Search Results (12)

This study aimed to investigate the effect of an essential oil/fumaric combination, mannan-oligosaccharide, galactooligosaccharide, and a mannan-oligosaccharide/galactooligosaccharide combination on the dry matter disappearance (DMD), gas production, greenhouse gasses, volatile fatty acid, and microbial community of a total mixed ration using a 24 h in vitro batch culture technique. The study design was a completely randomized design with four treatments as follows: a control treatment without any additives, the control treatment supplemented with galactooligosaccharide at 3% (Gos treatment), a galactooligosaccharide and mannan-oligosaccharide mixture at 1:1 at 3% (Gosmos treatment), or an essential oil blend (200 μL/g feed) and fumaric acid at 3% combination (Eofumaric treatment). The Gosmos treatment had the highest (p < 0.05) DMD (63.8%) and the numerical lowest acetate–propionate ratio (p = 0.207), which was 36.9% higher compared to the control. The lowest Shannon index, Simpson’s index, and all the diversity indices were recorded for the Eofumaric treatment, while the other treatments had similar Shannon index, Simpson’s index, and diversity index. The Z-score differential abundance between the Eofumaric and the control indicated that the inclusion of the Eofumaric treatment differentially increased the abundance of Patescibacteria, Synergistota, Chloroflexi, Actinobacteriota, Firmicutes, and Euryarchaeota while Verrucomicrobiota, WPS-2, Fibrobacterota, and Spirochaetota were decreased. The Random Forest Classification showed that the lower relative abundance of Fibrobacterota, Spirochaetota, and Elusimicrobiota and the higher relative abundance of Firmicutes and Chloroflexi were most impactful in explaining the microbial community data. Overall, the essential oil blend showed great potential as a methane gas mitigation strategy by modifying rumen fermentation through changes in the microbial community dynamics. Full article

Essential oils are natural feed additives that improve animal health and enhance their performance. This study investigated the effects of the rumen infusion of five essential oil blends (EOBs) on greenhouse gas (GHG) emissions, rumen fermentation parameters, and rumen metabolome and metabolic pathways in Black Angus cows. Using a 6 × 6 Latin Square experimental design, a 90-day study was conducted with six cattle. A daily dosage of 4 mL of EOBs was administered during each infusion. Volcano plot analyses between the control (CON) and each of the EOBs (EOB1, EOB2, EOB3, EOB4, and EOB5) revealed several differentially abundant (p ≤ 0.05; absolute fold change ≥1.5) metabolites. The EOB5 treatment exhibited the most significant impact, with 26 differentially abundant metabolites, including elevated valine and reduced gallic acid. Volatile fatty acids (VFAs), including valerate, isobutyrate, and isovalerate, were significantly increased (p < 0.05). GHG emissions were not significantly affected, but a numerical decrease was observed in the animals infused with the EOB5 treatment. Ammonia nitrogen concentrations remained within the suitable range for rumen microbes’ growth, indicating a normal internal environment for microbial crude protein synthesis. In conclusion, the study has demonstrated that the direct infusion of EOBs significantly improved the generation of VFAs and impacted the energy production, protein synthesis, and microbial activity of the animals. Full article

Introducing or correcting disease-causing mutations through genome editing in human pluripotent stem cells (hPSCs) followed by tissue-specific differentiation provide sustainable models of multiorgan diseases, such as cystic fibrosis (CF). However, low editing efficiency resulting in extended cell culture periods and the use of specialised equipment for fluorescence activated cell sorting (FACS) make hPSC genome editing still challenging. We aimed to investigate whether a combination of cell cycle synchronisation, single-stranded oligodeoxyribonucleotides, transient selection, manual clonal isolation, and rapid screening can improve the generation of correctly modified hPSCs. Here, we introduced the most common CF mutation, ΔF508, into the CFTR gene, using TALENs into hPSCs, and corrected the W1282X mutation using CRISPR-Cas9, in human-induced PSCs. This relatively simple method achieved up to 10% efficiency without the need for FACS, generating heterozygous and homozygous gene edited hPSCs within 3–6 weeks in order to understand genetic determinants of disease and precision medicine. Full article

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types. Full article

Individuals with cystic fibrosis (CF) suffer from severe respiratory disease due to a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which impairs airway epithelial ion and fluid secretion. New CFTR modulators that restore mutant CFTR function have been recently approved for a large group of people with CF (pwCF), but ~19% of pwCF cannot benefit from CFTR modulators Restoration of epithelial fluid secretion through non-CFTR pathways might be an effective treatment for all pwCF. Here, we developed a medium-throughput 384-well screening assay using nasal CF airway epithelial organoids, with the aim to repurpose FDA-approved drugs as modulators of non-CFTR-dependent epithelial fluid secretion. From a ~1400 FDA-approved drug library, we identified and validated 12 FDA-approved drugs that induced CFTR-independent fluid secretion. Among the hits were several cAMP-mediating drugs, including β2-adrenergic agonists. The hits displayed no effects on chloride conductance measured in the Ussing chamber, and fluid secretion was not affected by TMEM16A, as demonstrated by knockout (KO) experiments in primary nasal epithelial cells. Altogether, our results demonstrate the use of primary nasal airway cells for medium-scale drug screening, target validation with a highly efficient protocol for generating CRISPR-Cas9 KO cells and identification of compounds which induce fluid secretion in a CFTR- and TMEM16A-indepent manner. Full article

The microbial communities that inhabit the intestinal tract play an important role in modulating health and productivity. Environmental stressors can impact microbial communities, which can significantly influence host physiology. Cattle are subjected to several environmental stressors when placed on feedlots, such as transportation stress, exposure to feedlot environments and change in diet and management. Exposure to these stressors could influence host gut microbiota, which in turn, could potentially influence host health and performance. The aim of the current study was to characterise the temporal changes that occur in intestinal microbiota as a consequence of feedlot placement by profiling 16s rRNA sequences in rectal faecal samples. When faecal microbiome profiles were compared in terms of relative abundances and alpha diversity metrics, the results showed significant, observable changes in profiles 2 days post-feedlot induction. Furthermore, beta-diversity analysis indicated that the phylogenetic similarity between samples significantly decreased on day 2 (PERMANOVA, p < 0.001). These trends were suggestive of a short-term reduction in microbial diversity coupled with decreased similarity between animals. These changes warrant further investigation and could provide opportunities for improved performance, health and even welfare of feedlot cattle in future. Full article

Background: The 2014–2016 Ebola outbreak in West Africa recapitulated that nosocomial spread of Ebola virus could occur and that health care workers were at particular risk including notable cases in Europe and North America. These instances highlighted the need for centers to better prepare for potential Ebola virus cases; including understanding how the virus spreads and which interventions pose the greatest risk. Methods: We created a fully equipped intensive care unit (ICU), within a Biosafety Level 4 (BSL4) laboratory, and infected multiple sedated non-human primates (NHPs) with Ebola virus. While providing bedside care, we sampled blood, urine, and gastric residuals; as well as buccal, ocular, nasal, rectal, and skin swabs, to assess the risks associated with routine care. We also assessed the physical environment at end-point. Results: Although viral RNA was detectable in blood as early as three days post-infection, it was not detectable in the urine, gastric fluid, or swabs until late-stage disease. While droplet spread and fomite contamination were present on a few of the surfaces that were routinely touched while providing care in the ICU for the infected animal, these may have been abrogated through good routine hygiene practices. Conclusions: Overall this study has helped further our understanding of which procedures may pose the highest risk to healthcare providers and provides temporal evidence of this over the clinical course of disease. Full article

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens. Full article

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression. Full article

Glioblastoma multiforme (GBM), a common type of brain cancer, has a very poor prognosis. In general, viable GBM cells exhibit elevated phosphatidylserine (PS) on their membrane surface compared to healthy cells. We have developed a drug, saposin C-dioleoylphosphatidylserine (SapC-DOPS), that selectively targets cancer cells by honing in on this surface PS. To examine whether SapC-DOPS, a stable, blood–brain barrier-penetrable nanovesicle, could be an effective delivery system for precise targeted therapy of radiation, we iodinated several carbocyanine-based fluorescent reporters with either stable iodine (¹²⁷I) or radioactive isotopes (¹²⁵I and ¹³¹I). While all of the compounds, when incorporated into the SapC-DOPS delivery system, were taken up by human GBM cell lines, we chose the two that best accumulated in the cells (DiI (22,3) and DiD (16,16)). Pharmacokinetics were conducted with ¹²⁵I-labeled compounds and indicated that DiI (22,3)-SapC-DOPS had a time to peak in the blood of 0.66 h and an elimination half-life of 8.4 h. These values were 4 h and 11.5 h, respectively, for DiD (16,16)-SapC-DOPS. Adult nude mice with GBM cells implanted in their brains were treated with ¹³¹I-DID (16,16)-SapC-DOPS. Mice receiving the radionuclide survived nearly 50% longer than the control groups. These data suggest a potential novel, personalized treatment for a devastating brain disease. Full article

A method is proposed for estimating the acoustic power output of ultrasound transducers using a two-port model with electrical impedance measurements made in three different propagation media. When evaluated for two high-intensity focused ultrasound transducers at centre frequencies between 0.50 and 3.19 MHz, the resulting power estimates exceeded acoustic estimates by 4.5–21.8%. The method was shown to be valid for drive levels producing up to 20 MPa in water and should therefore be appropriate for many HIFU (high-intensity focused ultrasound) applications, with the primary advantage of employing relatively low-cost, non-specialist materials and instrumentation. Full article

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference was held in Halifax, Nova Scotia, 20–22 September 2018. Experts in radiation oncology, medical oncology, surgical oncology, and pathology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of pancreatic cancer, pancreatic neuroendocrine tumours, hepatocellular cancer, and rectal and colon cancer, including (1) surgical management of pancreatic adenocarcinoma, (2) adjuvant and metastatic systemic therapy options in pancreatic adenocarcinoma, (3) the role of radiotherapy in the management of pancreatic adenocarcinoma, (4) systemic therapy in pancreatic neuroendocrine tumours, (5) updates in systemic therapy for patients with advanced hepatocellular carcinoma, (6) optimum duration of adjuvant systemic therapy for colorectal cancer, and (7) sequence of therapy in oligometastatic colorectal cancer. Full article