The effect of local thermal fluctuations on the folding kinetics: a study from the perspective of the nonextensive statistical mechanics

Protein folding is a universal process, very fast and accurate, which works consistently (as it should be) in a wide range of physiological conditions. The present work is based on three premises, namely: ($i$) folding reaction is a process with two consecutive and independent stages, namely the search mechanism and the overall productive stabilization; ($ii$) the folding kinetics results from a mechanism as fast as can be; and ($iii$) at nanoscale dimensions, local thermal fluctuations may have important role on the folding kinetics. Here the first stage of folding process (search mechanism) is focused exclusively. The effects and consequences of local thermal fluctuations on the configurational kinetics, treated here in the context of non extensive statistical mechanics, is analyzed in detail through the dependence of the characteristic time of folding ($\tau$) on the temperature $T$ and on the nonextensive parameter $q$.The model used consists of effective residues forming a chain of 27 beads, which occupy different sites of a $3-$D infinite lattice, representing a single protein chain in solution. The configurational evolution, treated by Monte Carlo simulation, is driven mainly by the change in free energy of transfer between consecutive configurations. ...Comment: 19 pages, 3 figures, 1 tabl

Inclusion of multiple high‐risk histopathological criteria improves the prediction of adjuvant chemotherapy efficacy in lung adenocarcinoma

AIMS: The decision to consider adjuvant chemotherapy (AC) for non-small cell lung cancer is currently governed by clinical stage. This study aims to assess other routinely collected pathological variables related to metastasis and survival for their ability to predict the efficacy of AC in lung adenocarcinoma. METHODS AND RESULTS: A retrospective single-centre series of 620 resected lung non-mucinous adenocarcinoma cases from 2005-2015 was used. Digital images of all slides were subjected to central review, and data on tumour histopathology, AC treatment and patient survival were compiled. A statistical case matching approach was used to counter selection bias. Several high-risk pathological criteria predict both pathological nodal involvement and early death: positive vascular invasion status (VI+) (HR=2.10 P<0.001), positive visceral pleural invasion status (VPI+) (HR=2.16 P<0.001), and solid/micropapillary-predominant WHO tumour type (SPA/MPPA) (HR=3.29 P<0.001). Crucially, these criteria also identify patient groups benefiting from AC (VI+ HR=0.69 P=0.167, VPI+ HR=0.44 P=0.004, SPA/MPPA HR=0.36 P=0.006). Cases showing VI+/VPI+/SPA/MPPA histology in the absence of AC stage criteria were common (170 of 620 total), and 8 had actually received AC. This group showed much better outcomes than equivalent untreated cases in matched analysis (3-year OS 100.0% vs 31.3%). Inclusion of patients with VI+/VPI+/SPA/MPPA histology would increase AC-eligible patients from 51.0% to 84.0% of non-mucinous tumours in our cohort. CONCLUSIONS: Our data provide preliminary evidence that the consideration of AC in patients with additional high-risk pathological indicators may significantly improve outcomes in operable lung adenocarcinoma, and that AC may be currently underused

A Stochastic Approach to Shortcut Bridging in Programmable Matter

In a self-organizing particle system, an abstraction of programmable matter, simple computational elements called particles with limited memory and communication self-organize to solve system-wide problems of movement, coordination, and configuration. In this paper, we consider a stochastic, distributed, local, asynchronous algorithm for "shortcut bridging", in which particles self-assemble bridges over gaps that simultaneously balance minimizing the length and cost of the bridge. Army ants of the genus Eciton have been observed exhibiting a similar behavior in their foraging trails, dynamically adjusting their bridges to satisfy an efficiency trade-off using local interactions. Using techniques from Markov chain analysis, we rigorously analyze our algorithm, show it achieves a near-optimal balance between the competing factors of path length and bridge cost, and prove that it exhibits a dependence on the angle of the gap being "shortcut" similar to that of the ant bridges. We also present simulation results that qualitatively compare our algorithm with the army ant bridging behavior. Our work gives a plausible explanation of how convergence to globally optimal configurations can be achieved via local interactions by simple organisms (e.g., ants) with some limited computational power and access to random bits. The proposed algorithm also demonstrates the robustness of the stochastic approach to algorithms for programmable matter, as it is a surprisingly simple extension of our previous stochastic algorithm for compression.Comment: Published in Proc. of DNA23: DNA Computing and Molecular Programming - 23rd International Conference, 2017. An updated journal version will appear in the DNA23 Special Issue of Natural Computin

Dimer-induced signal propagation in Spo0A

Spo0A, the response regulator protein controlling the initiation of sporulation in Bacillus, has two distinct domains, an N-terminal phosphoacceptor (or receiver) domain and a C-terminal DNA-binding (or effector) domain. The phosphoacceptor domain mediates dimerization of Spo0A on phosphorylation. A comparison of the crystal structures of phosphorylated and unphosphorylated response regulators suggests a mechanism of activation in which structural changes originating at the phosphorylatable aspartate extend to the alpha(4)beta(5)alpha(5) surface of the protein. In particular, the data show an important role in downstream signalling for a conserved aromatic residue (Phe-105 in Spo0A), the conformation of which alters upon phosphorylation. In this study, we have prepared a Phe-105 to Ala mutant to probe the contribution of this residue to Spo0A function. We have also made an alanine substitution of the neighbouring residue Tyr-104 that is absolutely conserved in the Spo0As of spore-forming Bacilli. The spo0A(Y104A) and spo0A(F105A) alleles severely impair sporulation in vivo. In vitro phosphorylation of the purified proteins by phosphoramidate is unaffected, but dimerization and DNA binding are abolished by the mutations. We have identified intragenic suppressor mutations of spo0A(F105A) and shown that these second-site mutations in the purified proteins restore phosphorylation-dependent dimer formation. Our data support a model in which dimerization and signal transduction between the two domains of Spo0A are mediated principally by the alpha(4)beta(5)alpha(5) signalling surface in the receiver domain

A Bayesian approach to the modelling of alpha Cen A

Determining the physical characteristics of a star is an inverse problem consisting in estimating the parameters of models for the stellar structure and evolution, knowing certain observable quantities. We use a Bayesian approach to solve this problem for alpha Cen A, which allows us to incorporate prior information on the parameters to be estimated, in order to better constrain the problem. Our strategy is based on the use of a Markov Chain Monte Carlo (MCMC) algorithm to estimate the posterior probability densities of the stellar parameters: mass, age, initial chemical composition,... We use the stellar evolutionary code ASTEC to model the star. To constrain this model both seismic and non-seismic observations were considered. Several different strategies were tested to fit these values, either using two or five free parameters in ASTEC. We are thus able to show evidence that MCMC methods become efficient with respect to more classical grid-based strategies when the number of parameters increases. The results of our MCMC algorithm allow us to derive estimates for the stellar parameters and robust uncertainties thanks to the statistical analysis of the posterior probability densities. We are also able to compute odds for the presence of a convective core in alpha Cen A. When using core-sensitive seismic observational constraints, these can raise above ~40%. The comparison of results to previous studies also indicates that these seismic constraints are of critical importance for our knowledge of the structure of this star.Comment: 21 pages, 6 figures, to be published in MNRA

The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation

Background: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. Methodology/Principal Findings: We found that Per2Brdm1 mutant mice as well as mice lacking Cry2-/- displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2Brdm1 mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2-/- displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2-/- mutants despite the simultaneous inactivation of Per2. Conclusions/Significance: This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters

High-order chromatin architecture determines the landscape of chromosomal alterations in cancer

The rapid growth of cancer genome structural information provides an opportunity for a better understanding of the mutational mechanisms of genomic alterations in cancer and the forces of selection that act upon them. Here we test the evidence for two major forces, spatial chromosome structure and purifying (or negative) selection, that shape the landscape of somatic copy-number alterations (SCNAs) in cancer1. Using a maximum likelihood framework we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule (FG) model2. This analysis provides evidence that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and additionally suggests that purifying selection as well as positive selection shapes the landscape of SCNAs during somatic evolution of cancer cells

Cancer Cachexia: Traditional Therapies and Novel Molecular Mechanism-Based Approaches to Treatment

The complex syndrome of cancer cachexia (CC) that occurs in 50% to 80% cancer patients has been identified as an independent predictor of shorter survival and increased risk of treatment failure and toxicity, contributing to the mortality and morbidity in this population. CC is a pathological state including a symptom cluster of loss of muscle (skeletal and visceral) and fat, manifested in the cardinal feature of emaciation, weakness affecting functional status, impaired immune system, and metabolic dysfunction. The most prominent feature of CC is its non-responsiveness to traditional treatment approaches; randomized clinical trials with appetite stimulants, 5-HT3 antagonists, nutrient supplementation, and Cox-2 inhibitors all have failed to demonstrate success in reversing the metabolic abnormalities seen in CC. Interventions based on a clear understanding of the mechanism of CC, using validated markers relevant to the underlying metabolic abnormalities implicated in CC are much needed. Although the etiopathogenesis of CC is poorly understood, studies have proposed that NFkB is upregulated in CC, modulating immune and inflammatory responses induce the cellular breakdown of muscle, resulting in sarcopenia. Several recent laboratory studies have shown that n-3 fatty acid may attenuate protein degradation, potentially by preventing NFkB accumulation in the nucleus, preventing the degradation of muscle proteins. However, clinical trials to date have produced mixed results potentially attributed to timing of interventions (end stage) and utilizing outcome markers such as weight which is confounded by hydration, cytotoxic therapies, and serum cytokines. We propose that selective targeting of proteasome activity with a standardized dose of omega-3-acid ethyl esters, administered to cancer patients diagnosed with early stage CC, in addition to a standard intervention with nutritionally adequate diet and appetite stimulants, will alter metabolic abnormalities by downregulating NFkB, preventing the breakdown of myofibrillar proteins and resulting in increasing serum protein markers, lean body mass, and functional status

The Economics of Tobacco and Tobacco Control

This monograph, a joint effort of the U.S. National Cancer Institute and World Health Organization, examines economic issues in tobacco and tobacco control, including the supply and demand of tobacco products. This first chapter frames the issues addressed in the monograph and describes its organization around key topic areas. Each monograph chapter focuses on the global evidence on these issues, particularly the evidence from low- and middle-income countries (LMICs). The closing sections of this chapter present chapter conclusions and major overall conclusions generated by the work presented here. Experts in economics, tobacco control, public policy, public health, and other related fields from every region in the world, including high-income countries and LMICs, were assembled to provide the research and analyses presented within these pages. It is hoped that this monograph will help inform the implementation of global tobacco control efforts in the 21st century.Additional co-authors: Dongbo Fu, C.K. Gajalakshmi, Vendhan Gajalakshmi, Mark Goodchild, Emmanuel Guindon, Prakash Gupta, Reviva Hasson, Luminita S Hayes, Sara Hitchman, Kinh Hoang-Van, Jidong Huang, Andrew Hyland, Nathan Jones, John Keyser, Pierre Kopp, Harry Lando, David Levy, James Lightwood, Christine Logel, Benn McGrady, Yumiko Mochizuki-Kobayashi, Mario Monsour, Nigar Nargis, Richard J. O’Connor, Maizurah Omar, Zeynep Önder, William Onzivu, Anne-Marie Perucic, Armando Peruga, Vinayak M. Prasad, Martin Raw, Cecily S. Ray, Lyn Reed, Bung-on Ritthiphakdee, Hana Ross, Jennifer Ruger, Henry Saffer, Genevieve Sansone, Natalie Sansone, Fatwa Sari Tetra Dewi, Kerstin Schotte, Omar Shafey, Yoon-Jeong Shin, Giorgio Sincovich, John Tauras, Mark Travers, Édouard Tursan d’Espaignet, Marco Vargas, Mandeep K. Virk-Baker, Corné van Walbeek, Charles W. Warren, Marzenna Anna Weresa, Xin Xu, Eduard Zaloshnja, Lei Zhang, Ping Zhan

Loss of flight promotes beetle diversification

The evolution of flight is a key innovation that may enable the extreme diversification of insects. Nonetheless, many species-rich, winged insect groups contain flightless lineages. The loss of flight may promote allopatric differentiation due to limited dispersal power and may result in a high speciation rate in the flightless lineage. Here we show that loss of flight accelerates allopatric speciation using carrion beetles (Coleoptera: Silphidae). We demonstrate that flightless species retain higher genetic differentiation among populations and comprise a higher number of genetically distinct lineages than flight-capable species, and that the speciation rate with the flightless state is twice that with the flight-capable state. Moreover, a meta-analysis of 51 beetle species from 15 families reveals higher genetic differentiation among populations in flightless compared with flight-capable species. In beetles, which represent almost one-fourth of all described species, repeated evolution of flightlessness may have contributed to their steady diversification since the Mesozoic era