ORCHIDEE‐STICS,a process‐based model of sugarcane biomass production: calibration of model parameters governing phenology

Agro‐Land Surface Models (agro‐LSM) combine detailed crop models and large‐scale vegetation models (DGVMs) to model the spatial and temporal distribution of energy, water, and carbon fluxes within the soil–vegetation–atmosphere continuum worldwide. In this study, we identify and optimize parameters controlling leaf area index (LAI) in the agro‐LSM ORCHIDEE‐STICS developed for sugarcane. Using the Morris method to identify the key parameters impacting LAI, at eight different sugarcane field trial sites, in Australia and La Reunion island, we determined that the three most important parameters for simulating LAI are (i) the maximum predefined rate of LAI increase during the early crop development phase, a parameter that defines a plant density threshold below which individual plants do not compete for growing their LAI, and a parameter defining a threshold for nitrogen stress on LAI. A multisite calibration of these three parameters is performed using three different scoring functions. The impact of the choice of a particular scoring function on the optimized parameter values is investigated by testing scoring functions defined from the model‐data RMSE, the figure of merit and a Bayesian quadratic model‐data misfit function. The robustness of the calibration is evaluated for each of the three scoring functions with a systematic cross‐validation method to find the most satisfactory one. Our results show that the figure of merit scoring function is the most robust metric for establishing the best parameter values controlling the LAI. The multisite average figure of merit scoring function is improved from 67% of agreement to 79%. The residual error in LAI simulation after the calibration is discussed.     

From the Skin to the Brain: Pathophysiology of Colonization and Infection of External Ventricular Drain,a Prospective Observational Study

Ventriculostomy-related infection (VRI) is a serious complication of external ventricular drain (EVD) but its natural history is poorly studied. We prospectively tracked the bacteria pathways from skin towards ventricles to identify the infectious process resulting in ventriculostomy-related colonization (VRC), and VRI. We systematically sampled cerebrospinal fluid (CSF) on a daily basis and collected swabs from both the skin and stopcock every 3.0 days for microbiological analysis including in 101 neurosurgical patient. Risk factors for positive event defined as either VRC or VRI were recorded and related to our microbiological findings. A total of 1261 CSF samples, 473 skin swabs, and 450 stopcock swabs were collected. Skin site was more frequently colonized than stopcock (70 (60%) vs 34 (29%), p = 0.023), and earlier (14 ±1.4 vs 24 ±1.5 days, p<0.0001). Sixty-one (52%) and 32 (27%) skin and stopcock sites were colonized with commensal bacteria, 1 (1%) and 1 (1%) with pathogens, 8 (7%) and 1 (1%) with combined pathogens and commensal bacteria, respectively. Sixteen positive events were diagnosed; a cutaneous origin was identified in 69% of cases. The presence of a pathogen at skin site (6/16 vs 4/85, OR: 11.8, [2.5–56.8], p = 0.002) and CSF leakage (7/16 vs 6/85, OR 10 [2.4–41.2], p = 0.001)) were the two independent significant risk factors statistically linked to positive events occurrence. Our results suggest that VRC and VRI mainly results from an extra-luminal progression of pathogens initially colonizing the skin site where CSF leaks.     

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results.     

Setting the pace of life: membrane composition of flight muscle varies with metabolic rate of hovering orchid bees

Patterns of metabolic rate variation have been documented extensively in animals, but their functional basis remains elusive. The membrane pacemaker hypothesis proposes that the relative abundance of polyunsaturated fatty acids in membrane phospholipids sets the metabolic rate of organisms. Using species of tropical orchid bees spanning a 16-fold range in body size, we show that the flight muscles of smaller bees have more linoleate (%18 : 3) and stearate (%18 : 0), but less oleate (%18 : 1). More importantly, flight metabolic rate (FlightMR) varies with the relative abundance of 18 : 3 according to the predictions of the membrane pacemaker hypothesis. Although this relationship was found across large differences in metabolic rate, a direct association could not be detected when taking phylogeny and body mass into account. Higher FlightMR, however, was related to lower %16 : 0, independent of phylogeny and body mass. Therefore, this study shows that flight muscle membrane composition plays a significant role in explaining diversity in FlightMR, but that body mass and phylogeny are other factors contributing to their variation. Multiple factors are at play to modulate metabolic capacity, and changing membrane composition can have gradual and stepwise effects to achieve a new range of metabolic rates. Orchid bees illustrate the correlated evolution between membrane composition and metabolic rate, supporting the functional link proposed in the membrane pacemaker hypothesis.     

A Quartet of Leucine Residues in the Guanylate Kinase Domain of CaVβ Determines the Plasma Membrane Density of the CaV2.3 Channel

Ca_Vβ subunits are formed by a Src homology 3 domain and a guanylate kinase-like (GK) domain connected through a variable HOOK domain. Complete deletion of the Src homology 3 domain (75 residues) as well as deletion of the HOOK domain (47 residues) did not alter plasma membrane density of Ca_V2.3 nor its typical activation gating. In contrast, six-residue deletions in the GK domain disrupted cell surface trafficking and functional expression of Ca_V2.3. Mutations of residues known to carry nanomolar affinity binding in the GK domain of Ca_Vβ (P175A, P179A, M195A, M196A, K198A, S295A, R302G, R307A, E339G, N340G, and A345G) did not significantly alter cell surface targeting or gating modulation of Ca_V2.3. Nonetheless, mutations of a quartet of leucine residues (either single or multiple mutants) in the α3, α6, β10, and α9 regions of the GK domain were found to significantly impair cell surface density of Ca_V2.3 channels. Furthermore, the normalized protein density of Ca_V2.3 was nearly abolished with the quadruple Ca_Vβ3 Leu mutant L200G/L303G/L337G/L342G. Altogether, our observations suggest that the four leucine residues in Ca_Vβ3 form a hydrophobic pocket surrounding key residues in the α-interacting domain of Ca_V2.3. This interaction appears to play an essential role in conferring Ca_Vβ-induced modulation of the protein density of Ca_Vα1 subunits in Ca_V2 channels.     

Computing thermomechanical properties of dry homopolymers used as raw materials for formulation of biomedical hydrogels

Different static properties have been calculated with COMPASS force field for polyacrylamide, poly(2-hydroxyethylacrylate) (HEA), poly(2-hydroxyethylmethacrylate) (HEMA), poly(glycidylmethacrylate) (GMA), polyethylene glycol (PEG), and poly(2,2,2-trifluoroethylmethacrylate) (TFEM). For each polymers, the calculated values were averaged on five equilibrated configurations of amorphous cell composed of one atactic chain containing 100 repeat units. The ranking obtained from the densities calculated at 300 K is TFEM?>?HEA?≈?xpolycrylamide?>?HEMA?≈?GMA?>?PEG. Concerning the glass transition temperature we have obtained polyacrylamide?>?HEMA?≈?GMA?≈?HEA?>?PEG, and polyacrylamide?>?HEMA?≈?HEA?>?GMA?≈?PEG?>?TFEM for the bulk modulus. The calculated results, when available, have been compared with experimental data coming from literature.     

A drug-resistant mutation in plant target of rapamycin validates the specificity of ATP-competitive TOR inhibitors in vivo

Kinases are major components of cellular signaling pathways, regulating key cellular activities through phosphorylation. Kinase inhibitors are efficient tools for studying kinase targets and functions, however assessing their kinase specificity in vivo is essential. The identification of resistant kinase mutants has been proposed to be the most convincing approach to achieve this goal. Here, we address this issue in plants via a pharmacogenetic screen for mutants resistant to the ATP-competitive TOR inhibitor AZD-8055. The eukaryotic TOR (Target of Rapamycin) kinase is emerging as a major hub controlling growth responses in plants largely thanks to the use of ATP-competitive inhibitors. We identified a dominant mutation in the DFG motif of the Arabidopsis TOR kinase domain that leads to very strong resistance to AZD-8055. This resistance was characterized by measuring root growth, photosystem II (PSII) activity in leaves and phosphorylation of YAK1 (Yet Another Kinase 1) and RPS6 (Ribosomal protein S6), a direct and an indirect target of TOR respectively. Using other ATP-competitive TOR inhibitors, we also show that the dominant mutation is particularly efficient for resistance to drugs structurally related to AZD-8055. Altogether, this proof-of-concept study demonstrates that a pharmacogenetic screen in Arabidopsis can be used to successfully identify the target of a kinase inhibitor in vivo and therefore to demonstrate inhibitor specificity. Thanks to the conservation of kinase families in eukaryotes, and the possibility of creating amino acid substitutions by genome editing, this work has great potential for extending studies on the evolution of signaling pathways in eukaryotes.     

Social Priming Increases Nonverbal Expressive Behaviors in Schizophrenia

Semantic priming tasks are classically used to influence and implicitly promote target behaviors. Recently, several studies have demonstrated that prosocial semantic priming modulated feelings of social affiliation. The main aim of this study was to determine whether inducing feelings of social affiliation using priming tasks could modulate nonverbal social behaviors in schizophrenia. We used the Scrambled Sentence Task to prime schizophrenia patients according to three priming group conditions: pro-social, non-social or anti-social. Forty-five schizophrenia patients, diagnosed according to DSM-IV-TR, were randomly assigned to one of the three priming groups of 15 participants. We evaluated nonverbal social behaviors using the Motor-Affective subscale of the Motor-Affective-Social-Scale. Results showed that schizophrenia patients with pro-social priming had significantly more nonverbal behaviors than schizophrenia patients with anti-social and non-social priming conditions. Schizophrenia patient behaviors are affected by social priming. Our results have several clinical implications for the rehabilitation of social skills impairments frequently encountered among individuals with schizophrenia.