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Molecular Interaction Network Approach (MINA) was used to elucidate candidate disease genes. The approach was implemented to identify novel gene association with commonly known autoimmune diseases [1]. In MINA, we evaluated the hypothesis that “network proximity” within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. There are now numerous examples of gene discoveries based upon network proximity between novel and previously identified disease genes (Yin et al., 2017 [2], Wang et al., 2011 [3], and Barrenas et al., 2009 [4]). This study extends the application of interaction networks to the interrogation of Genome Wide Association studies: first, by showing that a group of nine autoimmune diseases (AuD) genes “seed genes”, are connected in a highly non-random manner within a whole genome network; and second, by showing that the minimal number of connecting genes required to connect a maximal number of AuD candidate genes are highly enriched as candidate genes for AuD predisposing mutations. The findings imply that a threshold number of candidate genes for any heritable disorder can be used to “seed” a molecular interaction network that • Serves to validate the disease status of closely associated seed genes • Identifies genes that are highly enriched as novel candidate disease genes • Provides a strategy for elucidation of epistatic gene x gene interactionsThe method could provide a critical toll for understanding the genetic architecture of common traits and disorders. Method name: MINA, Molecular Interaction Network Approach, Keywords: Autoimmune diseases, Crohn’s disease (CD), Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), Psoriasis (PSO), Type-1 diabetes (T1D), Type-2 diabetes (T2D), Celiac disease (CeD), Multiple sclerosis (MS), Association, Molecular network

Spiroligomers are a class of peptidomimetics that connect interchangeable, stereochemically pure, cyclic monomers through pairs of amide bonds to form diketopiperazines between the monomers. This enables them to adopt predictable and programmable structure due to the rigidity of the final molecule. We present a new method for the solid phase synthesis of highly functionalized spiroligomers that incorporates the use of the p-nitrobenzyloxycarbonyl (pNZ) as a temporary amine protecting group and the pentafluorophenyl ester for monomer activation. This new method allows for the synthesis of spiroligomers with higher purity and increased yields when compared to previous methods. This improved method of synthesis of functionalized spiroligomers will facilitate the development of applications as catalysts, therapeutics and membrane channels.

trans-4-Hydroxy-l-proline derived bis-amino acids are chiral, cyclic building blocks that display two alpha-amino acids that are differentiated from each other with protecting groups. They are assembled into spiroligomers—rigid, shape-programmable spirocyclic oligomers that are both stereochemically and functionally diverse. The synthesis presented here focuses on recent improvements that allow for a convenient, large-scale synthesis of twelve stereochemically pure bis-amino acids from inexpensive trans-4-hydroxy-l-proline. The bis-amino acids differ in stereochemistry as well as the amine protecting group, one of which (para-nitrobenzyl carbamate) has not been previously incorporated into bis-amino acids.

Objective Due to the fundamental differences in treatment delivery, linear-accelerator-based radiosurgery can be complementary to Gamma Knife (GK) for intracranial lesions. We reviewed the effect of adding GK to an existing linear accelerator (Linac)-based radiosurgery practice and analyzed case selections for the two modalities. Patients and methods UC Davis Medical Center installed a Leksell Gamma Knife Model C in October 2003 to supplement an established Linac-based radiosurgery program. Radiosurgery indications for the 15 months before and after installation were compared. Results Radiosurgery cases expanded by twofold from 68 patients before GK installation to 139 after, with 106 treated by GK and 33 by Linac. Besides a major increase for trigeminal neuralgia and a general growth for acoustic neuroma, meningioma and brain metastases, case numbers for glioma and arteriovenous malformation (AVM) remained stable. Considering case selections for Linac, glioma decreased from 28 to 18%, while meningioma and metastases increased from 9 to 21% and 38–46%, respectively. The Linac patients receiving fractionated treatment also increased from 37 to 61%. Conclusions While the majority of patients were treated with GK, a significant proportion was judged to be suited for Linac treatment. This latter group included particularly patients who benefit from fractionated therapy.

This paper presents the results of a combined experimental and theoretical study of the effects of Na2O addition on the microstructure, viscoelastic toughening and thermal shock resistance of aluminosilicate refractory ceramics. The Na2O was added to change the viscosity–temperature characteristics of the glassy phase and to promote viscoelastic toughening. It was observed that doping of an aluminosilicate with 4–6 wt.% Na2O significantly alters the microstructure, from mullite within a glassy matrix to aluminum oxide laths within a glassy matrix. The glassy matrix is shown to form viscoelastic ligaments. These bridge cracks form and grow during cold shock from elevated temperatures (1100–1400 °C). The viscoelastic bridges have the net effect of shielding the crack tips from transient thermal stresses due to thermal shock. They therefore improve the cold shock resistance of the ceramic. The insights developed from the experiments were used to guide the development of a fracture mechanics model for the prediction of viscoelastic toughening due to crack bridging.

Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b−/− mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b−/− livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.

PUBLISHED, PMID: 12802785, Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for ?very narrow? (i.e., BP-I and schizoaffective disorder?BP) and ?narrow? (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A ?broad? model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (, Higher Education Authority

This paper presents a group-based incentive reward program (IRP) to encourage workers to minimize avoidable wastes of construction materials by rewarding them according to the amounts and values of materials they saved. Bar-code technique is used to facilitate effective management of construction materials. An IRP-integrated construction management system is also introduced to avoid jerrybuilding and solve reschedule problem due to rework of quality failure. An experiment is conducted on a residential project in Hong Kong and results from the experiment demonstrate the effectiveness of the IRP in motivating workers to reduce construction wastes. Discussions on the relationship between construction waste reduction and time and cost performances are also presented. Difficulties and challenges of applying IRP are also discussed.

Purpose: The authors undertook a study to analyze the impact of collimator leaf width on stereotactic radiosurgery and 3D conformal radiotherapy treatment plans. Methods and Materials: Twelve cases involving primary brain tumors, metastases, or arteriovenous malformations that had been planned with BrainLAB’s conventional circular collimator-based radiosurgery system were re-planned using a β-version of BrainLAB’s treatment planning software that is compatible with MRC Systems’ and BrainLAB’s micro-multileaf collimators. These collimators have a minimum leaf width of 1.7 mm and 3.0 mm, respectively, at isocenter. The clinical target volumes ranged from 2.7–26.1 cc and the number of static fields ranged from 3–5. In addition, for 4 prostate cancer cases, 2 separate clinical target volumes were planned using MRC Systems’ and BrainLAB’s micro-multileaf collimators and Varian’s multileaf collimator: the smaller clinical target volume consisted of the prostate gland and the larger clinical target volume consisted of the prostate and seminal vesicles. For the prostate cancer cases, treatment plans were generated using either 6 or 7 static fields. A “PITV ratio,” which the Radiation Therapy Oncology Group defines as the volume encompassed by the prescription isodose surface divided by the clinical target volume, was used as a measure of the quality of treatment plans (a PITV ratio of 1.0–2.0 is desirable). Bladder and rectal volumes encompassed by the prescription isodose surface, isodose distributions and dose volume histograms were also analyzed for the prostate cancer patients. Results: In 75% of the cases treated with radiosurgery, a PITV ratio between 1.0–2.0 could be achieved using a micro-multileaf collimator with a leaf width of 1.7-3.0 mm at isocenter and 3–5 static fields. When the clinical target volume consisted of the prostate gland, the micro-multileaf collimator with a minimum leaf width of 3.0 mm allowed one to decrease the median volume of bladder and rectum within the prescription isodose surface by 26% and 17%, respectively, compared to the multileaf collimator with a leaf width of 10 mm. Use of the 1.7 mm leaf width micro-multileaf collimator allowed one to decrease the median volume of bladder and rectum within the prescription isodose surface by 48% and 39%, respectively, compared to the multileaf collimator with a leaf width of 10 mm. Conclusions: For most lesions treated with radiosurgery, the use of a micro-multileaf collimator with a leaf width of 1.7–3.0 mm at isocenter and 3–5 static fields allows one to meet the Radiation Therapy Oncology Group guidelines for treatment planning. Both planning and treatment are relatively straightforward with a micro-multileaf collimator, allowing for efficient treatment of non-spherical targets with either stereotactic radiosurgery or fractionated stereotactic radiotherapy. When the clinical target volume consists of the prostate gland, micro-multileaf collimators with a minimum leaf width of 1.7–3.0 mm allow one to spare more bladder and rectum than one can with a multileaf collimator that has a 10-mm leaf width based on an analysis of PITV ratios, isodose distributions, and dose volume histograms. Keywords

Background : The purpose of this study is to compare arc-based and mini-multileaf collimator (mMLC)-based radiosurgery treatment plans using isodose distributions and dose-volume histograms. Methods : Of 11 patients who underwent conventional arc-based radiosurgery for intracranial malignancies, four were treated with one isocenter, four were treated with two isocenters and three were treated with three isocenters. The same cases were re-planned using a test version of mMLC-based radiosurgery software for multiple static non-coplanar fields. Results and conclusion : For non-spherical targets, treatment planning is relatively intuitive with mMLC-based radiosurgery, reducing the amount of time required for planning. Moreover, a lower dose of radiation is delivered to normal tissue with mMLC-based radiosurgery than with arc-based radiosurgery, which theoretically should lead to a reduced risk of complications.

The rabbit tooth-pulp assay is well established as a method for measuring the efficacy and potency of parenteral analgesic drugs. We describe a method for administration of local anesthetic drugs into the maxillary arch and subsequent measurements of antinociceptive action. It was possible to use two different methods of ED50 estimation and to provide measures of the potency, efficacy, and duration of local anesthetic drugs. These measurements corresponded with in vitro estimates of potency and duration and with intrinsic observations of the clinical actions.