Miracle-dz/UniFAR-FTUs huggingface dataset:
The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB

Expression of the stress-induced ligands MICA, MICB and ULBP 1–6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines. We also discovered that IMP3 indirectly targets MICB with a mechanism functionally distinct from that of ULBP2. Importantly, IMP3-mediated regulation of stress-ligands leads to impaired NK cell recognition of transformed cells. Our findings shed new light on the regulation of NKG2D ligands and on the mechanism of action of a powerful oncogenic RBP, IMP3. DOI: http://dx.doi. org/10.7554/eLife.13426. 001
Transitioning From Community-Based to Institutional Long-term Care: Comparing 1915(c) Waiver and PACE Enrollees

Purpose of the Study To compare the risk of long-term nursing home (NH) admission and the level of functional and cognitive impairment at the time of long-term NH admission in the Program of All-Inclusive Care for the Elderly (PACE) and in 1915(c) aged and aged and disabled waiver programs. Design and Methods Cohorts of new waiver and PACE enrollees in 12 states were identified (in 2005-2007) and followed (through 2009) using the Medicaid Analytic Extract and the Minimum Data Set. Individual-level outcomes of interest were time from waiver or PACE enrollment to long-term (90+ days) NH admission and functional (29-point activities of daily living [ADL]) and cognitive (7-point Cognitive Performance Scale [CPS]) impairment at NH admission. An overall measure of impairment was also created and categorized as low (ADL < 17 and CPS < 3) versus high (ADL ≥ 17 or CPS ≥ 3). The key independent variable was enrollment in PACE versus waiver program. County-level covariates were included. Analyses employed multivariable models including competing risk proportional hazard and linear and logistic regressions. Results Compared with waiver enrollees, PACE enrollees had 31% lower risk of long-term NH admission (p < .001). At NH admission, they were overall significantly (p < .0001) more cognitively impaired (0.34 point), with 55% higher odds of severe (CPS ≥ 4) cognitive impairment (p < .001) and 45% higher odds of having overall high impairment (p = .003). Implications PACE may be more effective than 1915(c) aged and aged and disabled waiver programs in reducing long-term NH use and may be particularly well suited to supporting cognitively impaired individuals, enabling them to remain in the community longer.
Using Positive Youth Development Constructs to Design a Drug Education Curriculum for Junior Secondary Students in Hong Kong

This paper outlines the design of a new curriculum for positive youth development (P.A.T.H.S. II) in Hong Kong. The paper discusses the conceptual base for designing a drug-education curriculum for junior-secondary students using four positive youth development constructs—cognitive competence, emotional competence, beliefs in the future, and self-efficacy. The program design is premised on the belief that adolescents do have developmental assets; therefore, the curriculum is designed to develop their psychosocial competencies. The goal of the curriculum is to develop the selfhood of these youths and ultimately achieve the goal of successful adolescent development.
Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke

Background and Purpose— We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. Methods— We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed. Results— Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09–1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59–2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13–1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P=0.065; 29.1% versus 16.5% for old lesions, P<0.001), infarct location in the brain stem (12.4% versus 6.9%, P<0.001), and in white matter (27.8% versus 21.1%, P=0.001). Microbleeds (16.3% versus 4.7%, P=0.001), higher grades of white matter hyperintensities (P<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST (P=0.018) were more often present in patients with dolichoectasia. Conclusions— Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials. gov. Unique identifier: NCT00414583.
Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation

The purpose of this work was to explore the particle size reduction effect of carvedilol on dissolution and absorption. Three suspensions containing different sized particles were prepared by antisolvent precipitation method or in combination with an ultrasonication process. The suspensions were characterized for particle size, surface morphology, and crystalline state. The crystalline form of carvedilol was changed into amorphous form after antisolvent precipitation. The dissolution rate of carvedilol was significantly accelerated by a reduction in particle size. The intestinal absorption of carvedilol nanosuspensions was greatly improved in comparison with microsuspensions and solution in the in situ single-pass perfusion experiment. The in vivo evaluation demonstrated that carvedilol nanosuspensions and microsuspensions exhibited markedly increased Cmax (2.09- and 1.48-fold) and AUC0−t (2.11- and 1.51-fold), and decreased Tmax (0.34- and 0.48-fold) in contrast with carvedilol coarse suspensions. Moreover, carvedilol nanosuspensions showed good biocompatibility with the rat gastric mucosa in in vivo gastrointestinal irritation test. The entire results implicated that the dissolution rate and the oral absorption of carvedilol were significantly affected by the particle size. Particle size reduction to form nanosized particles was found to be an efficient method for improving the oral bioavailability of carvedilol.
Thromboembolic and Major Bleeding Events With Rivaroxaban Versus Warfarin Use in a Real-World Setting

Background: Although randomized trials demonstrate the noninferiority of rivaroxaban compared with warfarin in the context of nonvalvular atrial fibrillation (AF), little is known about how these drugs compare in practice. Objective: To assess the relative effectiveness and safety of rivaroxaban versus warfarin in a large health system and to evaluate this association by time in therapeutic range (TTR). Methods: We conducted a retrospective cohort study with propensity matching in the Cleveland Clinic Health System. The study included patients initiated on warfarin or rivaroxaban for thromboembolic prevention in nonvalvular AF between January 2012 and July 2016. The main outcomes were thromboembolic events and major bleeds. Analyses were stratified by warfarin patients’ TTR. Results: The cohort consisted of 472 propensity-matched pairs. The mean age was 73.6 years (SD = 11.7), and the mean CHADS2 score was 1.8. The median TTR for warfarin patients was 64%. In the propensity-matched analysis, there was no significant difference in thromboembolic or major bleeding events between groups. Among warfarin patients with a TTR <64% and their matched rivaroxaban pairs, there was also no significant difference in thromboembolic or major bleeding events. Conclusions: Under real-world conditions, warfarin and rivaroxaban were associated with similar safety and effectiveness, even among those with suboptimal therapeutic control. Individualized decision making, taking into account the nontherapeutic tradeoffs associated with these medications (eg, monitoring, half-life, cost) is warranted.
Genomic and phenotypic differentiation of Arabidopsis thaliana along altitudinal gradients in the North Italian Alps

Altitudinal gradients in mountain regions are short‐range clines of different environmental parameters such as temperature or radiation. We investigated genomic and phenotypic signatures of adaptation to such gradients in five Arabidopsis thaliana populations from the North Italian Alps that originated from 580 to 2350 m altitude by resequencing pools of 19–29 individuals from each population. The sample includes two pairs of low‐ and high‐altitude populations from two different valleys. High‐altitude populations showed a lower nucleotide diversity and negative Tajima's D values and were more closely related to each other than to low‐altitude populations from the same valley. Despite their close geographic proximity, demographic analysis revealed that low‐ and high‐altitude populations split between 260 000 and 15 000 years before present. Single nucleotide polymorphisms whose allele frequencies were highly differentiated between low‐ and high‐altitude populations identified genomic regions of up to 50 kb length where patterns of genetic diversity are consistent with signatures of local selective sweeps. These regions harbour multiple genes involved in stress response. Variation among populations in two putative adaptive phenotypic traits, frost tolerance and response to light/UV stress was not correlated with altitude. Taken together, the spatial distribution of genetic diversity reflects a potentially adaptive differentiation between low‐ and high‐altitude populations, whereas the phenotypic differentiation in the two traits investigated does not. It may resemble an interaction between adaptation to the local microhabitat and demographic history influenced by historical glaciation cycles, recent seed dispersal and genetic drift in local populations.
Thermal and water management of evaporatively cooled fuel cell vehicles

Proton Exchange Membrane Fuel Cells (PEMFCs) present a promising alternative to the conventional internal combustion engine for automotive applications because of zero harmful exhaust emissions, fast refuelling times and possibility to be powered by hydrogen generated through renewable energy. However, several issues need to be addressed before the widespread adoption of PEMFCs, one such problem is the removal of waste heat from the fuel cell electrochemical reaction at high ambient temperatures. Automotive scale fuel cells are most commonly liquid cooled, evaporative cooling is an alternative cooling method where liquid water is added directly into the fuel cell flow channels. The liquid water evaporates within the flow channel, both cooling and humidifying the cell. The evaporated water, along with some of the product water, is then condensed from the fuel cell exhaust, stored, and re-used in cooling the fuel cell. This work produces a system level model of an evaporatively cooled fuel cell vehicle suitable for the study of water balance and heat exchanger requirements across steady state operation and transient drive cycles. Modelling results demonstrate the ability of evaporatively cooled fuel cells to self regulate temperature within a narrow region (±2°C) across a wide operating range, provided humidity is maintained within the flow channels through sufficient liquid water addition. The heat exchanger requirements to maintain a self sufficient water supply are investigated, demonstrating that overall heat exchange area can be reduced up to 40% compared to a liquid cooled system due to the presence of phase change within the vehicle radiator improving heat transfer coefficients. For evaporative cooling to remain beneficial in terms of heat exchange area, over 90% of the condensed liquid water needs to be extracted from the exhaust stream. Experimental tests are conducted to investigate the condensation of water vapour from a saturated air stream in a compact plate heat exchanger with chevron flow enhancements. Thermocouples placed within the condensing flow allow the local heat transfer coefficient to be determined and an empirical correlation obtained. The corresponding correlation is used to produce a heat exchanger model and study the influence different heat exchanger layouts have on the overall required heat transfer area for an evaporatively cooled fuel cell vehicle. A one-dimensional, non-isothermal model is also developed to study the distribution of species, current density and temperature along the flow channel of an evaporatively cooled fuel cell using different methods of liquid water addition. Results show that good performance can be achieved with cathode inlet humidities as low as 20%, although some anode liquid water addition may be required at high current densities due to increased electro-osmotic drag. It is also demonstrated that both good membrane hydration and temperature regulation can be managed by uniform addition of liquid water across the cell to maintain a target exhaust relative humidity.
Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers

Abstract Histone deacetylase inhibitors (HDACIs) are known to alter gene expression by both up- and down-regulation of protein-coding genes in normal and cancer cells. However, the exact regulatory mechanisms of action remain uncharacterized. Here we investigated genome wide dose-dependent epigenetic and transcriptome changes in response to HDACI largazole in a transformed and a non-transformed cell line. Exposure to low nanomolar largazole concentrations (<GI50) predominantly resulted in upregulation of gene transcripts whereas higher largazole doses (≥GI50) triggered a general decrease in mRNA accumulation. Largazole induces elevation of histone H3 acetylation at Lys-9 and Lys-27 along many gene bodies but does not correlate with up- or down-regulation of the associated transcripts. A higher dose of largazole results in more RNA polymerase II pausing at the promoters of actively transcribed genes and cell death. The most prevalent changes associated with transcriptional regulation occur at distal enhancer elements. Largazole promotes H3K27 acetylation at a subset of poised enhancers and unexpectedly, we also found active enhancers that become decommissioned in a dose and cell type-dependent manner. In particular, largazole decreases RNA polymerase II accumulation at super-enhancers (SEs) and preferentially suppresses SE-driven transcripts that are associated with oncogenic activities in transformed cells.
Clinical Evaluation of the Measurement Performance of the Philips Health Watch: A Within-Person Comparative Study

Background Physical inactivity is an important modifiable risk factor for chronic diseases. A new wrist-worn heart rate and activity monitor has been developed for unobtrusive data collection to aid prevention and management of lifestyle-related chronic diseases by means of behavioral change programs. Objective The objective of the study was to evaluate the performance of total energy expenditure and resting heart rate measures of the Philips health watch. Secondary objectives included the assessment of accuracy of other output parameters of the monitor: heart rate, respiration rate at rest, step count, and activity type recognition. Methods A within-person comparative study was performed to assess the performance of the health watch against (medical) reference measures. Participants executed a protocol including 15 minutes of rest and various activities of daily life. A two one-sided tests approach was adopted for testing equivalence. In addition, error metrics such as mean error and mean absolute percentage error (MAPE) were calculated. Results A total of 29 participants (14 males; mean age 41.2, SD 14.4, years; mean weight 77.2, SD 10.2, kg; mean height 1.8, SD 0.1, m; mean body mass index 25.1, SD 3.1, kg/m2) completed the 81-minute protocol. Their mean resting heart rate in beats per minute (bpm) was 64 (SD 7.3). With a mean error of −10 (SD 38.9) kcal and a MAPE of 10% (SD 8.7%), total energy expenditure estimation of the health watch was found to be within the 15% predefined equivalence margin in reference to a portable indirect calorimeter. Resting heart rate determined during a 15-minute rest protocol was found to be within a 10% equivalence margin in reference to a wearable electrocardiogram (ECG) monitor, with a mean deviation of 0 bpm and a maximum deviation of 3 bpm. Heart rate was within 10 bpm and 10% of the ECG monitor reference for 93% of the duration of the protocol. Step count estimates were on average 21 counts lower than a waist-mounted step counter over all walking activities combined, with a MAPE of 3.5% (SD 2.4%). Resting respiration rate was on average 0.7 (SD 1.1) breaths per minute lower than the reference measurement by the spirometer embedded in the indirect calorimeter during the 15-minute rest, resulting in a MAPE of 8.3% (SD 7.0%). Activity type recognition of walking, running, cycling, or other was overall 90% accurate in reference to the activities performed. Conclusions The health watch can serve its medical purpose of measuring resting heart rate and total energy expenditure over time in an unobtrusive manner, thereby providing valuable data for the prevention and management of lifestyle-related chronic diseases. Trial Registration Netherlands trial register NTR5552; http://www.trialregister. nl/trialreg/admin/rctview.asp? TC=5552 (Archived by WebCite at http://www.webcitation.org/6neYJgysl)
Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation— the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study

Abstract Aim We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF). Methods and results This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75–1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49–0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32–0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29–0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH. Conclusions LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status. Clinical trial registration http:www.clinicaltrials. gov. Unique identifier: NCT00262600.
Adolescent Cannabinoid Exposure Induces a Persistent Sub‐Cortical Hyper‐Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex

Abstract Considerable evidence suggests that adolescent exposure to delta‐9‐tetrahydrocanabinol (THC), the psychoactive component in marijuana, increases the risk of developing schizophrenia‐related symptoms in early adulthood. In the present study, we used a combination of behavioral and molecular analyses with in vivo neuronal electrophysiology to compare the long‐term effects of adolescent versus adulthood THC exposure in rats. We report that adolescent, but not adult, THC exposure induces long‐term neuropsychiatric‐like phenotypes similar to those observed in clinical populations. Thus, adolescent THC exposure induced behavioral abnormalities resembling positive and negative schizophrenia‐related endophenotypes and a state of neuronal hyperactivity in the mesocorticolimbic dopamine (DA) pathway. Furthermore, we observed profound alterations in several prefrontal cortical molecular pathways consistent with sub‐cortical DAergic dysregulation. Our findings demonstrate a profound dissociation in relative risk profiles for adolescent versus adulthood exposure to THC in terms of neuronal, behavioral, and molecular markers resembling neuropsychiatric pathology.
Risk of cardiovascular events after infection-related hospitalizations in older patients on dialysis.

BACKGROUND AND OBJECTIVES Infection and cardiovascular disease are leading causes of hospitalization and death in patients on dialysis. The objective of this study was to determine whether an infection-related hospitalization increased the short-term risk of a cardiovascular event in older patients on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS With use of the United States Renal Data System, patients aged 65 to 100 years who started dialysis between January 1, 2000, and December 31, 2002, were examined. All hospitalizations were examined from study entry until time of transplant, death, or December 31, 2004. All discharge diagnoses were examined to determine if an infection occurred during hospitalization. Only principal discharge diagnoses were examined to ascertain cardiovascular events of interest. We used the self-controlled case-series method to estimate the relative incidence of a cardiovascular event within 90 days after an infection-related hospitalization as compared with other times not within 90 days of such a hospitalization. RESULTS A total of 16,874 patients had at least one cardiovascular event and were included in the self-controlled case-series analysis. The risk of a cardiovascular event was increased by 25% in the first 30 days after an infection and was overall increased 18% in the 90 days after an infection-related hospitalization relative to control periods. CONCLUSIONS The first 90 days, and in particular the first 30 days, after an infection-related hospitalization is a high-risk period for cardiovascular events and may be an important timeframe for cardiovascular risk reduction, monitoring, and intervention in older patients on dialysis.