Variation in IGF2BP2 Interacts With Adiposity to Alter Insulin Sensitivity in Mexican Americans

Genome‐wide association studies showed variation in insulin‐like growth factor‐2 binding protein 2 (IGF2BP2) to be associated with type 2 diabetes mellitus (T2DM). We examined a 20‐kb region of IGF2BP2 for association with T2DM‐related quantitative traits in Mexican American families of a proband with gestational diabetes mellitus (GDM) from the BetaGene study. We genotyped 14 single‐nucleotide polymorphisms (SNPs) in 717 individuals from 146 families phenotyped by oral glucose tolerance test (OGTT), intravenous glucose tolerance tests (IVGTTs) with minimal model analysis, and dual‐energy X‐ray absorptiometry scan for percent body fat. Three SNPs and one SNP combination that captured the majority of the variation in the region were tested for association with T2DM‐related quantitative traits using a variance components framework. After correction for multiple testing, rs11705701 showed association with percent body fat (P_ACT = 0.041) with body fat decreasing ～1.5–2% per copy of the A allele. We next tested whether the interaction between rs11705701 and body fat was associated with T2DM‐relative quantitative traits. rs11705701 was significantly associated with insulin sensitivity (Bonferroni P = 0.028) and marginally associated with OGTT 2‐h insulin (Bonferroni P = 0.066) and disposition index (DI) (Bonferroni P = 0.072). We conclude that rs11705701 in IGF2BP2 is associated with body fat and this effect on body fat influences insulin resistance which may contribute to T2DM risk.     

Fluorous tolerance of the estrogen receptor alpha as probed by 11-polyfluoroalkylestradiol derivatives

The concern of this work was to try to delineate factors, inherent to fluorination, susceptible to influence estradiol binding to the estrogen receptor alpha (ERalpha). For this purpose, fluorinated chains were linked at 11beta position of the steroid (i.e., C(6)F(13), CH(2)CH(2)C(4)F(9), CH(2)CH(2)C(8)F(17)). Relative binding affinity (RBA) for ERalpha of these compounds and of other related fluorinated derivatives was compared to those of non-fluorinated analogs. Despite being relatively well accepted by the receptor, investigated compounds exhibited lower RBA values at 0 degrees C than their non-fluorinated counterparts. Nevertheless, heavily fluorinated chains were tolerated in so far as they are not too long (C-4) and insulated from the steroidal core by a two methylene spacer unit. Increase of the temperature of our binding assay (25 degrees C) failed to change the RBA values of two selected polyfluorohexyl derivatives while it drastically enhanced the value of the corresponding non-fluorinated analogs. Rigidity of the chain induced by fluorination as well as the oleophilic (fluorophobic) nature of the estradiol binding cavity of ERalpha is proposed to explain these properties.     

Lysophosphatidic acid generation by pulmonary NKT cell ENPP-2/autotaxin exacerbates hyperoxic lung injury

Hyperoxia is still broadly used in clinical practice in order to assure organ oxygenation in critically ill patients, albeit known toxic effects. In this present study, we hypothesize that lysophosphatidic acid (LPA) mediates NKT cell activation in a mouse model of hyperoxic lung injury. In vitro, pulmonary NKT cells were exposed to hyperoxia for 72 h, and the induction of the ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP-2) was examined and production of lysophosphatidic acid (LPA) was measured. In vivo, animals were exposed to 100 % oxygen for 72 h and lungs and serum were harvested. Pulmonary NKT cells were then incubated with the LPA antagonist Brp-LPA. Animals received BrP-LPA prior to oxygen exposure. Autotaxin (ATX, ENPP-2) was significantly up-regulated on pulmonary NKT cells after hyperoxia (p < 0.01) in vitro. LPA levels were increased in supernatants of hyperoxia-exposed pulmonary NKT cells. LPA levels were significantly reduced by incubating NKT cells with LPA-BrP during oxygen exposure (p < 0,05) in vitro. Hyperoxia-exposed animals showed significantly increased serum levels of LPA (p ≤ 0,05) as well as increased pulmonary NKT cell numbers in vivo. BrP-LPA injection significantly improved survival as well as significantly decreased lung injury and lowered pulmonary NKT cell numbers. We conclude that NKT cell-induced hyperoxic lung injury is mediated by pro-inflammatory LPA generation, at least in part, secondary to ENPP-2 up-regulation on pulmonary NKT cells. Being a potent LPA antagonist, BrP-LPA prevents hyperoxia-induced lung injury in vitro and in vivo.     

Identification and characterization of naturally occurring variants of the macrophage scavenger receptor (SR-A)

The scavenger receptor (SR) family comprises a group of cell surface proteins functionally defined by their ability to bind chemically modified lipoproteins. In macrophages, the class A Type I and Type II SRs (SR-AI/II) are thought to play a key role in adherence to and phagocytosis of infectious agents. Immunoprecipitation studies show that the rat anti-SR-AI/II monoclonal antibody 2F8 detects the mature, trimeric form of the receptor expressed in peritoneal macrophages from A/J, but not from C57Bl/6J (B6) mice. Subsequent sequencing of cDNA and genomic clones indicates that SR-AI and AII of A/J and B6 mice differ in sequence at nine positions, two in the cytoplasmic domain and seven in the extracellular spacer and α-helical coiled coil domains. These sequence polymorphisms are non-conservative and produce distinct receptor molecules that differ by four charged residues and alter recognition of the receptor by the monoclonal 2F8 antibody. The B6 SR-AI/II haplotype appears unique, since most inbred strains analyzed show the A/J-type haplotype. Interestingly, several of the B6 polymorphic variant residues are conserved in human and bovine receptors, suggesting a recent divergence of the A/J haplotype. Initial studies in CHO-derived cells expressing individual receptor isoforms indicate that the A/J and B6 receptors are stable and can mature into oligomers expressed in the membrane fractions of these cells. In these transfectants, no major functional differences were detected between receptors of the two haplotypes with respect to internalization and degradation of ¹²⁵I-labeled acetylated LDL. However, since SR-AI/II recognizes a large number of structurally unrelated anionic molecules, the possibility that different haplotypes may affect either binding and release of other ligands, or receptor recycling, cannot be excluded. Received: 11 January 2000 / Accepted: 30 March 2000     

Differences in mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine immunogenicity among patients undergoing dialysis

Background:Differences in immunogenicity between mRNA SARS-CoV-2 vaccines have not been well characterized in patients undergoing dialysis. We compared the serologic response in patients undergoing maintenance hemodialysis after vaccination against SARS-CoV-2 with BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna).Methods:We conducted a prospective observational cohort study at 2 academic centres in Toronto, Canada, from Feb. 2, 2021, to July 20, 2021, which included 129 and 95 patients who received the BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines, respectively. We measured SARS-CoV-2 immunoglobulin G antibodies to the spike protein (anti-spike), receptor binding domain (anti-RBD) and nucleocapsid protein (anti-NP) at 6–7 and 12 weeks after the second dose of vaccine and compared those levels with the median convalescent serum antibody levels from 211 controls who were previously infected with SARS-CoV-2.Results:At 6–7 weeks after 2-dose vaccination, we found that 51 of 70 patients (73%) who received BNT162b2 and 83 of 87 (95%) who received mRNA-1273 attained convalescent levels of anti-spike antibody (p < 0.001). In those who received BNT162b2, 35 of 70 (50%) reached the convalescent level for anti-RBD compared with 69 of 87 (79%) who received mRNA-1273 (p < 0.001). At 12 weeks after the second dose, anti-spike and anti-RBD levels were significantly lower in patients who received BNT162b2 than in those who received mRNA-1273. For anti-spike, 70 of 122 patients (57.4%) who received BNT162b2 maintained the convalescent level versus 68 of 71 (96%) of those who received mRNA-1273 (p < 0.001). For anti-RBD, 47 of 122 patients (38.5%) who received BNT162b2 maintained the anti-RBD convalescent level versus 45 of 71 (63%) of those who received mRNA-1273 (p = 0.002).Interpretation:In patients undergoing hemodialysis, mRNA-1273 elicited a stronger humoral response than BNT162b2. Given the rapid decline in immunogenicity at 12 weeks in patients who received BNT162b2, a third dose is recommended in patients undergoing dialysis as a primary series, similar to recommendations for other vulnerable populations.

Patients with end-stage kidney disease who are receiving maintenance hemodialysis (HD) are at increased risk for severe COVID-19, with mortality rates ranging from 9% to 28%.^1,2 Highly effective vaccines have been developed against SARS-CoV-2, with 94.1%–95% efficacy in reducing the risk of severe COVID-19 (D614G strain) as confirmed by 2 large randomized controlled trials; however, these studies included limited numbers of patients with kidney disease.^3,4 Humoral response to vaccination appears to be heterogeneous in dialysis patients in comparison with the general population, and a review of 35 studies involving dialysis patients found that in the 1-month period after 2-dose vaccination, seroconversion rates ranged from 70% to 96%.⁵The BNT162b2 (Pfizer BioNTech) and mRNA-1273 (Moderna) SARS-CoV-2 vaccines are both lipid nanoparticle-encapsulated, nucleoside-modified mRNA encoding for the full-length SARS-CoV-2 spike protein stabilized in its prefusion conformation. The BNT162b2 vaccine is administered as a 30 μg dose 21 days apart and mRNA-1273 is administered as a 100 μg dose 28 days apart.^3,4 The spike protein and its receptor-binding domain of SARS-CoV-2 are antigens that are targeted by the currently available vaccines and are used as measures of humoral response to vaccination or natural infection. An antibody response to the amount of nucleocapsid protein (NP), which is not targeted by mRNA SARS-CoV-2 vaccines, may be used as a marker of natural exposure to SARS-CoV-2.Recognition of the high morbidity and mortality from COVID-19 and reduced immunogenicity to vaccination against SARS-CoV-2 in patients undergoing HD has resulted in the prioritization of vaccination of this population in many jurisdictions.^1,6 However, differences in immunogenicity among SARS-CoV-2 vaccines have not been well characterized in this vulnerable population. Therefore, we conducted a prospective observational study in a cohort of patients undergoing dialysis who received either the mRNA-1273 or BNT162b2 vaccine to evaluate humoral response through comparison of spike and receptor-binding domain antibodies in response to 2-dose vaccination.