The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism

Postcranial morphology of the middle Pleistocene humans from Sima de los Huesos, Spain

Current knowledge of the evolution of the postcranial skeleton in the genus Homo is hampered by a geographically and chronologically scattered fossil record. Here we present a complete characterization of the postcranium of the middle Pleistocene paleodeme from the Sima de los Huesos (SH) and its paleobiological implications. The SH hominins show the following: (i) wide bodies, a plesiomorphic char- acter in the genus Homo inherited from their early hominin ancestors; (ii) statures that can be found in modern human middle-latitude pop- ulations that first appeared 1.6–1.5 Mya; and (iii) large femoral heads in some individuals, a trait that first appeared during the middle Pleistocene in Africa and Europe. The intrapopulational size variation in SH shows that the level of dimorphism was similar to modern humans (MH), but the SH hominins were less encephalized than Ne- andertals. SH shares many postcranial anatomical features with Ne- andertals. Although most of these features appear to be either plesiomorphic retentions or are of uncertain phylogenetic polarity, a few represent Neandertal apomorphies. Nevertheless, the full suite of Neandertal-derived features is not yet present in the SH popula- tion. The postcranial evidence is consistent with the hypothesis based on the cranial morphology that the SH hominins are a sister group to the later Neandertals. Comparison of the SH postcranial skeleton to other hominins suggests that the evolution of the postcranium oc- curred in a mosaic mode, both at a general and at a detailed level

SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe

Aims The aim of this study was to develop, validate, and illustrate an updated prediction model (SCORE2) to estimate 10-year fatal and non-fatal cardiovascular disease (CVD) risk in individuals without previous CVD or diabetes aged 40-69 years in Europe.Methods and results We derived risk prediction models using individual-participant data from 45 cohorts in 13 countries (677 684 individuals, 30 121 CVD events). We used sex-specific and competing risk-adjusted models, including age, smoking status, systolic blood pressure, and total- and HDL-cholesterol. We defined four risk regions in Europe according to country-specific CVD mortality, recalibrating models to each region using expected incidences and risk factor distributions. Region-specific incidence was estimated using CVD mortality and incidence data on 10 776 466 individuals. For external validation, we analysed data from 25 additional cohorts in 15 European countries (1 133 181 individuals, 43 492 CVD events). After applying the derived risk prediction models to external validation cohorts, C-indices ranged from 0.67 (0.65-0.68) to 0.81 (0.76-0.86). Predicted CVD risk varied several-fold across European regions. For example, the estimated 10-year CVD risk for a 50-year-old smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL-cholesterol of 1.3 mmol/L, ranged from 5.9% for men in low- risk countries to 14.0% for men in very high-risk countries, and from 4.2% for women in low-risk countries to 13.7% for women in very high-risk countries.Conclusion SCORE2-a new algorithm derived, calibrated, and validated to predict 10-year risk of first-onset CVD in European populations-enhances the identification of individuals at higher risk of developing CVD across Europe.Cardiolog

Time resolved HWA measurements of the OTL flow field from a shrouded turbine HP rotor blade

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