| 1. |
- Klaric, Lucija, et al.
(författare)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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| 2. |
- Söderberg, Stefan, et al.
(författare)
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MEASURES OF WAIST AND HIP MODIFY SEX-SPECIFIC ASSOCIATIONS BETWEEN BODY MASS INDEX AND PREVALENCE OF CORONARY ARTERY CALCIFICATION IN OPPOSITE DIRECTIONS
- 2019
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Ingår i: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 73:9, s. 13-13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Obesity is associated with increased risk of cardiovascular disease. However, there is still a debate whether accumulation of fat in certain depots modifies this risk. Using data from the CArdioPulmonary bioImage Study (SCAPIS), we investigated if anthropometric measurements of obesity (waist and hip) modifies the risk of coronary artery calcification. Methods: In the first 15,810 participants in SCAPIS (mean age 58 years, 52% women), data on coronary artery calcification score (CACS) and anthropometry were recorded and traditional cardiovascular risk factors were measured. Body mass index (BMI) was categorized as; <25, 25-30, 30-35 and >35 kg/m2 , quartiles of waist and hip circumferences were constructed within each BMI category and compared using the lowest quartile as reference. Results were adjusted for site, age, smoking and diabetes status. Results: Obesity (BMI >30 kg/m2 ) was found in 21.9% of men and in 20.5% of women. In both sexes the odds ratio (OR) for CACS >0 increased with increasing BMI categories: comparing <25 and >35 kg/m2 , OR = 2.1 (95% CI: 1.6-2.7) for men and OR = 1.4 (1.2-1.8) for women. In addition, increasing quartiles of waist significantly increased the prevalence of CACS >0 for men [p = 0.05; OR = 1.2 (1.0-1.4) for highest quartile] and women [p = 0.005; OR = 1.3 (1.1-1.5)] while increasing quartiles of hip significantly decreased the prevalence for men [p = 0.005; OR = 0.8 (0.6-0.9)] and women [p = 0.04; OR = 0.8 (0.7-0.9)]. Data on education level and physical activity did not affect the model. Conclusion: Increased BMI is associated with increased prevalence of coronary artery calcification and the distribution of fat modifies this risk. Our results suggest that gluteofemoral adipose tissue (hip) counteracts the negative effects associated with BMI and abdominal adipose tissue (waist).
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| 3. |
- Afey Ali Zaidi, Zyed, et al.
(författare)
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Waveform and Numerology to Support 5G Services and Requirements
- 2016
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Ingår i: IEEE Communications Magazine. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 0163-6804 .- 1558-1896. ; 54:11, s. 90-98
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Tidskriftsartikel (refereegranskat)abstract
- The standardization of the next generation 5G radio access technology has just started in 3GPP with the ambition of making it commercially available by 2020. There are a number of features that are unique for 5G radio access compared to the previous generations such as a wide range of carrier frequencies and deployment options, diverse use cases with very different user requirements, small-size base stations, self-backhaul, massive MIMO, and large channel bandwidths. In this article, we propose a flexible physical layer for the NR to meet the 5G requirements. A symmetric physical layer design with OFDM is proposed for all link types, including uplink, downlink, device-to-device, and backhaul. A scalable OFDM waveform is proposed to handle the wide range of carrier frequencies and deployments.
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| 4. |
- Bixby, H., et al.
(författare)
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Rising rural body-mass index is the main driver of the global obesity epidemic in adults
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 569:7755, s. 260-4
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Tidskriftsartikel (refereegranskat)abstract
- Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
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| 5. |
- Braun, Emelie, et al.
(författare)
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Comprehensive cell atlas of the first-trimester developing human brain
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6667, s. 172-
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Tidskriftsartikel (refereegranskat)abstract
- The adult human brain comprises more than a thousand distinct neuronal and glial cell types, a diversity that emerges during early brain development. To reveal the precise sequence of events during early brain development, we used single-cell RNA sequencing and spatial transcriptomics and uncovered cell states and trajectories in human brains at 5 to 14 postconceptional weeks (pcw). We identified 12 major classes that are organized as ~600 distinct cell states, which map to precise spatial anatomical domains at 5 pcw. We described detailed differentiation trajectories of the human forebrain and midbrain and found a large number of region-specific glioblasts that mature into distinct pre-astrocytes and pre–oligodendrocyte precursor cells. Our findings reveal the establishment of cell types during the first trimester of human brain development.
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| 6. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 7. |
- Di Angelantonio, E., et al.
(författare)
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Association of Cardiometabolic Multimorbidity With Mortality
- 2015
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Ingår i: JAMA. - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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| 8. |
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| 9. |
- Ek, Staffan, et al.
(författare)
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A 28-nm FD-SOI 115-fs Jitter PLL-Based LO System for 24-30-GHz Sliding-IF 5G Transceivers
- 2018
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Ingår i: IEEE Journal of Solid-State Circuits. - 0018-9200. ; 53:7, s. 1988-2000
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Tidskriftsartikel (refereegranskat)abstract
- A system for local oscillator (LO) signal generation in 5G millimeter-wave (mmW) multi-antenna transceivers is presented. The system is modular with one phase locked loop (PLL) per antenna element transceiver, and a test circuit implemented in 28-nm fully depleted silicon on insulator (FD-SOI) CMOS features two such PLLs and a 491.52 MHz crystal oscillator (XO) generating a common frequency reference. A fractional-N architecture is employed to achieve high-frequency resolution, and the quantization noise is reduced using a novel frequency divider, which achieves full integer resolution while still using a pre-scaler. The system covers the 3rd Generation Partnership Project (3GPP) bands n257 and n258, achieved by a digital coarse tuning of the voltage-controlled oscillator (VCO). The chip area of each PLL is 0.11 mm², and 0.029 mm² for the XO. The total power consumption of the system is 35 mW, where each PLL consumes 15.4 mW and the XO consumes 0.84 mW. The total rms jitter from 20-kHz to 500-MHz offset for a 26-GHz carrier is just 115 fs, corresponding to an FOMj of -244 dB, which is the best reported figure for a fractional-N PLL above 15 GHz. The error-vector magnitude (EVM) due to phase noise is -34.6 dBc using an orthogonal frequency-division multiplexing (OFDM) signal with 120-kHz sub-carrier spacing, sufficient to support 256 QAM.
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| 10. |
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