Separation of early afterdepolarizations from arrhythmogenic substrate in the isolated perfused hypokalaemic murine heart through modifiers of calcium homeostasis

In human type 1 diabetes (T1D) and in its murine model, the major histocompatibility complex (MHC) class II molecules, human leukocyte antigens (HLA)-DQ and -DR and their murine orthologues, IA and IE, are the major genetic determinants. In this report, we have ranked HLA class II molecule-associated T1D risk in a two-sided gradient from very high to very low. Very low risk corresponded to dominant protection from T1D. We predicted the protein structure of DQ by using the published crystal structures of different allotypes of the murine orthologue of DQ, IA. We discovered marked similarities both within, and cross species between T1D protective class II molecules. Likewise, the T1D predisposing molecules showed conserved similarities that contrasted with the shared patterns observed between the protective molecules. We also found striking inter-isotypic conservation between protective DQ, IA allotypes and protective DR4 subtypes. The data provide evidence for a joint action of the class II peptide-binding pockets P1, P4 and P9 in disease susceptibility and resistance with a main role for P9 in DQ/IA and for P1 and P4 in DR/IE. Overall, these results suggest shared epitope(s) in the target autoantigen(s), and common pathways in human and murine T1D

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes

A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Papillomavirus Prophylactic Vaccines: Established Successes, New Approaches

Vaccines against the human papillomaviruses (HPVs) most frequently associated with cancer of the cervix are now available. These prophylactic vaccines, based on virus-like particles (VLPs), are extremely effective, providing protection from infection in almost 100% of cases. However, the vaccines present some limitations: they are effective primarily against the HPV type present in the vaccine, are expensive to produce, and need a cold chain. Vaccines based on the minor capsid protein L2 have been very successful in animal models and have been shown to provide a good level of protection against different papillomavirus types. The potential of L2-based vaccines to protect against many types of HPVs is discusse

Blind sequence detection of vector channels based on a novel clustering algorithm

Space diversity reception is known to be an excellent means of combating the detrimental effects of the mobile radio channel in data transmission. This paper addresses the problem of data detection for digital communications employing space diversity reception, where the system model contains a single input multiple output vector channel (this model may be further generalized to multiple-input multiple-output, MIMO vector channels). The received vector corrupted by AWGN is modeled as the noisy output of a finite state vector Markov source. Subsequently, a redundant discretely valued basis of minimal dimensionality is identified for the input space. Estimation of the output labels associated with these basis allows labeling of the state transition diagram. For this purpose, certain identifiable characteristics of the output sequences of the Markov source are used to classify its states and generate an initial codebook for a vector quantizer used to restore the output levels. Finally, an iterative implicit sequence detection algorithm is proposed for data detection

Blind estimation of output labels of SIMO channels based on a novel clustering algorithm

This paper addresses the problem of data detection for digital communications employing space diversity reception, where the system model contains a single-input multiple-output (SIMO) vector channel. The received vector corrupted by additive white Gaussian noise (AWGN) is modeled as the noisy output of a finite state vector Markov source. Subsequently, a discretely valued basis of minimal dimensionality is identified for the input space. Estimation of the output labels associated with this basis allows labeling of the state transition diagram. For this purpose, certain identifiable characteristics of the output sequences of the Markov source are used to classify its states and generate an initial codebook for a vector quantizer used to restore the output levels