The Cochaperone BAG2 Sweeps Paired Helical Filament-Insoluble Tau from the Microtubule

Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer`s disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here, we report an elegant mechanism of Tau degradation involving the cochaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades Sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune paired helical filament Tau levels in neurons. Thus, we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.

XRCC1 haploinsufficiency in mice has little effect on aging, but adversely modifies exposure-dependent susceptibility

Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of similar to 26 months and a nearly identical maximal life expectancy of similar to 37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.

Crystal Structure Determination for Eugenyl Acetate

Essential oils are good candidates for the substitution of conventional medicinal treatments. Many articles and patents for their use have been published in recent years. The most attractive aspects of using essential oils as medicaments are their natural source and rapid permeability. Besides permeability, the solubility behavior of a drug is a key determinant of its oral bioavailability. Based on these characteristics, the aim of this study was to synthesize an essential oil derivative compound, using the raw oil extracted from Syzygium aromaticum L., without previous purification. The Eugenol molecular modification may diminish the problems of water solubility and bioavailability. The Eugenyl acetate molecule was characterized and its molecular modification investigated, including its structural properties and stereochemistry. This study was performed applying techniques, such as carbon-13 nuclear magnetic resonance spectroscopy (C-13 NMR), X-ray crystallographic analysis (XRD), powder X-ray diffraction (PXRD) and microscopic recording.

Characterization of the raw essential oil eugenol extracted from Syzygium aromaticum L.

Eugenol is the main volatile compound extracted oil from clove bud, Syzygium aromaticum L., and used in traditional medicine, as a bactericide, fungicide, anesthetic, and others. Its extraction was performed using hydrodistillation which is the most common extraction technique. Its components and thermal behavior were evaluated using gas chromatography (GC) and differential scanning calorimetry (DSC), which provide a better characterization of these natural compounds. This extracted product was compared to the standard eugenol results. The GC results suggested similar to 90% eugenol was found in the total extracted oil, and some of its boiling characteristics were 270.1 A degrees C for peak temperature and 244.1 J g(-1) for the enthalpy variation.

Carpentry Students at Work

Carpentry students from the New York Trade School at work during a class. Black and white photograph.

Vem blir långtidsarbetslös?

I ett antal länder har man på senare tid utvecklat statistiska modeller som ett stöd för förmedlarna att förutsäga vilka arbetslösa som riskerar att bli långtidsarbetslösa, s k profiling. I den här rapporten redovisar vi resultaten av att skatta hasardmodeller för att förutsäga vem som riskerar att bli långtidsarbetslös bland dem som registrerar sig som arbetslösa arbetssökande vid arbetsförmedlingen. Av resultaten framgår det att den skattade modellen lyckas relativt väl med att förutsäga vem som riskerar att bli arbetslös i minst sex månader – träffsäkerheten i prognoser som görs utanför modellens skattningsperiod är nästan 70 %.

On statistical bounds of heuristic solutions to location problems

Solutions to combinatorial optimization problems, such as problems of locating facilities, frequently rely on heuristics to minimize the objective function. The optimum is sought iteratively and a criterion is needed to decide when the procedure (almost) attains it. Pre-setting the number of iterations dominates in OR applications, which implies that the quality of the solution cannot be ascertained. A small, almost dormant, branch of the literature suggests using statistical principles to estimate the minimum and its bounds as a tool to decide upon stopping and evaluating the quality of the solution. In this paper we examine the functioning of statistical bounds obtained from four different estimators by using simulated annealing on p-median test problems taken from Beasley’s OR-library. We find the Weibull estimator and the 2nd order Jackknife estimator preferable and the requirement of sample size to be about 10 being much less than the current recommendation. However, reliable statistical bounds are found to depend critically on a sample of heuristic solutions of high quality and we give a simple statistic useful for checking the quality. We end the paper with an illustration on using statistical bounds in a problem of locating some 70 distribution centers of the Swedish Post in one Swedish region. 

A stopping rule while searching for optimal solution of facility-location

Solutions to combinatorial optimization, such as p-median problems of locating facilities, frequently rely on heuristics to minimize the objective function. The minimum is sought iteratively and a criterion is needed to decide when the procedure (almost) attains it. However, pre-setting the number of iterations dominates in OR applications, which implies that the quality of the solution cannot be ascertained. A small branch of the literature suggests using statistical principles to estimate the minimum and use the estimate for either stopping or evaluating the quality of the solution. In this paper we use test-problems taken from Baesley's OR-library and apply Simulated Annealing on these p-median problems. We do this for the purpose of comparing suggested methods of minimum estimation and, eventually, provide a recommendation for practioners. An illustration ends the paper being a problem of locating some 70 distribution centers of the Swedish Post in a region.

Confidence in heuristic solutions?

Solutions to combinatorial optimization problems frequently rely on heuristics to minimize an objective function. The optimum is sought iteratively and pre-setting the number of iterations dominates in operations research applications, which implies that the quality of the solution cannot be ascertained. Deterministic bounds offer a mean of ascertaining the quality, but such bounds are available for only a limited number of heuristics and the length of the interval may be difficult to control in an application. A small, almost dormant, branch of the literature suggests using statistical principles to derive statistical bounds for the optimum. We discuss alternative approaches to derive statistical bounds. We also assess their performance by testing them on 40 test p-median problems on facility location, taken from Beasley’s OR-library, for which the optimum is known. We consider three popular heuristics for solving such location problems; simulated annealing, vertex substitution, and Lagrangian relaxation where only the last offers deterministic bounds. Moreover, we illustrate statistical bounds in the location of 71 regional delivery points of the Swedish Post. We find statistical bounds reliable and much more efficient than deterministic bounds provided that the heuristic solutions are sampled close to the optimum. Statistical bounds are also found computationally affordable.