Lucky or clever? From expectations to responsibility judgments

How do people hold others responsible for the consequences of their actions? We propose a computational model that attributes responsibility as a function of what the observed action reveals about the person, and the causal role that the person's action played in bringing about the outcome. The model first infers what type of person someone is from having observed their action. It then compares a prior expectation of how a person would behave with a posterior expectation after having observed the person's action. The model predicts that a person is blamed for negative outcomes to the extent that the posterior expectation is lower than the prior, and credited for positive outcomes if the posterior is greater than the prior. We model the causal role of a person's action by using a counterfactual model that considers how close the action was to having been pivotal for the outcome. The model captures participants' responsibility judgments to a high degree of quantitative accuracy across three experiments that cover a range of different situations. It also solves an existing puzzle in the literature on the relationship between action expectations and responsibility judgments. Whether an unexpected action yields more or less credit depends on whether the action was diagnostic for good or bad future performance

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage

Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUS(R521G), harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears

Hypertrophy Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM): A Randomized Placebo Controlled Double Blind Pilot Study

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with anti-oxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: Regression with N-AcetyLcysTeine in Hypertrophic CardioMyopathy (HALT-HCM) is a double blind randomized, sex-matched, placebo-control single center pilot study in patients with HCM. HCM patients, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated up to 2.4 g per day. Clinical evaluation, blood chemistry, and six-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR), the latter whenever not contraindicated, before and after 12 months of treatment. 85 out of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographics, echocardiographic, and CMR phenotypes at the baseline between the two groups were similar. Whole exome sequencing in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC and eleven in the placebo groups completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and CMR indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement, a surrogate for fibrosis, were small. CONCLUSIONS: Treatment with NAC for 12-months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM

II Diretriz Brasileira de Transplante Cardíaco

Universidade de São Paulo Faculdade de Medicina Hospital das ClínicasIIHospital de Messejana Dr. Carlos Alberto Studart GomesUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaInstituto Dante Pazzanese de CardiologiaUniversidade Federal de Minas Gerais Hospital das ClínicasFaculdade de Medicina de São José do Rio PretoPontifícia Universidade Católica do ParanáIHospital Israelita Albert EinsteinInstituto Nacional de Cardiologia, Fundação Universitária do Rio Grande do Sul Instituto de CardiologiaReal e Benemérita Sociedade de Beneficência Portuguesa, São PauloHospital Pró-Cardíaco do Rio de JaneiroSanta Casa do Rio de JaneiroUNIFESP, EPMSciEL

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression