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

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

Identification of Unique MicroRNA Signature Associated with Lupus Nephritis

MicroRNAs (miRNA) have emerged as an important new class of modulators of gene expression. In this study we investigated miRNA that are differentially expressed in lupus nephritis. Microarray technology was used to investigate differentially expressed miRNA in peripheral blood mononuclear cells (PBMCs) and Epstein-Barr Virus (EBV)-transformed cell lines obtained from lupus nephritis affected patients and unaffected controls. TaqMan-based stem-loop real-time polymerase chain reaction was used for validation. Microarray analysis of miRNA expressed in both African American (AA) and European American (EA) derived lupus nephritis samples revealed 29 and 50 differentially expressed miRNA, respectively, of 850 tested. There were 18 miRNA that were differentially expressed in both racial groups. When samples from both racial groups and different specimen types were considered, there were 5 primary miRNA that were differentially expressed. We have identified 5 miRNA; hsa-miR-371-5P, hsa-miR-423-5P, hsa-miR-638, hsa-miR-1224-3P and hsa-miR-663 that were differentially expressed in lupus nephritis across different racial groups and all specimen types tested. Hsa-miR-371-5P, hsa-miR-1224-3P and hsa-miR-423-5P, are reported here for the first time to be associated with lupus nephritis. Our work establishes EBV-transformed B cell lines as a useful model for the discovery of miRNA as biomarkers for SLE. Based on these findings, we postulate that these differentially expressed miRNA may be potential novel biomarkers for SLE as well as help elucidate pathogenic mechanisms of lupus nephritis. The investigation of miRNA profiles in SLE may lead to the discovery and development of novel methods to diagnosis, treat and prevent SLE

Tumor suppressive activity of prolyl isomerase Pin1 in renal cell carcinoma

Pin1 specifically recognizes and catalyzes the cis-trans isomerization of phosphorylated-Ser/Thr-Pro bonds, which modulate the stability, localization, and function of numerous Pin1 targets involved in tumor progression. However, the role of Pin1 in cancer remains enigmatic as the gene is located on chromosome 19p13.2, which is a region subject to loss of heterozygosity in several tumors. Since Pin1 protein is frequently under-expressed in kidney cancer, we have explored its role in human clear cell renal cell carcinoma (ccRCC). Here we show evidence for PIN1 gene deletion and mRNA under-expression as a mechanism of Pin1 reduction in ccRCC tumors. We demonstrate that restoration of Pin1 in cell lines found to be deficient in Pin1 protein expression can attenuate the growth of ccRCC cells in soft agar and a xenograft tumor model. Moreover, this ability of Pin1 to negatively influence tumor growth in ccRCC cells may be dependent on the presence of functional p53, which is infrequently mutated in ccRCC. These observations suggest Pin1 may have a mild tumor suppressive role in ccRCC

Highly Polarized Optically-Selected BL Lacertae Objects

Observations of candidate BL Lacertae objects spectroscopically selected from the Sloan Digital Sky Survey (SDSS) reveal a large fraction with high polarization (P > 3%). This result confirms that synchrotron radiation makes an important contribution to the observed optical continuum for most objects in the sample. The SDSS sample can be divided into separate categories, with objects of undetermined redshift generally having the highest optical polarization. Polarization as high as 23% and the lack of spectral features suggests that the synchrotron continuum completely dominates the spectra of these sources. The mean polarization levels observed for objects having measured redshifts is much lower, with the maximum observed polarization for this group being ~10%. The lower polarizations of these objects are reminiscent of the less spectacular polarization levels shown by BL Lac objects discovered in X-ray surveys. We find no SDSS BL Lac candidates at z > 1 with P > 3%, calling their classification as BL Lac objects into question. In addition, the existence of radio-quiet BL Lac objects is not verified since none of 10 potentially radio-weak BL Lac candidates observed are highly polarized. Regardless of whether the high-redshift and radio-weak objects are included in this optical sample, the overall levels of polarization observed are intermediate between those seen for X-ray and radio-selected BL Lac objects.Comment: 9 pages, 3 figures, 2 table

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

Software for Generating Troposphere Corrections for InSAR Using GPS and Weather Model Data

Atmospheric errors due to the troposphere are a limiting error source for spaceborne interferometric synthetic aperture radar (InSAR) imaging. This software generates tropospheric delay maps that can be used to correct atmospheric artifacts in InSAR data. The software automatically acquires all needed GPS (Global Positioning System), weather, and Digital Elevation Map data, and generates a tropospheric correction map using a novel algorithm for combining GPS and weather information while accounting for terrain. Existing JPL software was prototypical in nature, required a MATLAB license, required additional steps to acquire and ingest needed GPS and weather data, and did not account for topography in interpolation. Previous software did not achieve a level of automation suitable for integration in a Web portal. This software overcomes these issues. GPS estimates of tropospheric delay are a source of corrections that can be used to form correction maps to be applied to InSAR data, but the spacing of GPS stations is insufficient to remove short-wavelength tropospheric artifacts. This software combines interpolated GPS delay with weather model precipitable water vapor (PWV) and a digital elevation model to account for terrain, increasing the spatial resolution of the tropospheric correction maps and thus removing short wavelength tropospheric artifacts to a greater extent. It will be integrated into a Web portal request system, allowing use in a future L-band SAR Earth radar mission data system. This will be a significant contribution to its technology readiness, building on existing investments in in situ space geodetic networks, and improving timeliness, quality, and science value of the collected dat