Novel genetic variants associated with lumbar disc degeneration in northern Europeans: A meta-analysis of 4600 subjects

Objective: Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. Methods: We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. Results: This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10-8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10-8) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10-4, p=0.006). Conclusions: LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway. Copyright Article author (or their employer) 2012

Retrieval of Context-Associated Memory is Dependent on the Cav3.2 T-Type Calcium Channel

Among all voltage-gated calcium channels, the T-type Ca2+ channels encoded by the Cav3.2 genes are highly expressed in the hippocampus, which is associated with contextual, temporal and spatial learning and memory. However, the specific involvement of the Cav3.2 T-type Ca2+ channel in these hippocampus-dependent types of learning and memory remains unclear. To investigate the functional role of this channel in learning and memory, we subjected Cav3.2 homozygous and heterozygous knockout mice and their wild-type littermates to hippocampus-dependent behavioral tasks, including trace fear conditioning, the Morris water-maze and passive avoidance. The Cav3.2 −/− mice performed normally in the Morris water-maze and auditory trace fear conditioning tasks but were impaired in the context-cued trace fear conditioning, step-down and step-through passive avoidance tasks. Furthermore, long-term potentiation (LTP) could be induced for 180 minutes in hippocampal slices of WTs and Cav3.2 +/− mice, whereas LTP persisted for only 120 minutes in Cav3.2 −/− mice. To determine whether the hippocampal formation is responsible for the impaired behavioral phenotypes, we next performed experiments to knock down local function of the Cav3.2 T-type Ca2+ channel in the hippocampus. Wild-type mice infused with mibefradil, a T-type channel blocker, exhibited similar behaviors as homozygous knockouts. Taken together, our results demonstrate that retrieval of context-associated memory is dependent on the Cav3.2 T-type Ca2+ channel

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

Abstract: The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Guava Seed Oil: Potential Waste for the Rhamnolipids Production

Guava is consumed in natura and is also of considerable importance to the food industry. The seeds and peel of this fruit are discarded, however, guava seeds yield oil (~13%) that can be used for the bioproducts synthesis. The use of a by-product as a carbon source is advantageous, as it reduces the environmental impact of possible harmful materials to nature, while adding value to products. In addition, the use of untested substrates can bring new yield and characterization results. Thus, this research sought to study rhamnolipids (RLs) production from guava seed oil, a by-product of the fructorefinery. The experiments were carried out using Pseudomonas aeruginosa LBI 2A1 and experimental design was used to optimize the variables Carbon and Nitrogen concentration. Characterization of RLs produced occurred by LC-MS. In this study, variables in the quadratic forms and the interaction between them influenced the response (p &lt; 0.05). The most significant variable was N concentration. Maximum RLs yield achieved 39.97 g/L, predominantly of mono-RL. Characterization analysis revealed 9 homologues including the presence of RhaC10C14:2 (m/z 555) whose structure has not previously been observed. This research showed that guava seed oil is an alternative potential carbon source for rhamnolipid production with rare rhamnolipid homologues

Guava Seed Oil: Potential Waste for the Rhamnolipids Production

Guava is consumed in natura and is also of considerable importance to the food industry. The seeds and peel of this fruit are discarded, however, guava seeds yield oil (~13%) that can be used for the bioproducts synthesis. The use of a by-product as a carbon source is advantageous, as it reduces the environmental impact of possible harmful materials to nature, while adding value to products. In addition, the use of untested substrates can bring new yield and characterization results. Thus, this research sought to study rhamnolipids (RLs) production from guava seed oil, a by-product of the fructorefinery. The experiments were carried out using Pseudomonas aeruginosa LBI 2A1 and experimental design was used to optimize the variables Carbon and Nitrogen concentration. Characterization of RLs produced occurred by LC-MS. In this study, variables in the quadratic forms and the interaction between them influenced the response (p 10C14:2 (m/z 555) whose structure has not previously been observed. This research showed that guava seed oil is an alternative potential carbon source for rhamnolipid production with rare rhamnolipid homologues