Miracle-dz/UniFAR-FTUs huggingface dataset:
Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation

Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that β-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between β-TrCP and GLI1, and induces β-TrCP-mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the β-TrCP and GLI1 interaction, and diminishes β-TrCP-mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with β-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with β-TrCP, which is accompanied by reduced β-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with β-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and β-TrCP ultimately impact GLI1 degradation.
A pragmatic regional interdependence approach to primary frozen shoulder: a retrospective case series*

Abstract Objectives: Although the shoulder is known to move together with the scapula and other upper quarter joints, the current frozen shoulder clinical practice guidelines describe only physical therapy study treatments directed to the shoulder. None received a strong recommendation, highlighting the need for alternate interventions. This retrospective case series describes a pragmatic regional interdependence approach to frozen shoulder with impairment and functional outcomes, noting whether final ROM approached normal. Methods: Five consecutive patients referred with frozen shoulder diagnoses attended 11–21 sessions over 5–10 weeks with one physical therapist. Treatment addressed inter-related regions (shoulder, shoulder girdle, scapulothoracic/humerothoracic, and spine) following a pragmatic approach using impairment-based interventions (joint/soft tissue mobilization, muscle stretching/strengthening) as well as patient education, modalities and warm up that addressed individual presentations. Results: All patients improved on all outcomes. Mean shoulder ROM at discharge, the impairment outcome, demonstrated large effect size increases: flexion (117 ± 10–179 ± 12, d = 5.9), abduction (74 ± 8–175 ± 9, d = 9.3), external rotation (23 ± 7–89 ± 2, d = 12.0). The Disability of Arm Shoulder Hand functional outcome score upon follow up demonstrated a large effect size improvement (d = 1.5) from 40.0 ± 19.4–6.2 ± 3.7. Final ROM approached normal. Discussion: This case series utilized a regional interdependence approach to frozen shoulder that included manual therapy interventions directed to consistent upper quarter body segments. Shoulder ROM was returned to near normal with functional improvements evident months after discharge. A pragmatic regional interdependence approach addressing multiple joints related to shoulder function may benefit other people with frozen shoulder. Level of Evidence: 4
Association of Fetuin-A With Incident Diabetes Mellitus in Community-Living Older Adults: The Cardiovascular Health Study

Background— The liver-secreted protein fetuin-A induces peripheral insulin resistance in vitro. In a pilot study, we observed that higher fetuin-A levels were associated with diabetes mellitus in older persons. However, this finding has not been confirmed in large cohorts. We sought to confirm the association of fetuin-A with incident diabetes mellitus in older persons and to determine whether the association differs by age, sex, and race and among persons with cardiovascular disease (CVD). Methods and Results— Among 3710 community-living individuals ≥65 years of age without diabetes mellitus at baseline, fetuin-A was measured in serum collected in 1992 to 1993. Participants were followed up for 10.6 years (median) for incident diabetes mellitus. Cox regression models evaluated the association of fetuin-A with incident diabetes mellitus. Interaction terms evaluated heterogeneity by age, sex, race, and CVD. Mean age was 75 years; 60 were female; 15 were black; and 16 had CVD. Mean fetuin-A concentrations were 0.47±0.10 g/L. During follow-up, 305 incident diabetes cases occurred. Each 0.10-g/L (SD)-greater fetuin-A was associated with 19 higher risk of diabetes mellitus (hazard ratio, 1.19; 95 confidence interval, 1.06–1.33) after adjustment for demographics, lifestyle factors, albumin, kidney function, and CVD. Further adjustment for potential mediators (body mass index, waist circumference, hypertension, lipids, and C-reactive protein) moderately attenuated the association (hazard ratio, 1.13; 95 confidence interval, 1.00–1.28). Results were similar by sex, race, and CVD status but were stronger in persons <75 years old (P for interaction=0.01). Conclusions— Higher fetuin-A is associated with incident diabetes mellitus in older persons regardless of sex, race, or prevalent CVD status. The association may be attenuated in those ≥75 years of age.
Hierarchical Auditory Processing Directed Rostrally along the Monkey's Supratemporal Plane

Connectional anatomical evidence suggests that the auditory core, containing the tonotopic areas A1, R, and RT, constitutes the first stage of auditory cortical processing, with feedforward projections from core outward, first to the surrounding auditory belt and then to the parabelt. Connectional evidence also raises the possibility that the core itself is serially organized, with feedforward projections from A1 to R and with additional projections, although of unknown feed direction, from R to RT. We hypothesized that area RT together with more rostral parts of the supratemporal plane (rSTP) form the anterior extension of a rostrally directed stimulus quality processing stream originating in the auditory core area A1. Here, we analyzed auditory responses of single neurons in three different sectors distributed caudorostrally along the supratemporal plane (STP): sector I, mainly area A1; sector II, mainly area RT; and sector III, principally RTp (the rostrotemporal polar area), including cortex located 3 mm from the temporal tip. Mean onset latency of excitation responses and stimulus selectivity to monkey calls and other sounds, both simple and complex, increased progressively from sector I to III. Also, whereas cells in sector I responded with significantly higher firing rates to the “other” sounds than to monkey calls, those in sectors II and III responded at the same rate to both stimulus types. The pattern of results supports the proposal that the STP contains a rostrally directed, hierarchically organized auditory processing stream, with gradually increasing stimulus selectivity, and that this stream extends from the primary auditory area to the temporal pole.
Improvement of Immediate Performance in Neonatal Resuscitation Through Rapid Cycle Deliberate Practice Training.

Background Simulation training is an effective method to teach neonatal resuscitation (NR), yet many pediatrics residents do not feel comfortable with NR. Rapid cycle deliberate practice (RCDP) allows the facilitator to provide debriefing throughout the session. In RCDP, participants work through the scenario multiple times, eventually reaching more complex tasks once basic elements have been mastered. Objective We determined if pediatrics residents have improved observed abilities, confidence level, and recall in NR after receiving RCDP training compared to the traditional simulation debriefing method. Methods Thirty-eight pediatrics interns from a large academic training program were randomized to a teaching simulation session using RCDP or simulation debriefing methods. The primary outcome was the intern's cumulative score on the initial Megacode Assessment Form (MCAF). Secondary outcome measures included surveys of confidence level, recall MCAF scores at 4 months, and time to perform critical interventions. Results Thirty-four interns were included in analysis. Interns in the RCDP group had higher initial MCAF scores (89% versus 84%, P < .026), initiated positive pressure ventilation within 1 minute (100% versus 71%, P < .05), and administered epinephrine earlier (152 s versus 180 s, P < .039). Recall MCAF scores were not different between the 2 groups. Conclusions Immediately following RCDP interns had improved observed abilities and decreased time to perform critical interventions in NR simulation as compared to those trained with the simulation debriefing. RCDP was not superior in improving confidence level or retention.
How truth wins in opinion dynamics along issue sequences

Significance Investigations of the conditions of truth wins in social groups present mixed findings and have not included a network science modeling of the opinion dynamics that alter individuals’ positions. This paper presents evidence that an attention to such dynamics substantially clarifies how truth wins. The findings of our experiments on groups of human subjects suggest that the mixed findings on truth wins in social groups can be integrated as special-case realizations of a general model of opinion dynamics on influence networks. How truth wins in social groups is an important open problem. Classic experiments on social groups dealing with truth statement issues present mixed findings on the conditions of truth abandonment and reaching a consensus on the truth. No theory has been developed and evaluated that might integrate these findings with a mathematical model of the interpersonal influence system that alters some or all of its members’ positions on an issue. In this paper we provide evidence that a general model in the network science on opinion dynamics substantially clarifies how truth wins in groups.
Enuresis and Punishment: The Adverse Effects on Child Development and on Treatment

Objective: To investigate the role of punishment in enuretic children and how the punishments can influence therapy response. Methods: We enrolled 218 enuretic children. The children and their families were asked to participate in the study at the end of the clinical evaluation. Results: The analysis of the questionnaires shows that at least one punishment because of nocturnal enuresis (NE) had been applied to 27 out of 218 (12.4%) children. Punishment methods were reprimanding in 19 out of 27 (70.4%), depriving of sleep in 11 out of 27 (40.7%), mildly beating in 3 out of 27 (11.1%), leaving the child wet in 1 out of 27 (3.7%) and other methods in 2 out of 27 (7.4%). In the group of punished children, a full or partial response in terms of a decreased number of wet nights was achieved in 40.7 vs. 59.2% in children who had not been punished. Conclusions: Parents should be sensitized on the adverse effects of punishment on child development. It is important in childcare to explain the definitions of the disorder and find the best treatment (behavioural and/or medicinal) depending on the single patient, his/her family and compliance of both. Successful management of NE has benefits to both the child and the family.
Intention toward the continuation of female genital mutilation in Bale Zone, Ethiopia

Background Female genital mutilation (FGM) is a harmful traditional practice that is deeply rooted in Africa. It is associated with health complications and human rights violations. Research on intention for the continuation of FGM and the social determinants underpinning this practice are scarce. Therefore, this study intended to assess the intention of women toward the continuation of FGM among Bale Zone reproductive-age women. Methods A community-based cross-sectional study design supplemented by qualitative methods was conducted in 2014. A total of 634 reproductive-age women were involved in the quantitative part of the study. The respondents were drawn from five randomly selected districts of Bale Zone. The total sample was allocated proportionally to each district based on the number of reproductive-age women it has. Purposive sampling method was used for qualitative study. Then, data were collected using a pretested and structured questionnaire. The collected data were analyzed by Statistical Package for Social Sciences for Windows version 16.0. Multiple logistic regressions were carried out to examine the existence of a relationship between intentions for the continuation of FGM and selected determinant factors. Results This study revealed that 26.7% of the respondents had intention for the continuation of FGM. Religion, safeguarding virginity, tradition, and social values were the major reasons for the perpetuation of this practice. Circumcised respondents and those who were not able to read and write were ~3 (adjusted odds ratio = 2.89, 95% confidence interval = [1.33, 6.20]) and 7.58 (adjusted odds ratio = 7.58, 95% confidence interval = [3.47, 16.54]) times more likely intending the continuation of FGM than uncircumcised and those who attended secondary-level education and above, respectively. Conclusion The study shows that the intention toward the persistence of the practice is high in Bale Zone. Rural residents, those who were not able to read and write, and circumcised respondents were more likely to continue the practice.
A Prospective Study of Leukocyte Telomere Length and Risk of Renal Cell Carcinoma

Background: It has been hypothesized that genomic instability related to telomere dysfunction may contribute to carcinogenesis. There is some evidence from case–control studies suggesting that short leukocyte telomere length may be associated with an increased risk of renal cell carcinoma (RCC); however, this association has not been investigated prospectively. Methods: We conducted a nested case–control study (209 cases, 410 controls) of RCC risk in relation to prediagnostic leukocyte telomere length in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. ORs and 95% confidence intervals (CI) were estimated using conditional logistic regression. Results: Leukocyte telomere length was not significantly associated with future risk of RCC (highest quartile vs. lowest: OR, 0.8; 95% CI, 0.5–1.5; Ptrend = 0.6). Analyses stratified by sex, age, and time from blood collection to RCC diagnosis were similarly null. Conclusions: The results of this study, to our knowledge the first prospective investigation of its kind, do not support an association between prediagnostic leukocyte telomere length and risk of RCC. Impact: In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of RCC. Cancer Epidemiol Biomarkers Prev; 22(5); 997–1000. ©2013 AACR.
Cholesterol reduction and macrophage function: role of paraoxonases

Purpose of review Unregulated uptake of oxidized LDL by macrophages to form foam cells is the hallmark for atherosclerosis. The paraoxonase (PON) family of enzymes plays a critical role in attenuating atherosclerotic lesion formation by hydrolyzing lipid peroxides (LOOHs) and preventing the oxidation of LDL particles and by enhancing HDL-mediated cholesterol efflux. Findings in recent years suggest novel mechanisms by which PON isoforms interact with macrophages to regulate cholesterol metabolism and cellular function. Recent findings The association of PON with HDL particles facilitates binding of the particle to macrophages and ABCA1-dependent cholesterol efflux. The hydrolysis of membrane phospholipids by PON generates lysophosphatidylcholine which is shown to regulate expression of cholesterol transport proteins. The PON family also regulates multiple aspects of macrophage function. PON attenuates inflammation and prevents induction of apoptosis via activation of a scavenger receptor class B type-1-dependent signaling mechanism. PON limits macrophage-dependent oxidant formation by preventing the activation of the membrane-associated NADPH oxidase and by stabilizing mitochondria. PON also promotes the differentiation of macrophages to an anti-inflammatory phenotype. This function appears to be independent of PON enzymatic activity and, rather, is dependent on the ability of endogenous sulfhydryls to neutralize pro-inflammatory peroxides. Summary In recent years, the therapeutic efficacy of HDL-based therapies has been subject to dispute. Pharmacological approaches that target an increase in the expression and/or activity of PON may facilitate macrophage cholesterol metabolism and attenuate inflammatory injury.
Complement Opsonization of HIV-1 Enhances the Uptake by Dendritic Cells and Involves the Endocytic Lectin and Integrin Receptor Families

Interaction with the complement system is an underappreciated aspect of HIV-1 infection; even in primary infection, complement fragments are found on virions with potential to affect the interplay between the virus and dendritic cells (DC). Since opsonization may affect the efficiency of uptake and the type of receptors utilized, we compared the interactions of DC with free HIV-1 (F-HIV) and complement opsonized HIV-1 (C-HIV). We demonstrate that C-HIV significantly enhanced the uptake by immature DC (IDC) and mature DC (MDC) and that the internalization rate was dependent on both opsonization of the virus and DC maturation state. Increased DC uptake of C-HIV was not due to opsonization related increased binding of virus to the surface of DC but rather increased internalization of C-HIV despite utilizing a similar repertoire of receptors as F-HIV. Both F-HIV and C-HIV interacted with C-type lectins, integrins, and CD4 and blocking these receptor families prevented HIV-1 from binding to DC at 4°C. Blocking integrins significantly reduced the binding and uptake of F-HIV and C-HIV implicating the involvement of several integrins such as β1-integrin, CR3, LFA-1, and α4β7. Distinctive for C-HIV was usage of β1-integrin and for F-HIV, usage of β7-integrin, whereas both F-HIV and C-HIV utilized both integrin chains of CR3. We have in this study identified the receptor types used by both F-HIV and C-HIV to bind to DC. Noteworthy, C-HIV was internalized more efficiently by DC than F-HIV, probably via receptor mediated endocytosis, which may entail different intracellular processing of the virus leading to both elevated infection and altered activation of HIV specific immune responses.
Modified Glasgow Prognostic Score at Recurrence Predicts Poor Survival in Resected Non-Small Cell Lung Cancer (NSCLC) Patients

Background The purpose of this study was to investigate the impact of the modified Glasgow Prognostic Score (GPS) at the time of recurrence on post-recurrence survival (PRS) in non-small cell lung cancer (NSCLC) patients after surgical resection. Material/Methods The clinicopathologic characteristics and outcome data of 266 patients with recurrent NSCLC were collected and reviewed retrospectively. The prognostic impact of mGPS at recurrence in patients with recurrent NSCLC was investigated in univariate and multivariate analyses. Results A total of 266 patients were analyzed. The mGPS at the time of recurrence of 0, 1, and 2 was assigned to 60.9%, 33.1%, and 6.0% of total patients, respectively. In univariate analyses, the median post-recurrence survival times for those with mGPS 0, 1, and 2 were 19, 14, and 4 months, respectively (log-rank test; P=0.005). No statistically significant difference in post-recurrence survival was observed among the patients with different mGPS before surgery (log-rank test; P=0.064). Age at surgery, histological type, C-reactive protein (CRP), albumin, and mGPS at recurrence significantly predicted PRS. After adjusting for confounding variables in the model, age (hazard ratio 1.59, P=0.003) as well as disease-free interval (DFI) (hazard ratio 1.40, P=0.023), and mGPS at recurrence (hazard ratio 1.47, P=0.002) remained independent predictors of PRS. Conclusions mGPS at the time of recurrence might be an independent adverse prognostic factor in recurrent NSCLC.
Paternalism in chimpanzees : do chimpanzees help conspecifics by giving them what they want or by responding to what they need?

Prosocial behavior has been of interest in social, developmental, as well as in evolutionary psychology as an essential component of cooperation and altruism. In particular the phylogenetic origins of helping behavior and the degree in which it is unique in humans, are still a matter of debate. To further our understanding of the evolution of cooperative and prosocial behavior in humans it is fundamental to compare it to humans’ closest living genetic relative, chimpanzees. While recent research has investigated the motivation underlying helping behavior in young children, very little is known about the factors affecting helping behavior in non-human primates. The question is whether such behavior is motivated by a genuine concern for others’ need. In the present study, nine chimpanzees (Pan troglodytes) of the A group from the Leipziger Zoo were presented in a situation in which a conspecific needs an object to continue a task. Crucially, subjects were faced with two alternatives. They could either provide the tool, relevant to the conspecifics need or an irrelevant tool, which would not fulfill the actual need. Moreover the conspecific, the stooge, was trained to always reach for the irrelevant object because an occluder obstructed his view. Therefore the subjects could either help by simply completing the reach (and providing the irrelevant object) or help paternalistically by correcting the conspecifics and providing the tool relevant to his genuine need. The results showed that chimpanzees were more motivated to provide a tool compared to closely matched control in which the type of the object did not matter for the conspecifics. Moreover the majority of the subjects helped by correcting the beneficiary more often in the experimental compared to the control condition. These findings provide some evidence that chimpanzees are not merely motivated to complete action sequences but actually respond to the need of others’. The phylogenetic roots of genuine prosocial behavior may run deeper than previously assumed.
Prevalence of prescription errors in general practice in Jeddah, Saudi Arabia

Abstract Purpose: Prescription errors are a common cause of adverse drug events (ADEs). Recognizing ADEs can significantly contribute to the reduction of morbidity and mortality. This study aims to investigate the type and prevalence of errors in prescription writing, directed toward a needs assessment for developing educational interventions. Materials and methods: A cross-sectional descriptive study was conducted in Jeddah community pharmacies (January–February 2016). A random sample of 117 prescriptions were reviewed and analyzed by community pharmacists for legibility and omission of the information in the prescription. Results: Results revealed that 51% of the prescriptions included diagnosis, in which 62% included the recommended drug dosage. Only 7% of drug interactions were reported between the prescribed drugs, 17% of the physicians prescribed drugs that prevented the adverse effects used for diagnosis. Prescriptions for chronic conditions were scrutinized to be 18%. It was noteworthy that 29% of the pharmacists reported difficulty in reading the handwriting of prescriptions. Conclusions: The quality of prescription writing is deficient in some elements and strategies for improvement are needed. These findings underscore a crucial requirement to upgrade the quality of prescription writing by encouraging continuous medical education programs to facilitate delivery of excellent therapeutic outcomes.