Potential health risks of mRNA-based vaccine therapy: A hypothesis.

Therapeutic applications of synthetic mRNA were proposed more than 30 years ago, and are currently the basis of one of the vaccine platforms used at a massive scale as part of the public health strategy to get COVID-19 under control. To date, there are no published studies on the biodistribution, cellular uptake, endosomal escape, translation rates, functional half-life and inactivation kinetics of synthetic mRNA, rates and duration of vaccine-induced antigen expression in different cell types. Furthermore, despite the assumption that there is no possibility of genomic integration of therapeutic synthetic mRNA, only one recent study has examined interactions between vaccine mRNA and the genome of transfected cells, and reported that an endogenous retrotransposon, LINE-1 is unsilenced following mRNA entry to the cell, leading to reverse transcription of full length vaccine mRNA sequences, and nuclear entry. This finding should be a major safety concern, given the possibility of synthetic mRNA-driven epigenetic and genomic modifications arising. We propose that in susceptible individuals, cytosolic clearance of nucleotide modified synthetic (nms-mRNAs) is impeded. Sustained presence of nms-mRNA in the cytoplasm deregulates and activates endogenous transposable elements (TEs), causing some of the mRNA copies to be reverse transcribed. The cytosolic accumulation of the nms-mRNA and the reverse transcribed cDNA molecules activates RNA and DNA sensory pathways. Their concurrent activation initiates a synchronized innate response against non-self nucleic acids, prompting type-I interferon and pro-inflammatory cytokine production which, if unregulated, leads to autoinflammatory and autoimmune conditions, while activated TEs increase the risk of insertional mutagenesis of the reverse transcribed molecules, which can disrupt coding regions, enhance the risk of mutations in tumour suppressor genes, and lead to sustained DNA damage. Susceptible individuals would then expectedly have an increased risk of DNA damage, chronic autoinflammation, autoimmunity and cancer. In light of the current mass administration of nms-mRNA vaccines, it is essential and urgent to fully understand the intracellular cascades initiated by cellular uptake of synthetic mRNA and the consequences of these molecular events.

Demographic histories and genetic diversity across pinnipeds are shaped by human exploitation, ecology and life-history.

A central paradigm in conservation biology is that population bottlenecks reduce genetic diversity and population viability. In an era of biodiversity loss and climate change, understanding the determinants and consequences of bottlenecks is therefore an important challenge. However, as most studies focus on single species, the multitude of potential drivers and the consequences of bottlenecks remain elusive. Here, we combined genetic data from over 11,000 individuals of 30 pinniped species with demographic, ecological and life history data to evaluate the consequences of commercial exploitation by 18th and 19th century sealers. We show that around one third of these species exhibit strong signatures of recent population declines. Bottleneck strength is associated with breeding habitat and mating system variation, and together with global abundance explains much of the variation in genetic diversity across species. Overall, bottleneck intensity is unrelated to IUCN status, although the three most heavily bottlenecked species are endangered. Our study reveals an unforeseen interplay between human exploitation, animal biology, demographic declines and genetic diversity.

Effects of polychlorinated biphenyls (PCB) on California sea lion (Zalophus californianus) lymphocyte functions upon in vitro exposure.

Polychorinated biphenyl (PCB) congeners are a cause for concern due to their persistence in the environment, their lipophilic properties that cause them to bio-accumulate in top predators, and their adverse effects on mammalian health. For example, the common urogenital carcinoma reported in California sea lions (Zalophus californianus) (CSL) is associated with high tissue levels of PCBs, but the mechanisms responsible for this association are unknown. This study investigated the effect of exposure to six PCB congeners and a congener mix at low and environmentally relevant concentrations on NK cell-like and T cell activity using in vitro assays on cryopreserved lymph node mononuclear cells isolated from dead CSL. Non dioxin-like congeners 153 and 180 increased lymphocyte proliferation at 5 and 10 ppm, while congener 138 decreased proliferation by up to 43% at 15 ppm. Dioxin-like PCBs 118 and 169 did not affect lymphocyte proliferation, while the effects of congener 105 depended on the mitogen concentration; these did not correlate with their predicted toxic equivalent factors. NK cell-like activity was affected only by the highest concentration of PCBs tested; it was increased by non-dioxin-like congeners 138 and 153, and decreased by dioxin-like congener 169. The PCB congener mix suggested that the effects of PCB congeners were not simply additive. Our results concur with effects of PCBs reported for other pinniped's lymphocytes and add further experimental support to the observation that dioxin-like PCBs are not the most toxic congeners for marine mammals, contrary to effects in other species. This is the first evidence of in vitro suppression of NK cell-like cytotoxicity by a dioxin-like congener in a pinniped. More importantly, the observed results suggest that PCBs can modulate the CSL immune system, increasing exposed individuals' susceptibility to viral and oncogenic challenges.

Changes in mucosal and serum immunoglobulin levels of California sea lions during early development.

To date, most studies on pinniped immunoglobulins have focused on circulating antibodies. However, systemic and local immune activities differ in terms of maturation, intensity, and types of effectors that participate. Here, we examined levels of three immunoglobulin isotypes, IgG, IgM and IgA, in the blood and mucosal membranes of free-living California sea lion pups. We investigated whether age, body condition and sex influenced their concentration. Isotype levels varied among tissues, with age-related patterns that could be indicative of differential regulation along development. Serum IgG and IgA increased linearly with age, reaching adult levels at five months of age, while IgM remained unchanged. Mucosal isotypes tended to be low in newborns and remained so until five months of age. Regardless of age, pups with better condition tended to have higher anal IgG levels and higher genital IgA levels, suggesting that their synthesis and transport to the mucosal membranes is costly. Intersex differences were only observed in the genital mucosa, where all isotypes differed between male and female pups, regardless of age, presumably due to histological and anatomical differences.

Relating professionalism and conscientiousness to develop an objective, scalar, proxy measure of professionalism in anaesthetic trainees.

BACKGROUND: The concept of professionalism is complex and subjective and relies on expert judgements. Currently, there are no existing objective measures of professionalism in anaesthesia. However, it is possible that at least some elements of professionalism may be indicated by objective measures. A number of studies have suggested that conscientiousness as a trait is a significant contributor to professionalism. METHODS: A 'Conscientiousness Index' (CI) was developed by collation of routinely collected data from tasks expected to be carried out by anaesthetic trainees such as punctual submission of holiday and 'not-on-call' requests, attendance at audit meetings, timely submission of completed appraisal documentation and sickness/absence notifications. The CI consists of a sum of points deducted from a baseline of 50 for non-completion of these objective and measurable behaviours related to conscientiousness. This was correlated with consultants' formal and informal subjective measures of professionalism in those trainees. Informal, subjective measures of professionalism consisted of a 'Professionalism Index' (PI). The PI consisted of a score developed from consultants' expert, subjective views of professionalism for those trainees. Formal, subjective measures of professionalism consisted of a score derived from comments made by consultants in College Tutor feedback forms on their views on the professionalism of those trainees (College Tutor feedback; CT). The PI and CT scores were correlated against the CI using a Pearson or Spearman correlation coefficient. RESULTS: There was a negative, but not statistically significant, relationship between the CI and formal, subjective measures of professionalism; CT scores (r = -0.341, p = 0.06), but no correlation between CI and consultants informal views of trainees' professionalism; the PI scores (r s = -0.059, p = 0.759). CONCLUSIONS: This may be due the 'failure to fail' phenomenon due to the high stakes nature of raising concerns of professionalism in postgraduate healthcare professionals or may be that the precision of the tool may be insufficient to distinguish between trainees who generally show highly professional behaviour. Future development of the tool may need to include more of the sub-facets of conscientiousness. Independently of a relationship with the construct of professionalism, a measure of conscientiousness might be of interest to future employers.

Increases in the longevity of desiccation-phase developing rice seeds: response to high-temperature drying depends on harvest moisture content.

BACKGROUND AND AIMS: Previous studies have suggested that the drying conditions routinely used by genebanks may not be optimal for subsequent seed longevity. The aim of this study was to compare the effect of hot-air drying and low-temperature drying on subsequent seed longevity for 20 diverse rice accessions and to consider how factors related to seed production history might influence the results. METHODS: Seeds of rice, Oryza sativa, were produced according to normal regeneration procedures at IRRI. They were harvested at different times [harvest date and days after anthesis (DAA), once for each accession] and dried either in a drying room (DR; 15 % relative humidity, 15 °C) or in a flat-bed heated-air batch dryer (BD; 45 °C, 8 h d(-1)) for up to six daily cycles followed by drying in the DR. Relative longevity was assessed by storage at 10·9 % moisture content and 45 °C. KEY RESULTS: Initial drying in the BD resulted in significantly greater longevity compared with the DR for 14 accessions (seed lots): the period of time for viability to fall to 50 % for seeds dried in the BD as a percentage of that for seeds dried throughout in the DR varied between 1.3 and 372·2 % for these accessions. The seed lots that responded the most were those that were harvested earlier in the season and at higher moisture content. Drying in the BD did not reduce subsequent longevity compared with DR drying for any of the remaining accessions. CONCLUSIONS: Seeds harvested at a moisture content where, according to the moisture desorption isotherm, they could still be metabolically active (>16·2 %) may be in the first stage of the post-mass maturity, desiccation phase of seed development and thus able to increase longevity in response to hot-air drying. The genebank standards regarding seed drying for rice and, perhaps, for other tropical species should therefore be reconsidered.

Vestibular schwannomas - when should conservative management be reconsidered?

OBJECTIVE: To document the natural history of vestibular schwannomas treated conservatively, and to find if there are any predictive factors for growth and need for active intervention. DESIGN: A retrospective review of patient notes and radiology, mostly MRIs. SUBJECTS: Eighty-eight patients managed conservatively for unilateral vestibular schwannoma and that have had at least two radiological investigations. OUTCOME MEASURES: Change in tumour size over time was evaluated. Linear and logistic regression, respectively, were used to determine which factors (of age, size at diagnosis, audiology at presentation, length of follow-up or growth within first year of follow-up) would predict overall growth and active intervention. Characteristics of those that required active intervention is also demonstrated. RESULTS: Of the 88 patients, the average size of schwannoma at diagnosis was 10.88 mm. The mean length of radiological follow-up was 3.65 years. 51.1% of schwannomas grew, 12.5% shrank and 36.4% remained the same size. The mean rate of growth was 1.24 mm per year. 25.0% failed conservative treatment, with 19 patients having stereotactic radiosurgery and three undergoing microsurgery. Only growth in the first year of follow-up was found to significantly predict total growth. Size at diagnosis and growth in first year of follow-up were significantly found to predict active intervention. CONCLUSIONS: There remains a place for conservative treatment in those with small tumours, the elderly and those with significant co-morbidities. Growth in the first year of follow-up should be considered in determining whether to treat actively or not.

Influence of methylmalonyl-CoA mutase alleles on resistance to bovine tuberculosis in the European wild boar (Sus scrofa).

An association study was carried out to examine the influence of methylmalonyl-CoA mutase (MUT) polymorphisms on the susceptibility of a well-studied wild boar population from southern Spain to develop bovine tuberculosis (bTB). To this end, we examined polymorphisms at a closely linked dinucleotide microsatellite flanking exon 2 of the MUT gene in 37 wild boars with bTB and 36 non-infected individuals. The microsatellite showed low polymorphism in the studied population, with only three alleles (MUTm-A, MUTm-B and MUTm-C) found, in contrast to the 11 alleles previously reported for domestic pigs. Our case-control study showed that the MUTm-B allele was associated with disease in a dominant pattern (odds ratio = 3.36; 95% CI = 1.05-10.72; P = 0.04), while the MUTm AA genotype appeared to have a protective effect against bTB infection (odds ratio = 4.33; 95% CI = 1.20-14.96; P = 0.02). Interestingly, infected wild boars heterozygous for MUTm AB are at an advantage (11-fold) to contain the systemic spread of the disease when compared to other genotypes, implying that a balanced polymorphism may be present in the population. These results strengthen previous observations regarding the importance of the MUT gene on bTB resistance in wild boars and indicate that polymorphisms at this locus will influence the risk of acquiring and maintaining bTB in the studied population.

Hepatic carcinoma with spleen metastasis in a California sea lion from the Gulf of California.

A primary hepatic carcinoma with a neuroendocrine pattern was detected in an adult female California sea lion (Zalophus californianus) found dead on Granito Island in the Gulf of California (Mexico) in January 1996. At necropsy, several light yellow nodules of different sizes were observed on the entire surface of the liver and spleen. Microscopic examination of these nodules using routine haematoxylin-eosin stain, revealed cubic, polyhedral and pleomorphic cells with three to four bizarre mitotic figures per field (40X). An immunohistochemistry test revealed a positive reaction of indirect immunoperoxide to cytokeratin (CK2). This is the first known case of a primary hepatic carcinoma in free-ranging California sea lions from Mexican waters.