TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.

This paper seeks to understand the treatment effect of Prescription Drug Monitoring Programs (PDMPs) on opioid prescription rates. Using county-level panel data on all opioid prescriptions in the U.S. between 2006 and 2015, we investigate whether state interventions like PDMPs have heterogeneous treatment effects at the sub-state level, based on regional and temporal variations in policy design, extent of urbanization, race, and income. Our models comprehensively control for a set of county and time fixed effects, countyspecific and time-varying demographic controls, potentially endogenous time-series trends in prescription rates, and other state-level opioid interventions such as Naloxone Access and Good Samaritan laws, Medicaid expansion, and the provision of Methadone Assistance Treatment. We find that PDMPs are only effective in reducing prescription rates if they obligate doctors to check for patients' history prior to filling out a prescription, but the frequency at which a state requires its PDMP to be updated is irrelevant to its effectiveness. Moreover, the significant treatment effects of PDMPs are almost exclusively driven by urban and predominantly white counties, with the relatively more affluent regions showing greater responsiveness than their less affluent counterparts.

Hydroxyproline (Hyp) is a collagen-specific amino acid formed by post-translational hydroxylation of Pro residues. Various Hyp-containing oligopeptides are transported into the blood at high concentrations after oral ingestion of collagen hydrolysate. Here we investigated the angiotensin-converting enzyme (ACE) inhibitory activity of X-Hyp-Gly-type tripeptides. In an in vitro assay, ginger-degraded collagen hydrolysate enriched with X-Hyp-Gly-type tripeptides dose-dependently inhibited ACE and various synthetic X-Hyp-Gly-type tripeptides showed ACE-inhibitory activity. In particular, strong inhibition was observed for Leu-Hyp-Gly, Ile-Hyp-Gly, and Val-Hyp-Gly with IC50 values of 5.5, 9.4, and 12.8 μM, respectively. Surprisingly, substitution of Hyp with Pro dramatically decreased inhibitory activity of X-Hyp-Gly, indicating that Hyp is important for ACE inhibition. This finding was supported by molecular docking experiments using Leu-Hyp-Gly/Leu-Pro-Gly. We further demonstrated that prolyl hydroxylation significantly enhanced resistance to enzymatic degradation by incubation with mouse plasma. The strong ACE-inhibitory activity and high stability of X-Hyp-Gly-type tripeptides highlight their potential for hypertension control.

Although nonhormonal methods are preferred during breastfeeding, progestin-only contraceptives such as depot medroxyprogesterone acetate (DMPA) are considered the hormonal contraceptives of choice during all stages of lactation. Fair quality evidence indicates that DMPA does not adversely affect the composition of milk, the growth and development of the infant, or the milk supply.[1][2][3][4] Some evidence indicates that progestin-only contraceptives may offer protection against bone mineral density loss during lactation, or at least do not exacerbate it.[5][6][7] The timing of initiation of DMPA is controversial.[8] The product labeling states that it should be started no sooner than 6 weeks postpartum, based on data submitted for product approval. Studies of fair quality seem to indicate that concerns about immediate adverse effects on the infants is unfounded; however, starting too soon theoretically could affect the newborn infant adversely because of slower metabolism of the drug than older infants. Of concern is that no data exist on the effects of progesterone on brain and liver development at this age. Administration sooner than 6 weeks postpartum could interfere with the exclusivity or duration of lactation. A systematic review of studies using early postpartum initiation of DMPA concluded that all of the studies were of low quality and inadequate to disprove the concern about DMPA's effects on milk production if given sooner than 6 weeks after delivery.[9] A subsequent study raised the possibility of a slight reduction in breastfeeding duration in women given DMPA before hospital discharge,[10] and another study found that breastfeeding was less like to be initiated if mothers received immediate postpartum DMPA.[11] Expert opinion in the United States holds that the risks of progestin-only contraceptive products usually are acceptable for nursing mothers at any time postpartum.[12]The World Health Organization recommends that injectable depot medroxyprogesterone acetate should not used before 6 weeks postpartum.[13]

1. This work investigates the apparent metabolisable energy (AME), its nitrogen-corrected form (AMEn) and amino acid (AA) digestibility coefficients of the microalgae Spirulina platensis as an ingredient in broiler chicken diets. 2. One group of birds was fed with a basal control diet (BD), and another was fed with a test diet composed of the BD with the addition of the microalgae at a proportion of 200 g/kg. AME and AMEn were assessed by total excreta collection and indigestibility analysis using acid-insoluble ash (AIA) as a marker. 3. The microalgae comprised 888.0 g/kg dry matter (DM), 18.42 MJ/kg gross energy, 514.7 g/kg crude protein, 9.9 g/kg ether extract, 10.6 g/kg crude fibre, 94.4 g/kg ash, 3.1 g/kg Ca and 11.0 g/kg P. 4. The values obtained for AME (13.48 MJ/kg DM) and AMEn (11.72 MJ/kg DM) were higher (p < 0.01) than those obtained using the AIA method (9.39-8.29 MJ/kg DM). The microalgae ileal digestibility coefficients were 0.80 ± 0.04 and 0.78 ± 0.04 for essential and non-essential AA, respectively. 5. Overall, the metabolisable energy content and digestibility of AA for S. platensis indicated that the microalgae are potentially an alternative nutrient source for broilers. The AIA method underestimated AME and AMEn in comparison to the total excreta collection method.

1. An experiment was conducted to evaluate the effects of technical feed ingredients between 14 and 28 d of age on performance and health status of broilers (d 14-35) fed diets with a high inclusion rate of rapeseed meal as a nutritional challenge. It was hypothesized that the feed ingredients would improve health status related parameters. 2. A total of 1008 one-day-old male Ross 308 chicks were distributed over 36 floor pens and allocated to one of six iso-caloric (AMEN 13 MJ/kg) growing diets (d 15-28): a control and five test diets supplemented with quercetin (400 mg/kg), oat hulls (50 g/kg), β-glucan (100 mg/kg), lysozyme (40 mg/kg) or fish oil ω-3 fatty acids (40 g/kg), with six replicate pens per treatment. 3. Dietary inclusion of oat hulls and lysozyme resulted in a reduction in broiler performance during the first week after providing the experimental diets. 4. No effect of interventions on the microbiota diversity in the jejunum and ileum was observed. Ileal microbiota composition of birds fed oat hulls differed from the other groups, as shown by a higher abundance of the genus Enterococcus, mainly at the expense of the genus Lactobacillus. 5. In the jejunum, villus height and crypt depth of lysozyme-fed birds at d 28 were decreased compared to the control group. Higher total surface area of villi occupied by goblet cells and total villi surface area in jejunum (d 21 and 28) were observed in chickens fed oat hulls compared to other groups. 6. Genes related to the growth-factor-activity pathway were more highly expressed in birds fed β-glucan compared to the control group, while the genes related to anion-transmembrane-transporter-activity pathway in the quercetin- and oat hull-fed birds were less expressed. The genes differently expressed between dietary interventions did not seem to be directly involved in immune related processes. 7. It was concluded that the tested nutritional interventions in the current experiment only marginally effected health status related parameters.

Wheat is the primary grain fed to poultry in western Canada, but its nutritional quality, including the nature of its starch digestibility, may be affected by wheat market class. The objectives of this study were to determine the rate and extent of starch digestibility of wheat market classes in broiler chickens, and to determine the relationship between starch digestibility and wheat apparent metabolizable energy (AME). In vitro starch digestion was assessed using gastric and small intestinal phases mimicking the chicken digestive tract, while in vivo evaluation used 468 male broiler chickens randomly assigned to dietary treatments from 0 to 21 d of age. The study evaluated 2 wheat cultivars from each of 6 western Canadian wheat classes: Canadian Prairie Spring (CPS), Canadian Western Amber Durum (CWAD), CW General Purpose (CWGP), CW Hard White Spring (CWHWS), CW Red Spring (CWRS), and CW Soft White Spring (CWSWS). All samples were analyzed for relevant grain characteristics. Data were analyzed as a randomized complete block design and cultivars were nested within market class. Pearson correlation was used to determine relationships between measured characteristics. Significance level was P ≤ 0.05. The starch digestibility range and wheat class rankings were: proximal jejunum - 23.7 to 50.6% (CWHWSc, CPSbc, CWSWSbc, CWRSab, CWGPa, CWADa); distal jejunum - 63.5 to 76.4% (CWHWSc, CPSbc, CWSWSbc, CWRSab, CWGPa, CWADa); proximal ileum - 88.7 to 96.9% (CWSWSc, CPSbc, CWHWSbc, CWRSb, CWGPb, CWADa); distal ileum - 94.4 to 98.5% (CWSWSb, CWHWSb, CPSb, CWRSab, CWGPab, CWADa); excreta - 98.4 to 99.3% (CPSb, CWRSb, CWHWSb, CWSWSab, CWGPab, CWADa). Wheat class affected wheat AMEn with levels ranging from 3,203 to 3,411 kcal/kg at 90% DM (CWRSc, CWSWSc, CPSb, CWGPb, CWADa, CWHWSa). Significant and moderately strong positive correlations were observed between in vitro and in vivo starch digestibility, but no correlations were found between AME and starch digestibility. In conclusion, rate and extent of starch digestibility and AME were affected by western Canadian wheat class, but starch digestibility did not predict AME.

1. This study assessed the impact of drying temperature (54, 90, and 130°C) and maize grain moisture content at harvest (36% and 29%) on in vitro digestibility, the growth performance and ileal digestibility of broiler chickens. 2. In contrast to the results from the in vitro digestibility, apparent ileal digestibility of starch and energy decreased when the drying temperature was raised from 54 to 130°C, and this effect was more pronounced in maize grain harvested at high initial moisture content (36%). Ileal protein digestibility of maize grain decreased significantly when dried at the intermediate temperature (90°C) and with a high harvest moisture content (36%). Drying temperature and initial moisture content did not significantly affect AMEn. 3. When maize was dried at 130°C, the particle sizes of flour recovered after standard milling procedures decreased significantly, which would influence animal growth performance and in vivo digestibility through animal feed selection.