3D global multi-species Hall-MHD simulation of the Cassini T9 flyby

The wake region of Titan is an important component of Titan's interaction with its surrounding plasma and therefore a thorough understanding of its formation and structure is of primary interest. The Cassini spacecraft passed through the distant downstream region of Titan on 18: 59: 30 UT Dec. 26, 2005, which is referred to as the T9 flyby and provided a great opportunity to test our understanding of the highly dynamic wake region. In this paper we compare the observational data (from the magnetometer, plasma analyzer and Langmuir probe) with numerical results using a 7-species Hall MHD Titan model. There is a good agreement between the observed and modeled parameters, given the uncertainties in plasma measurements and the approximations inherent in the Hall MHD model. Our simulation results also show that Hall MHD model results fit the observations better than the non-Hall MHD model for the flyby, consistent with the importance of kinetic effects in the Titan interaction. Based on the model results, we also identify various regions near Titan where Hall MHD models are applicable

The impact of DMARD and anti-TNF therapy on functional characterization of short-term T-cell activation in patients with rheumatoid arthritis - A follow-up study

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a systemic dysfunction of T-cells. In this study we tested the impact of DMARD and anti-TNF agents on short-term activation characteristics of T-cells. We enrolled 12 patients with newly diagnosed RA (naïve RA) who were treated with methothrexate (MTX) and glucocorticsteroid (GCS) and 22 patients with established RA non responding to conventional DMARD therapy who were treated with different anti-TNF agents. Nine healthy volunteers served as controls. Blood samples were taken at baseline, then at 4th and 8th week of therapy. The characteristics of several intracellular activation processes during short-term activation of T-cells including cytoplasmic Ca2+ level, mitochondrial Ca2+ level, reactive oxygen species (ROS) and nitric oxide (NO) generation were determined by a novel flow-cytometry technique. At baseline, the tested processes were comparable to controls in naïve RA. During GCS therapy, cytoplasmic Ca2+ level and ROS generation decreased. After the addition of MTX to GCS cytoplasmic Ca2+ level became comparable to controls, while ROS generation decreased further. In DMARD non responders, cytoplasmic Ca2+ level was higher than controls at baseline. The cytoplasmic Ca2+ level became comparable to controls and ROS generation decreased during each of the three anti-TNF-α agent therapies. Mitochondrial Ca2+ level and NO generation were unaltered in all of the patient groups. These results indicate that intracellular machinery is affected in T-cells of RA patients. This may alter the behavior of T-cells during activation. Different therapeutic approaches may modulate the abnormal T-cell functions. © 2014 Szalay et al

Efficient Generation of Germ Line Transmitting Chimeras from C57BL/6N ES Cells by Aggregation with Outbred Host Embryos

Genetically modified mouse strains derived from embryonic stem (ES) cells have become essential tools for functional genomics and biomedical research. Large scale mutagenesis projects are producing libraries of mutant C57BL/6 (B6) ES cells to enable the functional annotation of every gene of the mouse genome. To realize the utility of these resources, efficient and accessible methods of generating mutant mice from these ES cells are necessary. Here, we describe a combination of ICR morula aggregation and a chemically-defined culture medium with widely available and accessible components for the high efficiency generation of germline transmitting chimeras from C57BL/6N ES cells. Together these methods will ease the access of the broader biomedical research community to the publicly available B6 ES cell resources

Protein crystals in adenovirus type 5-infected cells: requirements for intranuclear crystallogenesis, structural and functional analysis

Intranuclear crystalline inclusions have been observed in the nucleus of epithelial cells infected with Adenovirus serotype 5 (Ad5) at late steps of the virus life cycle. Using immuno-electron microscopy and confocal microscopy of cells infected with various Ad5 recombinants modified in their penton base or fiber domains, we found that these inclusions represented crystals of penton capsomers, the heteromeric capsid protein formed of penton base and fiber subunits. The occurrence of protein crystals within the nucleus of infected cells required the integrity of the fiber knob and part of the shaft domain. In the knob domain, the region overlapping residues 489–492 in the FG loop was found to be essential for crystal formation. In the shaft, a large deletion of repeats 4 to 16 had no detrimental effect on crystal inclusions, whereas deletion of repeats 8 to 21 abolished crystal formation without altering the level of fiber protein expression. This suggested a crucial role of the five penultimate repeats in the crystallisation process. Chimeric pentons made of Ad5 penton base and fiber domains from different serotypes were analyzed with respect to crystal formation. No crystal was found when fiber consisted of shaft (S) from Ad5 and knob (K) from Ad3 (heterotypic S5-K3 fiber), but occurred with homotypic S3K3 fiber. However, less regular crystals were observed with homotypic S35-K35 fiber. TB5, a monoclonal antibody directed against the Ad5 fiber knob was found by immunofluorescence microscopy to react with high efficiency with the intranuclear protein crystals in situ. Data obtained with Ad fiber mutants indicated that the absence of crystalline inclusions correlated with a lower infectivity and/or lower yields of virus progeny, suggesting that the protein crystals might be involved in virion assembly. Thus, we propose that TB5 staining of Ad-infected 293 cells can be used as a prognostic assay for the viability and productivity of fiber-modified Ad5 vectors

A three arm cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the SMART work & life intervention for reducing daily sitting time in office workers : study protocol

Background:Office-based workers typically spend 70-85% of working hours, and a large proportion of leisure time, sitting. High levels of sitting have been linked to poor health. There is a need for fully powered randomised controlled trials (RCTs) with long-term follow-up to test the effectiveness of interventions to reduce sitting. This paper describes the methodology of a three-arm cluster RCT designed to determine the effectiveness and cost-effectiveness of the SMART Work & Life intervention, delivered with and without a height-adjustable desk, for reducing daily sitting. Methods/Design:A three-arm cluster RCT of 33 clusters (660 council workers) will be conducted in three areas in England (Leicester; Manchester; Liverpool). Office groups (clusters) will be randomised to the SMART Work & Life intervention delivered with (group 1) or without (group 2) a height-adjustable desk or a control group (group 3). SMART Work & Life includes organisational (e.g., management buy-in, provision/support for standing meetings), environmental (e.g., relocating waste bins, printers), and group/individual (education, action planning, goal setting, addressing barriers, coaching, self-monitoring, social support) level behaviour change strategies, with strategies driven by workplace champions. Baseline, 3, 12 and 24 month measures will be taken. Objectively measured daily sitting time (activPAL3). objectively measured sitting, standing, stepping, prolonged sitting and moderate-to-vigorous physical activity time and number of steps at work and daily; objectively measured sleep (wrist accelerometry). Adiposity, blood pressure, fasting glucose, glycated haemoglobin, cholesterol (total, HDL, LDL) and triglycerides will be assessed from capillary blood samples. Questionnaires will examine dietary intake, fatigue, musculoskeletal issues, job performance and satisfaction, work engagement, occupational and general fatigue, stress, presenteeism, anxiety and depression and sickness absence (organisational records). Quality of life and resources used (e.g. GP visits, outpatient attendances) will also be assessed. We will conduct a full process evaluation and cost-effectiveness analysis. Discussion:The results of this RCT will 1) help to understand how effective an important simple, yet relatively expensive environmental change is for reducing sitting, 2) provide evidence on changing behaviour across all waking hours, and 3) provide evidence for policy guidelines around population and workplace health and well-being. Trial registration: ISRCTN11618007 . Registered on 21 January 2018

Association of Impulsivity and Polymorphic MicroRNA-641 Target Sites in the SNAP-25 Gene.

Impulsivity is a personality trait of high impact and is connected with several types of maladaptive behavior and psychiatric diseases, such as attention deficit hyperactivity disorder, alcohol and drug abuse, as well as pathological gambling and mood disorders. Polymorphic variants of the SNAP-25 gene emerged as putative genetic components of impulsivity, as SNAP-25 protein plays an important role in the central nervous system, and its SNPs are associated with several psychiatric disorders. In this study we aimed to investigate if polymorphisms in the regulatory regions of the SNAP-25 gene are in association with normal variability of impulsivity. Genotypes and haplotypes of two polymorphisms in the promoter (rs6077690 and rs6039769) and two SNPs in the 3' UTR (rs3746544 and rs1051312) of the SNAP-25 gene were determined in a healthy Hungarian population (N = 901) using PCR-RFLP or real-time PCR in combination with sequence specific probes. Significant association was found between the T-T 3' UTR haplotype and impulsivity, whereas no association could be detected with genotypes or haplotypes of the promoter loci. According to sequence alignment, the polymorphisms in the 3' UTR of the gene alter the binding site of microRNA-641, which was analyzed by luciferase reporter system. It was observed that haplotypes altering one or two nucleotides in the binding site of the seed region of microRNA-641 significantly increased the amount of generated protein in vitro. These findings support the role of polymorphic SNAP-25 variants both at psychogenetic and molecular biological levels

Advances in Understanding Environmental Risks of Red Mud After the Ajka Spill, Hungary

In the 5 years since the 2010 Ajka red mud spill (Hungary), there have been 46 scientific studies assessing the key risks and impacts associated with the largest single release of bauxite-processing residue (red mud) to the environment. These studies have provided insight into the main environmental concerns, as well as the effectiveness of remedial efforts that can inform future management of red mud elsewhere. The key immediate risks after the spill were associated with the highly caustic nature of the red mud slurry and fine particle size, which once desiccated, could generate fugitive dust. Studies on affected populations showed no major hazards identified beyond caustic exposure, while red mud dust risks were considered equal to or lesser than those provided by urban dusts of similar particle size distribution. The longer-term environmental risks were related to the saline nature of the spill material (salinization of inundated soils) and the release and the potential cycling of oxyanion-forming metals and metalloids (e.g., Al, As, Cr, Mo, and V) in the soil–water environment. Of these, those that are soluble at high pH, inefficiently removed from solution during dilution and likely to be exchangeable at ambient pH are of chief concern (e.g., Mo and V). Various ecotoxicological studies have identified negative impacts of red mud-amended soils and sediments at high volumes (typically [5 %) on different test organisms, with some evidence of molecularlevel impacts at high dose (e.g., genotoxic effects on plants and mice). These data provide a valuable database to inform future toxicological studies for red mud. However, extensive management efforts in the aftermath of the spill greatly limited these exposure risks through leachate neutralization and red mud recovery from the affected land. Monitoring of affected soils, stream sediments, waters and aquatic biota (fungi, invertebrates and fish) have all shown a very rapid recovery toward prespill conditions. The accident also prompted research that has also highlighted potential benefits of red mud use for critical raw material recovery (e.g., Ga, Co, V, rare earths, inform), carbon sequestration, biofuel crop production, and use as a soil ameliorant

Cytogerontology since 1881: A reappraisal of August Weismann and a review of modern progress

Cytogerontology, the science of cellular ageing, originated in 1881 with the prediction by August Weismann that the somatic cells of higher animals have limited division potential. Weismann's prediction was derived by considering the role of natural selection in regulating the duration of an organism's life. For various reasons, Weismann's ideas on ageing fell into neglect following his death in 1914, and cytogerontology has only reappeared as a major research area following the demonstration by Hayflick and Moorhead in the early 1960s that diploid human fibroblasts are restricted to a finite number of divisions in vitro. In this review we give a detailed account of Weismann's theory, and we reveal that his ideas were both more extensive in their scope and more pertinent to current research than is generally recognised. We also appraise the progress which has been made over the past hundred years in investigating the causes of ageing, with particular emphasis being given to (i) the evolution of ageing, and (ii) ageing at the cellular level. We critically assess the current state of knowledge in these areas and recommend a series of points as primary targets for future research

Mother Positivity and Family Adjustment in Households with Children with a Serious Disability

Only limited attention has been given to parent coping resources in the positive adjustment of families of children with a disability. This study is the first to explore maternal positivity as a psychological coping resource related to family adjustment in these families. Consistent with broaden-and-build theory and prior positivity research, positivity was operationalized through a ratio of positive to negative affect scores. We employed longitudinal tracking over a 1 year interval. Children’s diagnostic categories included developmental conditions or impairments, mental health disorders, complex health conditions, physical/motor conditions or impairments, sensory impairments, and provisionally diagnosed conditions or impairments. We used a computer assisted telephone survey to gather psychological, family, and demographic information from 152 mothers in Alberta, Canada. Hierarchical regression analysis indicated mothers’ level of positivity and age, when controlled for family adjustment at Time 1, accounted for 46% of the variance in family adjustment at Time 2. That is, older mothers with higher positivity scores were found to live in households with higher levels of family adjustment after 1 year. These findings provide promising support for broaden-and-build theory, which posits that positive experienced emotions can offset and diminish the negative health and relationship impacts of chronic stress. Study findings support the salience of mothers’ positivity as a psychological coping resource, which is related to enhanced family adjustment in situations of childhood disability