Dopamine receptor D4 (DRD4) polymorphisms with reduced functional potency intensify atrophy in syndrome-specific sites of frontotemporal dementia.

ObjectiveWe aimed to understand the impact of dopamine receptor D4 (DRD4) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD4dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration.Methods337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures.ResultsDRD4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity.ConclusionsWe conclude that DRD4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD

On Effective Action of Multiple M5-branes and ABJM Action

We calculate the fluctuations from the classical multiple M5-brane solution of ABJM action which we found in the previous paper. We obtain D4-brane-like action but the gauge coupling constant depends on the spacetime coordinate. This is consistent with the expected properties of M5-brane action, although we will need to take into account the monopole operators in order to fully understand M5-branes. We also see that the Nambu-Poisson bracket is hidden in the solution.Comment: 21 pages; v2:version to appear in JHE

Caspase-8 binding to cardiolipin in giant unilamellar vesicles provides a functional docking platform for bid

Caspase-8 is involved in death receptor-mediated apoptosis in type II cells, the proapoptotic programme of which is triggered by truncated Bid. Indeed, caspase-8 and Bid are the known intermediates of this signalling pathway. Cardiolipin has been shown to provide an anchor and an essential activating platform for caspase-8 at the mitochondrial membrane surface. Destabilisation of this platform alters receptor-mediated apoptosis in diseases such as Barth Syndrome, which is characterised by the presence of immature cardiolipin which does not allow caspase-8 binding. We used a simplified in vitro system that mimics contact sites and/or cardiolipin-enriched microdomains at the outer mitochondrial surface in which the platform consisting of caspase-8, Bid and cardiolipin was reconstituted in giant unilamellar vesicles. We analysed these vesicles by flow cytometry and confirm previous results that demonstrate the requirement for intact mature cardiolipin for caspase-8 activation and Bid binding and cleavage. We also used confocal microscopy to visualise the rupture of the vesicles and their revesiculation at smaller sizes due to alteration of the curvature following caspase-8 and Bid binding. Biophysical approaches, including Laurdan fluorescence and rupture/tension measurements, were used to determine the ability of these three components (cardiolipin, caspase-8 and Bid) to fulfil the minimal requirements for the formation and function of the platform at the mitochondrial membrane. Our results shed light on the active functional role of cardiolipin, bridging the gap between death receptors and mitochondria

Epidemiology of Coxiella burnetii infection in Africa: a OneHealth systematic review

Background: Q fever is a common cause of febrile illness and community-acquired pneumonia in resource-limited settings. Coxiella burnetii, the causative pathogen, is transmitted among varied host species, but the epidemiology of the organism in Africa is poorly understood. We conducted a systematic review of C. burnetii epidemiology in Africa from a “One Health” perspective to synthesize the published data and identify knowledge gaps.<p></p> Methods/Principal Findings: We searched nine databases to identify articles relevant to four key aspects of C. burnetii epidemiology in human and animal populations in Africa: infection prevalence; disease incidence; transmission risk factors; and infection control efforts. We identified 929 unique articles, 100 of which remained after full-text review. Of these, 41 articles describing 51 studies qualified for data extraction. Animal seroprevalence studies revealed infection by C. burnetii (≤13%) among cattle except for studies in Western and Middle Africa (18–55%). Small ruminant seroprevalence ranged from 11–33%. Human seroprevalence was <8% with the exception of studies among children and in Egypt (10–32%). Close contact with camels and rural residence were associated with increased seropositivity among humans. C. burnetii infection has been associated with livestock abortion. In human cohort studies, Q fever accounted for 2–9% of febrile illness hospitalizations and 1–3% of infective endocarditis cases. We found no studies of disease incidence estimates or disease control efforts.<p></p> Conclusions/Significance: C. burnetii infection is detected in humans and in a wide range of animal species across Africa, but seroprevalence varies widely by species and location. Risk factors underlying this variability are poorly understood as is the role of C. burnetii in livestock abortion. Q fever consistently accounts for a notable proportion of undifferentiated human febrile illness and infective endocarditis in cohort studies, but incidence estimates are lacking. C. burnetii presents a real yet underappreciated threat to human and animal health throughout Africa.<p></p&gt

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

A No-Go Theorem for M5-brane Theory

The BLG model for multiple M2-branes motivates an M5-brane theory with a novel gauge symmetry defined by the Nambu-Poisson structure. This Nambu-Poisson gauge symmetry for an M5-brane in large C-field background can be matched, on double dimension reduction, with the Poisson limit of the noncommutative gauge symmetry for a D4-brane in B-field background. Naively, one expects that there should exist a certain deformation of the Nambu-Poisson structure to match with the full noncommutative gauge symmetry including higher order terms. However, We prove the no-go theorem that there is no way to deform the Nambu-Poisson gauge symmetry, even without assuming the existence of a deformation of Nambu-Poisson bracket, to match with the noncommutative gauge symmetry in 4+1 dimensions to all order, regardless of how the double dimension reduction is implemented.Comment: v4: minor modifications

Protective behaviour of citizens to transport accidents involving hazardous materials: A discrete choice experiment applied to populated areas nearby waterways

Background To improve the information for and preparation of citizens at risk to hazardous material transport accidents, a first important step is to determine how different characteristics of hazardous material transport accidents will influence citizens' protective behaviour. However, quantitative studies investigating citizens' protective behaviour in case of hazardous material transport accidents are scarce. Methods A discrete choice experiment was conducted among subjects (19-64 years) living in the direct vicinity of a large waterway. Scenarios were described by three transport accident characteristics: odour perception, smoke/vapour perception, and the proportion of people in the environment that were leaving at their own discretion. Subjects were asked to consider each scenario as realistic and to choose the alternative that was most appealing to them: staying, seekin

Has education lost sight of children?

The reflections presented in this chapter are informed by clinical and personal experiences of school education in the UK. There are many challenges for children and young people in the modern education system and for the professionals who support them. In the UK, there are significant gaps between the highly selective education provided to those who pay privately for it and to the majority of those educated in the state-funded system. Though literacy rates have improved around the world, many children, particularly boys, do not finish their education for reasons such as boredom, behavioural difficulties or because education does not ‘pay’. Violence, bullying, and sexual harassment are issues faced by many children in schools and there are disturbing trends of excluding children who present with behavioural problems at school whose origins are not explored. Excluded children are then educated with other children who may also have multiple problems which often just make the situation worse. The experience of clinicians suggests that school-related mental health problems are increasing in severity. Are mental health services dealing with the consequences of an education system that is not meeting children’s needs? An education system that is testing- and performance-based may not be serving many children well if it is driving important decisions about them at increasingly younger ages. Labelling of children and setting them on educational career paths can occur well before they reach secondary schools, limiting potential very early on in their developmental trajectory. Furthermore, the emphasis at school on testing may come at the expense of creativity and other forms of intelligence, which are also valuable and important. Meanwhile the employment marketplace requires people with widely different skills, with an emphasis on innovation, creativity, and problem solving. Is education losing sight of the children it is educating

Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Kinematic analisys of the knee when climbing up/down stairs in patellofemoral instability

OBJECTIVE: To analyze and to identify possible gait adaptations by individuals with objective patellofemoral instability when climbing up/down stairs. METHODS: A control group (group A) composed by nine women with mean age = 25 years (±1.87), height = 1.62 m (±0.05) and weight = 56.20 kg (±7.34), and; nine women with objective patellofemoral instability (group B) with mean age = 24 years (±6.02), height = 1.62 m (±0.06) and weight = 60.33 kg (±10.31) were analyzed. The groups underwent kinematic analysis while climbing up/down stairs, in a previously determined area. Images were obtained by six cameras (Qualysis) and data analysis utilized the Q gait software program. RESULTS: Group B presented, in the support phase, less knee flexion when climbing up (p = 0.0268), and lower speed (p = 0.0076/ p =0.0243) and pace (p = 0.0027/ p = 0.0165) when climbing up and down stairs, respectively. CONCLUSION: It is suggested that group B used functional changes such as reduced knee flexion, speed and pace when climbing up and down stairs.OBJETIVO: Analisar e identificar possíveis adaptações da marcha em indivíduos com diagnóstico de instabilidade patelofemoral objetiva, durante a atividade de subida e descida de escada. MÉTODOS: Foram analisados um grupo controle (grupo A), composto por 9 mulheres com média de idade de 25 anos (±1,87), média de altura de 1,62m (±0,05) e média de peso de 56,20kg (±7,34); e, um grupo de 9 mulheres com instabilidade patelofemoral objetiva (grupo B), média de idade de 24 anos (±6,02), média de altura de 1,62m (±0,06) e média de peso de 60,33kg (±10,31). Os grupos foram submetidos a uma análise cinemática, onde as voluntárias subiram e desceram degraus, em uma área previamente selecionada. As imagens foram obtidas por seis câmeras (Qualysis) e a análise dos dados foi realizada através do programa Q gait. RESULTADOS: O grupo B apresentou, no período de apoio, menor flexão do joelho durante a subida (p=0,0268), além de menores velocidade (p=0,0076/ p=0,0243) e cadência (p=0,0027/ p=0,0165) na subida e na descida, respectivamente. CONCLUSÃO: Sugere-se que o grupo B utilizou adaptações funcionais como redução da flexão do joelho, da velocidade e da cadência, durante a subida e a descida de degraus.UNICAMP FCM Departamento de Ortopedia e TraumatologiaUniversidade Federal de São Paulo (UNIFESP)UNIFESPSciEL