INTERSNP : Genomweite Interaktionsanalyse mit a-priori Information

Das Ziel der Genetischen Epidemiologie ist DNA Sequenzvarianten im menschlichen Genom zu finden, die an der Entstehung von Krankheiten beteiligt sind. Genomweite Assoziationsstudien haben zur Identifikation von hunderten Regionen im Genom geführt, die mit komplexen Krankheiten assoziiert sind. Dennoch bleibt ein großer Teil der Heritabilität unerklärt. Interaktion zwischen genetischen Varianten könnten unter anderem eine Erklärung für den Fall der "missing heritability" [Maher, 2008] sein. Jedoch ist die genomweite Interaktionsanalyse (GWIA) aller SNP-Paare (SNP, engl. Single Nucleotide Polymorphism) aus einem Standard Marker Panel rechnerisch ohne massive Parallelisierung unmöglich. Darüber hinaus, wäre eine GWIA mit allen SNP-Tripeln utopisch. Ziel der Software INTERSNP ist es, trotzdem eine genomweite Interaktionsanalyse zu ermöglichen. Um die rechnerischen Hindernisse zu überwinden, werden nur bestimmte Kombinationen von SNPs anhand von a-priori Information für die Interaktionsanalyse auswählt. Grundlage dieser Informationen können statistische Kriterien (moderate Einzelmarkerassoziation), genetische Relevanz (Lokalisation im Genom) und biologische Relevanz (SNP Funktionsklassen und Pathwayinformation) sein. Das Softwarepaket INTERSNP bietet für die Multimakeranalyse der SNPs Tests der logistischen/linearen Regression sowie eines log-linear Modells. Zur Korrektur für multiples Testen wurden Monte-Carlo Simulationen implementiert. Zusätzlich steht eine parallelisierte Version zur Verfügung. Unsere Ergebnisse zeigen, dass die Interaktionsanalyse und insbesondere die Verwendung von a-priori Information sinnvolle Ansätze sind, um zusätzliche Krankheits-Loci zu finden, die mit herkömmlichen Methoden unentdeckt bleiben.INTERSNP - Genome-wide Interaction Analysis with a-priori information The main goal of genetic epidemiology is to find DNA sequence variation in the human genome that is involved in disease development. Genome-wide association studies (GWAS) have led to the identification of hundreds of genomic regions associated with complex diseases. Nevertheless, a large fraction of their heritability remains unexplained. Interaction between genetic variants is one of several putative explanations for the "case of missing heritability" [Maher, 2008]. However, genome-wide interaction analysis (GWIA) of all pairs of SNPs (Single Nucleotide Polymorphisms) from a standard marker panel is computationally unfeasible without massive parallelization. Furthermore, GWIA of all SNP triples is utopian. Despite these difficulties, the aim of the software package INTERSNP is to make a genome-wide interaction analysis feasible. In order to overcome the computational constraints, only certain combinations of SNPs based on a priori information are selected for the interaction analysis. Sources of information are statistical evidence (single marker association at a moderate level), genetic relevance (genomic location) and biologic relevance (SNP function class and pathway information). The software package INTERSNP provides tests for joint analysis of multiple SNPs: logistic/linear regression as well as log-linear models. To judge genome-wide significance Monte-Carlo simulations are implemented. In addition, a parallelized version is available. Our results show that interaction analysis is a valuable tool to identify disease loci that would be undetected with conventional methods

Complement activation via the lectin and alternative pathway in patients with severe COVID-19

Complement plays an important role in the direct defense to pathogens, but can also activate immune cells and the release of pro-inflammatory cytokines. However, in critically ill patients with COVID-19 the immune system is inadequately activated leading to severe acute respiratory syndrome (SARS) and acute kidney injury, which is associated with higher mortality. Therefore, we characterized local complement deposition as a sign of activation in both lungs and kidneys from patients with severe COVID-19. Using immunohistochemistry we investigated deposition of complement factors C1q, MASP-2, factor D (CFD), C3c, C3d and C5b-9 as well as myeloperoxidase (MPO) positive neutrophils and SARS-CoV-2 virus particles in lungs and kidneys from 38 patients who died from COVID-19. In addition, tissue damage was analyzed using semi-quantitative scores followed by correlation with complement deposition. Autopsy material from non-COVID patients who died from cardiovascular causes, cerebral hemorrhage and pulmonary embolism served as control (n=8). Lung injury in samples from COVID-19 patients was significantly more pronounced compared to controls with formation of hyaline membranes, thrombi and edema. In addition, in the kidney tubular injury was higher in these patients and correlated with lung injury (r=0.361*). In autopsy samples SARS-CoV-2 spike protein was detected in 22% of the lungs of COVID-19 patients but was lacking in kidneys. Complement activation was significantly stronger in lung samples from patients with COVID-19 via the lectin and alternative pathway as indicated by deposition of MASP-2, CFD, C3d and C5b9. Deposits in the lung were predominantly detected along the alveolar septa, the hyaline membranes and in the alveolar lumina. In the kidney, complement was significantly more deposited in patients with COVID-19 in peritubular capillaries and tubular basement membranes. Renal COVID-19-induced complement activation occurred via the lectin pathway, while activation of the alternative pathway was similar in both groups. Furthermore, MPO-positive neutrophils were found in significantly higher numbers in lungs and kidneys of COVID-19 patients and correlated with local MASP-2 deposition. In conclusion, in patients who died from SARS-CoV-2 infection complement was activated in both lungs and kidneys indicating that complement might be involved in systemic worsening of the inflammatory response. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury in COVID-19

A Comprehensive Study on the Livestock Sub-Sector Analysis and its Role in Fostering Sustainable Development in Zambia: Insights from the 2022 Livestock Survey Report

This study provides a comprehensive analysis of Zambia\u27s dynamic livestock sub-sector as of April 30, 2022, drawing insights from the 2022 Livestock Survey Report. With 1,801,075 households actively engaged in livestock activities, the sub-sector emerges as a vital component of the country\u27s rural livelihoods. Understanding the interplay of household characteristics and livestock populations is pivotal for crafting sustainable development policies that enhance the well-being of the sub-sector\u27s participants. Gender dynamics within the livestock sub-sector underscore the central role of men as household heads and primary decision-makers. This necessitates targeted initiatives to empower women, fostering their active involvement and amplifying contributions that lead to improved household prosperity, expanded economic opportunities, and the preservation of indigenous knowledge. Zambia\u27s diverse livestock population, with a significant presence of 4,698,972 cattle, plays a crucial role in ensuring protein availability, bolstering nutritional security, and contributing to household incomes. Goats, sheep, and pigs also feature prominently, meeting various demands for meat, milk and other essentials. Recognizing the unique contributions of each livestock species allows for tailored strategies to improve their productivity and welfare. Addressing provincial disparities in livestock production and resource utilization is imperative for achieving sustainable development goals. Provincial variations in agro-ecological conditions, market access, and infrastructure necessitate context-specific interventions. Such approaches can harness provincial strengths, optimize resource utilization, and stimulate value chain development. Moreover, this study highlights opportunities in honey production and milk output. Apiculture and beekeeping investment can aid biodiversity conservation through pollination services while fostering high-quality honey production. Tailored capacity-building and infrastructure development can address provincial disparities in milk production, benefiting smallholder dairy farmers and the broader dairy industry. This study underscores the livestock sub-sector\u27s pivotal role in sustainable development, food security, and rural livelihood enhancement in Zambia. By embracing responsible, inclusive strategies and evidence-based insights, policymakers, stakeholders, and development practitioners can optimize the sub-sector\u27s potential. Focusing on household well-being, gender inclusivity, and provincial equity will foster a resilient and thriving livestock sub-sector, benefiting all segments of society and paving the way for a brighter and more sustainable future for Zambia

XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase

Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.publishedVersio

Adjusting heterogeneous ascertainment bias for genetic association analysis with extended families

Background: In family-based association analysis, each family is typically ascertained from a single proband, which renders the effects of ascertainment bias heterogeneous among family members. This is contrary to case–control studies, and may introduce sample or ascertainment bias. Statistical efficiency is affected by ascertainment bias, and careful adjustment can lead to substantial improvements in statistical power. However, genetic association analysis has often been conducted using family-based designs, without addressing the fact that each proband in a family has had a great influence on the probability for each family member to be affected. Method We propose a powerful and efficient statistic for genetic association analysis that considered the heterogeneity of ascertainment bias among family members, under the assumption that both prevalence and heritability of disease are available. With extensive simulation studies, we showed that the proposed method performed better than the existing methods, particularly for diseases with large heritability. Results: We applied the proposed method to the genome-wide association analysis of Alzheimer’s disease. Four significant associations with the proposed method were found. Conclusion: Our significant findings illustrated the practical importance of this new analysis method. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0198-6) contains supplementary material, which is available to authorized users

IFNs Modify the Proteome of <i>Legionella</i>-Containing Vacuoles and Restrict Infection Via IRG1-Derived Itaconic Acid

Macrophages can be niches for bacterial pathogens or antibacterial effector cells depending on the pathogen and signals from the immune system. Here we show that type I and II IFNs are master regulators of gene expression during Legionella pneumophila infection, and activators of an alveolar macrophage-intrinsic immune response that restricts bacterial growth during pneumonia. Quantitative mass spectrometry revealed that both IFNs substantially modify Legionella-containing vacuoles, and comparative analyses reveal distinct subsets of transcriptionally and spatially IFN-regulated proteins. Immune-responsive gene (IRG)1 is induced by IFNs in mitochondria that closely associate with Legionella-containing vacuoles, and mediates production of itaconic acid. This metabolite is bactericidal against intravacuolar L. pneumophila as well as extracellular multidrug-resistant Gram-positive and -negative bacteria. Our study explores the overall role IFNs play in inducing substantial remodeling of bacterial vacuoles and in stimulating production of IRG1-derived itaconic acid which targets intravacuolar pathogens. IRG1 or its product itaconic acid might be therapeutically targetable to fight intracellular and drug-resistant bacteria

Pediatricians' perspectives on the impact of MRSA in primary care: a qualitative study

<p>Abstract</p> <p>Background</p> <p>The incidence of skin and soft-tissue infections (SSTIs) has rapidly increased among children in primary care settings since the emergence of community-associated methicillin-resistant <it>Staphylococcus aureus </it>(CA-MRSA). Recent treatment recommendations emphasize CA-MRSA as the primary cause, performing incision and drainage (I&D) as the primary therapy, and not prescribing antibiotics for uncomplicated cases. It is unknown how this epidemic has impacted primary care pediatricians in terms of their practice patterns and barriers they face to providing recommended therapies.</p> <p>Methods</p> <p>3 Focus groups among 29 primary care pediatricians in the San Francisco Bay Area were conducted. Transcripts were reviewed and coded into major themes by two investigators using modified grounded theory.</p> <p>Results</p> <p>Substantial changes in clinical practice have occurred since the emergence of CA-MRSA. These include increased office visits for SSTIs, patients with multiple recurrences and transmission within households. Additionally, our participants reported increased visits for mild skin problems due to media reports contributing to fears about CA-MRSA. Participants routinely prescribed antibiotics for SSTIs, however, few performed I&D. Few were aware of recent SSTI treatment recommendations. Barriers to prescribing antibiotics with CA-MRSA activity included concerns about side-effects and lack of local epidemiologic data showing that it is the primary etiology. Barriers to performing I&D included lack of training, resources and skepticism about its necessity. Important clinical challenges included increased time demands for follow-up visits and patient education along with the lack of evidence-based strategies for preventing recurrent inections and household transmission.</p> <p>Conclusion</p> <p>CA-MRSA has influenced the presentation and treatment of SSTIs especially in terms of case numbers and recurrences. Barriers to providing recommended therapies can be addressed through improved dissemination of treatment guidelines and epidemiologic data. Studies are urgently needed toimprove theevidence-base for treatment and prevention strategies.</p

Stereotactic or conformal radiotherapy for adrenal metastases: patient characteristics and outcomes in a multicenter analysis

To report outcome (freedom from local progression: FFLP, overall survival: OS, and toxicity) after stereotactic, palliative, or highly conformal fractionated (&gt; 12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤ 12 fractions, biologically effective dose, (BED10) ≥ 50 Gy), 3DCRT/IMRT (&gt; 12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 &lt; 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/Log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). 326 patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT, and Pall-RT in 260, 27, and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%), and melanoma (6.7%). Unadjusted FFLP was higher after SBRT v. Pall-RT (p&nbsp;=&nbsp;0.026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4%, and 27.7%). OS was longer after SBRT v. other groups (p &lt; 0.05) and increased in patients with locally-controlled metastases in a landmark analysis (p &lt; 0.0001). Toxicity was mostly mild; notably, 4 cases of adrenal insufficiency occurred, 2 of which were likely caused by immunotherapy or tumor progression. RT for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. 1-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway