Using nonequilibrium fluctuation theorems to understand and correct errors in equilibrium and nonequilibrium discrete Langevin dynamics simulations

Common algorithms for computationally simulating Langevin dynamics must discretize the stochastic differential equations of motion. These resulting finite time step integrators necessarily have several practical issues in common: Microscopic reversibility is violated, the sampled stationary distribution differs from the desired equilibrium distribution, and the work accumulated in nonequilibrium simulations is not directly usable in estimators based on nonequilibrium work theorems. Here, we show that even with a time-independent Hamiltonian, finite time step Langevin integrators can be thought of as a driven, nonequilibrium physical process. Once an appropriate work-like quantity is defined -- here called the shadow work -- recently developed nonequilibrium fluctuation theorems can be used to measure or correct for the errors introduced by the use of finite time steps. In particular, we demonstrate that amending estimators based on nonequilibrium work theorems to include this shadow work removes the time step dependent error from estimates of free energies. We also quantify, for the first time, the magnitude of deviations between the sampled stationary distribution and the desired equilibrium distribution for equilibrium Langevin simulations of solvated systems of varying size. While these deviations can be large, they can be eliminated altogether by Metropolization or greatly diminished by small reductions in the time step. Through this connection with driven processes, further developments in nonequilibrium fluctuation theorems can provide additional analytical tools for dealing with errors in finite time step integrators.Comment: 11 pages, 4 figure

Let-7 MicroRNA-Binding-Site Polymorphism in the 3′UTR of KRAS and Colorectal Cancer Outcome: A Systematic Review and Meta-Analysis

There is a small but growing body of literature regarding the predictive utility of a Let-7 microRNA-binding-site polymorphism in the 30 -untranslated region (UTR) of KRAS (KRAS-LCS6) for colorectal cancer outcome, although the results are conflicting. We performed a review and meta-analysis in an attempt to better clarify this relationship. A PubMed search was conducted to identify all studies reporting on KRAS let-7 microRNA-binding site polymorphism (LCS6; rs61764370) and colorectal cancer outcome. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) were extracted or estimated from each manuscript. Log HRs and log CIs were combined across studies using the inverse-variance weight to calculate fixed- and random-effects summary estimates and corresponding 95% CIs for overall and progression-free survival. We did not observe any significant association between overall or progression-free survival, neither when considering all colorectal cancer patients nor for subgroup analyses (metastatic, anti-EGFR [epidermal growth factor receptor] treatment, or KRAS wild type). There was substantial heterogeneity across studies, overall and among subgroups analyzed. We have found no clear evidence to support an association between the KRAS-LCS6 genotype and overall or progression-free survival among colorectal cancer patients, even after conducting subgroup analyses by stage and anti-EGFR treatment status. This information helps to clarify the confusing body of literature regarding the clinical implications of the KRAS-LCS6 genetic variant on colorectal cancer outcomes, indicating that it should not be used at the present time to personalize therapeutic strategies (PROSPERO registration number: CRD42013005325)

Penicillin kills chlamydia following the fusion of bacteria with Lysosomes and prevents genital inflammatory lesions in C. muridarum-infected mice

The obligate intracellular bacterium Chlamydia exists as two distinct forms. Elementary bodies (EBs) are infectious and extra-cellular, whereas reticulate bodies (RBs) replicate within a specialized intracellular compartment termed an ‘inclusion’. Alternative persistent intra-cellular forms can be induced in culture by diverse stimuli such as IFNγ or adenosine/EHNA. They do not grow or divide but revive upon withdrawal of the stimulus and are implicated in several widespread human diseases through ill-defined in vivo mechanisms. β-lactam antibiotics have also been claimed to induce persistence in vitro. The present report shows that upon penicillin G (pG) treatment, inclusions grow as fast as those in infected control cells. After removal of pG, Chlamydia do not revert to RBs. These effects are independent of host cell type, serovar, biovar and species of Chlamydia. Time-course experiments demonstrated that only RBs were susceptible to pG. pG-treated bacteria lost their control over host cell apoptotic pathways and no longer expressed pre-16S rRNA, in contrast to persistent bacteria induced with adenosine/EHNA. Confocal and live-video microscopy showed that bacteria within the inclusion fused with lysosomal compartments in pG-treated cells. That leads to recruitment of cathepsin D as early as 3 h post pG treatment, an event preceding bacterial death by several hours. These data demonstrate that pG treatment of cultured cells infected with Chlamydia results in the degradation of the bacteria. In addition we show that pG is significantly more efficient than doxycycline at preventing genital inflammatory lesions in C. muridarum-C57Bl/6 infected mice. These in vivo results support the physiological relevance of our findings and their potential therapeutic applications

Learning Strategies of Students Attending a “Second Chance” School

This study was conducted in Quebec with 608 students (aged 16-19) in four “second chance” schools of the greater Montreal area. The objectives were twofold: (a) to identify the strategies of these students in the context of five learning activities; and (b) to compare the strategies of students who had withdrawn from school after their mandatory attendance period (age 16-17) with those of students exceeding the age limit for high school (age 18-19). Results from a self-reported questionnaire in French show that the students lack many learning strategies, particularly for two of the five activities. The differences between the two groups always favor the older students and pertain to a specific aspect of the activity. These results argue for differentiation in research and classroom practices according to the activities presented to the students and according to the two age groups.Cette étude a été réalisée au Québec auprès de 608 élèves (âgés de 16 à 19 ans) de quatre écoles de « raccrocheurs » de la région métropolitaine de Montréal. La recherche a poursuivi deux objectifs : (a) identifier les stratégies des élèves « raccrocheurs » dans le cadre de cinq activités d’apprentissage; et (b) comparer les stratégies des élèves qui avaient abandonné l’école après la période de fréquentation obligatoire (16-17 ans) à celles des élèves qui avaient dépassé l’âge limite de fréquentation de l’école secondaire (18-19 ans). Les résultats à un questionnaire validé en français indiquent que tous les élèves, en général, disent avoir recours à un nombre restreint de stratégies d’apprentissage, notamment dans deux des cinq activités. Les différences entre les deux groupes favorisent toujours les élèves plus âgés et sont pertinentes pour un aspect spécifique de l’activité. Ces résultats militent en faveur d’une différenciation de la recherche et des pratiques pédagogiques selon les activités présentées aux élèves d’une part, et les deux groupes d’âge d’autre part

Polaron Recombination in Pristine and Annealed Bulk Heterojunction Solar Cells

The major loss mechanism of photogenerated polarons was investigated in P3HT:PCBM solar cells by the photo-CELIV technique. For pristine and annealed devices, we find that the experimental data can be explained by a bimolecular recombination rate reduced by a factor of about ten (pristine) and 25 (annealed) as compared to Langevin theory. Aided by a macroscopic device model, we discuss the implications of the lowered loss rate on the characteristics of polymer:fullerene solar cells.Comment: 3 pages, 4 figure

Agrotechnologies towards Ecotechnologies the three pillars for developing Eco-design

International audienceTo boost agrotechnologies towards ecotechnologies ("environmental technologies" according to ETAP programme of EU, or "more ecologically productive technologies" in the context of agriculture), we need to strengthen a "triple bottom" system: -To take into account, in "Life Cycle Analysis" methodologies, the natural variability in time and space of these applications in land use. - To develop an overall approach for realistic machinery qualification, in order to feed the environmental burdens accurately through relevant data bases collected on agrotechnologies in real action. - To work on Eco-innovation processes, by deepening specific innovation tools and methods, for implementation of innovative solutions chosen according to LCA results. This paper presents the concept, develops the methods and illustrates them by examples of results on organic spreading technologies

Preface

Water and chemical fluxes across the sea bottom provide an important linkage between terrestrial and marine environments. From the marine perspective, these water fluxes, commonly referred to as submarine groundwater discharge (SGD), may contain elevated nutrient concentrations or high levels of other potentially harmful contaminants. Terrestrially derived SGD can also be an important source of freshwater for estuarine ecosystems that require relatively low salinities. For these reasons, the past decade has shown a rapid increase in the level of interest from estuary and marine scientists toward a better understanding of SGD. From the terrestrial perspective, SGD has also been a topic of interest to those studying saltwater intrusion and management of coastal aquifers. Saltwater intrusion studies commonly employ some form of a water balance method, whether through numerical modelling or volumetric calculations, to explain intrusion patterns and develop predictions and management plans. In developing a water balance for a coastal aquifer, estimates for all of the key components, including SGD, are synthesized. Although the motivation may be different depending on whether one works from the marine or terrestrial perspective, both groups have a common goal of obtaining accurate SGD estimate

Background and summary: a new focus on groundwater-seawater interactions

Water and chemical fluxes across the sea floor provide an important linkage between terrestrial and marine environments. Oceanographers recognize that these fluxes may act as a source of nutrients or other harmful contaminants to marine systems (e.g. Johannes, 1980; Valiela et al., 1990). These fluxes may also act as a beneficial source of freshwater for coastal marine estuaries that require relatively low salinities. Hydrologists and hydrogeologists recognize that fluxes across the sea floor comprise an important part of the water balance for coastal aquifers. Most fresh groundwater discharge to the ocean is derived from terrestrial aquifer recharge. Management of coastal aquifers requires careful estimates of recharge and other hydrological components, such as groundwater discharge. These estimates are commonly combined into a comprehensive water budget to evaluate how much groundwater might be available for municipal uses and whether saltwater intrusion may be a potential concern. Excessive groundwater withdrawals can cause saltwater intrusion by intercepting the seaward flux of freshwater that prevents saltwater from intruding a coastal aquifer. Quantitative estimates of fresh groundwater discharge toward the coast can provide a basis for determining safe withdrawal rates. Oceanographers, marine scientists, and those studying and managing saltwater intrusion in coastal aquifers, share a common goal of quantification and understanding of groundwater and seawater interactions. Submarine groundwater discharge, or SGD, has become a popular term in the literature for describing the flux of water across the sea floor. Burnett et al. (2003) specifically define SGD as the discharge of aquifer porewater across the sea floor and into the ocean. They define flow in the opposite direction as submarine groundwater recharge (SGR). SGR is the recharging flux of seawater into the aquifer. The presence of SGR does not necessarily indicate saltwater intrusion, which occurs when saline water moves into parts of the aquifer previously occupied by freshwater. A conceptual model of the types of flow patterns that are expected to exist in many coastal aquifers at the terrestrial–marine boundary is shown. Through a detailed field study, Kohout (1960) showed that as fresh groundwater flows seaward, it meets and mixes with saline groundwater before discharging into the ocean. Because of this mixing and subsequent discharge to the ocean, seawater is drawn into the aquifer to replace the saline groundwater that discharged to the ocean. Seawater drawn into the aquifer is sometimes referred to as recirculated seawater. Michael et al. (2005) suggest that the seasonality of terrestrial recharge may also act as a mechanism for recirculating seawater through a coastal aquifer. As the mixing zone moves landward and seaward in response to seasonal fluctuations in recharge, seawater may be drawn in and flushed out of the aquifer over the course of a year. SGD can also occur at the bottom of the open ocean, even in the absence of a terrestrial connection. Waves, tides, and ocean currents can create hydraulic gradients that pump seawater across the sea floor. Interest in groundwater–seawater interactions continues to receive a significant amount of attention in the literature. Saltwater intrusion, freshwater deliveries to marine estuaries, and nutrient loading are persistent problems of global importance. The problems are difficult to address, however, because of the elusive nature of SGD. Fortunately, the science is advancing. The journal Biogeochemistry, dedicated the entire November 2003 issue to the subject of SGD as did the journal Ground Water, in the December 2004 issue. Zektser & Dzhamalov (2007) released a comprehensive review on the subject of SGD and groundwater–seawater interactions in a new book: Submarine Groundwater. In their book, they suggest that SGD and related studies should be categorized into a new field called “Marine Hydrogeology”. The concentrated efforts of numerous researchers from a wide range of disciplines have led to substantial advancements in characterizing SGD, but there is still more work to be done

Optical properties of cometary particles collected by the COSIMA mass spectrometer on-board <i>Rosetta</i> during the rendezvous phase around comet 67P/Churyumov–Gerasimenko

40 000 collected cometary particles have been identified on the 21 targets exposed by the COSIMA experiment on-board Rosetta to the environment of comet 67P/Churyumov–Gerasimenko from 2014 August to 2016 September. The images of the targets where obtained by the COSIMA microscope (Cosiscope, 13.95 μm pixel−1) with near grazing incidence, which is optimal for the primary objective (detection of collected particles) but very challenging for photometry. However, more than 300 of the collected particles are larger than 100 μm which makes it possible to derive constraints on the optical properties from the distribution of light levels within the particles. Two types of particles collected by COSIMA (compact particles and cluster particles) have been identified in Langevin et al. The best estimate reflectance factors of compact particles range from 10 per cent to 23 per cent. For cluster particles (>90 per cent of large collected particles), the comparison of the signal profiles with illumination from two opposite directions shows that there is scattering within the particles, with a mean free path in the 20–25 μm range, which requires high porosity. The best estimate reflectance factors of cluster particles range from 3 per cent to 22 per cent. This range of reflectance factors overlaps with that obtained from observations of the cometary nucleus at macroscopic scales by OSIRIS and it is consistent with that measured for interplanetary dust particles collected in the stratosphere of the Earth