A sensitized RNA interference screen identifies a novel role for the PI3K p110γ isoform in medulloblastoma cell proliferation and chemoresistance.

Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo-like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110γ (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110γ phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma.

An LFG approach to the syntax of quotation

This paper attempts to give an account of the syntax of quotation from an LFG perspective. I claim that quotes are inserted at N’ positions by making use of a special phrase structure rule that makes the quote’s f-structure the PRED value of the mother f-structure. However, in order to reach to this conclusion, the concept of quotation has to be restricted to only include metalinguistic and direct reported speech quotes, by making use of the property of grammatical opacity, i.e. only subsegments whose ungrammaticality does not affect the grammaticality of the whole sentence are quotes. The main advantage of this is this distinguishes the syntax of direct quotes from the one of other citational but not quotational structures like Davidson’s (1979) and Cappelen and Lepore’s (2007) mixed quotation.

Measurement with Some Theory: a New Approach to Evaluate Business Cycle Models

We propose a method to evaluate cyclical models which does not require knowledge of the DGP and the exact empirical specification of the aggregate decision rules. We derive robust restrictions in a class of models; use some to identify structural shocks and others to evaluate the model or contrast sub-models. The approach has good size and excellent power properties, even in small samples. We show how to examine the validity of a class of models, sort out the relevance of certain frictions, evaluate the importance of an added feature, and indirectly estimate structural parameters.

Advancing hypoxic training in team sports: from intermittent hypoxic training to repeated sprint training in hypoxia.

Over the past two decades, intermittent hypoxic training (IHT), that is, a method where athletes live at or near sea level but train under hypoxic conditions, has gained unprecedented popularity. By adding the stress of hypoxia during 'aerobic' or 'anaerobic' interval training, it is believed that IHT would potentiate greater performance improvements compared to similar training at sea level. A thorough analysis of studies including IHT, however, leads to strikingly poor benefits for sea-level performance improvement, compared to the same training method performed in normoxia. Despite the positive molecular adaptations observed after various IHT modalities, the characteristics of optimal training stimulus in hypoxia are still unclear and their functional translation in terms of whole-body performance enhancement is minimal. To overcome some of the inherent limitations of IHT (lower training stimulus due to hypoxia), recent studies have successfully investigated a new training method based on the repetition of short (<30 s) 'all-out' sprints with incomplete recoveries in hypoxia, the so-called repeated sprint training in hypoxia (RSH). The aims of the present review are therefore threefold: first, to summarise the main mechanisms for interval training and repeated sprint training in normoxia. Second, to critically analyse the results of the studies involving high-intensity exercises performed in hypoxia for sea-level performance enhancement by differentiating IHT and RSH. Third, to discuss the potential mechanisms underpinning the effectiveness of those methods, and their inherent limitations, along with the new research avenues surrounding this topic.

Injuries Resulted From Breastfeeding: A New Approach To A Known Problem

This study aimed at analyzing nipple trauma resulted from breastfeeding based on dermatological approach. Two integrative reviews of literature were conducted, the first related to definitions, classification and evaluation methods of nipple trauma and another about validation studies related to this theme. In the first part were included 20 studies and only one third defined nipple trauma, more than half did not defined the nipple’s injuries reported, and each author showed a particular way to assess the injuries, without consensus. In the second integrative review, no validation study or algorithm related to nipple trauma resulted from breastfeeding was found. This fact demonstrated that the nipple’s injuries mentioned in the first review did not go through validation studies, justifying the lack of consensus identified as far as definition, classification and assessment methods of nipple trauma.


Factors associated with the quality of prenatal care: an approach to premature birth

OBJECTIVETo assess the quality of prenatal care in mothers with premature and term births and identify maternal and gestational factors associated with inadequate prenatal care.METHODCross-sectional study collecting data with the pregnant card, hospital records and interviews with mothers living in Maringa-PR. Data were collected from 576 mothers and their born alive infants who were attended in the public service from October 2013 to February 2014, using three different evaluation criteria. The association of prenatal care quality with prematurity was performed by univariate analysis and occurred only at Kessner criteria (CI=1.79;8.02).RESULTSThe indicators that contributed most to the inadequacy of prenatal care were tests of hemoglobin, urine, and fetal presentation. After logistic regression analysis, maternal and gestational variables associated to inadequate prenatal care were combined prenatal (CI=2.93;11.09), non-white skin color (CI=1.11;2.51); unplanned pregnancy (CI=1.34;3.17) and multiparity (CI=1.17;4.03).CONCLUSIONPrenatal care must follow the minimum recommended protocols, more attention is required to black and brown women, multiparous and with unplanned pregnancies to prevent preterm birth and maternal and child morbimortality.

Aitchison Geometry for Probability and Likelihood as a new approach to mathematical statistics

The Aitchison vector space structure for the simplex is generalized to a Hilbert space structure A2(P) for distributions and likelihoods on arbitrary spaces. Centralnotations of statistics, such as Information or Likelihood, can be identified in the algebraical structure of A2(P) and their corresponding notions in compositional data analysis, such as Aitchison distance or centered log ratio transform.In this way very elaborated aspects of mathematical statistics can be understoodeasily in the light of a simple vector space structure and of compositional data analysis. E.g. combination of statistical information such as Bayesian updating,combination of likelihood and robust M-estimation functions are simple additions/perturbations in A2(Pprior). Weighting observations corresponds to a weightedaddition of the corresponding evidence.Likelihood based statistics for general exponential families turns out to have aparticularly easy interpretation in terms of A2(P). Regular exponential families formfinite dimensional linear subspaces of A2(P) and they correspond to finite dimensionalsubspaces formed by their posterior in the dual information space A2(Pprior).The Aitchison norm can identified with mean Fisher information. The closing constant itself is identified with a generalization of the cummulant function and shown to be Kullback Leiblers directed information. Fisher information is the local geometry of the manifold induced by the A2(P) derivative of the Kullback Leibler information and the space A2(P) can therefore be seen as the tangential geometry of statistical inference at the distribution P.The discussion of A2(P) valued random variables, such as estimation functionsor likelihoods, give a further interpretation of Fisher information as the expected squared norm of evidence and a scale free understanding of unbiased reasoning

The achievable region approach to the optimal control of stochastic systems

The achievable region approach seeks solutions to stochastic optimisation problems by: (i) characterising the space of all possible performances(the achievable region) of the system of interest, and (ii) optimisingthe overall system-wide performance objective over this space. This isradically different from conventional formulations based on dynamicprogramming. The approach is explained with reference to a simpletwo-class queueing system. Powerful new methodologies due to the authorsand co-workers are deployed to analyse a general multiclass queueingsystem with parallel servers and then to develop an approach to optimalload distribution across a network of interconnected stations. Finally,the approach is used for the first time to analyse a class of intensitycontrol problems.

A subsampling approach to estimating the distribution of diversing statistics with application to assessing financial market risks

In this paper we propose a subsampling estimator for the distribution ofstatistics diverging at either known rates when the underlying timeseries in strictly stationary abd strong mixing. Based on our results weprovide a detailed discussion how to estimate extreme order statisticswith dependent data and present two applications to assessing financialmarket risk. Our method performs well in estimating Value at Risk andprovides a superior alternative to Hill's estimator in operationalizingSafety First portofolio selection.

A new approach to accurate measurement of uniaxial joint angles based on a combination of accelerometers and gyroscopes.

A new method of measuring joint angle using a combination of accelerometers and gyroscopes is presented. The method proposes a minimal sensor configuration with one sensor module mounted on each segment. The model is based on estimating the acceleration of the joint center of rotation by placing a pair of virtual sensors on the adjacent segments at the center of rotation. In the proposed technique, joint angles are found without the need for integration, so absolute angles can be obtained which are free from any source of drift. The model considers anatomical aspects and is personalized for each subject prior to each measurement. The method was validated by measuring knee flexion-extension angles of eight subjects, walking at three different speeds, and comparing the results with a reference motion measurement system. The results are very close to those of the reference system presenting very small errors (rms = 1.3, mean = 0.2, SD = 1.1 deg) and excellent correlation coefficients (0.997). The algorithm is able to provide joint angles in real-time, and ready for use in gait analysis. Technically, the system is portable, easily mountable, and can be used for long term monitoring without hindrance to natural activities.

A unifying approach to the empirical evaluation of asset pricing models

Two main approaches are commonly used to empirically evaluate linear factor pricingmodels: regression and SDF methods, with centred and uncentred versions of the latter.We show that unlike standard two-step or iterated GMM procedures, single-step estimatorssuch as continuously updated GMM yield numerically identical values for prices of risk,pricing errors, Jensen s alphas and overidentifying restrictions tests irrespective of the modelvalidity. Therefore, there is arguably a single approach regardless of the factors being tradedor not, or the use of excess or gross returns. We illustrate our results by revisiting Lustigand Verdelhan s (2007) empirical analysis of currency returns.