The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease

Multifunctional adaptive façade at iba 2013; design studies for an integral energy harvesting façade shading system

As part of the international exhibition ‘Bauausstellung’ IBA 2013 in Hamburg, Germany, architects from KVA MATx team and engineers from Knippers Helbig Advanced Engineering have developed an integral energy harvesting façade shading system for their ‘Softhouse’ project. Its overall concept includes an energy harvesting hybrid textile roof featuring flexible photovoltaics, which contributes to create a micro-climate for the building as a shading roof for the terrace and glass façade. This responsive façade is based on a textile hybrid system, using textile membranes and glass fibre reinforced plastics (GFRP) in an intricate form- and bending-active structure. This paper will discuss the multiple design studies that were undertaken to develop a system that satisfies the, at times, diametrically opposed demands from architecture, building physics, structural engineering and technical approval. Furthermore, detailed information will be given on the design specifications for using GFRP in bending-active elements and the Finite-Element simulation techniques used for the form-finding and structural analysis

Molecular semiconductors and the Ioffe–Regel criterion: A terahertz study on band transport in DBTTT

Terahertz electromodulation spectroscopy provides insight into the physics of charge carrier transport in molecular semiconductors. The work focuses on thin-film devices of dibenzothiopheno[6,5-b:6′,5′-f]thieno[3,2-b]thiophene. Frequency-resolved data show a Drude-like response of the hole gas in the accumulation region. The temperature dependence of the mobilities follows a T1/2 power law. This indicates that the thermal mean free path of the charge carriers is restricted by disorder. Only a fraction of approximately 5% of the injected carriers fulfills the Ioffe–Regel criterion and participates in band transport.info:eu-repo/semantics/publishe

Headache in 25 consecutive patients with atrial septal defects before and after percutaneous closure – a prospective case series

In contrast to patent foramen ovale, that is highly prevalent in the general population, atrial septal defect (ASD) is a rare congenital heart defect. The effect of ASD closure on headache and migraine remains a matter of controversy. The objectives of the study were (i) to determine headache prevalence in consecutive patients with ASD scheduled for percutaneous closure for cardiologic indications, using the classification of the International Headache Society and (ii) to compare headache characteristics before and after closure of ASD. In this observational case series no a priori power analysis was performed. Twenty-five consecutive patients were prospectively included over 27 months. Median duration of follow-up was 12 months, [Interquartile range 0]. Prevalence of active headache seemed to be increased compared to the general population: Any headaches 88% (95% confidence interval 70-96), migraine without aura 28% (14-48), migraine with aura 16% (6-35). After ASD closure, we observed a slightly lower headache frequency (median frequency 1.0 [2.6] vs. 0.3 [1.5] headaches per month; p=0.067). In patients with ongoing headaches, a significant decrease in headache intensity (median VAS 7 [3] vs. 5 [4]; p=0.036) was reported. Three patients with migraine with aura before the intervention reported no migraine with aura attacks at followup, two of them reported ongoing tension-type headache, one migraine without aura. In summary, this prospective observational study confirms the high prevalence of headache, particularly migraine, in ASD patients and suggests a possible small beneficial effect of ASD closure

Activation of interferon regulatory factor 3 by replication-competent Vaccinia viruses improves antitumor efficacy mediated by T-cell responses

Recently, oncolytic vaccinia viruses (VACVs) have shown their potential to provide for clinically effective cancer treatments. The reason for this clinical usefulness is not only the direct destruction of infected cancer cells but also activation of immune responses directed against tumor antigens. For eliciting a robust antitumor immunity, a dominant T helper 1 (Th1) cell differentiation of the response is preferred, and such polarization can be achieved by activating the Toll-like receptor 3 (TLR3)-interferon regulatory factor 3 (IRF3) signaling pathway. However, current VACVs used as oncolytic viruses to date still encode several immune evasion proteins involved in the inhibition of this signaling pathway. By inactivating genes of selected regulatory virus proteins, we aimed for a candidate virus with increased potency to activate cellular antitumor immunity but at the same time with a fully maintained replicative capacity in cancer cells. The removal of up to three key genes (C10L, N2L, and C6L) from VACV did not reduce the strength of viral replication, both in vitro and in vivo, but resulted in the rescue of IRF3 phosphorylation upon infection of cancer cells. In syngeneic mouse tumor models, this activation translated to enhanced cytotoxic T lymphocyte (CTL) responses directed against tumor-associated antigens and neo-epitopes and improved antitumor activity

High Throughput Sequencing and Proteomics to Identify Immunogenic Proteins of a New Pathogen: The Dirty Genome Approach

BACKGROUND:With the availability of new generation sequencing technologies, bacterial genome projects have undergone a major boost. Still, chromosome completion needs a costly and time-consuming gap closure, especially when containing highly repetitive elements. However, incomplete genome data may be sufficiently informative to derive the pursued information. For emerging pathogens, i.e. newly identified pathogens, lack of release of genome data during gap closure stage is clearly medically counterproductive. METHODS/PRINCIPAL FINDINGS:We thus investigated the feasibility of a dirty genome approach, i.e. the release of unfinished genome sequences to develop serological diagnostic tools. We showed that almost the whole genome sequence of the emerging pathogen Parachlamydia acanthamoebae was retrieved even with relatively short reads from Genome Sequencer 20 and Solexa. The bacterial proteome was analyzed to select immunogenic proteins, which were then expressed and used to elaborate the first steps of an ELISA. CONCLUSIONS/SIGNIFICANCE:This work constitutes the proof of principle for a dirty genome approach, i.e. the use of unfinished genome sequences of pathogenic bacteria, coupled with proteomics to rapidly identify new immunogenic proteins useful to develop in the future specific diagnostic tests such as ELISA, immunohistochemistry and direct antigen detection. Although applied here to an emerging pathogen, this combined dirty genome sequencing/proteomic approach may be used for any pathogen for which better diagnostics are needed. These genome sequences may also be very useful to develop DNA based diagnostic tests. All these diagnostic tools will allow further evaluations of the pathogenic potential of this obligate intracellular bacterium

Estimation of the solubility parameters of model plant surfaces and agrochemicals: a valuable tool for understanding plant surface interactions

Background Most aerial plant parts are covered with a hydrophobic lipid-rich cuticle, which is the interface between the plant organs and the surrounding environment. Plant surfaces may have a high degree of hydrophobicity because of the combined effects of surface chemistry and roughness. The physical and chemical complexity of the plant cuticle limits the development of models that explain its internal structure and interactions with surface-applied agrochemicals. In this article we introduce a thermodynamic method for estimating the solubilities of model plant surface constituents and relating them to the effects of agrochemicals. Results Following the van Krevelen and Hoftyzer method, we calculated the solubility parameters of three model plant species and eight compounds that differ in hydrophobicity and polarity. In addition, intact tissues were examined by scanning electron microscopy and the surface free energy, polarity, solubility parameter and work of adhesion of each were calculated from contact angle measurements of three liquids with different polarities. By comparing the affinities between plant surface constituents and agrochemicals derived from (a) theoretical calculations and (b) contact angle measurements we were able to distinguish the physical effect of surface roughness from the effect of the chemical nature of the epicuticular waxes. A solubility parameter model for plant surfaces is proposed on the basis of an increasing gradient from the cuticular surface towards the underlying cell wall. Conclusions The procedure enabled us to predict the interactions among agrochemicals, plant surfaces, and cuticular and cell wall components, and promises to be a useful tool for improving our understanding of biological surface interactions

Hydrokinetic pancreatic function and insulin secretion are moduled by Cl− uniporter Slc26a9 in mice

Aim: Slc26a9 is a member of the Slc26 multifunctional anion transporter family. Polymorphisms in Slc26a9 are associated with an increased incidence of meconium ileus and diabetes in cystic fibrosis patients. We investigated the expression of Slc26a9 in the murine pancreatic ducts, islets and parenchyma, and elucidated its role in pancreatic ductal electrolyte and fluid secretion and endocrine function. Methods: Pancreatic Slc26a9 and CFTR mRNA expression, fluid and bicarbonate secretion were assessed in slc26a9−/− mice and their age- and sex-matched wild-type (wt) littermates. Glucose and insulin tolerance tests were performed. Results: Compared with stomach, the mRNA expression of Slc26a9 was low in pancreatic parenchyma, 20-fold higher in microdissected pancreatic ducts than parenchyma, and very low in islets. CFTR mRNA was ~10 fold higher than Slc26a9 mRNA expression in each pancreatic cell type. Significantly reduced pancreatic fluid secretory rates and impaired glucose tolerance were observed in female slc26a9−/− mice, whereas alterations in male mice did not reach statistical significance. No significant difference was observed in peripheral insulin resistance in slc26a9−/− compared to sex- and aged-matched wt controls. In contrast, isolated slc26a9−/− islets in short term culture displayed no difference in insulin content, but a significantly reduced glucose-stimulated insulin secretion compared to age- and sex-matched wt islets, suggesting that the impaired glucose tolerance in the absence of Slc26a9 expression these is a pancreatic defect. Conclusions: Deletion of Slc26a9 is associated with a reduction in pancreatic fluid secretion and impaired glucose tolerance in female mice. The results underline the importance of Slc26a9 in pancreatic physiology. © 2021 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society