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Contains fulltext : 291985.pdf (Publisher’s version ) (Open Access) We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Supplementary Figures 1-3 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure Legends 1-13, Methods from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure 13 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure 12 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure 10 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figures 6-9 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure 4 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, β-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of β-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors. Cancer Res; 70(14); 5963–73. ©2010 AACR.

Supplementary Figure 5 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Supplementary Figure 11 from A Useful Approach to Identify Novel Small-Molecule Inhibitors of Wnt-Dependent Transcription

Meet an early evangelist, an education reformer, and a preacher who held Bible studies with the royal family.

BackgroundChildren with cerebral palsy (CP) show progressive loss of ambulatory function characterized by kinematic deviations at the hip, knee, and ankle. Functional electrical stimulation (FES) can lead to more typical lower limb kinematics during walking by eliciting appropriately timed muscle contractions. FES-assisted walking interventions have shown mixed to positive results in improving lower limb kinematics through immediate correction of gait during the application of FES, or long-term, persisting effects of non-FES-assisted gait improvements following multi-week FES-assisted gait training, at the absence of stimulation, i.e., neurotherapeutic effects. It is unknown, however, if children with CP will demonstrate a neurotherapeutic response following FES-assisted gait training because of the CP population's heterogeneity in gait deviations and responses to FES. Identifying the neurotherapeutic responders is, therefore, important to optimize the training interventions to those that have higher probability of benefiting from the intervention.ObjectiveThe purpose of this case study was to investigate the relationship between immediate and neurotherapeutic effects of FES-assisted walking to identify responders to a FES-assisted gait training protocol.MethodsThe primary outcome was Gait Deviation Index (GDI) and secondary outcome was root mean squared error (RMSE) of the lower extremity joint angles in the sagittal plane between participants with CP and a typically developing (TD) dataset. Potential indicators were defined as immediate improvements from baseline during FES-assisted walking followed by neurotherapeutic improvements at the end of training.Case descriptionGait analysis of two adolescent female participants with spastic diplegia (Gross Motor Function Classification System level II and III) was conducted at the start and end of a 12-week FES-assisted treadmill training protocol. Participant 1 had scissoring crouch gait, while participant 2 had jump gait.OutcomesThe GDI showed both immediate (presence of FES) and neurotherapeutic (absence of FES after training period) improvements from baseline in our two participants. Joint angle RMSE showed mixed trends between immediate and neurotherapeutic changes from baseline. The GDI warrants investigation in a larger sample to determine if it can be used to identify responders to FES-assisted gait training.

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Sommige christenen vinden het misschien spannend zich uit te spreken voor vrouwenrechten of rechten van lhbti+-mensen. Maar volgens Samuel Lee is het juist christelijk om op te komen voor de kwetsbaren...

Hebben we het westerse Christendom nodig om kerk te zijn?

We will validate a new measure of moral neutralization by assessing its factor structure and how it is correlated with other variables

De westerse en Afrikaanse kijk op het slavernijverleden...

De westerse en Afrikaanse kijk op het slavernijverleden...

In the version of this Article initially published, the Acknowledgements statement contained an error. Originally appearing with thanks for support given in part as follows, “R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease,” the last number (R011EY023173) was mistakenly added and is not in fact a grant or one provided by the NIAID. The mention has been removed. The changes have been made to the online version of the Article.

The implementation of technology in the hospitality sector is rapidly growing. Although there are practical, economic, and experiential benefits of hospitality technology, the increased adoption of guest service technologies such as digital room keys, check-in kiosks, and service robots can also introduce friction points in a guest’s hotel experience. Technostress is any form of stress induced by the usage of technology and this study is among the first to apply this concept to consumer behavior. Based on the transactional model of stress and coping and social cognitive theory, this dissertation examined the effects of technostress on hotel guests, using a mixed-method approach comprised of three sequential phases. A qualitative examination of guest experiences with hotel technology indicated Wi-Fi, hotel smartphone apps, and smart TVs to be the most prominent stress-inducing technologies with particular themes pertaining to each technology. These technologies were also associated with the technostress factors: techno-overload, techno-invasion, techno-complexity, and techno-uncertainty. Quantitative data showed significant relationships between technology self-efficacy, one’s locus of control, and technostress; additionally, technostress was shown to significantly impact guest satisfaction. The findings of this dissertation extend technostress beyond workplace applications and drive recommendations for hotels to better address the technostress that negatively impacts guest satisfaction.

Coronary artery disease (CAD) is one of the leading causes of mortality worldwide, and is driven by atherosclerosis development that can lead to occlusive thrombus formation and myocardial infarction. Platelets are known to contribute to atherosclerosis development and thrombosis. Scavenger receptor class B type 1 (SR-B1) deficiency in apolipoprotein E (ApoE) knockout or low-density lipoprotein receptor (LDLR) knockout mice results in occlusive coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. In this thesis, we examine the effects of genetically inactivating neurobeachin-like 2 (NBEAL2), which has a prominent role in platelet function, on CAD development in SR-B1/ApoE double knockout mice. NBEAL2 deficiency in SR-B1/ApoE double knockout mice reduced aortic sinus and coronary artery atherosclerosis and platelet accumulation in atherosclerotic coronary arteries, but increased myocardial fibrosis levels and reduced survival. NBEAL2 deficiency in SR-B1/ApoE double knockout mice reduced neutrophil granularity and the proportion of myeloperoxidase-positive neutrophils in the myocardium, which may in part contribute to the increased myocardial fibrosis levels. Protease-activated receptor 4 (PAR4) also has a prominent role in platelet function. By using a novel pepducin (RAG8), we examine the effects of pharmacological inhibition of PAR4 on CAD development in high-fat, high-cholesterol, cholate (HFCC) diet-fed SR-B1/LDLR double knockout mice. RAG8 treatment did not alter aortic sinus atherosclerosis levels, but reduced coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. These protective effects are not dependent on changes in circulating lipids, cytokines, and immune cells, but may be due to reduced vascular cell adhesion 1 (VCAM-1) protein expression in coronary arteries. We also examine the effects of aging on CAD development in HFCC diet-fed SR-B1 single KO mice. Older age in SR-B1 single KO mice did not alter susceptibility to HFCC diet-induced aortic sinus atherosclerosis, but increased susceptibility to HFCC diet-induced coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. Older-aged SR-B1 KO mice exhibited reduced survival when fed the HFCC diet. These age-dependent changes are not driven by changes in plasma lipids, but likely driven by a combination of increased VCAM-1 protein levels in coronary arteries and circulating cytokines and neutrophils. This thesis demonstrates the potential effects of platelet inhibition and aging on CAD development in mice, and demonstrates that SR-B1 single KO mice may be a versatile and useful diet-inducible mouse model for atherosclerosis studies. Moreover, this thesis highlights the importance of analyzing atherosclerosis at multiple sites and utilizing mice that develop CAD and myocardial fibrosis when investigating the effects of interventions on atherosclerosis and/or CAD development. Dissertation Doctor of Philosophy (PhD)

\(\textbf {Background:}\) The aim of the present study was to analyze incidence, risk factors, and association with long-term outcome of postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR). \(\textbf {Methods:}\) Six hundred and sixty one consecutive patients undergoing TAVR were prospectively enrolled from January 2016 to December 2017. POD was assessed regularly during ICU-stay using the CAM-ICU test. \(\textbf {Results:}\) The incidence of POD was 10.0% (\(\it n\) = 66). Patients developing POD were predominantly male (65%), had higher EuroSCORE II (5.4% vs. 3.9%; \(\it P\) = 0.041) and were more often considered frail (70% vs. 26%; \(\it P\) < 0.001). POD was associated with more peri-procedural complications including vascular complications (19.7 vs. 9.4; \(\it P\) = 0.017), bleeding (12.1 vs. 5.4%; \(\it P\) = 0.0495); stroke (4.5 vs. 0.7%; \(\it P\) = 0.025), respiratory failure requiring ventilation (16.7% vs. 1.8%; \(\it P\) < 0.001), and pneumonia (34.8% vs. 7.1%; \(\it P\) < 0.001). Consequently, patients with POD had significantly longer ICU- (7.9 vs. 3.2 days \(\it P\) < 0.001) and hospital-stay (14.9 vs. 9.0 days; \(\it P\) < 0.001), and higher in-hospital mortality (6.1 vs. 2.1%; \(\it P\) = 0.017). Logistic regression analysis identified male sex (odds ratio (OR) 2.2 [95% confidence interval (CI) 1.2–4.0); \(\it P\) = 0.012], atrial fibrillation [OR 3.0 (CI 1.6–5.6); \(\it P\) < 0.001], frailty [OR 4.3 (CI 2.4–7.9); \(\it P\) < 0.001], pneumonia [OR 4.4 (CI 2.3–8.7); \(\it P\) < 0.001], stroke [OR 7.0 (CI 1.2–41.6); \(\it P\) = 0.031], vascular complication [OR 2.9 (CI 1.3–6.3); \(\it P\) = 0.007], and general anesthesia [OR 2.0 (CI 1.0–3.7); \(\it P\) = 0.039] as independent predictors of POD. On Cox proportional hazard analysis POD emerged as a significant predictor of 2-year mortality [HR 1.89 (CI 1.06–3.36); \(\it P\) = 0.030]. \(\textbf {Conclusion:}\) POD is a frequent finding after TAVR and is significantly associated with reduced 2-year survival. Predictors of delirium include not only peri-procedural parameters like stroke, pneumonia, vascular complications and general anesthesia but also baseline characteristics as male sex, atrial fibrillation and frailty.

The World Health Organization (WHO) set a goal to eliminate hepatitis C (HCV) infection globally by 2030, with specific targets to reduce new viral hepatitis infections by 80% and reduce related deaths by 65%. However, an overlooked aspect that may hinder these efforts is the impact other liver diseases could have by continuing to drive liver disease progression and offset the beneficial impact of DAAs on end-stage liver disease and hepatocellular carcinoma (HCC). In particular, the decrease in HCV prevalence has been countered by a marked increase in the prevalence of metabolic-associated fatty liver disease (MAFLD).

Nature in Singapore, 14, 1-9

In the version of this Article initially published, the Acknowledgements statement contained an error. Originally appearing with thanks for support given in part as follows, “R01EY023173 from The National Eye Institute, U01MH105982 from the National Institute of Mental Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development, and R011EY023173 from The National Institute of Allergy and Infectious Disease,” the last number (R011EY023173) was mistakenly added and is not in fact a grant or one provided by the NIAID. The mention has been removed. The changes have been made to the online version of the Article.

Online cognitive tests offer a cost-effective, accessible means of cognitive screening and may prove especially important for individuals with memory complaints, a risk factor for cognitive impairment (Kaup et al., 2015). Although older adults’ perceptions of everyday technologies impact their uptake and adoption, there is limited understanding about how perceptions of online cognitive screening tests impact test performance. The purpose of the current study was to examine relationships between performance on a brief, self-administered, web-based cognitive assessment tool (SMART) and user perceptions (e.g., ratings of challenge and length), technology confidence, brain health activities, and memory complaints. Participants were 1336 adults without a diagnosis of cognitive impairment (Mage=60.48 years, SD=15.18; 65.8% female; 81.8% White; 21.2% with subjective memory complaints). Most participants (97%) were willing to complete the SMART again, with over half (53.5%) willing to complete the SMART on at least a weekly basis. After adjusting for age and education, better SMART performance (i.e., faster completion time) was associated with user ratings of greater ease of completion, higher technology confidence, and greater participation in brain health activities (p

Embryonic precursors of liver and heart, whilst not sharing cellular origin, develop in close proximity through a dynamic series of inductive signaling events. During gastrulation anterior endoderm (AE) provides cardiogenic signals that act on adjacent mesoderm, resulting in induction of cardiac precursors. Subsequently cardiogenic mesoderm generates a FGF signal that acts on adjacent AE to induce foregut organ specification. Additional signals such as BMP and Wnt provide further information required for liver specification. Most findings on liver specification were derived from mouse explant studies as well as experiments with Xenopus and zebrafish embryos. To address some of the limitations of these models, here we used two complementary ex vivo models based on Xenopus embryos: pluripotent animal cap explants expressing Gata4 transcription factor and conjugates of gastrula-stage AE with animal caps (AC). We show that in these models liver specification is not sensitive to Wnt signaling manipulation, in contrast to the requirement for Wnt antagonism shown in vivo. FGF pathway is not necessary for Gata4-induced liver specification in animal cap explants but is required for prolonged period in sandwiches of AE and AC. In contrast, BMP signaling is shown to be essential for Gata4-induced liver specification. Our findings may have implications for research on liver differentiation from embryonic stem cells.

Insulin resistance and type 2 diabetes are pathogenetically linked to increased risk of cardiovascular disease. While insulin resistance is defined by a dysregulation in hepatic insulin signaling, it is unclear how this impairment relates to the development of cardiovascular disease. Recently, there has been evidence showing that in insulin resistant individuals, cardiovascular disease is associated with a defect in reverse cholesterol transport – the cardioprotective process by which excess cholesterol is removed from the periphery, and returned to the liver for biliary excretion. Reverse cholesterol transport is facilitated by high-density lipoprotein (HDL) metabolism. Thus, malfunction in HDL turnover during reverse cholesterol transport may contribute to the buildup of atherosclerotic plaques, and subsequent cardiovascular disease in insulin resistant individuals. In this thesis, we seek to establish a better understanding of HDL metabolism and reverse cholesterol transport, as they relate to key transcription factors that mediate hepatic insulin signaling, namely the insulin-repressible forkhead transcription factors, FoxO1, FoxO3, and FoxO4 (FoxOs). We demonstrate that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4) have increased HDL-cholesterol (HDL-C), associated with decreased expression of HDL-C clearance factors, scavenger receptor class B type I (SR-BI) and hepatic lipase, and defective selective uptake of HDL-cholesteryl ester by the liver. As such, we uncover a novel mechanism by which HDL-mediated reverse cholesterol transport to the liver is regulated by the hepatic insulin-->FoxO signaling pathway.

Samuel J Lee,1Meghan C O’Leary,1 Karl E Umble,1 Stephanie B Wheeler1–31Department of Health Policy and Management, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Center for Health Promotion and Disease Prevention, University of North Carolina at Chapel Hill, Chapel Hill, NC, USABackground: Patient preferences are important to consider in the decision-making process for colorectal cancer (CRC) screening. Vulnerable populations, such as racial/ethnic minorities and low-income, veteran, and rural populations, exhibit lower screening uptake. This systematic review summarizes the existing literature on vulnerable patient populations’ preferences regarding CRC screening. Methods: We searched the CINAHL, PsycINFO, PubMed, Scopus, and Web of Science databases for articles published between January 1, 1996 and December 31, 2017. We screened studies for eligibility and systematically abstracted and compared study designs and outcomes. Results: A total of 43 articles met the inclusion criteria, out of 2,106 articles found in our search. These 43 articles were organized by the primary sub-population(s) whose preferences were reported: 27 report on preferences among racial/ethnic minorities, eight among low-income groups, six among veterans, and two among rural populations. The majority of studies (n=34) focused on preferences related to test modality. No single test modality was overwhelmingly supported by all sub-populations, although veterans seemed to prefer colonoscopy. Test attributes such as accuracy, sensitivity, cost, and convenience were also noted as important features. Furthermore, a preference for shared decision-making between vulnerable patients and providers was found. Conclusion: The heterogeneity in study design, populations, and outcomes of the selected studies revealed a wide spectrum of CRC screening preferences within vulnerable populations. More decision aids and discrete choice experiments that focus on vulnerable populations are needed to gain a more nuanced understanding of how vulnerable populations weigh particular features of screening methods. Improved CRC screening rates may be achieved through the alignment of vulnerable populations’ preferences with screening program design and provider practices. Collaborative decision-making between providers and vulnerable patients in preventive care decisions may also be important.Keywords: colorectal cancer screening, systematic review, vulnerable populations, patient preference

After a cerebrovascular accident (CVA) aerobic deconditioning contributes to diminished physical function. Functional electrical stimulation (FES)-assisted cycling is a promising exercise paradigm designed to target both aerobic capacity and locomotor function. This pilot study aimed to evaluate the effects of an FES-assisted cycling intervention on aerobic capacity and locomotor function in individuals post-CVA.Eleven individuals with chronic (6 months) post-CVA hemiparesis completed an 8-wk (three times per week; 24 sessions) progressive FES-assisted cycling intervention. V˙O2peak, self-selected, and fastest comfortable walking speeds, gait, and pedaling symmetry, 6-min walk test (6MWT), balance, dynamic gait movements, and health status were measured at baseline and posttraining.Functional electrical stimulation-assisted cycling significantly improved V˙O2peak (12%, P = 0.006), self-selected walking speed (SSWS, 0.05 ± 0.1 m·s, P = 0.04), Activities-specific Balance Confidence scale score (12.75 ± 17.4, P = 0.04), Berg Balance Scale score (3.91 ± 4.2, P = 0.016), Dynamic Gait Index score (1.64 ± 1.4, P = 0.016), and Stroke Impact Scale participation/role domain score (12.74 ± 16.7, P = 0.027). Additionally, pedal symmetry, represented by the paretic limb contribution to pedaling (paretic pedaling ratio [PPR]) significantly improved (10.09% ± 9.0%, P = 0.016). Although step length symmetry (paretic step ratio [PSR]) did improve, these changes were not statistically significant (-0.05% ± 0.1%, P = 0.09). Exploratory correlations showed moderate association between change in SSWS and 6-min walk test (r = 0.74), and moderate/strong negative association between change in PPR and PSR.These results support FES-assisted cycling as a means to improve both aerobic capacity and locomotor function. Improvements in SSWS, balance, dynamic walking movements, and participation in familial and societal roles are important targets for rehabilitation of individuals after CVA. Interestingly, the correlation between PSR and PPR suggests that improvements in pedaling symmetry may translate to a more symmetric gait pattern.