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Current American Academy of Pediatrics (AAP) Guidelines recommend monitoring thyroid function in infants with Down syndrome (DS) at birth, 6 and 12 months, and annually thereafter. This study aimed to determine whether these guidelines are optimal for early diagnosis and treatment of (subclinical) hypothyroidism. Enrolled infants with DS less than age 7 months, born at ≥ 30 weeks gestation to monitor thyroid function test (TFT). A filter paper (FP) blood sample was analyzed for TSH and total T4 at ages 2 and 4 weeks and monthly thereafter until 12 months. Subjects with abnormal FP sample and confirmatory serum TFT for hypothyroidism promptly started treatment. Subjects with thyroid dysfunction identified had thyroid antibodies measured at diagnosis and 12 months. Descriptive statistics determined average time to diagnosis of abnormal TFT. Sixteen (30%) of 54 subjects were diagnosed with a thyroid disorder, the majority with subclinical hypothyroidism (SH) and 1 with hyperthyroidism. Diagnosis occurred in 6 (11%), 9 (17%), and 12 (22.2%) infants in the first 30, 60, and 90 days of life (DOL), respectively. Eight infants had an abnormal NBS and half were diagnosed with a thyroid disorder by DOL 8 and the remainder prior to 4 months. Among subjects with a normal NBS, four were diagnosed at a mean of 104 days and three at a mean of 101 days prior to the 6-month and 12-month routine screens, respectively. Conclusion: Based on current AAP guidelines, thyroid disorder diagnosis would have been delayed in nearly 20% of the subjects. An additional TFT screen at 1 and 3 months can lead to earlier diagnosis and treatment. What is Known: • Current American Academy of Pediatrics (AAP) Guidelines recommend thyroid function tests (TFT) in infants with Down syndrome (DS) at birth and 6 and 12 months. • Peer- reviewed retrospective studies report an increased incidence of hypothyroidism in infants with DS undetected by the newborn screen (NBS) and prior to 6 months. What is New: • This prospective study monitored TFT in infants with DS at age 2 weeks and monthly throughout the first year of life. • The findings in this study support additional TFT screens at 1 and 3 months in infants with DS. [ABSTRACT FROM AUTHOR]

A novel HLA‐A*33 allele, officially designated HLA‐A*33:237, was identified by next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP. We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491. The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1.523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10−5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010). In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP. [ABSTRACT FROM AUTHOR]

Background: Interoperability between formats is a recurring problem in systems biology research. Many tools have been developed to convert computational models from one format to another. However, they have been developed independently, resulting in redundancy of efforts and lack of synergy. Results: Here we present the System Biology Format Converter (SBFC), which provide a generic framework to potentially convert any format into another. The framework currently includes several converters translating between the following formats: SBML, BioPAX, SBGN-ML, Matlab, Octave, XPP, GPML, Dot, MDL and APM. This software is written in Java and can be used as a standalone executable or web service. Conclusions: The SBFC framework is an evolving software project. Existing converters can be used and improved, and new converters can be easily added, making SBFC useful to both modellers and developers. The source code and documentation of the framework are freely available from the project web site. [ABSTRACT FROM AUTHOR]

JSBML, the official pure Java programming library for the Systems Biology Markup Language (SBML) format, has evolved with the advent of different modeling formalisms in systems biology and their ability to be exchanged and represented via extensions of SBML. JSBML has matured into a major, active open-source project with contributions from a growing, international team of developers who not only maintain compatibility with SBML, but also drive steady improvements to the Java interface and promote ease-of-use with end users. Availability and implementation: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML. More information about JSBML can be found in the user guide at http://sbml.org/Software/JSBML/docs/. [ABSTRACT FROM AUTHOR]

Newborns with prenatal opioid exposure (POE) are commonly diagnosed with neonatal abstinence/opioid-withdrawal syndromes due to characteristic symptoms and overt behaviors. However, little is known about the underlying physiology of opioid-exposed newborns. Cardiac, respiratory and movement activity were measured to identify physiologic dysregulation and quantify pathophysiologic instabilities of the central and autonomic nervous systems in POE newborns. In this pilot study, 30 hospitalized POE newborns (>35 wks gestational age) participated in one of two study phases wherein physiologic activity was measured for an 8-10 h session. In Phase 1, 17 infants received usual treatment to provide a general assessment of physiologic activity. In Phase 2, 13 infants participated in an interventional study (NCT02768844) using a prototype mattress that delivered stochastic vibratory stimulation (SVS). Changes in physiologic activity were compared for device on (N) and off (F) for three interfeed periods (FNF or NFN). Phase 1 showed that although infants' heart rate was on average within normal newborn range (mean 137 bpm, SD 7), infants were tachycardic 16% of the study period and tachypneic (mean 74 breaths/min, SD 13) 62% of the period. Infants moved 33% of the period; 17% were durations >30 s. In Phase 2, heart rate, respiratory rate, movement duration and frequency were each reduced for SVS N compared to SVS F in the FNF protocol (P < 0.05). Findings support that physiologic measures can identify dysregulation not captured with current withdrawal scoring assessments. Larger studies are warranted to assess if mattress SVS helps regulate pathophysiologic instabilities in infants with POE. • Little is known about underlying physiology in opioid-exposed newborns. • Conventional assessments do not capture physiologic dysregulation. • This study identified dysregulation using cardiac and respiratory measures. • Movement activity was used to quantify infant irritability versus calm. • A prototype vibrating mattress reduced pathophysiologic dysregulation. [ABSTRACT FROM AUTHOR]

Background Systems biology projects and omics technologies have led to a growing number of biochemical pathway models and reconstructions. However, the majority of these models are still created de novo, based on literature mining and the manual processing of pathway data. Results To increase the efficiency of model creation, the Path2Models project has automatically generated mathematical models from pathway representations using a suite of freely available software. Data sources include KEGG, BioCarta, MetaCyc and SABIO-RK. Depending on the source data, three types of models are provided: kinetic, logical and constraint-based. Models from over 2 600 organisms are encoded consistently in SBML, and are made freely available through BioModels Database at http://www.ebi.ac.uk/biomodelsmain/ path2models. Each model contains the list of participants, their interactions, the relevant mathematical constructs, and initial parameter values. Most models are also available as easyto- understand graphical SBGN maps. Conclusions To date, the project has resulted in more than 140 000 freely available models. Such a resource can tremendously accelerate the development of mathematical models by providing initial starting models for simulation and analysis, which can be subsequently curated and further parameterized. [ABSTRACT FROM AUTHOR]

Background: Computing accurate nucleic acid melting temperatures has become a crucial step for the efficiency and the optimisation of numerous molecular biology techniques such as in situ hybridization, PCR, antigene targeting, and microarrays. MELTING is a free open source software which computes the enthalpy, entropy and melting temperature of nucleic acids. MELTING 4.2 was able to handle several types of hybridization such as DNA/DNA,R NA/RNA, DNA/RNA and provided corrections to melting temperatures due to the presence of sodium. The program can use either an approximative approach or a more accurate Nearest-Neighbor approach. Results: Two new versions of the MELTING software have been released. MELTING 4.3 is a direct update of version 4.2, integrating newly available thermodynamic parameters for inosine, a modified adenine base with an universal base capacity, and incorporates a correction for magnesium. MELTING 5 is a complete reimplementation which allows much greater flexibility and extensibility. It incorporates all the thermodynamic parameters and corrections provided in MELTING 4.x and introduces a large set of thermodynamic formulae and parameters, to facilitate the calculation of melting temperatures for perfectly matching sequences, mismatches, bulge loops, CNG repeats, dangling ends, inosines, locked nucleic acids, 2-hydroxyadenines and azobenzenes. It also includes temperature corrections fo rmonovalent ions (sodium, potassium, Tris), magnesium ions and commonly used denaturing agents such as formamide and DMSO. Conclusions: MELTING is a useful and very flexible tool for predicting melting temperatures using approximative formulae or Nearest-Neighbor approaches, where one can select different sets of Nearest-Neighbor parameters, corrections and formulae. Both versions are freely available at http://sourceforge.net/projects/melting/ and at http://www.ebi.ac.uk/compneur-srv/melting/ under the terms of the GPL license. [ABSTRACT FROM AUTHOR]

Voltage-dependent potassium (Kv) channels are tetramers of six transmembrane domain (S1-S6) proteins. Crystallographic data demonstrate that the tetrameric pore (S5-S6) is surrounded by four voltage sensor domains (S1-S4). One key question remains: how do voltage sensors (S4) regulate pore gating? Previous mutagenesis data obtained on the Kv channel KCNQ1 highlighted the critical role of specific residues in both the S4-S5 linker (S4S5L) and S6 C terminus (S6T). From these data, we hypothesized that S4S5L behaves like a ligand specifically interacting with S6T and stabilizing the closed state. To test this hypothesis, we designed plasmid-encoded peptides corresponding to portions of S4S5L and S6T of the voltage-gated potassium channel KCNQ1 and evaluated their effects on the channel activity in the presence and absence of the ancillary subunit KCNE1. We showed that S4S5L peptides inhibit KCNQ1, in a reversible and state-dependent manner. S4S5L peptides also inhibited a voltage-independent KCNQ1 mutant. This inhibition was competitively prevented by a peptide mimicking S6T, consistent with S4S5L binding to S6T. Val254 in S4S5L is known to contact Leu353 in S6T when the channel is closed, and mutations of these residues alter the coupling between the two regions. The same mutations introduced in peptides altered their effects, further confirming S4S5L binding to S6T. Our results suggest a mechanistic model in which S4S5L acts as a voltage-dependent ligand bound to its receptor on S6 at rest. This interaction locks the channel in a closed state. Upon plasma membrane depolarization, S4 pulls S4S5L away from S6T, allowing channel opening. [ABSTRACT FROM AUTHOR]

This work shows the results of four Electro-Fenton laboratory tests to reduce the chemical oxygen demand (COD) in spent caustic solutions. The treatment consisted of (i) a pH reduction followed by (ii) an Electro-Fenton process, which was analyzed in this work. The Fenton's reagent was produced in a specially designed reactor, where the waste stream flowed through a labyrinth made by ferrous plates. These plates acted as sacrificial anodes—releasing Fe2 + cations to the solution, where H2O2 was also added. The Electro-Fenton process was analyzed varying the ferrous ion concentration ([Fe+ 2]), the spent caustic's initial temperature and the initial pH. Close to 95% removal of COD (from 8800 mg L- 1) was achieved at a pH of 4, a temperature of 40°C and 100 mg L- 1 of Fe+ 2 (applying 1 A). Two models were considered to simulate the behavior of the reactor considering (i) axial dispersion and (ii) kinetic rate, respectively. The model that was based on kinetics, proved to be the slightly closest fit to the experimental values. [ABSTRACT FROM AUTHOR]

KCNQ1 is the pore-forming subunit of a channel complex whose expression and function have been rather well characterized in the heart. Almost 300 mutations of KCNQ1 have been identified in patients and a vast majority of the described mutations are linked to the long QT syndrome. Only a few mutations are linked to other pathologies such as atrial fibrillation and the short QT syndrome. However, a considerable amount of work remains to be done to get a clear picture of the molecular mechanisms responsible for the pathogenesis related to each mutation. The present review gives three examples of recent studies towards this goal and illustrates the diversity of the molecular mechanisms involved. [ABSTRACT FROM AUTHOR]

Background: The need to build a tool to facilitate the quick creation and editing of models encoded in the Systems Biology Markup language (SBML) has been growing with the number of users and the increased complexity of the language. SBMLeditor tries to answer this need by providing a very simple, low level editor of SBML files. Users can create and remove all the necessary bits and pieces of SBML in a controlled way, that maintains the validity of the final SBML file. Results: SBMLeditor is written in JAVA using JCompneur, a library providing interfaces to easily display an XML document as a tree. This decreases dramatically the development time for a new XML editor. The possibility to include custom dialogs for different tags allows a lot of freedom for the editing and validation of the document. In addition to Xerces, SBMLeditor uses libSBML to check the validity and consistency of SBML files. A graphical equation editor allows an easy manipulation of MathML. SBMLeditor can be used as a module of the Systems Biology Workbench. Conclusion: SBMLeditor contains many improvements compared to a generic XML editor, and allow users to create an SBML model quickly and without syntactic errors. [ABSTRACT FROM AUTHOR]

The transbilayer diffusion of unlabeled ceramides with different acyl chains (C6-Cer, C10-Cer, and C16-Cer) was investigated in giant unilamellar vesicles (GUVs) and in human erythrocytes. Incorporation of a very small percentage of ceramides (∼0.1% of total lipids) to the external leaflet of egg phosphatidylcholine GUVs suffices to trigger a shape change from prolate to pear shape vesicle. By observing the reversibility of this shape change the transmembrane diffusion of lipids was inferred. We found a half-time for unlabeled ceramide flip-flop below 1 min at 37 °C. The rapid diffusion of ceramides in a phosphatidylcholine bilayer was confirmed by flip-flop experiments with a spin-labeled ceramide analogue incorporated into large unilamellar vesicles. Shape change experiments were also carried out with human erythrocytes to determine the trans-membrane diffusion of unlabeled ceramides into a biological membrane. Addition of exogenous ceramides to the external leaflet of human erythrocytes did not trigger echinocyte formation immediately as one would anticipate from an asymmetrical accumulation of new amphiphiles in the outer leaflet but only after ∼15 min of incubation at 20 °C in the presence of an excess of ceramide. We interpret these data as being indicative of a rapid ceramide equilibration between both erythrocyte leaflets as indicated also by electron spin resonance spectroscopy with a spin-labeled ceramide. The late appearance of echinocytes could reveal a progressive trapping of a fraction of the ceramide molecules in the outer erythrocytes leaflet. Thus, we cannot exclude the trapping of ceramides into plasma membrane domains. [ABSTRACT FROM AUTHOR]

Abstract: Giant unilamellar vesicles (diameter of a few tens of micrometers) are commonly produced by hydration of a dried lipidic film. After addition of the aqueous solution, two major protocols are used: (i) the gentle hydration method where the vesicles spontaneously form and (ii) the electroformation method where an ac electric field is applied. Electroformation is known to improve the rate of unilamellarity of the vesicles though it imposes more restricting conditions for the lipidic composition of the vesicles. Here we further characterize these methods by using fluorescence microscopy. It enables not only a sensitive detection of the defects but also an evaluation of the quantity of lipids in these defects. A classification of the defects is proposed and statistics of their relative importance in regard to both methods and lipid composition are presented: it shows for example that 80% of the vesicles obtained by electroformation from 98% 1,2-Dioleoyl-sn-Glycero-3-Phosphocholine are devoid of significant defects against only 40% of the vesicles with the gentle hydration method. It is also shown that the presence of too many negatively charged lipids does not favor the formation of unilamellar vesicles with both methods. For the gentle hydration, we checked if the negatively charged lipids were inserted in the vesicles membrane in the same proportion as that of the lipid mixture from which they are formed. The constant incorporation of a negatively charged labeled lipid despite an increasing presence of negatively charged 1,2-Dioleoyl-sn-Glycero-3-[Phospho-l-Serine] tends to confirm that the composition of vesicles is indeed close to that of the initial mixture. [Copyright &y& Elsevier]

• Provides a novel online predictive model of aircraft landing performance using data collected on-board an aircraft during the approach phase. • Demonstrates accurate prediction of the critical metrics further ahead in time than existing approaches and at a higher accuracy. • Introduces innovations in generating feature vectors and target labels using a flexible approach that can be easily replicated for other metrics of interest. • Significantly improves over previous similar work in literature both in terms of accuracy and applicability in an online setting. In recent years, due to the increased availability of data and improvements in computing power, application of machine learning techniques to various aviation safety problems for identifying, isolating, and reducing risk has gained momentum. Data collected from on-board recorders in commercial aircraft contain thousands of parameters in the form of multivariate time-series (continuous, discrete, categorical, etc.) which are used to train the machine learning models. Among the phases of flight, approach and landing phases result in the most accidents and incidents. The performance and trajectory of the aircraft during the approach phase is an indicator of its landing performance which, in turn, affects incident or accident probability such as runway excursions. Landing performance is commonly measured using metrics such as landing airspeed, vertical speed, location of touchdown point on runway, etc. While current applications of machine learning to aviation focus on retrospective insights to implement corrective measures, they offer limited value for real-time risk identification or decision-making as they are inherently reactive in nature. In this work, a novel offline-online framework is developed for building a global predictive model offline to predict landing performance metrics online. The framework leverages flight data from the approach phase between certain approach altitudes (also called gates) in order to train the offline model to predict the landing true airspeed and ground speed using a Random Forest regression algorithm. Permutation importance is used to identify and retain important features among those available and the training data is balanced with respect to flight safety events to ensure a good performing model. The developed global model is robust and can predict landing true airspeed and ground speed with root mean square errors of 2.62 and 2.98 knots respectively over six different airframes operating at over seventy airports. The model operates fast in prediction mode which, coupled with the ability to provide the prediction at an altitude where a go-around decision may be made, makes it particularly suitable for online application. The framework is demonstrated using data obtained from commercial airline operations that contains thousands of flight records and performs better than existing techniques in literature at predicting true airspeed and ground speed at touchdown. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 disease presents different phenotypes of severity. Comorbidities, age, and being overweight are well established risk factors for severe disease. However, innate immunity plays a key role in the early control of viral infections and may condition the gravity of COVID-19. Natural Killer (NK) cells are part of innate immunity and are important in the control of virus infection by killing infected cells and participating in the development of adaptive immunity. Therefore, we studied the short tandem repeat (STR) transmembrane polymorphisms of the major histocompatibility complex class I chain-related A (MICA), an NKG2D ligand that induces activation of NK cells, among other cells. We compared the alleles and genotypes of MICA in COVID-19 patients versus healthy controls and analyzed their relation to disease severity. Our results indicate that the MICA*A9 allele is related to infection as well as to symptomatic disease but not to severe disease. The MICA*A9 allele may be a risk factor for SARS-CoV-2 infection and symptomatic disease. [ABSTRACT FROM AUTHOR]

Identification of the novel HLA‐C*05:279 allele that differs from C*05:01:01:11 by two nucleotide substitutions. [ABSTRACT FROM AUTHOR]

Catchment travel times integrate the variety of hydrological flow processes and give additional insights into catchment functioning beyond the hydrograph. StorAge Selection (SAS) functions describe how residence times of water in storage are related to travel times of water in catchment outflows. As such, SAS functions can completely summarize transport processes in catchments and are ideal to simulate catchment outflows and their concentrations in various solutes and tracers. Previous studies using SAS functions suggested that single analytical shapes commonly used for SAS functions may not be sufficient to fully describe transport processes in various hydrological systems. In this study we define composite SAS functions as a weighted sum of several components. The parameterization of these SAS functions uses not only catchment storage as a state variable and thus goes beyond recent studies in other catchments. Composite SAS functions allowed realistic simulations of the complex high resolution (sub-daily) streamflow deuterium (δ2H) dynamics measured for 2 years in the Weierbach, a forested headwater catchment in Luxembourg, whereas a single SAS functions of variable shapes failed. The three components of the SAS functions could furthermore be related to the existence of streamflow generation mechanisms with contrasting travel times that are superimposed in this catchment. Composite SAS functions therefore describe accurately the transport processes in the catchment. Our work suggests that future studies should also consider more components in the SAS functions to correspond to the increase in tracer sampling frequency allowing more inferences on catchment transport processes. [ABSTRACT FROM AUTHOR]

Summary: The specifications of the Systems Biology Markup Language (SBML) define standards for storing and exchanging computer models of biological processes in text files. In order to perform model simulations, graphical visualizations and other software manipulations, an in-memory representation of SBML is required. We developed JSBML for this purpose. In contrast to prior implementations of SBML APIs, JSBML has been designed from the ground up for the Java™ programming language, and can therefore be used on all platforms supported by a Java Runtime Environment. This offers important benefits for Java users, including the ability to distribute software as Java Web Start applications. JSBML supports all SBML Levels and Versions through Level 3 Version 1, and we have strived to maintain the highest possible degree of compatibility with the popular library libSBML. JSBML also supports modules that can facilitate the development of plugins for end user applications, as well as ease migration from a libSBML-based backend.Availability: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website http://sbml.org/Software/JSBML.Contact: jsbml-team@sbml.orgSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM PUBLISHER]

The mechanism of cell-penetrating peptides entry into cells is unclear, preventing the development of more efficient vectors for biotechnological or therapeutic purposes. Here, we developed a protocol relying on fluorometry to distinguish endocytosis from direct membrane translocation, using Penetratin, TAT and R9. The quantities of internalized CPPs measured by fluorometry in cell lysates converge with those obtained by our previously reported mass spectrometry quantification method. By contrast, flow cytometry quantification faces several limitations due to fluorescence quenching processes that depend on the cell line and occur at peptide/cell ratio >6.108 for CF-Penetratin. The analysis of cellular internalization of a doubly labeled fluorescent and biotinylated Penetratin analogue by the two independent techniques, fluorometry and mass spectrometry, gave consistent results at the quantitative and qualitative levels. Both techniques revealed the use of two alternative translocation and endocytosis pathways, whose relative efficacy depends on cell-surface sugars and peptide concentration. We confirmed that Penetratin translocates at low concentration and uses endocytosis at high μM concentrations. We further demonstrate that the hydrophobic/hydrophilic nature of the N-terminal extremity impacts on the internalization efficiency of CPPs. We expect these results and the associated protocols to help unraveling the translocation pathway to the cytosol of cells. [ABSTRACT FROM AUTHOR]

Many prominent biological processes are driven by protein assembling between membranes. Understanding the mechanisms then entails determining the assembling pathway of the involved proteins. Because the intermediates are by nature transient and located in the intermembrane space, this determination is generally a very difficult, not to say intractable, problem. Here, by designing a setup with sphere/plane geometry, we have been able to freeze one transient state in which the N-terminal domains of SNARE proteins are assembled. A single camera frame is sufficient to obtain the complete probability of this state with the transmembrane distance. We show that it forms when membranes are 20 nm apart and stabilizes by further assembling of the SNAREs at 8 nm. This setup that fixes the intermembrane distance, and thereby the transient states, while optically probing the level of molecular assembly by Förster resonance energy transfer (FRET) can be used to characterize any other transient transmembrane complexes. [ABSTRACT FROM AUTHOR]

The fusion between two lipid membranes is a ubiquitous mechanism in cell traffic and pathogens invasion. Yet it is not well understood how two distinct bilayers overcome the energy barriers towards fusion and reorganize themselves to form a unique continuous bilayer. The magnitudes and numbers of these energy barriers are themselves an open question. To tackle these issues, we developed a new tool that allows to control the forces applied between two supported lipid bilayers (SLBs) deposited on superparamagnetic beads. By applying a magnetic field, the beads self-organize along field lines in chains of beads and compress the two membranes on the contact zone. Using the diffusion of fluorescently labelled lipids from one bilayer to the other allows us to identify fusion of the bilayers in contact. We applied increasing forces on SLBs and increased the occurrence of fusion. This experimental system allows the simultaneous study of tens of facing bilayers in a single experiment and mitigates the stochasticity of the fusion process. It is thus a powerful tool to test the various parameters involved in the membrane fusion process. [Display omitted] • A simple new method to study supported membrane fusion using magnetic beads • Compressive force on the apposed membranes is tunable up to 500 pN. • Fusion is assessed directly through the rapid diffusion of fluorescent lipids. • The occurrence of fusion increases with the compressive force intensity. [ABSTRACT FROM AUTHOR]

Background: Quantitative models of biochemical and cellular systems are used to answer a variety of questions in the biological sciences. The number of published quantitative models is growing steadily thanks to increasing interest in the use of models as well as the development of improved software systems and the availability of better, cheaper computer hardware. To maximise the benefits of this growing body of models, the field needs centralised model repositories that will encourage, facilitate and promote model dissemination and reuse. Ideally, the models stored in these repositories should be extensively tested and encoded in community-supported and standardised formats. In addition, the models and their components should be cross-referenced with other resources in order to allow their unambiguous identification. Description: BioModels Database http://www.ebi.ac.uk/biomodels/ is aimed at addressing exactly these needs. It is a freely-accessible online resource for storing, viewing, retrieving, and analysing published, peer-reviewed quantitative models of biochemical and cellular systems. The structure and behaviour of each simulation model distributed by BioModels Database are thoroughly checked; in addition, model elements are annotated with terms from controlled vocabularies as well as linked to relevant data resources. Models can be examined online or downloaded in various formats. Reaction network diagrams generated from the models are also available in several formats. BioModels Database also provides features such as online simulation and the extraction of components from large scale models into smaller submodels. Finally, the system provides a range of web services that external software systems can use to access up-to-date data from the database. Conclusions: BioModels Database has become a recognised reference resource for systems biology. It is being used by the community in a variety of ways; for example, it is used to benchmark different simulation systems, and to study the clustering of models based upon their annotations. Model deposition to the database today is advised by several publishers of scientific journals. The models in BioModels Database are freely distributed and reusable; the underlying software infrastructure is also available from SourceForge https://sourceforge.net/projects/biomodels/ under the GNU General Public License. [ABSTRACT FROM AUTHOR]

This work shows the results of four Electro-Fenton laboratory tests to reduce the chemical oxygen demand in spent caustic solutions. The treatment consisted of i) a pH reduction followed by ii) an Electro-Fenton process, which was analyzed in this work. The efficiency of the Electro-Fenton process was analyzed as the COD reduction in pure phenol and sulphide solutions and real spent caustic samples. Close to 97% COD removal was achieved for sulphide treatment, and around 81% for phenol treatment. In the real spent caustic sample, 93% COD reduction was obtained. The sulphide content is lowered by both a pH reduction and the Electro-Fenton process, whereas the phenol concentration is not affected by the pH reduction - only by the Electro Fenton process. [ABSTRACT FROM AUTHOR]

• Variations is explained by ecological and climatic characteristics than with the meteorological variations. • Only night temperatures would explain variations in oviposition activity. • Variables are strong affected by Ecoregional, and ecoregional effects are stronger in small towns than in large cities. • Ae. aegypti first recorded at High Monte ecoregion. Probably result of town size effect. (i. e. Cafayate a city has 18,000 inhabitants where Ae. aegypti was detected, and next town San Carlos (7000 habitants, 21 km away, 20 min by road). Mosquitoes were not detected. We strongly recommend carry out new studies to verify this. We assessed the presence of Aedes aegypti in five ecorregions of Salta province and compared the oviposition activity of Ae. aegypti using ovitraps in towns of two contrasting ecoregions (yungas and Chaco dry forests) in the province of Salta, Argentina, a major contrast in these ecoregions are rain patterns and altitude. Our aim was to estimate how oviposition activities were associated with the ecoregion and site scale local environmental variables. Mosquito oviposition activity was monitored weekly during the summer using ovitraps. Predictor variables were ecoregion, town, and meteorological variables. The effect of the predictor variables was measured on the response variables using multi-model inference. Besides yungas, the presence of Aedes aegypti was confirmed in towns of dry Chaco and High Monte. The only factor that had a significant effect on the presence of eggs in the ovitraps was the ecoregion, with the frequency of positives being higher in yungas. For the number of eggs, the ecoregion, the night temperature of the first week and the NDVI would explain said variable. Overall, results indicate that the variations between towns would be more related with their ecological and climatic characteristics than with the more immediate meteorological variations. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignancy. They also may contribute to the search of new targets for cancer treatment, such as FAP-expressing cancer-associated fibroblasts, in refractory bladder tumors. [ABSTRACT FROM AUTHOR]

The molecular mechanisms and forces involved in the translocation of bacterial toxins into host cells are still a matter of intense research. The adenylate cyclase (CyaA) toxin from Bordetella pertussis displays a unique intoxication pathway in which its catalytic domain is directly translocated across target cell membranes. The CyaA translocation region contains a segment, P454 (residues 454–484), which exhibits membrane‐active properties related to antimicrobial peptides. Herein, the results show that this peptide is able to translocate across membranes and to interact with calmodulin (CaM). Structural and biophysical analyses reveal the key residues of P454 involved in membrane destabilization and calmodulin binding. Mutational analysis demonstrates that these residues play a crucial role in CyaA translocation into target cells. In addition, calmidazolium, a calmodulin inhibitor, efficiently blocks CyaA internalization. It is proposed that after CyaA binding to target cells, the P454 segment destabilizes the plasma membrane, translocates across the lipid bilayer and binds calmodulin. Trapping of CyaA by the CaM:P454 interaction in the cytosol may assist the entry of the N‐terminal catalytic domain by converting the stochastic motion of the polypeptide chain through the membrane into an efficient vectorial chain translocation into host cells. [ABSTRACT FROM AUTHOR]

The time that water takes to travel through the terrestrial hydrological cycle and the critical zone is of great interest in Earth system sciences with broad implications for water quality and quantity. Most water age studies to date have focused on individual compartments (or subdisciplines) of the hydrological cycle such as the unsaturated or saturated zone, vegetation, atmosphere, or rivers. However, recent studies have shown that processes at the interfaces between the hydrological compartments (e.g., soil‐atmosphere or soil‐groundwater) govern the age distribution of the water fluxes between these compartments and thus can greatly affect water travel times. The broad variation from complete to nearly absent mixing of water at these interfaces affects the water ages in the compartments. This is especially the case for the highly heterogeneous critical zone between the top of the vegetation and the bottom of the groundwater storage. Here, we review a wide variety of studies about water ages in the critical zone and provide (1) an overview of new prospects and challenges in the use of hydrological tracers to study water ages, (2) a discussion of the limiting assumptions linked to our lack of process understanding and methodological transfer of water age estimations to individual disciplines or compartments, and (3) a vision for how to improve future interdisciplinary efforts to better understand the feedbacks between the atmosphere, vegetation, soil, groundwater, and surface water that control water ages in the critical zone. Plain language Summary: Investigating how long it takes for a drop of rainwater until it is either evaporated back to the atmosphere, taken up by plants, or infiltrated into groundwater or discharged in streams provides new understanding of how water flows through the water cycle. Knowledge about the time water travels further helps assessing groundwater recharge, transport of contaminants, and weathering rates. Such water age studies typically focus either on water in individual compartments of the water cycle such as soils, groundwater, or stream runoff. But we argue that the interfaces between these compartments can have an influence on the water age. Here, we present methods how water ages can be estimated using tracers and hydrological models. We further discuss the "demographics of water" (water age distribution) in the critical zone that spans from the tree canopy to the bottom of the groundwater. Our review highlights how water flows and mixes between plants, soils, groundwater, and streams and how this interaction affects the water ages. This way, our work contributes toward a better understanding of vital resource water sustaining the life in the Earth's living skin. Key Points: New tracer techniques now allow tracking water at high spatiotemporal resolution across the vastly varying water ages in the water cycleExchanges of water between hydrological compartments at key interfaces influence the water age distribution more than previously assumedVariation from complete to nearly absent mixing of water at the interfaces in the critical zone affects the water ages in compartments [ABSTRACT FROM AUTHOR]

Background With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. Results We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software. Conclusions The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering. [ABSTRACT FROM AUTHOR]

The Computational Modeling in Biology Network (COMBINE) is an initiative to coordinate the development of community standards and formats in computational systems biology and related fields. This report summarizes the topics and activities of the fourth edition of the annual COMBINE meeting, held in Paris during September 16-20 2013, and attended by a total of 96 people. This edition pioneered a first day devoted to modeling approaches in biology, which attracted a broad audience of scientists thanks to a panel of renowned speakers. During subsequent days, discussions were held on many subjects including the introduction of new features in the various COMBINE standards, new software tools that use the standards, and outreach efforts. Significant emphasis went into work on extensions of the SBML format, and also into community-building. This year's edition once again demonstrated that the COMBINE community is thriving, and still manages to help coordinate activities between different standards in computational systems biology. [ABSTRACT FROM AUTHOR]

Little is known about the molecular mechanisms that induce gamete fusion during mammalian fertilization. After initial contact, adhesion between gametes only leads to fusion in the presence of three membrane proteins that are necessary, but insufficient, for fusion: Izumo1 on sperm, its receptor Juno on egg and Cd9 on egg. What happens during this adhesion phase is a crucial issue. Here, we demonstrate that the intercellular adhesion that Izumo1 creates with Juno is conserved in mouse and human eggs. We show that, along with Izumo1, egg Cd9 concomitantly accumulates in the adhesion area. Without egg Cd9, the recruitment kinetics of Izumo1 are accelerated. Our results suggest that this process is conserved across species, as the adhesion partners, Izumo1 and its receptor, are interchangeable between mouse and human. Our findings suggest that Cd9 is a partner of Juno, and these discoveries allow us to propose a new model of the molecular mechanisms leading to gamete fusion, in which the adhesion-induced membrane organization assembles all key players of the fusion machinery. [ABSTRACT FROM AUTHOR]

Background: With the increasing availability of high dimensional time course data for metabolites, genes, and fluxes, the mathematical description of dynamical systems has become an essential aspect of research in systems biology. Models are often encoded in formats such as SBML, whose structure is very complex and difficult to evaluate due to many special cases. Results: This article describes an efficient algorithm to solve SBML models that are interpreted in terms of ordinary differential equations. We begin our consideration with a formal representation of the mathematical form of the models and explain all parts of the algorithm in detail, including several preprocessing steps. We provide a flexible reference implementation as part of the Systems Biology Simulation Core Library, a community-driven project providing a large collection of numerical solvers and a sophisticated interface hierarchy for the definition of custom differential equation systems. To demonstrate the capabilities of the new algorithm, it has been tested with the entire SBML Test Suite and all models of BioModels Database. Conclusions: The formal description of the mathematics behind the SBML format facilitates the implementation of the algorithm within specifically tailored programs. The reference implementation can be used as a simulation backend for Java™-based programs. Source code, binaries, and documentation can be freely obtained under the terms of the LGPL version 3 from http://simulation-core.sourceforge.net. Feature requests, bug reports, contributions, or any further discussion can be directed to the mailing list simulation-core-development@lists.sourceforge.net. [ABSTRACT FROM AUTHOR]

Background Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. Results We present the Systems Biology Markup Language (SBML) Qualitative Models Package ("qual"), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. Conclusion SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks. [ABSTRACT FROM AUTHOR]

Motivation: The biological pathway exchange language (BioPAX) and the systems biology markup language (SBML) belong to the most popular modeling and data exchange languages in systems biology. The focus of SBML is quantitative modeling and dynamic simulation of models, whereas the BioPAX specification concentrates mainly on visualization and qualitative analysis of pathway maps. BioPAX describes reactions and relations. In contrast, SBML core exclusively describes quantitative processes such as reactions. With the SBML qualitative models extension (qual), it has recently also become possible to describe relations in SBML. Before the development of SBML qual, relations could not be properly translated into SBML. Until now, there exists no BioPAX to SBML converter that is fully capable of translating both reactions and relations.Results: The entire nature pathway interaction database has been converted from BioPAX (Level 2 and Level 3) into SBML (Level 3 Version 1) including both reactions and relations by using the new qual extension package. Additionally, we present the new webtool BioPAX2SBML for further BioPAX to SBML conversions. Compared with previous conversion tools, BioPAX2SBML is more comprehensive, more robust and more exact.Availability: BioPAX2SBML is freely available at http://webservices.cs.uni-tuebingen.de/ and the complete collection of the PID models is available at http://www.cogsys.cs.uni-tuebingen.de/downloads/Qualitative-Models/.Contact: finja.buechel@uni-tuebingen.deSupplementary Information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Abstract: The explosion sensitivity of various gas or vapor/dust mixtures has been studied thanks to specifically modified apparatuses based on a 20L sphere and a Hartmann tube. Experiments have shown that concentration of gas/vapors as low as 1% vol. causes a significant decrease of the minimum ignition energy and induces changes in the rate-limiting step of the combustion reaction, from boundary diffusion to homogeneous gas phase reaction. They also confirm that a hybrid mixture explosion is possible even when both dust and vapor concentrations are respectively lower than their minimum explosion concentration and lower explosivity limit. Comparisons have been done between our experimental data and classical models such as those developed by Bartknecht or Le Chatelier. It appears that these laws are not always conservative from a safety point of view. The influences of the diameter, of the adiabatic flame temperatures and of the critical ignition kernel, directly related to the quenching distance, have also been highlighted. This work demonstrates the peculiar behavior of gas or vapor/dust explosions and proposes simple models in order to estimate their ignition sensitivity. [Copyright &y& Elsevier]

KCNQ1 osmosensitivity is of physiological and pathophysiological relevance in epithelial and cardiac cells, but the mechanism involved remains elusive. In COS-7 cells expressing the KCNE1-KCNQ1 fusion protein, extracellular hypoosmolarity and hyperosmolarity modify the channel biophysical parameters. These changes are consistent with hypoosmolarity increasing the level of membrane phosphatidylinositol-4,5-bisphosphate (PIP2), which in turn upregulates KCNE1-KCNQ1 channels. We showed that increasing PIP2 levels with a water-soluble PIP2 analogue prevented channel upregulation in hypoosmotic condition, suggesting a variation of the channel-PIP2 interaction during channel osmoregulation. Furthermore, we showed that polyamines and Mg2+, already known to tonically inhibit KCNQ channels by screening PIP2 negative charges, are involved in the osmoregulatory process. Indeed, intracellular Mg2+ removal and polyamines chelation inhibited the channel osmoregulation. Thus, the dilution of those cations during cell swelling might decrease channel inhibition and explain the channel upregulation by hypoosmolarity. To support this idea, we quantified the role of Mg2+ in the osmodependent channel activity. Direct measurement of intracellular [Mg2+] variations during osmotic changes and characterization of the channel Mg2+ sensitivity showed that Mg2+ participates significantly to the osmoregulation. Using intracellular solutions that mimic the variation of Mg2+ and polyamines, we were able to recapitulate the current amplitude variations in response to extracellular osmolarity changes. Altogether, these results support the idea of a modulation of the channel-PIP2 interactions by Mg2+ and polyamines during cell volume changes. It is likely that this mechanism applies to other channels that are sensitive to both osmolarity and PIP2. [ABSTRACT FROM AUTHOR]

Living cells sense the rigidity of their environment and adapt their activity to it. In particular, cells cultured on elastic substrates align their shape and their traction forces along the direction of highest stiffness and preferably migrate towards stiffer regions. Although numerous studies investigated the role of adhesion complexes in rigidity sensing, less is known about the specific contribution of acto-myosin based contractility. Here we used a custom-made single-cell technique to measure the traction force as well as the speed of shortening of isolated myoblasts deflecting microplates of variable stiffness. The rate of force generation increased with increasing stiffness and followed a Hill force-velocity relationship. Hence, cell response to stiffness was similar to muscle adaptation to load, reflecting the force-dependent kinetics of myosin binding to actin. These results reveal an unexpected mechanism of rigidity sensing, whereby the contractile acto-myosin units themselves can act as sensors. This mechanism may translate anisotropy in substrate rigidity into anisotropy in cytoskeletal tension, and could thus coordinate local activity of adhesion complexes and guide cell migration along rigidity gradients. [ABSTRACT FROM AUTHOR]

Hybrid nanoparticles composed of an efficient nonlinear optical core and a gold shell can enhance and tune the nonlinear optical emission thanks to the plasmonic effect. However the influence of an incomplete gold shell, i.e., isolated gold nano-islands, is still not well studied. Here LiNbO3 (LN) core nanoparticles of 45 nm were coated with various densities of gold nano-seeds (AuSeeds). As both LN and AuSeeds bear negative surface charge, a positively-charged polymer was first coated onto LN. The number of polymer chains per LN was evaluated at 1210 by XPS and confirmed by fluorescence titration. Then, the surface coverage percentage of AuSeeds onto LN was estimated to a maximum of 30% using ICP-AES. The addition of AuSeeds was also accompanied with surface charge reversal, the negative charge increasing with the higher amount of AuSeeds. Finally, the first hyperpolarizability decreased with the increase of AuSeeds density while depolarization values for Au-seeded LN were close to the one of bare LN, showing a predominance of the second harmonic volumic contribution. [ABSTRACT FROM AUTHOR]

Following publication of the original article [1], the author requested this addition to the ‘Acknowledgements’ section of the article: “DW is funded by the German Federal Ministry of Education and Research (e: Bio program SEMS, FKZ 031 6194)”. [ABSTRACT FROM AUTHOR]