Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia ...and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.
To evaluate the benefit of next-generation sequencing (NGS)–based preimplantation genetic testing for aneuploidy (PGT-A) for embryo selection in frozen-thawed embryo transfer.
Randomized controlled ...trial.
Not applicable.
Women aged 25–40 years undergoing IVF with at least two blastocysts that could be biopsied.
Randomization for single frozen-thawed embryo transfer with embryo selection based on PGT-A euploid status versus morphology.
Ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer.
A total of 661 women (average age 33.7 ± 3.6 years) were randomized to PGT-A (n = 330) or morphology alone (n = 331). The OPR was equivalent between the two arms, with no significant difference per embryo transfer (50% 137/274 vs. 46% 143/313) or per intention to treat (ITT) at randomization (41.8% 138/330 vs. 43.5% 144/331). Post hoc analysis of women aged 35–40 years showed a significant increase in OPR per embryo transfer (51% 62/122 vs. 37% 54/145) but not per ITT.
PGT-A did not improve overall pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT. There was a significant increase in OPR per embryo transfer with the use of PGT-A in the subgroup of women aged 35–40 years who had two or more embryos that could be biopsied, but this was not significant when analyzed by ITT.
NCT02268786.
El diagnóstico genético preimplantacionalpara aneuploidías versus la morfología como criterio de selección para transferencia de un único embrión criopreservado en pacientes de buen pronóstico: un estudio clínico multicéntrico aleatorizado
Evaluar el beneficio de las nuevas técnicas de secuenciación (next-generation sequencing (NGS) aplicadas al diagnóstico genético preimplantatorio para aneuploidías (PGT-A) para la selección embrionaria en transferencias de embriones criopreservados.
Estudio controlado aleatorizado.
No aplica.
Mujeres entre 25-40 años que se sometieron a un ciclo de FIV en el que al menos pudieron ser biopsiados dos blastocistos.
Aleatorización para la transferencia de un embrión criopreservado con selección embrionaria basada en el estado euploide de PGT-A versus morfología.
Tasa de gestación evolutiva (OPR) hasta las 20 semanas por transferencia embrionaria.
Un total de 661 mujeres (edad media de 33.7 ± 3.6 años) fueron aleatorizadas para PGT-A (n=330) o solo morfología (n=331). La OPR fue equivalente entre los dos brazos, sin diferencia significativa por transferencia embrionaria (50% 137/274 vs. 46% 143/313) ni en la intención de tratar (ITT) en la aleatorización (41.8% 138/330 vs. 43.5% 144/331). Análisis post-hoc en mujeres entre 35-40 años mostró un aumento significativo en la OPR por transferencia embrionaria (51% 62/122 vs. 37% 54/145) pero no por la ITT.
PGT-A no mejoró los resultados generales de gestación en todas las mujeres, cuando se analizó por transferencia embrionaria o por ITT. Hubo un aumento significativo en la OPR por transferencia embrionaria con el uso de PGT-A en el subgrupo de mujeres de 35 a 40 años que tuvieron dos o más embriones para biopsiar, pero esto no fue significativo cuando fue analizado por ITT.
In this retrospective study, we measured enterovirus D68 (EV-D68) genomic RNA in wastewater solids longitudinally at 2 California, USA, wastewater treatment plants twice per week for 26 months. ...EV-D68 RNA was undetectable except when concentrations increased from mid-July to mid-December 2022, which coincided with a peak in confirmed EV-D68 cases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ghrelin O-acyltransferase (GOAT) plays a central role in the maturation and activation of the peptide hormone ghrelin, which performs a wide range of endocrinological signaling roles. Using a ...tight-binding fluorescent ghrelin-derived peptide designed for high selectivity for GOAT over the ghrelin receptor GHSR, we demonstrate that GOAT interacts with extracellular ghrelin and facilitates ligand cell internalization in both transfected cells and prostate cancer cells endogenously expressing GOAT. Coupled with enzyme mutagenesis, ligand uptake studies support the interaction of the putative histidine general base within GOAT with the ghrelin peptide acylation site. Our work provides a new understanding of GOAT’s catalytic mechanism, establishes that GOAT can interact with ghrelin and other peptides located outside the cell, and raises the possibility that other peptide hormones may exhibit similar complexity in their intercellular and organismal-level signaling pathways.
We performed a genome scan at an average resolution of 8 cM in 719 Finnish sib pairs with type 2 diabetes. Our strongest results are for chromosome 20, where we observe a weighted maximum LOD score ...(MLS) of 2.15 at map position 69.5 cM from pter and secondary weighted LOD-score peaks of 2.04 at 56.5 cM and 1.99 at 17.5 cM. Our next largest MLS is for chromosome 11 (MLS = 1.75 at 84.0 cM), followed by chromosomes 2 (MLS = 0.87 at 5.5 cM), 10 (MLS = 0.77 at 75.0 cM), and 6 (MLS = 0.61 at 112.5 cM), all under an additive model. When we condition on chromosome 2 at 8.5 cM, the MLS for chromosome 20 increases to 5.50 at 69.0 cM (
P=.0014). An ordered-subsets analysis based on families with high or low diabetes-related quantitative traits yielded results that support the possible existence of disease-predisposing genes on chromosomes 6 and 10. Genomewide linkage-disequilibrium analysis using microsatellite marker data revealed strong evidence of association for D22S423 (
P=.00007). Further analyses are being carried out to confirm and to refine the location of these putative diabetes-predisposing genes.
The current study adopts a relational vulnerability model to examine the association between hostile attribution bias and relational aggression. Specifically, the relational vulnerability model ...implicates the interactive effects of a number of relational risk factors in the development of relational aggression. A sample of 635 3rd, 4th, and 5th grade students (50.2% females) completed a self-report measure assessing hostile attribution bias and emotional distress for relational provocations. Peer nominations and teacher reports of relational aggression and relational victimization were also collected. Results supported the relational vulnerability model for girls only. Specifically, hostile attribution bias was associated with relational aggression only when relational victimization and emotional distress were also high. Implications for future research and clinical practice are discussed.
Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes–related quantitative traits in 580 Finnish ...families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score MLS = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.
A Large Set of Finnish Affected Sibling Pair Families With Type 2 Diabetes Suggests Susceptibility Loci on Chromosomes 6,
11, and 14
Kaisa Silander 1 ,
Laura J. Scott 2 ,
Timo T. Valle 3 ,
Karen L. ...Mohlke 1 ,
Heather M. Stringham 2 ,
Kerry R. Wiles 1 ,
William L. Duren 2 ,
Kimberly F. Doheny 4 ,
Elizabeth W. Pugh 4 ,
Peter Chines 1 ,
Narisu Narisu 1 ,
Peggy P. White 2 ,
Tasha E. Fingerlin 2 ,
Anne U. Jackson 2 ,
Chun Li 2 ,
Soumitra Ghosh 1 ,
Victoria L. Magnuson 1 ,
Kimberly Colby 1 ,
Michael R. Erdos 1 ,
Jason E. Hill 1 ,
Pablo Hollstein 1 ,
Kathleen M. Humphreys 1 ,
Roshni A. Kasad 1 ,
Jessica Lambert 1 ,
Konstantinos N. Lazaridis 1 ,
George Lin 1 ,
Anabelle Morales-Mena 1 ,
Kristin Patzkowski 1 ,
Carrie Pfahl 1 ,
Rachel Porter 1 ,
David Rha 1 ,
Leonid Segal 1 ,
Yong D. Suh 1 ,
Jason Tovar 1 ,
Arun Unni 1 ,
Christian Welch 1 ,
Julie A. Douglas 2 ,
Michael P. Epstein 2 ,
Elizabeth R. Hauser 2 ,
William Hagopian 5 ,
Thomas A. Buchanan 6 ,
Richard M. Watanabe 2 7 ,
Richard N. Bergman 8 ,
Jaakko Tuomilehto 3 9 ,
Francis S. Collins 1 and
Michael Boehnke 2
1 Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland
2 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
3 Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, and Department of Biochemistry, National
Public Health Institute, Helsinki, Finland
4 Center for Inherited Disease Research, Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
5 Pacific Northwest Research Institute, Seattle, Washington
6 Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
7 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
8 Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
9 Department of Public Health, University of Helsinki, Helsinki, Finland
Address correspondence and reprint requests to Michael Boehnke, PhD, Department of Biostatistics, School of Public Health,
University of Michigan, 1420 Washington Heights, Ann Arbor, Michigan 48109-2029. E-mail: boehnke{at}umich.edu
Abstract
The aim of the Finland-United States Investigation of NIDDM Genetics (FUSION) study is to identify genes that predispose to
type 2 diabetes or are responsible for variability in diabetes-related traits via a positional cloning and positional candidate
gene approach. In a previously published genome-wide scan of 478 Finnish affected sibling pair (ASP) families (FUSION 1),
the strongest linkage results were on chromosomes 20 and 11. We now report a second genome-wide scan using an independent
set of 242 Finnish ASP families (FUSION 2), a detailed analysis of the combined set of 737 FUSION 1 + 2 families (495 updated
FUSION 1 families), and fine mapping of the regions of chromosomes 11 and 20. The strongest FUSION 2 linkage results were
on chromosomes 6 (maximum logarithm of odds score MLS = 2.30 at 95 cM) and 14 (MLS = 1.80 at 57 cM). For the combined FUSION
1 + 2 families, three results were particularly notable: chromosome 11 (MLS = 2.98 at 82 cM), chromosome 14 (MLS = 2.74 at
58 cM), and chromosome 6 (MLS = 2.66 at 96 cM). We obtained smaller FUSION 1 + 2 MLSs on chromosomes X (MLS = 1.27 at 152
cM) and 20p (MLS = 1.21 at 20 cM). Among the 10 regions that showed nominally significant evidence for linkage in FUSION 1,
four (on chromosomes 6, 11, 14, and X) also showed evidence for linkage in FUSION 2 and stronger evidence for linkage in the
combined FUSION 1 + 2 sample.
ASP, affected sibling pair
CEPH, Centre d’Etude du Polymorphisme Humain
CIDR, Center for Inherited Disease Research
FUSION, Finland-United States Investigation of NIDDM Genetics
IBD, identity by descent
LOD, logarithm of odds
MLS, maximum LOD score
QTL, quantitative trait locus
WHO, World Health Organization
Footnotes
Accepted December 4, 2003.
Received July 21, 2003.
DIABETES
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