The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.To investigate bone health and body composition in young women with long-duration type 1 diabetes (T1D) in relation to matched controls. Twenty-three Swedish women, age 19.2-27.9 years, with a T1D duration of 10 years or more were recruited from the Swedish National Diabetes Registry (NDR). An age-, gender- and geography-matched control group was recruited. Bone mass and body composition were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Data was retrieved from the NDR and SWEDIABKIDS registries. T1D individuals had a mean diabetes duration of 19 years. T1D individuals had reduced lean mass (40.0 ± 6.1 kg vs. 43.9 ± 4.9 kg) and were shorter (1.66 ± 0.06 m vs. 1.71 ± 0.06 m) although comparable BMI. Subjects with T1D had lower muscle area (P = 0.0045). No differences were observed for fractures; physical activity; total, lumbar spine or femur areal bone mineral density. The cortical bone strength strain index was lower for TD1 patients (1875 ± 399 mm3 vs. 2277 ± 332 mm3). In conclusion, young women with long-term diabetes duration showed reduced cortical bone strength, decreased periosteal circumference, endosteal circumference and altered body composition. These factors contribute to the health burden of TD1, which warrants further attention for advancing bone health in women with T1D.COVID-19 pandemic in Italy displayed a spatial distribution that made the tracking of its time course quite difficult. The most relevant anomaly was the marked spatial heterogeneity of COVID-19 diffusion. Lombardia region accounted for around 60% of fatal cases (while hosting 15% of Italian population). Moreover, 86% of fatalities concentrated in four Northern Italy regions. The ‘explosive’ outbreak of COVID-19 in Lombardia at the very beginning of pandemic fatally biased the R-like statistics routinely used to control the disease dynamics. To (at least partially) overcome this bias, we propose a new index RI = dH/dI (daily derivative ratio of H and I, given H = Healed and I = Infected), corresponding to the ratio between healed and infected patients relative daily changes. The proposed index is less flawed than R by the uncertainty related to the estimated number of infected persons and allows to follow (and possibly forecast) epidemic dynamics in a largely model-independent way. Tamoxifen To analyze the dynamics of tct the qualitatively different character of the ‘so-called’ second wave with respect to the previous epidemic peak.In vivo mutagenesis systems accelerate directed protein evolution but often show restricted capabilities and deleterious off-site mutations on cells. To overcome these limitations, here we report an in vivo platform to diversify specific DNA segments based on protein fusions between various base deaminases (BD) and the T7 RNA polymerase (T7RNAP) that recognizes a cognate promoter oriented towards the target sequence. Transcriptional elongation of these fusions generates transitions C to T or A to G on both DNA strands and in long DNA segments. To delimit the boundaries of the diversified DNA, the catalytically dead Cas9 (dCas9) is tethered with custom-designed crRNAs as a “roadblock” for BD-T7RNAP elongation. Using this T7-targeted dCas9-limited in vivo mutagenesis (T7-DIVA) system, rapid molecular evolution of the antibiotic resistance gene TEM-1 is achieved. While the efficiency is demonstrated in E. coli, the system can be adapted to a variety of bacterial and eukaryotic hosts.We aimed to analyse clinical characteristics and identify risk factors predicting all-cause mortality in older patients with severe coronavirus disease 2019 (COVID-19). A total of 281 older patients with severe COVID-19 were categorized into two age groups (60-79 years and ≥ 80 years). Epidemiological, clinical, and laboratory data, and outcome were obtained. Patients aged ≥ 80 years had higher mortality (63.6%) than those aged 60-79 years (33.5%). Anorexia and comorbidities including hypertension, diabetes and COPD, higher levels of lactate dehydrogenase (LDH), osmotic pressure, C-reactive protein, D-dimer, high-sensitivity troponin I and procalcitonin, and higher SOFA scores were more common in patients aged > 80 years than those aged 60-79 years and also more common and higher in non-survivors than survivors. LDH, osmotic pressure, C-reactive protein, D-dimer, high-sensitivity troponin I, and procalcitonin were positively correlated with age and sequential organ failure assessment (SOFA), whereas CD8+ and lymphocyte counts were negatively correlated with age and SOFA. Anorexia, comorbidities including hypertension, diabetes, and chronic obstructive pulmonary disease (COPD), LDH, osmotic pressure, and SOFA were significantly associated with 28-day all-cause mortality. LDH, osmotic pressure and SOFA were valuable for predicting 28-day all-cause mortality, whereas the area under the receiver operating characteristic curve of LDH was the largest, with sensitivity of 86.0% and specificity of 80.8%. Therefore, patients with severe COVID-19 aged ≥ 80 years had worse condition and higher mortality than did those aged 60-79 years, and anorexia and comorbidities including hypertension, diabetes, COPD, elevated plasma osmotic pressure, LDH, and high SOFA were independent risk factors associated with 28-day all-cause mortality in older patients with severe COVID-19. LDH may have the highest predictive value for 28-day all-cause mortality in all examined factors.