To evaluate predictive model ability to determine whether an animal finished the feeding period using data known at first treatment for bovine respiratory disease (BRD). Additional comparisons ...evaluated the potential benefits of predictions by adding weather data, utilizing balancing techniques, and creating models for individual feedyards.
This retrospective study included animal, pen, and feedyard data from 12 US feedyards from 2016 to 2021. The final dataset consisted of 96,382 BRD cases of which 14.2% did not finish the feeding phase.
Five predictive models were trained and underwent threshold probability adjustment to maximize F1 score. Model performance was evaluated using accuracy, sensitivity specificity, positive and negative predictive values, and area under the receiver operating characteristics curve (AUC).
Overall, model performance was low with a median AUC value of 0.675. The addition of weather data had little effect on AUC but resulted in more variation in sensitivity and specificity. Resampling the dataset had a limited effect on performance. Individual feedlot models had higher AUC values than others with the decision tree typically performing best in most feedyards.
Results indicated some utility of predictive models evaluating BRD cases to predict cattle that did not finish the feeding phase. These models could be valuable in assisting health providers making decisions on individual cases.
Abstract Context The mechanisms mediating the short- and long-term improvements in glucose homeostasis following bariatric/metabolic surgery remain incompletely understood. Objective To investigate ...whether a reduction in adipose tissue inflammation plays a role in the metabolic improvements seen after bariatric/metabolic surgery, both in the short-term and longer-term. Design Fasting blood and subcutaneous abdominal adipose tissue were obtained before ( n = 14), at one month ( n = 9), and 6–12 months ( n = 14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication. Adipose tissue inflammation was assessed by a combination of whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes. Results One month after surgery, body weight was reduced by 13.5 ± 4.4 kg ( p < 0.001), with improvements in glucose tolerance reflected by a decrease in area-under-the-curve (AUC) glucose in 3-h oral glucose tolerance tests (− 105 ± 98 mmol/L * min; p = 0.009) and enhanced pancreatic β-cell function (insulinogenic index: + 0.8 ± 0.9 pmol/mmol; p = 0.032), but no change in estimated insulin sensitivity (Matsuda insulin sensitivity index ISI; p = 0.720). Furthermore, although biomarkers of systemic inflammation and pro-inflammatory gene expression in adipose tissue remained unchanged, the number of neutrophils increased in adipose tissue 15–20 fold ( p < 0.001), with less substantial increases in other leukocyte populations. By the 6–12 month follow-up visit, body weight was reduced by 34.8 ± 10.8 kg ( p < 0.001) relative to baseline, and glucose tolerance was further improved (AUC glucose − 276 ± 229; p < 0.001) along with estimated insulin sensitivity (Matsuda ISI: + 4.6 ± 3.2; p < 0.001). In addition, improvements in systemic inflammation were reflected by reductions in circulating C-reactive protein (CRP; − 2.0 ± 5.3 mg/dL; p = 0.002), and increased serum adiponectin (+ 1358 ± 1406 pg/mL; p = 0.003). However, leukocyte infiltration of adipose tissue remained elevated relative to baseline, with pro-inflammatory cytokine mRNA expression unchanged, while adiponectin mRNA expression trended downward ( p = 0.069). Conclusion Both the short- and longer-term metabolic improvements following bariatric/metabolic surgery occur without significant reductions in measures of adipose tissue inflammation, as assessed by measuring the expression of genes encoding key mediators of inflammation and by flow cytometric immunophenotyping and quantification of adipose tissue leukocytes.
Abstract
Summary
Large-scale human genetics studies are now employing whole genome sequencing with the goal of conducting comprehensive trait mapping analyses of all forms of genome variation. ...However, methods for structural variation (SV) analysis have lagged far behind those for smaller scale variants, and there is an urgent need to develop more efficient tools that scale to the size of human populations. Here, we present a fast and highly scalable software toolkit (svtools) and cloud-based pipeline for assembling high quality SV maps—including deletions, duplications, mobile element insertions, inversions and other rearrangements—in many thousands of human genomes. We show that this pipeline achieves similar variant detection performance to established per-sample methods (e.g. LUMPY), while providing fast and affordable joint analysis at the scale of ≥100 000 genomes. These tools will help enable the next generation of human genetics studies.
Availability and implementation
svtools is implemented in Python and freely available (MIT) from https://github.com/hall-lab/svtools.
Supplementary information
Supplementary data are available at Bioinformatics online.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic ...mutations, of which 12 were in the coding sequences of genes and 52 were in conserved regions or regions with regulatory potential. Four mutations were found to be recurrent in AML, including mutations in
NRAS, NPM1, IDH1,
and a conserved region on chromosome 10.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic mutations. Four mutations were found to be recurrent in AML.
Acute myeloid leukemia (AML) is a clonal hematopoietic disease caused by both inherited and acquired genetic alterations.
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Current AML classification and prognostic systems incorporate genetic information but are limited to known abnormalities that have previously been identified with the use of cytogenetics, array comparative genomic hybridization (CGH), gene-expression profiling, and the resequencing of candidate genes (see the Glossary).
The karyotyping of AML cells remains the most powerful predictor of the outcome in patients with AML and is routinely used by clinicians.
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As an adjunct to cytogenetic studies, small subcytogenetic amplifications and deletions can be identified with the use . . .
The construction and maintenance of normal epithelia relies on local signals that guide cells into their proper niches and remove unwanted cells. Failure to execute this process properly may result ...in aberrant development or diseases, including cancer and associated metastasis. Here, we show that local environment influences the behavior of
dCsk-deficient cells. Broad loss of
dCsk led to enlarged and mispatterned tissues due to overproliferation, a block in apoptosis, and decreased cadherin-mediated adhesion. Loss of
dCsk in discrete patches led to a different outcome: epithelial exclusion, invasive migration, and apoptotic death. These latter phenotypes required sharp differences in
dCsk activity between neighbors; dE-cadherin, P120-catenin, Rho1, JNK, and MMP2 mediated this signal. Together, our data demonstrate how the cellular microenvironment plays a central role in determining the outcome of altered
dCsk activity, and reveal a role for P120-catenin in a mechanism that protects epithelial integrity by removing abnormal cells.
Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, ...here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER- 'collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information.
Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses ...of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform ...an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses has been reported. We evaluated cell lines commonly used to isolate viruses and diagnose related ...diseases for their susceptibility to SARS-CoV-2. Although multiple kidney cell lines from monkeys were susceptible to SARS-CoV-2, we found many cell types derived from humans, dogs, minks, cats, mice, and chicken were not. We analyzed MDCK cells, which are most commonly used for surveillance and study of influenza viruses, and found that they were not susceptible to SARS-CoV-2. The low expression level of the angiotensin converting enzyme 2 receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by overexpression of canine angiotensin converting enzyme 2 in trans, strengthened the cellular barrier to productive infection. Moreover, a D614G mutation in the spike protein did not appear to affect SARS-CoV-2 cell tropism. Our findings should help avert inadvertent propagation of SARS-CoV-2 from diagnostic cell lines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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