A crucial sequence for transglutaminase type 2 extracellular trafficking in renal tubular epithelial cells lies in its N-terminal {beta}-sandwich domain

Transglutaminase type 2 (TG2) catalyzes the formation of an -( -glutamyl)-lysine isopeptide bond between adjacent peptides or proteins including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlie tissue scarring and fibrosis. The extracellular trafficking of TG2 is crucial to its role in ECM homeostasis; however, the mechanism by which TG2 escapes the cell is unknown as it has no signal leader peptide and therefore cannot be transported classically. Understanding TG2 transport may highlight novel mechanisms to interfere with the extracellular function of TG2 as isoform-specific TG2 inhibitors remain elusive. Mammalian expression vectors were constructed containing domain deletions of TG2. These were transfected into three kidney tubular epithelial cell lines, and TG2 export was assessed to identify critical domains. Point mutation was then used to highlight specific sequences within the domain required for TG2 export. The removal of -sandwich domain prevented all TG2 export. Mutations of Asp94 and Asp97 within the N-terminal -sandwich domain were identified as crucial for TG2 externalization. These form part of a previously identified fibronectin binding domain (88WTATVVDQQDCTLSLQLTT106). However, siRNA knockdown of fibronectin failed to affect TG2 export. The sequence 88WTATVVDQQDCTLSLQLTT106 within the -sandwich domain of TG2 is critical to its export in tubular epithelial cell lines. The extracellular trafficking of TG2 is independent of fibronectin

Durable and ductile double-network material for dust control

Dust generation is a world-wide issue due to its serious deleterious effects on the environment, human health and safety, and the economy. Although various dust suppression methods have been used for decades, some critical drawbacks in state-of-the-art technology still remain unsolved, such as short-lasting, ground water impact, and prone to water. This work reports a soil stabilizer based on non-toxic material and forms a ductile and durable double-network in soil, namely “D3 soil stabilizer”, which not only improves soil mechanical toughness of surface soil but also suppresses dust generation. A copolymer comprising hydrophilic and hydrophobic components combined with enzyme-induced carbonate precipitation is utilized as an in-situ gelation binder to soil particle. The tunable hydrophobic-to-hydrophilic component ratio minimizes undesirable soil matrix expansion and mechanical strength loss upon experiencing wet-dry processes, while still retains good water affinity. We further demonstrated controllable treatment depth by fine-tuning precursor composition, which is essential to minimize environmental impact. The double-network morphology with carbonate precipitate embedded uniformly in polymer matrix is observed via microscopic imaging. The nature of outstanding ductility, high durability against water, and good long-term stability were supported by systematic unconfined compressive strength (UCS) measurements on treated soil, which show strong inter-particles binding, good retention of peak strength, increased strain at peak strength, and increased toughness after soil samples have experienced wet-dry processes

Ontogenetic Patterns of Agonistic Behavior in a Guild of Larval Ambystomatid Salamanders

Agonistic behavior is a common feature of larval amphibians inhabiting temporary ponds. Given the temporally staggered sequence of hatching by pond-breeding amphibians, ontogenetic patterns of aggression can influence coexistence if larvae of certain species or ages are subject to increased aggression. To determine whether aggression changes through larval ontogeny, we observed agonistic behavior of Ambystoma opacum, Ambystoma tigrinum, and Ambystoma maculatum at four stages of development spanning the larval period. We tracked aggression rates among individual larvae to determine whether previous success, in the form of increased aggression, facilitated success in subsequent contests. All species exhibited distinct ontogenetic patterns of aggression, with the highest and lowest rates of aggression exhibited during rear leg development and metamorphosis, respectively. Species-specific aggression rates were observed, with A. tigrinum consistently displaying the highest levels of aggression. Winner or loser effects were not evident, because increased aggression early in the larval period did not result in increased aggression throughout ontogeny. We hypothesize that the observed patterns of behavior may represent a baseline level of aggression upon which other biotic and abiotic factors act in mediating coexistence among larval amphibians

Access to high cost medicines in Australia: ethical perspectives

Access to "high cost medicines" through Australia's Pharmaceutical Benefits Scheme (PBS) is tightly regulated. It is inherently difficult to apply any criteria-based system of control in a way that provides a fair balance between efficient use of limited resources for community needs and equitable individual access to care. We suggest, in relation to very high cost medicines, that the present arrangements be re-considered in order to overcome potential inequities. The biological agents for the treatment of rheumatoid arthritis are used as an example by which to discuss the ethical issues associated with the current scheme. Consideration of ethical aspects of the PBS and similar programs is important in order to achieve the fairest outcomes for individual patients, as well as for the community

Time-dependent density functional theory based Ehrenfest dynamics

Time-dependent density functional theory based Ehrenfest dynamics with atom-centered basis functions is developed in present work. The equation of motion for electrons is formulated in terms of first-order reduced density matrix and an additional term arises due to the time-dependence of basis functions through their dependence on nuclear coordinates. This time-dependence of basis functions together with the imaginary part of density matrix leads to an additional term for nuclear force. The effects of the two additional terms are examined by studying the dynamics of H 2 and C 2H 4, and it is concluded that the inclusion of these two terms is essential for correct electronic and nuclear dynamics. © 2011 American Institute of Physics.published_or_final_versio

An efficient semiparametric maxima estimator of the extremal index

The extremal index $\theta$, a measure of the degree of local dependence in the extremes of a stationary process, plays an important role in extreme value analyses. We estimate $\theta$ semiparametrically, using the relationship between the distribution of block maxima and the marginal distribution of a process to define a semiparametric model. We show that these semiparametric estimators are simpler and substantially more efficient than their parametric counterparts. We seek to improve efficiency further using maxima over sliding blocks. A simulation study shows that the semiparametric estimators are competitive with the leading estimators. An application to sea-surge heights combines inferences about $\theta$ with a standard extreme value analysis of block maxima to estimate marginal quantiles.Comment: 17 pages, 7 figures. Minor edits made to version 1 prior to journal publication. The final publication is available at Springer via http://dx.doi.org/10.1007/s10687-015-0221-

A three-year multifaceted intervention to prevent obesity in children of Mexican-heritage.

BackgroundObesity and overweight have increased dramatically in the United States over the last decades. The complexity of interrelated causal factors that result in obesity needs to be addressed within the cultural dynamic of sub-populations. In this study, we sought to estimate the effects of a multifaceted, community-based intervention on body mass index (BMI) among Mexican-heritage children.MethodsNiños Sanos, Familia Sana (Healthy Children, Healthy Family) was a quasi-experimental intervention study designed to reduce the rate of BMI growth among Mexican-heritage children in California's Central Valley. Two rural communities were matched based on demographic and environmental characteristics and were assigned as the intervention or comparison community. The three-year intervention included parent workshops on nutrition and physical activity; school-based nutrition lessons and enhanced physical education program for children; and a monthly voucher for fruits and vegetables. Eligible children were between 3 and 8 years old at baseline. Intent-to-treat analyses were estimated using linear mixed-effect models with random intercepts. We ran a series of models for each gender where predictors were fixed except interactions between age groups and obesity status at baseline with intervention to determine the magnitude of impact on BMI.ResultsAt baseline, mean (SD) BMI z-score (zBMI) was 0.97 (0.98) in the intervention group (n = 387) and 0.98 (1.02) in the comparison group (n = 313) (NS). The intervention was significantly associated with log-transformed BMI (β = 0.04 (0.02), P = 0.03) and zBMI (β = 0.25 (0.12), P = 0.04) among boys and log-transformed BMI among obese girls (β = - 0.04 (0.02), P = 0.04). The intervention was significantly and inversely associated with BMI in obese boys and girls across all age groups and normal weight boys in the oldest group (over 6 years) relative to their counterparts in the comparison community.ConclusionsA community-based, multifaceted intervention was effective at slowing the rate of BMI growth among Mexican-heritage children. Our findings suggest that practitioners should consider strategies that address gender disparities and work with a variety of stakeholders to target childhood obesity.Trial registrationclinicaltrials.gov Identifier: NCT01900613 . Registered 16th July 2013

Monster black holes

A combination of ground-based and spacecraft observations has uncovered two black holes of 10 billion solar masses in the nearby Universe. The finding sheds light on how these cosmic monsters co-evolve with galaxies.Comment: 2 pages, 1 figure, LaTeX. Published in Nature "News & Views