Probing a Complex of Cytochromecand Cardiolipin by Magnetic Circular Dichroism Spectroscopy: Implications for the Initial Events in Apoptosis

Oxidation of cardiolipin (CL) by its complex with cytochrome c (cyt c) plays a crucial role in triggering apoptosis. Through a combination of magnetic circular dichroism spectroscopy and potentiometric titrations, we show that both the ferric and ferrous forms of the heme group of a CL:cyt c complex exist as multiple conformers at a physiologically relevant pH of 7.4. For the ferric state, these conformers are His/Lys- and His/OH–-ligated. The ferrous state is predominantly high-spin and, most likely, His/–. Interconversion of the ferric and ferrous conformers is described by a single midpoint potential of -80 ± 9 mV vs SHE. These results suggest that CL oxidation in mitochondria could occur by the reaction of molecular oxygen with the ferrous CL:cyt c complex in addition to the well-described reaction of peroxides with the ferric form

Positive words carry less information than negative words

We show that the frequency of word use is not only determined by the word length \cite{Zipf1935} and the average information content \cite{Piantadosi2011}, but also by its emotional content. We have analyzed three established lexica of affective word usage in English, German, and Spanish, to verify that these lexica have a neutral, unbiased, emotional content. Taking into account the frequency of word usage, we find that words with a positive emotional content are more frequently used. This lends support to Pollyanna hypothesis \cite{Boucher1969} that there should be a positive bias in human expression. We also find that negative words contain more information than positive words, as the informativeness of a word increases uniformly with its valence decrease. Our findings support earlier conjectures about (i) the relation between word frequency and information content, and (ii) the impact of positive emotions on communication and social links.Comment: 16 pages, 3 figures, 3 table

Quantum coherent control of highly multipartite continuous-variable entangled states by tailoring parametric interactions

The generation of continuous-variable multipartite entangled states is important for several protocols of quantum information processing and communication, such as one-way quantum computation or controlled dense coding. In this article we theoretically show that multimode optical parametric oscillators can produce a great variety of such states by an appropriate control of the parametric interaction, what we accomplish by tailoring either the spatio-temporal shape of the pump, or the geometry of the nonlinear medium. Specific examples involving currently available optical parametric oscillators are given, hence showing that our ideas are within reach of present technology.Comment: 14 pages, 5 figure

What Makes Entrepreneurs Happy? Determinants of Satisfaction Among Founders

This study empirically investigates factors influencing satisfaction levels of founders of new ventures, using a representative sample of 1,107 Dutch founders. We relate entrepreneurial satisfaction (with income, psychological burden and leisure time) to firm performance, motivation and human capital. Founders with high levels of specific human capital are more satisfied with income than those with high levels of general human capital. Intrinsic motivation and that of combining responsibilities lowers stress and leads to more satisfaction with leisure time. Women are more satisfied with their income than men, even though they have a lower average monthly turnover

Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

Purpose of review: This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings: The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5–40 mg/L and for anticancer 20–100 μM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary: Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules