12 research outputs found
The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor
Structural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp(2.50) and Asn(7.49) residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn(1.50(53)) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins
Genomic characterization of pediatric Bâlymphoblastic lymphoma and Bâlymphoblastic leukemia using formalinâfixed tissues
BackgroundRecurrent genomic changes in Bâlymphoblastic leukemia (BâALL) identified by genomeâwide singleânucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, Bâlymphoblastic lymphoma (BâLBL), is limited by the low incidence and lack of fresh tissue for genomic testing.ProcedureWe used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalinâfixed paraffinâembedded pediatric BâLBL (n = 23) and BâALL (n = 55).ResultsSimilar to BâALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) BâLBL cases. Eleven of 23 (48%) BâLBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of BâALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of BâLBL, respectively, which was similar to the reported frequency in BâALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) BâLBL cases, compared with only 1% in BâALL samples. None of the BâLBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of BâALL.ConclusionsOur study demonstrates that the copy number profile of BâLBL is distinct from BâALL, suggesting possible differences in pathogenesis between these closely related diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/1/pbc26363.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137353/2/pbc26363_am.pd
Incidence of SARS-CoV-2 in people with cystic fibrosis in Europe between February and June 2020
Background
Viral infections can cause significant morbidity in cystic fibrosis (CF). The current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic could therefore have a serious impact on the health of people with CF (pwCF).
Methods
We used the 38-country European Cystic Fibrosis Society Patient Registry (ECFSPR) to collect case data about pwCF and SARS-CoV-2 infection.
Results
Up to 30 June 2020, 16 countries reported 130 SARS-CoV-2 cases in people with CF, yielding an incidence of 2.70/1000 pwCF. Incidence was higher in lung-transplanted patients (n=23) versus non-transplanted patients (n=107) (8.43 versus 2.36 cases/1000). Incidence was higher in pwCF versus the age-matched general population in the age groups <15, 15-24, and 25-49 years (p<0.001), with similar trends for pwCF with and without lung transplant. Compared to the general population, pwCF (regardless of transplantation status) had significantly higher rates of admission to hospital for all age groups with available data, and higher rates of intensive care, although not statistically significant. Most pwCF recovered (96.2%), however 5 died, of whom 3 were lung transplant recipients. The case fatality rate for pwCF (3.85%, 95% CI: 1.26-8.75) was non-significantly lower than that of the general population (7.46%; p=0.133).
Conclusions
SARS-CoV-2 infection can result in severe illness and death for pwCF, even for younger patients and especially for lung transplant recipients. PwCF should continue to shield from infection and should be prioritized for vaccination