Biallelic transcription of Igf2 and H19 in individual cells suggests a post-transcriptional contribution to genomic imprinting

AbstractThe H19 and insulin-like growth factor 2 (Igf2) genes in the mouse are models for genomic imprinting during development. The genes are located only 90 kb apart in the same transcriptional orientation [1], but are reciprocally imprinted: Igf2 is paternally expressed while H19 is maternally expressed. It has been suggested that expression of H19 and repression of Igf2 (or the converse) on a given chromosome are mechanistically linked and that the parental imprint operates at the level of transcription [2]. Although expression of Igf2 and H19 is thought to be monoallelic, the data have so far been obtained exclusively by looking at steady-state RNA levels using techniques that reflect the average activity of the genes in a cell population [3,4]. Here, we have adapted a fluorescent in situ hybridisation (FISH) method to detect nascent RNA molecules of Igf2 and H19 at the initial transcription sites in the nuclei of wild-type mouse embryonic liver cells. Nine different transcription patterns were observed, reflecting a high heterogeneity of transcription at the single-cell level. Our observations suggest that regulation of Igf2 and H19 by parental imprinting is much more complex than previously proposed and acts at both transcriptional and post-transcriptional levels

Impact of age and race on outcomes of a program to prevent excess weight gain and disordered eating in adolescent girls

Interpersonal psychotherapy (IPT) prevents weight gain and reduces loss-of-control (LOC)-eating in adults. However, IPT was not superior to health-education (HE) for preventing excess weight gain and reducing LOC-eating over 1-year in adolescent girls at risk for excess weight gain and eating disorders. Limited data suggest that older and non-White youth may be especially responsive to IPT. In secondary analyses, we examined if age or race moderated weight and LOC-eating outcomes. The 113 participants (12–17 years; 56.6% White) from the original trial were re-contacted 3 years later for assessment. At baseline and follow-up visits through 3 years, we assessed BMI, adiposity by dual energy X-ray absorptiometry, and LOC-eating presence. In linear mixed models, baseline age moderated 3-year BMI outcome; older girls in IPT had the lowest 3-year BMI gain compared to younger girls in IPT and all girls in HE, p = 0.04. A similar pattern was observed for adiposity. Race moderated 3-year LOC-eating; non-White girls in IPT were most likely to abstain from LOC-eating at 3 years compared to all other girls, p = 0.04. This hypothesis-generating analysis suggests future studies should determine if IPT is especially efficacious at reducing LOC-eating in older, non-White adolescents

IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism

Temperament Factors and Dimensional, Latent Bifactor Models of child psychopathology: Transdiagnostic and Specific Associations in Two Youth Samples

Common emotional and behavioral symptoms co-occur and are associated with core temperament factors. This study investigated links between temperament and dimensional, latent psychopathology factors, including a general common psychopathology factor (p factor) and specific latent internalizing and externalizing liabilities, as captured by a bifactor model, in two independent samples of youth. Specifically, we tested the hypothesis that temperament factors of negative affectivity (NA), positive affectivity (PA), and effortful control (EC) could serve as both transdiagnostic and specific risks in relation to recent bifactor models of child psychopathology. Sample 1 included 571 youth (average age 13.6, SD = 2.37, range 9.3–17.5) with both youth and parent report. Sample 2 included 554 preadolescent children (average age 7.7, SD = 1.35, range = 5–11 years) with parent report. Structural equation modeling showed that the latent bifactor models fit in both samples. Replicated in both samples, the p factor was associated with lower EC and higher NA (transdiagnostic risks). Several specific risks replicated in both samples after controlling for co-occurring symptoms via the p factor: internalizing was associated with higher NA and lower PA, lower EC related to externalizing problems

Casein phosphopeptides drastically increase the secretion of extracellular proteins in Aspergillus awamori. Proteomics studies reveal changes in the secretory pathway

<p>Abstract</p> <p>Background</p> <p>The secretion of heterologous animal proteins in filamentous fungi is usually limited by bottlenecks in the vesicle-mediated secretory pathway.</p> <p>Results</p> <p>Using the secretion of bovine chymosin in <it>Aspergillus awamori </it>as a model, we found a drastic increase (40 to 80-fold) in cells grown with casein or casein phosphopeptides (CPPs). CPPs are rich in phosphoserine, but phosphoserine itself did not increase the secretion of chymosin. The stimulatory effect is reduced about 50% using partially dephosphorylated casein and is not exerted by casamino acids. The phosphopeptides effect was not exerted at transcriptional level, but instead, it was clearly observed on the secretion of chymosin by immunodetection analysis. Proteomics studies revealed very interesting metabolic changes in response to phosphopeptides supplementation. The oxidative metabolism was reduced, since enzymes involved in fermentative processes were overrepresented. An oxygen-binding hemoglobin-like protein was overrepresented in the proteome following phosphopeptides addition. Most interestingly, the intracellular pre-protein enzymes, including pre-prochymosin, were depleted (most of them are underrepresented in the intracellular proteome after the addition of CPPs), whereas the extracellular mature form of several of these secretable proteins and cell-wall biosynthetic enzymes was greatly overrepresented in the secretome of phosphopeptides-supplemented cells. Another important 'moonlighting' protein (glyceraldehyde-3-phosphate dehydrogenase), which has been described to have vesicle fusogenic and cytoskeleton formation modulating activities, was clearly overrepresented in phosphopeptides-supplemented cells.</p> <p>Conclusions</p> <p>In summary, CPPs cause the reprogramming of cellular metabolism, which leads to massive secretion of extracellular proteins.</p

The Iranian Integrated Care Electronic Health Record

E-health plays a crucial role in E-government by proposing healthcare services based on information technology. However, the way to administer these services by using E-health solutions is one of the challenging issues. One of these significant challenges is how one integrates heterogeneous healthcare information of the different point of care systems. This paper introduces the Iranian integrated care electronic health record using the information gathered from several point-of-care systems in healthcare enterprises in Iran. This service-oriented architecture has a remarkable characteristic - its accessibility to medical knowledge and medical concepts through archetypes and ontology, respectively. The Ministry of Health and Medical Education of the Islamic Republic of Iran has designed and implemented this national architecture

Personalized Depression Prevention: A Randomized Controlled Trial to Optimize Effects Through Risk-Informed Personalization

Objective: To evaluate whether evidence-based depression prevention programs can be optimized by matching youths to interventions that address their psychosocial vulnerabilities. Method: This randomized controlled trial included 204 adolescents (mean [SD] age ¼ 14.26 [1.65] years; 56.4% female). Youths were categorized as high or low on cognitive and interpersonal risks for depression and randomly assigned to Coping With Stress (CWS), a cognitive-behavioral program, or Interpersonal Psychotherapy–Adolescent Skills Training (IPT-AST), an interpersonal program. Some participants received a match between risk and prevention (eg, high cognitive–low interpersonal risk teen in CWS, low cognitive–high interpersonal risk teen in IPT-AST), others received a mismatch (eg, low cognitive-high interpersonal risk teen in CWS). Outcomes were depression diagnoses and symptoms through 18 months postintervention (21 months total). Results: Matched adolescents showed significantly greater decreases in depressive symptoms than mismatched adolescents from postintervention through 18-month follow-up and across the entire 21-month study period (effect size [d] ¼ 0.44, 95% CI ¼ 0.02, 0.86). There was no significant difference in rates of depressive disorders among matched adolescents compared with mismatched adolescents (12.0% versus 18.3%, t193 ¼ .78, p ¼ .44). Conclusion: This study illustrates one approach to personalizing depression prevention as a form of precision mental health. Findings suggest that risk-informed personalization may enhance effects beyond a one-size-fits-all approach. Clinical trial registration information: Bending Adolescent Depression Trajectories Through Personalized Prevention; https://www.clinicaltrials. gov/; NCT01948167

IKKα negatively regulates ASC-dependent inflammasome activation.

The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes

The implementation of a mobile problem-specific electronic CEX for assessing directly observed student—patient encounters

Background: Facilitating direct observation of medical students&#x0027; clinical competencies is a pressing need. Methods: We developed an electronic problem-specific Clinical Evaluation Exercise (eCEX) based on a national curriculum. We assessed its feasibility in monitoring and recording students&#x0027; competencies and the impact of a grading incentive on the frequency of direct observations in an internal medicine clerkship. Students (n=56) at three clinical sites used the eCEX and comparison students (n=56) at three other clinical sites did not. Students in the eCEX group were required to arrange 10 evaluations with faculty preceptors. Students in the second group were required to document a single, faculty observed &#x2018;Full History and Physical&#x2019; encounter with a patient. Students and preceptors were surveyed at the end of each rotation. Results: eCEX increased students&#x0027; and evaluators&#x0027; understanding of direct-observation objectives and had a positive impact on the evaluators&#x0027; ability to provide feedback and assessments. The grading incentive increased the number of times a student reported direct observation by a resident preceptor. Conclusions: eCEX appears to be an effective means of enhancing student evaluation