Safety Considerations and Proposed Workflow for Laboratory-Scale Chemical Synthesis by Ball Milling

Chemical reactions that take place in a ball mill and in the absence of a bulk reaction solvent present different safety profiles to stirred solution reactions. Herein, we present and describe steps that a researcher may take to better ensure that they have considered some of the hazards and measures that emerge and minimize the risk to themselves and their colleagues

CD98hc facilitates B cell proliferation and adaptive humoral immunity.

The proliferation of antigen-specific lymphocytes and resulting clonal expansion are essential for adaptive immunity. We report here that B cell-specific deletion of the heavy chain of CD98 (CD98hc) resulted in lower antibody responses due to total suppression of B cell proliferation and subsequent plasma cell formation. Deletion of CD98hc did not impair early B cell activation but did inhibit later activation of the mitogen-activated protein kinase Erk1/2 and downregulation of the cell cycle inhibitor p27. Reconstitution of CD98hc-deficient B cells with CD98hc mutants showed that the integrin-binding domain of CD98hc was required for B cell proliferation but that the amino acid-transport function of CD98hc was dispensable for this. Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates

Prior Mating Experience Modulates the Dispersal of Drosophila in Males More Than in Females

Cues from both an animal’s internal physiological state and its local environment may influence its decision to disperse. However, identifying and quantifying the causative factors underlying the initiation of dispersal is difficult in uncontrolled natural settings. In this study, we automatically monitored the movement of fruit flies and examined the influence of food availability, sex, and reproductive status on their dispersal between laboratory environments. In general, flies with mating experience behave as if they are hungrier than virgin flies, leaving at a greater rate when food is unavailable and staying longer when it is available. Males dispersed at a higher rate and were more active than females when food was unavailable, but tended to stay longer in environments containing food than did females. We found no significant relationship between weight and activity, suggesting the behavioral differences between males and females are caused by an intrinsic factor relating to the sex of a fly and not simply its body size. Finally, we observed a significant difference between the dispersal of the natural isolate used throughout this study and the widely-used laboratory strain, Canton-S, and show that the difference cannot be explained by allelic differences in the foraging gene

Residential end-uses disaggregation and demand response evaluation using integral transforms

[EN] Demand response is a basic tool used to develop modern power systems and electricity markets. Residential and commercial segments account for 40%-50% of the overall electricity demand. These segments need to overcome major obstacles before they can be included in a demand response portfolio. The objective of this paper is to tackle some of the technical barriers and explain how the potential of enabling technology (smart meters) can be harnessed, to evaluate the potential of customers for demand response (end-uses and their behaviors) and, moreover, to validate customers' effective response to market prices or system events by means of non-intrusive methods. A tool based on the Hilbert transform is improved herein to identify and characterize the most suitable loads for the aforesaid purpose, whereby important characteristics such as cycling frequency, power level and pulse width are identified. The proposed methodology allows the filtering of aggregated load according to the amplitudes of elemental loads, independently of the frequency of their behaviors that could be altered by internal or external inputs such as weather or demand response. In this way, the assessment and verification of customer response can be improved by solving the problem of load aggregation with the help of integral transforms.This work has been supported by Spanish Government (Ministerio de Economia, Industria y Competitividad) and EU FEDER fund (No. ENE2013-48574-C2-2-P&1-P, No. ENE2015-70032-REDT).Gabaldón Marín, A.; Molina, R.; Marin-Parra, A.; Valero, S.; Álvarez, C. (2017). Residential end-uses disaggregation and demand response evaluation using integral transforms. Journal of Modern Power Systems and Clean Energy. 5(1):91-104. https://doi.org/10.1007/s40565-016-0258-8S9110451Chardon A, Almén O, Lewis PE (2009) Demand response: a decisive breakthrough for Europe. Capgemini, Enerdata. https://www.capgemini.com/resources/demand_response_a_decisive_breakthrough_for_europeFaruqui A, Harris D, Hledick R (2010) Unlocking the €53 billion savings from smart meters in the EU: how increasing the adoption of dynamic tariffs could make or break the EU’s smart grid investment. Energy Policy 38(10):6222–6231Federal Energy Regulatory Commission (FERC) (2015) Assessment of demand response and advanced metering, staff report. http://www.ferc.gov/legal/staff-reports/2015/demand-response.pdfFERC Order 745 (December 2011) & 719 (December 2009). http://www.ferc.gov/legal/maj-ord-reg.aspEuropean Commission (2011) Energy efficiency plan 2011, COM (2011) 109 final. http://eur-lex.europa.eu/LexUriServJoitn Research Center (JRC), European Commission (2010) Energy Service Companies market in Europe, status report 2010. http://publications.jrc.ec.europa.eu/repository/handle/111111111/15108European Commission (2011) Impact assessment accompanying document “Energy Efficiency Plan 2011”, SEC (2011) 277 final. http://www.eurosfaire.prd.fr/7pc/bibliotheque/consulter.php?id=2357European Environment Agency (EEA) (2012) Final energy consumption by sector and fuel. http://www.eea.europa.eu/data-and-maps/indicators/final-energy-consumption-by-sector-8/assessment-2Piette MA, Watson D, Motegi N et al (2007) Automated critical peak pricing field tests: 2006 pilot program description and results. California Energy Commission, PIER Energy Systems Integration Research Program: CEC-500-03-026Gomatom K, Holmes C, Kresta D (2013) Non-intrusive load monitoring. https://www.e3tnw.orgDimetrosky S, Parkinson K, Lieb N (2013) Residential lighting evaluation protocol, Report NREl/SR-7A30-53827. National Renewable Energy LaboratoryZeifman M, Roth K (2011) Nonintrusive appliance load monitoring: review and outlook. IEEE Trans Consum Electron 57(1):76–84Liang J, Simon K, Kendall G et al (2010) Load signature study part I: basic concept, structure and methodology. IEEE Trans Power Deliv 25(2):551–560Hart GW (1992) Nonintrusive appliance load monitoring. Proc IEEE 80(12):1870–1891Powers J, Margossian B, Smith B (1991) Using a rule-based algorithm to disaggregate end-use load profiles from premise-level data. IEEE Comput Appl Power 4(2):42–47Farinaccio L, Zmeureanu R (1999) Using a pattern recognition approach to disaggregate the total electricity consumption in a house into the major end-uses. Energy Build 30(3):245–259Marceau ML, Zmeureanu R (2000) Nonintrusive load disaggregation computer program to estimate the energy consumption of major end uses in residential buildings. Energy Convers Manag 41(13):1389–1403Baransju M, Voss J (2004) Genetic algorithm for pattern detection in NIALM systems. In: IEEE international conference on systems, man and cybernetics, 10–13 Oct, pp 3462–3468Baranski H, Voss J (2004) Detecting patterns of appliances from total load data using a dynamic programming approach. In: Fourth IEEE international conference on data mining (ICDM’04), 1–4 Nov, Brighton, UK, pp 327–330Sankara A (2015) Energy disaggregation in NIALM using hidden Markov models. Masters Theses, Missouri University of Science and Technology, Paper 7414Kolter J, Jaakkola T (2012) Approximate inference in additive factorial HMMs with application to energy disaggregation. J Mach Learn 22:1472–1482Leeb SB, Shaw SR, Kirtley SL (1995) Transient event detection in spectral envelope estimates for nonintrusive load monitoring. IEEE Trans Power Deliv 10(3):1200–1210Patel SN, Robertson T, Kientz JA et al (2007) At the flick of a switch: detecting and classifying unique electrical events on the residential power line. In: Conference on ubiquitous computing, pp 271–288Bonglifi R, Squartini S, Fagiani M et al (2015) Unsupervised algorithms for non-intrusive load monitoring: an up-to-date overview. In: EEEIC conference. doi: 10.1109/EEEIC.2015.7165334Browne TJ, Vittal V, Heydt GT et al (2008) A comparative assessment of two techniques for modal identification from power system measurements. IEEE Trans Power Syst 23(3):1408–1415Senroy N, Suryanarayanan S, Ribeiro PF (2007) An improved Hilbert–Huang method for analysis of time-varying waveforms in power quality. IEEE Trans Power Syst 22(4):1843–1850Gabaldon A, Ortiz M, Molina R et al (2014) Disaggregation of electric loads of small customers through the application of the Hilbert transform. Energ Effic 7(4):711–728. doi: 10.1007/s12053-013-9250-6Kolter JZ, Johnson MJ (2011) REDD: a public data set for energy disaggregation research. http://101.96.10.59/people.csail.mit.edu/mattjj/papers/kddsust2011.pdfFibaro wall switches. http://www.fibaro.com/en/the-fibaro-system/IP-Symcon: innovative centre for the entire building automation. https://www.symcon.de/Energy Information Administration (2001) End-use consumption electricity 2001. http://www.eia.gov/emeu/recs/recs2001/enduse2001/enduse2001.htmlPoularikas AD (1999) The Hilbert transform, handbook of formulas and tables for signal processing. CRC Press LLC, Boca RatonHuang NE, Shen Z, Long SR et al (1998) The empirical mode decomposition and the Hilbert spectrum for nonlinear and nonstationary time series analysis. Proced R Soc Lond 454(1971):903–995Deering R, Kaiser JF (2005) The use of a masking signal to improve empirical mode decomposition. In: Proceedings IEEE international conference acoustic, speech, and signal processing, pp 485–488Liang J, Simon K, Kendall G, Cheng J et al (2010) Load signature study part II: disaggregation framework, simulation, and applications. IEEE Trans Power Deliv 25(2):561–569Load participation in ancillary services. http://www1.eere.energy.gov/analysis/pdfsGabaldón A, Guillamón A, Ruiz MC et al (2010) Development of a methodology for clustering electricity-price series to improve customer response initiatives. IET Gener Transm Distrib 4(6):706–71

The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice

5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1−/− and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1−/− mice (>100 mg kg−1) than in wild-type mice (27.5 mg kg−1). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg−1) was strongly attenuated in tumour necrosis factor receptor-1−/− mice. However, the reduced toxicity in tumour necrosis factor receptor-1−/− mice allowed the demonstration that at a higher dose (50 mg kg−1), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg−1) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1−/− mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies

Induction of endothelial cell apoptosis by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid

5,6-Dimethylxanthenone-4-acetic acid, synthesised in this laboratory, reduces tumour blood flow, both in mice and in patients on Phase I trial. We used TUNEL (TdT-mediated dUTP nick end labelling) assays to investigate whether apoptosis induction was involved in its antivascular effect. 5,6-Dimethylxanthenone-4-acetic acid induced dose-dependent apoptosis in vitro in HECPP murine endothelial cells in the absence of up-regulation of mRNA for tumour necrosis factor. Selective apoptosis of endothelial cells was detected in vivo in sections of Colon 38 tumours in mice within 30 min of administration of 5,6-Dimethylxanthenone-4-acetic acid (25 mg kg−1). TUNEL staining intensified with time and after 3 h, necrosis of adjacent tumour tissue was observed. Apoptosis of central vessels in splenic white pulp was also detected in tumour-bearing mice but not in mice without tumours. Apoptosis was not observed in liver tissue. No apoptosis was observed with the inactive analogue 8-methylxanthenone-4-acetic acid. Positive TUNEL staining of tumour vascular endothelium was evident in one patient in a Phase I clinical trial, from a breast tumour biopsy taken 3 and 24 h after infusion of 5,6-Dimethylxanthenone-4-acetic acid (3.1 mg m−2). Tumour necrosis and the production of tumour tumour necrosis factor were not observed. No apoptotic staining was seen in tumour biopsies taken from two other patients (doses of 3.7 and 4.9 mg m−2). We conclude that 5,6-Dimethylxanthenone-4-acetic acid can induce vascular endothelial cell apoptosis in some murine and human tumours. The action is rapid and appears to be independent of tumour necrosis factor induction

Factorial validity and measurement invariance across gender groups of the German version of the Interpersonal Reactivity Index

The Interpersonal Reactivity Index (IRI) is the most widely used measure of empathy, but its factorial validity has been questioned. The present research investigates the factorial validity of the German adaptation of the IRI, the "Saarbrücker Persönlichkeitsfragebogen SPF-IRI". Confirmatory Factor Analyses (CFA) and Exploratory Structural Equation Modeling (ESEM) were used to test the theoretically predicted four-factor model. Across two subsamples ESEM outperformed CFA. Substantial cross-loadings were evident in ESEM. Measurement invariance (MI) across gender groups was tested using ESEM in the combined sample. Strict MI (invariant factor loadings, intercepts, residuals) could be established, and variances and covariances were also equal. Differences for latent means were evident. Women scored higher on fantasy, empathic concern, and personal distress. No significant differences were found for perspective taking. Mean differences were due to real differences on latent variables and not a result of measurement bias. Results support the factorial validity of the German SPF-IRI. The heterogeneity of empathy and the unclear differentiation between cognitive and emotional aspects might be a source for the unclear differentiation of scales

Mutagenesis Objective Search and Selection Tool (MOSST): an algorithm to predict structure-function related mutations in proteins

<p>Abstract</p> <p>Background</p> <p>Functionally relevant artificial or natural mutations are difficult to assess or predict if no structure-function information is available for a protein. This is especially important to correctly identify functionally significant non-synonymous single nucleotide polymorphisms (nsSNPs) or to design a site-directed mutagenesis strategy for a target protein. A new and powerful methodology is proposed to guide these two decision strategies, based only on conservation rules of physicochemical properties of amino acids extracted from a multiple alignment of a protein family where the target protein belongs, with no need of explicit structure-function relationships.</p> <p>Results</p> <p>A statistical analysis is performed over each amino acid position in the multiple protein alignment, based on different amino acid physical or chemical characteristics, including hydrophobicity, side-chain volume, charge and protein conformational parameters. The variances of each of these properties at each position are combined to obtain a global statistical indicator of the conservation degree of each property. Different types of physicochemical conservation are defined to characterize relevant and irrelevant positions. The differences between statistical variances are taken together as the basis of hypothesis tests at each position to search for functionally significant mutable sites and to identify specific mutagenesis targets. The outcome is used to statistically predict physicochemical consensus sequences based on different properties and to calculate the amino acid propensities at each position in a given protein. Hence, amino acid positions are identified that are putatively responsible for function, specificity, stability or binding interactions in a family of proteins. Once these key functional positions are identified, position-specific statistical distributions are applied to divide the 20 common protein amino acids in each position of the protein's primary sequence into a group of functionally non-disruptive amino acids and a second group of functionally deleterious amino acids.</p> <p>Conclusions</p> <p>With this approach, not only conserved amino acid positions in a protein family can be labeled as functionally relevant, but also non-conserved amino acid positions can be identified to have a physicochemically meaningful functional effect. These results become a discriminative tool in the selection and elaboration of rational mutagenesis strategies for the protein. They can also be used to predict if a given nsSNP, identified, for instance, in a genomic-scale analysis, can have a functional implication for a particular protein and which nsSNPs are most likely to be functionally silent for a protein. This analytical tool could be used to rapidly and automatically discard any irrelevant nsSNP and guide the research focus toward functionally significant mutations. Based on preliminary results and applications, this technique shows promising performance as a valuable bioinformatics tool to aid in the development of new protein variants and in the understanding of function-structure relationships in proteins.</p

Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity