Nutritional and Physiological Constraints Contributing to Limitations in Small Intestinal Starch Digestion and Glucose Absorption in Ruminants

Increased efficiency of nutrient utilization can potentially be gained with increased starch digestion in the small intestine in ruminants. However, ruminants have quantitative limits in the extent of starch disappearance in the small intestine. The objective is to explore the nutritional and physiological constraints that contribute to limitations of carbohydrate assimilation in the ruminant small intestine. Altered digesta composition and passage rate in the small intestine, insufficient pancreatic α-amylase and/or small intestinal carbohydrase activity, and reduced glucose absorption could all be potentially limiting factors of intestinal starch assimilation. The absence of intestinal sucrase activity in ruminants may be related to quantitative limits in small intestinal starch hydrolysis. Multiple sequence alignment of the sucrase-isomaltase complex gives insight into potential molecular mechanisms that may be associated with the absence of intestinal sucrase activity, reduced capacity for intestinal starch digestion, and limitations in the efficiency of feed utilization in cattle and sheep. Future research efforts in these areas will aid in our understanding of small intestinal starch digestion and glucose absorption to optimize feeding strategies for increased meat and milk production efficiency

Book Reviews

Reviews of the following books: Mount Hope Cemetery of Bangor, Maine: The Complete History by Trudy Irene Scee; The Reverend Jacob Bailey, Maine Loyalist: For God, King, Country and for Self by James S. Leamon; The Barns of Maine: Our History, Our Stories by Don Perkins; Gateway to Vacationland: The Making of Portland, Maine by John F. Bauman; Maine: The Wilder Half of New England by William David Berry; The Cross of War: Christian Nationalism and U.S. Expansion in the Spanish-American War by Matthew McCullough; Omaha Beach: The Life and Military Service of a Penobscot Indian Elder by Charles Norman Shay

Thermal Stability of Frozen Volatiles in the North Polar Region of Mercury

Earth-based radar observations have revealed the presence on Mercury of anomalously bright, depolarizing features that appear to be localized in the permanently shadowed regions of high-latitude impact craters [1]. Observations of similar radar signatures over a range of radar wavelengths implies that they correspond to deposits that are highly transparent at radar wavelengths and extend to depths of several meters below the surface [1]. Thermal models using idealized crater topographic profiles have predicted the thermal stability of surface and subsurface water ice at these same latitudes [2]. One of the major goals of the MESSENGER mission is to characterize the nature of radar-bright craters and presumed associated frozen volatile deposits at the poles of Mercury through complementary orbital observations by a suite of instruments [3]. Here we report on an examination of the thermal stability of water ice and other frozen volatiles in the north polar region of Mercury using topographic profiles obtained by the Mercury Laser Altimeter (MLA) instrument [4] in conjunction with a three-dimensional ray-tracing thermal model previously used to study the thermal environment of polar craters on the Moon [5]

Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.

While liposarcoma is the second most common soft tissue malignant tumor, the molecular pathogenesis in this malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade liposarcomas and benign lipomas across multiple disease sites, as well as two liposarcoma cell lines, using multiplexed mutational analysis. Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways. Liposarcoma cell lines were used to determine the effects of PI3K targeted drug treatment with or without chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human liposarcoma patients (22%). No PIK3CA mutations were identified in benign lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant liposarcoma samples. PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in liposarcoma cell lines and induced apoptosis. Importantly, combination with PI-103 treatment strongly synergized the growth-inhibitory effects of the chemotherapy drugs doxorubicin and cisplatin in liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important cancer mechanism in liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with chemotherapy could be exploited as a novel strategy in the treatment of liposarcoma

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BackgroundThe large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).MethodsPROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal.ResultsIn 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively.ConclusionsPROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings

Feasibility and validity of a low-cost racing simulator in driving assessment after stroke

There is a myriad of methodologies to assess driving performance after a stroke. These include psychometric tests, driving simulation, questionnaires, and/or road tests. Research-based driving simulators have emerged as a safe, convenient way to assess driving performance after a stroke. Such traditional research simulators are useful in recreating street traffic scenarios, but are often expensive, with limited physics models and graphics rendering. In contrast, racing simulators developed for motorsport professionals and enthusiasts offer high levels of realism, run on consumer-grade hardware, and can provide rich telemetric data. However, most offer limited simulation of traffic scenarios. This pilot study compares the feasibility of research simulation and racing simulation in a sample with minor stroke. We determine that the racing simulator is tolerated well in subjects with a minor stroke. There were correlations between research and racing simulator outcomes with psychometric tests associated with driving performance, such as the Trails Making Test Part A, Snellgrove Maze Task, and the Motricity Index. We found correlations between measures of driving speed on a complex research simulator scenario and racing simulator lap time and maximum tires off track. Finally, we present two models, using outcomes from either the research or racing simulator, predicting road test failure as linked to a previously published fitness-to-drive calculator that uses psychometric screening

The Lack of an Inherent Membrane Targeting Signal Is Responsible for the Failure of the Matrix (M1) Protein of Influenza A Virus To Bud into Virus-Like Particles

The matrix protein (M1) of influenza A virus is generally viewed as a key orchestrator in the release of influenza virions from the plasma membrane during infection. In contrast to this model, recent studies have indicated that influenza virus requires expression of the envelope proteins for budding of intracellular M1 into virus particles. Here we explored the mechanisms that control M1 budding. Similarly to previous studies, we found that M1 by itself fails to form virus-like-particles (VLPs). We further demonstrated that M1, in the absence of other viral proteins, was preferentially targeted to the nucleus/perinuclear region rather than to the plasma membrane, where influenza virions bud. Remarkably, we showed that a 10-residue membrane targeting peptide from either the Fyn or Lck oncoprotein appended to M1 at the N terminus redirected M1 to the plasma membrane and allowed M1 particle budding without additional viral envelope proteins. To further identify a functional link between plasma membrane targeting and VLP formation, we took advantage of the fact that M1 can interact with M2, unless the cytoplasmic tail is absent. Notably, native M2 but not mutant M2 effectively targeted M1 to the plasma membrane and produced extracellular M1 VLPs. Our results suggest that influenza virus M1 may not possess an inherent membrane targeting signal. Thus, the lack of efficient plasma membrane targeting is responsible for the failure of M1 in budding. This study highlights the fact that interactions of M1 with viral envelope proteins are essential to direct M1 to the plasma membrane for influenza virus particle release

The Impact of Feeding Cannabidiol (CBD) Containing Treats on Canine Response to a Noise-Induced Fear Response Test

Interest is increasing regarding use of Cannabidiol (CBD) in companion animals due to anecdotal evidence of beneficial behavioral and health effects. The purpose of this investigation was to evaluate the influence of CBD on behavioral responses to fear-inducing stimuli in dogs. Sixteen dogs (18.1 ± 0.2 kg) were utilized in a replicated 4 × 4 Latin square design experiment with treatments arranged in a 2 × 2 factorial, consisting of control, 25 mg CBD, trazodone (100 mg for 10–20 kg BW, 200 mg for 20.1–40 kg BW), and the combination of CBD and trazodone. A fireworks model of noise-induced fear was used to assess CBD effectiveness after 7 d of supplementation. Each test lasted a total of 6 min and consisted of a 3 min environmental habituation phase with no noise and a 3 min noise phase with a fireworks track. Plasma was collected 1 h before, immediately after, and 1 h following testing for cortisol analysis. Behaviors in each 3 min block were video recorded, and heart rate (HR) sensors were fitted for collection of HR and HR variability parameters. Research personnel administering treats and analyzing behavioral data were blinded as to the treatments administered. Data were tested for normality using the UNIVARIATE procedure in SAS, then differences examined using the MIXED procedure with fixed effects of treatment, period, time, and treatment x time interaction. Inactivity duration and HR increased during the first minute of the fireworks track compared with 1 min prior (P \u3c 0.001 and P = 0.011, respectively), indicating the fireworks model successfully generated a fear response. Trazodone lowered plasma cortisol (P \u3c 0.001), which was unaffected by CBD (P = 0.104) or the combination with CBD (P = 0.238). Neither CBD nor trazodone affected the duration of inactivity (P = 0.918 and 0.329, respectively). Trazodone increased time spent with tail relaxed (P = 0.001). CBD tended to increase HR (P = 0.093) and decreased the peak of low- and high-frequency bands (LF and HF, P = 0.011 and 0.022, respectively). These results do not support an anxiolytic effect of CBD in dogs given 1.4 mg CBD/kg BW/d

Craters Hosting Radar-Bright Deposits in Mercury's North Polar Region: Areas of Persistent Shadow Determined from MESSENGER Images

Radar-bright features near Mercury's poles were discovered in Earth-based radar images and proposed to be water ice present in permanently shadowed areas. Images from MESSENGER's one-year primary orbital mission provide the first nearly complete view of Mercury’s north polar region, as well as multiple images of the surface under a range of illumination conditions. We find that radar-bright features near Mercury's north pole are associated with locations persistently shadowed in MESSENGER images. Within 10 degrees of the pole, almost all craters larger than 10 km in diameter host radar-bright deposits. There are several craters located near Mercury's north pole with sufficiently large diameters to enable long-lived water ice to be thermally stable at the surface within regions of permanent shadow. Craters located farther south also host radar-bright deposits and show a preference for cold-pole longitudes; thermal models suggest that a thin insulating layer is required to cover these deposits if the radar-bright material consists predominantly of longlived water ice. Many small (less than 10 km diameter) and low-latitude (extending southward to 66 degrees N) craters host radar-bright material, and water ice may not be thermally stable in these craters for ~1 Gy, even beneath an insulating layer. The correlation of radar-bright features with persistently shadowed areas is consistent with the deposits being composed of water ice, and future thermal modeling of small and low-latitude craters has the potential to further constrain the nature, source, and timing of emplacement of the radar-bright material