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Circular RNAs are generated from many protein-coding genes, but their role in cardiovascular health and disease states remains unknown. Here we report identification of circRNA transcripts that are differentially expressed in post myocardial infarction (MI) mouse hearts including circFndc3b which is significantly down-regulated in the post-MI hearts. Notably, the human circFndc3b ortholog is also significantly down-regulated in cardiac tissues of ischemic cardiomyopathy patients. Overexpression of circFndc3b in cardiac endothelial cells increases vascular endothelial growth factor-A expression and enhances their angiogenic activity and reduces cardiomyocytes and endothelial cell apoptosis. Adeno-associated virus 9 -mediated cardiac overexpression of circFndc3b in post-MI hearts reduces cardiomyocyte apoptosis, enhances neovascularization and improves left ventricular functions. Mechanistically, circFndc3b interacts with the RNA binding protein Fused in Sarcoma to regulate VEGF expression and signaling. These findings highlight a physiological role for circRNAs in cardiac repair and indicate that modulation of circFndc3b expression may represent a potential strategy to promote cardiac function and remodeling after MI. Circular RNAs (circRNAs) are non-coding RNAs generated from pre-mRNAs of coding genes by the splicing machinery whose function in the heart is poorly understood. Here the authors show that AAV-mediated delivery of the circRNA circFndc3b prevents cardiomyocyte apoptosis, enhances angiogenesis, and attenuates LV dysfunction post-MI in mice by regulating FUS-VEGF-A signalling.

Several types of psychological treatment for posttraumatic stress disorder (PTSD) are considered well established and effective, but evidence of their long-term efficacy is limited. This systematic review and meta-analysis aimed to investigate the long-term outcomes across psychological treatments for PTSD. MEDLINE, Cochrane Library, PTSDpubs, PsycINFO, PSYNDEX, and related articles were searched for randomized controlled trials with at least 12 months of follow-up. Twenty-two studies (N = 2638) met inclusion criteria, and 43 comparisons of cognitive behavioral therapy (CBT) were available at follow-up. Active treatments for PTSD yielded large effect sizes from pretest to follow-up and a small controlled effect size compared with non-directive control groups at follow-up. Trauma-focused treatment (TFT) and non-TFT showed large improvements from pretest to follow-up, and effect sizes did not significantly differ from each other. Active treatments for comorbid depressive symptoms revealed small to medium effect sizes at follow-up, and improved PTSD and depressive symptoms remained stable from treatment end to follow-up. Military personnel, low proportion of female patients, and self-rated PTSD measures were associated with decreased effect sizes for PTSD at follow-up. The findings suggest that CBT for PTSD is efficacious in the long term. Future studies are needed to determine the lasting efficacy of other psychological treatments and to confirm benefits beyond 12-month follow-up.

The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity.

IntroductionInvasive meningococcal disease (IMD, septicaemia and/or meningitis) has a severe acute and long-term burden: 5–10% of patients die within 48 h, and long-term sequelae have been reported in 10–20% of survivors. Health-related quality of life (HRQoL) is increasingly but inconsistently assessed.MethodsA systematic literature review on Neisseria meningitidis IMD sequelae and HRQoL in survivors of all ages and their caregivers, including family, was conducted for high-income countries from 2001 to 2016 (in Medline and Embase, following Cochrane and PRISMA guidelines).ResultsA total of 31 studies, mostly of childhood IMD cases, were included. A broad range of physical, neurological and psychological IMD sequelae were identified. The literature has evolved, with more types of sequelae reported in more recent studies; however, meningococcal disease-specific and sequelae-specific HRQoL data are lacking, and existing studies used a wide variety of instruments. Physical sequelae included: amputations (up to 8% of children, 3% adolescents/adults) and skin scars (up to 55% of children, 18% adolescents, 2% adults). Neurologic sequelae included: hearing loss (up to 19% of infants, 13% children, 12% adolescents, 8% adults). Psychological sequelae included: anxiety, learning difficulties, emotional and behavioural difficulties. IMD negatively affects HRQoL in patients and also in their family and close caregiver network, both in the short- and long-term. Even IMD survivors without sequelae experienced an adverse impact on HRQoL after many years, affecting self-esteem, physical, mental and psychosocial health, and HRQoL was worse in those with cognitive and behavioural sequelae.ConclusionA high proportion of IMD survivors are affected by a broad range of sequelae and reduced HRQoL that persists years after infection. Childhood IMD survivors had more sequelae and more severe sequelae compared with adult survivors. HRQoL was affected in patients and also in their families, caregivers and surrounding network over the long term. More research is needed to resolve data gaps and to standardise HRQoL assessment.FundingGlaxoSmithKline Biologicals SA (Rixensart, Belgium).

The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I K1 ), which is important for maintenance of the cell resting membrane potential, and the sodium current (I Na ), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I K1 modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation. Additionally, I K1 –I Na interactions are key determinants of electrical rotor frequency responsible for abnormal, often lethal, cardiac reentrant activity. Here, we have used a multidisciplinary approach based on molecular and biochemical techniques, acute gene transfer or silencing, and electrophysiology to show that I K1 –I Na interactions involve a reciprocal modulation of expression of their respective channel proteins (Kir2.1 and Na V 1.5) within a macromolecular complex. Thus, an increase in functional expression of one channel reciprocally modulates the other to enhance cardiac excitability. The modulation is model-independent; it is demonstrable in myocytes isolated from mouse and rat hearts and with transgenic and adenoviral-mediated overexpression/silencing. We also show that the p ost synaptic density, d iscs large, and z onula occludens-1 (PDZ) domain protein SAP97 is a component of this macromolecular complex. We show that the interplay between Na v 1.5 and Kir2.1 has electrophysiological consequences on the myocardium and that SAP97 may affect the integrity of this complex or the nature of Na v 1.5–Kir2.1 interactions. The reciprocal modulation between Na v 1.5 and Kir2.1 and the respective ionic currents should be important in the ability of the heart to undergo self-sustaining cardiac rhythm disturbances.

Circulating tumor cells (CTCs) are promising biomarkers for diagnosis and therapy in systemic cancer. However, their infrequent and unreliable detection, especially in nonmetastatic cancer, currently impedes the clinical use of CTCs. Because leukapheresis (LA) targets peripheral blood mononuclear cells, which have a similar density to CTCs, and usually involves processing the whole circulating blood, we tested whether LA could substantially increase CTC detection in operable cancer patients. Therefore, we screened LA products generated from up to 25 L of blood per patient in two independent studies, and found that CTCs can be detected in more than 90% of nonmetastatic breast cancer patients. Interestingly, complete white blood cell sampling enabled determining an upper level for total CTC numbers of about 100,000 cells (median, 7,500 CTCs) per patient and identified a correlation of CTC numbers with anatomic disease spread. We further show that diagnostic leukapheresis can be easily combined with the US Food and Drug Administration-approved CellSearch system for standardized enumeration of CTCs. Direct comparison with 7.5 mL of blood revealed a significantly higher CTC frequency in matched LA samples. Finally, genomic single-cell profiling disclosed highly aberrant CTCs as therapy-escaping variants in breast cancer. In conclusion, LA is a clinically safe method that enabled a reliable detection of CTCs at high frequency even in nonmetastatic cancer patients, and might facilitate the routine clinical use of CTCs as in the sense of a liquid biopsy. Combined with technologies for single-cell molecular genetics or cell biology, it may significantly improve prediction of therapy response and monitoring of early systemic cancer.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events. Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms. Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (d SMC ) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms. Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (k observations  = 25, d SMC  = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = −.18 [−.35; −.01]), higher state happiness (k = 8, r = −.34 [−.59; −.03], variable inverted) and lower state anger (k = 9, r = −.14 [−.26; −.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = −.20 [−.33; −.06]) and lower state sadness (k = 17, r = −.16 [−.25; −.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]). Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms. Experimental trauma paradigms successfully induced a cortisol response. Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms. Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

Most animals use multiple sensory modalities to obtain information about objects in their environment. There is a clear adaptive advantage to being able to recognize objects cross-modally and spontaneously (without prior training with the sense being tested) as this increases the flexibility of a multisensory system, allowing an animal to perceive its world more accurately and react to environmental changes more rapidly. So far, spontaneous cross-modal object recognition has only been shown in a few mammalian species, raising the question as to whether such a high-level function may be associated with complex mammalian brain structures, and therefore absent in animals lacking a cerebral cortex. Here we use an object-discrimination paradigm based on operant conditioning to show, for the first time to our knowledge, that a nonmammalian vertebrate, the weakly electric fish Gnathonemus petersii, is capable of performing spontaneous cross-modal object recognition and that the sensory inputs are weighted dynamically during this task. We found that fish trained to discriminate between two objects with either vision or the active electric sense, were subsequently able to accomplish the task using only the untrained sense. Furthermore we show that cross-modal object recognition is influenced by a dynamic weighting of the sensory inputs. The fish weight object-related sensory inputs according to their reliability, to minimize uncertainty and to enable an optimal integration of the senses. Our results show that spontaneous cross-modal object recognition and dynamic weighting of sensory inputs are present in a nonmammalian vertebrate.

Background Reproductive mood disorders indicate that within-person variation in depressive symptoms across the menstrual cycle can be related to ovarian hormone changes. Until now, such cycle-related symptom changes have been measured once daily, even though depression research indicates systematic diurnal changes in symptoms. Further, previous research often focused on aggregated depression scores. This study examined whether three daily assessments of depressive symptoms follow similar trajectories across the menstrual cycle and investigated within-person cyclical fluctuation of all individual symptoms and the aggregated score. Methods 77 naturally-cycling participants (35 with and 42 without depressive disorder) provided three daily ratings of depressive symptoms across one menstrual cycle to evaluate individual and summarized symptoms. Results Reliability estimates (w) of the three diurnal measurements ranged from 0.56 to 0.78. Cyclicity showed statistically significant interindividual differences for all symptoms, and individual symptoms differed significantly from each other in their magnitude of cyclicity. Limitations Only one menstrual cycle was assessed to reduce participant burden. Further, ovulation testing dates were based on self-reported cycle lengths, and only LH (luteinizing hormone) peaks were tested without subsequent progesterone rises. Conclusions The results highlight the need for a symptom-specific approach to assess individual variance in cyclicity of depressive symptoms. Reliability for one daily assessment can be improved by using the afternoon value, a sum score for depressiveness, or multiple items per symptom. Furthermore, this study emphasizes, that depressive symptoms can systematically change across the menstrual cycle, and it is, therefore, important to include it in depression research. Exploring female-specific risk factors of depression will enable the development of person-tailored treatments. Trial registration The study was preregistered at ClinicalTrials.gov (NCT04086316) with the first registration on 27/08/2019.

Purposeβ-Adrenergic receptors (βAR) are essential targets for the treatment of heart failure (HF); however, chronic use of βAR agonists as positive inotropes to increase contractility in a Gs protein-dependent manner is associated with increased mortality. Alternatively, we previously reported that allosteric modulation of β2AR with the pepducin intracellular loop (ICL)1-9 increased cardiomyocyte contractility in a β-arrestin (βarr)-dependent manner, and subsequently showed that ICL1-9 activates the Ras homolog family member A (RhoA). Here, we aimed to elucidate both the proximal and downstream signaling mediators involved in the promotion of cardiomyocyte contractility in response to ICL1-9.MethodsWe measured adult mouse cardiomyocyte contractility in response to ICL1-9 or isoproterenol (ISO, as a positive control) alone or in the presence of inhibitors of various potential components of βarr- or RhoA-dependent signaling. We also assessed the contractile effects of ICL1-9 on cardiomyocytes lacking G protein-coupled receptor (GPCR) kinase 2 (GRK2) or 5 (GRK5).ResultsConsistent with RhoA activation by ICL1-9, both Rho-associated protein kinase (ROCK) and protein kinase D (PKD) inhibition were able to attenuate ICL1-9-mediated contractility, as was inhibition of myosin light chain kinase (MLCK). While neither GRK2 nor GRK5 deletion impacted ICL1-9-mediated contractility, pertussis toxin attenuated the response, suggesting that ICL1-9 promotes downstream RhoA-dependent signaling in a Gi protein-dependent manner.ConclusionAltogether, our study highlights a novel signaling modality that may offer a new approach to the promotion, or preservation, of cardiac contractility during HF via the allosteric regulation of β2AR to promote Gi protein/βarr-dependent activation of RhoA/ROCK/PKD signaling.