Differential aging-related changes of D1, D2, and D3 dopamine receptor expression in the striatum

Advisor: Stefan Clemens, Ph.D., HdRAging is associated with a decrease in motor function and a concomitant increase in muscle stiffness and tone. The striatum plays a critical role in the control of motor function, and it receives strong dopamine (DA) innervation from the substantia nigra. DA actions are mediated by both excitatory D1-like (D1 and D5) and inhibitory D2-like (D2, D3, and D4) receptors, and D1, D2, and D3 receptor subtypes are thought to be involved in motor control, however there is a lack of data on aging-related DA receptor expression levels in the striatum. We hypothesize that the observed behavioral aging-related changes in motor control might be associated with a change in striatal DA receptor with age, possibly via a shift in inhibitory/excitatory DA receptor expression. Three groups of mice (C57BL/6) aged 2 months (n=4), 1 year (n=4), and 2 years (n=4) were used in this study. Striatal tissue was removed from the left hemisphere and Western blots were performed, to detect DA receptors D1, D2, and D3 expression levels (Abcam, D1: ab78021; D2: ab21218, D3: ab42114). DA receptor expression levels were normalized to ß-actin and the respective DA receptor expression in 2-month old animals. We found that with age, D1 receptor expression increased continuously and significantly over a ~4 fold increase (383.2 ±62.4 %) in the 1 year old and reached a ~5 fold increase (474± 49.5 %) in the 2 year old animals (p<0.001). In contrast, D2 receptor expression did not change with age (1 year: 110.8 ±2.81 %; 2 year: 121.0 ± 17.0 %, p = 0.556). Similarly, D3 receptor expression showed no change with age (1 4 year: 147.1 ± 6.83 %; 2 year: 122.1 ± 11.4 %, p = 0.078). Together these data indicate an increase in excitatory striatal DA receptor expression levels with age. Our data suggest that this net excitatory increase may play a role in the decline in motor function with age. It is tempting to speculate that the increase in D1 receptor expression might be a homeostatic compensation for the well-established reduction of DA levels with age

Energy analysis and conservation opportunities in spray dryers

[EN] Dryers are used for removal of moisture from an raw materials (such as effluent) to form a dried solids as per the requirements. For removal of the moisture, energy requirement is huge. Therefore, in this paper, methodology for heat recovery in one of the type of dryers as spray dryers is developed, which is simple and easy to apply. The proposed methodology is illustrated with the help of an example taken from literature. It is observed that the indirect heat recovery method could save energy maximum up to 82 % as compared to literature and 41 % higher than without heat recovery.Patel, S.; Bade, M. (2018). Energy analysis and conservation opportunities in spray dryers. En IDS 2018. 21st International Drying Symposium Proceedings. Editorial Universitat Politècnica de València. 139-146. https://doi.org/10.4995/IDS2018.2018.7512OCS13914

Approximated Computation of Belief Functions for Robust Design Optimization

This paper presents some ideas to reduce the computational cost of evidence-based robust design optimization. Evidence Theory crystallizes both the aleatory and epistemic uncertainties in the design parameters, providing two quantitative measures, Belief and Plausibility, of the credibility of the computed value of the design budgets. The paper proposes some techniques to compute an approximation of Belief and Plausibility at a cost that is a fraction of the one required for an accurate calculation of the two values. Some simple test cases will show how the proposed techniques scale with the dimension of the problem. Finally a simple example of spacecraft system design is presented.Comment: AIAA-2012-1932 14th AIAA Non-Deterministic Approaches Conference. 23-26 April 2012 Sheraton Waikiki, Honolulu, Hawai

The appendage role of insect disco genes and possible implications on the evolution of the maggot larval form

AbstractThough initially identified as necessary for neural migration, Disconnected and its partially redundant paralog, Disco-related, are required for proper head segment identity during Drosophila embryogenesis. Here, we present evidence that these genes are also required for proper ventral appendage development during development of the adult fly, where they specify medial to distal appendage development. Cells lacking the disco genes cannot contribute to the medial and distal portions of ventral appendages. Further, ectopic disco transforms dorsal appendages toward ventral fates; in wing discs, the medial and distal leg development pathways are activated. Interestingly, this appendage role is conserved in the red flour beetle, Tribolium (where legs develop during embryogenesis), yet in the beetle we found no evidence for a head segmentation role. The lack of an embryonic head specification role in Tribolium could be interpreted as a loss of the head segmentation function in Tribolium or gain of this function during evolution of flies. However, we suggest an alternative explanation. We propose that the disco genes always function as appendage factors, but their appendage nature is masked during Drosophila embryogenesis due to the reduction of limb fields in the maggot style Drosophila larva

PTEN Deficiency Mediates a Reciprocal Response to IGFI and mTOR Inhibition

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing Sarcoma, a highly malignant bone and soft tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyper-activation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF-1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF-1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies

Late gastrointestinal tissue effects after hypofractionated radiation therapy of the pancreas

Background To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model. Methods Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1–5 % of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4. Results A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1 % and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38–0.63, m = 0.48–0.49, and TD50 = 35–95 Gy. Regression analysis showed that among various study characteristics, dose was the only significant predictor of toxicity. Conclusions Published gastrointestinal toxicity reports after hypofractionated radiotherapy for pancreatic cancer were compiled. Median dose was predictive of late grade ≥ 3 gastrointestinal toxicity. Preliminary NTCP parameters were derived for multiple volume constraints

Improved ChIP-chip analysis by a mixture model approach

<p>Abstract</p> <p>Background</p> <p>Microarray analysis of immunoprecipitated chromatin (ChIP-chip) has evolved from a novel technique to a standard approach for the systematic study of protein-DNA interactions. In ChIP-chip, sites of protein-DNA interactions are identified by signals from the hybridization of selected DNA to tiled oligomers and are graphically represented as peaks. Most existing methods were designed for the identification of relatively sparse peaks, in the presence of replicates.</p> <p>Results</p> <p>We propose a data normalization method and a statistical method for peak identification from ChIP-chip data based on a mixture model approach. In contrast to many existing methods, including methods that also employ mixture model approaches, our method is more flexible by imposing less restrictive assumptions and allowing a relatively large proportion of peak regions. In addition, our method does not require experimental replicates and is computationally efficient. We compared the performance of our method with several representative existing methods on three datasets, including a spike-in dataset. These comparisons demonstrate that our approach is more robust and has comparable or higher power than the other methods, especially in the context of abundant peak regions.</p> <p>Conclusion</p> <p>Our data normalization and peak detection methods have improved performance to detect peak regions in ChIP-chip data.</p