Lesions of the paraventricular nucleus of the thalamus differentially affect sign‐ and goal‐tracking conditioned responses

Recently, evidence has emerged suggesting a role for the paraventricular nucleus of the thalamus (PVT) in the processing of reward‐associated cues. However, the specific role of the PVT in these processes has yet to be elucidated. Here we use an animal model that captures individual variation in response to discrete reward‐associated cues to further assess the role of the PVT in stimulus–reward learning. When rats are exposed to a Pavlovian conditioning paradigm, wherein a discrete cue predicts food reward, two distinct conditioned responses emerge. Some rats, termed sign‐trackers, approach and manipulate the cue, whereas others, termed goal‐trackers, approach the location of reward delivery upon cue presentation. For both sign‐ and goal‐trackers the cue is a predictor, but only for sign‐trackers is it also an incentive stimulus. We investigated the role of the PVT in the acquisition and expression of these conditioned responses using an excitotoxic lesion. Results indicate that PVT lesions prior to acquisition amplify the differences between phenotypes – increasing sign‐tracking and attenuating goal‐tracking behavior. Lesions of the PVT after rats had acquired their respective conditioned responses also attenuated the expression of the goal‐tracking response, and increased the sign‐tracking response, but did so selectively in goal‐trackers. These results suggest that the PVT acts to suppress the attribution of incentive salience to reward cues, as disruption of the functional activity within this structure enhances the tendency to sign‐track.Here we utilized animal models that capture individual differences in the propensity to attribute incentive salience to reward cues (i.e. sign‐trackers vs. goal‐trackers) to further elucidate the role of the PVT in cue‐motivated behaviors. We report that lesions of this structure increase the tendency for individuals to attribute incentive motivational value to reward cues. These findings suggest that the PVT is a critical part of the circuitry underlying maladaptive behavior, such as addiction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115973/1/ejn13031-sup-0001-TableS1-FigureS1-S5.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115973/2/ejn13031.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/115973/3/ejn13031_am.pd

Gastrointestinal Stromal Tumors: a Rare Neoplasm Presenting with Gastrointestinal Bleeding

Gastrointestinal stromal tumors (GIST) are rare tumors of the gastrointestinal (GI) tract that arise from primitive mesenchymal cells. GISTs occur throughout the GI tract but are usually located in the stomach and small intestine. GISTs are known with myoid, neural or mixed features of differentiation. Clinical findings are gastrointestinal bleeding, abdominal pain, and weight loss. GISTs express a heterogeneous clinical course not easily predicted. The histologic features that correlate best with development of recurrence and metastasis are mitotic activity, tumor size and the presence of tumor necrosis and most recently, mutation in the c-kit gene. Some authors specifically use the term GIST to refer to only those mesenchymal tumors that express CD117, whereas others believe that the diagnosis can be made in the absence of CD117 positivity based on clinical and morphologic features. Surgical resection remains the treatment of choice, since chemotherapy and radiation are ineffective. Long-term follow-up is imperative and recurrence rates are high. We report the case of a 60 years old female patient who presented with intermittent melena, chronic dyspepsia, and anemia. Upper digestive tract endoscopy showed a submucosal tumor, broad-based, centrally ulcerated, projection of >5 cm in the gastric corpus-antral wall as the cause of the upper gastrointestinal bleeding. Endoscopic biopsies were negative for neoplastic changes. After triple eradication therapy of Helicobacter pylori and treatment continued with proton pump inhibitor agent, the patient underwent distal gastrectomy with Billroth-I reconstruction. Histopatological studies on the surgical resection specimen revealed a GIST of smooth muscle with spindle cell, no evidence of mitotic activity but of uncertain biological behavior. One year after surgery the patient is was improved with no signs of residual Malignancy. However, metastases were found later in the liver in the next two year

Effects of a selectively bred novelty-seeking phenotype on the motivation to take cocaine in male and female rats

<p>Abstract</p> <p>Background</p> <p>Gender and enhanced novelty reactivity can predispose certain individuals to drug abuse. Previous research in male and female rats selectively bred for high or low locomotor reactivity to novelty found that bred High Responders (bHRs) acquire cocaine self-administration more rapidly than bred Low Responders (bLRs) and that bHR females in particular self-administered more cocaine than the other groups. The experiments presented here aimed to determine whether an individual's sex and behavioral phenotype interact to affect motivation to take cocaine.</p> <p>Methods</p> <p>We examined motivation for taking cocaine in two experiments using a range of doses on a progressive ratio (PR) schedule of responding in bHR or bLR males and females. Additionally, we included a measure of continuing to respond in the absence of reinforcement, a feature of addiction that has been recently incorporated into tests of animal models on the basis of the criteria for substance use disorder in the <it>Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition</it>. Statistical analyses were performed using PASW Statistics 18.0 software. Data were analyzed using repeated-measures analysis of variance followed by a Bonferroni correction <it>post hoc </it>test when applicable.</p> <p>Results</p> <p>We found sex differences as well as effects of novelty reactivity on the motivation to self-administer cocaine. Specifically, females demonstrated higher breaking points on the PR schedule compared with males, regardless of phenotype, and bHR males and females exhibited higher motivation than bLR animals at a number of the doses studied.</p> <p>Conclusions</p> <p>An individual's sex continues to be a predisposing factor with respect to drug abuse liability and can be compounded by additional individual differences such as reactivity to novelty.</p

Lateral hypothalamic innervation of the cerebral cortex: Immunoreactive staining for a peptide resembling but immunochemically distinct from pituitary/arcuate [alpha]-melanocyte stimulating hormone

The combination of retrograde transport of fluorescent dyes and indirect immunofluorescence has been used to study the putative neurotransmitter specificity of the tuberal lateral hypothalamic projection to the cerebral cortex. Injections of either fast blue or diamidino yellow dye into the cerebral cortex or hippocampus retrogradely labeled large, multipolar neurons scattered through the lateral hypothalamic area and zona incerta at the level of the ventromedial nucleus of the hypothalamus. Approximately 80% of these neurons stained immunohistochemically with an antiserum against [alpha]-melanocyte stimulating hormone ([alpha]-MSH). A second population of smaller, predominantly bipolar [alpha]-MSH-like immunoreactive neurons was seen in the arcuate nucleus and retrochiasmatic area, but none of these projected to the cerebral cortex. Immunohistochemical staining for ACTH (18-24), another proopiomelanocortin series peptide, or with an antiserum against [alpha]-MSH (4-10) demonstrated only the second of these cell groups. Our results indicate that the tuberal lateral hypothalamic projection to the cerebral cortex contains a substance similar but not identical to [alpha]-MSH, and that this material is probably not derived from the same proopiomelanocortin precursor as true [alpha]-MSH.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26352/1/0000439.pd

Design and synthesis of new thiazolidinone/uracil derivatives as antiproliferative agents targeting EGFR and/or BRAFV600E^{V600E}

Thiourea derivatives of uracil were efficiently synthesized via the reaction of 5-aminouracil with isothiocyanates. Then, we prepared uracil-containing thiazoles via condensation of thioureas with diethyl/dimethyl acetylenedicarboxylates. The structures of the products were confirmed by a combination of spectral techniques including infra-red (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and elemental analyses. A rationale for the formation of the products is presented. The newly synthesized compounds were evaluated for their in vitro antiproliferative activity against four cancer cell lines. The compounds tested showed promising antiproliferative activity, with GI$_{50}$ values ranging from 1.10 µM to 10.00 µM. Compounds 3c, 5b, 5c, 5h, 5i, and 5j were the most potent derivatives, with GI$_{50}$ values ranging from 1.10 µM to 1.80 µM. Compound 5b showed potent inhibitory activity against EGFR and BRAF$^{V600E}$ with IC$_{50}$ of 91 ± 07 and 93 ± 08 nM, respectively, indicating that this compound could serve as a dual inhibitor of EGFR and BRAF$^{V600E}$ with promising antiproliferative properties. Docking computations revealed the great potency of compounds 5b and 5j towards EGFR and BRAF$^{V600E}$ with docking scores of −8.3 and −9.7 kcal/mol and −8.2 and −9.3 kcal/mol, respectively

Point Mutations in the 90-kDa Heat Shock Protein Binding Region of the Glucocorticoid Receptor Affect the Functional Characteristics of the Receptor a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72162/1/j.1749-6632.1995.tb31403.x.pd

Design, synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents

In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI$_{50}$ values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI$_{50}$ = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAF$^{V600E}$. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAF$^{V600E}$ with values of − 9.1 and − 8.6, −9.0 and − 8.5, and − 8.4 and − 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability

Conventional Electrode Materials for Microbial Fuel Cells

The use of microbial fuel cells (MFCs) has gained a lot of attention as a means to combat both energy shortages and water pollution. Despite their best efforts, MFCs are unable to produce substantial amounts of energy or effectively remove pollutants due to a number of difficulties, one of which being the electrode. One of the most significant components of an MFC is the electrode. Different types of electrode materials have recently been developed to boost pollutant removal rates and energy production efficiency. Carbon-based materials have been used as the most often used electrode material in MFCs. A wide range of potentials is now accessible for use in the manufacturing of electrode materials, which can significantly reduce current issues such as the demand for high-quality materials and their cost. In the present chapter, the conventional electrode material is briefly discussed with their influence and role in MFC operation and performance. A brief discussion of the current issues and future views of electrode materials is also included