Filetype
Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson’s disease3,4, su
Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants
The acceleration of DNA sequencing in samples from patients and population studies has resulted in extensive catalogues of human genetic variation, but the interpretation of rare genetic variants remains problematic. A notable example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Here, by manual curation of puta
Structural variants (SVs) rearrange large segments of DNA1 and can have profound consequences in evolution and human disease2,3. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD)4 have become integral in the interpretation of single-nucleotide v
Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors,
OBJECTIVE: To determine whether exposure to cardiovascular medications and statins is associated with increased risk of giant cell arteritis (GCA). DESIGN: The population-based case-control study comprised a cohort of patients with biopsy-confirmed GCA linked to the Swedish Prescribed Drug Register to identify all exposure to drugs prior to diagnosis of GCA. Ten controls per GCA case, matched for
With the rising prevalence of both diabetes mellitus (DM) and peripheral arterial disease (PAD), the aim of this project was to examine the association between dietary intake and lifestyle on the risk of developing PAD among individuals with DM. The Malmö Diet and Cancer study was a prospective cohort study with baseline examinations carried out between 1991 and 1996 in Malmö, Sweden (n = 30,446).
Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whethe
Previous studies have suggested that thyroid function is associated with breast cancer risk, which could have an important clinical impact, as one in eight women will develop a thyroid disorder during her lifetime. However, the underlying pathomechanism behind the association is still unknown. We used the Malmö Diet and Cancer Study (a population-based prospective study consisting of 17,035 women)
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and
Fibrotic disorders account for over one third of mortalities worldwide. Despite great efforts to study the cellular and molecular processes underlying fibrosis, there are currently few effective therapies. Dual-stage polymerization reactions are an innovative tool for recreating heterogeneous increases in extracellular matrix (ECM) modulus, a hallmark of fibrotic diseases in vivo. Here, we present
We present the first experimental study of the frontier orbitals in an ultrathin film of the novel hexa-carbene photosensitizer [Fe(btz)3]3+, where btz is 3,3′-dimethyl-1,1′-bis(p-tolyl)-4,4′-bis(1,2,3-triazol-5-ylidene). Resonant photoelectron spectroscopy (RPES) was used to probe the electronic structure of films where the molecular and oxidative integrities had been confirmed with optical and X
Fragmented micro- and nanoplastics are widespread pollutants with adverse effects on the environment. However, the breakdown process does not end with micro- and nanoplastics but is expected to continue until carbon dioxide has been formed. During this process the plastics will undergo chemical changes and small molecules may be released. We have broken down small amine-modified (∅53 nm) and carbo
X-ray methods can offer unique insights into the structural and electronic properties of nanomaterials. Recent years have seen a dramatic improvement in both x-ray sources and x-ray optics, providing unprecedented resolution and sensitivity. These developments are particularly useful for nanowires, which are inherently small and give weak signals. This review gives an overview of how different x-r
High-order harmonic generation (HHG) in gases is inherently inefficient, prompting ongoing efforts to enhance the output of coherent table-top XUV sources. In this study, we investigate the influence of the laser pulse duration on HHG using a compact post-compression method featuring a bulk multi-pass cell. This setup enables tunable Fourier-limited pulse durations as short as 42 fs. We examine th
BACKGROUND: Statins have been suggested to protect against breast cancer risk, but the observational evidence is inconclusive. We examined the association between statin use and breast cancer incidence among women at higher risk of breast cancer due to a history of benign breast disease (BBD).METHODS: Using Danish registries, we identified cancer-free women aged ≥50 years during 1996-2018 with a h
The chemical forms of zinc in fly ash from municipal solid waste incineration (MSWI) crucially affect ash management, influencing both material recovery options and the risk of unwanted leaching into ecosystems. The zinc speciation was investigated in fly ash samples sourced from full-scale MSWI plants, including four grate fired boilers (GB) and one fluidized bed boiler (FB). We applied X-ray Abs
Radiolabeled targeting agents have emerged as valuable tools for the treatment of disseminated cancer. Monoclonal antibodies (mAbs) are widely employed as carriers for diagnostic and therapeutic radionuclides due to their exceptional specificity and affinity. However, their prolonged circulatory half-life can diminish diagnostic efficacy and increase radiation exposure to non-target tissues in the
