Mean field approaches to the totally asymmetric exclusion process with quenched disorder and large particles

The process of protein synthesis in biological systems resembles a one dimensional driven lattice gas in which the particles (ribosomes) have spatial extent, covering more than one lattice site. Realistic, nonuniform gene sequences lead to quenched disorder in the particle hopping rates. We study the totally asymmetric exclusion process with large particles and quenched disorder via several mean field approaches and compare the mean field results with Monte Carlo simulations. Mean field equations obtained from the literature are found to be reasonably effective in describing this system. A numerical technique is developed for computing the particle current rapidly. The mean field approach is extended to include two-point correlations between adjacent sites. The two-point results are found to match Monte Carlo simulations more closely

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology

Accelerating slip rates on the Puente Hills blind thrust fault system beneath metropolitan Los Angeles, California, USA

Slip rates represent the average displacement across a fault over time and are essential to estimating earthquake recurrence for probabilistic seismic hazard assessments. We demonstrate that the slip rate on the western segment of the Puente Hills blind thrust fault system, which is beneath downtown Los Angeles, California (USA), has accelerated from ∼0.22 mm/yr in the late Pleistocene to ∼1.33 mm/yr in the Holocene. Our analysis is based on syntectonic strata derived from the Los Angeles River, which has continuously buried a fold scarp above the blind thrust. Slip on the fault beneath our field site began during the late-middle Pleistocene and progressively increased into the Holocene. This increase in rate implies that the magnitudes and/or the frequency of earthquakes on this fault segment have increased over time. This challenges the characteristic earthquake model and presents an evolving and potentially increasing seismic hazard to metropolitan Los Angeles

Factors Associated with Sexual Violence against Men Who Have Sex with Men and Transgendered Individuals in Karnataka, India

There is a lack of information on sexual violence (SV) among men who have sex with men and transgendered individuals (MSM-T) in southern India. As SV has been associated with HIV vulnerability, this study examined health related behaviours and practices associated with SV among MSM-T.Data were from cross-sectional surveys from four districts in Karnataka, India.Multivariable logistic regression models were constructed to examine factors related to SV. Multivariable negative binomial regression models examined the association between physician visits and SV.A total of 543 MSM-T were included in the study. Prevalence of SV was 18% in the past year. HIV prevalence among those reporting SV was 20%, compared to 12% among those not reporting SV (p = .104). In multivariable models, and among sex workers, those reporting SV were more likely to report anal sex with 5+ casual sex partners in the past week (AOR: 4.1; 95%CI: 1.2-14.3, p = .029). Increased physician visits among those reporting SV was reported only for those involved in sex work (ARR: 1.7; 95%CI: 1.1-2.7, p = .012).These results demonstrate high levels of SV among MSM-T populations, highlighting the importance of integrating interventions to reduce violence as part of HIV prevention programs and health services

A near 90-year record of the evolution of El Morado Glacier and its proglacial lake, Central Chilean Andes

Using an ensemble of close- and long-range remote sensing, lake bathymetry and regional meteorological data, we present a detailed assessment of the geometric changes of El Morado Glacier in the Central Andes of Chile and its adjacent proglacial lake between 1932 and 2019. Overall, the results revealed a period of marked glacier down wasting, with a mean geodetic glacier mass balance of −0.39 ± 0.15 m w.e.a−1 observed for the entire glacier between 1955 and 2015 with an area loss of 40% between 1955 and 2019. We estimate an ice elevation change of −1.00 ± 0.17 m a−1 for the glacier tongue between 1932 and 2019. The increase in the ice thinning rates and area loss during the last decade is coincident with the severe drought in this region (2010–present), which our minimal surface mass-balance model is able to reproduce. As a result of the glacier changes observed, the proglacial lake increased in area substantially between 1955 and 2019, with bathymetry data suggesting a water volume of 3.6 million m3 in 2017. This study highlights the need for further monitoring of glacierised areas in the Central Andes. Such efforts would facilitate a better understanding of the downstream impacts of glacier downwasting

Bifunctional Small Molecules Enhance Neutrophil Activities Against Aspergillus fumigatus in vivo and in vitro

Aspergillosis is difficult to treat and carries a high mortality rate in immunocompromised patients. Neutrophils play a critical role in control of infection but may be diminished in number and function during immunosuppressive therapies. Here, we measure the effect of three bifunctional small molecules that target Aspergillus fumigatus and prime neutrophils to generate a more effective response against the pathogen. The molecules combine two moieties joined by a chemical linker: a targeting moiety (TM) that binds to the surface of the microbial target, and an effector moiety (EM) that interacts with chemoattractant receptors on human neutrophils. We report that the bifunctional compounds enhance the interactions between primary human neutrophils and A. fumigatus in vitro, using three microfluidic assay platforms. The bifunctional compounds significantly enhance the recruitment of neutrophils, increase hyphae killing by neutrophils in a uniform concentration of drug, and decrease hyphal tip growth velocity in the presence of neutrophils compared to the antifungal targeting moiety alone. We validated that the bifunctional compounds are also effective in vivo, using a zebrafish infection model with neutrophils expressing the appropriate EM receptor. We measured significantly increased phagocytosis of A. fumigatus conidia by neutrophils expressing the EM receptor in the presence of the compounds compared to receptor-negative cells. Finally, we demonstrate that treatment with our lead compound significantly improved the antifungal activity of neutrophils from immunosuppressed patients ex vivo. This type of bifunctional compounds strategy may be utilized to redirect the immune system to destroy fungal, bacterial, and viral pathogens

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change ≥2) and significantly altered in GBM (p ≤ 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

Air-Combat Strategy Using Approximate Dynamic Programming

Unmanned Aircraft Systems (UAS) have the potential to perform many of the dangerous missions currently own by manned aircraft. Yet, the complexity of some tasks, such as air combat, have precluded UAS from successfully carrying out these missions autonomously. This paper presents a formulation of a level flight, fixed velocity, one-on-one air combat maneuvering problem and an approximate dynamic programming (ADP) approach for computing an efficient approximation of the optimal policy. In the version of the problem formulation considered, the aircraft learning the optimal policy is given a slight performance advantage. This ADP approach provides a fast response to a rapidly changing tactical situation, long planning horizons, and good performance without explicit coding of air combat tactics. The method's success is due to extensive feature development, reward shaping and trajectory sampling. An accompanying fast and e ffective rollout-based policy extraction method is used to accomplish on-line implementation. Simulation results are provided that demonstrate the robustness of the method against an opponent beginning from both off ensive and defensive situations. Flight results are also presented using micro-UAS own at MIT's Real-time indoor Autonomous Vehicle test ENvironment (RAVEN).Defense University Research Instrumentation Program (U.S.) (grant number FA9550-07-1-0321)United States. Air Force Office of Scientific Research (AFOSR # FA9550-08-1-0086)American Society for Engineering Education (National Defense Science and Engineering Graduate Fellowship

Solutions to the Wheeler-Dewitt Equation Inspired by the String Effective Action

The Wheeler-DeWitt equation is derived from the bosonic sector of the heterotic string effective action assuming a toroidal compactification. The spatially closed, higher dimensional Friedmann-Robertson-Walker (FRW) cosmology is investigated and a suitable change of variables rewrites the equation in a canonical form. Real- and imaginary-phase exact solutions are found and a method of successive approximations is employed to find more general power series solutions. The quantum cosmology of the Bianchi IX universe is also investigated and a class of exact solutions is found.Comment: 21 pages of plain LaTeX, Fermilab-Pub-93/100-