Near optimal solutions to least-squares problems with stochastic uncertainty

In this paper, we consider least-squares (LS) problems where the regression data is affected by parametric stochastic uncertainty. In this setting, we study the problem of minimizing the expected value with respect to the uncertainty of the LS residual. For general nonlinear dependence of the data on the uncertain parameters, determining an exact solution to this problem is known to be computationally prohibitive. Here, we follow a probabilistic approach, and determine a probable near optimal solution by minimizing the empirical mean of the residual. Finite sample convergence of the proposed method is assessed using statistical learning methods. In particular, we prove that if one constructs the empirical approximation of the mean using a finite number N of samples, then the minimizer of this empirical approximation is, with high probability, an ε-suboptimal solution for the original problem. Moreover, this approximate solution can be efficiently determined numerically by a standard recursive algorithm. Comparisons with gradient algorithms for stochastic optimization are also discussed in the paper and several numerical examples illustrate the proposed methodology.     

Externalizing lupus: A therapist/patient's challenge.

Coping with a serious and chronic illness poses unique challenges for individuals in helping professions. What techniques and resources can be used to help the helpers? A narrative framework using the process of externalizing the problem is presented as a potentially useful approach for psychotherapists experiencing a serious illness. The author describes her own experience with lupus and offers recommendations for therapists struggling to balance their professional responsibilities with their own personal needs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Transmission line routing for reduced external field disturbance

When immersed in a disturbing electromagnetic field, electronic systems are subject to interference due to the energy injected by the external field into the system through the electronic units and, especially, through the transmission lines connecting units one another. The issue of reducing the unwanted energy injection through connecting transmission lines is addressed in this contribution from the point of view of the routing, i.e. of the disposition of the connecting lines that minimizes the injection. The problem is formulated as an optimization problem, dealt with by the simulated annealing minimization technique combined with an efficient way of computing the field coupling to the lines. Results are reported for various cases, and the relation between the characteristics of the interfering field and the efficiency of the reduction is discussed.     

A VLSI structure forX(modm) operation

High-computing speed and modularity have made RNS-based arithmetic processors attractive for a long time, especially in signal processing, where additions and multiplications are very frequent. The VLSI technology renewed this interest because RNS-based circuits are becoming more feasible; however, intermodular operations degradate their performance and a great effort results on this topic. In this paper, we deal with the problem of performing the basic operationX(modm), that is the remainder of the integer divisionX/m, for large values of the integerX, following an approximating and correcting approach, which guarantees the correctness of the result. We also define a structure to computeX(modm) by means of few fast VLSI binary multipliers, which is exemplified for 32-bit long numbers, obtaining a total response time lower than 200 nsec. Furthermore, such a structure is evaluated in terms of VLSI complexity and area and time figuresA=?(n ² T _m ² ) andT=?(T _M ) for the parameterT _M in \([\log n,\sqrt n ]\) are derived. A simple positional-to-residue converter is finally presented, based on this structure; it improves some complexity results previously obtained by authors.     

Microfluidic motion for a direct investigation of solvent interactions with PDMS microchannels

Solid surface/liquid interactions play an important role in microfluidics and particularly in manipulation of films, drops and bubbles, a basic requirement for a number of lab-on-chip applications. The behavior of solvents in coated microchannels is difficult to be predicted considering theories; therefore, experimental methods able to estimate the properties at the interface in real time and during the operational regime are amenable. Here, we propose to use an experimental setup to evaluate the effective dynamics of solvents inside PDMS microchannels. The influence of the solvent properties as well as of the channel wall’s wettability on the fluid movements was evaluated. Modification of the channel properties was achieved by introducing Teflon coatings that allow producing stable hydrophobic microchannel walls. The results were fitted according to Washburn-type power-law and compared with theoretical calculations of the parameter β that expresses the dependence of capillary dynamics on surface tension γ, liquid viscosity η, contact angles θ and the hydraulic radius R _H. A comparison between the calculated and the experimental values reveled that parameters other than the contemplated ones influenced the measurements. The main parameter that affects the flow of solvents such as water, methanol ethanol, dimethylformamide, acetonitrile and acetone was found to be the γ/η ratio. Considering these results, the investigation tool described here is believed to be promising to predict the dynamics of common organic solvents inside integrated functional fluidic devices and to accurately control solvent flow, particularly in capillary-driven pumpless systems, a basic requirement for widening the application range of PDMS lab-on-chip devices.     

The GAUGAA Motif Is Responsible for the Binding between circSMARCA5 and SRSF1 and Related Downstream Effects on Glioblastoma Multiforme Cell Migration and Angiogenic Potential

Circular RNAs (circRNAs) are a large class of RNAs with regulatory functions within cells. We recently showed that circSMARCA5 is a tumor suppressor in glioblastoma multiforme (GBM) and acts as a decoy for Serine and Arginine Rich Splicing Factor 1 (SRSF1) through six predicted binding sites (BSs). Here we characterized RNA motifs functionally involved in the interaction between circSMARCA5 and SRSF1. Three different circSMARCA5 molecules (Mut1, Mut2, Mut3), each mutated in two predicted SRSF1 BSs at once, were obtained through PCR-based replacement of wild-type (WT) BS sequences and cloned in three independent pcDNA3 vectors. Mut1 significantly decreased its capability to interact with SRSF1 as compared to WT, based on the RNA immunoprecipitation assay. In silico analysis through the “Find Individual Motif Occurrences” (FIMO) algorithm showed GAUGAA as an experimentally validated SRSF1 binding motif significantly overrepresented within both predicted SRSF1 BSs mutated in Mut1 (q-value = 0.0011). U87MG and CAS-1, transfected with Mut1, significantly increased their migration with respect to controls transfected with WT, as revealed by the cell exclusion zone assay. Immortalized human brain microvascular endothelial cells (IM-HBMEC) exposed to conditioned medium (CM) harvested from U87MG and CAS-1 transfected with Mut1 significantly sprouted more than those treated with CM harvested from U87MG and CAS-1 transfected with WT, as shown by the tube formation assay. qRT-PCR showed that the intracellular pro- to anti-angiogenic Vascular Endothelial Growth Factor A (VEGFA) mRNA isoform ratio and the amount of total VEGFA mRNA secreted in CM significantly increased in Mut1-transfected CAS-1 as compared to controls transfected with WT. Our data suggest that GAUGAA is the RNA motif responsible for the interaction between circSMARCA5 and SRSF1 as well as for the circSMARCA5-mediated control of GBM cell migration and angiogenic potential.     

Mutual Prodrugs of 5-Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad-spectrum chemotherapeutics available for clinical use today, 5-fluorouracil (5-FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5-FU-based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.