Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model

Introduction: Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Despite extensive studies to understand the disease process utilizing human and mouse models, the intersection between these species remains elusive. To address this gap, we utilized a novel systems biology approach to identify disease-related gene modules and signaling pathways that overlap between humans and mice. Methods: Parotid gland tissues were harvested from 24 pSS and 16 non-pSS sicca patients and 25 controls. For mouse studies, salivary glands were harvested from C57BL/6.NOD-Aec1Aec2 mice at various times during development of pSS-like disease. RNA was analyzed with Affymetrix HG U133+2.0 arrays for human samples and with MOE430+2.0 arrays for mouse samples. The images were processed with Affymetrix software. Weighted-gene co-expression network analysis was used to identify disease-related and functional pathways. Results: Nineteen co-expression modules were identified in human parotid tissue, of which four were significantly upregulated and three were downregulated in pSS patients compared with non-pSS sicca patients and controls. Notably, one of the human disease-related modules was highly preserved in the mouse model, and was enriched with genes involved in immune and inflammatory responses. Further comparison between these two species led to the identification of genes associated with leukocyte recruitment and germinal center formation. Conclusion: Our systems biology analysis of genome-wide expression data from salivary gland tissue of pSS patients and from a pSS mouse model identified common dysregulated biological pathways and molecular targets underlying critical molecular alterations in pSS pathogenesis

The Presence–Absence Situation and Its Impact on the Assemblage Structure and Interspecific Relations of Pronophilina Butterflies in the Venezuelan Andes (Lepidoptera: Nymphalidae)

Assemblage structure and altitudinal patterns of Pronophilina, a species-rich group of Andean butterflies, are compared in El Baho and Monte Zerpa, two closely situated and ecologically similar Andean localities. Their faunas differ only by the absence of Pedaliodes ornata Grose-Smith in El Baho. There are, however, important structural differences between the two Pronophilina assemblages. Whereas there are five co-dominant species in Monte Zerpa, including P. ornata, Pedaliodes minabilis Pyrcz is the only dominant with more than half of all the individuals in the sample in El Baho. The absence of P. ornata in El Baho is investigated from historical, geographic, and ecological perspectives exploring the factors responsible for its possible extinction including climate change, mass dying out of host plants, and competitive exclusion. Although competitive exclusion between P. ornata and P. minabilis is a plausible mechanism, considered that their ecological niches overlap, which suggests a limiting influence on each other’s populations, the object of competition was not identified, and the reason of the absence of P. ornata in El Baho could not be established. The role of spatial interference related to imperfect sexual behavioral isolation is evaluated in maintaining the parapatric altitudinal distributions of three pairs of phenotypically similar and related species of Pedaliodes, Corades, and Lymanopoda

ICF components of corresponding outcome measures in flexor tendon rehabilitation – a systematic review

<p>Abstract</p> <p>Background</p> <p>The International Classification of Functioning, Disability and Health (ICF) delivers a holistic approach to health conditions. The objective of the present study is to provide an overview of flexor tendon rehabilitation outcome measures with respect to ICF components. Furthermore, it aims to investigate to which extent current assessments measure aspects of health according to these components primarily focussing on <it>activity </it>and <it>participation</it>.</p> <p>Methods</p> <p>A systematic literature review was conducted to identify all studies meeting the inclusion criteria. Studies were only included if they assessed more than <it>body function and body structure </it>and referred to the ICF components <it>activity </it>and <it>participation</it>. The outcome measures were analysed and their linkage to the ICF components were investigated to examine to which degree aspects of health outcome as defined by the ICF were considered.</p> <p>Results</p> <p>As anticipated, the application of outcome measures after flexor tendon repair is non conform. In many studies the emphasis still lies on physical impairment neglecting activity limitations and participation restrictions.</p> <p>Aspects of health after flexor tendon repair could be assessed more adequately and cover patients' needs more sufficiently by choosing outcome measures which refer to all aspects of functioning.</p> <p>Conclusion</p> <p>The ICF can help to identify aspects of health which are not being considered. The ICF can help promote further development of adequate outcome measures including activity limitation and participation restrictions by targeting patient centred goals and respecting patients' needs.</p

Qualitative meta-synthesis of user experience of computerised therapy for depression and anxiety

Objective: Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. Method: Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. Results: 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a comorbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the ‘non-specific’ or ‘common’ factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. Conclusion: Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of ‘self’ in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement

A European study on alcohol and drug use among young drivers : The TEND by night study design and methodology

Background. Young individuals are the age group with the highest risk of car accidents. One of main explanations relies on the use of psychoactive substances (alcohol, illegal and medicinal drugs), which are known to be major risk factors of road accidents, and whose consumption is almost universally more common among younger drivers. Although the correlation between psychoactive substances use and decrease in driving performance has been established in controlled experimental or laboratory settings, few studies were conducted in naturalistic circumstances. The TEND by Night project has been designed to evaluate the relationship between driving performance and psychoactive substances assumption in young drivers enrolled at typical places of consumption. Methods/Design. The TEND by Night project, endorsed by the European Commission, is a multidisciplinary, multi-centric, cross-sectional study conducted in six European countries (Italy, Belgium/Netherlands, Bulgaria, Spain, Poland and Latvia). The study population consists of 5000 young drivers aged 16-34 years, attending recreational sites during weekend nights. The intervention is based on the portal survey technique and includes several steps at the entrance and exit of selected sites, including the administration of semi-structured questionnaires, breath alcohol test, several drug assumption test, and measurement of the reaction time using a driving simulator. The main outcome is the difference in reaction time between the entrance and exit of the recreation site, and its correlation with psychoactive substances use. As a secondary outcome it will be explored the relationship between reaction time difference and the amount of consumption of each substance. All analyses will be multivariate. Discussion. The project methodology should provide some relevant advantages over traditional survey systems. The main strengths of the study include the large and multicentric sample, the objective measurement of substance assumption (which is typically self-reported), the application of a portal survey technique and the simultaneous evaluation of several psychoactive substances.publishersversionPeer reviewe

Regulation of Mycobacterium-Specific Mononuclear Cell Responses by 25-Hydroxyvitamin D3

The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has been shown to be an important regulator of innate and adaptive immune function. In addition, synthesis of 1,25(OH)2D3 from 25-hydroxyvitamin D3 (25(OH)D3) by the enzyme 1α-hydroxylase in monocytes upon activation by TLR signaling has been found to regulate innate immune responses of monocytes in an intracrine fashion. In this study we wanted to determine what cells expressed 1α-hydroxylase in stimulated peripheral blood mononuclear cell (PBMC) cultures and if conversion of 25(OH)D3 to 1,25(OH)2D3 in PBMC cultures regulated antigen-specific immune responses. Initially, we found that stimulation of PBMCs from animals vaccinated with Mycobacterium bovis (M. bovis) BCG with purified protein derivative of M. bovis (M. bovis PPD) induced 1α-hydroxylase gene expression and that treatment with a physiological concentration of 25(OH)D3 down-regulated IFN-γ and IL-17F gene expression. Next, we stimulated PBMCs from M. bovis BCG-vaccinated and non-vaccinated cattle with M. bovis PPD and sorted them by FACS according to surface markers for monocytes/macrophages (CD14), B cells (IgM), and T cells (CD3). Sorting the PBMCs revealed that 1α-hydroxylase expression was induced in the monocytes and B cells, but not in the T cells. Furthermore, treatment of stimulated PBMCs with 25(OH)D3 down-regulated antigen-specific IFN-γ and IL-17F responses in the T cells, even though 1α-hydroxylase expression was not induced in the T cells. Based on evidence of no T cell 1α-hydroxylase we hypothesize that activated monocytes and B cells synthesize 1,25(OH)2D3 and that 1,25(OH)2D3 down-regulates antigen-specific expression of IFN-γ and IL-17F in T cells in a paracrine fashion

Ocean Acidification at High Latitudes: Potential Effects on Functioning of the Antarctic Bivalve Laternula elliptica

Ocean acidification is a well recognised threat to marine ecosystems. High latitude regions are predicted to be particularly affected due to cold waters and naturally low carbonate saturation levels. This is of concern for organisms utilising calcium carbonate (CaCO3) to generate shells or skeletons. Studies of potential effects of future levels of pCO2 on high latitude calcifiers are at present limited, and there is little understanding of their potential to acclimate to these changes. We describe a laboratory experiment to compare physiological and metabolic responses of a key benthic bivalve, Laternula elliptica, at pCO2 levels of their natural environment (430 µatm, pH 7.99; based on field measurements) with those predicted for 2100 (735 µatm, pH 7.78) and glacial levels (187 µatm, pH 8.32). Adult L. elliptica basal metabolism (oxygen consumption rates) and heat shock protein HSP70 gene expression levels increased in response both to lowering and elevation of pH. Expression of chitin synthase (CHS), a key enzyme involved in synthesis of bivalve shells, was significantly up-regulated in individuals at pH 7.78, indicating L. elliptica were working harder to calcify in seawater undersaturated in aragonite (ΩAr = 0.71), the CaCO3 polymorph of which their shells are comprised. The different response variables were influenced by pH in differing ways, highlighting the importance of assessing a variety of factors to determine the likely impact of pH change. In combination, the results indicate a negative effect of ocean acidification on whole-organism functioning of L. elliptica over relatively short terms (weeks-months) that may be energetically difficult to maintain over longer time periods. Importantly, however, the observed changes in L. elliptica CHS gene expression provides evidence for biological control over the shell formation process, which may enable some degree of adaptation or acclimation to future ocean acidification scenarios

Active learning and optimal climate policy

This paper develops a climate-economy model with uncertainty, irreversibility, and active learning. Whereas previous papers assume learning from one observation per period, or experiment with control variables to gain additional information, this paper considers active learning from investment in monitoring, specifically in improved observations of the global mean temperature. We find that the decision maker invests a significant amount of money in climate research, far more than the current level, in order to increase the rate of learning about climate change. This helps the decision maker make improved decisions. The level of uncertainty decreases more rapidly in the active learning model than in the passive learning model with only temperature observations. As the uncertainty about climate change is smaller, active learning reduces the optimal carbon tax. The greater the risk, the larger is the effect of learning. The method proposed here is applicable to any dynamic control problem where the quality of monitoring is a choice variable, for instance, the precision at which we observe GDP, unemployment, or the quality of education

Challenges Using Extrapolated Family-level Macroinvertebrate Metrics in Moderately Disturbed Tropical Streams: a Case-study From Belize

Family-level biotic metrics were originally designed to rapidly assess gross organic pollution effects, but came to be regarded as general measures of stream degradation. Improvements in water quality in developed countries have reignited debate about the limitations of family-level taxonomy to detect subtle change, and is resulting in a shift back towards generic and species-level analysis to assess smaller effects. Although the scale of pollution characterizing past condition of streams in developed countries persists in many developing regions, some areas are still considered to be only moderately disturbed. We sampled streams in Belize to investigate the ability of family-level macroinvertebrate metrics to detect change in stream catchments where less than 30% of forest had been cleared. Where disturbance did not co-vary with natural gradients of change, and in areas characterized by low intensity activities, none of the metrics tested detected significant change, despite evidence of environmental impacts. We highlight the need for further research to clarify the response of metrics to disturbance over a broader study area that allows replication for confounding sources of natural variation. We also recommend research to develop more detailed understanding of the taxonomy and ecology of Neotropical macroinvertebrates to improve the robustness of metric use