bluuebunny/crossref_metadata_2025 huggingface dataset:
Acoustic startle responses of rats with cerebral developmental abnormalities: implications for schizophrenia
Authors: Talamini L.M. , Ellenbroek B. , Koch T. , Korf J.
Published: July 2016

Mounting evidence suggests involvement of prenatal factors in the pathogenesis of schizophrenia. The objective of the present study was to provide evidence for the hypothesis on schizophrenia that abnormal fetal brain development leads to impaired sensorimotor gating of acoustic startle stimuli. To this purpose, pregnant rats were treated with methylazoxymethanol acetate on one of four subsequent days of gestation, from E9 to E12. These procedures inhibit early stages of cortical proliferation in the foetuses, resulting in adult brain abnormalities that were mainly found in the entorhinal region. At the adult age, habituation andprepulse inhibition (PPI) of startle responses to acoustic stimuli were investigated. Our results show impaired habituation and PPI in rats treated at embryonic days 10 and 11. It is concluded that sensorimotor gating deficits can result from a developmental abnormality involving the entorhinal region, supporting the hypothesis that similar deficits, often observed in schizophrenic subjects, may be the result of entorhinal cortex dysfunction.
Behavioural genetics: An introduction
Authors: Sluyter F. , Ellenbroek B.A.
Published: July 2016

Behavioural genetics is the study of the hereditary influence on behaviour, and can therefore be regarded as the intersection between behavioural sciences and genetics. As with most other fields of research it is difficult to exactly pinpoint when behavioural genetics started. In fact, one might say that the notion behavioural traits can be inherited may have appeared in human thought as early at 8000 BC, when the domestication of the dog began.

The scientific era of behavioural genetics is generally considered to start with Charles Darwin. In his famous book On the Origin of Species by Means of natural Selection, or the Preservation of favoured Races in the Struggle for Life, published in 1859 (and sold out the first day), he devoted an entire chapter on instinctive behavioural patterns. Some years later, in his book The Descent of Man and Selection in Relation to Sex, he clearly stated that the difference between the mind of a human being and the mind of an animal ‘is certainly one of degree and not of kind’. Moreover he gave considerable thought that mental powers (and insanity) are heritable aspects.
Methodology of genetic research in psychiatry
Authors: McGuffin P.
Published: July 2016

Most forms of behaviour whether normal or abnormal, show a tendency to run in families. However, these can range from symptoms of dementia and movement disorder caused by the comparatively rare autosomal dominant Huntington's disease to common everyday aspects of behaviour such as religious persuasion or career choice. Normal behaviours and most common disorders do not show simple mendelian inheritance but instead have more complex patterns of transmission involving either major genes with incomplete penetrance, multiple genes of small effect, or a combination of the two. In addition, common complex phenotypes usually involve the combination of genetic and environmental factors. Therefore once family studies have shown that a disorder or trait is familial the next stage is to perform twin studies and, if possible adoption studies to investigate whether this results from shared genes, shared environment or a combination of the two.
The developing role of pharmacogenetics in psychiatry
Authors: Touw D.J.
Published: July 2016

A great interindividual variability exists in biological response to drugs. This variability is partly attributable to pharmacodynamic factors (drug - receptor interactions) and partly to pharmacokinetic factors. Drugs can be eliminated from the body by renal clearance, metabolism or both. Although every tissue has some ability to metabolise xenobiotics like drugs, the liver is the principal organ of biotransformation. Major metabolising enzymes are the cytochrome-P450 mono-oxygenases, epoxide hydrolase, glucuronosyl-transferase, acetyl-transferase, sulfo-transferase and xanthine oxidase. Some of these enzymes display in a subset of subjects a ‘normal’ activity and in another subset of subjects a reduced or a greatly increased activity. This altered activity may be genetically determined and is then called genetic polymorphism. Clinically relevant metabolic differences traditionally have been defined by their genotypie expression such as ‘poor’ and ‘extensive’ metaboliser. The recent developments of powerful methods for DNA (or genomic) analysis portends a revolutionary expansion of our understanding of physiology as well as pathology. Pharmacogenetics is the study of genetic variation underlying differential response to drugs. Genotyping may become a useful tool in optimising drug treatment. Another part of the genetic research is directed towards the discovery of genetic alterations leading to diseases. Once identified, these genetic alterations can become targets for drug treatment (e.g. gene therapy). Pharmaco-genomics applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism or disease pathway. Table I gives some examples of genetic alterations that are identified together with their effects. Some of these examples will be briefly discussed here.
Dimensional models and neurobiology of personality disorders
Authors: van den Brink W.
Published: July 2016

Since the introduction of a separate axis in DSM-III (1980), the validity of the categorical nature of the classification of personality disorders has been seriously questioned. Subsequently, a number of multidimensional alternatives have been proposed based on statistical procedures or theoretical considerations. At the same time, the study of the neurobiological underpinnings of personality and personality disorders has created a better understanding of etiological and pathogenetic processes responsible for these chronic disorders. The findings of these studies corroborate some of the major findings of statistical studies regarding the nature of the frequent comorbidity of axis II disorders. In the discussion, a mixed, two-tier diagnostic model is proposed to serve both scientific and clinical aims without the disadvantages of an exclusive choice for either categorical or dimensional approaches to the classification of personality pathology.
Cognitive aging and early neurophychological diagnostics
Authors: Jolies J.
Published: July 2016

With aging, most cognitive functions decline, especially processes concerning memorizing, attention, concentration, organizing, planning and problem solving. Neuropsychology can make an important contribution in early and differential diagnostics. The borderline between normal and pathological cognitive aging is especially important in this respect. The neuropsychologist gains insight in medical, biological, psychological and social factors of the aging person. Has the profile of complaints and deficits a normal background or is a pathological process taking place? It is important to people who are unnecessarily worried about possible dementia.

Neuropsychological assessment also provides information about a patient's disturbed and undisturbed cognitive functions, their personality and their way of coping with problems in every day's life. This is of major importance, because it provides information and possibilities for biological or psychological interventions. Because of the complexity of problems that may occur, it is necessary that the neuropsychologist is experienced and works in a multidisciplinary team in which neurological and psychiatric expertise is present.
The role of serotonin in Parkinsons' Disease: An integrated approach for research of motor, cognitive and affective symptoms with functional intervention studies
Authors: Leentjens A.F.G. , Verhey F.R.J. , Vreeling F.W. , van Praag H.M.
Published: July 2016

Serotonin seems to play an important role in the regulation of dopaminergic and cholinergic neurotransmitter activities. In patients with Parkinsons' Disease, serotonergic activity is generally reduced, which is considered a compensating mechanism for the reduced dopaminergic activity. At the same time, reduction of serotonin activity may play a role in the expression of cognitive and affective symptoms. Functional intervention with serotonergic agents makes it possible to temporarily enhance or reduce the availability of serotonin in the brain. This will provide the opportunity to study motor, cognitive and affective symptoms in an integrated approach. This type of research has hardly been preformed in patients with Parkinson's Disease.
Het meten van psychomotorische vertraging bij depressie deel II
Authors: Sabbe B. , Hoof J. Van , Hulstijn W. , Zitman F.
Published: July 2016

This review (part I and II) contains an overview of the literature of the past fifteen years over psychomotor retardation in depressed patients, as measured by the following methods:

observation scales (part I);

observation, coding and analysis of specific nonverbal behaviour (part I);

speech research (part I);

(choice) reaction time tasks (part II);

analysis of gross motor activity (part II);

of fine motor behaviour (part II).

In each section the results of the different studies are summarized and discussed, in order to answer the following questions: (a) did the depressed patients show any retardation?, (b) how did this retardation manifest itself?, (c) what was the nature of the retardation?, (d) were there any correlations with the results of other methods? and (e) what were the effects of antidepressive treatment?
Hersenveranderingen en ‘sprongen’ in de eerste 20 levensmaanden en de invloed van de context op gedragsmaten van regressieperioden
Authors: Plooij F.X.
Published: July 2016

Het idee dat er een koppeling te leggen valt tussen rijping van het zenuwstelsel en ontwikkelings-mijlpalen of -transities, zoals voor het eerst grijpen, kruipen of lopen, is onhoudbaar gebleken. Wel valt er een koppeling in de tijd te leggen tussen hersenveranderingen en regressieperioden zoals beschreven door Van de Rijt-Plooij en Plooij (1992). De vraag hoe de regressieperioden zieh ‘biologisch’ en gedragsmatig manifesteren is daarom van belang. Dat blijkt minder eenvoudig te zijn dan men zou denken. De context blijkt van invloed te zijn. Daarover gaat dit artikel.

De opzet van het artikel is als volgt. Eerst wordt de koppeling tussen hersenveranderingen en regressieperioden besproken. Dan wordt onze visie op de relatie tussen regressieperioden en ontwikkelingstransities of wel nieuwe vaardigheden toegelicht. Tenslotte wordt de invloed van de context op ‘biologische’ en gedragsmaten van regressie beschreven.
Empirische indicatoren voor regressies en sprangen bij baby's
Authors: van Geert P. , de Weerth C.
Published: July 2016

Het is al lang bekend dat het optreden van ontwikke-lingsmijlpalen sterk van baby tot baby kan verschillen. Theorieën of modellen die daarentegen een strakke timing, gepaard gaande met geringe individuele verschillen, voor ontwikkelingsverschijnselen postuleren, hebben dan ook een zware bewijslast te torsen. Het model van Van de Rijt-Plooij en Plooij van tien strak getimede regressieperioden tijdens de eerste achttien levensmaanden is een voorbeeld van een dergelijk model. In het licht van het feit dat het model mede ten grondslag ligt aan een wijd verspreid praktisch adviezenboek voor ouders, mag worden verwacht dat de empirische ondersteuning er-voor uitgebreid en hecht is. In deze bijdrage zullen we de empirische evidentie voor en tegen het model bespreken en ingaan op de methodologische problemen die bij het verifiëren dan wel falsifiëren van dit model kornen kijken.
Olanzapine as medication of first choice in therapy-resistant schizophrenia?
Authors: à Campo J. , Nijman H. , Merckelbach H.
Published: July 2016

A case history of a thirty-one year old schizophrenic female who was treated with olanzapine is described. Olanzapine is a relatively new atypical antipsychotic drug with a dopamine antagonistic as well as a potent serotonine antagonistic effect. Olanzapine was prescribed effectively after haloperidol, flupentixol chloride, and clozapine had not lead to (lasting) improvements of the psychiatric condition of the patient. Considering the efficacy and the limited risks of this relatively new antipsychotic medication the question arises as to whether olanzapine should be considered as the drug of first choice for patients who do not benefit from treatment with a typical neuroleptic drug.
The prospects of new antipsychotic principles
Authors: Carlsson A.
Published: July 2016

Biological schizophrenia research has been dominated by the dopamine hypothesis for decades, but in recent years a more diversified view has gained increasing attention. Several neurotransmitters are now being discussed, and especially their interaction in complex circuitries.

The demonstration of an atypical profile of clozapine (Leponex®), with lessened extrapyramidal side effects and somewhat increased efficacy, has stimulated this research field considerably. This agent has high affinity not only for the different dopamine receptor subtypes, but also for serotonergic, alpha-adrenergic and muscarinic receptors. Different workers have stressed one or more of these sites as being of major importance for the atypical profile of clozapine, and several drug companies have made attempts to mimic the profile of clozapine by developing molecules with affinity for these receptors in varying proportions. A number of such agents have reached or will soon reach the market and appear to be promising, even though they may not match clozapine in terms of atypicality.
Biological concepts of anxiety disorders
Authors: Westenberg H.G.M.
Published: July 2016

Since the seminal work of Geller and Blum there is a vast expanding literature relating anxiety symptoms to serotonin (5-hydroxytryptamine; 5-HT). The general picture emerging from animal research is that increasing 5-HT function is anxiogenic. However, animal research is confined by the fact that extrapolations from animal behavior to human emotions have limited validity. Human anxiety can range from normal emotions to clinical syndromes. It can be a component of different physical and mental disorders, but also the central feature of a syndromes.

During the last decade, a wealth of knowledge about the origin and anatomical distribution of 5-HT neuronal systems has been obtained. Our understanding of the neuroanatomy and neurochemistry of anxiety has also considerably advanced, but the picture is still puzzling. We are faced with a large number of 5-HT-receptor subtypes, each with its own specific distribution and presumably specific function. The complexity of the 5-HT system in terms of receptor heterogeneity offers a dazzling opportunity to the development of new drugs affecting selective 5-HT functions, but it also precludes that firm conclusions can be drawn when less selective agents are being used.
Phencyclidine, excitatory amino acids, psychiatry and drug abuse: Historical perspectives on clinical-laboratory interactions
Authors: Zukin S.R.
Published: July 2016

Some 40 years ago phencyclidine (PCP) was developed as the prototype of a proposed new class of ‘dissociative’ general anesthetics, so called because it induced a marked dissociation from the environment without complete loss of consciousness. In the earliest clinical trials of PCP anesthesia, it was observed that as many as half the subjects experienced severe psychotic reactions during and beyond emergence. This striking clinical observation at once marked the failure of PCP as a suitable general anesthetic, and the beginning of a remarkable new era in basic and clinical neuroscience which can serve as an example of the interaction between clinical observation and basic science. At once, clinical researchers turned their focus upon the characterization of the PCP-induced psychosis, and recognized striking similarities between PCP-induced symptoms and signs and both the negative and positive symptoms of schizophrenia, proposing the PCP psychosis as a new model of that illness. Several years later PCP suddenly emerged as a major drug of abuse, with the result that emergency rooms and psychiatric inpatient units were observing and treating large numbers of these patients, in many of whom a diagnosis of schizophrenia could not be ruled out until toxicological analyses were performed. This natural experiment yielded a huge amount of additional data, and contributed a strong public-health based impetus to research into the nature and treatment of PCP intoxication.
The prediction of response in the anxiety disorders
Authors: Slaap B.R. , van Vliet I.M. , Westenberg H.G.M. , den Boer J.A.
Published: July 2016

In this review the results are discussed on the prediction of response to pharmacotherapy in panic disorder (PD) and social phobia (SP). From the literature it appears that in PD variables indicative of illness severity are predictors of non-response. In our own studies we found that non-responders to pharmacotherapy in PD are characterised by a higher score on the Blood-Injury subscale of the Fear Questionnaire, a higher plasma MHPG and a higher heart rate. In SP non-responders to pharmacotherapy were also characterised by a higher heart rate. They also appeared to have a higher blood pressure. Furthermore non-responders to pharmacotherapy in SP had higher scores on several psychometric scales, indicative of illness severity.
De Widlöcher Remmingsschaal, een Nederlandse Schaal Voor het Meten van Psychomotorische Remming
Authors: de Weme R.J.C. , Hoeksema T. , Goekoop J.G.
Published: July 2016

Aim: Translation of a specific instrument to measure psychomotor retardation, the “Widlöcher Retardation Rating Scale” and validation of this Dutch translation (Widlöcher remmingsschaal, WRS). Method: In three separate studies, we studied reliability (n = 26), concurrent and divergent validity (n = 25) and predictive validity (n = 28) of the WRS. In- and outpatients with a depressive disorder or schizophrenia participated, and scores on the WRS were compared with those on the Montgomery Asberg Depression Rating Scale (MADRS) and retardation items of the Comprehensive Psychopathological Rating Scale (CPRS).

Results: The internal consistency was good (Cronbach alpha = 0.86), interrater reliability was sufficient to good, the correlation between the sumscores of both raters was r = 0.84, n = 23, p <0.01 and the kappa's were between 0.23 and 0.80. Convergent and divergent validity showed in comparing the correlation between the sum scores on the WRS and the CPRS retardation items (r = 0.91, n = 25, p < 0.01 ) with the correlation between the sumscores on the WRS and the MADRS (r = 0.40, n = 25, p = 0.1). The decrease of the sum scores on the WRS after two weeks of treatment with antide-pressants predicted remission after six weeks. A subgroup of the patients who were not in remission after six weeks, showed a predominance of retardation signs over mood disturbances. The same clinical picture was seen in a group of patients with a chronic disorder.

Conclusion: De Widlöcher Retardation Rating Scale in this Dutch translation is a usefull instrument to measure psychomotor retardation. The connection between remaining retardation symptoms and longterm prognosis deserves further investigation.
Magneto-encefalografie
Authors: Peters M.J. , Reinders F.
Published: July 2016

A magnetoencephalogram (MEG) is the registration of the magnetic field in points near the head. Because MEG's are weak fields, they have to be measured by means of superconducting sensors. The electric active population of neurons can be computed from the distribution of the magnetic field at a certain instant of time. This is called the inverse problem. In order to solve this probem, both the generators and the head have to be modelled. Usually, a patch of active neurons is modelled as a current dipole. Commonly, the head is described by three compartments, representing the brain, the skull and the scalp. The compartments may have the shape of spheres or they may have a realistic shape. Integration of EEG and MEG with MRI leads to a technique for functional imaging of the brain with a time resolution of one millisecond and a spatial resolution of one centimetre. Clinical applications are the non-invasive localization of an epileptic focus or the presurgical mapping of the sensorimotor cortex.
Letters from readers. Does electrophysiological investigation in psychiatry still have a future?
Authors: van Sweden B.
Published: July 2016

In de neurologische praktijk is het diagnostisch gebruik van EEG-onderzoek drastisch verminderd ten bate van radiologische beeldvorming. In de klinische psychiatrie bestaan twee grote indicatiegebieden voor klinisch-neurofysiologisch onderzoek: de evaluatie van organische psychosyndromen en van stoornissen met episodisch of paroxysmaal karakter. Mits het een overlappingsgebied met de neurologie betreft, merkt men hier dezelfde trend.
Antidepressive interventions: on state and vulnerability of the brain
Authors: Korf J.
Published: July 2016

An attempt is made to relate drug and non-drug antidepressive interventions to brain processes. In the present context two concepts are proposed: vulnerability towards depressogenic factors and depression as a state of the brain. Accordingly, it is assumed that the current antidepressants make the brain less vulnerable by inhibiting monoaminergic neurons and by reducing the number or efficacy of their postsynaptic receptors. In contrast, electroconvulsive therapie and sleep-deprivation affect primarily the state of the brain and can produce spectacular (but often short lasting) improvements. It is proposed that the combination of the two aspects may lead to fast and lasting antidepressive effects.
Biology of personality disorders
Authors: Tuinier S. , Verhoeven W.M.A.
Published: July 2016

Since the introduction of international psychiatric classification systems, systematic diagnostic methods have become available for personality disorders. Recent developments in the dimensional diagnostic approach of personality disorders have yielded relationships between this type of disorders and neurobiological processes including both monoaminergic and stress-hormonal systems. It is hypothesized that the pathogenesis of borderline personality disorders is related to an enhanced serotonergic tone in septo-hippocampal structures. Preliminary clinical data are suggestive for potential therapeutic effects of serotonin-modulating compounds in borderline personality disorders
Pharmacotherapeutical treatment of personality disorders
Authors: Hesselink J.M. Keppel
Published: July 2016

Since some years it has become evident that objective disturbances can be found in patients suffering from personality disorders. Research findings from earlier date already demonstrated low levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid, especially in patients with personality disorders, under exclusion of depressive features. Furthermore, data have been collected on the correlation between a hyposerotonergic state and disturbances in aggression and impulse control in a variety of syndromes such as automutilation, bulimia nervosa, suicide attempts and various states of drug abuse.

However, psychopharmacological research in personality disorders is rare and to date mainly patients with borderline and schizotypical personality disorders have been studied. It is quite remarkable for this area to find more review articles than original contributions based on the results of clinical trials. A great variety of recommendations for pharmacotherapy in these patients exists in literature, among which treatment with carbamazepine, lithium, low-dose neuroleptics, tricyclic antidepressants and serotonin uptake inhibitors. In this article we will analyze the research methodology and the results of clinical trials forming the base for pharmacotherapeutic treatment recommendations.

Only the results of well-controlled studies will be reviewed.
The clinical relevance of treatment with antidepressants
Authors: Nolen W.A.
Published: July 2016

Oince the discovery in the late 1950's of imipramine (Tofranil®), the first tricyclic antidepressant (TCA), and iproniazid, the first monoamine oxidase inhibitor (MAOI), many other TCAs and MAOIs, now being considered the classical antidepressants, have become available. Their effectiveness has been shown in numerous studies, although according to nowadays standards well designed studies (placebo-controlled, defined diagnostic groups, the use of standardized rating scales) with these compounds are relatively scarce.

From the early 1980's the so called modern antidepressants have been introduced: the selective serotonin re-uptake inhibitors (SSRIs), the reversible selective monoamine oxidase-A inhibitors (RIMAs) and a variety of other compounds. All these drugs have been registered after their effectiveness had been shown in well designed, placebo-controlled studies. In defining the efficacy of antidepressants, registration authorities consider two aspects important: statistical evidence and clinical relevance.
Attunement of non-verbal behaviour between depressed patients and a psychiatrist at admission is related to persistence of depression
Authors: Geerts E. , Bouhuys A.L. , van den Hoofdakker R.H.
Published: July 2016

According to interpersonal theories on depression, the type of interaction between depression-prone subjects and their social environment plays a causal role in the development and course of depression (e.g. Coyne et al.). So far, interpersonal theories have been tackled mostly by psychometrical methods. However, non-verbal behaviour plays an important role in human social interactions. It is assumed that 60-65% of human communication is non-verbal. Ethological observations have shown that non-verbal interpersonal behaviour of depressed subjects, as assessed prior to treatment, is related to treatment-response or subsequent course of depression. These results are in line with an interpersonal approach of depression.
The rat hippocampus as a target for prolonged stress: Biochemical and behavioral effects
Authors: Krugers H.J. , Korf J.
Published: July 2016

The probability that an individual will suffer from a major depressive episode is often considered to be influenced by risk factors such as gender, premature parental loss, exposure to pathogenic parental rearing, personality, a history of traumatic events, a previous history of major depression, low social support, recent stressful life events and difficulties and predisposing genetic influences. Although several studies suffer from methodological limitations, major depression (endogenous depression) is regarded as a multifactorial disorder and understanding its etiology requires the rigorous integration of several risk factors.
Seroprevalence and associated risk factors of Toxocara infection in Korean, Manchu, Mongol, and Han ethnic groups in northern China
Authors: YANG G.-L. , ZHANG X.-X. , SHI C.-W. , YANG W.-T. , JIANG Y.-L. , WEI Z.-T. , WANG C.-F. , ZHAO Q.
Published: July 2016

Toxocariasis is a very prevalent zoonotic disease worldwide. Recently, investigators have focused more on Toxocara spp. seroprevalence in humans. Information regarding Toxocara seroprevalence in people from different ethnic backgrounds in China is limited. For this study, blood samples were collected from a total of 802 Han, 520 Korean, 303 Manchu, and 217 Mongol subjects from Jilin and Shandong provinces. The overall Toxocara seroprevalence was 16·07% (14·21% Han, 20·58% Korean, 11·22% Manchu, 18·89% Mongol). Living in suburban or rural areas, having dogs at home, exposure to soil, and consumption of raw/undercooked meat were risk factors for Toxocara infection. Exposure to soil was identified as the major risk factor for Toxocara seropositivity in all of the tested ethnicities. To the best of our knowledge, this is the first report concerning Toxocara infection in Manchus and Mongols in China. The present study provided baseline data for effective prevention strategies of toxocariasis in northeast China and recommends improvements in personal hygiene standards to achieve this goal.
An Examination of the Surface and Sub-Surface of Modern and Historical Platinum Photographic Prints Using Low Vacuum High-Resolution Scanning Electron Microscopy
Authors: Ravines Patrick , Erdman Natasha , McElroy Rob
Published: July 2016

Photographic prints of platinum metal on paper supports are some of the most exquisite and expressive in the world of fine art photography. Platinum prints were produced from about 1890 to 1920 in the USA and Europe. The chemical and material nature of these valuable prints is of great interest to many who are interested in their long-term preservation, in the intersection of science and art, and in the scientific and technical study of cultural heritage. This paper presents the results of a characterization study using newer electron microscopy techniques. In this study, a low vacuum high-resolution scanning electron microscope was used to study the surface and sub-surface of historic and modern platinum and/or palladium print samples. Using environmental SEM pressures allowed us to investigate the actual top surface and sub-surface with cross-sections without any preparation; no coatings of carbon or other material. Cross-sections were prepared using an argon plasma cross-polishing system. This study shows that the photographic image of platinum prints is composed of platinum nanoparticles embedded in the upper layers of the paper’s cellulosic fibers.
The missing large impact craters on Ceres
Authors: Marchi S. , Ermakov A. I. , Raymond C. A. , Fu R. R. , O’Brien D. P. , Bland M. T. , Ammannito E. , De Sanctis M. C. , Bowling T. , Schenk P. , Scully J. E. C. , Buczkowski D. L. , Williams D. A. , Hiesinger H. , Russell C. T.
Published: July 2016

Asteroids provide fundamental clues to the formation and evolution of planetesimals. Collisional models based on the depletion of the primordial main belt of asteroids predict 10–15 craters >400 km should have formed on Ceres, the largest object between Mars and Jupiter, over the last 4.55 Gyr. Likewise, an extrapolation from the asteroid Vesta would require at least 6–7 such basins. However, Ceres’ surface appears devoid of impact craters >∼280 km. Here, we show a significant depletion of cerean craters down to 100–150 km in diameter. The overall scarcity of recognizable large craters is incompatible with collisional models, even in the case of a late implantation of Ceres in the main belt, a possibility raised by the presence of ammoniated phyllosilicates. Our results indicate that a significant population of large craters has been obliterated, implying that long-wavelength topography viscously relaxed or that Ceres experienced protracted widespread resurfacing.
Structure-guided development of heterodimer-selective GPCR ligands
Authors: Hübner Harald , Schellhorn Tamara , Gienger Marie , Schaab Carolin , Kaindl Jonas , Leeb Laurin , Clark Timothy , Möller Dorothee , Gmeiner Peter
Published: July 2016

Crystal structures of G protein-coupled receptor (GPCR) ligand complexes allow a rational design of novel molecular probes and drugs. Here we report the structure-guided design, chemical synthesis and biological investigations of bivalent ligands for dopamine D2receptor/neurotensin NTS1receptor (D2R/NTS1R) heterodimers. The compounds of types 1–3 consist of three different D2R pharmacophores bound to an affinity-generating lipophilic appendage, a polyethylene glycol-based linker and the NTS1R agonist NT(8-13). The bivalent ligands show binding affinity in the picomolar range for cells coexpressing both GPCRs and unprecedented selectivity (up to three orders of magnitude), compared with cells that only express D2Rs. A functional switch is observed for the bivalent ligands 3b,c inhibiting cAMP formation in cells singly expressing D2Rs but stimulating cAMP accumulation in D2R/NTS1R-coexpressing cells. Moreover, the newly synthesized bivalent ligands show a strong, predominantly NTS1R-mediated β-arrestin-2 recruitment at the D2R/NTS1R-coexpressing cells.
Genetic variability in a frozen batch of MCF-7 cells invisible in routine authentication affecting cell function
Authors: Kleensang Andre , Vantangoli Marguerite M. , Odwin-DaCosta Shelly , Andersen Melvin E. , Boekelheide Kim , Bouhifd Mounir , Fornace Albert J. , Li Heng-Hong , Livi Carolina B. , Madnick Samantha , Maertens Alexandra , Rosenberg Michael , Yager James D. , Zhao Liang , Hartung Thomas
Published: July 2016

Common recommendations for cell line authentication, annotation and quality control fall short addressing genetic heterogeneity. Within the Human Toxome Project, we demonstrate that there can be marked cellular and phenotypic heterogeneity in a single batch of the human breast adenocarcinoma cell line MCF-7 obtained directly from a cell bank that are invisible with the usual cell authentication by short tandem repeat (STR) markers. STR profiling just fulfills the purpose of authentication testing, which is to detect significant cross-contamination and cell line misidentification. Heterogeneity needs to be examined using additional methods. This heterogeneity can have serious consequences for reproducibility of experiments as shown by morphology, estrogenic growth dose-response, whole genome gene expression and untargeted mass-spectroscopy metabolomics for MCF-7 cells. Using Comparative Genomic Hybridization (CGH), differences were traced back to genetic heterogeneity already in the cells from the original frozen vials from the same ATCC lot, however, STR markers did not differ from ATCC reference for any sample. These findings underscore the need for additional quality assurance in Good Cell Culture Practice and cell characterization, especially using other methods such as CGH to reveal possible genomic heterogeneity and genetic drifts within cell lines.
Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists
Authors: Mishra Rama K. , Shum Andrew K. , Platanias Leonidas C. , Miller Richard J. , Schiltz Gary E.
Published: July 2016

The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics.
Entanglement classification with matrix product states
Authors: Sanz M. , Egusquiza I. L. , Di Candia R. , Saberi H. , Lamata L. , Solano E.
Published: July 2016

We propose an entanglement classification for symmetric quantum states based on their diagonal matrix-product-state (MPS) representation. The proposed classification, which preserves the stochastic local operation assisted with classical communication (SLOCC) criterion, relates entanglement families to the interaction length of Hamiltonians. In this manner, we establish a connection between entanglement classification and condensed matter models from a quantum information perspective. Moreover, we introduce a scalable nesting property for the proposed entanglement classification, in which the families for N parties carry over to the N + 1 case. Finally, using techniques from algebraic geometry, we prove that the minimal nontrivial interaction length n for any symmetric state is bounded by "Equation missing".
Addition of lysophospholipids with large head groups to cells inhibits Shiga toxin binding
Authors: Ailte Ieva , Lingelem Anne Berit Dyve , Kavaliauskiene Simona , Bergan Jonas , Kvalvaag Audun Sverre , Myrann Anne-Grethe , Skotland Tore , Sandvig Kirsten
Published: July 2016

Shiga toxin (Stx), an AB5 toxin, binds specifically to the neutral glycosphingolipid Gb3 at the cell surface before being transported into cells. We here demonstrate that addition of conical lysophospholipids (LPLs) with large head groups inhibit Stx binding to cells whereas LPLs with small head groups do not. Lysophosphatidylinositol (LPI 18:0), the most efficient LPL with the largest head group, was selected for in-depth investigations to study how the binding of Stx is regulated. We show that the inhibition of Stx binding by LPI is reversible and possibly regulated by cholesterol since addition of methyl-β-cyclodextrin (mβCD) reversed the ability of LPI to inhibit binding. LPI-induced inhibition of Stx binding is independent of signalling and membrane turnover as it occurs in fixed cells as well as after depletion of cellular ATP. Furthermore, data obtained with fluorescent membrane dyes suggest that LPI treatment has a direct effect on plasma membrane lipid packing with shift towards a liquid disordered phase in the outer leaflet, while lysophosphoethanolamine (LPE), which has a small head group, does not. In conclusion, our data show that cellular treatment with conical LPLs with large head groups changes intrinsic properties of the plasma membrane and modulates Stx binding to Gb3.
Production of full-length soluble Plasmodium falciparum RH5 protein vaccine using a Drosophila melanogaster Schneider 2 stable cell line system
Authors: Hjerrild Kathryn A. , Jin Jing , Wright Katherine E. , Brown Rebecca E. , Marshall Jennifer M. , Labbé Geneviève M. , Silk Sarah E. , Cherry Catherine J. , Clemmensen Stine B. , Jørgensen Thomas , Illingworth Joseph J. , Alanine Daniel G. W. , Milne Kathryn H. , Ashfield Rebecca , de Jongh Willem A. , Douglas Alexander D. , Higgins Matthew K. , Draper Simon J.
Published: July 2016

The Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has recently emerged as a leading candidate antigen against the blood-stage human malaria parasite. However it has proved challenging to identify a heterologous expression platform that can produce a soluble protein-based vaccine in a manner compliant with current Good Manufacturing Practice (cGMP). Here we report the production of full-length PfRH5 protein using a cGMP-compliant platform called ExpreS2, based on a Drosophila melanogaster Schneider 2 (S2) stable cell line system. Five sequence variants of PfRH5 were expressed that differed in terms of mutagenesis strategies to remove potential N-linked glycans. All variants bound the PfRH5 receptor basigin and were recognized by a panel of monoclonal antibodies. Analysis following immunization of rabbits identified quantitative and qualitative differences in terms of the functional IgG antibody response against the P. falciparum parasite. The antibodies induced by one protein variant were shown to be qualitatively similar to responses induced by other vaccine platforms. This work identifies Drosophila S2 cells as a clinically-relevant platform suited for the production of ‘difficult-to-make’ proteins from Plasmodium parasites, and identifies a PfRH5 sequence variant that can be used for clinical production of a non-glycosylated, soluble full-length protein vaccine immunogen.
Do symptom-based questions help screen COPD among Chinese populations?
Authors: Zhang Qun , Wang Min , Li Xiaona , Wang Hong , Wang Jianming
Published: July 2016

Spirometry is required to confirm a chronic obstructive pulmonary disease (COPD) diagnosis, but it is difficult to perform in resource-limited settings. This study aimed to evaluate symptom-based questions for screening of individuals with COPD among Chinese populations. We recruited 3969 adult subjects from the First Affiliated Hospital of Nanjing Medical University. Spirometric measurements of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were collected to confirm the COPD diagnosis. A symptom-based questionnaire was administered to collect data related to COPD. The sensitivity and specificity together with the area under the curve (AUC) were calculated. The traditional IPAG eight-item questionnaire yielded an AUC of 0.80(95% CI: 0.78–0.82), with a sensitivity of 67.8% and specificity of 76.8%. After removing and adding questions, a revised eleven-item questionnaire exhibited a significantly increased diagnostic accuracy, with an AUC of 0.85(95% CI: 0.84–0.87). At the inflection point of the curve, it demonstrated a sensitivity of 82.5% and specificity of 72.9%. We showed that the revised symptom-based questionnaire could be used to screen individuals with a high likelihood of COPD among Chinese populations. Further validation is required before we claim it is a useful diagnostic for primary care populations.
Percutaneous Reduction and Fixation with Kirschner Wires versus Open Reduction Internal Fixation for the Management of Calcaneal Fractures: A Meta-Analysis
Authors: Wu Jianbin , Zhou Feiya , Yang Lei , Tan Jun
Published: July 2016

The aim of our meta-analysis was to compare outcomes for two surgical treatments of calcaneal fractures, percutaneous reduction and fixation with Kirschner wires (PRFK) and open reduction internal fixation (ORIF), with the intent of evaluating the quality of evidence to inform practice. Search of MEDLINE, Cochrane and CNKI databases to identify randomized controlled trials (RCTs) comparing PRKF and ORIF on the following outcomes: post-operative function, complications and quality of the reduction. Odd ratios (OR) and weighted mean differences were pooled using either a fixed-effects or random-effects model, depending on the heterogeneity of the trials included in the analysis. Eighteen RCTs provided the data from 1407 patients. PRFK was associated with a lower risk of surgical wound complications and ORIF with better post-operative function, angle of Gissane, calcaneal height and calcaneal width. There were no statistically significant differences between the techniques with regards to post-operative Böhler’s angle. PRFK does not provide a substantive advantage over ORIF for the treatment of calcaneal fractures in adults. PRFK may, however, yield comparable functional outcomes to ORIF for closed Sanders type II calcaneal fractures but with less complication related to surgical wound healing.
Generation of femtosecond γ-ray bursts stimulated by laser-driven hosing evolution
Authors: Ma Yong , Chen Liming , Li Dazhang , Yan Wenchao , Huang Kai , Chen Min , Sheng Zhengming , Nakajima Kazuhisa , Tajima Toshiki , Zhang Jie
Published: July 2016

The promising ability of a plasma wiggler based on laser wakefield acceleration to produce betatron X-rays with photon energies of a few keV to hundreds of keV and a peak brilliance of 1022–1023 photons/s/mm2/mrad2/0.1%BW has been demonstrated, providing an alternative to large-scale synchrotron light sources. Most methods for generating betatron radiation are based on two typical approaches, one relying on an inherent transverse focusing electrostatic field, which induces transverse oscillation, and the other relying on the electron beam catching up with the rear part of the laser pulse, which results in strong electron resonance. Here, we present a new regime of betatron γ-ray radiation generated by stimulating a large-amplitude transverse oscillation of a continuously injected electron bunch through the hosing of the bubble induced by the carrier envelope phase (CEP) effect of the self-steepened laser pulse. Our method increases the critical photon energy to the MeV level, according to the results of particle-in-cell (PIC) simulations. The highly collimated, energetic and femtosecond γ-ray bursts that are produced in this way may provide an interesting potential means of exploring nuclear physics in table top photo nuclear reactions.
The effect of counteranions on the molecular structures of phosphanegold(i) cluster cations formed by polyoxometalate (POM)-mediated clusterization
Authors: Nagashima Eri , Yoshida Takuya , Matsunaga Satoshi , Nomiya Kenji
Published: July 2016

In intercluster compounds composed of phosphanegold(i) cluster cations and polyoxometalate (POM) anions, the POM anions were successfully exchanged with smaller anions such as PF6− and OTf−.
Chelating bis-N-heterocyclic carbene complexes of iron(ii) containing bipyridyl ligands as catalyst precursors for oxidation of alcohols
Authors: Pinto Mara F. , Cardoso Bernardo de P. , Barroso Sónia , Martins Ana M. , Royo Beatriz
Published: July 2016

Chelating bis-N-heterocyclic carbene (bis-NHC) complexes of iron(ii) containing pyridyl ligands have been prepared by the reaction of [FeCl2L] [L = bipy (1), phen (2)] with [LiN(SiMe3)2] and a bis(imidazolium) salt.
Visible-light initiated direct oxysulfonylation of alkenes with sulfinic acids leading to β-ketosulfones
Authors: Yang Daoshan , Huang Ben , Wei Wei , Li Jin , Lin Gu , Liu Yaru , Ding Jiehua , Sun Pengfei , Wang Hua
Published: July 2016

Highly efficient visible-light initiated direct oxysulfonylation of alkenes with sulfinic acids leading to β-ketosulfones has been realized under metal-free conditions.
Diffusion-ordered spectroscopy NMR DOSY: an all-in-one tool to simultaneously follow side reactions, livingness and molar masses of polymethylmethacrylate by nitroxide mediated polymerization
Authors: Cherifi N. , Khoukh A. , Benaboura A. , Billon L.
Published: July 2016

From diffusion coefficients measurement by NMR DOSY, weight average molar masses Mw, non-reversible termination or livingness of the PMMA chains were simultaneously followed.
Equilibrium acidities of BINOL type chiral phenolic hydrogen bonding donors in DMSO
Authors: Ni Xiang , Li Xin , Li Zhen , Cheng Jin-Pei
Published: July 2016

The pKavalues of fifteen BINOL type chiral phenolic catalysts were determined by the overlapping indicator method in DMSOviaUV spectrophotometric titrations. The pKavalues are in the range of 9.30–16.43.
Fluorescent periodic mesoporous organosilica nanoparticles dual-functionalized via click chemistry for two-photon photodynamic therapy in cells
Authors: Croissant Jonas G. , Picard Sébastien , Aggad Dina , Klausen Maxime , Mauriello Jimenez Chiara , Maynadier Marie , Mongin Olivier , Clermont Guillaume , Genin Emilie , Cattoën Xavier , Wong Chi Man Michel , Raehm Laurence , Garcia Marcel , Gary-Bobo Magali , Blanchard-Desce Mireille , Durand Jean-Olivier
Published: July 2016

The synthesis of ethenylene-based periodic mesoporous organosilica nanoparticles for two-photon imaging and photodynamic therapy of breast cancer cells is described.
Understanding misfit strain releasing mechanisms via molecular dynamics simulations of CdTe growth on {112}zinc-blende CdS
Authors: Zhou X. W. , Chavez J. J. , Almeida S. , Zubia D.
Published: July 2016

Molecular dynamics simulations have been used to analyse microstructures of CdTe films grown on {112} surfaces of zinc-blende CdS. Interestingly, CdTe films grow in ⟨331⟩ orientations as opposed to ⟨112⟩ epitaxial orientations. At the CdTe-{331}/CdS-{112} interface, however, there exists an axis that is parallel to the ⟨110⟩ orientation of both CdS and CdTe. It is the direction orthogonal to this ⟨110⟩ that becomes different, being ⟨116⟩ for CdTe and ⟨111⟩ for CdS, respectively. Missing CdTe-{110} planes are found along the ⟨110⟩ axis, suggesting that the misfit strain is released by the conventional misfit dislocation mechanism along this axis. In the orthogonal axis, the misfit strain is found to be more effectively released by the new grain orientation mechanism. Our finding is supported by literature experimental observations of the change of growth direction when Cd0.96Zn0.04Te films are deposited on GaAs. Analyses of energetics clearly demonstrate the cause for the formation of the new orientation, and the insights gained from our studies can help understand the grain structures experimentally observed in lattice mismatched systems.