Warner-Bratzler shear force values and ranges of steaks from cattle of known sires

Carcass data and Warner-Bratzler shear force (WBSF) data on strip loin steaks were collected from nearly 8,500 cattle in contemporary groups of progeny from the more popular sires in 14 different beef cattle breeds in the Carcass Merit Traits project funded by Beef Checkoff dollars, the breed associations, and MMI Genomics. In addition, trained sensory panel evaluations were conducted on over 2,500 strip loin steaks from contemporary groups of progeny from five sires included in the DNA marker validation component of the project. The correlation between WBSF and tenderness scored by the trained sensory panel was -0.82, indicating that as WBSF increased, tenderness scored by the sensory panel decreased. Our results showed that a WBSF value of ≥ 11.0 lb generally results in a sensory score of slightly tough or tougher. In this study, 22.8% of the cattle had WBSF values ≥ 11.0 lb and 26.3% had sensory scores of slightly tough or tougher. The phenotypic range of WBSF means for sires within breeds ranged from 1.9 to 6.6 lb. The phenotypic range of WBSF means across breeds was 8.9 lb, whereas the range among sires across breeds was a dramatic 14.4 lb. The phenotypic range for flavor intensity scores among sires within and across breeds was much smaller than for tenderness, with juiciness scores being intermediate. The 40 widely used sires that produced progeny with steaks that were unacceptable in tenderness in this study might be expected to be sires of several thousand bulls used in commercial herds. This demonstrates that seedstock producers should aggressively utilize sires that have genetics for tender meat

Design of dual ligands using excessive pharmacophore query alignment

Dual- or multi-target ligands have gained increased attention in the past years due to several advantages, including more simple pharmacokinetic and phamarcodynamic properties compared to a combined application of several drugs. Furthermore multi-target ligands often possess improved efficacy. We present a new approach for the discovery of dual-target ligands using aligned pharmacophore models combined with a shape-based scoring. Starting with two sets of known active compounds for each target, a number of different pharmacophore models is generated and subjected to pairwise graph-based alignment using the Kabsch-Algorithm. Since a compound may be able to bind to different targets in different conformations, the algorithm aligns pairs of pharmacophore models sharing the same features which are not necessarily at the exactly same spatial distance. Using the aligned models, a pharmacophore search on a multi-conformation-database is performed to find compounds matching both models. The potentially “dual” ligands are scored by a shape-based comparison with the known active molecules using ShaEP. Using this approach, we performed a prospective fragment-based virtual screening for dual 5-LO/sEH inhibitors. Both enzymes play an important role in the arachidonic acid cascade and are involved in inflammatory processes, pain, cardiovascular diseases and allergic reactions. Beside several new selective inhibitors we were able to find a compound inhibiting both enzymes in low micromolar concentrations. The results indicate that the idea of aligned pharmacophore models can be successfully employed for the discovery of dual-target ligands

Constructing a man-made c-type cytochrome maquette in vivo:electron transfer, oxygen transport and conversion to a photoactive light harvesting maquette

The successful use of man-made proteins to advance synthetic biology requires both the fabrication of functional artificial proteins in a living environment, and the ability of these proteins to interact productively with other proteins and substrates in that environment. Proteins made by the maquette method integrate sophisticated oxidoreductase function into evolutionarily naive, non-computationally designed protein constructs with sequences that are entirely unrelated to any natural protein. Nevertheless, we show here that we can efficiently interface with the natural cellular machinery that covalently incorporates heme into natural cytochromes c to produce in vivo an artificial c-type cytochrome maquette. Furthermore, this c-type cytochrome maquette is designed with a displaceable histidine heme ligand that opens to allow functional oxygen binding, the primary event in more sophisticated functions ranging from oxygen storage and transport to catalytic hydroxylation. To exploit the range of functions that comes from the freedom to bind a variety of redox cofactors within a single maquette framework, this c-type cytochrome maquette is designed with a second, non-heme C, tetrapyrrole binding site, enabling the construction of an elementary electron transport chain, and when the heme C iron is replaced with zinc to create a Zn porphyrin, a light-activatable artificial redox protein. The work we describe here represents a major advance in de novo protein design, offering a robust platform for new c-type heme based oxidoreductase designs and an equally important proof-of-principle that cofactor-equipped man-made proteins can be expressed in living cells, paving the way for constructing functionally useful man-made proteins in vivo

Genetic relationships among temperament, immune function, and carcass merit

Cattle producers historically have selected for docile temperaments simply for management convenience because calmer animals are conducive to safe environments for their peers as well as their handlers. As many producers would acknowledge, there seems to be a relationship between temperament and health, and calmer cattle tend to frequent the working chute for treatment of disease less often. Positive correlations have been found in cattle between temperament traits (chute scores, pen scores, and chute exit velocities) and cortisol concentration in the blood, suggesting that more excitable cattle are easily stressed (Curley et al., 2006; Cooke et al., 2009). In addition, Curley et al. (2007) found that easily excitable animals sustain elevated cortisol concentrations for a longer duration and had greater pituitary and adrenal responses following a stressor than calm cattle. Temperamental cattle have significantly higher mean temperament responses at all points (Oliphint, 2006). Higher basal serum cortisol concentrations may suggest that easily excitable cattle are chronically stressed (Curley et al., 2007), possibly resulting in a compromised immune system, illness, and decreased fat and protein deposition. Common measures of cattle temperament are pen scores, chute scores, and exit velocities. Temperament appears to be moderately heritable, with estimates ranging from 0.15 to 0.44 (Burrow and Corbet, 2000; Kadel et al., 2006; Schrode and Hammack, 1971; Stricklin et al., 1980; Fordyce et al., 1988). If genetic correlations are found between temperament and production traits or immunological factors, they may aid cattle breeders in producing profitable cattle. Such relationships have been found between exit velocity and hot carcass weight (r = -0.54), exit velocity and marbling score (r = 0.10), exit velocity and yield grade (r = -0.22) (Nkrumah et al., 2007), and post-weaning weight gain and exit velocity (Weaber et al., 2006). Bovine respiratory disease (BRD) susceptibility has been estimated to be lowly heritable (Muggli-Cockett et al., 1992; Snowder et al., 2005, 2006, 2007; Schneider et al., 2008). This study was conducted to further investigate the genetic relationships between cattle temperament measured by chute score and exit velocity, immunological factors, and a range of economically relevant performance traits

Detection of Early-Stage Pancreatic Ductal Adenocarcinoma From Blood Samples : Results of a Multiplex Biomarker Signature Validation Study

INTRODUCTION: The IMMray PanCan-d test combines an 8-plex biomarker signature with CA19-9 in a proprietary algorithm to detect pancreatic ductal adenocarcinoma (PDAC) in serum samples. This study aimed to validate the clinical performance of the IMMray PanCan-d test and to better understand test performance in Lewis-null (le/le) individuals who cannot express CA19-9. METHODS: Serum samples from 586 individuals were analyzed with the IMMray PanCan-d biomarker signature and CA19-9 assay, including 167 PDAC samples, 203 individuals at high risk of familial/hereditary PDAC, and 216 healthy controls. Samples were collected at 11 sites in the United States and Europe. The study was performed by Immunovia, Inc (Marlborough, MA), and sample identity was blinded throughout the study. Test results were automatically generated using validated custom software with a locked algorithm and predefined decision value cutoffs for sample classification. RESULTS: The IMMray PanCan-d test distinguished PDAC stages I and II (n = 56) vs high-risk individuals with 98% specificity and 85% sensitivity and distinguished PDAC stages I-IV vs high-risk individuals with 98% specificity and 87% sensitivity. We identified samples with a CA19-9 value of 2.5 U/mL or less as probable Lewis-null (le/le) individuals. Excluding these 55 samples from the analysis increased the IMMray PanCan-d test sensitivity to 92% for PDAC stages I-IV (n = 157) vs controls (n = 379) while maintaining specificity at 99%; test sensitivity for PDAC stages I and II increased from 85% to 89%. DISCUSSION: These results demonstrate the IMMray PanCan-d blood test can detect PDAC with high specificity (99%) and sensitivity (92%).Peer reviewe

MIND food and speed of processing training in older adults with low education, the MINDSpeed Alzheimer's disease prevention pilot trial

Background Multiple national organizations and leaders have called for increased attention to dementia prevention in those most vulnerable, for example persons with limited formal education. Prevention recommendations have included calls for multicomponent interventions that have the potential to improve both underlying neurobiological health and the ability to function despite neurobiological pathology, or what has been termed cognitive reserve. Objectives Test feasibility, treatment modifier, mechanism, and cognitive function effects of a multicomponent intervention consisting of foods high in polyphenols (i.e., MIND foods) to target neurobiological health, and speed of processing training to enhance cognitive reserve. We refer to this multicomponent intervention as MINDSpeed. Design MINDSpeed is being evaluated in a 2 × 2 randomized factorial design with 180 participants residing independently in a large Midwestern city. Qualifying participants are 60 years of age or older with no evidence of dementia, and who have completed 12 years or less of education. All participants receive a study-issued iPad to access the custom study application that enables participants, depending on randomization, to select either control or MIND food, and to play online cognitive games, either speed of processing or control games. Methods All participants complete informed consent and baseline assessment, including urine and blood samples. Additionally, up to 90 participants will complete neuroimaging. Assessments are repeated immediately following 12 weeks of active intervention, and at 24 weeks post-randomization. The primary outcome is an executive cognitive composite score. Secondary outcomes include oxidative stress, pro-inflammatory cytokines, and neuroimaging-captured structural and functional metrics of the hippocampus and cortical brain regions. Summary MINDSpeed is the first study to evaluate the multicomponent intervention of high polyphenol intake and speed of processing training. It is also one of the first dementia prevention trials to target older adults with low education. The results of the study will guide future dementia prevention efforts and trials in high risk populations

Effect of mammographic screening from age 40 years on breast cancer mortality (UK Age trial):final results of a randomised, controlled trial

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.BACKGROUND: The appropriate age range for breast cancer screening remains a matter of debate. We aimed to estimate the effect of mammographic screening at ages 40-48 years on breast cancer mortality. METHODS: We did a randomised, controlled trial involving 23 breast screening units across Great Britain. We randomly assigned women aged 39-41 years, using individual randomisation, stratified by general practice, in a 1:2 ratio, to yearly mammographic screening from the year of inclusion in the trial up to and including the calendar year that they reached age 48 years (intervention group), or to standard care of no screening until the invitation to their first National Health Service Breast Screening Programme (NHSBSP) screen at approximately age 50 years (control group). Women in the intervention group were recruited by postal invitation. Women in the control group were unaware of the study. The primary endpoint was mortality from breast cancers (with breast cancer coded as the underlying cause of death) diagnosed during the intervention period, before the participant's first NHSBSP screen. To study the timing of the mortality effect, we analysed the results in different follow-up periods. Women were included in the primary comparison regardless of compliance with randomisation status (intention-to-treat analysis). This Article reports on long-term follow-up analysis. The trial is registered with the ISRCTN registry, ISRCTN24647151. FINDINGS: 160 921 women were recruited between Oct 14, 1990, and Sept 24, 1997. 53 883 women (33·5%) were randomly assigned to the intervention group and 106 953 (66·5%) to the control group. Between randomisation and Feb 28, 2017, women were followed up for a median of 22·8 years (IQR 21·8-24·0). We observed a significant reduction in breast cancer mortality at 10 years of follow-up, with 83 breast cancer deaths in the intervention group versus 219 in the control group (relative rate [RR] 0·75 [95% CI 0·58-0·97]; p=0·029). No significant reduction was observed thereafter, with 126 deaths versus 255 deaths occurring after more than 10 years of follow-up (RR 0·98 [0·79-1·22]; p=0·86). INTERPRETATION: Yearly mammography before age 50 years, commencing at age 40 or 41 years, was associated with a relative reduction in breast cancer mortality, which was attenuated after 10 years, although the absolute reduction remained constant. Reducing the lower age limit for screening from 50 to 40 years could potentially reduce breast cancer mortality. FUNDING: National Institute for Health Research Health Technology Assessment programme.Peer reviewe

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN