Biological aspects of mTOR in leukemia

The mammalian target of rapamycin (mTOR) is a central processor of intra-and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds

Lower bounds for on-line graph colorings

We propose two strategies for Presenter in on-line graph coloring games. The first one constructs bipartite graphs and forces any on-line coloring algorithm to use $2\log_2 n - 10$ colors, where $n$ is the number of vertices in the constructed graph. This is best possible up to an additive constant. The second strategy constructs graphs that contain neither $C_3$ nor $C_5$ as a subgraph and forces $\Omega(\frac{n}{\log n}^\frac{1}{3})$ colors. The best known on-line coloring algorithm for these graphs uses $O(n^{\frac{1}{2}})$ colors

Design of a five-axis ultra-precision micro-milling machine—UltraMill. Part 2: Integrated dynamic modelling, design optimisation and analysis

Using computer models to predict the dynamic performance of ultra-precision machine tools can help manufacturers to substantially reduce the lead time and cost of developing new machines. However, the use of electronic drives on such machines is becoming widespread, the machine dynamic performance depending not only on the mechanical structure and components but also on the control system and electronic drives. Bench-top ultra-precision machine tools are highly desirable for the micro-manufacturing of high-accuracy micro-mechanical components. However, the development is still at the nascent stage and hence lacks standardised guidelines. Part 2 of this two-part paper proposes an integrated approach, which permits analysis and optimisation of the entire machine dynamic performance at the early design stage. Based on the proposed approach, the modelling and simulation process of a novel five-axis bench-top ultra-precision micro-milling machine tool—UltraMill—is presented. The modelling and simulation cover the dynamics of the machine structure, the moving components, the control system and the machining process and are used to predict the entire machine performance of two typical configurations

Online Multi-Coloring with Advice

We consider the problem of online graph multi-coloring with advice. Multi-coloring is often used to model frequency allocation in cellular networks. We give several nearly tight upper and lower bounds for the most standard topologies of cellular networks, paths and hexagonal graphs. For the path, negative results trivially carry over to bipartite graphs, and our positive results are also valid for bipartite graphs. The advice given represents information that is likely to be available, studying for instance the data from earlier similar periods of time.Comment: IMADA-preprint-c

Unary probabilistic and quantum automata on promise problems

We continue the systematic investigation of probabilistic and quantum finite automata (PFAs and QFAs) on promise problems by focusing on unary languages. We show that bounded-error QFAs are more powerful than PFAs. But, in contrary to the binary problems, the computational powers of Las-Vegas QFAs and bounded-error PFAs are equivalent to deterministic finite automata (DFAs). Lastly, we present a new family of unary promise problems with two parameters such that when fixing one parameter QFAs can be exponentially more succinct than PFAs and when fixing the other parameter PFAs can be exponentially more succinct than DFAs.Comment: Minor correction

Thermal quenches in N=2* plasmas

We exploit gauge/gravity duality to study `thermal quenches' in a plasma of the strongly coupled N=2* gauge theory. Specifically, we consider the response of an initial thermal equilibrium state of the theory under variations of the bosonic or fermionic mass, to leading order in m/T<<1. When the masses are made to vary in time, novel new counterterms must be introduced to renormalize the boundary theory. We consider transitions the conformal super-Yang-Mills theory to the mass deformed gauge theory and also the reverse transitions. By construction, these transitions are controlled by a characteristic time scale \calt and we show how the response of the system depends on the ratio of this time scale to the thermal time scale 1/T. The response shows interesting scaling behaviour both in the limit of fast quenches with T\calt<<1 and slow quenches with T\calt>>1. In the limit that T\calt\to\infty, we observe the expected adiabatic response. For fast quenches, the relaxation to the final equilibrium is controlled by the lowest quasinormal mode of the bulk scalar dual to the quenched operator. For slow quenches, the system relaxes with a (nearly) adiabatic response that is governed entirely by the late time profile of the mass. We describe new renormalization scheme ambiguities in defining gauge invariant observables for the theory with time dependant couplings.Comment: 78 pages, 17 figure

Heterogeneous Host Susceptibility Enhances Prevalence of Mixed-Genotype Micro-Parasite Infections

Dose response in micro-parasite infections is usually shallower than predicted by the independent action model, which assumes that each infectious unit has a probability of infection that is independent of the presence of other infectious units. Moreover, the prevalence of mixed-genotype infections was greater than predicted by this model. No probabilistic infection model has been proposed to account for the higher prevalence of mixed-genotype infections. We use model selection within a set of four alternative models to explain high prevalence of mixed-genotype infections in combination with a shallow dose response. These models contrast dependent versus independent action of micro-parasite infectious units, and homogeneous versus heterogeneous host susceptibility. We specifically consider a situation in which genome differences between genotypes are minimal, and highly unlikely to result in genotype-genotype interactions. Data on dose response and mixed-genotype infection prevalence were collected by challenging fifth instar Spodoptera exigua larvae with two genotypes of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), differing only in a 100 bp PCR marker sequence. We show that an independent action model that includes heterogeneity in host susceptibility can explain both the shallow dose response and the high prevalence of mixed-genotype infections. Theoretical results indicate that variation in host susceptibility is inextricably linked to increased prevalence of mixed-genotype infections. We have shown, to our knowledge for the first time, how heterogeneity in host susceptibility affects mixed-genotype infection prevalence. No evidence was found that virions operate dependently. While it has been recognized that heterogeneity in host susceptibility must be included in models of micro-parasite transmission and epidemiology to account for dose response, here we show that heterogeneity in susceptibility is also a fundamental principle explaining patterns of pathogen genetic diversity among hosts in a population. This principle has potentially wide implications for the monitoring, modeling and management of infectious diseases

Can disordered mobile phone use be considered a behavioral addiction? An update on current evidence and a comprehensive model for future research

Despite the many positive outcomes, excessive mobile phone use is now often associated with potentially harmful and/or disturbing behaviors (e.g., symptoms of deregulated use, negative impact on various aspects of daily life such as relationship problems, and work intrusion). Problematic mobile phone use (PMPU) has generally been considered as a behavioral addiction that shares many features with more established drug addictions. In light of the most recent data, the current paper reviews the validity of the behavioral addiction model when applied to PMPU. On the whole, it is argued that the evidence supporting PMPU as an addictive behavior is scarce. In particular, it lacks studies that definitively show behavioral and neurobiological similarities between mobile phone addiction and other types of legitimate addictive behaviors. Given this context, an integrative pathway model is proposed that aims to provide a theoretical framework to guide future research in the field of PMPU. This model highlights that PMPU is a heterogeneous and multi-faceted condition

Acute WNT signalling activation perturbs differentiation within the adult stomach and rapidly leads to tumour formation

A role for WNT signalling in gastric carcinogenesis has been suggested due to two major observations. First, patients with germline mutations in adenomatous polyposis coli (APC) are susceptible to stomach polyps and second, in gastric cancer, WNT activation confers a poor prognosis. However, the functional significance of deregulated WNT signalling in gastric homoeostasis and cancer is still unclear. In this study we have addressed this by investigating the immediate effects of WNT signalling activation within the stomach epithelium. We have specifically activated the WNT signalling pathway within the mouse adult gastric epithelium via deletion of either glycogen synthase kinase 3 (GSK3) or APC or via expression of a constitutively active β-catenin protein. WNT pathway deregulation dramatically affects stomach homoeostasis at very short latencies. In the corpus, there is rapid loss of parietal cells with fundic gland polyp (FGP) formation and adenomatous change, which are similar to those observed in familial adenomatous polyposis. In the antrum, adenomas occur from 4 days post-WNT activation. Taken together, these data show a pivotal role for WNT signalling in gastric homoeostasis, FGP formation and adenomagenesis. Loss of the parietal cell population and corresponding FGP formation, an early event in gastric carcinogenesis, as well as antral adenoma formation are immediate effects of nuclear β-catenin translocation and WNT target gene expression. Furthermore, our inducible murine model will permit a better understanding of the molecular changes required to drive tumourigenesis in the stomach