Synthesis of 5-Hydroxyectoine from Ectoine: Crystal Structure of the Non-Heme Iron(II) and 2-Oxoglutarate-Dependent Dioxygenase EctD

As a response to high osmolality, many microorganisms synthesize various types of compatible solutes. These organic osmolytes aid in offsetting the detrimental effects of low water activity on cell physiology. One of these compatible solutes is ectoine. A sub-group of the ectoine producer's enzymatically convert this tetrahydropyrimidine into a hydroxylated derivative, 5-hydroxyectoine. This compound also functions as an effective osmostress protectant and compatible solute but it possesses properties that differ in several aspects from those of ectoine. The enzyme responsible for ectoine hydroxylation (EctD) is a member of the non-heme iron(II)-containing and 2-oxoglutarate-dependent dioxygenases (EC 1.14.11). These enzymes couple the decarboxylation of 2-oxoglutarate with the formation of a high-energy ferryl-oxo intermediate to catalyze the oxidation of the bound organic substrate. We report here the crystal structure of the ectoine hydroxylase EctD from the moderate halophile Virgibacillus salexigens in complex with Fe3+ at a resolution of 1.85 Å. Like other non-heme iron(II) and 2-oxoglutarate dependent dioxygenases, the core of the EctD structure consists of a double-stranded β-helix forming the main portion of the active-site of the enzyme. The positioning of the iron ligand in the active-site of EctD is mediated by an evolutionarily conserved 2-His-1-carboxylate iron-binding motif. The side chains of the three residues forming this iron-binding site protrude into a deep cavity in the EctD structure that also harbours the 2-oxoglutarate co-substrate-binding site. Database searches revealed a widespread occurrence of EctD-type proteins in members of the Bacteria but only in a single representative of the Archaea, the marine crenarchaeon Nitrosopumilus maritimus. The EctD crystal structure reported here can serve as a template to guide further biochemical and structural studies of this biotechnologically interesting enzyme family

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

Measurement of the Ratio of b Quark Production Cross Sections in Antiproton-Proton Collisions at 630 GeV and 1800 GeV

We report a measurement of the ratio of the bottom quark production cross section in antiproton-proton collisions at 630 GeV to 1800 GeV using bottom quarks with transverse momenta greater than 10.75 GeV identified through their semileptonic decays and long lifetimes. The measured ratio sigma(630)/sigma(1800) = 0.171 +/- .024 +/- .012 is in good agreement with next-to-leading order (NLO) quantum chromodynamics (QCD)

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

The evaluation of risk for obstructive sleep apnea in patients with type 2 diabetes

Cilj istraživanja je procijeniti rizik za opstrukcijsku apneju tijekom spavanja (engl. Obstructive sleep apnea, OSA) u bolesnika sa šećernom bolešću tipa 2, s pomoću STOP upitnika (engl. Snoring, Tiredness, Observed, Pressure; STOP). S pomoću Epworthove ljestvice pospanosti (ESS) procijenjena je prekomjerna dnevna pospanost i ispitana povezanost pospanosti i rizika za OSA-u u bolesnika sa šećernom bolešću tipa 2. Dosadašnja istraživanja pokazala su da oštećena tolerancije glukoze i šećerna bolest tipa 2 predstavljaju čimbenik rizika za OSA-u, ali i da OSA predstavlja čimbenik rizika za šećernu bolest tipa 2. U našem istraživanju sudjelovala su 252 ispitanika sa šećernom bolešću tipa 2, koji su bili anketirani za vrijeme redovitih pregleda u Kliničkom bolničkom centru Split. Rezultati našeg istraživanja pokazali su da je 156 ispitanika (61,9%) imalo povećan rizik za OSA-u prema rezultatima STOP upitnika. Nadalje, ispitanici koji su imali povećani rizik u odnosu na ispitanike koji nisu imali rizik za OSA-u bili su stariji (65 vs. 61 godina, p < 0,05), imali viši indeks tjelesne mase (28,6 ± 5,1 vs. 26,5 ± 4,1, p < 0,001), veći opseg vrata (41,5 ± 4,7 vs. 39,6 ± 6,2, p < 0,009) i bili pospaniji prema rezultatima ESS (5,3 ± 3,1 vs. 3,9 ± 2,5, p < 0,001). Uz šećernu bolest, većina ispitanika imala je i pridružene bolesti: arterijska hipertenzija (46%), gastroezofagealna refluksna bolest (28%), depresija (10%) i astma (8%). OSA je dio širokoga spektra poremećaja disanja tijekom spavanja koja se dovodi u vezu s metaboličkim poremećajima poput šećerne bolesti tipa 2, a epidemiološki podaci o zastupljenosti OSA u Hrvatskoj su nedostatni. Ovo istraživanje ukazuje na potrebu provođenja probira za OSA u bolesnika sa šećernom bolešću tipa 2, koristeći STOP upitnik.The aim of this study was to evaluate the risk for obstructive sleep apnea (OSA) in patients with type 2 diabetes using the STOP questionnaire (Snoring, Tiredness, Observed, Pressure; STOP). Excessive daytime sleepiness was evaluated with the Epworth sleepiness scale (ESS). Previous studies support the idea that glucose intolerance and type 2 diabetes might represent risk factors for OSA, as well as the idea of OSA being the risk factor for type 2 diabetes. A total of 252 patients with type 2 diabetes were surveyed during the regular follow-up in the Regional Centre for Diabetes, Endocrinology and Metabolic Diseases of Split University Hospital. The results of our study indicate that 156 patients (61.9%) had increased risk for OSA according to STOP questionnaire score. In addition, those at high risk for OSA were older (65 vs. 61 years of age, p < 0.05), had higher body mass index (BMI, 28.6 ± 5.1 vs. 26.5 ± 4.1, p < 0.001), higher neck circumference (41.5 ± 4.7 vs. 39.6 ± 6.2, p < 0.009), and had excessive daytime sleepiness according to the ESS score (5.3 ± 3.1 vs. 3.9 ± 2.5, p < 0.001). Individuals with type 2 diabetes reported to have comorbidities, mainly hypertension (46%), gastroesophageal reflux disease (28%), depression (10%), and asthma (8%). Based on current evidence from literature, OSA could be related to clinical conditions such as diabetes and essential hypertension. More epidemiological data are needed to establish the prevalence of OSA in Croatian patients with type 2 diabetes. Our findings indicate the relevance of STOP questionnaire use as a screening tool for obstructive sleep apnea in patients with type 2 diabetes in Croatia

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Non-random fertilization in mice correlates with the MHC and something else

One evolutionary explanation for the success of sexual reproduction assumes that sex is an advantage in the coevolutionary arms race between pathogens and hosts. Accordingly, an important criterion in mate choice and maternal selection thereafter could be the allelic specificity at polymorphic loci involved in parasite-host interactions, e.g. the MHC (major histocompatibility complex). The MHC has been found to influence mate choice and selective abortions in mice and humans. However, it could also influence the fertilization process itself, i.e. (i) the oocyte's choice for the fertilizing sperm, and (ii) the outcome of the second meiotic division after the sperm has entered the egg. We tested both hypotheses in an in vitro fertilization experiment with two inbred mouse strains congenic for their MHC. The genotypes of the resulting blastocysts were determined by polymerase chain reaction. We found nonrandom MHC combinations in the blastocysts which may result from both possible choice mechanisms. The outcome changed significantly over time, indicating that a choice for MHC combinations during fertilization may be influenced by one or several external factors