Epidemiological situation of bovine brucellosis in the State of Rio Grande do Sul, Brazil

Realizou-se um estudo para caracterizar a situação epidemiológica da brucelose bovina. O Estado foi dividido em sete regiões. Em cada região foram amostradas aleatoriamente cerca de 300 propriedades, e dentro dessas foi escolhido de forma aleatória um número pré-estabelecido de animais, dos quais foi obtida uma amostra de sangue. No total foram amostrados 16.072 animais, provenientes de 1.957 propriedades. Em cada propriedade amostrada foi aplicado um questionário epidemiológico para verificar o tipo de exploração e as práticas zootécnicas e sanitárias que poderiam estar associadas ao risco de infecção pela doença. O protocolo de testes utilizado foi o da triagem com o teste do antígeno acidificado tamponado e o reteste dos positivos com o teste do 2-mercaptoetanol. O rebanho foi considerado positivo se pelo menos um animal foi reagente às duas provas sorológicas. Para o Estado, as prevalências de focos e de animais infectados foram, respectivamente, 2,1% [1,5-2,6%] e 1,0% [0,60-1,4%]. Para os circuitos, a prevalência de focos e a de animais foram, respectivamente: circuito 1, 3,1% [1,4-5,7%] e 0,95% [0,0-2,0%]; circuito 2, 7,7% [4,9-11,3%] e 1,0% [0,40-1,7%]; circuito 3, 5,7% [3,4-8,8%] e 2,1% [0,41-3,8%]; circuito 4, 0,66% [0,08-2,4%] e 0,66% [0,0-1,8%]; circuito 5, 0,66% [0,08-2,4%] e 0,05% [0,0-0,13%]; circuito 6, 0,0% [0,0-1,3%] e 0,0% [0,0-0,25%]; circuito 7, 5,4% [2,5-10,1%] e 2,9% [0,49-5,3%]. Os fatores de risco (odds ratio, OR) associados à condição de foco foram: exploração de corte (OR= 4,27 [1,82-10,01]) e histórico de aborto (OR=3,27,1,71-6,25]). ____________________________________________________________________________________________________________ ABSTRACTA study to characterize the epidemiological status of bovine brucellosis was carried out in the State of Rio Grande do Sul. The State was divided in seven regions. Three hundred herds were randomly sampled in each region and a pre-established number of animals were sampled in each of these herds. A total of 16,072 serum samples from 1,957 herds, were collected. In each herd, it was applied an epidemiological questionnaire focused on herd traits as well as husbandry and sanitary practices that could be associated with the risk of infection. The serum samples were screened for antibodies against Brucella spp. by the Rose-Bengal Test and all positive sera were re-tested by the 2-mercaptoethanol test. The herd was considered positive if at least one animal was positive on both tests. The prevalences of infected herds and animals in the State were, respectively 2.1% [1.5-2.6%] and 1.0% [0.60-1.4%]. In the regions, the prevalences of infected herds and animals were, respectively: region 1, 3.1% [1.4-5.7%] and 0.95% [0.0-2.0%]; region 2, 7.7% [4.9-11.3%] and 1.0% [0.40-1.7%]; region 3, 5.7% [3.4-8.8%] and 2.1% [0.41-3.8%]; region 4, 0.66% [0.08-2.4%] and 0.66% [0.0-1.8%]; region 5, 0.66% [0.08-2.4%] and 0.05% [0.0-0.13%]; region 6, 0.0% [0.0-1.3%] and 0.0% [0.0-0.25%]; and region 7, 5.4% [2.5-10.1%] and 2.9% [0.49-5.3%]. The risk factors (odds ratio, OR) associated with the presence of infection were: beef herd (OR= 4.27 [1.82-10.01]) and recent history of abortion (OR= 3.27-1.71-6.25])

Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages

Funding Information: This work was financially supported by FCT (Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Education) through national funds and co‐funded by FEDER under the PT2020 Partnership (Ref. PTDC/MED‐PAT/29395/2017, 2022.01305.PTDC and 2022.03249.PTDC). The Coimbra Chemistry Center (CQC) is supported by the FCT through Project UID/QUI/00313/2019. MSCA‐RISE: “Genetic and Small Molecule Modifiers of Lysosomal Function” (LysoMod), financed by Horizon 2020. Ref 734825. Twinning on “Excel in Rare Diseases' Research: Focus on LYSOsomal Disorders and CILiopathies”, Ref (H2020‐TWINN‐2017: GA 81108). Neuza Domingues was a holder of PhD fellowship from the FCT (Ref. No: SFRH/BD/51877/2012), attributed by Inter‐University Doctoral Programme in Ageing and Chronic Disease (PhDOC). André R.A. Marques was funded by the FCT Stimulus of Scientific Employment Individual Support Call 2017 (CEECIND/01006/2017). Rosa Puertollano was funded by the NHLBI Division of Intramural Research (ZIA HL006151‐10). Publisher Copyright: © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins (LDL) in lysosomes. This event culminates in the loss of cell homeostasis, inflammation, and cell death. Nevertheless, the exact chemical etiology of atherogenesis and the molecular and cellular mechanisms responsible for the impairment of lysosome function in plaque macrophages are still unknown. Here, we demonstrate that macrophages exposed to cholesteryl hemiazelate (ChA), one of the most prevalent products of LDL-derived cholesteryl ester oxidation, exhibit enlarged peripheral dysfunctional lysosomes full of undigested ChA and neutral lipids. Both lysosome area and accumulation of neutral lipids are partially irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences for the pathology. We further demonstrate that this phenotype is mechanistically linked to the nuclear translocation of the MiT/TFE family of transcription factors. The induction of lysosome biogenesis by ChA appears to partially protect macrophages from lipid-induced cytotoxicity. In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles. This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.publishersversionpublishe

Changing state of the climate system

Chapter 2 assesses observed large-scale changes in climate system drivers, key climate indicators and principal modes of variability. Chapter 3 considers model performance and detection/attribution, and Chapter 4 covers projections for a subset of these same indicators and modes of variability. Collectively, these chapters provide the basis for later chapters, which focus upon processes and regional changes. Within Chapter 2, changes are assessed from in situ and remotely sensed data and products and from indirect evidence of longer-term changes based upon a diverse range of climate proxies. The time-evolving availability of observations and proxy information dictate the periods that can be assessed. Wherever possible, recent changes are assessed for their significance in a longer-term context, including target proxy periods, both in terms of mean state and rates of change

Automated workflow-based exploitation of pathway databases provides new insights into genetic associations of metabolite profiles

Background: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) that associate with clinical phenotypes, but these SNPs usually explain just a small part of the heritability and have relatively modest effect sizes. In contrast, SNPs that associate with metabolite levels generally explain a higher percentage of the genetic variation and demonstrate larger effect sizes. Still, the discovery of SNPs associated with metabolite levels is challenging since testing all metabolites measured in typical metabolomics studies with all SNPs comes with a severe multiple testing penalty. We have developed an automated workflow approach that utilizes prior knowledge of biochemical pathways present in databases like KEGG and BioCyc to generate a smaller SNP set relevant to the metabolite. This paper explores the opportunities and challenges in the analysis of GWAS of metabolomic phenotypes and provides novel insights into the genetic basis of metabolic variation through the re-analysis of published GWAS datasets. Results: Re-analysis of the published GWAS dataset from Illig et al. (Nature Genetics, 2010) using a pathway-based workflow (http://www.myexperiment.org/packs/319.html), confirmed previously identified hits and identified a new locus of human metabolic individuality, associating Aldehyde dehydrogenase family1 L1 (ALDH1L1) with serine/glycine ratios in blood. Replication in an independent GWAS dataset of phospholipids (Demirkan et al., PLoS Genetics, 2012) identified two novel loci supported by additional literature evidence: GPAM (Glycerol-3 phosphate acyltransferase) and CBS (Cystathionine beta-synthase). In addition, the workflow approach provided novel insight into the affected pathways and relevance of some of these gene-metabolite pairs in disease development and progression. Conclusions: We demonstrate the utility of automated exploitation of background knowledge present in pathway databases for the analysis of GWAS datasets of metabolomic phenotypes. We report novel loci and potential biochemical mechanisms that contribute to our understanding of the genetic basis of metabolic variation and its relationship to disease development and progression