Intracellular insulin in human tumors: examples and implications

Insulin is one of the major metabolic hormones regulating glucose homeostasis in the organism and a key growth factor for normal and neoplastic cells. Work conducted primarily over the past 3 decades has unravelled the presence of insulin in human breast cancer tissues and, more recently, in human non-small cell lung carcinomas (NSCLC). These findings have suggested that intracellular insulin is involved in the development of these highly prevalent human tumors. A potential mechanism for such involvement is insulin's binding and inactivation of the retinoblastoma tumor suppressor protein (RB) which in turn is likely controlled by insulin-degrading enzyme (IDE). This model and its supporting data are collectively covered in this survey in order to provide further insight into insulin-driven oncogenesis and its reversal through future anticancer therapeutics

When IoT Meets DevOps: Fostering Business Opportunities

The Internet of Things (IoT) is the new digital revolution for the near-future society, the second after the creation of the Internet itself. The software industry is converging towards the large-scale deployment of IoT devices and services, and there’s broad support from the business environment for this engineering vision. The Development and Operations (DevOps) project management methodology, with continuous delivery and integration, is the preferred approach for achieving and deploying applications to all levels of the IoT architecture. In this paper we also discuss the promising trend of associating devices with microservices, which are further encapsulated into functional packages called containers. Docker is considered the market leader in container-based service delivery, though other important software companies are promoting this concept as part of the technology solution for their IoT customers. In the experimental section we propose a three-layer IoT model, business-oriented, and distributed over multiple cloud environments, comprising the Physical, Fog/Edge, and Application layers.     Keywords: Internet-of-Things, software technologies, project management, business environment Heading

Far-From-Equilibrium Time Evolution between Two Gamma Distributions

Many systems in nature and laboratories are far from equilibrium and exhibit significant fluctuations, invalidating the key assumptions of small fluctuations and short memory time in or near equilibrium. A full knowledge of Probability Distribution Functions (PDFs), especially time-dependent PDFs, becomes essential in understanding far-from-equilibrium processes. We consider a stochastic logistic model with multiplicative noise, which has gamma distributions as stationary PDFs. We numerically solve the transient relaxation problem and show that as the strength of the stochastic noise increases, the time-dependent PDFs increasingly deviate from gamma distributions. For sufficiently strong noise, a transition occurs whereby the PDF never reaches a stationary state, but instead, forms a peak that becomes ever more narrowly concentrated at the origin. The addition of an arbitrarily small amount of additive noise regularizes these solutions and re-establishes the existence of stationary solutions. In addition to diagnostic quantities such as mean value, standard deviation, skewness and kurtosis, the transitions between different solutions are analysed in terms of entropy and information length, the total number of statistically-distinguishable states that a system passes through in time

Diffuse Neutron Scattering Study of Magnetic Correlations in half-doped La0.5Ca0.5-xSrxMnO3 (x = 0.1, 0.3 and 0.4) Manganites

The short range ordered magnetic correlations have been studied in half doped La0.5Ca0.5-xSrxMnO3 (x = 0.1, 0.3 and 0.4) compounds by polarized neutron scattering technique. On doping Sr2+ for Ca2+ ion, these compounds with x = 0.1, 0.3, and 0.4 exhibit CE-type, mixture of CE-type and A-type, and A-type antiferromagnetic ordering, respectively. Magnetic diffuse scattering is observed in all the compounds above and below their respective magnetic ordering temperatures and is attributed to magnetic polarons. The correlations are primarily ferromagnetic in nature above T\_N, although a small antiferromagnetic contribution is also evident. Additionally, in samples x = 0.1 and 0.3 with CE-type antiferromagnetic ordering, superlattice diffuse reflections are observed indicating correlations between magnetic polarons. On lowering temperature below T\_N the diffuse scattering corresponding to ferromagnetic correlations is suppressed and the long range ordered antiferromagnetic state is established. However, the short range ordered correlations indicated by enhanced spin flip scattering at low Q coexist with long range ordered state down to 3K. In x = 0.4 sample with A-type antiferromagnetic ordering, superlattice diffuse reflections are absent. Additionally, in comparison to x = 0.1 and 0.3 sample, the enhanced spin flip scattering at low Q is reduced at 310K, and as temperature is reduced below 200K, it becomes negligibly low. The variation of radial correlation function, g(r) with temperature indicates rapid suppression of ferromagnetic correlations at the first nearest neighbor on approaching TN. Sample x = 0.4 exhibits growth of ferromagnetic phase at intermediate temperatures (~ 200K). This has been further explored using SANS and neutron depolarization techniques.Comment: 13 pages, 12 figures, To appear in Physical Review

Interaction of paraffin wax gels with random crystalline/amorphous hydrocarbon copolymers

The control mechanisms involved in the modification of wax crystal dimensions in crude oils and refined fuels are of joint scientific and practical interest. An understanding of these mechanisms allows strategies to be developed that lead to decreases in crude oil pour points or (for refined fuels) cold filter plugging points. The attainment of these goals involves the control and modification of wax crystals that spontaneously form in mixed hydrocarbon systems upon decreasing temperature. This work reports on the influence of random crystalline-amorphous block copolymers (ethylene-butene) upon the rheology of model oils. In a parallel fashion small-angle neutron scattering was exploited to gain microscopic insight as to how added poly(ethylene-butene) copolymers modify the wax crystal structures. The copolymers with different contents of polyethylene are highly selective with respect to wax crystal modification. Thus, the copolymer with the highest crystalline tendency is more efficient for the larger wax molecules while the less crystalline one is more efficient for the lower waxes

Dense packing on uniform lattices

We study the Hard Core Model on the graphs ${\rm {\bf \scriptstyle G}}$ obtained from Archimedean tilings i.e. configurations in $\scriptstyle \{0,1\}^{{\rm {\bf G}}}$ with the nearest neighbor 1's forbidden. Our particular aim in choosing these graphs is to obtain insight to the geometry of the densest packings in a uniform discrete set-up. We establish density bounds, optimal configurations reaching them in all cases, and introduce a probabilistic cellular automaton that generates the legal configurations. Its rule involves a parameter which can be naturally characterized as packing pressure. It can have a critical value but from packing point of view just as interesting are the noncritical cases. These phenomena are related to the exponential size of the set of densest packings and more specifically whether these packings are maximally symmetric, simple laminated or essentially random packings.Comment: 18 page

Coincidence isometries of a shifted square lattice

We consider the coincidence problem for the square lattice that is translated by an arbitrary vector. General results are obtained about the set of coincidence isometries and the coincidence site lattices of a shifted square lattice by identifying the square lattice with the ring of Gaussian integers. To illustrate them, we calculate the set of coincidence isometries, as well as generating functions for the number of coincidence site lattices and coincidence isometries, for specific examples.Comment: 10 pages, 1 figure; paper presented at Aperiodic 2009 (Liverpool

Ordering and Demixing Transitions in Multicomponent Widom-Rowlinson Models

We use Monte Carlo techniques and analytical methods to study the phase diagram of multicomponent Widom-Rowlinson models on a square lattice: there are M species all with the same fugacity z and a nearest neighbor hard core exclusion between unlike particles. Simulations show that for M between two and six there is a direct transition from the gas phase at z < z_d (M) to a demixed phase consisting mostly of one species at z > z_d (M) while for M \geq 7 there is an intermediate ``crystal phase'' for z lying between z_c(M) and z_d(M). In this phase, which is driven by entropy, particles, independent of species, preferentially occupy one of the sublattices, i.e. spatial symmetry but not particle symmetry is broken. The transition at z_d(M) appears to be first order for M \geq 5 putting it in the Potts model universality class. For large M the transition between the crystalline and demixed phase at z_d(M) can be proven to be first order with z_d(M) \sim M-2 + 1/M + ..., while z_c(M) is argued to behave as \mu_{cr}/M, with \mu_{cr} the value of the fugacity at which the one component hard square lattice gas has a transition, and to be always of the Ising type. Explicit calculations for the Bethe lattice with the coordination number q=4 give results similar to those for the square lattice except that the transition at z_d(M) becomes first order at M>2. This happens for all q, consistent with the model being in the Potts universality class.Comment: 26 pages, 15 postscript figure

Quantitative super-resolution imaging of pathological aggregates reveals distinct toxicity profiles in different synucleinopathies.

Protein aggregation is a hallmark of major neurodegenerative disorders. Increasing data suggest that smaller aggregates cause higher toxic response than filamentous aggregates (fibrils). However, the size of small aggregates has challenged their detection within biologically relevant environments. Here, we report approaches to quantitatively super-resolve aggregates in live cells and ex vivo brain tissues. We show that Amytracker 630 (AT630), a commercial aggregate-activated fluorophore, has outstanding photophysical properties that enable super-resolution imaging of α-synuclein, tau, and amyloid-β aggregates, achieving ∼4 nm precision. Applying AT630 to AppNL-G-F mouse brain tissues or aggregates extracted from a Parkinson's disease donor, we demonstrate excellent agreement with antibodies specific for amyloid-β or α-synuclein, respectively, confirming the specificity of AT630. Subsequently, we use AT630 to reveal a linear relationship between α-synuclein aggregate size and cellular toxicity and discovered that aggregates smaller than 450 ± 60 nm (aggregate450nm) readily penetrated the plasma membrane. We determine aggregate450nm concentrations in six Parkinson's disease and dementia with Lewy bodies donor samples and show that aggregates in different synucleinopathies demonstrate distinct potency in toxicity. We further show that cell-penetrating aggregates are surrounded by proteasomes, which assemble into foci to gradually process aggregates. Our results suggest that the plasma membrane effectively filters out fibrils but is vulnerable to penetration by aggregates of 450 ± 60 nm. Together, our findings present an exciting strategy to determine specificity of aggregate toxicity within heterogeneous samples. Our approach to quantitatively measure these toxic aggregates in biological environments opens possibilities to molecular examinations of disease mechanisms under physiological conditions

A Prospective Observational Study of Antihemophilic Factor (Recombinant) Prophylaxis Related to Physical Activity Levels in Patients with Hemophilia A in the United States (SPACE)

Introduction: High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. Aim: To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA). Methods: SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. Results: Fifty-four patients aged 11– 58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were ≤ 24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (≤ 24 to \u3e 24 hours) from last infusion to physical activity start (odds ratio 2.65, p \u3c 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. Conclusion: These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding