Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer.

Mutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.

Renoprotective Effect of a Dipeptidyl Peptidase-4 Inhibitor on Aging Mice.

Dipeptidyl peptidase 4 (DPP-4) inhibitors exert pleiotropic effects beyond glycemic control. We investigated the renoprotective effects of DPP-4 inhibitors on aging mice mediated by the renin-angiotensin system (RAS). C57BL/6 mice were divided into three groups: the two-month-old mice (YM group), the eighteen-month-old mice (AM group) and the eighteen-month-old, linagliptin-treated mice (AM + LIN group). Renal function was improved, based on serum creatinine and cystatin-C levels (p < 0.05 compared with the AM group for both parameters). Fibrotic areas and the levels of proteins related to fibrosis improved in the AM + LIN group (p < 0.001 compared with the AM group for all parameters). In the AM + LIN group, the DPP-4-positive area and activity and expressions of DPP-4 were decreased (p < 0.05 compared with the AM group for all parameters). The levels of proteins related to the RAS, including prorenin receptor, angiotensin-converting enzyme, angiotensin II and angiotensin 1 receptor, were decreased in the AM + LIN group (p < 0.05, p < 0.01, p < 0.05, and p < 0.01 compared with the AM group, respectively). NADPH oxidase 2 and NADPH oxidase 4 levels decreased in the AM + LIN group (p < 0.001 compared with the AM group for both proteins), whereas the levels of endothelial nitric oxide synthase (eNOS) phosphorylated at serine1177 and superoxide dismutase 1 were increased (p < 0.01 compared with the AM group for both proteins). DPP-4 inhibitors may exert renoprotective effects via prorenin receptor/angiotensin-converting enzyme/angiotensin II/angiotensin 1 receptor axis.

Relationship between clinical severity of "new" bronchopulmonary dysplasia and HRCT abnormalities in VLBW infants.

BACKGROUND: To assess the relationship between HRCT abnormalities and the clinical severity of "new" bronchopulmonary dysplasia (BPD) and respiratory assistance in <1500 g preterm infants. METHODS: HRCT was performed at the time of discharge in 109 preterm infants with BPD who were born between 2008 and 2014. BPD severity was defined as mild, moderate, or severe according to the NIH diagnostic criteria. Total HRCT scores for each infant were obtained from the sum of the number of BPD lobes assessed by two radiologists: a hyperaeration score (Hs) composed of decreased attenuation, mosaic attenuation, and bulla/bleb, and a parenchyma score (Ps) composed of linear lesions, consolidation, bronchial wall thickening, and bronchiectasis. We compared HRCT scores based on BPD severity and respiratory modes, such as invasive mechanical ventilation (IMV), non-invasive MV (NIMV), and oxygen therapy. RESULTS: Among the group of included infants (n = 101), mild BPD was found in 46.5%, moderate BPD in 45.5%, and severe BPD in 7.9%. When partial correlation was adjusted by gestational age (GA) and birth weight, the duration of NIMV was correlated with Ps (r = 0.382, P < 0.001), Hs (r = 0.223, P = 0.027), and total score (r = 0.384, P < 0.001). The duration of oxygen therapy was correlated with Ps (r = 0.374, P < 0.001) and Hs (r = 0.227, P = 0.023). Ps showed a correlation with BPD severity (r = 0.381, P = 0.007) in infants born at ≤26 weeks (GA) and those born at >27 weeks GA (r = 0.298, P = 0.042). CONCLUSIONS: Parenchymal changes showed a greater correlation with the clinical severity of "new" BPD cases, especially in infants born at ≤26 weeks GA. The use of NIMV showed a greater correlation with Ps than Hs.

The secret to happiness: Feeling good or feeling right?

Which emotional experiences should people pursue to optimize happiness? According to traditional subjective well-being research, the more pleasant emotions we experience, the happier we are. According to Aristotle, the more we experience the emotions we want to experience, the happier we are. We tested both predictions in a cross-cultural sample of 2,324 participants from 8 countries around the world. We assessed experienced emotions, desired emotions, and indices of well-being and depressive symptoms. Across cultures, happier people were those who more often experienced emotions they wanted to experience, whether these were pleasant (e.g., love) or unpleasant (e.g., hatred). This pattern applied even to people who wanted to feel less pleasant or more unpleasant emotions than they actually felt. Controlling for differences in experienced and desired emotions left the pattern unchanged. These findings suggest that happiness involves experiencing emotions that feel right, whether they feel good or not. (PsycINFO Database Record

Knowing when to seek anger: Psychological health and context-sensitive emotional preferences.

According to hedonic approaches to psychological health, healthy individuals should pursue pleasant and avoid unpleasant emotions. According to instrumental approaches, however, healthy individuals should pursue useful and avoid harmful emotions, whether pleasant or unpleasant. We sought to reconcile these approaches by distinguishing between preferences for emotions that are aggregated across contexts and preferences for emotions within specific contexts. Across five days, we assessed daily confrontational and collaborative demands and daily preferences for anger and happiness. Somewhat consistent with hedonic approaches, when averaging across contexts, psychologically healthier individuals wanted to feel less anger, but not more happiness. Somewhat consistent with instrumental approaches, when examined within contexts, psychologically healthier individuals wanted to feel angrier in more confrontational contexts, and some wanted to feel happier in more collaborative contexts. Thus, although healthier individuals are motivated to avoid unpleasant emotions over time, they are more motivated to experience them when they are potentially useful.

Exposure to intrauterine inflammation leads to impaired function and altered structure in the preterm heart of fetal sheep.

Intrauterine inflammation is a major contributor to preterm birth and has adverse effects on preterm neonatal cardiovascular physiology. Cardiomyocyte maturation occurs in late gestation in species such as humans and sheep. We tested the hypothesis that intrauterine inflammation has deleterious effects on cardiac function in preterm sheep which might be explained by altered cardiomyocyte proliferation and maturation. Pregnant ewes received an ultrasound-guided intra-amniotic injection of lipopolysaccharide (LPS) or saline 7 days prior to delivery at day 127 of pregnancy (term 147 days). Cardiac contractility was recorded in spontaneously beating hearts of the offspring, perfused in a Langendorff apparatus. Saline-filled latex balloons were inserted into the left ventricle (LV) and right ventricle (RV). Responsiveness to isoprenaline and stop-flow/reperfusion was assessed. In other experiments, hearts were perfusion-fixed, and cardiomyocyte nuclearity, volume and number were determined. ß-Adrenoceptor mRNA levels were determined in unfixed tissue. In hearts of LPS-exposed fetuses, contractility in the LV and RV was suppressed by ~40% and cardiomyocyte numbers were reduced by ~25%. Immature mono-nucleated cardiomyocytes had lower volumes (~18%), whereas mature bi-nucleated cardiomyocyte volume was ~77% greater. Although basal coronary flow was significantly increased by 21±7% in LPS-exposed hearts, following ischaemia/reperfusion (IR), end-diastolic pressure was increased 2.4±0.3-fold and infarct area was increased 3.2±0.6-fold compared with those in controls. Maximum responsiveness to isoprenaline was enhanced by LPS, without an increase in ß-adrenoceptor mRNA, suggesting altered second messenger signalling. Intrauterine inflammation altered cardiac growth, suppressed contractile function and enhanced responsiveness to stress. Although these effects may ensure immediate survival, they probably contribute to the increased vulnerability of organ perfusion in preterm neonates.

Tau and GSK3beta dephosphorylations are required for regulating Pin1 phosphorylation.

Pin1 binds mitotically phosphorylated Thr231-Pro232 and Thr212-Pro213 sites on tau, and a Pin1 deficiency in mice leads to tau hyperphosphorylation. The aim of this study was to determine if the dephosphorylation or inhibition of tau and GSK3beta phosphorylation induces the Pin1 phosphorylation. To test this, human SK-N-MC cells were stably transfected with a fusion gene containing neuron-specific enolase (NSE)-controlled APPsw gene(NSE/APPsw), to induce Abeta-42. The stable transfectants were then transiently transfected with NSE/Splice, lacking human tau (NSE/Splice), or NSE/hTau, containing human tau, into the cells. The NSE/Splice- and NSE/hTau-cells were then treated with lithium. We concluded that (i) there was more C99-beta APP accumulation than C83-betaAPP in APPsw-tansfectant and thereby promoted Abeta-42 production in transfectants. (ii) the inhibition of tau and GSK3beta phosphorylations correlated with increase in Pin1 activation in NSE/hTau- cells. Thus, these observations suggest that Pin1 might have an inhibitive role in phosphorylating tau and GSK3beta for protecting against Alzheimer's disease.