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International audience; Spin-polarized charge transfer at the interface between a ferromagnetic (FM)metal and a molecule can lead to ferromagnetic coupling and to a high spinpolarization at room temperature. The magnetic properties of these interfacescan not only alter those of the ferromagnet but can also stabilize molecularspin chains with interesting opportunities toward quantum computing. Withthe aim to enhance an organic spintronic device’s functionality, external controlover this spin polarization may thus be achieved by altering the ferromagnet/molecule interface’s magnetic properties. To do so, the magnetoelectricproperties of an underlying ferroelectric/ferromagnetic interface are utilized.Switching the ferroelectric polarization state of a PbZr0.2Ti0.8O3 (PZT) bottomlayer within a PZT/Co/FePc-based (Pc - phthalocyanine) device alters the X-raymagnetic circular dichroism of the Fe site within the phthalocyanine moleculartop layer. Thus, how to electrically alter the magnetic properties of an interfacewith high spin polarization at room temperature is demonstrated. Thisexpands electrical control over spin-polarized FM/molecule interfaces, which isfirst demonstrated using ferroelectric molecules, to all molecular classes.

Background To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. Methods We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. Results Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. Conclusions Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans.

Neuropathic pain affects multiple brain functions, including motivational processing. However, little is known about the structural and functional brain changes involved in the transition from an acute to a chronic pain state. Here we combined behavioral phenotyping of pain thresholds with multimodal neuroimaging to longitudinally monitor changes in brain metabolism, structure and connectivity using the spared nerve injury (SNI) mouse model of chronic neuropathic pain. We investigated stimulus-evoked pain responses prior to SNI surgery, and one and twelve weeks following surgery. A progressive development and potentiation of stimulus-evoked pain responses (cold and mechanical allodynia) were detected during the course of pain chronification. Voxel-based morphometry demonstrated striking decreases in volume following pain induction in all brain sites assessed - an effect that reversed over time. Similarly, all global and local network changes that occurred following pain induction disappeared over time, with two notable exceptions: the nucleus accumbens, which played a more dominant role in the global network in a chronic pain state and the prefrontal cortex and hippocampus, which showed lower connectivity. These changes in connectivity were accompanied by enhanced glutamate levels in the hippocampus, but not in the prefrontal cortex. We suggest that hippocampal hyperexcitability may contribute to alterations in synaptic plasticity within the nucleus accumbens, and to pain chronification.

Purpose: The main purpose of this study was to assess the reliability of shape and heterogeneity features in both Positron Emission Tomography (PET) and low-dose Computed Tomography (CT) components of PET/CT. A secondary objective was to investigate the impact of image quantization. Material and methods: A Health Insurance Portability and Accountability Act -compliant secondary analysis of deidentified prospectively acquired PET/CT test-retest datasets of 74 patients from multi-center Merck and ACRIN trials was performed. Metabolically active volumes were automatically delineated on PET with Fuzzy Locally Adaptive Bayesian algorithm. 3DSlicerTM was used to semi-automatically delineate the anatomical volumes on low-dose CT components. Two quantization methods were considered: a quantization into a set number of bins (quantizationB) and an alternative quantization with bins of fixed width (quantizationW). Four shape descriptors, ten first-order metrics and 26 textural features were computed. Bland-Altman analysis was used to quantify repeatability. Features were subsequently categorized as very reliable, reliable, moderately reliable and poorly reliable with respect to the corresponding volume variability. Results: Repeatability was highly variable amongst features. Numerous metrics were identified as poorly or moderately reliable. Others were (very) reliable in both modalities, and in all categories (shape, 1st-, 2nd- and 3rd-order metrics). Image quantization played a major role in the features repeatability. Features were more reliable in PET with quantizationB, whereas quantizationW showed better results in CT. Conclusion: The test-retest repeatability of shape and heterogeneity features in PET and low-dose CT varied greatly amongst metrics. The level of repeatability also depended strongly on the quantization step, with different optimal choices for each modality. The repeatability of PET and low-dose CT features should be carefully taken into account when selecting metrics to build multiparametric models.

A novel symmetrical selenium-based reversible addition-fragmentation chain transfer (RAFT) agent, Se,Se’-dibenzyl carbonodiselenothioate (Se-RAFT), is synthesized and used in the RAFT polymerization of styrene. The results obtained show that the Se-RAFT agent is involved in the polymerization of styrene, as evidenced by narrow molar-mass distributions (M¯w/M¯n < 1.6) and the incorporation of the Se-RAFT moiety into the resultant polymer. The latter is confirmed by aminolysis, NMR spectroscopy, size-exclusion chromatography (SEC) and UV spectroscopy. This work provides detailed insight into the Se-RAFT polymerization mechanism. The Se-RAFT agent is unique in that the stabilizing and leaving groups are identical.

Accurate visualization and quantification of β-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including (64)Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent (64)Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 μCi/μg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (

MRI and MRS in small rodents demand very high sensitivity. Cryogenic transmit/receive radiofrequency probes (CryoProbes) designed for (1) H MRI of mouse brain provide an attractive option for increasing the performance of small-animal MR systems. As the Larmor frequency of (13) C nuclei is four times lower than that for (1) H nuclei, an even larger sensitivity improvement is expected for (13) C applications. The aim of this work was to evaluate the performance of a prototype (13) C CryoProbe™ for mouse brain MRS. To investigate the possible gain of the (13) C CryoProbe™, we acquired localized single-voxel (13) C spectra and chemical shift images of a dimethyl sulfoxide phantom with the CryoProbe™, as well as with two room temperature resonators. The cryogenically cooled resonator achieved approximately four-fold higher signal-to-noise ratio in phantom tests when compared with the best-performing room temperature coil. In addition, we present localized (13) C spectra of mouse brain obtained with the CryoProbe™, as well as with one of the room temperature coils, demonstrating the performance in vivo. In summary, the cryogenic cooling technique significantly enhances the (13) C signal sensitivity at 9.4 T and enables the investigation of metabolism within mouse brain.

In this contribution the eigenfrequencies of a special linear vibration system are investigated. Based on the properties of the corresponding mass and stiffness matrices of the chain structured mass-spring vibration system with arbitrary n degrees of freedom an algebraic proof for the determination of the eigenfrequencies is given.

Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the function and specificity of the brain circuits involved. To investigate disease-related alterations of brain function we used a genetic animal model of TRD, congenital learned helplessness (cLH), and functional magnetic resonance imaging as a translational tool. High-resolution regional cerebral blood volume (rCBV) and resting-state functional connectivity measurements were acquired at 9.4T to determine regional dysfunction and interactions that could serve as vulnerability markers for TRD. Effects of cLH on rCBV were determined by statistical parametric mapping using 35 atlas-based regions of interest. Effects of cLH on functional connectivity were assessed by seed region analyses. Significant bilateral rCBV reductions were observed in the lateral habenula, dentate gyrus and subiculum of cLH rats. In contrast, focal bilateral increase in rCBV was observed in the bed nucleus of stria terminalis (BNST), a component of the habenular neurocircuitry. Functional connectivity was primarily enhanced in cLH rats, most notably with respect to serotonergic projections from the dorsal raphe nucleus to the forebrain, within the hippocampal-prefrontal network and between the BNST and lateral frontal regions. Dysregulation of neurocircuitry similar to that observed in depressed patients was detected in cLH rats, supporting the validity of the TRD model and suitability of high-field fMRI as a translational technology to detect and monitor vulnerability markers. Our findings also define neurocircuits that can be studied for TRD treatment in patients, and could be employed for translational research in rodent models.

The utilization of magnetic resonance imaging (MRI) methods in rodent models of psychiatric disorders provides considerable benefits for the identification of disease-associated brain circuits and metabolic changes. In this review, we discuss advantages and challenges of animal MRI and provide an overview of the major structural (voxel-based morphometry and diffusion tensor imaging) and functional approaches [resting-state functional MRI (rs-fMRI), MR spectroscopy (MRS), regional cerebral blood volume measurement and arterial spin labelling] that are applied in animal MRI research. The review mainly focuses on rs-fMRI and MRS. Finally, we take a look at some recent developments and refinements in the field.

Background The treatment of mCRPC is a major medical challenge. The beta-emitting Lu-177-PSMA radioligand therapy (RLT) is a new option but its antitumor effect can decrease over time. The aim of this retrospective analysis was to investigate safety and efficacy of the alpha emitting Ac-225-PSMA-617 RLT in mCRPC after Lu-177-PSMA failure. Methods At data analysis 03/19 18 patients (pts) underwent Ac-225-PSMA-617 RLT between 10/17 and 12/18. All pts had previously received second line antihormonal treatment and 17/18 pts taxane based chemotherapy. All pts had shown progression after Lu-177-PSMA therapy (median 2 cycles). High PSMA-expression of the tumor lesions in PSMA-PET/CT before Ac-225-PSMA-617 was mandatory. Pts were treated at 8 weekly intervals until progression or intolerable side effects. Prostate-specific antigen (PSA) and blood cell count were measured every 2-3 weeks. We report updated data of hematological and non-hematological side effects, biochemical response and a subgroupanalysis. Results A total of 36 cycles of Ac-225-PSMA-617 (median dose 8 MBq, range 4,4–12.8) were applied. 7 pts received only 1 cycle, 5 pts 2 cycles, 5 pts 3 cycles and 1 patient 4 cycles. Baseline PSA was 822 ng/ml (range 49–4073). ECOG score was grade 0, 1 and 2 in 3, 13 and 2 pts. 15/18 pts showed any PSA-decline, 5/18 a PSA-decline of more than 50% and 3 pts no PSA-decline at any time. 6 weeks after treatment 12/18 showed any PSA decline and 4/18 a PSA-decline of > 50%. Grade 1 xerostomia occurred in 17 and grade 2 in 1 patient. 6/18 pts (33%) requested to stop treatment due to xerostomia. 2 pts developed grade 2 renal insufficiency, 5 pts grade 3-4 anemia, 2 pts grade 3-4 thrombocytopenia and 2 pts 3-4 leucopenia. 7/18 pts died during the observation period (median overall survival 9,6 months). The PSA-progression free survival was 1,3 months. In a subgroupanalysis of 9 pts with a rapid progression under a previous Lu-177-PSMA treatment 7 pts achieved any PSA-decline and 4 pts a decline of more than 50%. Conclusions In this small cohort Ac-225-PSMA-617 RLT showed antitumor effect in mCRPC after Lu-177-PSMA failure even after rapid tumour progression. However, treatment had to be stopped in one third of the pts due to xerostomia. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

INTRODUCTION AND OBJECTIVES:While 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being used for restaging patients with suspected biochemical recurrence (BCR) ...

Previously reported MRS findings in the aging brain include lower N-acetylaspartate (NAA) and higher myo-inositol (mI), total creatine (Cr) and choline-containing compound (Cho) concentrations. Alterations in the sodium channel voltage gated type I, alpha subunit SCN1A variant rs10930201 have been reported to be associated with several neurological disorders with cognitive deficits. MRS studies in SCN1A-related diseases have reported striking differences in the mI concentrations between patients and controls. In a study on ‘healthy aging’, we investigated metabolite spectra in a sample of 83 healthy volunteers and determined their age dependence. We also investigated a potential link between SCN1A and mI. We observed a significantly negative association of NAA (p = 0.004) and significantly positive associations of mI (p ≤ 0.001), Cr (p ≤ 0.001) and Cho (p = 0.034) with age in frontal white matter. The linear association of Cho ends at the age of about 50 years and is followed by an inverted ‘U’-shaped curve. Further, mI was higher in C allele carriers of the SCN1A variant rs10930201. Our results corroborated the age-related changes in metabolite concentrations, and found evidence for a link between SCN1A and frontal white matter mI in healthy subjects. Copyright © 2013 John Wiley & Sons, Ltd.

This contribution deals with the identification of the right-eigenvectors of a linear vibration system with arbitrary n degrees of freedom as given in [1]. Applying the special distribution of stiffnesses and masses given in [1] yields a remarkable sequence of matrices for arbi- trary n. For computing the (right-)eigenvectors a generalised approach allowing the use of Laguerre polynomials is performed.

Phospholipid (PL) metabolism is investigated by in vivo 31P magnetic resonance spectroscopy (MRS). Inconsistent alterations of phosphocholine (PC), phosphoethanolamine (PE), glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) have been described in schizophrenia, which might be overcome by specific editing techniques. The selective refocused insensitive nuclei-enhanced polarization transfer (RINEPT) technique was applied in a cross-sectional study involving 11 schizophrenia spectrum disorder patients (SZP) on stable antipsychotic monotherapy and 15 matched control subjects. Metabolite signals were found to be modulated by cerebrospinal fluid (CSF) content and gray matter/brain matter ratio. Corrected metabolite concentrations of PC, GPC and PE differed between patients and controls in both subcortical and cortical regions, whereas antipsychotic medication exerted only small effects. Significant correlations were found between the severity of clinical symptoms and the assessed signals. In particular, psychotic symptoms correlated with PC levels in the cerebral cortex, depression with PC levels in the cerebellum and executive functioning with GPC in the insular and temporal cortices. In conclusion, after controlling for age and tissue composition, this investigation revealed alterations of metabolite levels in SZP and correlations with clinical properties. RINEPT 31P MRS should also be applied to at-risk-mental-state patients as well as drug-naïve and chronically treated schizophrenic patients in order to enhance the understanding of longitudinal alterations of PL metabolism in schizophrenia.

Recently, a larger hippocampus was found in exercising mice and men. Here we studied the morphological underpinnings in wheel running mice by longitudinal magnetic resonance imaging. Voxel-based morphometry revealed that running increases hippocampal volume by inhibiting an early age-related gray matter loss. Disruption of neurogenesis-related neuroplasticity by focalized irradiation is sufficient to block positive effects of exercise on macroscopic brain morphology.

Amyloid-b (Ab) deposition is a pathologic hallmark of Alzheimer disease (AD). Although the typical spatial distribution pattern of Ab deposition in early AD mainly involves regions distant from the hippocampus, the predominant clinical feature is impairment of hippocampusdependent memory. We aimed at elucidating the relationship between neocortical Ab load, regional neuronal function, and memory impairment. Methods: Thirty patients with early AD underwent combined 11 C-Pittsburgh compound B ( 11 C-PIB) and 18 F-FDG PET and memory assessments. Composite measures of hemispheric Ab load were calculated by volume-weighted mean values of neocortical 11 C-PIB binding. Voxelwise 18 F-FDG uptake was used as a measure of regional glucose metabolism reflecting neuronal activity. We investigated the relationship between left- and right-hemispheric Ab load and regional glucose metabolism (voxelwise analyses). In addition, we assessed the correlations of hemispheric Ab load (region-ofinterest–based analyses) and regional glucose metabolism (voxelwise analysis) with memory performance. Analyses were corrected for age and sex. Results: Higher Ab load in the left hemisphere was associated with reduced glucose metabolism of the left medial temporal lobe (MTL; r 2 5 0.38) and correlated with worse wordlist recall (r 52 0.37; partial correlation controlled for sex and age). Furthermore, wordlist recall correlated with regional glucose metabolism in the bilateral MTL and precuneus–posterior cingulate cortex and right lingual gyrus (r2 5 0.24). Conclusion: We demonstrated an association between the left-hemispheric Ab load and impairment of the left MTL in AD at 2 different levels: regional hypometabolism and verbal memory. This correlation suggests that neocortical amyloid deposition is connected to or even drives neuronal dysfunction and neurodegeneration of the MTL, which is associated with impaired episodic memory processing as a clinical core symptom of AD.

Dopamine D 2 receptor antagonists effectively reduce positive symptoms in schizophrenia, implicating abnormal dopaminergic neurotransmission as an underlying mechanism of psychosis. Despite the well-established, albeit incomplete, clinical efficacies of D 2 antagonists, no studies have examined their effects on functional interaction between brain regions. We hypothesized that haloperidol, a widely used antipsychotic and D 2 antagonist, would modulate functional connectivity in dopaminergic circuits. Ten male Sprague-Dawley rats received either haloperidol (1 mg/kg, s.c.) or the same volume of saline a week apart. Resting-state functional magnetic resonance imaging data were acquired 20 min after injection. Connectivity analyses were performed using two complementary approaches: correlation analysis between 44 atlas-derived regions of interest, and seed-based connectivity mapping. In the presence of haloperidol, reduced correlation was observed between the substantia nigra and several brain regions, notably the cingulate and prefrontal cortices, posterodorsal hippocampus, ventral pallidum, and motor cortex. Haloperidol induced focal changes in functional connectivity were found to be the most strongly associated with ascending dopamine projections. These included reduced connectivity between the midbrain and the medial prefrontal cortex and hippocampus, possibly relating to its therapeutic action, and decreased coupling between substantia nigra and motor areas, which may reflect dyskinetic effects. These data may help in further characterizing the functional circuits modulated by antipsychotics that could be targeted by innovative drug treatments.

In humans, resting-state blood oxygen level-dependent (BOLD) signals in the default mode network (DMN) are temporally anti-correlated with those from a lateral cortical network involving the frontal eye fields, secondary somatosensory and posterior insular cortices. Here, we demonstrate the existence of an analogous lateral cortical network in the rat brain, extending laterally from anterior secondary sensorimotor regions to the insular cortex and exhibiting low-frequency BOLD fluctuations that are temporally anti-correlated with a midline "DMN-like" network comprising posterior/anterior cingulate and prefrontal cortices. The primary nexus for this anti-correlation relationship was the anterior secondary motor cortex, close to regions that have been identified with frontal eye fields in the rat brain. The anti-correlation relationship was corroborated after global signal removal, underscoring this finding as a robust property of the functional connectivity signature in the rat brain. These anti-correlated networks demonstrate strong anatomical homology to networks identified in human and monkey connectivity studies, extend the known preserved functional connectivity relationships between rodent and primates, and support the use of resting-state functional magnetic resonance imaging as a translational imaging method between rat models and humans.

Die Schutzwirkung von bewehrten Feinbetonpaneelen bei dynamischen Einwirkungen bereits im Bemessungsprozess ausreichend genau einzuschatzen, ist eine Aufgabe von hoher Bedeutung und Aktualitat. Ziel dieses Beitrages ist die analytische Beschreibung der Wellenausbreitung in einem solchen Bauteil, welches mit Stahlfasergelegen verstarkt ist. Das analytische Modell kann entsprechende experimentelle Untersuchungen begleiten und daruber hinaus an numerische Methoden gekoppelt werden. Es ist damit geeignet, die (Weiter-)Entwicklung von Regelwerken zur Bemessung von Feinbetonpaneelen unter stosartigen Einwirkungen aktiv zu begleiten. In einem ersten Schritt der Modellbildung erfolgt eine Beschrankung auf die Behandlung von Scherwellen. Ausgangspunkt ist ein mechanisches Modell, welches die einzelnen Bewehrungselemente einschlieslich des Ubergangsbereichs zur homogenen Feinbetonmatrix separat abbildet. Die hierdurch entstehenden Differentialgleichungen werden anschliesend analytisch gelost. Den im Bauwesen inharenten Abweichungen vom geplanten Soll-Zustand wird beispielhaft dadurch Rechnung getragen, dass die Dicke dieses Ubergangsbereichs als Zufallsgrose modelliert wird. Die sich hierdurch ergebenden Auswirkungen auf die Wellenausbreitung werden anschliesend aufgezeigt und bewertet. Wave propagation within panels made of FRC Properly estimating the protective effect of slender walls made of fine-grained concrete under dynamic loading is a major task in civil engineering. The aim of this contribution is to analytically describe the wave propagation in such a structural element reinforced with steel fibres. The analytical model may be an addendum to experimental studies and can be coupled to numerical methods. In a first step of modelling shear waves are dealt with. Within the mechanical model every reinforcement element is treated as a single inclusion surrounded by a so-called interphase embedded in a homogeneous matrix of fine-grained concrete. The differential equations resulting from this mechanical model are then solved analytically. In civil engineering praxis structural elements produced on-site regularly differ from the intended configuration. These deviances are exemplarily taken into account by modelling the thicknesses of the interphases surrounding the reinforcement elements as random variables. The consequences of this consideration to the wave propagation are presented and evaluated.

PurposeThe purpose of this paper is to analyze the wave scattering behaviour of an inhomogeneous and eccentric inclusion in a homogeneous matrix material. Another purpose is to evaluate the influence of epistemic uncertainty on the wave scattering behaviour, particularly on the lack of knowledge about this eccentricity. This task calls for a multidisciplinary model.Design/methodology/approachThe inclusion is modelled as a multi‐layered obstacle, with all layers being eccentric with respect to each other. The material behaviour of the embedding matrix is linear elastic and isotropic. In a multidisciplinary approach, the interaction of the inhomogeneous inclusion and the embedding matrix with respect to an incoming shear wave of arbitrary shape is solved analytically. The purely analytical solution process takes place in the frequency‐domain. Due to the lack of knowledge about the eccentric configuration of the matrix inclusion and its influence on the total wave field inside the matrix material, the mechanical model is coupled with fuzzy set theory for modelling this non‐stochastic uncertainty.FindingsAn analytical model for describing the wave scattering behaviour of an elastic matrix inclusion with eccentric set‐up is found and intimately connected with the framework of fuzzy set theory. Hence it is shown that the treatment of epistemic uncertainty with the derived analytical model is possible and fruitful. Additionally, it is shown that eccentric configurations lead to highly increased amplitudes with respect to the reference case of a concentric or even homogenous set‐up of the inclusion.Originality/valueThe value of this contribution is in the analytical model, which allows one to predict the wave scattering behaviour of eccentric configurations of multi‐layered fibres including the surrounding interphase, and its coupling with fuzzy set theory to cope with the epistemic uncertainty inherent in the geometric set‐up of the matrix inclusion.

Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvβ3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.

Hintergrund Neuroendokrine Tumoren konne in fast allen Geweben und Organen des Korpers entstehen. Dieser Beitrag fokussiert auf neuroendokrine Neoplasien des Verdauungstrakts und des Pankreas, sog. gastroenteropankreatische neuroendokrine Tumoren (GEP-NET).

The synthesis of 2,2,4,4-tetrathio substituted 1,3-dithietanes and their intermediates by reaction of thiophosgene with carbonotrithioates or O-ethyldithiocarbonate is reported. Their reactivity against thermolysis and aminolysis was investigated.

Interactions between the hippocampus and the prefrontal cortex (PFC) are of major interest in the neurobiology of psychiatric and neurodegenerative disorders and are central to many experimental rodent models. Non-invasive imaging techniques offer a translatable approach to probing this system if homologous features can be identified across species. The objective of the present study was to systematically characterize the rat brain connectivity signature derived from low-frequency resting blood oxygenation level-dependent (BOLD) oscillations associated with and within the hippocampal–prefrontal network, using an array of small seed locations within the relatively large anatomical structures comprising this system. A heterogeneous structure of functional connectivity, both between and within the hippocampal–prefrontal brain structures, was observed. In the hippocampal formation, the posterior (subiculum) region correlated more strongly than the anterior dorsal hippocampus with the PFC. A homologous relationship was found in the human hippocampus, with differential functional connectivity between hippocampal locations proximal to the fornix body relative to locations more distal being localized to the medial prefrontal regions in both species. The orbitofrontal cortex correlated more strongly with sensory cortices and a heterogeneous dependence of functional coupling on seed location was observed along the midline cingulate and retrosplenial cortices. These findings are all convergent with known anatomical connectivity, with stronger BOLD correlations corresponding to known monosynaptic connections. These functional connectivity relationships may provide a useful translatable probe of the hippocampal–prefrontal system for the further study of rodent models of disease and potential treatments, and inform electrode placement in electrophysiology to yield more precise descriptors of the circuits at risk in psychiatric disease.

CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses (19) F-bearing fragments as (18) F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.

We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease.A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C-choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography-computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression.Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years.Based on (11)C/(18)F-choline positron emission tomography-computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response.

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS) in the long-term. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating early effects of a cafeteria-diet on gray and white brain matter volume by means of voxel-based morphometry (VBM) and region-of-interest (ROI) analysis. Half of the mice performed voluntary wheel running to study if regular physical exercise prevents unfavorable effects of a cafeteria-diet. In addition, histological analyses for myelination and neurogenesis were performed. As expected, wheel running resulted in a significant increase of gray matter volume in the CA1-3 areas, the dentate gyrus and stratum granulosum of the hippocampus in the VBM analysis, while a positive effect of the cafeteria-diet was shown for the whole hippocampal CA1-3 area only in the ROI analysis, indicating a regional volume effect. It was earlier found that hippocampal neurogenesis may be related to volume increases after exercise. Interestingly, while running resulted in a significant increase in neurogenesis assessed by doublecortin (DCX)-labeling, this was not true for cafeteria diet. This indicates different underlying mechanisms for gray matter increase. Moreover, animals receiving cafeteria diet only showed mild deficits in long-term memory assessed by the puzzle-box paradigm, while executive functioning and short term memory were not affected. Our data therefore highlight that high caloric diet impacts on the brain and behavior. Physical exercise seems not to interact with these mechanisms.

Spin-polarized charge transfer between a ferromagnet and a molecule can promote molecular ferromagnetism 1, 2 and hybridized interfacial states3, 4. Observations of high spin-polarization of Fermi level states at room temperature5 designate such interfaces as a very promising candidate toward achieving a highly spin-polarized, nanoscale current source at room temperature, when compared to other solutions such as half-metallic systems and solid-state tunnelling over the past decades. We will discuss three aspects of this research. 1) Does the ferromagnet/molecule interface, also called an organic spinterface, exhibit this high spin-polarization as a generic feature? Spin-polarized photoemission experiments reveal that a high spin-polarization of electronics states at the Fermi level also exist at the simple interface between ferromagnetic cobalt and amorphous carbon6. Furthermore, this effect is general to an array of ferromagnetic and molecular candidates7. 2) Integrating molecules with intrinsic properties (e.g. spin crossover molecules) into a spinterface toward enhanced functionality requires lowering the charge transfer onto the molecule8 while magnetizing it1,2. We propose to achieve this by utilizing interlayer exchange coupling within a more advanced organic spinterface architecture. We present results at room temperature across the fcc Co(001)/Cu/manganese phthalocyanine (MnPc) system9. 3) Finally, we discuss how the Co/MnPc spinterface’s ferromagnetism stabilizes antiferromagnetic ordering at room temperature onto subsequent molecules away from the spinterface, which in turn can exchange bias the Co layer at low temperature10. Consequences include tunnelling anisotropic magnetoresistance across a CoPc tunnel barrier11. This augurs new possibilities to transmit spin information across organic semiconductors using spin flip excitations12.

Background Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats. Methods Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence. Results In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model. Conclusions Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity.

Due to the lack of causative immunotherapies, individuals with food allergies have to rely on correct labelling for even minute amounts of allergenic constituents. It is not relevant to the allergic whether the source of the culprit food is an ingredient or an allergen that entered the food unintentionally, as is the case with so-called cross-contacts or hidden allergens.Efficient allergen management is the manufacturer's prerequisite for coping with allergenic foods in the food production environment and handling them in a way that avoids cross-contact. If it is technically not feasible to eliminate cross-contacts entirely, it must be ensured that these cross-contacts do not enter the final product without being detected.This article discusses measures that should be considered in allergen management. Examples include recording all relevant allergens in the production facility, staff sensitization and training, and taking into account all areas of production from incoming raw materials to outgoing goods.For the evaluation of unavoidable cross-contacts, it is possible today to draw on data from clinical trials for many of the substances that are subject to labelling. This data can be used to assess the risk of the final product.However, the data from threshold studies is not legally binding, so it is left to the manufacturer to assess the level up to which the food is safe for the allergic. In particular the non-harmonized approach of the EU member countries' food safety authorities currently represents a major obstacle, as this can lead to food recalls even though existing levels were evaluated as being safe according to the risk assessments performed.

In this paper a pragmatic method is presented, how the parameters of the dynamics of an industrial robot can be determined. This method can be easily automated and can be applied to a broad class of industrial robots. The parameters of the dynamics of the single links or arm parts, such as the mass, the coordinates of the center of gravity and the inertia matrix are not identified separately here. The parameters are determined in combination. The identified model is sufficient for different control schemes. The results achieved here are appropriate and were confirmed by simulations with Matlab and tested on the industrial robot TX60L of the company Staubli. The equations of the dynamics are mainly influenced by the first three axes. Though the identification of the parameters for these axes is preferred. In comparison to the common used least squares methods this pragmatic method can be applied in an automatic way. The identification process is very fast. An application of the pragmatic method to more industrial robots with articulated structure should not pose the biggest hurdle, but the availability of similar interfaces like LLI (Low Level Interface) is a prerequisite. The interfaces should allow at least the access to the actuating torques, the joint positions and the joint velocities.

The fundamental requirement when testing for and ensuring compliance with legally required labelling regulations is the reliable analysis of food allergens. This can be carried out by means of either DNA (deoxyribonucleic acid) or protein detection. Protein detection has the advantage of directly detecting the allergenic component and can currently be carried out using immunological (enzyme-linked immunosorbent assay [ELISA])/lateral flow devices [LFD]) or mass spectrometry-based techniques. DNA detection is indirect, but allows the presence of food allergens to be validated through the use of another marker. Each method has its pros and cons, which have to be considered on a case-by-case basis. ELISA is quantitative, quick and easy to carry out and has high sensitivity. LFD testing is ideal for industrial applications, as the tests can be carried out on-site. Both antibody-based tests may have problems with processed foods and false positive results. Mass-spectrometric techniques show a lot of promise, but are currently still time-consuming and complex to carry out. They also run into problems with processed foods and their degree of sensitivity is matrix and parameter dependent. For these reasons, this technique is only occasionally used. Polymerase chain reaction (PCR) provides the highest specificity and, depending on the target sequence, a very good to good level of sensitivity. Despite the high stability of DNA, PCR is still subject to the influence of processing and matrix related factors. Due to natural variation and production-related changes in the structures relevant in the process of detection, all methods exhibit a relatively high level of uncertainty of measurement. At present, there is no method which provides the absolute correct quantification. However, by means of laboratory-based analyses it is possible to calibrate for the allergen in question and thus be able to make reliable measurements using methods that are already available.

International audience; A breakdown of the spin dependence of the electron reflection due to organic molecules or amorphous carbon deposited onto a metallic film has been observed in the past. The goal of the present work is to further elucidate the physics of this phenomenon by studying it in ways not yet studied in the past. The most intriguing observation of the present study is that the breakdown phenomenon appears in a relatively well defined electron energy range between 2 and about 200 eV kinetic energy. Outside this energy range the breakdown phenomenon is not observed. However, an explanation of the breakdown phenomenon is still missing.

Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1H-MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice.

Semiempirical orthogonalization-corrected methods (OM1, OM2, and OM3) go beyond the standard MNDO model by explicitly including additional interactions into the Fock matrix in an approximate manner (Pauli repulsion, penetration effects, and core–valence interactions), which yields systematic improvements both for ground-state and excited-state properties. In this Article, we describe the underlying theoretical formalism of the OMx methods and their implementation in full detail, and we report all relevant OMx parameters for hydrogen, carbon, nitrogen, oxygen, and fluorine. For a standard set of mostly organic molecules commonly used in semiempirical method development, the OMx results are found to be superior to those from standard MNDO-type methods. Parametrized Grimme-type dispersion corrections can be added to OM2 and OM3 energies to provide a realistic treatment of noncovalent interaction energies, as demonstrated for the complexes in the S22 and S66×8 test sets.