Improved spatial separation of neutral molecules

We have developed and experimentally demonstrated an improved electrostatic deflector for the spatial separation of molecules according to their dipole-moment-to-mass ratio. The device features a very open structure that allows for significantly stronger electric fields as well as for stronger deflection without molecules crashing into the device itself. We have demonstrated its performance using the prototypical OCS molecule and we discuss opportunities regarding improved quantum-state-selectivity for complex molecules and the deflection of unpolar molecules.Comment: 6 figure

Interaction-induced delocalization of two particles in a random potential: Scaling properties

The localization length $\xi_2$ for coherent propagation of two interacting particles in a random potential is studied using a novel and efficient numerical method. We find that the enhancement of $\xi_2$ over the one-particle localization length $\xi_1$ satisfies the scaling relation $\xi_2/\xi_1=f(u/\Delta_\xi)$, where $u$ is the interaction strength and $\Delta_{\xi}$ the level spacing of a wire of length $\xi_1$. The scaling function $f$ is linear over the investigated parameter range. This implies that $\xi_2$ increases faster with $u$ than previously predicted. We also study a novel mapping of the problem to a banded-random-matrix model.Comment: 5 pages and two figures in a uuencoded, compressed tar file; uses revtex and psfig.sty (included); substantial revision of a previous version of the paper including newly discovered scaling behavio

Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: clinical and basic science aspects

The ventral striatum / nucleus accumbens has been implicated in the craving for drugs and alcohol which is a major reason for relapse of addicted people. Craving might be induced by drug-related cues. This suggests that disruption of craving-related neural activity in the nucleus accumbens may significantly reduce craving in alcohol-dependent patients. Here we report on preliminary clinical and neurophysiological evidence in three male patients who were treated with high frequency deep brain stimulation of the nucleus accumbens bilaterally. All three had been alcohol dependent for many years, unable to abstain from drinking, and had experienced repeated relapses prior to the stimulation. After the operation, craving was greatly reduced and all three patients were able to abstain from drinking for extended periods of time. Immediately after the operation but prior to connection of the stimulation electrodes to the stimulator, local field potentials were obtained from the externalized cables in two patients while they performed cognitive tasks addressing action monitoring and incentive salience of drug related cues. LFPs in the action monitoring task provided further evidence for a role of the nucleus accumbens in goal-directed behaviors. Importantly, alcohol related cue stimuli in the incentive salience task modulated LFPs even though these cues were presented outside of the attentional focus. This implies that cue-related craving involves the nucleus accumbens and is highly automatic

Subtype-specific differentiation of cardiac pacemaker cell clusters from human induced pluripotent stem cells

Background: Human induced pluripotent stem cells (hiPSC) harbor the potential to differentiate into diverse cardiac cell types. Previous experimental efforts were primarily directed at the generation of hiPSC-derived cells with ventricular cardiomyocyte characteristics. Aiming at a straightforward approach for pacemaker cell modeling and replacement, we sought to selectively differentiate cells with nodal-type properties. Methods: hiPSC were differentiated into spontaneously beating clusters by co-culturing with visceral endoderm-like cells in a serum-free medium. Subsequent culturing in a specified fetal bovine serum (FBS)-enriched cell medium produced a pacemaker-type phenotype that was studied in detail using quantitative real-time polymerase chain reaction (qRT-PCR), immunocytochemistry, and patch-clamp electrophysiology. Further investigations comprised pharmacological stimulations and co-culturing with neonatal cardiomyocytes. Results: hiPSC co-cultured in a serum-free medium with the visceral endoderm-like cell line END-2 produced spontaneously beating clusters after 10–12 days of culture. The pacemaker-specific genes HCN4, TBX3, and TBX18 were abundantly expressed at this early developmental stage, while levels of sarcomeric gene products remained low. We observed that working-type cardiomyogenic differentiation can be suppressed by transfer of early clusters into a FBS-enriched cell medium immediately after beating onset. After 6 weeks under these conditions, sinoatrial node (SAN) hallmark genes remained at high levels, while working-type myocardial transcripts (NKX2.5, TBX5) were low. Clusters were characterized by regular activity and robust beating rates (70–90 beats/min) and were triggered by spontaneous Ca2+ transients recapitulating calcium clock properties of genuine pacemaker cells. They were responsive to adrenergic/cholinergic stimulation and able to pace neonatal rat ventricular myocytes in co-culture experiments. Action potential (AP) measurements of cells individualized from clusters exhibited nodal-type (63.4%) and atrial-type (36.6%) AP morphologies, while ventricular AP configurations were not observed. Conclusion: We provide a novel culture media-based, transgene-free approach for targeted generation of hiPSC-derived pacemaker-type cells that grow in clusters and offer the potential for disease modeling, drug testing, and individualized cell-based replacement therapy of the SAN

Transport theory yields renormalization group equations

We show that dissipative transport and renormalization can be described in a single theoretical framework. The appropriate mathematical tool is the Nakajima-Zwanzig projection technique. We illustrate our result in the case of interacting quantum gases, where we use the Nakajima-Zwanzig approach to investigate the renormalization group flow of the effective two-body interaction.Comment: 11 pages REVTeX, twocolumn, no figures; revised version with additional examples, to appear in Phys. Rev.

Rationale, design and conduct of a randomised controlled trial evaluating a primary care-based complex intervention to improve the quality of life of heart failure patients: HICMan (Heidelberg Integrated Case Management) : study protocol

Background: Chronic congestive heart failure (CHF) is a complex disease with rising prevalence, compromised quality of life (QoL), unplanned hospital admissions, high mortality and therefore high burden of illness. The delivery of care for these patients has been criticized and new strategies addressing crucial domains of care have been shown to be effective on patients' health outcomes, although these trials were conducted in secondary care or in highly organised Health Maintenance Organisations. It remains unclear whether a comprehensive primary care-based case management for the treating general practitioner (GP) can improve patients' QoL. Methods/Design: HICMan is a randomised controlled trial with patients as the unit of randomisation. Aim is to evaluate a structured, standardized and comprehensive complex intervention for patients with CHF in a 12-months follow-up trial. Patients from intervention group receive specific patient leaflets and documentation booklets as well as regular monitoring and screening by a prior trained practice nurse, who gives feedback to the GP upon urgency. Monitoring and screening address aspects of disease-specific selfmanagement, (non)pharmacological adherence and psychosomatic and geriatric comorbidity. GPs are invited to provide a tailored structured counselling 4 times during the trial and receive an additional feedback on pharmacotherapy relevant to prognosis (data of baseline documentation). Patients from control group receive usual care by their GPs, who were introduced to guidelineoriented management and a tailored health counselling concept. Main outcome measurement for patients' QoL is the scale physical functioning of the SF-36 health questionnaire in a 12-month follow-up. Secondary outcomes are the disease specific QoL measured by the Kansas City Cardiomyopathy questionnaire (KCCQ), depression and anxiety disorders (PHQ-9, GAD-7), adherence (EHFScBS and SANA), quality of care measured by an adapted version of the Patient Chronic Illness Assessment of Care questionnaire (PACIC) and NTproBNP. In addition, comprehensive clinical data are collected about health status, comorbidity, medication and health care utilisation. Discussion: As the targeted patient group is mostly cared for and treated by GPs, a comprehensive primary care-based guideline implementation including somatic, psychosomatic and organisational aspects of the delivery of care (HICMAn) is a promising intervention applying proven strategies for optimal care. Trial registration: Current Controlled Trials ISRCTN30822978

Fibrillar Aβ (beta) triggers microglial proteome alterations and dysfunction in Alzheimer mouse models

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid beta (A beta) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial A beta Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of A beta deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar A beta, rather than dystrophic neurites, suggesting that fibrillar A beta may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy

The Dung Beetle Dance: An Orientation Behaviour?

An interesting feature of dung beetle behaviour is that once they have formed a piece of dung into a ball, they roll it along a straight path away from the dung pile. This straight-line orientation ensures that the beetles depart along the most direct route, guaranteeing that they will not return to the intense competition (from other beetles) that occurs near the dung pile. Before rolling a new ball away from the dung pile, dung beetles perform a characteristic “dance,” in which they climb on top of the ball and rotate about their vertical axis. This dance behaviour can also be observed during the beetles' straight-line departure from the dung pile. The aim of the present study is to investigate the purpose of the dung beetle dance. To do this, we explored the circumstances that elicit dance behaviour in the diurnal ball-rolling dung beetle, Scarabaeus (Kheper) nigroaeneus. Our results reveal that dances are elicited when the beetles lose control of their ball or lose contact with it altogether. We also find that dances can be elicited by both active and passive deviations of course and by changes in visual cues alone. In light of these results, we hypothesise that the dung beetle dance is a visually mediated mechanism that facilitates straight-line orientation in ball-rolling dung beetles by allowing them to 1) establish a roll bearing and 2) return to this chosen bearing after experiencing a disturbance to the roll path

The TATA-binding protein regulates maternal mRNA degradation and differential zygotic transcription in zebrafish

Early steps of embryo development are directed by maternal gene products and trace levels of zygotic gene activity in vertebrates. A major activation of zygotic transcription occurs together with degradation of maternal mRNAs during the midblastula transition in several vertebrate systems. How these processes are regulated in preparation for the onset of differentiation in the vertebrate embryo is mostly unknown. Here, we studied the function of TATA-binding protein (TBP) by knock down and DNA microarray analysis of gene expression in early embryo development. We show that a subset of polymerase II-transcribed genes with ontogenic stage-dependent regulation requires TBP for their zygotic activation. TBP is also required for limiting the activation of genes during development. We reveal that TBP plays an important role in the degradation of a specific subset of maternal mRNAs during late blastulation/early gastrulation, which involves targets of the miR-430 pathway. Hence, TBP acts as a specific regulator of the key processes underlying the transition from maternal to zygotic regulation of embryogenesis. These results implicate core promoter recognition as an additional level of differential gene regulation during development