Synthesis and characterization of new alkoxide and aryloxide derivatives of titanium and zirconium. X-ray molecular structure of [ZrCp2(OC6F5)2]

Lithium or sodium alkoxides MOR (R double bond; length as m-dashCH2CHdouble bond; length as m-dashCMe2; M double bond; length as m-dash Li1; Na2; R double bond; length as m-dash C6F5; M double bond; length as m-dash Li3 were prepared by reaction of the alcohols with n-butyl lithium or sodium metal in hexane. Reaction of a hexane suspension of3 with SiClMe, afforded SiMe3(OC6F5)4, whereas the reaction of 3 equivalents of C6F5OH with AlMe3 in hexane led to Al(OC6F5)35. Compounds1 or2 react with one equivalent of [TiCp*Cl2Me] (Cp*double bond; length as m-dash C5Me5) in toluene to give [TiCp*ClMe(OCH2CHdouble bond; length as m-dashCMe2)]6. Complex6 reacts with AlEtCl2 to give quantitatively [TiCp*Cl3]. In the presence of water, the hydrolysis of6 takes palce giving the μ-oxo compound [{(TiCp*Cl)(μ − O)}3]. [TiCp*Cl2Me] reacted with an excess of the alcohol C6F5OH to give [TiCp*(OC6F5)3]7. [ZrCp2Cl2] reacted with two equivalents of pentaflurophenol in the presence of aniline to give the dialkoxide [ZrCp2(OC6F5)2]8. When the same reaction was carried out in a 1:1 molar ratio, a mixture of8 and the chloroalkoxide [ZrCp2Cl(OC6F5)]9 was obtained. A cleac reaction takes place when the μ-oxo compound [(ZrCp2Me)2(μ-O)] is treated with two equivalents of pentaflurophenol, leading to the isolation of the alkoxo complex [{ZrCp2(OC6F5)}2(μ-O)]10. The methylalkoxo derivative [ZrCp2Me(OC6F5)]11, was obtained by rection of [ZrCp2ClMe] with one equivalent of3. Alternative methods can be also be followed to synthesize8 and11. The crystal and molecular structure of8 has been determined by X-ray diffraction methods. The most interesting feature of this structure is the disposition of the (C6F5) ring planes, which are located practically on the reflection plane defined by O(1), Zr(1) and O(1)′

Genetically modified NT2N human neuronal cells mediate long-term gene expression as CNS grafts in vivo and improve functional cognitive outcome following experimental traumatic brain injury

Human Ntera-2 (NT2) cells can be differentiated in vitro into well-characterized Populations of NT2N neurons that engraft and mature when transplanted into the adult CNS of rodents and humans. Them ha e shown promise as treatments for neurologic disease, trauma, and ischemic stroke. Although these features suggest that NT2N neurons would be an excellent platform for ex vivo gene therapy in the CNS, stable gene expression has been surprisingly difficult to achieve in these cells. In this report we demonstrate stable, efficient. and nontoxic gene transfer into undifferentiated NT2 cells using a pseudotyped lentiviral vector encoding the human elongation factor 1-alpha promoter and the reporter gene eGFP, Expression of eGFP was maintained when the NT2 cells were differentiated into NT2N neurons after treatment with retinoic acid, When transplanted into the striatum of adult nude mice, transduced NT2N neurons survived, engrafted, and continued to express the reporter gene for long-term time points in vivo. Furthermore. transplantation of NT2N neurons genetically modified to express nerve growth factor significantly attenuated cognitive dysfunction following traumatic brain injure in mice. These results demonstrate that defined populations of genetically modified human NT2N neurons are a practical and effective platform for stable ex vivo gene delivery into the CNS

Evolution of the use of corticosteroids for the treatment of hospitalised COVID-19 patients in Spain between March and November 2020: SEMI-COVID national registry

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID- 19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years; p < 0.001), with hypertension (57.0% vs. 47.7%; p < 0.001), obesity (26.4% vs. 19.3%; p < 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%; p < 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7-160) vs. 49.3 (16-109) mg/dL; p < 0.001), ferritin (791 (393-1534) vs. 470 (236- 996) µg/dL; p < 0.001), D dimer (750 (430-1400) vs. 617 (345-1180) µg/dL; p < 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101); p < 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September; p < 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation </=90%

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice.

The ability of brain-derived neurotrophic factor (BDNF) to attenuate secondary damage and influence behavioral outcome after experimental traumatic brain injury (TBI) remains controversial. Because TBI can result in decreased expression of the trkB receptor, thereby preventing BDNF from exerting potential neuroprotective effects, the contribution of both BDNF and its receptor trkB to hippocampal neuronal loss and cognitive dysfunction were evaluated. METHODS: Full-length trkB was overexpressed in the left hippocampus of adult C57Bl/6 mice using recombinant adeno-associated virus serotype 2/5 (rAAV 2/5). EGFP (enhanced green fluorescent protein) expression was present at two weeks after AAV-EGFP injection and remained sustained up to four weeks after the injection. At 2 weeks following gene transduction, mice were subjected to parasagittal controlled cortical impact (CCI) brain injury, followed by either BDNF or PBS infusion into the hippocampus. RESULTS: No differences were observed in learning ability at two weeks post-injury or in motor function from 48 hours to two weeks among treatment groups. The number of surviving pyramidal neurons in the CA2-CA3 region of the hippocampus was also not different among treatment groups. CONCLUSIONS: These data suggest that neither overexpression of trkB, BNDF infusion or their combination affects neuronal survival or behavioral outcome following experimental TBI in mic

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease