The role of the complement system in traumatic brain injury: a review

Traumatic brain injury (TBI) is an important cause of disability and mortality in the western world. While the initial injury sustained results in damage, it is the subsequent secondary cascade that is thought to be the significant determinant of subsequent outcomes. The changes associated with the secondary injury do not become irreversible until some time after the start of the cascade. This may present a window of opportunity for therapeutic interventions aiming to improve outcomes subsequent to TBI. A prominent contributor to the secondary injury is a multifaceted inflammatory reaction. The complement system plays a notable role in this inflammatory reaction; however, it has often been overlooked in the context of TBI secondary injury. The complement system has homeostatic functions in the uninjured central nervous system (CNS), playing a part in neurodevelopment as well as having protective functions in the fully developed CNS, including protection from infection and inflammation. In the context of CNS injury, it can have a number of deleterious effects, evidence for which primarily comes not only from animal models but also, to a lesser extent, from human post-mortem studies. In stark contrast to this, complement may also promote neurogenesis and plasticity subsequent to CNS injury. This review aims to explore the role of the complement system in TBI secondary injury, by examining evidence from both clinical and animal studies. We examine whether specific complement activation pathways play more prominent roles in TBI than others. We also explore the potential role of complement in post-TBI neuroprotection and CNS repair/regeneration. Finally, we highlight the therapeutic potential of targeting the complement system in the context of TBI and point out certain areas on which future research is needed

Increasing awareness and reputation of MERCK S.A. Portugal through employee advocacy

Merck KGaA is a global Science and Technology company, focusing on the Healthcare Industry, Life Science and Performance Materials. Merck in Portugal is a relatively small subsidiary with a midsized office employing approximately 114 employees. Merck S.A. Portugal focuses mainly on the Healthcare Market. As the company went through a major transformation in 2016, it created a need to communicate on a low cost basis and in an efficient way, using digital as its main channel. The current paper shows the implementation of an employee advocacy strategic plan as a solution to digital communication. Employee Advocacy is a new communications concept derived from employee social media usage and employee word of mouth. It has been noted that employee networks are wider than company’s own and employee word of mouth is more trustworthy. Before the tool could be implemented a research on what motivates employees to commit to Brand Citizenship Behavior was performed. Findings revealed that in the case of Merck S.A. Portugal employees individual internal drive and brand knowledge are factors affecting willingness to share on social media. Based on the results a series of internal strategies were applied on- and offline.info:eu-repo/semantics/acceptedVersio

Soil and crop residue CO2-C emission under tillage systems in sugarcane-producing areas of southern Brazil

Appropriate management of agricultural crop residues could result in increases on soil organic carbon (SOC) and help to mitigate gas effect. To distinguish the contributions of SOC and sugarcane (Saccharum spp.) residues to the short-term CO2-C loss, we studied the influence of several tillage systems: heavy offset disk harrow (HO), chisel plow (CP), rotary tiller (RT), and sugarcane mill tiller (SM) in 2008, and CP, RT, SM, moldboard (MP), and subsoiler (SUB) in 2009, with and without sugarcane residues relative to no-till (NT) in the sugarcane producing region of Brazil. Soil CO2-C emissions were measured daily for two weeks after tillage using portable soil respiration systems. Daily CO2-C emissions declined after tillage regardless of tillage system. In 2008, total CO2-C from SOC and/or residue decomposition was greater for RT and lowest for CP. In 2009, emission was greatest for MP and CP with residues, and smallest for NT. SOC and residue contributed 47 % and 41 %, respectively, to total CO2-C emissions. Regarding the estimated emissions from sugarcane residue and SOC decomposition within the measurement period, CO2-C factor was similar to sugarcane residue and soil organic carbon decomposition, depending on the tillage system applied. Our approach may define new emission factors that are associated to tillage operations on bare or sugarcane-residue-covered soils to estimate the total carbon loss

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol. Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART. Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART. Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs

2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease

Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer's disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden

Propriedades físicas de um Nitossolo Vermelho em função dos sistemas de uso e manejo

O solo, um dos principais suportes da produção agrícola tem seu comportamento regido por um complexo conjunto de fatores físicos, químicos e biológicos, razão pela qual o presente trabalho teve como objetivo avaliar as modificações dos atributos físicos de um Nitossolo Vermelho distroférrico com diferentes manejos, na Faculdade de Ciências Agronômicas - UNESP, Campus de Botucatu, São Paulo, Brasil. O delineamento estatístico foi inteiramente casualizado, com seis repetições em três diferentes áreas, sendo uma área de mata nativa, uma área com sistema de preparo convencional do solo e uma área com plantio direto. Foram determinados: matéria orgânica, argila natural, porosidade total, macroporosidade, densidade do solo, resistência à penetração e diâmetro médio ponderado dos agregados. O sistema de preparo convencional apresentou os menores teores de matéria orgânica na camada até 0,20 m. Na resistência à penetração não houve diferença entre os tratamentos. Para as cinco profundidades do sistema de preparo convencional observaram-se maior densidade e teor de argila natural em comparação aos outros sistemas. O sistema de preparo convencional diferiu dos demais tratamentos quanto ao diâmetro médio ponderado, porosidade total e macroporosidade apresentando os menores valores desses atributos.The soil is a mainstay of agricultural production, and its behavior governed by a complex set of physical, chemical and biological processes. The aim of this study was to evaluate the changes in the physical attributes of a distroferric Red Nitosol under different managements in the Faculty of Agricultural Sciences - UNESP, Botucatu, São Paulo, Brazil. The experimental design was completely randomized with six replications, in three diferent areas, an area with ​​native forest, an area with conventional soil tillage and an area with no soil tillage. The organic matter, natural clay, total porosity, macroporosity, bulk density, penetration resistance and the mean diameter of the aggregates were determined. The conventional tillage had the lowest concentrations of organic matter in the layer up to 0,2 m. For penetration resistance, no differences among treatments were observed. For the five depths of conventional tillage, higher density and natural clay content were observed, compared to other systems. The conventional tillage treatments differed from the others for the mean diameter, total porosity and macroporosity, as it had the lowest values ​​of these attributes.UNESP FCAUNESP FC