treeclimbR pinpoints the data-dependent resolution of hierarchical hypotheses.

treeclimbR is for analyzing hierarchical trees of entities, such as phylogenies or cell types, at different resolutions. It proposes multiple candidates that capture the latent signal and pinpoints branches or leaves that contain features of interest, in a data-driven way. It outperforms currently available methods on synthetic data, and we highlight the approach on various applications, including microbiome and microRNA surveys as well as single-cell cytometry and RNA-seq datasets. With the emergence of various multi-resolution genomic datasets, treeclimbR provides a thorough inspection on entities across resolutions and gives additional flexibility to uncover biological associations.

Synoptic condition-driven summertime ozone formation regime in Shanghai and the implication for dynamic ozone control strategies.

Regarding the continuous worsening of tropospheric ozone pollution, the scenario in Shanghai is a microcosm of the entire China. Understanding the ozone formation regimes (OFRs), their variations, and driving factors is a prerequisite for formulating effective ozone control strategies. Traditional OFR estimation by numerical model, which often involves sensitivity analysis on at least tens of scenarios, is labor-intensive and time-consuming; therefore, it is not appropriate to make OFR forecasts to guide ozone contingency control. In this study, by using a localized modeling system consisting of the Weather Research and Forecasting, Sparse Matrix Operator Kernel Emissions, and Community Multiscale Air Quality models and considering the latest emission inventory over the Yangtze River Delta of China, we discovered a strong connection between the variations of large-scale circulation (LSC) and OFRs over Shanghai in July 2017, thereby providing an alternative way to infer OFR. During the northward movement of Western Pacific Subtropical High from South China Sea, the wind field over Shanghai changed from weak westerly to moderate southwesterly and to one without a distinct direction. The local OFR shifted from anthropogenic volatile organic compounds (AVOCs)-limited to NOx-limited and ultimately to the transitional regime. Such a variation in OFR is essentially driven by the spatial heterogeneity of NOx and AVOC emissions in different directions of Shanghai, brought on by the wind under different LSC patterns. With the existing weather forecasting technology, the LSC patterns can be well-predicted 48-72 h in advance. Hence, we propose the adoption of a dynamic ozone control strategy for Shanghai with the priority control target on AVOC or NOx emission sources adjusted according to the LSC pattern and OFR forecasts in a forthcoming O3 pollution episode. This would serve to maximize the peak ozone reduction under varying pollution conditions.

TreeSummarizedExperiment: a S4 class for data with hierarchical structure.

Data organized into hierarchical structures (e.g., phylogenies or cell types) arises in several biological fields. It is therefore of interest to have data containers that store the hierarchical structure together with the biological profile data, and provide functions to easily access or manipulate data at different resolutions. Here, we present TreeSummarizedExperiment, a R/S4 class that extends the commonly used SingleCellExperiment class by incorporating tree representations of rows and/or columns (represented by objects of the phylo class). It follows the convention of the SummarizedExperiment class, while providing links between the assays and the nodes of a tree to allow data manipulation at arbitrary levels of the tree. The package is designed to be extensible, allowing new functions on the tree (phylo) to be contributed. As the work is based on the SingleCellExperiment class and the phylo class, both of which are popular classes used in many R packages, it is expected to be able to interact seamlessly with many other tools.

Higher residential and employment densities are associated with more objectively measured walking in the home neighborhood.

Understanding where people walk and how the built environment influences walking is a priority in active living research. Most previous studies were limited by self-reported data on walking. In the present study, walking bouts were determined by integrating one week of accelerometry, GPS, and a travel log data among 675 adult participants in the baseline sample of the Travel Assessment and Community study. Home neighborhood was defined as being within 0.5 mi of each participants' residence (a 10-minute walk), with home neighborhood walking defined as walking bout lines with at least one GPS point within the home neighborhood. Home neighborhood walkability was constructed with seven built environment variables derived from spatially continuous objective values (SmartMaps). A Zero Inflated Negative Binomial (ZINB) served to estimate associations between home neighborhood environment characteristics and home neighborhood walking frequency. Higher residential density and job density were the two neighborhood walkability measures related to higher likelihood and more time walking in the home neighborhood, highest tertile residential density (22.44 - 62.63 unit/acre) (coefficient=1.434; 95th CI of 1.003, 2.049) and highest tertile job density (12.4 - 272.3 jobs/acre) (coefficient=1.616; 95th CI of 1.102, 2.370). The large proportion of walking that takes place in the home neighborhood highlights the importance of continuing to examine the impact of the home neighborhood environment on walking. Potential interventions to increase walking behavior may benefit from increasing residential and employment density within residential areas.

Probabilistic walking models using built environment and sociodemographic predictors.

BACKGROUND: Individual sociodemographic and home neighborhood built environment (BE) factors influence the probability of engaging in health-enhancing levels of walking or moderate-to-vigorous physical activity (MVPA). Methods are needed to parsimoniously model the associations. METHODS: Participants included 2392 adults drawn from a community-based twin registry living in the Seattle region. Objective BE measures from four domains (regional context, neighborhood composition, destinations, transportation) were taken for neighborhood sizes of 833 and 1666 road network meters from home. Hosmer and Lemeshow's methods served to fit logistic regression models of walking and MVPA outcomes using sociodemographic and BE predictors. Backward elimination identified variables included in final models, and comparison of receiver operating characteristic (ROC) curves determined model fit improvements. RESULTS: Built environment variables associated with physical activity were reduced from 86 to 5 or fewer. Sociodemographic and BE variables from all four BE domains were associated with activity outcomes but differed by activity type and neighborhood size. For the study population, ROC comparisons indicated that adding BE variables to a base model of sociodemographic factors did not improve the ability to predict walking or MVPA. CONCLUSIONS: Using sociodemographic and built environment factors, the proposed approach can guide the estimation of activity prediction models for different activity types, neighborhood sizes, and discrete BE characteristics. Variables associated with walking and MVPA are population and neighborhood BE-specific.

ARMOR: An Automated Reproducible MOdular Workflow for Preprocessing and Differential Analysis of RNA-seq Data.

The extensive generation of RNA sequencing (RNA-seq) data in the last decade has resulted in a myriad of specialized software for its analysis. Each software module typically targets a specific step within the analysis pipeline, making it necessary to join several of them to get a single cohesive workflow. Multiple software programs automating this procedure have been proposed, but often lack modularity, transparency or flexibility. We present ARMOR, which performs an end-to-end RNA-seq data analysis, from raw read files, via quality checks, alignment and quantification, to differential expression testing, geneset analysis and browser-based exploration of the data. ARMOR is implemented using the Snakemake workflow management system and leverages conda environments; Bioconductor objects are generated to facilitate downstream analysis, ensuring seamless integration with many R packages. The workflow is easily implemented by cloning the GitHub repository, replacing the supplied input and reference files and editing a configuration file. Although we have selected the tools currently included in ARMOR, the setup is modular and alternative tools can be easily integrated.

Light Rail Leads to More Walking Around Station Areas.

Areas around Light Rail Transit (LRT) stations offer ideal conditions for Transit-Oriented Development (TOD). Relatively dense, mixed-use neighborhoods can have positive impacts on mobility, health, and perceptions of neighborhood safety among nearby residents, primarily through walking activity for both transit and other purposes. To examine how station areas may attract new activity, this study analyzed changes in walking around station areas among people living close to an LRT station before and after the opening of a new transit system. This study examined walking behavior among the subset of 214 participants living within one mile of one of 13 LRT stations from among a sample of residents living close or further away from a new LRT line in Seattle. They completed a survey and a travel log and wore an accelerometer and a GPS for 7 days both before (2008) and after the opening of the Seattle area LRT (2010). Walking bouts were derived using a previously developed algorithm. The main outcome was the individual-level change in the proportion of daily walking within one quarter Euclidean mile of an LRT station. Overall walking decreased from before to after the LRT opening while station area walking did not change significantly, indicating a shift in walking activity to the station areas after the introduction of LRT. Increases in the proportion of station area walking were negatively related to participants' distance between home and the nearest LRT station, peaking at <0.25 mile and decaying beyond >0.75 mile. Male gender, college education, normal weight status, less access to cars, and frequent LRT use were also significantly associated with greater positive changes in the proportion of station area walking. The shift in walking to station areas after the completion of light rail provides evidence that the local proximate population is attracted to station areas, which may potentially benefit both transit use and TOD area economic activity. The residential catchment area for the shift in LRT area walking was < 0.75 mile of the LRT stations.

Prognostic value of long-term blood pressure changes in patients with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is the final stage of many heart diseases. To improve outcomes, important risk factors for adverse clinical events in the CHF population need to be identified. The aim of the present study was to delineate the influence of long-term blood pressure (BP) changes on prognosis and mortality in a real-world cohort of CHF patients. METHODS AND RESULTS: This is a retrospective longitudinal analysis. Repeated office BP measurements were scheduled during follow-up visits every 3-6 months. The primary endpoint was time to death or heart transplantation (HTx). A Cox regression with time-dependent strata was used to analyse the effect of systolic BP (SBP) values and its change during follow-up on the primary endpoint. A total of 927 patients presented with a median survival of 7.7 [95% confidence interval (CI) 6.6-9.8] years. During follow-up, 220 patients died and 70 patients underwent HTx. The BP stratum with the most stable values showed the best survival. Blood pressure changes with an increase or decrease greater than ±10 mmHg per year led to a significantly worse outcome [hazard ratio (HR) 1.8 and 2.0, respectively]. The stratum with the lowest SBP levels (<90 mmHg) had the highest mortality. Multiple regression analysis showed a HR factor of 17 (95% CI 9.7-29) in comparison with the stratum with SBP ≥130 mmHg. CONCLUSION: Low SBP (<90 mmHg) and pronounced long-term changes in SBP were associated with poor survival in patients with CHF. Additional prospective studies are warranted to further specify optimal BP targets in patients with CHF.

CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART.

Plasma HIV viral load is related to declining CD4 lymphocytes. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized so far. We examine if CD8 cell count is a prognostic factor for CD4 cell counts during an HIV infection.A longitudinal analysis is conducted using data from the Swiss HIV cohort study collected between January 2000 and October 2014. Linear mixed regression models were applied to observations from HIV-1-infected treatment naive patients (NAIVE) and cART-treated patients to predict the short-term evolution of CD4 cell counts. For each subgroup, it was quantified to which extent CD8 cell counts or CD4/CD8 ratios are prognostic factors for disease progression.In both subgroups, 2500 NAIVE and 8902 cART patients, past CD4 cells are positively (P < 0.0001) and past viral load is negatively (P < 0.0001) associated with the outcome. Including additionally past CD8 cell counts improves the fit significantly (P < 0.0001) and increases the marginal explained variation 31.7% to 40.7% for the NAIVE and from 44.1% to 50.7% for the cART group. The past CD4/CD8 ratio (instead of the past CD8 level) is positively associated with the outcome, increasing the explained variation further to 41.8% for NAIVE and 51.9% for cART.

Microbubble-Mediated Sonothrombolysis Improves Outcome After Thrombotic Microembolism-Induced Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Microthrombi originating from disintegrated clots or formed in situ may account for the poor clinical improvement of acute ischemic stroke after recanalization therapy. We attempted to determine whether microbubble-mediated sonothrombolysis could dissolve platelet-rich and erythrocyte-rich microthrombi, thereby reducing their brain injury-causing potential. METHODS: Platelet- and erythrocyte-rich microthrombosis were induced by periadventitial application of 5% ferric chloride or thrombin to mesenteric microvessels in 75 Sprague-Dawley rats. Acute ischemic stroke was induced by intracarotid injection of platelet- or erythrocyte-rich microthrombi in another 50 rats. Rats were randomly divided into control (CON), ultrasound (US), ultrasound and microbubble (US+MB), recombinant tissue-type plasminogen activator (r-tPA), and US+MB+r-tPA groups. The post-treatment mesenteric microvessel recanalization rates, cerebral infarct volumes, and neurological scores were determined. RESULTS: The recanalization rates of platelet- and erythrocyte-rich microthrombi in mesenteric microvessels were higher (P<0.05), and the cerebral infarct volumes and neurological scores of rats with either microthrombi were lower in the US+MB group than in the CON group (P<0.01). The infarct volumes and neurological scores were greater in the r-tPA group than in the US+MB and US+MB+r-tPA groups after treatment of rats with platelet-rich microthrombi (P<0.05). In contrast, after treatment of rats with erythrocyte-rich microthrombi, the infarct volumes and neurological scores were similar in the r-tPA and US+MB groups, but smaller in the US+MB+r-tPA group (P<0.05). CONCLUSIONS: Microbubble-mediated sonothrombolysis improved the outcomes of microthrombi-induced acute ischemic stroke. Thus, this method may serve as an attractive adjunct to recanalization therapy for acute ischemic stroke.

Stepping towards causation in studies of neighborhood and environmental effects: how twin research can overcome problems of selection and reverse causation.

No causal evidence is available to translate associations between neighborhood characteristics and health outcomes into beneficial changes to built environments. Observed associations may be causal or result from uncontrolled confounds related to family upbringing. Twin designs can help neighborhood effects studies overcome selection and reverse causation problems in specifying causal mechanisms. Beyond quantifying genetic effects (i.e., heritability coefficients), we provide examples of innovative measures and analytic methods that use twins as quasi-experimental controls for confounding by environmental effects. We conclude that collaboration among investigators from multiple fields can move the field forward by designing studies that step toward causation.

Genetic and environmental influences on residential location in the US.

We used a classical twin design and measures of neighborhood walkability and social deprivation, using each twin's street address, to examine genetic and environmental influences on the residential location of 1389 same-sex pairs from a US community-based twin registry. Within-pair correlations and structural equation models estimated these influences on walkability among younger (ages 18-24.9) and older (ages 25+) twins. Adjusting for social deprivation, walkability of residential location was primarily influenced by common environment with lesser contributions of unique environment and genetic factors among younger twins, while unique environment most strongly influenced walkability, with small genetic and common environment effects, among older twins. Thus, minimal variance in walkability was explained by shared genetic effects in younger and older twins, and confirms the importance of environmental factors in walkability of residential locations.

Ultrasound molecular imaging of arterial thrombi with novel microbubbles modified by cyclic RGD in vitro and in vivo.

Despite immense potential, ultrasound molecular imaging (UMI) of arterial thrombi remains very challenging because the high-shear arterial flow limits binding of site-targeted microbubbles to the thrombi. The linear Arg-Gly-Asp (RGD) peptides have been successfully applied to evaluate venous, atrial, and arteriolar thrombi, but have thus far failed in the detection of arterial thrombi. Cyclic RGD (Arg-Gly-Asp-D-Phe-Cys) is a cyclic conformation of linear RGD peptides, which has much higher binding-affinity and selectivity for binding to the glycoprotein (GP) IIb/IIIa receptor than its linear counterpart and thus is likely to be an optimal targeted molecular probe for ultrasound molecular imaging of arterial thrombi. In this study, we sought to assess the feasibility of a novel microbubble conjugated with cyclic RGD (Mb-cyclic RGD) in UMI of arterial thrombi in vitro and in vivo . As expected, Mb-cyclic RGD had greater GP IIb/IIIa-targeted binding capability in all shear stress conditions. In addition, the shear stress at half-maximal detachment of Mb-cyclic RGD was 5.7-fold higher than that of microbubbles with non-specific peptide (Mb-CON) (p<0.05). Mb-cyclic RGD enhanced the echogenicity of the platelet-rich thrombus in vitro whereas Mb-CON did not produce enhancement. In the in vivo setting, optimal signal enhancement of the abdominal aortic thrombus was displayed with Mb-cyclic RGD in all cases. Mean video intensity of the abdominal aortic thrombi with Mb-cyclic RGD was 3.2-fold higher than that with Mb-CON (p<0.05). The novel Mb-cyclic RGD facilitated excellent visualisation of arterial thrombi using UMI and showed great promise for clinical applications.

[Effects of high and low shear stress on vascular remodeling and endothelial vascular cell adhesion molecular-1 expression in mouse abdominal aorta].

OBJECTIVE: To establish a mouse model of abdominal aorta stenosis and analyze the alterations in the arterial wall response to high and low shear stress. METHODS: Twenty mouse were randomized equally into 4 groups, including 3 test groups (1, 7 and 14 day groups) with surgically induced stenosis of the abdominal aorta, and a sham-operated group without stenosis. The hemodynamics and the internal diameter of the blood vessel were measured by color Doppler flow imaging. The wall shear stress was calculated by Poiseiulle hydrodynamics formula (τ(m)=η×4×V(m)/D). Pathological examination and immunohistochemistry were performed to observe the arterial morphological changes and the endothelial vascular cell adhesion molecule-1 (VCAM-1) expression. The intimal-media thickness of the aorta was measured and endothelial VCAM-1 expression analyzed quantitatively. RESULTS: Regions of low and high flow shear stress were created upstream from the stenosis and within the stenosis, respectively. Compared with the sham-operated group, the mice with aorta stenosis showed gradually increased vascular intimal-media thickness and VCAM-1 expression intensity in the upstream aorta, but not within the regions of the stenosis. CONCLUSION: Vascular remodeling may occur shortly after exposure to low shear stress, which plays a significant role in initiation and progression of the pathological process of atherosclerosis mediated by VCAM-1, whereas high shear stress may exert an anti-atherosclerotic effect.