Antihypertensive medication uses and serum ACE2 levels

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with major respiratory failure where the old and those with an underlying chronic disease are at highest risk of mortality1. Several factors have been proposed that may be underlying the higher mortality rates in these high-risk groups. The most frequent comorbidities associated with COVID-19 related mortality are clinical hypertension and type 2 diabetes (T2D)2,3. Although lower survival can simply be attributed to the frailty of this population, it has been suggested that administration of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may affect the susceptibility to COVID-19 related outcomes by upregulating ACE24. It is well known that ACE2 is the cellular receptor that COVID-19 and other SARS coronaviruses bind to for entering the host cell5

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases

Genome-wide association identifies seven loci for pelvic organ prolapse in Iceland and the UK Biobank.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadPelvic organ prolapse (POP) is a downward descent of one or more of the pelvic organs, resulting in a protrusion of the vaginal wall and/or uterus. We performed a genome-wide association study of POP using data from Iceland and the UK Biobank, a total of 15,010 cases with hospital-based diagnosis code and 340,734 female controls, and found eight sequence variants at seven loci associating with POP (P 5%) and one with minor allele frequency of 4.87%. Some of the variants associating with POP also associated with traits of similar pathophysiology. Of these, rs3820282, which may alter the estrogen-based regulation of WNT4, also associates with leiomyoma of uterus, gestational duration and endometriosis. Rs3791675 at EFEMP1, a gene involved in connective tissue homeostasis, also associates with hernias and carpal tunnel syndrome. Our results highlight the role of connective tissue metabolism and estrogen exposure in the etiology of POP.UCL Hospitals NIHR Biomedical Research Centr

A proteogenomic signature of age-related macular degeneration in blood

© 2022. The Author(s). Funding Information: The authors acknowledge the contribution of the Icelandic Heart Association (IHA) staff to the AGES-RS, as well as the involvement of all study participants. We thank the IAMDGC consortium for supplying us with their GWAS summary statistics data. National Institute on Aging (NIA) contracts N01-AG-12100 and HHSN271201200022C for V.G. financed the AGES study; retinal image collection and AMD readings were funded by the NIH Intramural Research Program (ZIAEY000401). V.G. received a funding from the NIA (1R01AG065596), and IHA received a support from Althingi (the Icelandic Parliament). The Icelandic Research Fund (IRF) funded V.E. and Va.G. with grants 195761-051, 184845-053, and 206692-051, while Va.G. received a postdoctoral research grant from the University of Iceland Research Fund Funding Information: The study was supported by the Novartis Institute for Biomedical Research. M.T., N.F., S.P., X.L., R.E., Y.Z., S.J., C.L.H., S.M.L., J.L., C.L.G., A.A.N., B.L., R.P., Z.L., L.L.J., T.E.W., Q.Z., Q.H., and J.R.L. are employees and stockholders of Novartis. All other authors have no conflict of interests to declare. Publisher Copyright: © 2022, The Author(s).Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.Peer reviewe

Fabrication, characterization, and modeling of metallic source/drain MOSFETs

As scaling of CMOS technology continues, the control of parasitic source/drain (S/D) resistance (RSD) is becoming increasingly challenging. In order to control RSD, metallic source/drain MOSFETs have attracted significant attention, due to their low resistivity, abrupt junction and low temperature processing (≤700 °C). A key issue is reducing the contact resistance between metal and channel, since small Schottky barrier height (SBH) is needed to outperform doped S/D devices. A promising method to decrease the effective barrier height is dopant segregation (DS). In this work several relevant aspects of Schottky barrier (SB) contacts are investigated, both by simulation and experiment, with the goal of improving performance and understanding of SB-MOSFET technology:First, measurements of low contact resistivity are challenging, since systematic error correction is needed for extraction. In this thesis, a method is presented to determine the accuracy of extracted contact resistivity due to propagation of random measurement error.Second, using Schottky diodes, the effect of dopant segregation of beryllium (Be), bismuth (Bi), and tellurium (Te) on the SBH of NiSi is demonstrated. Further study of Be is used to analyze the mechanism of Schottky barrier lowering.Third, in order to fabricate short gate length MOSFETs, the sidewall transfer lithography process was optimized for achieving low sidewall roughness lines down to 15 nm. Ultra-thin-body (UTB) and tri-gate SB-MOSFET using PtSi S/D and As DS were demonstrated. A simulation study was conducted showing DS can be modeled by a combination of barrier lowering and doped Si extension.Finally, a new Schottky contact model was implemented in a multi-subband Monte Carlo simulator for the first time, and was used to compare doped-S/D to SB-S/D for a 17 nm gate length double gate MOSFET. The results show that a barrier of ≤ 0.15 eV is needed to comply with the specifications given by the International Technology Roadmap for Semiconductors (ITRS).QC 2011120

Human cystatin C expression and regulation by TGF-β1: Implications for the pathogenesis of hereditary cystatin C amyloid angiopathy causing brain hemorrhage

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldCystatin C amyloid (ACys) deposition in arteries of the brain is the primary cause of cerebral hemorrhage in hereditary cystatin C amyloid angiopathy (HCCAA). A missense mutation (codon 68; Leu 68 → Gln 68) in the human cystatin C gene renders cystatin C amyloidogenic and in addition leads to a significant reduction in the concentration of cystatin C in the cerebrospinal fluid. We show that the mutation does not affect the accumulation of cystatin C mRNA in monocytes of affected individuals. Further studies on tissue and cellular distribution of cystatin C mRNA reveal an ubiquitous expression of the molecule. However, these levels vary as much as 13 fold between different tissues, with highest expression levels in pancreas, testis and brain. Results are then presented showing that monocytes exposed to transforming growth factor beta 1 (TGF-β1) exhibit a several fold increase in the expression of cystatin C mRNA and cystatin Cprotein. Here, TGF-β1 stimulates secretion of cystatin C from normal monocytes whilst, in contrast, secretion of cystatin C from Leu 68/Gln 68 monocytes is markedly impaired. It is suggested that TGF-β1 is an effector molecule in acute and local phase regulation of cystatin C to prevent damage of cells and matrix by cysteine proteases. We postulate that synergism between ACys and deficiency of cystatin C, in the amyloid-involved areas, contributes to a more aggressive form of vascular damage and consequently earlier onset of cerebral hemorrhag

Radical cystectomy in the treatment of bladder cancer in Iceland: A population-based study.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageRadical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer. Postoperative complications are reported to be as high as 65%. The objective of this study was to investigate complications and survival in Icelandic patients with bladder cancer who underwent RC.All patients who had bladder cancer and underwent RC in Iceland from 2003 to 2012 were included. Information was obtained retrospectively from patients' medical records and from the Icelandic Cause of Death Registry. Complications were classified according to the Clavien-Dindo classification system. The Kaplan-Meier method was used in the survival analysis. Only patients with transitional cell carcinoma (TCC) were included in the survival analysis.Overall, 108 patients (male 81%, median age 68 years) underwent the procedure during the study period and 100 of them had TCC. Ileal conduit was performed in 86% of procedures and orthotopic neobladder in 14%. The median operation time was 266 min and the median blood loss during the procedure was 1000 ml. No patient died within 30 days of surgery, but one patient (0.9%) died within 90 days of surgery from complications of the surgery. Complications were reported for 62 patients (57%) overall. Major complications (Clavien 3-5) were reported in 32 patients (29%), and 30 patients (28%) had only minor complications (Clavien 1-2). Twenty-four patients (22%) had to undergo reoperation. Overall 5 year survival was 54%.Morbidity after RC is high but similar to that seen in other studies. Long-term survival of Icelandic patients is comparable to that in neighboring countries