Common Molecular Targets of a Quinolone Based Bumped Kinase Inhibitor in Neospora caninum and Danio rerio.

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii, and causes abortions, stillbirths and/or fetal malformations in livestock. Target-based drug development has led to the synthesis of calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs). Previous studies have shown that several BKIs have excellent efficacy against neosporosis in vitro and in vivo. However, several members of this class of compounds impair fertility in pregnant mouse models and cause embryonic malformation in a zebrafish (Danio rerio) model. Similar to the first-generation antiprotozoal drug quinine, some BKIs have a quinoline core structure. To identify common targets in both organisms, we performed differential affinity chromatography with cell-free extracts from N. caninum tachyzoites and D. rerio embryos using the 5-aminopyrazole-4-carboxamide (AC) compound BKI-1748 and quinine columns coupled to epoxy-activated sepharose followed by mass spectrometry. BKI-binding proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from BKI-1748 as well as quinine columns. In N. caninum, 12 proteins were bound specifically to BKI-1748 alone, and 105 proteins, including NcCDPK1, were bound to both BKI-1748 and quinine. For D. rerio, the corresponding numbers were 13 and 98 binding proteins, respectively. In both organisms, a majority of BKI-1748 binding proteins was involved in RNA binding and modification, in particular, splicing. Moreover, both datasets contained proteins involved in DNA binding or modification and key steps of intermediate metabolism. These results suggest that BKI-1748 interacts with not only specific targets in apicomplexans, such as CDPK1, but also with targets in other eukaryotes, which are involved in common, essential pathways

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spino-cerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory cir-cuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compro-mising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcit-able MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibi-tion of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level def-icits upstream of PNs are one of the main disease triggers in SCA1

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1

Mental Health Consultations in Immigration Detention: What Can We Learn From Clinical Records?

Objectives: Knowledge on mental health consultations in immigration detention and characteristics of people receiving consultations is scarce. Based on a sample of 230 adult men in immigration detention in Switzerland, we aimed to: (1) Quantify the proportion of persons receiving mental health consultations during detention; and (2) Identify socio-demographic and clinical characteristics associated with mental health consultations.Methods: Retrospective observational study with a cross-sectional design. Prevalence estimates, logistic regressions, and contingency tables were used to analyse the data.Results: A total of 30% of the sample received mental health consultations during detention. Time spent in immigration detention, mental health problems during detention, use of psychotropic medication, and self-harm were associated with mental health consultations. Although mental health consultations are provided to people with more severe mental health problems, 41% of persons with assessed mental health needs during the initial screening and 26% of those who self-harmed during detention did not receive mental health consultations.Conclusion: Mental health resources and screening procedures could be improved to ensure that mental health consultations are matched to clinical need in immigration detention settings

Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller’s dementia infantilis, a rare subtype of autism spectrum disorder

International audienceAbstractBackgroundDeletions and mutations involving the SHANK3 gene lead to a nonspecific clinical presentation with moderate to profound intellectual disability, severely delayed or absent speech, and autism spectrum disorders (ASD).Better knowledge of the clinical spectrum of SHANK3 haploinsufficiency is useful to facilitate clinical care monitoring and to guide molecular diagnosis, essential for genetic counselling.Case presentationHere, we report a detailed clinical description of a 10-year-old girl carrying a pathogenic interstitial 22q13.3 deletion encompassing only the first 17 exons of SHANK3.The clinical features displayed by the girl strongly suggested the diagnosis of dementia infantilis, described by Heller in 1908, also known as childhood disintegrative disorder.ConclusionOur present case confirms several observations according to which regression may be part of the clinical phenotype of SHANK3 haploinsufficiency. Therefore, we think it is crucial to look for mutations in the gene SHANK3 in patients diagnosed for childhood disintegrative disorder or any developmental disorder with a regressive pattern involving social and communicative skills as well as cognitive and instinctual functions, with onset around 3 years

Reading Text Increases Binocular Disparity in Dyslexic Children

Children with developmental dyslexia show reading impairment compared to their peers, despite being matched on IQ, socio-economic background, and educational opportunities. The neurological and cognitive basis of dyslexia remains a highly debated topic. Proponents of the magnocellular theory, which postulates abnormalities in the M-stream of the visual pathway cause developmental dyslexia, claim that children with dyslexia have deficient binocular coordination, and this is the underlying cause of developmental dyslexia. We measured binocular coordination during reading and a non-linguistic scanning task in three participant groups: adults, typically developing children, and children with dyslexia. A significant increase in fixation disparity was observed for dyslexic children solely when reading. Our study casts serious doubts on the claims of the magnocellular theory. The exclusivity of increased fixation disparity in dyslexics during reading might be a result of the allocation of inadequate attentional and/or cognitive resources to the reading process, or suboptimal linguistic processing per se

The Stakes in Bayh-Dole: Public Values Beyond the Pace of Innovation

Evaluation studies of the Bayh-Dole Act are generally concerned with the pace of innovation or the transgressions to the independence of research. While these concerns are important, I propose here to expand the range of public values considered in assessing Bayh-Dole and formulating future reforms. To this end, I first examine the changes in the terms of the Bayh-Dole debate and the drift in its design. Neoliberal ideas have had a definitive influence on U.S. innovation policy for the last thirty years, including legislation to strengthen patent protection. Moreover, the neoliberal policy agenda is articulated and justified in the interest of “competitiveness.” Rhetorically, this agenda equates competitiveness with economic growth and this with the public interest. Against that backdrop, I use Public Value Failure criteria to show that values such as political equality, transparency, and fairness in the distribution of the benefits of innovation, are worth considering to counter the “policy drift” of Bayh-Dole

The force of the sign. Terrorism as a symbolic phenomenon

Seit der radikalen Änderung der weltpolitischen Lage durch das Selbstmordattentat islamistischer Terroristen auf die Supermacht U.S.A. am 11.9.01 versucht die Weltöffentlichkeit, dem Phänomen des Terrorismus durch die verschiedensten Erklärungsstrategien Herr zu werden. Man führt den Kampf der Kulturen oder Religionen an, verweist auf die Ausbeutung der Peripherie des kapitalistischen Weltsystems durch den Hegemon U.S.A. oder pathologisiert bzw. dämonisiert die Taten der Terroristen. Uns scheinen diese Erklärungsstrategien den Machtkonstellationen der postmodernen Gesellschaften nicht gerecht zu werden, da sie ein zentrales soziales Phänomen der vergangenen Jahrzehnte nicht beachten: das Unbehagen an der pluralistischen Gesellschaft und der konsensuell-repräsentativen Demokratie. Um dieses Unbehagen angemessen beschreiben zu können, wollen wir uns ihm aus einer zeichentheoretischen Perspektive nähern, die soziale Formationen nicht durch (kooperative) Arbeit determiniert sieht, sondern durch die Instanz des Codes. Für Jean Baudrillard ist die Wahl des Ziels der beiden Türme bedeutend, die sich wechselseitig reflektieren und das System nach allen Seiten hin abschließen. Mit ihnen wurde das neuralgische Zentrum des Systems getroffen, das sich auf einem binären Code gründet. Die Twintowers bedeuteten nicht nur das Ende jedweder originalen Referenz, sondern auch den Abschluss des Bezeichneten durch die Wiederholung des Zeichens. Der Code führt eine symbolische Verteilung der gesellschaftlichen Körper durch und zielt auf eine möglichst genaue Übereinstimmung der Gemeinschaft mit sich selbst gemäß eines arithmetischen und geometrischen Kalküls. Die integrative Kraft dieses auf dem Identitätsprinzip basierenden Systems scheint immer häufiger nicht mehr in der Lage zu sein, das negative Potential antagonistischer Strategien binden zu können, die in Form von zivilem Ungehorsam, Politik von Minoritäten oder terroristischen Akten die symbolische Ordnung der westlichen Gesellschaften unterhöhlen. In diesem Tagungsband diskutieren wir das Ausmaß der Krise der konsensuellen Demokratie und ihrer Institutionen. Die Aufsätze behandeln folgende Themen: • Die Krise der pluralistischen Gesellschaft: Wie verständlich ist das kulturelle, politische und religiöse Unbehagen am westlichen Wertekanon? • Die Funktion der Medien in der konsensuellen Demokratie; die gesellschaftliche Wirkung der medialen Reproduktion terroristischer Akte; das Bild des Terrorismus in der Populärkultur • Ästhetischer Terror: Die Vernichtung von Sinn und Bedeutung in der zeitgenössischen Kunst und Kunsttheorie • Die politische Logik des Terrorismus (Ziele, Bedingungen u. Legitimität des Terrorismus in Abgrenzung zu alternativen politischen Ausdrucksformen wie z.B. dem zivilen Ungehorsam; die Bedeutung des terroristischen Opfertodes) • Geschichte des Terrorismus (speziell der Terrorismus der RAF) • Terror als irrationale Gewalt (der ontologische Status des Terrorismus)Since the radical changes in international politics caused by the suicide attacks on the USA by Islamic terrorists on the 11th of September in 2001, the world public tries to grasp the phenomenon of „Terrorism“ through different explanatory strategies. These include referring to the clash of cultures and of religions, to the exploitation of the periphery by the capitalist system incarnated by the USA, or pathologizing as well as demonizing the deeds of the terrorists. All these explanatory attempts do not seem to do justice to the actual constellations of power in postmodern societies, because they do not take a widespread social phenomenon of the past decades in consideration: the discomfort with the pluralistic society and with the concurrent-representative democracy. In order to describe this discomfort adequately we would like to approach the phenomenon from a semiotic perspective which does not consider social formations as determined by cooperative work but rather by the authority of the code. For Jean Baudrillard the target was meaningful since the two towers not only reflect each other but also completely close the system. With them the neuralgic center which is based upon the binary code was severely hit. The twin towers not only meant the end of every original reference but also the completion of the signified by the reduplication of the sign. The code conducts a symbolic distribution of the social bodies and aims at an as accurate as possible identification of the community with itself corresponding to an arithmetic and geometric calculus. The system which is based upon the principle of identity does not seem to have the ability to integrate antagonist energies properly. So these antagonist powers undermine the symbolic order of western societies in terms of civil disobedience, politics of minorities or terroristic acts. In this conference transcript we discuss the degree of crisis of consensual democracy and ist institutions. The essays cover the following topics: • The crisis of the pluralistic society: How comprehensible and justified is the cultural, political, and religious discomfort with western values? • The function of mass media in democratic systems: What is the impact of the reproduction of terrorist acts on society? How does popular culture deal with terrorism? • Aesthetic terror: the destruction of sense and meaning in contemporary arts and art theory • The political logic of terrorism (aims, legitimacy of terrorism as opposed to other forms of opposition like civil disobedience; the meaning of the terrorist self-sacrifice death) • History of terrorism (e.g. The German terrorism of the RAF) • Terrorism as an irrational power (ontological status of terrorism