Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogen-activated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.Comment: This work was supported by National Institutes of Health (NIH) Predoctoral Traineeship GM07232 and a University of California at Berkeley MacArthur and Lakhan-Pal Graduate Fellowship to K.L.L., Erwin Schroedinger Fellowship J3787-B21 from the Austrian Science Fund to AE-A, Marie Sklodowska-Curie Action H2020-MSCA-IF-2016 InsiliCardio, GA 75083 to CMA, and NIH R01 research grant GM21841 to J

Exploring the ‘middle ground’ between state and market: the example of China

Studies of housing systems lying in the ‘middle ground’ between state and market are subject to three important shortcomings. First, the widely used Esping-Andersen (EA) approach assesses only a subset of the key housing outcomes and may be less helpful for describing changes in housing policy regimes. Second, there is too much emphasis on tenure transitions, and an assumed close correspondence between tenure labels and effective system functioning may not be valid. Third, due attention has not been given to the spatial dimensions in which housing systems operate, in particular when housing policies have a significant devolved or localised emphasis. Updating EA’s framework, we suggest a preliminary list of housing system indicators in order to capture the nature of the housing systems being developed and devolved. We verified the applicability of this indicator system with the case of China. This illustrates clearly the need for a more nuanced and systematic basis for categorising differences and changes in welfare and housing policies

Atrazine and cancer incidence among pesticide applicators in the agricultural health study (1994-2007).

Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association

Digital Divides in Scene Recognition: Uncovering Socioeconomic Biases in Deep Learning Systems

Computer-based scene understanding has influenced fields ranging from urban planning to autonomous vehicle performance, yet little is known about how well these technologies work across social differences. We investigate the biases of deep convolutional neural networks (dCNNs) in scene classification, using nearly one million images from global and US sources, including user-submitted home photographs and Airbnb listings. We applied statistical models to quantify the impact of socioeconomic indicators such as family income, Human Development Index (HDI), and demographic factors from public data sources (CIA and US Census) on dCNN performance. Our analyses revealed significant socioeconomic bias, where pretrained dCNNs demonstrated lower classification accuracy, lower classification confidence, and a higher tendency to assign labels that could be offensive when applied to homes (e.g., "ruin", "slum"), especially in images from homes with lower socioeconomic status (SES). This trend is consistent across two datasets of international images and within the diverse economic and racial landscapes of the United States. This research contributes to understanding biases in computer vision, emphasizing the need for more inclusive and representative training datasets. By mitigating the bias in the computer vision pipelines, we can ensure fairer and more equitable outcomes for applied computer vision, including home valuation and smart home security systems. There is urgency in addressing these biases, which can significantly impact critical decisions in urban development and resource allocation. Our findings also motivate the development of AI systems that better understand and serve diverse communities, moving towards technology that equitably benefits all sectors of society.Comment: 20 pages, 3 figures, 3 table

Evaluation of Explanted CorMatrix Intracardiac Patches in Children With Congenital Heart Disease

Animal data demonstrate that intracardiac patches of decellularized porcine small intestine submucosa (CorMatrix; CorMatrix Cardiovascular, Inc, Atlanta, GA) become repopulated with native cells, suggesting the possibility of a substrate for regenerative tissue in humans. We report the only prospective series to date of explanted CorMatrix patches placed in infants with congenital heart disease

An objective spinal motion imaging assessment (OSMIA): reliability, accuracy and exposure data.

BACKGROUND: Minimally-invasive measurement of continuous inter-vertebral motion in clinical settings is difficult to achieve. This paper describes the reliability, validity and radiation exposure levels in a new Objective Spinal Motion Imaging Assessment system (OSMIA) based on low-dose fluoroscopy and image processing. METHODS: Fluoroscopic sequences in coronal and sagittal planes were obtained from 2 calibration models using dry lumbar vertebrae, plus the lumbar spines of 30 asymptomatic volunteers. Calibration model 1 (mobile) was screened upright, in 7 inter-vertebral positions. The volunteers and calibration model 2 (fixed) were screened on a motorized table comprising 2 horizontal sections, one of which moved through 80 degrees. Model 2 was screened during motion 5 times and the L2-S1 levels of the volunteers twice. Images were digitised at 5fps. Inter-vertebral motion from model 1 was compared to its pre-settings to investigate accuracy. For volunteers and model 2, the first digitised image in each sequence was marked with templates. Vertebrae were tracked throughout the motion using automated frame-to-frame registration. For each frame, vertebral angles were subtracted giving inter-vertebral motion graphs. Volunteer data were acquired twice on the same day and analysed by two blinded observers. The root-mean-square (RMS) differences between paired data were used as the measure of reliability. RESULTS: RMS difference between reference and computed inter-vertebral angles in model 1 was 0.32 degrees for side-bending and 0.52 degrees for flexion-extension. For model 2, X-ray positioning contributed more to the variance of range measurement than did automated registration. For volunteer image sequences, RMS inter-observer variation in intervertebral motion range in the coronal plane was 1.86 degrees and intra-subject biological variation was between 2.75 degrees and 2.91 degrees. RMS inter-observer variation in the sagittal plane was 1.94 degrees. Radiation dosages in each view were below the levels recommended for a plain film. CONCLUSION: OSMIA can measure inter-vertebral angular motion patterns in routine clinical settings if modern image intensifier systems are used. It requires skillful radiography to achieve optimal positioning and dose limitation. Reliability in individual subjects can be judged from the variance of their averaged inter-vertebral angles and by observing automated image registration

The geographical distribution and burden of trachoma in Africa.

BACKGROUND: There remains a lack of epidemiological data on the geographical distribution of trachoma to support global mapping and scale up of interventions for the elimination of trachoma. The Global Atlas of Trachoma (GAT) was launched in 2011 to address these needs and provide standardised, updated and accessible maps. This paper uses data included in the GAT to describe the geographical distribution and burden of trachoma in Africa. METHODS: Data assembly used structured searches of published and unpublished literature to identify cross-sectional epidemiological data on the burden of trachoma since 1980. Survey data were abstracted into a standardised database and mapped using geographical information systems (GIS) software. The characteristics of all surveys were summarized by country according to data source, time period, and survey methodology. Estimates of the current population at risk were calculated for each country and stratified by endemicity class. RESULTS: At the time of writing, 1342 records are included in the database representing surveys conducted between 1985 and 2012. These data were provided by direct contact with national control programmes and academic researchers (67%), peer-reviewed publications (17%) and unpublished reports or theses (16%). Prevalence data on active trachoma are available in 29 of the 33 countries in Africa classified as endemic for trachoma, and 1095 (20.6%) districts have representative data collected through population-based prevalence surveys. The highest prevalence of active trachoma and trichiasis remains in the Sahel area of West Africa and Savannah areas of East and Central Africa and an estimated 129.4 million people live in areas of Africa confirmed to be trachoma endemic. CONCLUSION: The Global Atlas of Trachoma provides the most contemporary and comprehensive summary of the burden of trachoma within Africa. The GAT highlights where future mapping is required and provides an important planning tool for scale-up and surveillance of trachoma control

Topological Diagnosis of Strongly Correlated Electron Systems

The intersection of electronic topology and strong correlations offers a rich platform to discover exotic quantum phases of matter and unusual materials. An overarching challenge that impedes the discovery is how to diagnose topology in strongly correlated settings, as exemplified by Mott insulators. Here, we develop a general framework to address this outstanding question and illustrate its power in the case of Mott insulators. The concept of Green's function Berry curvature -- which is frequency dependent -- is introduced. We apply this notion in a system that contains symmetry-protected nodes in its noninteracting bandstructure; strong correlations drive the system into a Mott insulating state, creating contours in frequency-momentum space where the Green's function vanishes. The Green's function Berry flux of such zeros is found to be quantized, and is as such direct probe of the system's topology. Our framework allows for a comprehensive search of strongly correlated topological materials with Green's function topology.Comment: 38 pages, 13 figures including Supplemental Informatio

Obesity, Type 2 Diabetes and Bone in Adults.

In an increasingly obese and ageing population, type 2 diabetes (T2DM) and osteoporotic fracture are major public health concerns. Understanding how obesity and type 2 diabetes modulate fracture risk is important to identify and treat people at risk of fracture. Additionally, the study of the mechanisms of action of obesity and T2DM on bone has already offered insights that may be applicable to osteoporosis in the general population. Most available evidence indicates lower risk of proximal femur and vertebral fracture in obese adults. However the risk of some fractures (proximal humerus, femur and ankle) is higher, and a significant number fractures occur in obese people. BMI is positively associated with BMD and the mechanisms of this association in vivo may include increased loading, adipokines such as leptin, and higher aromatase activity. However, some fat depots could have negative effects on bone; cytokines from visceral fat are pro-resorptive and high intramuscular fat content is associated with poorer muscle function, attenuating loading effects and increasing falls risk. T2DM is also associated with higher bone mineral density (BMD), but increased overall and hip fracture risk. There are some similarities between bone in obesity and T2DM, but T2DM seems to have additional harmful effects and emerging evidence suggests that glycation of collagen may be an important factor. Higher BMD but higher fracture risk presents challenges in fracture prediction in obesity and T2DM. Dual energy X-ray absorptiometry underestimates risk, standard clinical risk factors may not capture all relevant information, and risk is under-recognised by clinicians. However, the limited available evidence suggests that osteoporosis treatment does reduce fracture risk in obesity and T2DM with generally similar efficacy to other patients