora and Lyophyllum tylicolor, showed antagonistic deadlock and invaded the region containing mycelia of the non-ammonia fungi, P. citrinum and Trichoderma viride, on urea, nitrite and nitrate agar media in all pH conditions. The LP species, Hebeloma vinosophyllum, showed competing deadlock with Asp. niger and P. citrinum on urea medium and weak competition on nitrite and nitrate agar media at pH 9.0. These findings suggest that the successive occurrence of ammonia fungi is partly due to changes in the interactions between ammonia fungi and non-ammonia fungi based on changes in inorganic nitrogen. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein-producing carcinoma (AFPC)/hepatoid adenocarcinoma (HAC) and neuroendocrine carcinoma (NEC) are uncommon in the stomach. Composite tumors consisting of these carcinomas and their histologic phenotypes are not well known. Between 2002 and 2007, to estimate the prevalence of composite tumors consisting of tubular adenocarcinoma, AFPC/HAC and NEC, we reviewed specimens obtained from294 consecutive patients treated surgically for gastric cancer. We examined histological phenotype of tumors of AFPC or NEC containing the composite tumor by evaluating immunohistochemical expressions of MUC2, MUC5AC,MUC6, CDX2, and SOX2. Immunohistochemically, AFPC/HAC dominantly showed the intestinal ormixed phenotype, and NEC frequently showed the gastric phenotype. In the composite tumor, the tubular and hepatoid components showed the gastric phenotype, and the neuroendocrine component showed the mixed type. The unique composite tumor predominantly showed the gastric phenotype, and the hepatoid and neuroendocrine components were considered to be differentiated from the tubular component. [ABSTRACT FROM AUTHOR]

Alpha-fetoprotein-producing carcinoma (AFPC)/hepatoid adenocarcinoma (HAC) and neuroendocrine carcinoma (NEC) are uncommon in the stomach. Composite tumors consisting of these carcinomas and their histologic phenotypes are not well known. Between 2002 and 2007, to estimate the prevalence of composite tumors consisting of tubular adenocarcinoma, AFPC/HAC and NEC, we reviewed specimens obtained from294 consecutive patients treated surgically for gastric cancer. We examined histological phenotype of tumors of AFPC or NEC containing the composite tumor by evaluating immunohistochemical expressions of MUC2, MUC5AC,MUC6, CDX2, and SOX2. Immunohistochemically, AFPC/HAC dominantly showed the intestinal ormixed phenotype, and NEC frequently showed the gastric phenotype. In the composite tumor, the tubular and hepatoid components showed the gastric phenotype, and the neuroendocrine component showed the mixed type. The unique composite tumor predominantly showed the gastric phenotype, and the hepatoid and neuroendocrine components were considered to be differentiated from the tubular component. [ABSTRACT FROM AUTHOR]

Background: Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined. Methods: The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively. Result: Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated. Conclusion: Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries. [ABSTRACT FROM AUTHOR]

Human rhinovirus (HRV) C was recently identified as the third species of HRV using a molecular technique. Infections caused by previously identified HRVs (A and B) are thought to be limited to the respiratory tract; however, pathogenesis of HRVC is still largely unknown. A total of 816 nasopharyngeal swabs from hospitalized children with severe respiratory infections in the Philippines (May 2008-May 2009) were tested for HRV by reverse transcription polymerase chain reaction (RT-PCR), and 243 samples (29.8%) were positive for HRV. Among these patients, serum samples were also tested to determine whether specific HRV species were associated with viremia. Only 30 serum samples (12.3%) were positive for HRV. However, the HRV positive rates were different among HRV species, 3% (4/135) for HRVA, 0% (0/25) for HRVB, and 31% (26/83) for HRVC, and were the highest on 2 days after the onset of symptoms. These results suggest that HRVC may have a different pathogenicity and can more commonly cause viremia than HRVA and HRVB. Serum positive rates for HRV are affected by age, i.e., higher positive rates for those aged 1 year or more. HRVC that were detected from serum exhibited the same level of sequence diversity as those positive only for nasopharyngeal samples in phylogenetic analysis. However, all HRVA which were detected from serum were clustered in a monophyletic clade based on their 5' non-coding region (NCR) sequences, which is closely related with a certain HRVC genotype (A2) in 5'-NCR. This finding suggests that the 5'NCR region may be associated with viremia. [ABSTRACT FROM AUTHOR]

The article focuses on the prevalence of acute respiratory illness related to human enterovirus 68 (HEV68) in Asia, Europe and the U.S. from 2008-2010, which included fatal cases from the Philippines and Japan. It is in the Philippine's Eastern Visayas that an outbreak of HEV68 was seen in late October 2008, which affected 21 patients who were mostly 0-4 years old. In Arizona, the state Department of Health Services detected HEV68 in 5 patients from August - September 2010.

Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of Kif3a results in activation of AG and increased CAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases CAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes CAMP, is also located in renal primary cilia and interacts with the AKAP15O com- plex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1β (HNF-1β), mutations of which produce kidney cysts. PDE4C is down-regulated and CAMP levels are increased in HNF-1β mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of CAMP signaling in cystic kidney diseases arising from different gene mutations. [ABSTRACT FROM AUTHOR]

Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genus Morbillivirus and is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV. We investigated divergence times using relaxed clock Bayesian phylogenetics. Our estimates reveal that MeV had an evolutionary rate of 6.0 - 6.5 × 10-4 substitutions/site/year. It was concluded that the divergence time of the most recent common ancestor of current MeV was the early 20th century. And, divergence between MeV and RPV occurred around the 11th to 12th centuries. The result was unexpected because emergence of MeV was previously considered to have occurred in the prehistoric age. MeV may have originated from virus of non-human species and caused emerging infectious diseases around the 11th to 12th centuries. In such cases, investigating measles would give important information about the course of emerging infectious diseases. [ABSTRACT FROM AUTHOR]

The frequency of the amantadine-resistant H1N1 influenza A virus has been increasing since the 2005-2006 season. It is unclear whether reassortment was involved in this trend. Here, we show that cocirculation of amantadine-resistant and -sensitive strains led to the genesis of amantadine-sensitive reassortant virus during the 2007-2008 season. Thereafter, the reassortant virus predominated. This contrasts with the trend for the H3N2 virus, in which the amantadine-resistant reassortant virus became predominant. The results suggest that it is necessary to monitor genome dynamics to understand the evolution and mechanism of the emergence and spread of antiviral resistance among influenza A viruses. [ABSTRACT FROM AUTHOR]

Background: Influenza A virus infects not only humans, but also other species including avian and swine. If a novel influenza A subtype acquires the ability to spread between humans efficiently, it could cause the next pandemic. Therefore it is necessary to understand the evolutionary processes of influenza A viruses in various hosts in order to gain better knowledge about the emergence of pandemic virus. The virus has segmented RNA genome and 7th segment, M gene, encodes 2 proteins. M1 is a matrix protein and M2 is a membrane protein. The M gene may be involved in determining host tropism. Besides, novel vaccines targeting M1 or M2 protein to confer cross subtype protection have been under development. We conducted the present study to investigate the evolution of the M gene by analyzing its sequence in different species. Results: Phylogenetic tree revealed host-specific lineages and evolution rates were different among species. Selective pressure on M2 was stronger than that on M1. Selective pressure on M1 for human influenza was stronger than that for avian influenza, as well as M2. Site-by-site analyses identified one site (amino acid position 219) in M1 as positively selected in human. Positions 115 and 121 in M1, at which consensus amino acids were different between human and avian, were under negative selection in both hosts. As to M2, 10 sites were under positive selection in human. Seven sites locate in extracellular domain. That might be due to host's immune pressure. One site (position 27) positively selected in transmembrane domain is known to be associated with drug resistance. And, two sites (positions 57 and 89) locate in cytoplasmic domain. The sites are involved in several functions. Conclusion: The M gene of influenza A virus has evolved independently, under different selective pressure on M1 and M2 among different hosts. We found potentially important sites that may be related to host tropism and immune responses. These sites may be important for evolutional process in different hosts and host adaptation. [ABSTRACT FROM AUTHOR]

Abstract: Tomato seedlings grown on nitric medium and treated with various cadmium concentrations (0 to 50 μM) were used. Results obtained show that cadmium remains predominantly located in the roots, which then seem to play the role of trap-organs. Increasing cadmium concentration in the medium leads particularly to a decrease in accumulation, together with a decrease in the activity of glutamine synthetase and in the quantity of plastidic isoform ARNm (GS2), and, on the contrary, to an increase of the cytosolic isoform ARNm (GS1). On the other hand, stimulations were observed for NADH-dependent glutamate synthase, NADH-dependent glutamate dehydrogenase, ARNm quantity of this enzyme, ammonium accumulation, and protease activity. In parallel, stimulations were observed for NAD+ and NADP+-dependent malate dehydrogenase and NADP+-dependent isocitrate dehydrogenase. These results were discussed in relation to the hypothesis attributing to the dehydrogenase enzymes (GDH, MDH, ICDH) an important role in the plant defence processes against cadmium-induced stresses. To cite this article: C. Chaffei et al., C. R. Biologies 329 (2006). [Copyright &y& Elsevier]

Abstract: A microreactor for supercritical water has been developed for chemical engineering process. Heat and fluid flow in a T-junction in this system are calculated using STREAM. Since the flow in the tube are in the wide range from laminar to turbulent flow, a nonlinear k–ε model taking into account the low-Reynolds-number effects (proposed by Abe, Kondoh and Nagano) are used. We assume that a supercritical water velocity is 2.0 m/s. The optimum condition for time fluctuation of temperature is when the substrate velocity is 0.4. In this case, the substrate temperature rises above the critical temperature immediately and the main reaction progresses efficiently. When v is 0.1, the temperature remains subcritical region for a while. On the other hand, when the v is larger than 0.4, the temperature does not reach the critical point. [Copyright &y& Elsevier]

Abstract: Yeast biomass was methylated in a 0.1 M HCl methyl alcohol solution at room temperature and the methylated yeast (MeYE) was applied to the adsorptive separation of Cr(VI) and As(V) anions from aqueous solutions. At near-neutral pH, while Cr(VI) and As(V) anions were scarcely adsorbed onto unmethylated yeast biomass, the amounts adsorbed increased with increasing methylation degree. The amount of Cr(VI) adsorbed onto MeYE was almost constant at pH 4–6 and decreased with increasing pH above pH 6. The amount of As(V) adsorbed onto MeYE was rather lower than that of Cr(VI) and it had a peak at about pH 7. A metal-binding model was used to describe the adsorption characteristics of Cr(VI) and As(V) on MeYE. The results showed that MeYE has two different types of adsorption sites. The saturated amount of Cr(VI) and As(V) adsorbed onto MeYE having methylation degree 0.94 was 0.55 mmol g-1. [Copyright &y& Elsevier]

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePtenflox/floxmice). AlbCrePtenflox/flox mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and β-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARγ and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePtenflox/flox livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCre tenflox/flox livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePtenflox/flox mice also showed insulin hypersensitivity. In vitro,AlbCrePtenflox/flox hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver. [ABSTRACT FROM AUTHOR]

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver. [ABSTRACT FROM AUTHOR]

We have used activation tagging with T-DNA carrying cauliflower mosaic virus 35S enhancers to investigate the complex signaling networks underlying disease resistance in Arabidopsis. From a screen of ~5000 lines, we identified constitutive disease resistance (CDR1) encoding an apoplastic aspartic protease, the overexpression of which causes dwarfing and resistance to virulent Pseudomonas syringae. These phenotypes reflect salicylic-acid-dependent activation of micro-oxidative bursts and various defense-related genes. Antisense CDR1 plants were compromised for resistance to avirulent P. syringae and more susceptible to virulent strains than wild type. CDR1 accumulates in intercellular fluid in response to pathogen attacks. Induction of CDR1 generates a small mobile signal, and CDR1 action is blocked by the protease inhibitor pepstatin and by mutations in the protease active sites. We propose that CDR1 mediates a peptide signal system involved in the activation of inducible resistance mechanisms. [ABSTRACT FROM AUTHOR]

A new biodegradable flocculant was prepared from a common and inexpensive protein. Milk casein was methylated in a 0.05 M HCl methyl alcohol solution at room temperature. The methylated milk casein (MeCS), having a methylation degree of 81%, was applied to the separation or flocculation of diatomite in seawater (pH 8.1±0.1) at room temperature (18–23 °C). The flocculating ability of MeCS was evaluated by a sedimentation balance method (cumulative measurement method). The diatomite suspension was effectively flocculated by the addition of a small amount of MeCS (0.25 wt% of the diatomite weight). The results of sedimentation analysis showed that the size–frequency curve had a very sharp and high peak; thus the diatomite floc formed by MeCS had a rather uniform size. The settling velocity of diatomite floc at the appropriate MeCS dosages (0.25–2 wt% of diatomite) was about 3×10−3 m s−1. [Copyright &y& Elsevier]

A new biosorbent, methylated yeast (MeYE), was prepared for the adsorptive separation of proteins from aqueous solutions. Yeast was methylated in a 0.1 M HCl methyl alcohol solution at room temperature. About 80% of the carboxylic groups of yeast could be methylated within 9 h. The adsorption of egg albumin onto MeYE was studied to evaluate the protein adsorption ability of MeYE. At near neutral pH, egg albumin was scarcely adsorbed onto unmethylated yeast and the adsorbed amount of egg albumin increased with increasing methylation degree. The amount of egg albumin adsorbed onto MeYE increased with increasing pH from 4 to 7 and steeply decreased above pH 7. The Langmuir isotherm was applied to determine the apparent adsorption constant and the saturated adsorbed amount of egg albumin on MeYE. Both the apparent adsorption constant and the saturated adsorbed amount increased with the degree of methylation. The saturated adsorbed amount of egg albumin onto MeYE having methylation degree 77% was 8.41×10−6 mol g−1 or 0.378 g g−1 at near neutral pH. [Copyright &y& Elsevier]

Platelet-derived growth factor plays a critical role to convert bone marrow cells into glomerular mesangial-like cells. Background. Despite increasing interest in bone marrow–derived stem cells, little is known about critical factors that determine their fates both in vitro and in vivo. Recently, we have reported that bone marrow is a reservoir for glomerular mesangial cells in rats. To find a key factor responsible for the differentiation of bone marrow–derived cells into mesangial cells, we established a new culture system of rat bone marrow, which is based on serial replating and differential attachment to collagen types I and IV. Methods. Bone marrow cells that did not adhere to collagen type I within 24 hours were transferred to collagen type IV–coated dishes. Then, the cells attached to collagen type IV in the following 24 hours were maintained in the presence of 2% horse serum, 200 ng/mL of platelet-derived growth factor (PDGF)-BB, and 1 μmol/L of all- trans retinoic acid. In vivo effect of PDGF-B was also examined by introducing human PDGF-B gene into glomeruli. Results. After cultivation under the above condition for 7 days, approximately 14% of cells expressed Thy-1 and desmin, both of which are markers for rat mesangial cells. Thy-1++/desmin+ cells were stellate-shaped, and contracted in response to angiotensin II. When human PDGF-B gene was overexpressed in the glomeruli of chimeric rats whose bone marrow was transplanted from enhanced green florescent protein (EGFP) transgenic rats, the number of EGFP+ mesangial cells increased. This effect was canceled by prior introduction of a neutralizing molecule that is composed of PDGF receptor-β ligand binding site and IgG-Fc. Conclusion. These results indicate that PDGF-B plays a critical role to direct bone marrow–derived cells toward mesangial-like cells both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

We give an alternative definition of comprehensive Gro¨bner bases in terms of Gro¨bner bases in polynomial rings over commutative Von Neumann regular rings. Our comprehensive Gro¨bner bases are defined as Gro¨bner bases in polynomial rings over certain commutative Von Neumann regular rings, hence they have two important properties which do not hold in standard comprehensive Gro¨bner bases. One is that they have canonical forms in a natural way. Another one is that we can define monomial reductions which are compatible with any instantiation. Our comprehensive Gro¨bner bases are wider than Weispfenning’s original comprehensive Gro¨bner bases. That is there exists a polynomial ideal generated by our comprehensive Gro¨bner basis which cannot be generated by any of Weispfenning’s original comprehensive Gro¨bner bases. [Copyright &y& Elsevier]

A common and inexpensive protein, egg albumin, was applied to the solid–liquid separation or flocculation of diatomite. Egg albumin was methylated in a 0.05 M HCl methyl alcohol solution at room temperature. About 90% of the carboxylic groups of egg albumin could be methylated within 24 h. The adsorption of egg albumin onto diatomite at pH 6.8 was remarkably enhanced by methylation. The adsorption constant of methylated egg albumin to diatomite at 30 °C was about 100-fold larger than that of native egg albumin; however, the adsorption constant of methylated egg albumin decreased to about 1/100 with temperature decreasing from 30 to 6 °C. The saturated adsorption amount of egg albumin was also increased by the methylation. The flocculating ability of methylated egg albumin was examined with a diatomite suspension at 6 and 30 °C in the pH range from pH 2 to 11. The diatomite suspension was effectively flocculated by the addition of small amounts of methylated egg albumin (only 0.5–1 wt% against diatomite) over a wide pH range from pH 3 to 10. [Copyright &y& Elsevier]

A fundamental study about the selective foam separation of protein mixture was carried out. A solution containing two proteins, ovalbumin (OA) and lysozyme (LZ), and an anionic surfactant, sodium dodecyl sulfate (SDS), was adjusted to pH 6.0, which referred to an intermediate state between the isoelectric points of the proteins. The solution was processed by continuous foam separation. The results showed that a proper addition of SDS greatly improved the selective recovery of LZ to OA. The experimental data were well explained by a simple model that most of cationic protein molecules (LZ) are associated with SDS and the adsorption of all the species including LZ–SDS complexes are subjected to Langmuir adsorption isotherm. The results also showed that one of the Langmuir parameters, which means a kind of lyophillic property of adsorbed material, of LZ–SDS complexes was extremely large as compared with that of primary protein. [Copyright &y& Elsevier]

Tornado extraction: A method to enrich and purify RNA from the nephrogenic zone of the neonatal rat kidney. Background. Development of the kidney is a complicated and tightly regulated process. Although several genes responsible for the renal development have been identified to date, the precise mechanisms of spatial and temporal regulation remain to be elucidated. Therefore, expanding our knowledge of molecules that are associated with nephrogenesis will be helpful to understand the whole process. Methods. To extract RNA selectively from the nephrogenic zone of the developing kidney, we developed a simple and reliable method. Results. This method, named “tornado extraction,” enriched RNA of the nephrogenic zone by about 30-fold. In combination with the suppression subtractive hybridization, a considerable number of genes that were differentially expressed in the nephrogenic zone were obtained. These genes included a series of endodermal markers such as albumin and α-fetoprotein as well as GDNF (glia-derived neurotrophic factor), osteoblast-specific factor-2 (OSF-2)/periostin and fetuin (one of the major serum proteins in the fetus). Conclusion. Tornado extraction has great value in studying genes in the nephrogenic zone of the developing kidney. Since the quality of RNA obtained by this method is excellent, tornado extraction is suitable in combination with other techniques including the subtractive hybridization method and DNA microarray analysis. [ABSTRACT FROM AUTHOR]

The palladium-catalyzed cross-coupling reaction between different types of organoboron compounds, sp2-, sp3-, and sp-hybridized carbon&z.sbnd;boron compounds and various organic electrophiles in the presence of base provides a powerful and general methodology for the formation of carbon&z.sbnd;carbon bonds. The coupling reaction offers several advantages. An overview of the coupling reaction will be presented. [Copyright &y& Elsevier]

Adsorption of cadmium and lead ions to floc-type biosorbents was reported in this work. Two types of biosorbents containing a marine microalga, Heterosigma akashiwo (Hada) Hada, or a purple non-sulfur bacterium, Rhodobacter sphaeroides, were prepared. The micro-organisms inactivated by steam sterilization were immobilized in casein floc and cross-linked with glutaraldehyde. In the present immobilizing method, we obtained the biosorbents comprising as much as 67% of micro-organism on a dry-weight basis. Simple metal-binding models were applied to explain the adsorption mechanism of bivalent metal ions to the biosorbents. The results showed that casein acted as both the immobilizing material and the adsorbent material. The adsorption of bivalent metal ions to the biosorbents was due to bidentate binding to the acidic sites on casein and monodentate binding to the acidic sites on micro-organisms. The metal-binding constants and the binding capacities of micro-organisms were scarcely influenced by immobilization. [Copyright &y& Elsevier]

A kinetic study of cadmium and lead biosorption to a brown alga, Kjellmaniella crassiforia, was carried out. The shrinking core model derived by M. Gopala Rao and A. K. Gupta (Chem. Eng. J.24, 181, (1982)) was modified and adapted for description of the rate process of cadmium and lead biosorption to the alga. The biosorption rate process was well described and average apparent diffusion coefficient of about 9×10−6 cm2 s−1 was found for both cadmium and lead ions. The value was 20 to 50 times higher than the apparent diffusion coefficients of cadmium and lead ions in strong-acid resins like Dowex 50W-X8. [Copyright &y& Elsevier]

The development of next-generation sequencing (NGS) has enabled the discovery of cancer-specific driver gene alternations, making precision medicine possible. However, accurate genetic testing requires a sufficient amount of tumor cells in the specimen. The evaluation of tumor content ratio (TCR) from hematoxylin and eosin (H&E)-stained images has been found to vary between pathologists, making it an important challenge to obtain an accurate TCR. In this study, three pathologists exhaustively labeled all cells in 41 regions from 41 lung cancer cases as either tumor, non-tumor or indistinguishable, thus establishing a "gold standard" TCR. We then compared the accuracy of the TCR estimated by 13 pathologists based on visual assessment and the TCR calculated by an AI model that we have developed. It is a compact and fast model that follows a fully convolutional neural network architecture and produces cell detection maps which can be efficiently post-processed to obtain tumor and non-tumor cell counts from which TCR is calculated. Its raw cell detection accuracy is 92% while its classification accuracy is 84%. The results show that the error between the gold standard TCR and the AI calculation was significantly smaller than that between the gold standard TCR and the pathologist's visual assessment ( p < 0.05 ). Additionally, the robustness of AI models across institutions is a key issue and we demonstrate that the variation in AI was smaller than that in the average of pathologists when evaluated by institution. These findings suggest that the accuracy of tumor cellularity assessments in clinical workflows is significantly improved by the introduction of robust AI models, leading to more efficient genetic testing and ultimately to better patient outcomes. [ABSTRACT FROM AUTHOR]

Presents information on a study which shows that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3'K/PKB/Akt signaling pathway. Overview of the study; Results; Discussion; Experimental procedures.

Ferredoxin (Fd)-dependent glutamate synthase is present in green leaves, etiolated leaves, shoots, and roots of Arabidopsis thaliana (ecotype Columbia). In photosynthetic green leaves and shoots, Fd-dependent glutamate synthase accounts for more than 96% of the total glutamate synthase activity in vitro with the remaining activity derived from an enzyme that uses NADH as the electron donor. In etiolated leaves and roots, Fd-dependent glutamate synthase is 3-4-fold less active than in green leaves, but represents 70-85% of the total glutamate synthase activity in these tissues. Fd-dependent glutamate synthase is detected as a single peptide of 165 kDa on a western blot of green leaf and shoot tissues, and this Fd-dependent glutamate synthase polypeptide is 3-4-fold less abundant in etiolated leaves and roots. In these non-photosynthetic tissues, there is a higher activity of NADH-dependent glutamate synthase. The A. thaliana gltS mutant (strain CS254) contains, only 1.7% and 17.5% of the wild-type Fd-dependent glutamate synthase activity in leaves and roots, respectively. Western blots indicate that the Fd-dependent glutamate synthase peptide of 165 kDa is absent from leaves and roots of the gltS mutant. In contrast, NADH-dependent glutamate synthase activity in leaves and roots is unaffected. During illumination of wild-type dark-grown leaves for 72 h, the levels of Fd-dependent glutamate synthase protein and its activity increased threefold to levels equivalent to those in green leaves. In contrast, NADH-dependent glutamate synthase activity decreases, twofold during illumination. The complete nucleotide sequence of the complementary DNA for A. thaliana Fd-dependent glutamate synthase has been determined. Analysis of the amino acid sequence deduced from the complete cDNA sequence (5178 bp) has revealed that A. thaliana Fd-dependent glutamate synthase is synthesized as a 1648-amino-acid precursor protein (180090 Da) which consists of a 131-amino-acid transit peptide (14603 Da) and a 1517-amino-acid mature peptide (165487 Da). The A. thaliana Fd-dependent glutamate synthase has a high similarity to maize Fd-dependent glutamate synthase (83%) and to the analogous region of NADH-dependent glutamate synthase (42%) and NADPH-dependent glutamate synthases (40-43%) from different organisms. The A. thaliana Fd-dependent glutamate synthase contains the purF-type glutamine-amido-transfer domare as well as ravin and iron-sulfur-cluster-binding domains. The deduced primary structures of A. thaliana Fd-dependent glutamate synthase and of glutamate synthases from other organisms indicate that Fd-dependent glutamate synthase may have evolved from bacterial NADPH-dependent glutamate synthase. The cDNA hybridized to RNA of about 5.3 kb from different tissues of A. thaliana. A high steadystate level of Fd-dependent glutamate synthase mRNA is found in photosynthetic green leaves and shoots, and roots contain less mRNA for Fd-dependent glutamate synthase. In the gltS mutant, there are twofold and fourfold lower levels of Fd-dependent glutamate synthase mRNA in leaves and roots, respectively, relative to those in wild-type A. thaliana. Under continuous illumination of dark-grown leaves, the Fddependent glutamate synthase mRNA is induced twofold to a level equivalent to that in green leaves. [ABSTRACT FROM AUTHOR]

Spinach leaf ferredoxin and ferredoxin : NADP oxidoreductase as well as pig adrenodoxin and adrenodoxin reductase have been purified to homogeneity. Ferredoxin-NADP reductase and adrenodoxin-NADP reductase can perform the same diaphorase reactions (dichloroindophenol, ferricyanide and cytochrome c reduction) albeit not with the same efficiency. Despite the differences in their redox potentials, animal and plant ferredoxins can be used as heterologous substrates by the ferredoxin-NADP reductases from both sources. In heterologous systems, however, the ferredoxin/adrenodoxin concentrations must be increased approximately 100-fold in order to reach rates similar to those obtained in homologous systems. Ferredoxin and adrenodoxin can form complexes with the heterologous reductases as demonstrated by binding experiments on ferredoxin-Sepharose or ferredoxin- NADP-reductase - Sepharose and by the realization of difference spectra. Adrenodoxin also weakly substitutes for ferredoxin in NADP photoreduction, and can be used as an electron carrier in the light activation of the chloroplastic enzyme NADP-dependent malate dehydrogenase. In addition adrenodoxin is a good catalyst of pseudocyclic photophosphorylation, but not of cyclic phosphorylation and can serve as a substrate of glutamate synthase. These results are discussed with respect to the known structures of plant and animals ferredoxins and their respective reductases. [ABSTRACT FROM AUTHOR]

A growing number of papers are published in the area of superconducting materials science. However, novel text and data mining (TDM) processes are still needed to efficiently access and exploit this accumulated knowledge, paving the way towards data-driven materials design. Herein, we present SuperMat (Superconductor Materials), an annotated corpus of linked data derived from scientific publications on superconductors, which comprises 142 articles, 16052 entities, and 1398 links that are characterised into six categories: the names, classes, and properties of materials; links to their respective superconducting critical temperature (Tc); and parametric conditions such as applied pressure or measurement methods. The construction of SuperMat resulted from a fruitful collaboration between computer scientists and material scientists, and its high quality is ensured through validation by domain experts. The quality of the annotation guidelines was ensured by satisfactory Inter Annotator Agreement (IAA) between the annotators and the domain experts. SuperMat includes the dataset, annotation guidelines, and annotation support tools that use automatic suggestions to help minimise human errors. [ABSTRACT FROM AUTHOR]

Thymus- and activation-regulated chemokine (TARC, also known as CCL17) is used as a biomarker for atopic dermatitis. The methods currently used for its measurement are complex, time-consuming, and require large machinery, warranting the need for a method that is simple, has a quick turnaround time, and requires less complex machinery. We evaluated the analytical performance of a novel latex turbidimetric immunoassay method, "Nanopia TARC", on 174 residual serum samples from patients with skin or allergic diseases. This evaluation included the assessment of the limit of blank/detection/quantification (LOB/D/Q), precision, accuracy, linearity, interference, and commutability between Nanopia TARC and "HISCL TARC", based on the chemiluminescent enzyme immunoassay (CLEIA) method. The LOB/D/Q values were 13, 57, and 141 pg/mL, respectively. The coefficient of variation of the repeatability was 0.9–3.8%, and that of the intermediate precision was 2.1–5.4%. The total error of the accuracy was 1.9–13.4%. The linearity was 141 and 19,804 pg/mL for TARC. The correlation coefficient between Nanopia TARC and HISCL TARC determined using the Passing–Bablok regression analysis was 0.999. Furthermore, the concordance of diagnostic criteria with AD was 92%. Nanopia TARC was confirmed to have the same analytical performance for TARC measurement as the existing CLEIA method. [ABSTRACT FROM AUTHOR]

The patient was a woman in her 60s. She was found to have proteinuria on a health checkup. She did not have any particular subjective symptoms, and no definitive diagnosis was made, despite serological findings indicative of immune abnormalities. A renal biopsy was performed. Light microscopy of renal tissue section revealed mesangial proliferative nephritis. Electron microscopic findings included electron-dense deposits and fibrillar/tubular structures with a diameter of 20–30 nm. These findings suggested the presence of cryoglobulin (CG), but CG was not detected in qualitative or quantitative hematologic tests. Thus, the serum samples were stored at 37°C for a long period of time and then cooled to 4°C. When the obtained precipitates were examined, CG was successfully detected. CG that precipitates only after a long period of time is referred to as slow cryoglobulin (sCG), and sCG is extremely rare. The present case is the first documented case, to our knowledge, of renal disorders caused by sCG. It should be noted that there are some cases in which it takes much time for CG to precipitate. Thus, when CG cannot be detected, it is necessary to spend much time to determine whether CG precipitates. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the fifth most common cancer of female cancer death and leading cause of lethal gynecological cancers. High‐grade serous ovarian carcinoma (HGSOC) is an aggressive malignancy that is rapidly fatal. Many cases of OC show amplification of the 8q24 chromosomal region, which contains the well‐known oncogene MYC. Although MYC amplification is more frequently observed in OCs than in other tumor types, due to the large size of the 8q24 amplicon, the functions of the vast majority of the genes it contains are still unknown. The TIGD5 gene is located at 8q24.3 and encodes a nuclear protein with a DNA‐binding motif, but its precise role is obscure. We show here that TIGD5 often co‐amplifies with MYC in OCs, and that OC patients with high TIGD5 mRNA expression have a poor prognosis. However, we also found that TIGD5 overexpression in ovarian cancer cell lines unexpectedly suppressed their growth, adhesion, and invasion in vitro, and also reduced tumor growth in xenografted nude mice in vivo. Thus, our work suggests that TIGD5 may in fact operate as a tumor suppressor in OCs rather than as an oncogene. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics which include the influence of fungi to other organisms such as entophytic fungi, Ophiocordyceps sinensis or Chinese caterpillar fungus, and fungal and plant cell structures.

Background: Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined.Methods: The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively.Result: Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated.Conclusion: Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries. [ABSTRACT FROM AUTHOR]

Bladder cancer (BlC) is the fourth most common cancer in males worldwide, but few systemic chemotherapy options for its effective treatment exist. The development of new molecularly‐targeted agents against BlC is therefore an urgent issue. The Hippo signaling pathway, with its upstream LATS kinases and downstream transcriptional co‐activators YAP1 and TAZ, plays a pivotal role in diverse cell functions, including cell proliferation. Recent studies have shown that overexpression of YAP1 occurs in advanced BlCs and is associated with poor patient prognosis. Accessing data from our previous screening of a chemical library of compounds targeting the Hippo pathway, we identified DMPCA (N‐(3,4‐dimethoxyphenethyl)‐6‐methyl‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐amine) as an agent able to induce the phosphorylation of LATS1 and YAP1/TAZ in BlC cells, thereby suppressing their viability both in vitro and in mouse xenografts. Our data indicate that DMPCA has a potent anti‐tumor effect, and raise the possibility that this agent may represent a new and effective therapeutic option for BlC. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yesassociated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is heterogeneous in terms of proteinuria. Patients with DKD who present with low-grade proteinuria are more likely to have nephrosclerosis rather than traditional diabetic nephropathy. The amount of proteinuria might reflect the underlying pathology of renal failure and influence the prognosis after dialysis initiation. Clinical implications of proteinuria at the start of dialysis have not been confirmed, while greater proteinuria is associated with higher risk of cardiovascular disease (CVD) in the predialysis stages of chronic kidney disease. We performed a retrospective multicenter cohort study enrolling incident hemodialysis patients with diabetes. Patients were stratified using proteinuria quartiles. We examined the association of proteinuria quartiles with types of subsequent CVD. Among the enrolled 361 patients, the estimated mean glomerular filtration rate and proteinuria was 5.4 mL/min/1.73 m2 and 6.3 g/gCr, respectively. Lower quartile of proteinuria (cut-offs: 3.0, 5.4, and 8.8 g/gCr) was significantly associated with male, older age, and history of atherosclerotic CVD including coronary artery disease, peripheral arterial disease, and cerebral infarction (Ptrend<0.05). Kidney size was smaller in patients with lower levels of proteinuria. Patients with higher levels of proteinuria were more likely to have proliferative diabetic retinopathy (Ptrend<0.05). Multivariate competing risk analysis revealed that the first quartile of proteinuria was associated with a greater risk of atherosclerotic CVD than the third quartile (subhazard ratio [95% confidence interval]: 2.04 [1.00–4.14]). This association was attenuated after additional adjustments for history of atherosclerotic CVD. Furthermore, patients with lower quartiles of proteinuria were more likely to die of atherosclerotic CVD than those with non-atherosclerotic CVD (Ptrend = 0.01). Diabetic patients with lower proteinuria at dialysis initiation were characterized by severer macroangiopathy, as shown by a more atrophic kidney and higher prevalence of past atherosclerotic CVD. Hence, they are at a high risk of developing atherosclerotic CVD. [ABSTRACT FROM AUTHOR]

Objective Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV. Methods NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats. Results When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum. Conclusion Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV. [ABSTRACT FROM AUTHOR]