Hepatic dysfunction in primary hypothyroidism

Twenty-seven patients with primary hypothyroidism were studied to evaluate the relationship between hepatic function and thyroid hormone deficiency in this disorder. In hypothyroidism, hypergammaglobulinemia was found in 71%, elevated glutamic oxaloacetic transaminase (GOT) in 48%, high lactic dehydrogenase (LDH) in 58%, hypercholesteremia in 52% and low elimination rate constant of indocyanin green (KICG) in 44%. In each criterion of liver function, these patients were divided into two groups, normal level and abnormal level group, respectively. T3 and T4 in patients with abnormal levels of GOT, glutamic pyruvic transaminase (GPT), gamma-glutamyl transpeptidase (gamma-GTP), leucine aminopeptidase (LAP), alkaline phosphatase (ALP) and 45 minutes retention rate of bromsulphalein (BSP) were not different from those in the normal level group. However, T3 and T4 in patients with abnormal levels of LDH, cholesterol, cholinesterase (ChE) and KICG were lower than those in the normal level group. The abnormal KICG group had a statistically higher cardio-thoracic ratio (CTR) than the normal group (65.7 +/- 18.8% vs 50.4 +/- 8.3%, p less than 0.05). In patients with pericardial effusion, CTR was 65.9 +/- 14.6%, while that in patients without pericardial effusion was 49.9 +/- 7.5% (p less than 0.05). These abnormalities of liver function were normalized in all cases after hormone replacement therapy. Liver biopsy in three cases disclosed normal liver in two cases and mild infiltration of monocyte into Glisson's capsule in one case.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isolation of methotrexate-resistant cell lines in Petunia hybrida upon stepwise selection procedure

Summary Cell suspensions of Petunia hybrida were subjected to a selection procedure in which the concentration of the selective agent, methotrexate (MTX), was gradually elevated. In mammalian cells, this procedure frequently results in MTX-resistant mutants due to amplification of the gene coding for dihydrofolate reductase (DHFR), the target protein of MTX.Five suspension lines were isolated, with degrees of resistance ranging from 10 to 500 M MTX (in wild type the LD_99.9 is 0.2 M). MTX^R phenotypes were unstable, as manifested by the loss of resistance upon prolonged growth in the absence of drug. All of the mutants also exhibited high values of MTX-binding protein (60- to 400-fold higher than that of the wild type), which declined to intermediate values upon MTX withdrawal. Finally, cellular extracts from all of the mutants also showed high specific staining of DHFR-activity in gels.The results suggest that the resistance of MTX in these plant cell-lines is mediated by the elevation of the amounts of DHFR, probably as a consequence of gene amplification.     

Concentration-dependent inducing activity of activin A

Summary Human recombinant activin A, which is identical with erythroid differentiation factor (EDF), was tested for its mesoderm-inducing activity in concentrations from 0.3–50 ng/ml, using ectoderm of Xenopus late blastula (Stage 9) as the responding tissue. At a low concentration of activin A, blood-like cells, mesenchyme, and coelomic epithelium were induced; at a moderate concentration muscle and neural tissue, and at a high concentration notochord. Activin A thus induced all mesodermal tissues in a dose-dependent manner, such that a low dose induced ventral structures and a high dose induced dorsal structures. Activin may act as an intrinsic inducing molecule responsible for establishing the dorso-ventral axis in early Xenopus development. Offprint requests to: M. Asashima     

Points of departure for a constructive critique of the Bolivarian Revolution

From what Left position, both intellectually and politically, does one formulate a critique of the Chávez-led Bolivarian Revolution without aligning with a right-wing opposition? For starters, we need reliable evidence of the achievements, problems, and mistakes of the Bolivarian project. At the same time, any engagement with social change in Venezuela necessitates attention to one’s positionality as well as scholarly and activist categories of analysis and practice.     

Matrilin-3 Induction of IL-1 receptor antagonist Is required for up-regulating collagen II and aggrecan and down-regulating ADAMTS-5 gene expression

Introduction

Deletion or mutation of the gene encoding the cartilage extracellular matrix (ECM) protein matrilin-3 (MATN3) results in the early onset of osteoarthritis (OA), suggesting chondroprotective properties of MATN3. To understand the mechanisms underlying these properties, we determined the effects of MATN3 protein on the expression of several key anabolic and catabolic genes involved in chondrocyte homeostasis, and the dependence of such regulation on the anti-inflammatory cytokine: IL-1 receptor antagonist (IL-1Ra).

Methods

The effects of recombinant human (rh) MATN3 protein were examined in C28/I2 immortalized human chondrocytes, primary human chondrocytes (PHCs), and primary mouse chondrocytes (PMCs). Messenger RNA levels of IL-1Ra, COL2A1, ACAN, MMP-13, and ADAMTS-4 and -5 were determined using real-time RT-PCR. Knocking down IL-1Ra was achieved by siRNA gene silencing. IL-1Ra protein levels were quantified by ELISA and the Bio-Plex Suspension Array System. COL2A1 protein level was quantified using Western blot analysis. Statistic analysis was done using the two-tailed t-test or one-way ANOVA.

Results

rhMATN3 protein induced gene expression of IL-1Ra in C28/I2 cells, PHCs, and PMCs in a dose- and time-dependent manner. Treatment of C28/I2 cells and PHCs with MATN3 protein stimulated gene expression of COL2A1 and ACAN. Conversely, mRNA levels of COL2A1 and ACAN were decreased in MATN3 KO mice. MATN3 protein treatment inhibited IL-1β-induced MMP-13, ADAMTS-4 and ADAMTS-5 in C28/I2 cells and PHCs. Knocking down IL-1Ra abolished the MATN3-mediated stimulation of COL2A1 and ACAN and inhibition of ADAMTS-5, but had no effect on MATN3 inhibition of MMP-13 mRNA.

Conclusion

Our findings point to a novel regulatory role of MATN3 in cartilage homeostasis due to its capacity to induce IL-1Ra, to upregulate gene expression of the major cartilage matrix components, and to downregulate the expression of OA-associated matrix-degrading proteinases in chondrocytes. The chondroprotective properties of endogenous MATN3 depend partly on its induction of IL-1Ra. Our findings raise a possibility to use rhMATN3 protein for anti-inflammatory and chondroprotective therapy.     

DNA methylation profiles provide a viable index for porcine pluripotent stem cells

Porcine induced pluripotent stem cells (iPSCs) provide useful information for translational research. The quality of iPSCs can be assessed by their ability to differentiate into various cell types after chimera formation. However, analysis of chimera formation in pigs is a labor‐intensive and costly process, necessitating a simple evaluation method for porcine iPSCs. Our previous study identified mouse embryonic stem cell (ESC)‐specific hypomethylated loci (EShypo‐T‐DMRs), and, in this study, 36 genes selected from these were used to evaluate porcine iPSC lines. Based on the methylation profiles of the 36 genes, the iPSC line, Porco Rosso‐4, was found closest to mouse pluripotent stem cells among 5 porcine iPSCs. Moreover, Porco Rosso‐4 more efficiently contributed to the inner cell mass (ICM) of blastocysts than the iPSC line showing the lowest reprogramming of the 36 genes (Porco Rosso‐622‐14), indicating that the DNA methylation profile correlates with efficiency of ICM contribution. Furthermore, factors known to enhance iPSC quality (serum‐free medium with PD0325901 and CHIR99021) improved the methylation status at the 36 genes. Thus, the DNA methylation profile of these 36 genes is a viable index for evaluation of porcine iPSCs. genesis 51:763–776. © 2013 Wiley Periodicals, Inc.     

Examining disruption of pheromone communication in Choristoneura rosaceana and Pandemis limitata using microencapsulated (Z)-11-tetradecenyl acetate applied in a laboratory flight tunnel

Pheromone‐based mating disruption of lepidopteran pests (Tortricidae) of pome fruits using hand‐applied dispensing systems has become standard management practice for many producers in western North America. Sprayable microencapsulated (MEC) pheromone formulations that enable the application of pheromone controls with other orchard sprays and assist in the development of multispecies mating‐disruption systems are currently under development. Responses of male Choristoneura rosaceana (Harris) and Pandemis limitata (Robinson) (Lepidoptera: Tortricidae) to calling females in clean air, and air treated with their major pheromone component (Z)‐11‐tetradecenyl acetate (Z11‐14:OAc), released from a 3M sprayable pheromone formulation containing proprietary 3M Phase I microcapsules, applied at doses of 1, 10, and 100 mg of active ingredient (ai) m^?2 to the upwind end of a flight tunnel (equivalent to field rates of 10, 100, and 1000 g ai ha^?1) were compared in laboratory flight tunnels. In both species, disorientation was found to be dose‐dependent, because relative to male orientation to calling females in clean air, the orientation of male P. limitata was disrupted 23.3, 46.3, and 71.3%, and orientation by male C. rosaceana was disrupted 31.6, 37.7, and 45.8% by treatment doses of 1, 10, and 100 mg m^?2, respectively. Latency of male responses to calling females in a background of Z11‐14:OAc relative to responses in clean air was also dose‐dependent. Albeit short, the disruption lasted 26, 74, and 218 h in P. limitata and 30, 54, and 174 h in C. rosaceana at each application rate, respectively. Disruption by pheromone treatment was greater in P. limitata than in C. rosaceana. This difference may be correlated with species’ differences in the pheromone release rates of females. Mechanisms of disruption invoked by this 3M MEC pheromone formulation are discussed in relation to issues of its longevity and observed differences in the effects against the two species. It appears possible to evaluate relative activity of MEC pheromones in a laboratory setting which may aid in development of new formulations for mating disruption.     

Unraveling the Genetic Etiology of Adult Antisocial Behavior: A Genome-Wide Association Study

Crime poses a major burden for society. The heterogeneous nature of criminal behavior makes it difficult to unravel its causes. Relatively little research has been conducted on the genetic influences of criminal behavior. The few twin and adoption studies that have been undertaken suggest that about half of the variance in antisocial behavior can be explained by genetic factors. In order to identify the specific common genetic variants underlying this behavior, we conduct the first genome-wide association study (GWAS) on adult antisocial behavior. Our sample comprised a community sample of 4816 individuals who had completed a self-report questionnaire. No genetic polymorphisms reached genome-wide significance for association with adult antisocial behavior. In addition, none of the traditional candidate genes can be confirmed in our study. While not genome-wide significant, the gene with the strongest association (p-value = 8.7×10⁻⁵) was DYRK1A, a gene previously related to abnormal brain development and mental retardation. Future studies should use larger, more homogeneous samples to disentangle the etiology of antisocial behavior. Biosocial criminological research allows a more empirically grounded understanding of criminal behavior, which could ultimately inform and improve current treatment strategies.     

ATP sensitive bi-quinoline activator of the AMP-activated protein kinase

The AMP-activated protein kinase (AMPK) regulates cellular and whole-body energy balance in response to changes in adenylate charge and hormonal signals. Activation of AMPK in tissues such as skeletal muscle and liver reverses many of the metabolic defects associated with obesity and Type 2 diabetes. Here we report a bi-quinoline (JJO-1) that allosterically activates all AMPK αβγ isoforms in vitro except complexes containing the γ3 subunit. JJO-1 does not directly activate the autoinhibited α subunit kinase domain and differs among other known direct activators of AMPK in that allosteric activation occurs only at low ATP concentrations, and is not influenced by either mutation of the γ subunit adenylate-nucleotide binding sites or deletion of the β subunit carbohydrate-binding module. Our findings indicate that AMPK has multiple modes of allosteric activation that may be exploited to design isoform-specific activators as potential therapeutics for metabolic diseases.