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Adrenal turmoil and mortality price throughout adrenal lack and genetic adrenal hyperplasia.
For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation. CONCLUSIONS Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. check details A gBRCA2 mutation was overrepresented in dnMBC.The plasma membrane adenosine triphosphate (ATP) release channel pannexin 1 (PANX1) has been implicated in many physiological and pathophysiological processes associated with purinergic signaling, including cancer progression, apoptotic cell clearance, inflammation, blood pressure regulation, oocyte development, epilepsy and neuropathic pain. Here we present near-atomic-resolution structures of human and frog PANX1 determined by cryo-electron microscopy that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide. An extracellular tryptophan ring located at the outer pore created a constriction site, potentially functioning as a molecular sieve that restricts the size of permeable substrates. The amino and carboxyl termini, not resolved in the density map, appeared to be structurally dynamic and might contribute to narrowing of the pore during channel gating. In combination with functional characterization, this work elucidates the previously unknown architecture of pannexin channels and establishes a foundation for understanding their unique channel properties.Protein phase separation drives the assembly of membraneless organelles, but little is known about how these membraneless organelles are maintained in a metastable liquid- or gel-like phase rather than proceeding to solid aggregation. Here, we find that human small heat-shock protein 27 (Hsp27), a canonical chaperone that localizes to stress granules (SGs), prevents FUS from undergoing liquid-liquid phase separation (LLPS) via weak interactions with the FUS low complexity (LC) domain. Remarkably, stress-induced phosphorylation of Hsp27 alters its activity, leading Hsp27 to partition with FUS LC to preserve the liquid phase against amyloid fibril formation. NMR spectroscopy demonstrates that Hsp27 uses distinct structural mechanisms for both functions. Our work reveals a fine-tuned regulation of Hsp27 for chaperoning FUS into either a polydispersed state or a LLPS state and suggests an essential role for Hsp27 in stabilizing the dynamic phase of stress granules.Telomeres arose from the need to stabilize natural chromosome ends, resulting in terminal chromatin structures with specific protective functions. Their constituent proteins also execute general functions within heterochromatin, mediating late replication and facilitating fork progression. Emerging insights into the mechanisms governing heterochromatin replication suggest telomeres and heterochromatin act in concert during development and aging. They also suggest a common evolutionary origin for these two chromosome regions that arose during eukaryogenesis.The current research investigates whether higher economic inequality disproportionately intensifies the financial hardship of low-income individuals. We propose that higher economic inequality increases financial hardship for low-income individuals by reducing their ability to rely on their community as a buffer against financial difficulties. This may occur, in part, because a frayed community buffer reduces low-income individuals' propensity to seek informal financial support from others. We provide empirical support across eight studies (sample size N = 1,029,900) from the United States, Australia and rural Uganda, through correlational and experimental data, as well as an instrumental variable analysis. On average across our studies, a 1 s.d. increase in economic inequality is associated with an increase of financial hardship among low-income individuals of 0.10 s.d. We discuss the implications of these results for policies aimed to help people living in poverty buffer against the adverse effects higher economic inequality imposes on them.Curiosity is often portrayed as a desirable feature of human faculty. However, curiosity may come at a cost that sometimes puts people in harmful situations. Here, using a set of behavioural and neuroimaging experiments with stimuli that strongly trigger curiosity (for example, magic tricks), we examine the psychological and neural mechanisms underlying the motivational effect of curiosity. We consistently demonstrate that across different samples, people are indeed willing to gamble, subjecting themselves to electric shocks to satisfy their curiosity for trivial knowledge that carries no apparent instrumental value. Also, this influence of curiosity shares common neural mechanisms with that of hunger for food. In particular, we show that acceptance (compared to rejection) of curiosity-driven or incentive-driven gambles is accompanied by enhanced activity in the ventral striatum when curiosity or hunger was elicited, which extends into the dorsal striatum when participants made a decision.As cognitive function is linked with academic achievement, career success and mental health, there is a need to understand how the cognitive benefits of long-term exercise can be optimized. Our meta-regression included 80 randomized controlled trials and examined moderators of the effects of exercise on cognition in healthy individuals. The summary effect was small and did not differ between cognitive domains. Higher benefits of exercise on cognitive function were found after coordinative exercise compared with other exercise types. With longer intervention length, the effect size increased with longer session duration. Exercise was less effective in female compared with male individuals, and the dose-response relationship differed between sexes. Our findings suggest a general rather than domain-specific effect of exercise on cognition, which is influenced by sex, exercise type and reciprocal relationships between dose parameters. We derive sex-specific recommendations on how cognitive benefits can be optimized by exercise intensity, its progression and exercise type.Research over the last fifty years has suggested that political attitudes and values around the globe are shaped by two ideological dimensions, often referred to as economic and social conservatism. However, it remains unclear why this ideological structure exists. Here we highlight the striking concordance between these dual dimensions of ideology and independent convergent evidence for two key shifts in the evolution of human group living. First, humans began to cooperate more and across wider interdependent networks. Second, humans became more group-minded, conforming to social norms in culturally marked groups and punishing norm-violators. We propose that fitness trade-offs and behavioural plasticity have maintained functional variation in willingness to cooperate and conform within modern human groups, naturally giving rise to the two dimensions of political ideology. Supported by evidence from across the behavioural sciences, this evolutionary framework provides insight into the biological and cultural basis of political ideology.Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.Adaptive changes in plant phenology are often considered to be a feature of the so-called 'domestication syndrome' that distinguishes modern crops from their wild progenitors, but little detailed evidence supports this idea. In soybean, a major legume crop, flowering time variation is well characterized within domesticated germplasm and is critical for modern production, but its importance during domestication is unclear. Here, we identify sequential contributions of two homeologous pseudo-response-regulator genes, Tof12 and Tof11, to ancient flowering time adaptation, and demonstrate that they act via LHY homologs to promote expression of the legume-specific E1 gene and delay flowering under long photoperiods. We show that Tof12-dependent acceleration of maturity accompanied a reduction in dormancy and seed dispersal during soybean domestication, possibly predisposing the incipient crop to latitudinal expansion. Better understanding of this early phase of crop evolution will help to identify functional variation lost during domestication and exploit its potential for future crop improvement.Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD) the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.Successful treatment of erectile dysfunction (ED) is associated with improvements in quality of life; however, treatment utilisation is sub-optimal. The aim of this systematic review was to identify the rates of ED treatment utilisation and the barriers and enablers men experience when using treatment. We searched MEDLINE®, Embase, the Cochrane library; AMED; HMIC; HTA; CINAHL; PsychARTICLES; PsychINFO up to August 2018. Data on rates of treatment utilisation and barriers and enablers of utilisation were extracted and summarised. Fifty studies were included. Discontinuation rates ranged from 4.4 to 76% for phosphodiesterase type 5 inhibitors, 18.6 to 79.9% for intracavernosal injections, and 32 to 69.2% for urethral suppositories. In relation to those with a penile prosthesis, 30% discontinued having sex due to, e.g. device complications, lack of partner or a loss of sexual interest. Most research included in the current review examined barriers to treatment utilisation and therefore focussed on reasons for discontinuing treatment.
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