2,5-Dimethyl­pyrazine 1,4-dioxide

The title compound, C6H8N2O2, was prepared from 2,5-dimethyl­pyrazine, acetic acid, and hydrogen peroxide. The 2,5-dimethyl­pyrazine 1,4-dioxide mol­ecule is located on an inversion center. π–π inter­actions between neighboring 2,5-dimethyl­pyrazine 1,4-dioxide mol­ecules are observed with an inter­planar distance of 3.191 Å. Each 2,5-dimethyl­pyrazine 1,4-dioxide mol­ecule is linked to four neighboring N-oxide mol­ecules through C—H⋯O hydrogen-bonding inter­actions, forming two-dimensional layers

An Alternant Method to the Traditional NASA Hindlimb Unloading Model in Mice

The Morey-Holton hindlimb unloading (HU) method is a widely accepted National Aeronautics and Space Administration (NASA) ground-based model for studying disuse-atrophy in rodents 4-6. Our study evaluated an alternant method to the gold-standard Morey-Holton HU tail-traction technique in mice. Fifty-four female mice (4-8 mo.) were HU for 14 days (n=34) or 28 days (n=20). Recovery from HU was assessed after 3 days of normal cage ambulation following HU (n=22). Aged matched mice (n=76) served as weight-bearing controls

Exploring Meaningful Patient Engagement in ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness).

BackgroundGenuine patient engagement can improve research relevance, impact and is required for studies using the National Patient-Centered Clinical Research Network including major multicenter research projects. It is unclear, however, how best to integrate patients into governance of such projects.MethodsADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-term Effectiveness) is the first major multicenter research project to be conducted in National Patient-Centered Clinical Research Network. Here, we provide a description of how we implemented patient engagement in ADAPTABLE thus far, including a description of committee structures and composition, first-hand patient testimonials, specific contributions, and lessons learned during the planning and early implementation of ADAPTABLE.ResultsWe recruited 1 patient leader from 6 of the 7 enrolling networks to serve on a Patient Review Board for ADAPTABLE, supported the Board with an experienced patient engagement team including an "investigator-advocate" not otherwise involved in the trial, and facilitated bidirectional communication between the Board and ADAPTABLE Coordinating Center. The Board has reviewed and provided substantial input on the informed consent procedure, recruitment materials, patient portal design, and study policy including compensation of participants. Although it was "too late" for some suggested modifications, most modifications suggested by the patient leaders have been implemented, and they are enthusiastic about the study and their role. The patient leaders also attend Steering and Executive Committee calls; these experiences have been somewhat less productive.ConclusionsWith adequate support, a cadre of committed patient leaders can provide substantial value to design and implementation of a major multicenter clinical trial

Decoupling the World Wide Web From Linked Lists in I/O Automata

E-business must work. After years of structured research into information retrieval systems, we argue the emulation of checksums. We propose new stable technology, which we call ILIUM

Control of protein palmitoylation by regulating substrate recruitment to a zDHHC-protein acyltransferase

Although palmitoylation regulates numerous cellular processes, as yet efforts to manipulate this post-translational modification for therapeutic gain have proved unsuccessful. The Na-pump accessory sub-unit phospholemman (PLM) is palmitoylated by zDHHC5. Here, we show that PLM palmitoylation is facilitated by recruitment of the Na-pump α sub-unit to a specific site on zDHHC5 that contains a juxtamembrane amphipathic helix. Site-specific palmitoylation and GlcNAcylation of this helix increased binding between the Na-pump and zDHHC5, promoting PLM palmitoylation. In contrast, disruption of the zDHHC5-Na-pump interaction with a cell penetrating peptide reduced PLM palmitoylation. Our results suggest that by manipulating the recruitment of specific substrates to particular zDHHC-palmitoyl acyl transferases, the palmitoylation status of individual proteins can be selectively altered, thus opening the door to the development of molecular modulators of protein palmitoylation for the treatment of disease

The Mechanism of Flexible Controlling as an Innovative Method in Management of Corporate Structures

У статті представлений принцип дії механізму гнучкого контролінгу як інноваційного методу управління корпоративними структурами. Розглянуто принципи застосування даного методу як інструменту ефективного управління корпоративними структурами, що дозволяють забезпечити різноманітність і гнучкість процесів управління для досягнення поставлених цілей. Розглянуто особливості контролінгу в управлінні корпоративними структурами в умовах нестабільного економічного середовища. Подано концепцію механізму контролінгу в управлінні корпоративними структурами, яка дозволяє забезпечити необхідну різноманітність процесів управління для досягнення динамічного комплексу цілей. Розглянуто особливості функціонування корпоративних структур у нестабільному ринковому оточенні. На прикладі механізму гнучкого контролінгу як способу адаптації до реалій сформованої нестабільності в економіці України представлена його здатність оперативно і тонко спрямовувати управління корпоративними структурами для прийняття правильних рішень та погодження роботи всіх підсистем підприємства.В статье представлен принцип действия механизма гибкого контроллинга как инновационного метода управления корпоративными структурами. Рассмотрены принципы применения данного метода как инструмента эффективного управления корпоративными структурами, позволяющие обеспечить разнообразие и гибкость процессов управления для достижения поставленных целей. Рассмотрены особенности контроллинга в управлении корпоративными структурами в условиях нестабильной экономической среды. Представлена концепция механизма контроллинга в управлении корпоративными структурами, которая позволяет обеспечить необходимое разнообразие процессов управления для достижения динамического комплекса целей. Рассмотрены особенности функционирования корпоративных структур в нестабильном рыночном окружении. На примере механизма гибкого контроллинга как способа адаптации к реалиям сложившейся нестабильности в экономике Украины представлена его способность оперативно и тонко направлять управление корпоративными структурами для принятия правильных решений и согласования работы всех подсистем предприятия.This article presents the principle of the mechanism controlling the flexible as an innovative method of managing corporate structures. The principles of this method as a tool for the effective management of corporate structures, allowing for variety and flexibility of management processes to achieve their goals. Features of controlling in management of corporate structures in the conditions of the unstable economic environment are considered. The concept of the mechanism of controlling in management of corporate structures which allows to provide a necessary variety of management processes for achievement of a dynamic complex of the purposes is presented. Features of functioning of corporate structures in an unstable market environment are considered. On the example of controlling a flexible mechanism as a way of adapting to the realities of the current instability in the economy of Ukraine, represented by its ability to quickly and subtly direct the management of the corporate structure to make the right decisions and coordination of all sub-systems of the enterprise

A Francisella tularensis Live Vaccine Strain That Improves Stimulation of Antigen-Presenting Cells Does Not Enhance Vaccine Efficacy

Vaccination is a proven strategy to mitigate morbidity and mortality of infectious diseases. The methodology of identifying and testing new vaccine candidates could be improved with rational design and in vitro testing prior to animal experimentation. The tularemia vaccine, Francisella tularensis live vaccine strain (LVS), does not elicit complete protection against lethal challenge with a virulent type A Francisella strain. One factor that may contribute to this poor performance is limited stimulation of antigen-presenting cells. In this study, we examined whether the interaction of genetically modified LVS strains with human antigen-presenting cells correlated with effectiveness as tularemia vaccine candidates. Human dendritic cells infected with wild-type LVS secrete low levels of proinflammatory cytokines, fail to upregulate costimulatory molecules, and activate human T cells poorly in vitro. One LVS mutant, strain 13B47, stimulated higher levels of proinflammatory cytokines from dendritic cells and macrophages and increased costimulatory molecule expression on dendritic cells compared to wild type. Additionally, 13B47-infected dendritic cells activated T cells more efficiently than LVS-infected cells. A deletion allele of the same gene in LVS displayed similar in vitro characteristics, but vaccination with this strain did not improve survival after challenge with a virulent Francisella strain. In vivo, this mutant was attenuated for growth and did not stimulate T cell responses in the lung comparable to wild type. Therefore, stimulation of antigen-presenting cells in vitro was improved by genetic modification of LVS, but did not correlate with efficacy against challenge in vivo within this model system

Abdominal obesity and other risk factors largely explain the high CRP in Indigenous Australians relative to the general population, but not gender differences: a cross-sectional study

Background: Previous studies reported high C-reactive protein (CRP) levels in Indigenous Australians, which may contribute to their high risk of cardiovascular disease. We compared CRP levels in Indigenous Australians and the general population, accounting for obesity and other risk factors.Methods: Cross-sectional study of CRP and risk factors (weight, height, waist and hip circumferences, blood pressure, lipids, blood glucose, and smoking status) in population-based samples from the Diabetes and Related conditions in Urban Indigenous people in the Darwin region (DRUID) study, and the Australian Diabetes, Obesity and Lifestyle study (AusDiab) follow-up.Results: CRP concentrations were higher in women than men and in DRUID than AusDiab. After multivariate adjustment, including waist circumference, the odds of high CRP (>3.0 mg/L) in DRUID relative to AusDiab were no longer statistically significant, but elevated CRP was still more likely in women than men. After adjusting for BMI (instead of waist circumference) the odds for elevated CRP in DRUID participants were still higher relative to AusDiab participants among women, but not men. Lower HDL cholesterol, impaired glucose tolerance (IGT), and higher diastolic blood pressure were associated with having a high CRP in both men and women, while current smoking was associated with high CRP in men but not women.Conclusions: High concentrations of CRP in Indigenous participants were largely explained by other risk factors, in particular abdominal obesity. Irrespective of its independence as a risk factor, or its aetiological association with coronary heart disease (CHD), the high CRP levels in urban Indigenous women are likely to reflect increased vascular and metabolic risk. The significance of elevated CRP in Indigenous Australians should be investigated in future longitudinal studies

Incidence of necrotising enterocolitis before and after introducing routine prophylactic Lactobacillus and Bifidobacterium probiotics

Objective: To compare rates of necrotising enterocolitis (NEC), late-onset sepsis, and mortality in 5-year epochs before and after implementation of routine daily multistrain probiotics administration in high-risk neonates. Design: Single-centre retrospective observational study over the 10-year period from 1 January 2008 to 31 December 2017. Setting: Level 3 neonatal intensive care unit (NICU) of the Norfolk and Norwich University Hospital, UK. Patients: Preterm neonates at high risk of NEC: Admitted to NICU within 3 days of birth at <32 weeks' gestation or at 32-36 weeks' gestation and of birth weight <1500 g. Intervention: Prior to 1 January 2013 probiotics were not used. Thereafter, dual-species Lactobacillus acidophilus and Bifidobacterium bifidum combination probiotics were routinely administered daily to high-risk neonates; from April 2016 triple-species probiotics (L.acidophilus,B.bifidum, and B.longum subspecies infantis) were used. Main outcome measures: Incidence of NEC (modified Bell's stage 2a or greater), late-onset sepsis, and mortality. Results: Rates of NEC fell from 7.5% (35/469 neonates) in the pre-implementation epoch to 3.1% (16/513 neonates) in the routine probiotics epoch (adjusted sub-hazard ratio=0.44, 95% CI 0.23 to 0.85, p=0.014). The more than halving of NEC rates after probiotics introduction was independent of any measured covariates, including breast milk feeding rates. Cases of late-onset sepsis fell from 106/469 (22.6%) to 59/513 (11.5%) (p<0.0001), and there was no episode of sepsis due to Lactobacillus or Bifidobacterium. All-cause mortality also fell in the routine probiotics epoch, from 67/469 (14.3%) to 47/513 (9.2%), although this was not statistically significant after multivariable adjustment (adjusted sub-hazard ratio=0.74, 95% CI 0.49 to 1.12, p=0.155). Conclusions: Administration of multispecies Lactobacillus and Bifidobacterium probiotics has been associated with a significantly decreased risk of NEC and late-onset sepsis in our neonatal unit, and no safety issues. Our data are consistent with routine use of Lactobacillus and Bifidobacterium combination probiotics having a beneficial effect on NEC prevention in very preterm neonates