Chlorpromazine reduces avoidance performance deficit in rats with dorsomedial thalamic lesions

Rats with bilateral lesions of the dorsomedial area of the thalamus were shown to have a significant performance deficit on the acquisition of a one-way active shock-avoidance task relative to sham-operated controls. Administration of chlorpromazine prior to testing was shown to reduce this deficit among the DMT-lesioned animals

Effects of harvest season on carcass characteristics of lambs in the Intermountain West

Objective: The objectives of this study were to survey characteristics including hot carcass weight (HCW), 12th rib fat thickness (RFT), body-wall thickness (BWT), longissimus muscle area (LMA), USDA yield grade (USDA YG), percentage closely trimmed retail cuts (RC), and calculated yield grade (Calc YG) of lamb carcasses in the Intermountain West to determine the effects of season of slaughter and interrelationships among carcass characteristics. Materials and Methods: Lamb carcass characteristics were evaluated in 2 commercial Intermountain West processing plants over one year (n = 10,027). Carcasses were evaluated by season: spring (December–April, n = 2,322) and summer (May–August, n = 7,705). Results and Discussion: Carcasses of lambs slaughtered in the spring had 3.4 kg heavier HCW (P = 0.04) than those slaughtered in the summer. Subcutaneous fat (RFT; P = 0.06) and Calc YG (P = 0.09) tended to be greater in the spring than summer. Correlation coefficients and models of fit with a linear covariate of HCW indicated negative relationship between HCW and RC and positive relationship with all other carcass traits (P \u3c 0.001). Overall, graded lamb carcasses exceeded commercial processing plant preferred HCW (38.6 kg) by 5% (mean = 40.5 kg) and industry acceptable RFT (6 mm) by 25% (mean = 8.03 mm). Furthermore, 70% of lamb carcasses exceed 6 mm RFT. Implications and Applications: Season of slaughter contributed to differences in HCW and USDA YG but no other carcass characteristics. Still, carcass data surveyed from the largest lamb-producing region of the United States suggests that the degree of fatness exceeds industry preferences. Although abattoirs mitigate adverse effects of excessive fat through trimming and diverse market outlets, industry-wide efforts that agree on acceptable standards of trimness are needed. Transparent dialog across industry segments should be prioritized in addition to consistent integration of value-based pricing to reduce the proportion of excessively finished lambs

Import of cytochrome c into mitochondria

The import of cytochrome c into mitochondria can be resolved into a number of discrete steps. Here we report on the covalent attachment of heme to apocytochrome c by the enzyme cytochrome c heme lyase in mitochondria from Neurospora crassa. A new method was developed to measure directly the linkage of heme to apocytochrome c. This method is independent of conformational changes in the protein accompanying heme attachment. Tryptic peptides of [35S]cysteine-labelled apocytochrome c, and of enzymatically formed holocytochrome c, were resolved by reverse-phase HPLC. The cysteine-containing peptide to which heme was attached eluted later than the corresponding peptide from apocytochrome c and could be quantified by counting 35S radioactivity as a measure of holocytochrome c formation. Using this procedure, the covalent attachment of heme to apocytochrome c, which is dependent on the enzyme cytochrome c heme lyase, could be measured. Activity required heme (as hemin) and could be reversibly inhibited by the analogue deuterohemin. Holocytochrome c formation was stimulated 5–10-fold by NADH > NADPH > glutathione and was independent of a potential across the inner mitochondrial membrane. NADH was not required for the binding of apocytochrome c to mitochondria and was not involved in the reduction of the cysteine thiols prior to heme attachment. Holocytochrome c formation was also dependent on a cytosolic factor that was necessary for the heme attaching step of cytochrome c import. The factor was a heat-stable, protease-insensitive, low-molecular-mass component of unknown function. Cytochrome c heme lyase appeared to be a soluble protein located in the mitochondrial intermembrane space and was distinct from the previously identified apocytochrome c binding protein having a similar location. A model is presented in which the covalent attachment of heme by cytochrome c heme lyase also plays an essential role in the import pathway of cytochrome c

Coping with the extremes : comparative osteology of the tepui-associated toad Oreophrynella and its bearing on the evolution of osteological novelties in the genus

The only study of the osteology of the toad genus Oreophrynella dates back to 1971 and was based on a single species. Here, we use high-resolution X-ray microcomputed tomography to analyse the osteology of all nine described Oreophrynella species, which are compared with representatives of other bufonid lineages. Oreophrynella is unique among bufonids in having opposable digits. Osteological synapomorphies confirmed for the genus are as follows: presence of parietal fontanelles and exposed frontoparietal fontanelle, absence of quadratojugal, five presacral vertebrae, distally enlarged terminal phalanges and urostyle greatly expanded into flanges. Ancestral character reconstruction indicates that arboreal habits in some Oreophrynella species are likely to have evolved after the evolution of opposable digits. Opposable digits, in combination with an extension of the interdigital integument and the relative length/orientation of the digits, are likely to be adaptations to facilitate life on rocky tepui summits and an exaptation to arboreality. Cranial simplification in Oreophrynella, in the form of cranial fontanelles and absence of the quadratojugal, is possibly driven by a reduction of developmental costs, increase in flexibility and reduction of body weight. Cranial simplification combined with the shortening of the vertebral column and the shift towards a partly firmisternal girdle might be adaptations to the peculiar tumbling behaviour displayed by Oreophrynella

Calmodulin-dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance

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Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).ConclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested