Lipidome alterations in human prefrontal cortex during development, aging, and cognitive disorders.

Lipids are essential to brain functions, yet they remain largely unexplored. Here we investigated the lipidome composition of prefrontal cortex gray matter in 396 cognitively healthy individuals with ages spanning 100 years, as well as 67 adult individuals diagnosed with autism (ASD), schizophrenia (SZ), and Down syndrome (DS). Of the 5024 detected lipids, 95% showed significant age-dependent concentration differences clustering into four temporal stages, and resulting in a gradual increase in membrane fluidity in individuals ranging from newborn to nonagenarian. Aging affects 14% of the brain lipidome with late-life changes starting predominantly at 50-55 years of age-a period of general metabolic transition. All three diseases alter the brain lipidome composition, leading-among other things-to a concentration decrease in glycerophospholipid metabolism and endocannabinoid signaling pathways. Lipid concentration decreases in SZ were further linked to genetic variants associated with disease, indicating the relevance of the lipidome changes to disease progression.

Immunogenicity and safety of a recombinant adenovirus type-5 COVID-19 vaccine in adults: Data from a randomised, double-blind, placebo-controlled, single-dose, phase 3 trial in Russia.

BACKGROUND: To determine the immunogenicity, efficacy, reactogenicity, and safety of a single dose of recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV, 5 × 1010 viral particles per 0.5 mL dose), we conducted a single-dose, randomised, double-blind, placebo-controlled, parallel group (3:1 Ad5-nCoV:placebo), phase 3 trial (Prometheus). METHODS: From 11-September-2020 to 05-May-2021, across six sites in the Russian Federation, 496 participants were injected with either placebo or Ad5-nCoV expressing the full-length spike (S) protein from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: Seroconversion (the primary endpoint) rates of 78.5% (95% CI: 73.9; 82.6) against receptor binding domain (RBD), 90.6% (95% CI: 87.2; 93.4) against S protein and 59.0% (95% CI: 53.3; 64.6) seroconversion of neutralising antibodies against SARS-CoV-2 at 28 days post-vaccination were observed. Geometric mean titres (GMTs) were also elevated for antibodies against the RBD (405 [95% CI: 366; 449]) and S protein (677 [95% CI: 608; 753]) compared to the GMT of neutralising antibodies against SARS-CoV-2 (16.7 [95% CI: 15.3; 18.3]). Using an IFN-γ ELISpot assay after stimulating the cells with recombinant S protein ectodomain we showed that the Ad5-nCoV vaccine induced the most robust cellular immune response on Days 14 and 28. Up to Day 28, the primary and all secondary endpoints of the Ad5-nCoV vaccine were statistically significant compared with the placebo (р<0.001). Systemic reactions were reported in 113 of 496 (22.8%) participants (Ad5-nCoV, 26.9%; Placebo, 10.5%), and local reactions were reported in 108 (21.8%) participants (Ad5-nCoV, 28.5%; Placebo, 1.6%). These were generally mild and resolved within 7 days after vaccination. Of the six serious adverse events reported, none of the events were vaccine related. There were no deaths or premature withdrawals. CONCLUSION: A single-dose of Ad5-nCoV vaccine induced a marked specific humoral and cellular immune response with a favourable safety profile. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov: NCT04540419.

Risk modeling of femoral neck fracture based on geometric parameters of the proximal epiphysis.

BACKGROUND: Fractures of the proximal femur epiphysis are problematic for state health care because they are associated with severe medical and social problems and high morbidity and mortality rates. AIM: To model the potential risk of hip fracture via femur geometric parameters. METHODS: Seventy educational cadaveric femurs from people aged 14 to 80 years, 10 X-ray images from the records of the Human Anatomy Department and 10 X-ray images from the Department of Traumatology, Orthopedics and Disaster Surgery of Sechenov University, were evaluated. The parameters of the fractured bone were measured using images captured with a Canon d60 camera. The projection values of the proximal epiphysis of the cadaveric femurs and geometric parameters of the bones shown in the X-ray images were measured with Autodesk software (AutoCAD 2018). Analysis of the video frames showing bone rotation reveal that the greater trochanter can be inscribed in a parallelepiped, where one of the faces is parallel to the plane of view in the frontal standard projection and is rectangular. The angle of bone rotation obtained by turning the cube corresponded to the angle measured with the second technique. This reliable method of calculating the rotation of the bone relative to the anterior projection was employed in subsequent calculations. The geometric parameters of the femur were measured using X-ray images according to the proposed method. RESULTS: The geometric parameters of 70 femurs were analyzed, and correlation coefficients were calculated. Our measurement results were compared with those reported by other authors. The potential influence of femur geometry on force distribution in the proximal epiphysis of the femur was described, and a 2-dimensional model of the femur epiphysis associated with minimal neck fracture risk was provided. The assessment of the geometric parameters of the femoral epiphysis indicated the greatest risk of a varus fracture of the neck if the angle of the minimal resistance zone (AMRZ) index > 24° and the neck-shaft angle (NSA) < 127.5°. In contrast, the minimum risk was observed at AMRZ < 14° and NSA > 128.87°. CONCLUSION: The proposed method provides the potential femur neck fracture risk based on geometric parameters.

Differences in lipidome and metabolome organization of prefrontal cortex among human populations.

Human populations, despite their overwhelming similarity, contain some distinct phenotypic, genetic, epigenetic, and gene expression features. In this study, we explore population differences at yet another level of molecular phenotype: the abundance of non-polar and polar low molecular weight compounds, lipids and metabolites in the prefrontal cortical region of the brain. We assessed the abundance of 1,670 lipids and 258 metabolites in 146 Han Chinese, 97 Western European, and 60 African American individuals of varying ages, covering most of the lifespan. The statistical analysis and logistic regression models both demonstrated extensive lipid and metabolic divergence of the Han Chinese individuals from the other two populations. This divergence was age-dependent, peaking in young adults, and involved metabolites and lipids clustering in specific metabolic pathways.

Metabolome signature of autism in the human prefrontal cortex.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with yet incompletely uncovered molecular determinants. Alterations in the abundance of low molecular weight compounds (metabolites) in ASD could add to our understanding of the disease. Indeed, such alterations take place in the urine, plasma and cerebellum of ASD individuals. In this work, we investigated mass-spectrometric signal intensities of 1,366 metabolites in the prefrontal cortex grey matter of 32 ASD and 40 control individuals. 15% of these metabolites showed significantly different intensities in ASD and clustered in 16 metabolic pathways. Of them, ten pathways were altered in urine and blood of ASD individuals (Fisher test, p < 0.05), opening an opportunity for the design of new diagnostic instruments. Furthermore, metabolic measurements conducted in 40 chimpanzees and 40 macaques showed an excess of metabolite intensity differences unique to humans, supporting the hypothesized disruption of evolutionary novel cortical mechanisms in ASD.