Changes in Milk Protein and Amino Acid Composition of Dairy Cows in Response to Fatty Liver and Intravenous Glucagon

Intravenous glucagon cures fatty liver by improving glucose bioavailability in early lactation. Amino acids, which would be otherwise used for milk protein synthesis, are metabolized to glucose. The objective of this study was to examine whether intravenous glucagon and fatty liver change milk protein and amino acid composition in dairy cows. Multiparous Holstein cows (n=25) were designated as either normal or susceptible to fatty liver and ketosis as based on the ratio of liver triacylglycerol to glycogen being smaller or greater than 2.0 at d 6 postpartum. Cows susceptible to fatty liver were subjected for 3 weeks to a protocol consisting of feed restriction and dietary 1,3- butanediol beginning at d 14 postpartum, which induced fatty liver and ketosis. Normal cows and cows with fatty liver were infused with glucagon for 14 d at 0 or 10 mg/d beginning at d 21 postpartum. Composite milk samples were obtained at d 20, 22, 34, and 36 postpartum and analyzed for milk protein and amino acid composition. Fatty liver decreased milk yield but had little effect on milk protein and amino acid composition except for increasing the proportion of glycosylated κ-casein. Intravenous glucagon decreased total milk protein concentrations and the proportion of α–lactalbumin and increased the proportion of glycosylated κ-casein, total κ-casein, and αS2-casein. Intravenous glucagon had little effect on milk amino acid composition. Our results suggest that milk protein and amino acid composition are under tight concomitant hormonal control and are affected little by changes in amino acid availability and/or insulin to glucagon ratio

Probing ISM Structure in Trumpler 14 & Carina I Using The Stratospheric Terahertz Observatory 2

We present observations of the Trumpler 14/Carina I region carried out using the Stratospheric Terahertz Observatory 2 (STO2). The Trumpler 14/Carina I region is in the west part of the Carina Nebula Complex, which is one of the most extreme star-forming regions in the Milky Way. We observed Trumpler 14/Carina I in the 158 $\mu$m transition of [C\,{\sc ii}] with a spatial resolution of 48$''$ and a velocity resolution of 0.17 km s$^{-1}$. The observations cover a 0.25$^\circ$ by 0.28$^\circ$ area with central position {\it l} = 297.34$^\circ$, {\it b} = -0.60$^\circ$. The kinematics show that bright [C\,{\sc ii}] structures are spatially and spectrally correlated with the surfaces of CO clouds, tracing the photodissociation region and ionization front of each molecular cloud. Along 7 lines of sight that traverse Tr 14 into the dark ridge to the southwest, we find that the [C\,{\sc ii}] luminosity from the HII region is 3.7 times that from the PDR. In same los we find in the PDRs an average ratio of 1:4.1:5.6 for the mass in atomic gas:dark-CO gas: molecular gas traced by CO. Comparing multiple gas tracers including HI 21cm, [C\,{\sc ii}], CO, and radio recombination lines, we find that the HII regions of the Carina Nebula Complex are well-described as HII regions with one-side freely expanding towards us, consistent with the champagne model of ionized gas evolution. The dispersal of the GMC in this region is dominated by EUV photoevaporation; the dispersal timescale is 20-30 Myr.Comment: ApJ accepte

Associations of physical inactivity and COVID-19 outcomes among subgroups

Introduction Physical activity before COVID-19 infection is associated with less severe outcomes. The study determined whether a dose‒response association was observed and whether the associations were consistent across demographic subgroups and chronic conditions. Methods A retrospective cohort study of Kaiser Permanente Southern California adult patients who had a positive COVID-19 diagnosis between January 1, 2020 and May 31, 2021 was created. The exposure was the median of at least 3 physical activity self-reports before diagnosis. Patients were categorized as follows: always inactive, all assessments at 10 minutes/week or less; mostly inactive, median of 0–60 minutes per week; some activity, median of 60–150 minutes per week; consistently active, median>150 minutes per week; and always active, all assessments>150 minutes per week. Outcomes were hospitalization, deterioration event, or death 90 days after a COVID-19 diagnosis. Data were analyzed in 2022. Results Of 194,191 adults with COVID-19 infection, 6.3% were hospitalized, 3.1% experienced a deterioration event, and 2.8% died within 90 days. Dose‒response effects were strong; for example, patients in the some activity category had higher odds of hospitalization (OR=1.43; 95% CI=1.26, 1.63), deterioration (OR=1.83; 95% CI=1.49, 2.25), and death (OR=1.92; 95% CI=1.48, 2.49) than those in the always active category. Results were generally consistent across sex, race and ethnicity, age, and BMI categories and for patients with cardiovascular disease or hypertension. Conclusions There were protective associations of physical activity for adverse COVID-19 outcomes across demographic and clinical characteristics. Public health leaders should add physical activity to pandemic control strategies

Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells

Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines

Antipsychotic Prescribing Pathways, Polypharmacy, and Clozapine Use in Treatment of Schizophrenia

Objective To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. Methods Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher’s exact test. Results Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%–2%). Conclusions Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials

Reference Intervals: Strengths, Weaknesses, and Challenges

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Quantitative signature for architectural organization of regulatory factors using intranuclear informatics

Regulatory machinery for replication and gene expression is punctately organized in supramolecular complexes that are compartmentalized in nuclear microenvironments. Quantitative approaches are required to understand the assembly of regulatory machinery within the context of nuclear architecture and to provide a mechanistic link with biological control. We have developed \u27intranuclear informatics\u27 to quantify functionally relevant parameters of spatially organized nuclear domains. Using this informatics strategy we have characterized post-mitotic reestablishment of focal subnuclear organization of Runx (AML/Cbfa) transcription factors in progeny cells. By analyzing point mutations that abrogate fidelity of Runx intranuclear targeting, we establish molecular determinants for the spatial order of Runx domains. Our novel approach provides evidence that architectural organization of Runx factors may be fundamental to their tissue-specific regulatory function

Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES.

Propensity for developing coronary heart disease (CHD) is linked with Framingham-defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category o