Comparison of two- and three-dimensional simulations of miscible Rayleigh-Taylor instability

A comparison of two-dimensional and three-dimensional high-resolution numerical large-eddy simulations of planar, miscible Rayleigh-Taylor instability flows are presented. The resolution of the three-dimensional simulation is sufficient to attain a fully turbulent state. A number of different statistics from the mixing region (e.g., growth rates, PDFs, mixedness measures, and spectra) are used to demonstrate that two-dimensional flow simulations differ substantially from the three-dimensional one. It is found that the two-dimensional flow grows more quickly than its three-dimensional counterpart at late times, develops larger structures, and is much less well mixed. These findings are consistent with the concept of inverse cascade in two-dimensional flow, as well as the influence of a reduced effective Atwood number on miscible flow

BCG-INDUCED PRO-INFLAMMATORY PHENOTYPE OF MESENCHYMAL STEM CELLS: EFFECT OF IMMUNE MODULATORS

In case of mycobacterial infection the granulomatous infiltration foci contain the significant amount of mesenchymal stem cells (MSC), which functional phenotype and respective function in anti-tuberculosis immune defense remain unknown.Goal of the study: to characterize the MSC phenotype, formed by their interaction with BCG of M. bovis and to evaluate the changes in this phenotype caused by the action of inhibitors and stimulants of immune regulatory action.Materials and methods: MSC retrieved from bone marrow of mice were cultured with the presence and absence of BCG of M. bovis and/or poludanum TLR3 agonist; and the effect of two latter on the production of pro- and anti-inflammatory cytokines was evaluated by enzyme multiplied immunoassay. Flow cytometry and radioactive testing were used to evaluate the impact of cultured BCG fluid and poludanum-conditioned MSC on the proliferative and apoptotic activity of splenocytes. The inhibitors of indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2 (COG-2) or NO synthase were added to certain cultures alone with BCG and poludanum, and the contributions of IDO, COG-2 and NO to BCG and poludanum-induced response were assessed.Results. Pro-inflammatory polarization of MSC under the action of BCG and poludanum was demonstrated. Pro-inflammatory MSC phenotype correlated to their anti-apoptogenic and growth-stimulating actions on the splenocytes. It was demonstrated that IDO and NO restrained BCG-induced polarization and conversely COG-2 promoted BCG-induced pro-inflammatory polarization of MSC.Conclusions. 1. MSC actively participate in the formation of immunologic anti-mycobacterial resistance. 2. Targeted regulation of IDO and NO production can be feasibly applied for formation of anti-tuberculous vaccinal immunity and control mycobacterial infection

БЦЖ-ИНДУЦИРОВАННЫЙ ПРОВОСПАЛИТЕЛЬНЫЙ ФЕНОТИП МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК: ВЛИЯНИЕ ИММУНОМОДУЛЯТОРОВ

In case of mycobacterial infection the granulomatous infiltration foci contain the significant amount of mesenchymal stem cells (MSC), which functional phenotype and respective function in anti-tuberculosis immune defense remain unknown.Goal of the study: to characterize the MSC phenotype, formed by their interaction with BCG of M. bovis and to evaluate the changes in this phenotype caused by the action of inhibitors and stimulants of immune regulatory action.Materials and methods: MSC retrieved from bone marrow of mice were cultured with the presence and absence of BCG of M. bovis and/or poludanum TLR3 agonist; and the effect of two latter on the production of pro- and anti-inflammatory cytokines was evaluated by enzyme multiplied immunoassay. Flow cytometry and radioactive testing were used to evaluate the impact of cultured BCG fluid and poludanum-conditioned MSC on the proliferative and apoptotic activity of splenocytes. The inhibitors of indoleamine 2,3-dioxygenase (IDO), cyclooxygenase-2 (COG-2) or NO synthase were added to certain cultures alone with BCG and poludanum, and the contributions of IDO, COG-2 and NO to BCG and poludanum-induced response were assessed.Results. Pro-inflammatory polarization of MSC under the action of BCG and poludanum was demonstrated. Pro-inflammatory MSC phenotype correlated to their anti-apoptogenic and growth-stimulating actions on the splenocytes. It was demonstrated that IDO and NO restrained BCG-induced polarization and conversely COG-2 promoted BCG-induced pro-inflammatory polarization of MSC.Conclusions. 1. MSC actively participate in the formation of immunologic anti-mycobacterial resistance. 2. Targeted regulation of IDO and NO production can be feasibly applied for formation of anti-tuberculous vaccinal immunity and control mycobacterial infection. При микобактериальной инфекции в очагах гранулематозной инфильтрации содержится большое количество мезенхимальных стволовых клеток (МСК), функциональный фенотип которых и, соответственно, функция в противотуберкулезном иммунитете неизвестны.Цель исследования: охарактеризовать фенотип МСК, формирующийся при их взаимодействии с M. bovis БЦЖ, и оценить изменения этого фенотипа под действием ингибиторов и стимуляторов иммунорегуляторной активности.Материалы и методы: МСК, полученные из костного мозга мышей, культивировали в присутствии или отсутствии M. bovis БЦЖ и/или агониста TLR3 полудана и методами иммуноферментного анализа оценивали влияние последних на продукцию про- и антивоспалительных цитокинов. Методами проточной цитометрии и радиоактивного анализа оценивали влияние культуральной жидкости БЦЖ- и полудан-кондиционированных МСК на пролиферативную и апоптотическую активность спленоцитов. В часть культур вместе с БЦЖ или полуданом добавляли ингибиторы индоламин-2,3-диоксигеназы (ИДО), циклооксигеназы-2 (ЦОГ-2) или NO синтазы и оценивали вклад ИДО, ЦОГ-2 и NO в БЦЖ- и полудан-индуцированный ответ.Результаты. Показана провоспалительная поляризация МСК под действием БЦЖ и полудана. Провоспалительный фенотип МСК коррелировал с их антиапоптогенной и ростостимулирующей активностью по отношению к спленоцитам. Продемонстрировано, что ИДО и NO сдерживают БЦЖ-индуцированную поляризацию, а активность ЦОГ-2, наоборот, способствует БЦЖ-индуцированной провоспалительной поляризации МСК.Выводы. 1. МСК являются активными участники формирования иммунологической антимикобактериальной резистентности. 2. Таргетное регулирование продукции ИДО и оксида азота может быть целесообразно для формирования противотуберкулезного вакцинального иммунитета и для борьбы с микобактериальной инфекцией

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Клинико-морфологические варианты дебюта гепатитов при врождённой цитомегаловирусной инфекции и гепатите С

We present comparative analysis of clinical – morphological data from infants with congenital cytomegalovirus and hepatitis C infection. 97 patients with hepatitis underwent a standard set of clinical and laboratory tests. ELISA and PCR were used to verify infectious agents. Informed consent to perform a liver biopsy was obtained from the parents of 28 children. immunohistochemical test of the liver samples managed to identify markers of cytomegalovirus (protein pp65 and p52) and hepatitis C (helicase NS3). The hepatitis C virus was detected in 41 patients: 3a genotype – 68.3%, 1b –31.7% respectively. Congenital hepatitis C onset presents itself as mild and atypical and causes chronic hepatitis with the 1st degree fibrosis. Cytomegalovirus replication markers were found in 56 children. The most common manifestations of hepatitis associated with cytomegalovirus infection are prolonged jaundice, cholestasis, gepatolienalny syndrome, early onset of the disease with increased transaminase levels and dominance in AST. Structural changes of the liver are characterized by the presence of inflammatory infiltration, cholestasis with duktulopenia, lobular structure damage. Congenital cytomegalovirus-related hepatitis is likely to result in liver cirrhosis and is associated with poor prognosis.Представлен сравнительный анализ клинико-морфологических данных у детей первого года жизни с врожденным гепатитом С и цитомегаловирусной инфекцией. У 97 больных гепатитом применён стандартный комплекс клинических и лабораторных исследований, верификация инфекционных агентов проведена методами ИФА и ПЦР-диагностики. Разрешение на проведение биопсии печени получено у родителей 28 детей. В гепатобиоптатах методом иммуногистохимии идентифицированы маркёры цитомегаловирусной инфекции (белок pp65 и p52) и гепатита С (хеликаза NS3). Вирус гепатита С выявлен у 41 ребёнка: 3а генотип – 68,3%, 1в – 31,7%. Врождённый гепатит С дебютирует в атипичной лёгкой форме и формирует хронический гепатит с фиброзом 1 степени. Маркёры репликации цитомегаловируса обнаружены у 56 детей. «Визитной карточкой» гепатита при цитомегаловирусной инфекции является затяжная желтуха, холестаз, гепатолиенальный синдром, ранний дебют болезни с повышением уровня трансаминаз и доминированием уровня АсАТ. Структурные изменения печени характеризуются наличием воспалительной инфильтрации, холестаза с признаками дуктулопении, нарушением долькового строения. При врождённом цитомегаловирусном гепатите высока вероятность исхода заболевания в цирроз печени и неблагоприятный прогноз

Eradication of Metastatic Renal Cell Carcinoma after Adenovirus-Encoded TNF-Related Apoptosis-Inducing Ligand (TRAIL)/CpG Immunotherapy

Despite evidence that antitumor immunity can be protective against renal cell carcinoma (RCC), few patients respond objectively to immunotherapy and the disease is fatal once metastases develop. We asked to what extent combinatorial immunotherapy with Adenovirus-encoded murine TNF-related apoptosis-inducing ligand (Ad5mTRAIL) plus CpG oligonucleotide, given at the primary tumor site, would prove efficacious against metastatic murine RCC. To quantitate primary renal and metastatic tumor growth in mice, we developed a luciferase-expressing Renca cell line, and monitored tumor burdens via bioluminescent imaging. Orthotopic tumor challenge gave rise to aggressive primary tumors and lung metastases that were detectable by day 7. Intra-renal administration of Ad5mTRAIL+CpG on day 7 led to an influx of effector phenotype CD4 and CD8 T cells into the kidney by day 12 and regression of established primary renal tumors. Intra-renal immunotherapy also led to systemic immune responses characterized by splenomegaly, elevated serum IgG levels, increased CD4 and CD8 T cell infiltration into the lungs, and elimination of metastatic lung tumors. Tumor regression was primarily dependent upon CD8 T cells and resulted in prolonged survival of treated mice. Thus, local administration of Ad5mTRAIL+CpG at the primary tumor site can initiate CD8-dependent systemic immunity that is sufficient to cause regression of metastatic lung tumors. A similar approach may prove beneficial for patients with metastatic RCC

Phase transition in Random Circuit Sampling

Quantum computers hold the promise of executing tasks beyond the capability of classical computers. Noise competes with coherent evolution and destroys long-range correlations, making it an outstanding challenge to fully leverage the computation power of near-term quantum processors. We report Random Circuit Sampling (RCS) experiments where we identify distinct phases driven by the interplay between quantum dynamics and noise. Using cross-entropy benchmarking, we observe phase boundaries which can define the computational complexity of noisy quantum evolution. We conclude by presenting an RCS experiment with 70 qubits at 24 cycles. We estimate the computational cost against improved classical methods and demonstrate that our experiment is beyond the capabilities of existing classical supercomputers

Two Dimensional Simulations of Plastic-Shell, Direct-Drive Implosions on OMEGA

Multidimensional hydrodynamic properties of high-adiabat direct-drive plastic-shell implosions on the OMEGA laser system [T. R. Boehly et al., Opt. Commun. 133, 495 (1997)] are investigated using the multidimensional hydrodynamic code, DRACO. Multimode simulations including the effects of nonuniform illumination and target roughness indicate that shell stability during the acceleration phase plays a critical role in determining target performance. For thick shells that remain integral during the acceleration phase, target yields are significantly reduced by the combination of the long-wavelength ({ell} < 10) modes due to surface roughness and beam imbalance and the intermediate modes (20 {le} {ell} {le} 50) due to single-beam nonuniformities. The neutron-production rate for these thick shells truncates relative to one-dimensional (1-D) predictions. The yield degradation in the thin shells is mainly due to shell breakup at short wavelengths ({lambda} {approx} {Delta}, where {Delta} is the in-flight shell thickness). The neutron-rate curves for the thinner shells have significantly lower amplitudes and a fall-off that is less steep than 1-D rates. DRACO simulation results are consistent with experimental observations