The gene transformer-2 of Anastrepha fruit flies (Diptera, Tephritidae) and its evolution in insects

<p>Abstract</p> <p>Background</p> <p>In the tephritids <it>Ceratitis</it>, <it>Bactrocera </it>and <it>Anastrepha</it>, the gene <it>transformer </it>provides the memory device for sex determination via its auto-regulation; only in females is functional Tra protein produced. To date, the isolation and characterisation of the gene <it>transformer-2 </it>in the tephritids has only been undertaken in <it>Ceratitis</it>, and it has been shown that its function is required for the female-specific splicing of <it>doublesex </it>and <it>transformer </it>pre-mRNA. It therefore participates in <it>transformer </it>auto-regulatory function. In this work, the characterisation of this gene in eleven tephritid species belonging to the less extensively analysed genus <it>Anastrepha </it>was undertaken in order to throw light on the evolution of <it>transformer-2</it>.</p> <p>Results</p> <p>The gene <it>transformer-2 </it>produces a protein of 249 amino acids in both sexes, which shows the features of the SR protein family. No significant partially spliced mRNA isoform specific to the male germ line was detected, unlike in <it>Drosophila</it>. It is transcribed in both sexes during development and in adult life, in both the soma and germ line. The injection of <it>Anastrepha transformer-2 </it>dsRNA into <it>Anastrepha </it>embryos caused a change in the splicing pattern of the endogenous <it>transformer </it>and <it>doublesex </it>pre-mRNA of XX females from the female to the male mode. Consequently, these XX females were transformed into pseudomales. The comparison of the eleven <it>Anastrepha </it>Transformer-2 proteins among themselves, and with the Transformer-2 proteins of other insects, suggests the existence of negative selection acting at the protein level to maintain Transformer-2 structural features.</p> <p>Conclusions</p> <p>These results indicate that <it>transformer-2 </it>is required for sex determination in <it>Anastrepha </it>through its participation in the female-specific splicing of <it>transformer </it>and <it>doublesex </it>pre-mRNAs. It is therefore needed for the auto-regulation of the gene <it>transformer</it>. Thus, the <it>transformer/transfomer-2 > doublesex </it>elements at the bottom of the cascade, and their relationships, probably represent the ancestral state (which still exists in the Tephritidae, Calliphoridae and Muscidae lineages) of the extant cascade found in the Drosophilidae lineage (in which <it>tra </it>is just another component of the sex determination gene cascade regulated by <it>Sex-lethal</it>). In the phylogenetic lineage that gave rise to the drosophilids, evolution co-opted for <it>Sex-lethal</it>, modified it, and converted it into the key gene controlling sex determination.</p

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Rotational radiotherapy of breast cancer with polyenergetic kilovoltage X-ray beams: An experimental and Monte Carlo phantom study

Purpose We investigated the feasibility of kilovoltage rotational radiotherapy for breast cancer (kV-EBRT) via Monte Carlo simulations and measurements on phantoms. Methods We derived the dose distributions for X-ray beams at 150 kV, 300 kVp and 320 kV irradiating breast cylindrical phantoms of 14 cm diameter, mimicking the pendant breast. Simulations were based on the Geant4 toolkit. The point-like X-ray source was rotated either over a full circle or on a limited arc around the phantom. We studied the influence on the surface dose of the distance between the tumor lesion to the skin, of the irradiation protocol (full scan or partial scan) and of the X-ray tube current modulation. Results Rotational kV-EBRT permitted a periphery-to-center dose ratio from 13% to 9% in homogeneous breast phantoms. Dose distributions in phantoms with off-center simulated lesions, showed a skin-to-tumor dose ratio of 16% and 34% for lesions at 3.25 and 5.25 cm from cylinder axis, respectively. Simulation of the X-ray tube current modulation during the rotation, permits to reach a dose ratio of 20% for the lesion located at 5.25 cm from phantom axis. Conclusions We showed the possibility of using low-energy X-ray spectra for kV-EBRT with collimated beams, for obtaining a periphery-to-center dose ratio in the same order of conventional accelerator based megavoltage radiotherapy, when the irradiated area is localized in the center of the breast. For tumors localized near the breast border, we showed that the tube current modulation can be a good solution in order to reduce the skin-to-tumor dose ratio

Hepatic arterial embolization in patients with neuroendocrine tumors.

Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient's quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases