Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophnl affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophnl display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CM, and showed an altered density of dendritic protrusions. Since Ophnl-deficient mice display overactivation of Rho-associated protein kinase (ROCK) and protein kinase A (PICA) signaling, we administered a clinically approved ROCK/PICA inhibitor (fasudil) to correct the neurogenesis defects. While administration of fasudil was not effective in rescuing axon formation, the same treatment completely restored spine density to control levels, and enhanced the long-term survival of adult-born neurons in mice lacking Ophn1. These results identify specific neurodevelopmental steps that are impacted by Ophn1 deletion, and indicate that they may be at least partially corrected by pharmacological treatment. (C) 2017 The Authors. Published by Elsevier Inc

Constraints on a possible variation of the fine structure constant from galaxy cluster data

We propose a new method to probe a possible time evolution of the fine structure constant $\alpha$ from X-ray and Sunyaev-Zeldovich measurements of the gas mass fraction ($f_{gas}$) in galaxy clusters. Taking into account a direct relation between variations of $\alpha$ and violations of the distance-duality relation, we discuss constraints on $\alpha$ for a class of dilaton runaway models. Although not yet competitive with bounds from high-$z$ quasar absorption systems, our constraints, considering a sample of 29 measurements of $f_{gas}$, in the redshift interval $0.14 < z < 0.89$, provide an independent estimate of $\alpha$ variation at low and intermediate redshifts. Furthermore, current and planned surveys will provide a larger amount of data and thus allow to improve the limits on $\alpha$ variation obtained in the present analysis.Comment: 7 pages, 2 figures, accepted for publication in JCA

Constraining the dark energy and smoothness parameter with type Ia Supernovae and Gamma-Ray Bursts

The existence of inhomogeneities in the observed Universe modifies the distance-redshift relations thereby affecting the results of cosmological tests in comparison to the ones derived assuming spatially uniform models. By modeling the inhomogeneities through a Zeldovich-Kantowski-Dyer-Roeder (ZKDR) approach which is phenomenologically characterized by a smoothness parameter $\alpha$, we rediscuss the constraints on the cosmic parameters based on Supernovae type Ia and Gamma-Ray Bursts (GRBs) data. The present analysis is restricted to a flat $\Lambda$CDM model with the reasonable assumption that $\Lambda$ does not clump. A $\chi^{2}$-analysis using 557 SNe Ia data from the Union2 Compilation Data (Amanullah {\it et al.} 2010) constrains the pair of parameters ($\Omega_m, \alpha$) to $\Omega_m=0.27_{-0.03}^{+0.08}$($2\sigma$) and $\alpha \geq 0.25$. A similar analysis based only on 59 Hymnium GRBs (Wei 2010) constrains the matter density parameter to be $\Omega_m= 0.35^{+0.62}_{-0.24}$ ($2\sigma$) while all values for the smoothness parameter are allowed. By performing a joint analysis, it is found that $\Omega_m = 0.27^{+0.06}_{-0.03}$ and $\alpha \geq 0.52$. As a general result, although considering that current GRB data alone cannot constrain the smoothness $\alpha$ parameter our analysis provides an interesting cosmological probe for dark energy even in the presence of inhomogeneities.Comment: 7 pages, 4 figures, corrected version accepted for publication in Physical Review

Additive effect of LRP8/APOER2 R952Q variant to APOE ε2/ε3/ε4 genotype in modulating apolipoprotein E concentration and the risk of myocardial infarction: a case-control study

BACKGROUND: The R952Q variant in the low density lipoprotein receptor-related protein 8 (LRP8)/apolipoprotein E receptor 2 (ApoER2) gene has been recently associated with familial and premature myocardial infarction (MI) by means of genome-wide linkage scan/association studies. We were interested in the possible interaction of the R952Q variant with another established cardiovascular genetic risk factor belonging to the same pathway, namely apolipoprotein E (APOE) epsilon2/epsilon3/epsilon4 genotype, in modulating apolipoprotein E (ApoE) plasma levels and risk of MI. METHODS: In the Italian cohort used to confirm the association of the R952Q variant with MI, we assessed lipid profile, apolipoprotein concentrations, and APOE epsilon2/epsilon3/epsilon4 genotype. Complete data were available for a total of 681 subjects in a case-control setting (287 controls and 394 patients with MI). RESULTS: Plasma ApoE levels decreased progressively across R952Q genotypes (mean levels +/- SD = RR: 0.045 +/- 0.020, RQ: 0.044 +/- 0.014, QQ: 0.040 +/- 0.008 g/l; P for trend = 0.047). Combination with APOE genotypes revealed an additive effect on ApoE levels, with the highest level observed in RR/non-carriers of the E4 allele (0.046 +/- 0.021 g/l), and the lowest level in QQ/E4 carriers (0.035 +/- 0.009 g/l; P for trend = 0.010). QQ/E4 was also the combined genotype with the most significant association with MI (OR 3.88 with 95\%CI 1.08-13.9 as compared with RR/non-carriers E4). CONCLUSION: Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population

Dark Energy Survey Year 1 results: the effect of intracluster light on photometric redshifts for weak gravitational lensing

We study the effect of diffuse intracluster light on the critical surface mass density estimated from photometric redshifts of lensing source galaxies, and the resulting bias in a weak lensing measurement of galaxy cluster mass. Under conservative assumptions, we find the bias to be negligible for imaging surveys like the Dark Energy Survey with a recommended scale cut of ≥200kpc distance from cluster centres. For significantly deeper lensing source galaxy catalogues from present and future surveys like the Large Synoptic Survey Telescope program, more conservative scale and source magnitude cuts or a correction of the effect may be necessary to achieve percent level lensing measurement accuracy, especially at the massive end of the cluster population

Dark Energy Survey Year 3 Results: Measuring the Survey Transfer Function with Balrog

We describe an updated calibration and diagnostic framework, Balrog, used to directly sample the selection and photometric biases of the Dark Energy Survey (DES) Year 3 (Y3) data set. We systematically inject onto the single-epoch images of a random 20% subset of the DES footprint an ensemble of nearly 30 million realistic galaxy models derived from DES Deep Field observations. These augmented images are analyzed in parallel with the original data to automatically inherit measurement systematics that are often too difficult to capture with generative models. The resulting object catalog is a Monte Carlo sampling of the DES transfer function and is used as a powerful diagnostic and calibration tool for a variety of DES Y3 science, particularly for the calibration of the photometric redshifts of distant "source" galaxies and magnification biases of nearer "lens" galaxies. The recovered Balrog injections are shown to closely match the photometric property distributions of the Y3 GOLD catalog, particularly in color, and capture the number density fluctuations from observing conditions of the real data within 1% for a typical galaxy sample. We find that Y3 colors are extremely well calibrated, typically within ∼1–8 mmag, but for a small subset of objects, we detect significant magnitude biases correlated with large overestimates of the injected object size due to proximity effects and blending. We discuss approaches to extend the current methodology to capture more aspects of the transfer function and reach full coverage of the survey footprint for future analyses

Clinical characteristics and outcomes of vaccinated patients hospitalised with SARS-CoV-2 breakthrough infection: Multi-IPV, a multicentre study in Northern Italy

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non -vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non -vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson's Chi-square and Mann -Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non -vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039-0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582-1.703, p = 0.987). Conclusions: This study provides real -world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first -booster uptake rates