Fut3 role in breast invasive ductal carcinoma: Investigating its gene promoter and protein expression.

Fucosylated glycans synthesized by α1,3/4-fucosyltransferase (FUT3) enzyme play an important role in breast cancer prognosis and metastasis, being involved in the binding of circulating tumor cells to the endothelium and being related to tumor stage, metastatic potential and chemoresistance. Despite the pro-tumor action of this enzyme, studies have demonstrated its role in natural killer-induced cytotoxicity through the recognition of sialyl Lewis X by C-type lectin receptors and through extrinsic apoptosis pathway triggered by Apo2L-TRAIL. This study aimed to investigate the expression pattern of FUT3 in invasive breast carcinoma (IDC) from patients of Pernambuco state, Northeast of Brazil, and genotype FUT3 promoter region to identify possible SNPs that could be associated with variations in FUT3 expression. Immunohistochemistry assay was used to access the FUT3 expression in normal (n=11) and tumor tissues (n=85). DNA sequencing was performed to genotype the FUT3 promoter region in patients with IDC (n=109) and healthy controls (n=110). Our results demonstrated that the absence of FUT3 enzyme is related to breast's IDC. The non-expression of FUT3 was more frequent in larger lesions and also in HER2 negative IDC tumors. Genomic analysis showed that two variations localized in FUT3 promoter region are possibly associated with IDC. Our results suggest that minor allele T of SNP rs73920070 (-6933 C>T) confers protection whereas minor allele T of SNP rs2306969 (-6951 C>T) triggers to susceptibility to IDC in the population of Pernambuco state, Northeast of Brazil.

Sterile protection against P. vivax malaria by repeated blood stage infection in the Aotus monkey model.

The malaria parasite Plasmodium vivax remains a major global public health challenge, and no vaccine is approved for use in humans. Here, we assessed whether P. vivax strain-transcendent immunity can be achieved by repeated infection in Aotus monkeys. Sterile immunity was achieved after two homologous infections, whereas subsequent heterologous challenge provided only partial protection. IgG levels based on P. vivax lysate ELISA and protein microarray increased with repeated infections and correlated with the level of homologous protection. Parasite transcriptional profiles provided no evidence of major antigenic switching upon homologous or heterologous challenge. However, we observed significant sequence diversity and transcriptional differences in the P. vivax core gene repertoire between the two strains used in the study, suggesting that partial protection upon heterologous challenge is due to molecular differences between strains rather than immune evasion by antigenic switching. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated homologous blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines.

A prenylated dsRNA sensor protects against severe COVID-19.

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.

Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides.

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10(-7) M PD123319, an AT(2) receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10(-6) M losartan, an antagonist of the AT(1) receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10(-8) M Ang II or 10(-8) M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7) M A779. 10(-6) M dibutyryl-cAMP increased the level of infection and 10(-7) M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.