THREaD Mapper Studio: a novel, visual web server for the estimation of genetic linkage maps

The estimation of genetic linkage maps is a key component in plant and animal research, providing both an indication of the genetic structure of an organism and a mechanism for identifying candidate genes associated with traits of interest. Because of this importance, several computational solutions to genetic map estimation exist, mostly implemented as stand-alone software packages. However, the estimation process is often largely hidden from the user. Consequently, problems such as a program crashing may occur that leave a user baffled. THREaD Mapper Studio (http://cbr.jic.ac.uk/threadmapper) is a new web site that implements a novel, visual and interactive method for the estimation of genetic linkage maps from DNA markers. The rationale behind the web site is to make the estimation process as transparent and robust as possible, while also allowing users to use their expert knowledge during analysis. Indeed, the 3D visual nature of the tool allows users to spot features in a data set, such as outlying markers and potential structural rearrangements that could cause problems with the estimation procedure and to account for them in their analysis. Furthermore, THREaD Mapper Studio facilitates the visual comparison of genetic map solutions from third party software, aiding users in developing robust solutions for their data sets

A multi-sector multi-region economic growth model of drought and the value of water: A case study in Pakistan

This study integrates ecohydrological vegetation and multi-sector multi-region economic growth models to evaluate the impacts of drought on markets and value the economic value of water. The values of several parameters of the agricultural production function are identified by applying leaf area indices that are simulated by the ecohydrological model, AgriCLVDAS. The three-sector three-region closed-economy model with the agricultural production functions of both irrigable and rainfed farmland as well as the stochastic process of precipitation and availability of river water are formulated to analyze the water rent as well as GDP growth in Pakistan under drought stress. According to the characteristics of the closed-economy model, the crop price is increased during drought periods because of the price hike in water (i.e., an increase in the marginal productivity of water, which is double that in high-water periods in Pakistan). The study further presents a way of investigating water resource management policies by applying comparative dynamics

Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.

IntroductionDisruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).MethodsWe examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).ResultsWe measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected q< 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.DiscussionOur results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD

Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations.

OBJECTIVES: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. METHODS: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. RESULTS: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). CONCLUSIONS: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression

Osteomimetic matrix components alter cell migration and drug response in a 3D tumour-engineered osteosarcoma model

vulnerable to recurring disease and pulmonary metastases. Developing 3D in vitro disease models to serve as a test bed for personalised treatment is a promising approach to address this issue. This study describes the generation of 3D osteosarcoma models termed “tumouroids”, which are geometrically compartmentalised to reproduce the bone cancer mass and its surrounding. Although the tumour microenvironment impacts osteosarcoma in many ways, this model focussed on interrogating the influence of a biomimetic matrix on tumour cell behaviour. The 3D matrix was supplemented with the bone-marrow proteins laminin, fibronectin and NuOss® bone granules. This led to increased invasion of osteosarcoma cell aggregates from within the bone-like matrix into the surrounding acellular bone marrow-like ECM. The presence of bone granules also yielded an atypical molecular profile of osteosarcoma cells, suggesting malignant metabolic reprogramming. Changes include decreased MMP-9 (p < 0.05) and increased PTEN (p < 0.05), MCP-1 (p < 0.01) and MCT-4 (p < 0.05) gene expression. This complex 3D biomimetic composition also changed cellular responses to doxorubicin, a common chemotherapeutic agent used to treat osteosarcoma, and reproduced key issues of in vivo treatment like drug penetrance and doxorubicin-induced bone toxicity. This work highlights the importance of a biomimetic matrix in 3D osteosarcoma models for both basic and translational research

Engineering a vascularised 3D in vitro model of cancer progression.

The hallmark of tumours is the ability of cancerous cells to promote vascular growth, to disseminate and invade to distant organs. The metastatic process is heavily influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment. These microenvironmental cues, which include hypoxia, also regulate the angiogenic processes within a tumour, facilitating the spread of cancer cells. We engineered compartmentalized biomimetic colorectal tumouroids with stromal surrounds that comprised a range of ECM densities, composition and stromal cell populations. Recapitulating tissue ECM composition and stromal cell composition enhanced cancer cell invasion. Manipulation of ECM density was associated with an altered migration pattern from glandular buds (cellular aggregates) to epithelial cell sheets. Laminin appeared to be a critical component in regulating endothelial cell morphology and vascular network formation. Interestingly, the disruption of vascular networks by cancer cells was driven by changes in expression of several anti-angiogenic genes. Cancer cells cultured in our biomimetic tumouroids exhibited intratumoural heterogeneity that was associated with increased tumour invasion into the stroma. These findings demonstrate that our 3D in vitro tumour model exhibits biomimetic attributes that may permit their use in studying microenvironment clues of tumour progression and angiogenesis

Genetic associations of PPARGC1A with Type 2 Diabetes : differences among populations with African origins

The aim of this study was to assess the differences in correlation of PPARGC1A polymorphisms with type 2 diabetes (T2D) risk in adults of African origins: African Americans and Haitian Americans. The case-control study consisted of >30 years old, self-identified Haitian Americans (n=110 cases and n=116 controls) and African Americans (n=124 cases and n=122 controls) living in South Florida with and without T2D. Adjusted logistic regression indicated that both SNP rs7656250 (OR = 0.22, P=0.005) and rs4235308 (OR = 0.42, P=0.026) showed protective association with T2D in Haitian Americans. In African Americans, however, rs4235308 showed significant risk association with T2D (OR = 2.53, P=0.028). After stratification with sex, in Haitian Americans, both rs4235308 (OR = 0.38, P=0.026) and rs7656250 (OR = 0.23, P=0.006) showed protective association with T2D in females whereas in African American males rs7656250 had statistically significant protective effect on T2D (OR = 0.37, P=0.043). The trends observed for genetic association of PPARGC1A SNPs, rs4235308, and rs7656250 for T2D between Haitian Americans and African Americans point out differences in Black race and warrant replicative study with larger sample size

The feasibility and effectiveness of high-intensity boxing training versus moderate-intensity brisk walking in adults with abdominal obesity: a pilot study

BACKGROUND: High-intensity interval training (HIIT) performed on exercise cycle or treadmill is considered safe and often more beneficial for fat loss and cardiometabolic health than moderate-intensity continuous training (MICT). The aim of this pilot study was to assess the feasibility and effectiveness of a 12-week boxing training (HIIT) intervention compared with an equivalent dose of brisk walking (MICT) in obese adults. METHODS: Men and women with abdominal obesity and body mass index >25 kg/m(2) were randomized to either a boxing group or a brisk walking (control) group for 12 weeks. Each group engaged in 4 training sessions per week, equated for total physical activity. Feasibility outcomes included recruitment rates, assessment of training intensities, adherence and adverse events. Effectiveness was assessed pre and post intervention via pertinent obesity-, cardiovascular-, and health-related quality of life (HRQoL) outcomes. RESULTS: Nineteen individuals expressed an interest and 63% (n = 12) consented. Recruitment was slower than anticipated (1.3 participants/week). The boxing group trained at a significantly higher intensity each week versus the brisk walking group (p < 0.05). Two participants in the boxing group experienced an adverse event; both continued to exercise with modifications to the exercise program. No other adverse events were noted. The boxing group attended more sessions (79% vs. 55%) and had a lower attrition rate (n = 0 vs. n = 2) than the walking group. Analysis of covariance revealed that the boxing group significantly improved body fat percentage (p = 0.047), systolic blood pressure (p = 0.026), augmentation index (AIx; p < 0.001), absolute VO2max (p = 0.015), and Physical Functioning (p = 0.042) and Vitality (p = 0.024) domains of HRQoL over time. The walking group did not improve any clinical outcomes, and experienced a worsening of Vitality (p = 0.043). CONCLUSIONS: Boxing training (HIIT) in adults with abdominal obesity is feasible and may elicit a better therapeutic effect on obesity, cardiovascular, and HRQoL outcomes than an equivalent dose of brisk walking (MICT). Robustly designed randomized controlled trials are required to confirm these findings and inform clinical guidelines and practice for obesity treatment. TRIAL REGISTRATION: TRIAL REGISTRATION: ACTRN12615000007538.Birinder S Cheema, Timothy B Davies, Matthew Stewart, Shona Papalia, and Evan Atlanti

Contact tracing over uncertain indoor positioning data

Pandemics often cause dramatic losses of human lives and impact our societies in many aspects such as public health, tourism, and economy. To contain the spread of an epidemic like COVID-19, efficient and effective contact tracing is important, especially in indoor venues where the risk of infection is higher. In this work, we formulate and study a novel query called Indoor Contact Query (ICQ) over raw, uncertain indoor positioning data that digitalizes people's movements indoors. Given a query object o, e.g., a person confirmed to be a virus carrier, an ICQ analyzes uncertain indoor positioning data to find objects that most likely had close contact with o for a long period of time. To process ICQ, we propose a set of techniques. First, we design an enhanced indoor graph model to organize different types of data necessary for ICQ. Second, for indoor moving objects, we devise methods to determine uncertain regions and to derive positioning samples missing in the raw data. Third, we propose a query processing framework with a close contact determination method, a search algorithm, and the acceleration strategies. We conduct extensive experiments on synthetic and real datasets to evaluate our proposals. The results demonstrate the efficiency and effectiveness of our proposals