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[This corrects the article DOI: 10.1371/journal.pone.0266608.].

PURPOSE: This study investigated the differential gene expression of BMPs in chick retinal pigment epithelium (RPE) during recovery from short term exposure to optical defocus and form-deprivation (FD) treatments. METHODS: 14-day old White-Leghorn chicks wore either monocular +10 or -10 D lenses, or diffusers for 2 or 48 h, after which eyes were allowed unobstructed vision for up to 96 h. Over this recovery period, refractive errors and choroidal thickness (ChT) were tracked using retinoscopy and high-frequency A-scan ultrasonography. Real-time PCR was used to examine the expression of BMP2, 4, and 7 genes in RPE samples collected 0, 15 min, 2, 24, 48, and 96 h after the termination of treatments. Expression levels in treated eyes and their contralateral control eyes were compared. RESULTS: After the termination of the lens and diffuser treatments, eyes gradually recovered from induced shifts in refractive error. With all three treatments, ChT changes reached statistical significance after 48 h of treatment, be it thinning with the -10 D lens and diffuser treatments (-0.06 ± 0.03mm, p < 0.05; -0.11 ± 0.04 mm, p < 0.05, resp.), or thickening with the +10 D lens (0.31 ± 0.04 mm, p < 0.001). BMP2 gene expression was rapidly upregulated in eyes wearing the +10 D lens, being statistical significance after 2 h, as well as 48 h of treatment. With the 2 h treatment, the latter gene expression pattern persisted for 15 min into the recovery period, before decreasing to the same level as that of contralateral control eyes, with a short-lived rebound, i.e., upregulation, 24 h into the recovery period. With the longer, 48 h treatment, BMP2 gene expression decreased more gradually, from 739 ± 121% at the end of the treatment period, to 72 ± 14% after 48 h of recovery. Two and 48 h of both -10 D and FD treatments resulted in BMP2 gene expression downregulation, with the time taken for gene expression levels to fully recover varying with the duration of initial treatments. In both cases, BMP2 gene expression downregulation persisted for 15 min into the recovery period, but reversed to upregulation by 2 h. Similar gene expression patterns were also observed for BMP4, although the changes were smaller. CONCLUSIONS: The observed changes in BMP gene expression in chick RPE imply dynamic, albeit complex regulation, with the duration of exposure and recovery being critical variables for all three types of visual manipulations. This study provides further evidence for a role of the RPE as an important signal relay linking the retina to the choroid and sclera in eye growth regulation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents an important but limited treatment for patients with severe COVID-19. We assessed the effects of an educational intervention on a persons ECMO care preference and examined whether patients and providers had similar ECMO preferences. METHODS: In the Video+Survey group, patients watched an educational video about ECMOs purpose, benefits, and risks followed by an assessment of ECMO knowledge and care preferences in seven scenarios varying by hypothetical patient age, function, and comorbidities. Patients in the Survey Only group and providers didnt watch the video. Logistic regression was used to estimate the probability of agreement for each ECMO scenario between the two patient groups and then between all patients and providers. RESULTS: Video+Survey patients were more likely (64% vs. 17%; p = 0.02) to correctly answer all ECMO knowledge questions than Survey Only patients. Patients in both groups agreed that ECMO should be considered across all hypothetical scenarios, with predicted agreement above 65%. In adjusted analyses, patients and providers had similar predicted agreement for ECMO consideration across six of the seven scenarios, but patients showed greater preference (84% vs. 41%, p = 0.003) for the scenario of a functionally dependent 65-year-old with comorbidities than providers. DISCUSSION AND CONCLUSIONS: An educational video increased a persons ECMO knowledge but did not change their ECMO preferences. Clinicians were less likely than patients to recommend ECMO for older adults, so advanced care planning discussion between patients and providers about treatment options in critically ill patients with COVID-19 is critical.

BackgroundGiven the waning of vaccine effectiveness and the shifting of the most dominant strains in the U.S., it is imperative to understand the association between vaccination coverage and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) disease and mortality at the community levels and whether that association might vary according to the dominant SARS-CoV-2 strains in the U.S.MethodsGeneralized estimating equations were used to estimate associations between U.S. county-level cumulative vaccination rates and booster distribution and the daily change in county-wide Coronavirus 2019 disease (COVID-19) risks and mortality during Alpha, Delta and Omicron predominance. Models were adjusted for potential confounders at both county and state level. A 2-week lag and a 4-week lag were introduced to assess vaccination rate impact on incidence and mortality, respectively.ResultsAmong 3,073 counties in 48 states, the average county population complete vaccination rate of all age groups was 50.79% as of March 11th, 2022. Each percentage increase in vaccination rates was associated with reduction of 4% (relative risk (RR) 0.9607 (95% confidence interval (CI): 0.9553, 0.9661)) and 3% (RR 0.9694 (95% CI: 0.9653, 0.9736)) in county-wide COVID-19 cases and mortality, respectively, when Alpha was the dominant variant. The associations between county-level vaccine rates and COVID-19 incidence diminished during the Delta and Omicron predominance. However, each percent increase in people receiving a booster shot was associated with reduction of 6% (RR 0.9356 (95% CI: 0.9235, 0.9479)) and 4% (RR 0.9595 (95% CI: 0.9431, 0.9761)) in COVID-19 incidence and mortality in the community, respectively, during the Omicron predominance.ConclusionsAssociations between complete vaccination rates and COVID-19 incidence and mortality appeared to vary with shifts in the dominant variant, perhaps due to variations in vaccine efficacy by variant or to waning vaccine immunity over time. Vaccine boosters were associated with notable protection against Omicron disease and mortality.

Chronic methamphetamine use, a widespread drug epidemic, has been associated with cardiac morphological and electrical remodeling, leading to the development of numerous cardiovascular diseases. While methamphetamine has been documented to induce arrhythmia, most results originate from clinical trials from users who experienced different durations of methamphetamine abuse, providing no documentation on the use of methamphetamine in standardized settings. Additionally, the underlying molecular mechanism on how methamphetamine affects the cardiovascular system remains elusive. A relationship was sought between cardiotoxicity and arrhythmia with associated methamphetamine abuse in zebrafish to identify and to understand the adverse cardiac symptoms associated with methamphetamine. Zebrafish were first treated with methamphetamine 3 times a week over a 2-week duration. Immediately after treatment, zebrafish underwent electrocardiogram (ECG) measurement using an in-house developed acquisition system for electrophysiological analysis. Subsequent analyses of cAMP expression and Ca2+ regulation in zebrafish cardiomyocytes were conducted. cAMP is vital to development of myocardial fibrosis and arrhythmia, prominent symptoms in the development of cardiovascular diseases. Ca2+ dysregulation is also a factor in inducing arrhythmias. During the first week of treatment, zebrafish that were administered with methamphetamine displayed a decrease in heart rate, which persisted throughout the second week and remained significantly lower than the heart rate of untreated fish. Results also indicate an increased heart rate variability during the early stage of treatment followed by a decrease in the late stage for methamphetamine-treated fish over the duration of the experiment, suggesting a biphasic response to methamphetamine exposure. Methamphetamine-treated fish also exhibited reduced QTc intervals throughout the experiment. Results from the cAMP and Ca2+ assays demonstrate that cAMP was upregulated and Ca2+ was dysregulated in response to methamphetamine treatment. Collagenic assays indicated significant fibrotic response to methamphetamine treatment. These results provide potential insight into the role of methamphetamine in the development of fibrosis and arrhythmia due to downstream effectors of cAMP.

Degenerative Suspensory Ligament Desmitis (DSLD) negatively impacts connective tissues in horses, which often leads to progressive chronic pain and lameness. DSLD has been shown to be a systemic disorder that affects multiple body systems, including tendons, sclerae, and the aorta. Currently, the diagnosis is confirmed by post mortem histological examination of a tendon or suspensory ligament. Histology reveals inappropriate accumulations of proteoglycans in the tendons and other tissues in DSLD-affected horses. Unfortunately, there is no reliable method to diagnose DSLD in living horses. Recently, bone morphogenetic protein 2 (BMP2) was identified in active DSLD lesions. In addition, recent data from RNA sequencing (RNA-seq) showed overexpression of numerous genes, among them BMP2, FOS and genes for keratins in DSLD skin biopsies-derived RNA. We hypothesized that some of these genes can be used as biomarkers for diagnosis of DSLD in a panel. Overexpression of some of them was verified in quantitative real time PCR. Immunohistochemistry and RNAscope in-situ hybridization (ISH) assays were used to determine the level of overexpression of specific genes in skin biopsies from control and DSLD-affected horses. The RNAscope ISH assay has shown to be more reliable and more specific that immunohistochemistry. ISH confirmed a significant increase in KRT83 and BMP-2 in hair follicles in DSLD cases, as well as abnormally high expression of FOS in the epidermis, especially in aging horses. Because statistically relevant specificity and sensitivity was documented only for FOS and BMP2, but not KRT83 we recommend the use of FOS and BMP2 panel to diagnose DSLD. We conclude that a panel of two markers from the studied group (BMP2 and FOS) can serve as an additional diagnostic tool for DSLD in living horses, especially in older animals. Further studies are necessary to confirm if this biomarker panel could be used as a prospective tool to identify DSLD in horses as they age.

ObjectivesAn isolated reduction in the diffusing capacity for carbon monoxide (DLco; iso↓DLco) is one of the most common pulmonary function test (PFT) abnormalities in people living with HIV (PWH), but its clinical implications are incompletely understood. In this study, we explored whether iso↓DLco in PWH is associated with a greater respiratory symptom burden.Study designCross-sectional analysis.MethodsWe used ATS/ERS compliant PFTs from PWH with normal spirometry (post-bronchodilator FEV1/FVC ≥0.7; FEV1, FVC ≥80% predicted) from the I AM OLD cohort in San Francisco, CA and Seattle, WA, grouped by DLco categorized as normal (DLco ≥lower limit of normal, LLN), mild iso↓DLco (LLN >DLco >60% predicted), and moderate-severe iso↓DLco (DLco ≤60% predicted). We performed multivariable analyses to test for associations between DLco and validated symptom-severity and quality of life questionnaires, including the modified Medical Research Council dyspnea scale (mMRC), the COPD Assessment Test (CAT), and St. George's Respiratory Questionnaire (SGRQ), as well as between DLco and individual CAT symptoms.ResultsMild iso↓DLco was associated only with a significantly higher SGRQ score. Moderate-severe iso↓DLco was associated with significantly higher odds of mMRC ≥2 and significantly higher CAT and SGRQ scores. PWH with moderate-severe iso↓DLco had increased odds of breathlessness, decreased activity, lower confidence leaving home, and less energy.ConclusionsIso↓DLco is associated with worse respiratory symptom scores, and this association becomes stronger with worsening DLco, suggesting that impaired gas exchange alone has a significant negative impact on the quality of life in PWH. Additional studies are ongoing to understand the etiology of this finding and design appropriate interventions.

BackgroundAlthough physical activity (PA) has been recognized as a favourable factor in the prevention of various diseases, including certain forms of cancer, the relationship between PA and gastric cancer (GC) is not yet fully understood. This study aims to provide data from a pooled analysis of case-control studies within the Stomach cancer Pooling (StoP) Project to estimate the association between leisure-time PA and the occurrence of GC.MethodsSix case-control studies from StoP project collected data on leisure-time PA, for a total of 2,343 cases and 8,614 controls. Subjects were classified into three leisure-time PA categories, either none/low, intermediate or high, based on study-specific tertiles. We used a two-stage approach. Firstly, we applied multivariable logistic regression models to obtain study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) then, we used a random-effect models to obtain pooled effect estimates. We performed stratified analyses according to demographic, lifestyle and clinical covariates.ResultsThe meta-analysis showed ORs of GC with no significant differences between intermediate vs low and high vs low PA level (OR 1.05 [95%CI 0.76-1.45]; OR 1.23 [95%CI 0.78-1.94], respectively). GC risk estimates did not strongly differ across strata of selected covariates except for age ≤ 55 years old (high vs low level: OR 0.72 [95%CI 0.55-0.94]) and for control population-based studies (high vs low level: OR 0.79 [95%CI 0.68-0.93]).ConclusionsNo association was found between leisure time PA and GC, apart from a slight suggestion of decreased risk below age 55 and in control population-based studies. These results may reflect specific characteristics of GC at a younger age, or the presence of a cohort effect mediating and interacting with socioeconomic determinants of GC The different distribution of PA levels among hospitalized controls could have led to an underestimated effect of PA on GC risk.

This is an exploratory study on the effect of electrolysis, delivered during the thawing stage of a cryoablation protocol, on tissue ablation. This treatment protocol, that combines freezing and electrolysis, is named "cryoelectrolysis". In cryoelectrolysis the cryoablation probe is also used as the electrolysis delivering electrode. The study was performed on the liver of Landrace pigs and the tissues were examined 24 hours after treatment (two pigs) and 48 hours after treatment (one pig). The cryoelectrolysis device and different cryoelectrolysis ablation configurations tested are described. This exploratory, non-statistical study shows that the addition of electrolysis expands the ablated area in comparison to cryoablation alone and that there is a substantial difference between the histological appearance of tissue treated by cryoablation alone, tissue treated by cryoablation and electrolysis at the anode and tissue treated by cryoablation and electrolysis at the cathode.

Quantifying the colors of objects is useful in a wide range of applications, including medical diagnosis, agricultural monitoring, and food safety. Accurate colorimetric measurement of objects is a laborious process normally performed through a color matching test in the laboratory. A promising alternative is to use digital images for colorimetric measurement, due to their portability and ease of use. However, image-based measurements suffer from errors caused by the non-linear image formation process and unpredictable environmental lighting. Solutions to this problem often perform relative color correction among multiple images through discrete color reference boards, which may yield biased results due to the lack of continuous observation. In this paper, we propose a smartphone-based solution, that couples a designated color reference board with a novel color correction algorithm, to achieve accurate and absolute color measurements. Our color reference board contains multiple color stripes with continuous color sampling at the sides. A novel correction algorithm is proposed to utilize a first-order spatial varying regression model to perform the color correction, which leverages both the absolute color magnitude and scale to maximize the correction accuracy. The proposed algorithm is implemented as a "human-in-the-loop" smartphone application, where users are guided by an augmented reality scheme with a marker tracking module to take images at an angle that minimizes the impact of non-Lambertian reflectance. Our experimental results show that our colorimetric measurement is device independent and can reduce up to 90% color variance for images collected under different lighting conditions. In the application of reading pH values from test papers, we show that our system performs 200% better than human reading. The designed color reference board, the correction algorithm, and our augmented reality guiding approach form an integrated system as a novel solution to measure color with increased accuracy. This technique has the flexibility to improve color reading performance in systems beyond existing applications, evidenced by both qualitative and quantitative experiments on example applications such as pH-test reading.

PurposeIn young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population.MethodsA retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS.ResultsAmong the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS (7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%- although not significantly associated with ARDS), and diabetes (32%).ConclusionTrough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.

Visible disruptions of appropriate food distribution for end consumers during the onset of the COVID-19 pandemic prompted calls for an urgent, renewed look at how the U.S. agri-food system is impacted by and responds to pandemics, natural disasters, and human-made crises. Previous studies suggest the COVID-19 pandemic yielded uneven impacts across agri-food supply chain segments and regions. For a rigorously comparable assessment of the impact of COVID-19 on agri-food businesses, a survey was administered from February to April 2021 to five segments of the agri-food supply chain in three study regions (California, Florida, and the two-state region of Minnesota-Wisconsin). Results (N = 870) measuring the self-reported changes in quarterly business revenue in 2020 compared to businesses' typical experience pre-COVID-19 suggest significant differences across supply chain segments and regions. In the Minnesota-Wisconsin region, restaurants took the largest hit and the upstream supply chains were relatively unaffected. In California, however, the negative impacts were felt throughout the supply chain. Two factors likely contributed to regional differences: (1) regional disparities in pandemic evolution and governance and (2) structural differences in regional agri-food systems. Regionalized and localized planning and the development of best-practices will be necessary for the U.S. agri-food system to enhance preparedness for and resilience to future pandemics, natural disasters, and human-made crises.

Asthma currently affects more than 339 million people worldwide. In the present preliminary study, we examined the efficacy of a new, inhalable soluble epoxide hydrolase inhibitor (sEHI), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), to attenuate airway inflammation, mucin secretion, and hyper-responsiveness (AHR) in an ovalbumin (OVA)-sensitized murine model. Male BALB/c mice were divided into phosphate-buffered saline (PBS), OVA, and OVA+TPPU (2- or 6-h) exposure groups. On days 0 and 14, the mice were administered PBS or sensitized to OVA in PBS. From days 26-38, seven challenge exposures were performed with 30 min inhalation of filtered air or OVA alone. In the OVA+TPPU groups, a 2- or 6-h TPPU inhalation preceded each 30-min OVA exposure. On day 39, pulmonary function tests (PFTs) were performed, and biological samples were collected. Lung tissues were used to semi-quantitatively evaluate the severity of inflammation and airway constriction and the volume of stored intracellular mucosubstances. Bronchoalveolar lavage (BAL) and blood samples were used to analyze regulatory lipid mediator profiles. Significantly (p < 0.05) attenuated alveolar, bronchiolar, and pleural inflammation; airway resistance and constriction; mucosubstance volume; and inflammatory lipid mediator levels were observed with OVA+TPPU relative to OVA alone. Cumulative findings indicated TPPU inhalation effectively inhibited inflammation, suppressed AHR, and prevented mucosubstance accumulation in the murine asthmatic model. Future studies should determine the pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (i.e., concentration/dose responses) of inhaled TPPU to explore its potential as an asthma-preventative or -rescue treatment.

With the advent of single cell/nucleus RNA sequencing (sc/snRNA-seq), the field of cell phenotyping is now a data-driven exercise providing statistical evidence to support cell type/state categorization. However, the task of classifying cells into specific, well-defined categories with the empirical data provided by sc/snRNA-seq remains nontrivial due to the difficulty in determining specific differences between related cell types with close transcriptional similarities, resulting in challenges with matching cell types identified in separate experiments. To investigate possible approaches to overcome these obstacles, we explored the use of supervised machine learning methods-logistic regression, support vector machines, random forests, neural networks, and light gradient boosting machine (LightGBM)-as approaches to classify cell types using snRNA-seq datasets from human brain middle temporal gyrus (MTG) and human kidney. Classification accuracy was evaluated using an F-beta score weighted in favor of precision to account for technical artifacts of gene expression dropout. We examined the impact of hyperparameter optimization and feature selection methods on F-beta score performance. We found that the best performing model for granular cell type classification in both datasets is a multinomial logistic regression classifier and that an effective feature selection step was the most influential factor in optimizing the performance of the machine learning pipelines.

Contrasting with the predominance of blade-based assemblages in the Eurasian Upper Paleolithic, the large-scale persistence of a core-and-flake technology remains one of the defining features of Late Pleistocene lithic technology in East Asia. In North China, Shuidonggou is an exceptional site where both technologies are documented, therefore, it is an important archaeological sequence to understand regional technological evolution during the Marine Isotopic Stage 3. Blade technology first occurred at Shuidonggou Locality 1 and 2 around 41 ka cal BP while core-and-flake assemblages were widespread in North China. However, systematic technological studies on assemblages postdating 34 ka cal BP have not been conducted to examine whether the blade technology appeared and disappeared over a short yet abrupt episode, or persists and integrates into other forms in the region. Here, we conducted qualitative and quantitative analyses to reconstruct lithic productions on the assemblages at Shuidonggou Locality 2, dated after 34 ka cal BP. Our results show that there is a total absence of laminar elements in stone artifacts dated to 34-28 ka cal BP at Shuidonggou. Instead, we observe a dominance of an expedient production of flakes in the younger assemblages, illustrating a rapid return to flake-based technology after a relatively brief episode of stone blade production. Combining archaeological, environmental, and genetic evidence, we suggest that this technological 'reversal' from blades back to core and flake technology reflect population dynamics and adaptive strategies at an ecological interface between East Asian winter and summer monsoon.

Investigating the 3D structures and rearrangements of organelles within a single cell is critical for better characterizing cellular function. Imaging approaches such as soft X-ray tomography have been widely applied to reveal a complex subcellular organization involving multiple inter-organelle interactions. However, 3D segmentation of organelle instances has been challenging despite its importance in organelle characterization. Here we propose an intensity-based post-processing tool to identify and separate organelle instances. Our tool separates sphere-like (insulin vesicle) and columnar-shaped organelle instances (mitochondrion) based on the intensity of raw tomograms, semantic segmentation masks, and organelle morphology. We validate our tool using synthetic tomograms of organelles and experimental tomograms of pancreatic β-cells to separate insulin vesicle and mitochondria instances. As compared to the commonly used connected regions labeling, watershed, and watershed + Gaussian filter methods, our tool results in improved accuracy in identifying organelles in the synthetic tomograms and an improved description of organelle structures in β-cell tomograms. In addition, under different experimental treatment conditions, significant changes in volumes and intensities of both insulin vesicle and mitochondrion are observed in our instance results, revealing their potential roles in maintaining normal β-cell function. Our tool is expected to be applicable for improving the instance segmentation of other images obtained from different cell types using multiple imaging modalities.

BackgroundThere is evidence from various models of hypoxic-ischemic injury (HII) that nitric oxide (NO) is protective. We hypothesized that either inhaled NO (iNO) or nitrite would alleviate brain injury in neonatal HII via modulation of mitochondrial function.MethodsWe tested the effects of iNO and nitrite on the Rice-Vannucci model of HII in 7-day-old rats. Brain mitochondria were isolated for flow cytometry, aconitase activity, electron paramagnetic resonance, and Seahorse assays.ResultsPretreatment of pups with iNO decreased survival in the Rice-Vannucci model of HII, while iNO administered post-insult did not. MRI analysis demonstrated that pre-HII iNO at 40 ppm and post-HII iNO at 20 ppm decreased the brain lesion sizes from 6.3±1.3% to 1.0±0.4% and 1.8±0.8%, respectively. Intraperitoneal nitrite at 0.165 μg/g improved neurobehavioral performance but was harmful at higher doses and had no effect on brain infarct size. NO reacted with complex IV at the heme a3 site, decreased the oxidative stress of mitochondria challenged with anoxia and reoxygenation, and suppressed mitochondrial oxygen respiration.ConclusionsThis study suggests that iNO administered following neonatal HII may be neuroprotective, possibly via its modulation of mitochondrial function.

BackgroundLittle information exists on how COVID-19 testing influences intentions to engage in risky behavior. Understanding the behavioral effects of diagnostic testing may highlight the role of adequate testing on controlling viral transmission. In order to evaluate these effects, simulated scenarios were conducted evaluating participant intentions to self-isolate based on COVID-19 diagnostic testing availability and results.MethodsParticipants from the United States were recruited through an online survey platform (Amazon Mechanical Turk) and randomized to one of three hypothetical scenarios. Each scenario asked participants to imagine having symptoms consistent with COVID-19 along with a clinical diagnosis from their physician. However, scenarios differed in either testing availability (testing available v. unavailable) or testing result (positive v. negative test). The primary outcome was intention to engage in high-risk COVID-19 behaviors, measured using an 11-item mean score (range 1-7) that was pre-registered prior to data collection. Multi-variable linear regression was used to compare the mean composite scores between conditions. The randomized survey was conducted between July 23rd to July 29th, 2020.ResultsA total of 1400 participants were recruited through a national, online, opt-in survey. Out of 1194 respondents (41.6% male, 58.4% female) with a median age of 38.5 years, participants who had no testing available in their clinical scenario showed significantly greater intentions to engage in behavior facilitating COVID-19 transmission compared to those who received a positive confirmatory test result scenario (mean absolute difference (SE): 0.14 (0.06), P = 0.016), equating to an 11.1% increase in mean score risky behavior intentions. Intention to engage in behaviors that can spread COVID-19 were also positively associated with male gender, poor health status, and Republican party affiliation.ConclusionTesting availability appears to play an independent role in influencing behaviors facilitating COVID-19 transmission. Such findings shed light on the possible negative externalities of testing unavailability.Trial registrationEffect of Availability of COVID-19 Testing on Choice to Isolate and Socially Distance, NCT04459520, https://clinicaltrials.gov/ct2/show/NCT04459520.

We aimed to elucidate the characteristics of HIV molecular epidemiology and identify transmission hubs in eastern China using genetic transmission network and lineage analyses. HIV-TRACE was used to infer putative relationships. Across the range of epidemiologically-plausible genetic distance (GD) thresholds (0.1-2.0%), a sensitivity analysis was performed to determine the optimal threshold, generating the maximum number of transmission clusters and providing reliable resolution without merging different small clusters into a single large cluster. Characteristics of genetically linked individuals were analyzed using logistic regression. Assortativity (shared characteristics) analysis was performed to infer shared attributes between putative partners. 1,993 persons living with HIV-1 were enrolled. The determined GD thresholds within subtypes CRF07_BC, CRF01_AE, and B were 0.5%, 1.2%, and 1.7%, respectively, and 826 of 1,993 (41.4%) sequences were linked with at least one other sequence, forming 188 transmission clusters of 2-80 sequences. Clustering rates for the main subtypes CRF01_AE, CRF07_BC, and B were 50.9% (523/1027), 34.2% (256/749), and 32.1% (25/78), respectively. Median cluster sizes of these subtypes were 2 (2-52, n = 523), 2 (2-80, n = 256), and 3 (2-6, n = 25), respectively. Subtypes in individuals diagnosed and residing in Hangzhou city (OR = 1.423, 95% CI: 1.168-1.734) and men who have sex with men (MSM) were more likely to cluster. Assortativity analysis revealed individuals were more likely to be genetically linked to individuals from the same age group (AIage = 0.090, P

BACKGROUND: Sensitive and high throughput molecular detection assays are essential during the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vast majority of the SARS-CoV-2 molecular assays use nasopharyngeal swab (NPS) or oropharyngeal swab (OPS) specimens collected from suspected individuals. However, using NPS or OPS as specimens has apparent drawbacks, e.g. the collection procedures for NPS or OPS specimens can be uncomfortable to some people and may cause sneezing and coughing which in turn generate droplets and/or aerosol particles that are of risk to healthcare workers, requiring heavy use of personal protective equipment. There have been recent studies indicating that self-collected saliva specimens can be used for molecular detection of SARS-CoV-2 and provides more comfort and ease of use for the patients. Here we report the performance of QuantiVirus™ SARS-CoV-2 test using saliva as the testing specimens with or without pooling. METHODS: Development and validation studies were conducted following FDA-EUA and molecular assay validation guidelines. Using SeraCare Accuplex SARS-CoV-2 reference panel, the limit of detection (LOD) and clinical performance studies were performed with the QuantiVirus™ SARS-CoV-2 test. For clinical evaluation, 85 known positive and 90 known negative clinical NPS samples were tested. Additionally, twenty paired NPS and saliva samples collected from recovering COVID-19 patients were tested and the results were further compared to that of the Abbott m2000 SARS-CoV-2 PCR assay. Results of community collected 389 saliva samples for COVID-19 screening by QuantiVirus™ SARS-CoV-2 test were also obtained and analyzed. Additionally, testing of pooled saliva samples was evaluated. RESULTS: The LOD for the QuantiVirus™ SARS-CoV-2 test was confirmed to be 100-200 copies/mL. The clinical performance studies using contrived saliva samples indicated that the positive percentage agreement (PPA) of the QuantiVirus™ SARS-CoV-2 test is 100% at 1xLOD, 1.5xLOD and 2.5xLOD. No cross-reactivity was observed for the QuantiVirus™ SARS-CoV-2 test with common respiratory pathogens. Testing of clinical samples showed a positive percentage agreement (PPA) of 100% (95% CI: 94.6% to 100%) and a negative percentage agreement (NPA) of 98.9% (95% CI: 93.1% to 99.9%). QuantiVirus™ SARS CoV-2 test had 80% concordance rate and no significant difference (p = 0.13) between paired saliva and NPS specimens by Wilcoxon matched pairs signed rank test. Positive test rate was 1.79% for 389 saliva specimens collected from local communities for COVID-19 screening. Preliminary data showed that saliva sample pooling up to 6 samples (1:6 pooling) for SARS-CoV-2 detection is feasible (sensitivity 94.8% and specificity 100%). CONCLUSION: The studies demonstrated that the QuantiVirus™ SARS-CoV-2 test has a LOD of 200 copies/mL in contrived saliva samples. The clinical performance of saliva-based testing is comparable to that of NPS-based testing. Pooling of saliva specimens for SARS-CoV-2 detection is feasible. Saliva based and high-throughput QuantiVirus™ SARS-CoV-2 test offers a highly desirable testing platform during the ongoing COVID-19 pandemic.

Human adults are faster to respond to small/large numerals with their left/right hand when they judge the parity of numerals, which is known as the SNARC (spatial-numerical association of response codes) effect. It has been proposed that the size of the SNARC effect depends on response latencies. The current study introduced a perceptual orientation task, where participants were asked to judge the orientation of a digit or a frame surrounding the digit. The present study first confirmed the SNARC effect with native Chinese speakers (Experiment 1) using a parity task, and then examined whether the emergence and size of the SNARC effect depended on the response latencies (Experiments 2, 3, and 4) using a perceptual orientation judgment task. Our results suggested that (a) the automatic processing of response-related numerical-spatial information occurred with Chinese-speaking participants in the parity task; (b) the SNARC effect was also found when the task did not require semantic access; and (c) the size of the effect depended on the processing speed of the task-relevant dimension. Finally, we proposed an underlying mechanism to explain the SNARC effect in the perceptual orientation judgment task.

Taxi order demand prediction is of tremendous importance for continuous upgrading of an intelligent transportation system to realise city-scale and personalised services. An accurate short-term taxi demand prediction model in both spatial and temporal relations can assist a city pre-allocate its resources and facilitate city-scale taxi operation management in a megacity. To address problems similar to the above, in this study, we proposed a multi-zone order demand prediction model to predict short-term taxi order demand in different zones at city-scale. A two-step methodology was developed, including order zone division and multi-zone order prediction. For the zone division step, the K-means++ spatial clustering algorithm was used, and its parameter k was estimated by the between-within proportion index. For the prediction step, six methods (backpropagation neural network, support vector regression, random forest, average fusion-based method, weighted fusion-based method, and k-nearest neighbour fusion-based method) were used for comparison. To demonstrate the performance, three multi-zone weighted accuracy indictors were proposed to evaluate the order prediction ability at city-scale. These models were implemented and validated on real-world taxi order demand data from a three-month consecutive collection in Shenzhen, China. Experiment on the city-scale taxi demand data demonstrated the superior prediction performance of the multi-zone order demand prediction model with the k-nearest neighbour fusion-based method based on the proposed accuracy indicator.

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in humans, yet the molecular etiology is currently unknown. Evidence suggests that genetic factors may play an important role in some cases of idiopathic BPPV, particularly in familial cases, but the responsible genetic variants have not been identified. In this study, we performed whole exome sequencing [including untranslated regions (UTRs)] of 12 families and Sanger sequencing of additional 30 families with recurrent BPPV in Caucasians from the United States (US) Midwest region, to identify the genetic variants responsible for heightened susceptibility to BPPV. Fifty non-BPPV families were included as controls. In silico and experimental analyses of candidate variants show that an insertion variant rs113784532 (frameshift causing truncation) in the neural cadherin gene PCDHGA10 (protocadherin-gamma A10) is an exceedingly strong candidate (p = 1.80x10-4 vs. sample controls; p = 5.85x10-19 vs. ExAC data; p = 4.9x10-3 vs. NHLBI exome data). The mutant protein forms large aggregates in BPPV samples even at young ages, and affected subjects carrying this variant have an earlier onset of the condition than those without [average 44.0±14.0 (n = 16) versus 54.4±16.1 (n = 36) years old, p = 0.054]. In both human and mouse inner ear tissues, PCDHGA10 is expressed in ganglia, hair cells and vestibular transitional epithelia. Fluorescent RNA in situ hybridization using mouse inner ear tissues shows that expression increases with age. In summary, our data show that a variant in the PCDHGA10 gene may be involved in causing or aggravating some familial cases of recurrent idiopathic BPPV.

Antibiotic resistance genes (ARGs) are emerging contaminants causing serious global health concern. Interventions to address this concern include improving our understanding of methods for treating waste material of human and animal origin that are known to harbor ARGs. Anaerobic digestion is a commonly used process for treating dairy manure, and although effective in reducing ARGs, its mechanism of action is not clear. In this study, we used three ARGs to conducted a longitudinal bench scale anaerobic digestion experiment with various temperatures (28, 36, 44, and 52°C) in triplicate using fresh dairy manure for 30 days to evaluate the reduction of gene abundance. Three ARGs and two mobile genetic elements (MGEs) were studied: sulfonamide resistance gene (sulII), tetracycline resistance genes (tetW), macrolide-lincosamide-streptogramin B (MLSB) superfamily resistance genes (ermF), class 1 integrase gene (intI1), and transposase gene (tnpA). Genes were quantified by real-time quantitative PCR. Results show that the thermophilic anaerobic digestion (52°C) significantly reduced (p < 0.05) the absolute abundance of sulII (95%), intI1 (95%), tnpA (77%) and 16S rRNA gene (76%) after 30 days of digestion. A modified Collins-Selleck model was used to fit the decay curve, and results suggest that the gene reduction during the startup phase of anaerobic digestion (first 5 days) was faster than the later stage, and reductions in the first five days were more than 50% for most genes.

The way an animal uses its habitat can serve as an indicator of habitat appropriateness for the species and individuals. Bottlenose dolphins (Tursiops truncatus and Tursiops aduncus) in accredited zoos and aquariums experience a range of habitat types and management programs that provide opportunities for dolphins to engage in species-appropriate behaviors and potentially influence their individual and group welfare. Data in the present study were collected as part of a larger study titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study). Non-invasive bio-logging devices (Movement Tags) recorded the diving behavior and vertical habitat movements of 60 bottlenose dolphins at 31 zoos and aquariums that were accredited by the Alliance for Marine Mammal Parks and Aquariums and/or the Association of Zoos & Aquariums. Bottlenose dolphins wore a Movement Tag one day per week for two five-week data collection periods. Demographic variables, environmental enrichment programs, training programs, and habitat characteristics were associated with habitat usage. Longer dive durations and use of the bottom third of the habitat were associated with higher enrichment program index values. Dolphins receiving new enrichment on a monthly/weekly schedule also used the bottom third of the habitat more often than those receiving new enrichment on a yearly/year+ schedule. Dolphins that were managed in a group that was split into smaller subgroups during the day and were reunited into one group at night spent less time in the top third of the habitat than those who remained in a single group with consistent members at all times. Dolphins that were managed as subgroups with rotating members but were never united as one group spent less time in the bottom third of the habitat than those who remained in a single group with consistent members at all times. Taken together, the results suggested that management practices, such as enrichment and training programs, played a greater role in how dolphins interacted with their environment relative to the physical characteristics of the habitat.

High-resolution non-invasive cetacean tagging systems can be used to investigate the influence of habitat characteristics and management factors on behavior by quantifying activity levels and distance traveled by bottlenose dolphins (Tursiops truncatus and Tursiops aduncus) in accredited zoos and aquariums. Movement Tags (MTags), a bio-logging device, were used to record a suite of kinematic and environmental information outside of formal training sessions as part of a larger study titled "Towards understanding the welfare of cetaceans in zoos and aquariums" (colloquially called the Cetacean Welfare Study). The purpose of the present study was to explore if and how habitat characteristics, environmental enrichment programs, and training programs were related to the distance traveled and energy expenditure of dolphins in accredited zoos and aquariums. Bottlenose dolphins in accredited zoos and aquariums wore MTags one day per week for two five-week data collection periods. Overall dynamic body acceleration (ODBA), a proxy for energy expenditure, and average distance traveled per hour (ADT) of 60 dolphins in 31 habitats were examined in relation to demographic, habitat, and management factors. Participating facilities were accredited by the Alliance for Marine Mammal Parks and/or Aquariums and the Association of Zoos & Aquariums. Two factors were found to be related to ADT while six factors were associated with ODBA. The results showed that enrichment programs were strongly related to both ODBA and ADT. Scheduling predictable training session times was also positively associated with ADT. The findings suggested that habitat characteristics had a relatively weak association with ODBA and were not related to ADT. In combination, the results suggested that management practices were more strongly related to activity levels than habitat characteristics.

A lack of comparative data across laboratories is often a barrier to the uptake and adoption of new technologies. Furthermore, data generated by different immunoassay methods may be incomparable due to a lack of harmonization. In this multicenter study, we describe validation experiments conducted in a single lab and cross-lab comparisons of assay results to assess the performance characteristics of the Q-plex™ 7-plex Human Micronutrient Array (7-plex), an immunoassay that simultaneously quantifies seven biomarkers associated with micronutrient (MN) deficiencies, inflammation and malarial antigenemia using plasma or serum; alpha-1-acid glycoprotein, C-reactive protein, ferritin, histidine-rich protein 2, retinol binding protein 4, soluble transferrin receptor, and thyroglobulin. Validations included repeated testing (n = 20 separately prepared experiments on 10 assay plates) in a single lab to assess precision and linearity. Seven independent laboratories tested 76 identical heparin plasma samples collected from a cohort of pregnant women in Niger using the same 7-plex assay to assess differences in results across laboratories. In the analytical validation experiments, intra- and inter-assay coefficients of variation were acceptable at

BackgroundIn 2013, a tuberculosis (TB) outbreak occurred in a middle school in Henan province of China. An outbreak survey was carried out in the school.ObjectivesThis study was undertaken to investigate the detection rate of TB cases and those with strong Mantoux positive (SMP), defined as tuberculin skin test (TST) indurations of 15mm or larger and/or blisters, necrosis or lymphangitis, and to identify their risk factors.MethodsThe TST, chest x-ray/radiography, and TB-suspicious symptoms interview were used to screen for TB cases. Their diagnosis was made by sputum smear microscopy, liquid culture, computed tomography (CT), and diagnostic therapy if necessary. We retrospectively analyzed the outbreak survey data of 4082 students and 278 staff in the school. Logistic regression models were used to identify the risk factors associated with SMP and TB disease.ResultsApproximately 3.55% of students and 16.55% of staff were SMP. SMP rate in students was significantly lower than that in staff (p

Sirtuin 5 (SIRT5) is a member of the NAD+-dependent sirtuin family of protein deacylase that catalyzes removal of post-translational modifications, such as succinylation, malonylation, and glutarylation on lysine residues. In light of the SIRT5's roles in regulating mitochondrion function, we show here that SIRT5 deficiency leads to suppression of mitochondrial NADH oxidation and inhibition of ATP synthase activity. As a result, SIRT5 deficiency decreases mitochondrial ATP production, increases AMP/ATP ratio, and subsequently activates AMP-activated protein kinase (AMPK) in cultured cells and mouse hearts under energy stress conditions. Moreover, Sirt5 knockout attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy and cardiac dysfunction in mice, which is associated with decreased ATP level, increased AMP/ATP ratio and enhanced AMPK activation. Our study thus uncovers an important role of SIRT5 in regulating cellular energy metabolism and AMPK activation in response to energy stress.

Glottal insufficiency due to vocal fold paralysis, paresis, or atrophy often leads to degraded voice quality. One of the primary surgical intervention procedures to treat glottal insufficiency is medialization laryngoplasty, in which an implant is inserted through a lateral window on the thyroid cartilage to medialize the vocal folds. While the goal of medialization is to modify the vocal fold structure to restore normal phonation, few studies have attempted to quantify such structural changes of the vocal folds. The goal of this study is to quantify the three-dimensional structural changes of the vocal folds due to implant insertion in medialization laryngoplasty, and evaluate its potential effect on voice production. Medialization laryngoplasty were performed in excised human larynges using implants of different stiffness. Magnetic resonance images of the larynges were obtained with and without implant insertion. The results showed that implant insertion significantly changed the original body-cover structure of the vocal folds, with the implant taking over the large space used to be occupied by the original body layer and the vocal fold being stretched into a thin layer wrapped around the implant. The medial-lateral dimension of the vocal fold was significantly reduced from about 4 mm to 1 mm, and the vocal fold was stretched in the coronal plane by about 70%. It is hypothesized that use of implants with stiffness comparable to that of the vocal folds is beneficial because the degree of medialization can be adjusted without much negative effects on phonation frequency, phonation threshold pressure, or vibration amplitude.

[This corrects the article DOI: 10.1371/journal.pone.0066464.].

The left ventricular (LV) end-systolic (ES) pressure volume relationship (ESPVR) is the cornerstone of systolic LV function analysis. We describe a 2D real-time (RT) MRI-based method (RTPVR) with separate software tools for 1) semi-automatic level set-based shape prior method (LSSPM) of the LV, 2) generation of synchronized pressure area loops and 3) calculation of the ESPVR. We used the RTPVR method to measure ventricular geometry, ES pressure area relationship (ESPAR) and ESPVR during vena cava occlusion (VCO) in normal sheep. 14 adult sheep were anesthetized and underwent measurement of LV systolic function. Ten of the 14 sheep underwent RTMRI and eight of the 14 underwent measurement with conductance catheter; 4 had both RTMRI and conductance measurements. 2D cross sectional RTMRI were performed at apex, mid-ventricle and base levels during separate VCOs. The Dice similarity coefficient was used to compare LSSPM and manual image segmentation and thus determine LSSPM accuracy. LV cross-sectional area, major and minor axis length, axis ratio, major axis orientation angle and ESPAR were measured at each LV level. ESPVR was calculated with a trapezoidal rule. The Dice similarity coefficient between LSSPM and manual segmentation by two readers was 87.31±2.51% and 88.13±3.43%. All cross sections became more elliptical during VCO. The major axis orientation shifted during VCO but remained in the septo-lateral direction. LV chamber obliteration at the apical level occurred during VCO in 7 of 10 sheep that underwent RTMRI. ESPAR was non-linear at all levels. Finally, ESPVR was non-linear because of apical collapse. ESPVR measured by conductance catheter (EES,Index = 2.23±0.66 mmHg/ml/m2) and RT (EES,Index = 2.31±0.31 mmHg/ml/m2) was not significantly different. LSSPM segmentation of 2D RT MRI images is accurate and allows calculation of LV geometry, ESPAR and ESPVR during VCO. In the future, RTPVR will facilitate determination of regional systolic material parameters underlying ESPVR.

Is it appropriate for scientists to engage in political advocacy? Some political critics of scientists argue that scientists have become partisan political actors with self-serving financial agendas. However, most scientists strongly reject this view. While social scientists have explored the effects of science politicization on public trust in science, little empirical work directly examines the drivers of scientists' interest in and willingness to engage in political advocacy. Using a natural experiment involving the U.S. National Science Foundation Graduate Research Fellowship (NSF-GRF), we causally estimate for the first time whether scientists who have received federal science funding are more likely to engage in both science-related and non-science-related political behaviors. Comparing otherwise similar individuals who received or did not receive NSF support, we find that scientists' preferences for political advocacy are not shaped by receiving government benefits. Government funding did not impact scientists' support of the 2017 March for Science nor did it shape the likelihood that scientists donated to either Republican or Democratic political groups. Our results offer empirical evidence that scientists' political behaviors are not motivated by self-serving financial agendas. They also highlight the limited capacity of even generous government support programs to increase civic participation by their beneficiaries.

In February 2020, the Novel Coronavirus (COVID-19) was raging in Wuhan, China and quickly spreading to the rest of the world. This period was fraught with uncertainty for those in the affected areas. The present investigation examined the role of two potential coping resources during this stressful period of uncertainty: flow and mindfulness. Participants in Wuhan and other major cities affected by COVID-19 (N = 5115) completed an online survey assessing subjective experiences of flow, mindfulness, and well-being. Longer quarantine was associated with poorer well-being; flow and mindfulness were associated with better well-being on some measures. However, flow-but not mindfulness-moderated the link between quarantine length and well-being, such that people who experienced high levels flow showed little or no association between quarantine length and poorer well-being. These findings suggest that experiencing flow (typically by engaging in flow-inducing activities) may be a particularly effective way to protect against potentially deleterious effects of a period of quarantine.

Digitization has facilitated the proliferation of crowd science by lowering the cost of finding individuals with the willingness to participate in science without pay. However, the factors that influence participation and the outcomes of voluntary participation are unclear. We report two findings from a field experiment on the worlds largest crowd science platform that tests how voluntary contributions to science are affected by providing clarifying information on either the desired outcome of a scientific task or the labor requirements for completing the task. First, there is significant heterogeneity in the motivations and ability of contributors to crowd science. Second, both of the information interventions lead to significant decreases in the quantity and increases in the quality of contributions. Combined, our findings are consistent with the information interventions improving match quality between the task and the volunteer. Our findings suggest that science can be democratized by engaging individuals with varying skill levels and motivations with small changes in the information provided to participants.

BACKGROUND: The perceived risk of developing type 2 diabetes mellitus (T2DM) can motivate individuals to adopt preventive health behaviors. Compared with fathers, mothers of young children often experience unique risk factors for developing T2DM: pregnancy-related weight gain, lifestyle changes related to child care, and the increased incidence of gestational diabetes mellitus. Understanding how actual risk factors affect the perceived risk of developing T2DM can foster effective diabetes prevention interventions for this population. The aims of this study were to describe the risk, perceived and actual, of developing T2DM and to explore the influencing factors of perceived risk for Chinese mothers of preschool children in China. METHODS: A multisite, cross-sectional survey was conducted and included 176 mothers (mean age of 31.19 years old) of preschool children (aged 3-7 years old) from four preschools in Changsha, the capital city of Hunan Province, China. The overall perceived risk of developing T2DM was measured by one item Your own personal health risk is at almost no risk, slight risk, moderate risk or high risk from diabetes from the Risk Perception Survey for Developing Diabetes (RPS-DD). PRS-DD and the Chinese version of the Canadian Diabetes Risk Assessment Questionnaire (CHINARISK) were used to assess perceived risk related worry, personal control, optimistic bias, and diabetes risk knowledge and actual risk of T2DM. Mothers also reported their height, weight, and waist circumference followed by the NIH protocol. Pearson correlation and stepwise multivariate linear regression were used to explore how the actual risk factors affected the perceived risk of developing diabetes (RPS-DD)). RESULTS: Nearly 90% of mothers perceived almost no/slight risk for developing diabetes. Nearly half of the mothers had parents or siblings with diabetes. Roughly 70% of the mothers did not eat five servings of fruits and vegetables per day, and more than 50% did not exercise at least 30 minutes a day. In the five stepwise multivariate linear regression models, young mothers (95% CI .400-1.311) and those with a family history of diabetes (95% CI -0.74- .000) were founded a higher overall perceived risk. Mothers who reported more sedentary time (95% CI -0.029- -0.008) and less physical activity had less personal control (95% CI -0.354- -0.046). Mothers with more sedentary time had more worries about developing T2DM(95% CI 0.008-0.035) . Mothers who were older (95% CI -0.440-0.055) or had more physical activities (95% CI 0.003-0.048) had more optimistic bias of not developing T2DM. Mothers who had a higher education level (95% CI .354-1.422) and a family history of diabetes (95% CI .029-2.231) had more diabetes risk knowledge of developing T2DM. CONCLUSION: This study found that Chinese mothers of preschool children in urban areas reported low perceived risk of developing T2DM, although they have actual risk factors. These women did not associate anthropometric, health history, or health behavior factors with the risk of developing T2DM. Anthropometrics and risk factors associated with behavioral risk factors may be the focus of diabetes prevention programs.

The multicomponent phosphoenolpyruvate (PEP)-dependent sugar-transporting phosphotransferase system (PTS) in Escherichia coli takes up sugar substrates from the medium and concomitantly phosphorylates them, releasing sugar phosphates into the cytoplasm. We have recently provided evidence that many of the integral membrane PTS permeases interact with the fructose PTS (FruA/FruB) [1]. However, the biochemical and physiological significance of this finding was not known. We have carried out molecular genetic/biochemical/physiological studies that show that interactions of the fructose PTS often enhance, but sometimes inhibit the activities of other PTS transporters many fold, depending on the target PTS system under study. Thus, the glucose (Glc), mannose (Man), mannitol (Mtl) and N-acetylglucosamine (NAG) permeases exhibit enhanced in vivo sugar transport and sometimes in vitro PEP-dependent sugar phosphorylation activities while the galactitol (Gat) and trehalose (Tre) systems show inhibited activities. This is observed when the fructose system is induced to high levels and prevented when the fruA/fruB genes are deleted. Overexpression of the fruA and/or fruB genes in the absence of fructose induction during growth also enhances the rates of uptake of other hexoses. The β-galactosidase activities of man, mtl, and gat-lacZ transcriptional fusions and the sugar-specific transphosphorylation activities of these enzyme transporters were not affected either by frustose induction or by fruAB overexpression, showing that the rates of synthesis of the target PTS permeases were not altered. We thus suggest that specific protein-protein interactions within the cytoplasmic membrane regulate transport in vivo (and sometimes the PEP-dependent phosphorylation activities in vitro) of PTS permeases in a physiologically meaningful way that may help to provide a hierarchy of preferred PTS sugars. These observations appear to be applicable in principle to other types of transport systems as well.

We do not have a full understanding of the mechanisms underlying plasticity in the human brain. Mouse models have well controlled environments and genetics, and provide tools to help dissect the mechanisms underlying the observed responses to therapies devised for humans recovering from injury of ischemic nature or trauma. We aimed to detect plasticity following learning of a unilateral reaching movement, and relied on MRI performed with a rapid structural protocol suitable for in vivo brain imaging, and a longer diffusion tensor imaging (DTI) protocol executed ex vivo. In vivo MRI detected contralateral volume increases in trained animals (reachers), in circuits involved in motor control, sensory processing, and importantly, learning and memory. The temporal association area, parafascicular and mediodorsal thalamic nuclei were also enlarged. In vivo MRI allowed us to detect longitudinal effects over the ~25 days training period. The interaction between time and group (trained versus not trained) supported a role for the contralateral, but also the ipsilateral hemisphere. While ex vivo imaging was affected by shrinkage due to the fixation, it allowed for superior resolution and improved contrast to noise ratios, especially for subcortical structures. We examined microstructural changes based on DTI, and identified increased fractional anisotropy and decreased apparent diffusion coefficient, predominantly in the cerebellum and its connections. Cortical thickness differences did not survive multiple corrections, but uncorrected statistics supported the contralateral effects seen with voxel based volumetric analysis, showing thickening in the somatosensory, motor and visual cortices. In vivo and ex vivo analyses identified plasticity in circuits relevant to selecting actions in a sensory-motor context, through exploitation of learned association and decision making. By mapping a connectivity atlas into our ex vivo template we revealed that changes due to skilled motor learning occurred in a network of 35 regions, including the primary and secondary motor (M1, M2) and sensory cortices (S1, S2), the caudate putamen (CPu), visual (V1) and temporal association cortex. The significant clusters intersected tractography based networks seeded in M1, M2, S1, V1 and CPu at levels > 80%. We found that 89% of the significant cluster belonged to a network seeded in the contralateral M1, and 85% to one seeded in the contralateral M2. Moreover, 40% of the M1 and S1 cluster by network intersections were in the top 80th percentile of the tract densities for their respective networks. Our investigation may be relevant to studies of rehabilitation and recovery, and points to widespread network changes that accompany motor learning that may have potential applications to designing recovery strategies following brain injury.

African American men are disproportionately affected by, not only HIV/AIDS, but also chronic non-communicable diseases. Despite the known benefits of physical activity for reducing chronic non-communicable diseases, scant research has identified factors that may influence physical activity in this population. A growing literature centers on the syndemic theory, the notion that multiple adverse conditions interact synergistically, contributing to excess morbidity. This secondary data analysis examined two primary questions: whether syndemic conditions prospectively predicted physical activity, and whether, consistent with the syndemic theory, syndemic conditions interacted to predict physical activity. Participants were 595 African American men who have sex with men (MSM), a population underrepresented in health research, enrolled in a health-promotion intervention trial from 2008-2011. We used generalized-estimating-equations models to test the associations of syndemic conditions and resilience factors measured pre-intervention to self-reported physical activity 6 and 12 months post-intervention. As hypothesized, reporting more syndemic conditions pre-intervention predicted reporting less physical activity 6 and 12 months post-intervention, adjusting for the intervention. However, contrary to the syndemic theory, we did not find evidence for the interaction effects of syndemic conditions in predicting physical activity. Receiving high school education and having greater social network diversity predicted more physical activity whereas older age predicted less physical activity. To our knowledge, this is the first study to examine the syndemic theory in relation to physical activity. Although reporting a greater number of syndemic conditions was related to reduced physical activity, there was no evidence for synergy among syndemic conditions.

As a special kind of handwriting with a brush, Chinese calligraphic handwriting (CCH) requires a large amount of practice with high levels of concentration and emotion regulation. Previous studies have showed that long-term CCH training has positive effects physically (induced by handwriting activities) and psychologically (induced by the state of relaxation and concentration), the latter of which is similar to the effects of meditation. The aim of this study was to investigate the long-term CCH training effect on anxiety and attention, as well as brain structure. Participants were 32 individuals who had at least five years of CCH experience and 44 controls. Results showed that CCH training benefited individuals' selective and divided attention but did not decrease their anxiety level. Moreover, the VBM analysis showed that long-term CCH training was mainly associated with smaller grey matter volumes (GMV) in the right precuneus/posterior cingulate cortex (PCC). No brain areas showed larger GMV in the CCH group than the control group. Using two sets of regions of interest (ROIs), one related to meditation and the other to handwriting, ROI analysis showed significant differences between the CCH and the control group only at the meditation-related ROIs, not at the handwriting-related ROIs. Finally, for the whole sample, the GMV of both the whole brain and the PCC were negatively correlated with selective attention and divided attention. The present study was cross-sectional and had a relatively small sample size, but its results suggested that CCH training might benefit attention and influence particular brain structure through mental processes such as meditation.

Biological materials such as chiton tooth, squid beak, and byssal threads of bivalves have inspired the development of new technologies. To this end, we have characterized the acellular components in the buccal mass of the terrestrial slug Ariolimax californicus (banana slug). These components are the radula, the jaw, and the odontophore. In the radula, calcium-rich denticles are tightly interlocked one to the other on top of a nanofibrous chitin membrane. The jaw has a nanostructured morphology made of chitin to achieve compression resistance and is directly linked to the foregut cuticle, which has a protective nanofibrous structure. Finally, in the odontophore, we observed a structurally elastic microstructure that interfaces soft tissues with a highly stressed radula membrane. Based on those observations, we discuss the interaction between these components and highlight how the materials in these task-specific components have evolved. This structure-properties-function study of the A. californicus' buccal mass may aid in the design and fabrication of novel bioinspired materials.

Previous studies showed that individuals' traits could be used to explain the similarity of behavioral patterns across different occasions. Such studies have typically focused on personality traits, and have not been extended to psychological needs. Our study used a large dataset of 1,715,078 anonymous users' App usage records to examine whether the individual's needs-based profiles of App usage were consistent across different situations (as indexed by categories of App functions). Results showed a high level of consistency across situations in a user's choice of Apps based on the needs the Apps could satisfy. These results provide clear evidence in support of cross-category App recommendation systems.

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are potentially life-threatening conditions whose partially overlapping phenomenology-distorted perception of appearance, obsessions/compulsions, and limited insight-can make diagnostic distinction difficult in some cases. Accurate diagnosis is crucial, as the effective treatments for AN and BDD differ. To improve diagnostic accuracy and clarify the contributions of each of the multiple underlying factors, we developed a two-stage machine learning model that uses multimodal, neurobiology-based, and symptom-based quantitative data as features: task-based functional magnetic resonance imaging data using body visual stimuli, graph theory metrics of white matter connectivity from diffusor tensor imaging, and anxiety, depression, and insight psychometric scores. In a sample of unmedicated adults with BDD (n = 29), unmedicated adults with weight-restored AN (n = 24), and healthy controls (n = 31), the resulting model labeled individuals with an accuracy of 76%, significantly better than the chance accuracy of 35% ([Formula: see text]). In the multivariate model, reduced white matter global efficiency and better insight were associated more with AN than with BDD. These results improve our understanding of the relative contributions of the neurobiological characteristics and symptoms of these disorders. Moreover, this approach has the potential to aid clinicians in diagnosis, thereby leading to more tailored therapy.

PurposeThe role of insulin resistance (IR) in developing postmenopausal breast cancer has not been thoroughly resolved and may be confounded by lifestyle factors such as obesity. We examined whether genetically determined IR is causally associated with breast cancer risk.MethodsWe conducted Mendelian randomization (MR) analyses using individual-level data from our previous meta-analysis of a genome-wide association study (GWAS) (n = 11,109 non-Hispanic white postmenopausal women). Four single-nucleotide polymorphisms were associated with fasting glucose (FG), 2 with fasting insulin (FI), and 6 with homeostatic model assessment-IR (HOMA-IR) but were not associated with obesity. We used this GWAS to employ hazard ratios (HRs) for breast cancer risk by adjusting for potential confounding factors.ResultsNo direct association was observed between comprising 12 IR genetic instruments and breast cancer risk (HR = 0.93, 95% CI: 0.76-1.14). In phenotype-specific analysis, genetically elevated FG was associated with reduced risk for breast cancer (main contributor of this MR-effect estimate: G6PC2 rs13431652; HR = 0.59, 95% CI: 0.35-0.99). Genetically driven FI and HOMA-IR were not significantly associated. Stratification analyses by body mass index, exercise, and dietary fat intake with combined phenotypes showed that genetically elevated IR was associated with greater breast cancer risk in overall obesity and inactive subgroups (single contributor: MTRR/LOC729506 rs13188458; HR = 2.21, 95% CI: 1.03-4.75).ConclusionsWe found complex evidence for causal association between IR and risk of breast cancer, which may support the potential value of intervention trials to lower IR and reduce breast cancer risk.

BackgroundAlthough increasingly studied in high-income countries, there is a paucity of data from the Chinese population on the patterns of cancer among people living with HIV (PLHIV).MethodsWe conducted a nationwide follow-up study using routinely collected data for adult PLHIV diagnosed on or before 31 December 2011 and alive and in care as of 1 January 2008. Participants were observed from 1 January 2008 (study start) to 30 June 2012 (study end). Main outcome measures were gender-stratified age-standardized incidence rates for China (ASIRC) and standardized incidence ratios (SIR) for all malignancy types/sites observed.ResultsAmong 399,451 subjects, a majority was aged 30-44 years (49.3%), male (69.8%), and Han Chinese (67.9%). A total of 3,819 reports of cancer were identified. Overall, ASIRC was 776.4 per 100,000 for males and 486.5 per 100,000 for females. Malignancy sites/types with highest ASIRC among males were lung (226.0 per 100,000), liver (145.7 per 100,000), and lymphoma (63.1 per 100,000), and among females were lung (66.8 per 100,000), lymphoma (48.0 per 100,000), stomach (47.8 per 100,000), and cervix (47.6 per 100,000). Overall SIR for males was 3.4 and for females was 2.6. Highest SIR was observed for Kaposi sarcoma (2,639.8 for males, 1,593.5 for females) and lymphoma (13.9 for males, 16.0 for females).ConclusionsThese results provide evidence of substantial AIDS-defining and non-AIDS-defining cancer burden among adult Chinese PLHIV between 2008 and 2011. Although further study is warranted, China should take action to improve cancer screening, diagnosis, and treatment for this vulnerable population.

Digitization has facilitated the proliferation of crowd science by lowering the cost of finding individuals with the willingness to participate in science without pay. However, the factors that influence participation and the outcomes of voluntary participation are unclear. We report two findings from a field experiment on the world's largest crowd science platform that tests how voluntary contributions to science are affected by providing clarifying information on either the desired outcome of a scientific task or the labor requirements for completing the task. First, there is significant heterogeneity in the motivations and ability of contributors to crowd science. Second, both of the information interventions lead to significant decreases in the quantity and increases in the quality of contributions. Combined, our findings are consistent with the information interventions improving match quality between the task and the volunteer. Our findings suggest that science can be democratized by engaging individuals with varying skill levels and motivations with small changes in the information provided to participants.

IntroductionPrognosis after resection of hepatocellular carcinoma (HCC) is highly variable. Compared to clinicopathologic factors, the use of molecular markers to predict outcome has not been well studied. We investigated the prognostic importance of thymidylate synthase (TS) gene expression and polymorphisms in patients after resection of HCC.MethodsPatients who underwent complete resection of HCC for whom tissue was available were identified. TS gene expression level and polymorphisms were determined in HCC specimens. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazard models.ResultsThe study included 67 patients. In univariate analysis, variables that negatively influenced survival included TNM stage, microvascular invasion, and high TS expression. For the high TS expression group, median survival was 54 months and 5-year actuarial survival was 47%. For the low TS expression group, median survival was not reached and the 5-year actuarial survival was 91%. In multivariate analysis, only high TS expression remained an independent predictor of poor survival (HR = 10.77, 95% CI 1.36-84.91; P = 0.02). TS gene polymorphisms were not associated with TS expression or overall survival.ConclusionsHigh TS expression predicts poor outcome after resection of HCC. Molecular markers might be robust predictors of patient outcome after resection of HCC.

Deployment of cultivars with genetic resistance is an effective approach to control the diseases of powdery mildew (PM) and yellow rust (YR). Chinese wheat cultivar XK0106 exhibits high levels of resistance to both diseases, while cultivar E07901 has partial, adult plant resistance (APR). The aim of this study was to map resistance loci derived from the two cultivars and analyze their effects against PM and YR in a range of environments. A doubled haploid population (388 lines) was used to develop a framework map consisting of 117 SSR markers, while a much higher density map using the 90K Illumina iSelect SNP array was produced with a subset of 80 randomly selected lines. Seedling resistance was characterized against a range of PM and YR isolates, while field scores in multiple environments were used to characterize APR. Composite interval mapping (CIM) of seedling PM scores identified two QTLs (QPm.haas-6A and QPm.haas-2A), the former being located at the Pm21 locus. These QTLs were also significant in field scores, as were Qpm.haas-3A and QPm.haas-5A. QYr.haas-1B-1 and QYr.haas-2A were identified in field scores of YR and were located at the Yr24/26 and Yr17 chromosomal regions respectively. A second 1B QTL, QYr.haas-1B-2 was also identified. QPm.haas-2A and QYr.haas-1B-2 are likely to be new QTLs that have not been previously identified. Effects of the QTLs were further investigated in multiple environments through the testing of selected lines predicted to contain various QTL combinations. Significant additive interactions between the PM QTLs highlighted the ability to pyramid these loci to provide higher level of resistance. Interactions between the YR QTLs gave insights into the pathogen populations in the different locations as well as showing genetic interactions between these loci.

Structural MRI (sMRI)-identified tissue "growth" after neuropsychological training has been reported in many studies but the origins of those apparent tissue changes (ATC) still remain elusive. One possible contributor to ATC is brain perfusion since T1-weighted MRI, the tool used to identify ATC, is sensitive to perfusion-change induced tissue T1 alterations. To test the hypothetical perfusion contribution to ATC, sMRI data were acquired before and after short-term global and regional perfusion manipulations via intaking a 200 mg caffeine pill and performing a sensorimotor task. Caffeine intake caused a global CBF reduction and apparent tissue density reduction in temporal cortex, anterior cingulate cortex, and the limbic area; sensorimotor task induced CBF increase and apparent tissue increase in spatially overlapped brain regions. After compensating CBF alterations through a voxel-wise regression, the ATC patterns demonstrated in both experiments were substantially suppressed. These data clearly proved existence of the perfusion contribution to short-term ATC, and suggested a need for correcting perfusion changes in longitudinal T1-weighted structural MRI analysis if a short-term design is used.

BackgroundPreviously, using microarrays and mRNA-Sequencing (mRNA-Seq) we found that occupational exposure to a range of benzene levels perturbed gene expression in peripheral blood mononuclear cells.ObjectivesIn the current study, we sought to identify gene expression biomarkers predictive of benzene exposure below 1 part per million (ppm), the occupational standard in the U.S.MethodsFirst, we used the nCounter platform to validate altered expression of 30 genes in 33 unexposed controls and 57 subjects exposed to benzene (0.7, p0.9 (p