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Unverkennbar wachsen Strom und Wärme immer mehr zusammen. Das augenscheinlichste Beispiel dafür ist die Wärmepumpentechnik. Kommt die Antriebsenergie „Strom“ aus 100 Prozent regenerativen Quellen, so ist auch die daraus resultierende Wärme CO2-neutral. Im Folgenden wird dargestellt, was für eine zielführende Kombination von Wärmepumpe, Photovoltaik und Speicher zu beachten ist.

The inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-mediated immune activation and pathogenicity remains speculative. Here, we selectively disrupted this Nef activity in SIVmac239 and analyzed the consequences for the virological, immunological, and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3-TCR does not impair viral replication during acute infection but is associated with increased immune activation and antiviral gene expression. Subsequent early reversion in three of six animals suggests strong selective pressure for this Nef function and is associated with high viral loads and progression to simian AIDS. In the absence of reversions, however, viral replication and the clinical course of infection are attenuated. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to simian immunodeficiency virus (SIV) infection and seems critical for efficient viral immune evasion., publishedVersion

SUMMARY The inability of Nef to downmodulate the CD3-T cell receptor (TCR) complex distinguishes HIV-1 from other primate lentiviruses and may contribute to its high virulence. However, the role of this Nef function in virus-mediated immune activation and pathogenicity remains speculative. Here, we selectively disrupted this Nef activity in SIVmac239 and analyzed the consequences for the virological, immunological, and clinical outcome of infection in rhesus macaques. The inability to downmodulate CD3-TCR does not impair viral replication during acute infection but is associated with increased immune activation and antiviral gene expression. Subsequent early reversion in three of six animals suggests strong selective pressure for this Nef function and is associated with high viral loads and progression to simian AIDS. In the absence of reversions, however, viral replication and the clinical course of infection are attenuated. Thus, Nef-mediated downmodulation of CD3 dampens the inflammatory response to simian immunodeficiency virus (SIV) infection and seems critical for efficient viral immune evasion., Graphical Abstract, In Brief HIV-1 lacks the CD3 downmodulation function of Nef that is otherwise conserved in primate lentiviruses. Joas et al. disrupted this Nef activity in SIVmac239 and show that Nef-mediated downmodulation of CD3 dampens inflammatory responses to SIV. This promotes effective immune evasion and maintenance of high viral loads in infected rhesus macaques.

Newly generated young neurons in the adult hippocampus receive GABAergic synaptic inputs, which are crucial for activity-dependent survival and functional maturation between 1-3 weeks after mitosis. We found synaptically driven action potential (AP) firing in these newborn young cells in adult mice. Although glutamatergic synaptic inputs remained subthreshold, activation of GABAergic synaptic inputs depolarized young neurons and reliably evoked APs. Furthermore, pairing of subthreshold excitatory postsynaptic potentials or somatic current injection with brief bursts of GABAergic inputs revealed efficient GABAergic excitation at conductances of ∼ 1.5 nS, corresponding to the activity of only three or four interneurons. Stronger GABAergic inputs (>4 nS) effectively blocked AP firing via shunting inhibition, which might be important to dynamically control spiking output in both directions. Taken together, GABAergic interneurons differentially recruit newborn young granule cells by supporting either AP generation or shunting inhibition dependent on hippocampal network activity.

Running increases adult neurogenesis and improves pattern separation in various memory tasks including context fear conditioning or touch-screen based spatial learning. However, it is unknown whether pattern separation is improved in spontaneous behavior, not emotionally biased by positive or negative reinforcement. Here we investigated the effect of voluntary running on pattern separation during novel object recognition in mice using relatively similar or substantially different objects.We show that running increases hippocampal neurogenesis but does not affect object recognition memory with 1.5 h delay after sample phase. By contrast, at 24 h delay, running significantly improves recognition memory for similar objects, whereas highly different objects can be distinguished by both, running and sedentary mice. These data show that physical exercise improves pattern separation, independent of negative or positive reinforcement. In sedentary mice there is a pronounced temporal gradient for remembering object details. In running mice, however, increased neurogenesis improves hippocampal coding and temporally preserves distinction of novel objects from familiar ones.

The role of the accessory viral Nef protein as a multifunctional manipulator of the host cell that is required for effective replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4 + T cells, which are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their T cell receptor (TCR)-CD3 downmodulation function in HIV-infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naive and memory CD4 + T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA + CD45RO + CD4 + T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4 + T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3, which distinguishes most primate lentiviruses from HIV type 1 (HIV-1) and its vpu -containing simian precursors, may promote a selective preservation of central memory CD4 + T cells, which are critical for the maintenance of a functional immune system. IMPORTANCE The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4 + T cells in multiple ways to promote viral replication and immune evasion in vivo . Here, we show that some effects of Nef are subset specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4 + T cells, and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4 + T cells are largely refractory to receptor downmodulation but are main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4 + T cells, which are critical for immune function, but has little effect on activated/proliferating CD4 + T cells, which are the main targets for viral replication.

In adult neurogenesis young neurons connect to the existing network via formation of thousands of new synapses. At early developmental stages, glutamatergic synapses are sparse, immature and functionally 'silent', expressing mainly NMDA receptors. Here we show in 2- to 3-week-old young neurons of adult mice, that brief-burst activity in glutamatergic fibers is sufficient to induce postsynaptic AP firing in the absence of AMPA receptors. The enhanced excitability of the young neurons lead to efficient temporal summation of small NMDA currents, dynamic unblocking of silent synapses and NMDA-receptor-dependent AP firing. Therefore, early synaptic inputs are powerfully converted into reliable spiking output. Furthermore, due to high synaptic gain, small dendritic trees and sparse connectivity, neighboring young neurons are activated by different distinct subsets of afferent fibers with minimal overlap. Taken together, synaptic recruitment of young neurons generates sparse and orthogonal AP firing, which may support sparse coding during hippocampal information processing.

Fahrerassistenzsysteme gewinnen zunehmend an Bedeutung, da diese das Auto komfortabler und sicherer machen. Während assistierende Funktionen bereits im Markt verfügbar sind, befinden sich Assistenzsysteme mit höherem Automatisierungsgrad vor allem noch im Fokus der Forschung. Eine mögliche Assistenzfunktion ist die Unterstützung des Fahrers im Niedergeschwindigkeitsbereich. Dieser umfasst Fahrhandlungen, mit denen sich ein Fahrer langsam durch ruhenden Verkehr navigiert, beispielsweise das Manövrieren durch enge Parkhäuser. Untersuchungen zeigen, dass ein Großteil der Sachschäden bei niederen Geschwindigkeiten bis 20km/h geschehen und Fahrer sich eine Assistenzfunktion speziell für diesen Bereiche wünschen. Die vorliegende Arbeit stellt Algorithmenkonzepte vor, die die Problemstellungen Umfeldmodellierung und Lokalisierung in diesem speziellen Wirkfeld adressieren und hinsichtlich Speicher- und Rechenkomplexität optimiert entworfen sind. Das Resultat der Arbeit bezüglich des Umfeldmodells stellt die GridTile-Methodik dar, bei der das Umfeld iterativ mit Kacheln ausgelegt wird. Dabei wird nur für Bereiche des Umfelds Speicher benötigt, an denen Objekte detektiert werden. Die Methodik zur Lokalisierung ermöglicht es, innerhalb von weniger als 10 ms das Fahrzeug auf weniger als 10 cm genau zu lokalisieren. Durch eine Kombination dieser beiden Methoden wird prototypisch eine vollständige Fahrerassistenzfunktion HomeZone realisiert und bewertet. Driver assistance functions are getting increasingly important, because they make driving more comfortable and safer. While assisting functions are already in the market, systems with a highly automated support are still mainly solely in the focus of research departments. One possible assistance function is to support the driver while driving at low speed. E.g. if a driver guides his vehicle slowly through a mostly still standing environment like narrow parking decks. Analysis has shown that a large part of material damage happens at low speed up to 20km/h and that driver want a specic assistance unction for this field. To realize such functions an assistance systems has to be able to observe its environment through sensors, aggregate those measurements into an environment model and localize the vehicle precisely. The functionalities environment modeling and localization are the core of this work. To analyze this field state of the art algorithms are presented and analyzed. It will be shown, that most of the time costly sensors are used combined with powerful computational units. But to create a driver assistance system the cost sensitivity of the market has to be considered. Hence in this work algorithms are going to be presented, that will work only in restricted circumstances, but within this area enable a car to drive with a highly automated support. The algorithms will be created with a strong focus on memory consumption and computational complexity. The evaluation of the algorithms will be tested and evaluated under real life conditions. The result of this work for the environment modelling is the GridTile algorithm, that iteratively models the environment with a set of tiles. Because tiles will be only created where the car drives, this method only uses memory for areas of the environment that are actually observed. A comparison to Open- Source algorithms will show, that this method is faster than the state of the art and consumes less memory. The presented localization algorithm is able to locate the car within less than 10 ms with an accuracy of 10 cm. At the end of the work those two algorithms will be combined to present a prototype of a system that enables a driver to record trajectories of several hundred meters length and afterwards gets automatically guided along these trajectories into a parking spot.

The cellular factor serine incorporator 5 (SERINC5) impairs HIV-1 infectivity but is antagonized by the viral Nef protein. We analyzed the anti-SERINC5 activity of Nef proteins across primate lentiviruses and examined whether SERINC5 represents a barrier to cross-species transmissions and/or within-species viral spread. HIV-1, HIV-2, and SIV Nefs counteract human, ape, monkey, and murine SERINC5 orthologs with similar potency. However, HIV-1 Nefs are more active against SERINC5 than HIV-2 Nefs, and chimpanzee SIV (SIVcpz) Nefs are more potent than those of their monkey precursors. Additionally, Nefs of HIV and most SIVs rely on the dileucine motif in the C-terminal loop for anti-SERINC5 activity, while the Nef from colobus SIV (SIVcol) evolved different inhibitory mechanisms. We also found a significant correlation between anti-SERINC5 potency and the SIV prevalence in the respective ape and monkey species. Thus, Nef-mediated SERINC5 antagonism may determine the ability of primate lentiviruses to spread within natural hosts.

Background Elderly HIV-1 infected individuals progress to AIDS more frequently and rapidly than people becoming infected at a young age. To identify possible reasons for these differences in clinical progression, we performed comprehensive phenotypic analyses of CD4+ T cells from uninfected young and elderly individuals, and examined their susceptibility to HIV-1 infection and programmed death. Results Peripheral blood mononuclear cells (PBMCs) from older people contain an increased percentage of central memory and Th17 CD4+ T cells that are main target cells of HIV-1 and strongly reduced proportions of naïve T cells that are poorly susceptible to HIV-1. Unstimulated T cells from elderly individuals expressed higher levels of activation markers, death receptors, and the viral CXCR4 co-receptor than those from young individuals but responded poorly to stimulation. CD4+ T cells from older individuals were highly susceptible to CXCR4- and CCR5-tropic HIV-1 infection but produced significantly lower quantities of infectious virus than cells from young individuals because they were highly prone to apoptosis and thus presumably had a very short life span. The increased susceptibility of T cells from the elderly to HIV-1 infection correlated directly with CXCR4 and inversely with CD4 expression. The levels of apoptosis correlated with the cell surface expression of FAS but not with the expression of programmed death receptor 1 (PD1) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Conclusions Increased levels of activated and highly susceptible HIV-1 target cells, reduced CD4 and enhanced CXCR4 cell surface expression, together with the high susceptibility to FAS-induced programmed cell death may contribute to the rapid CD4+ T cell depletion and accelerated clinical course of infection in elderly HIV-1-infected individuals. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0213-1) contains supplementary material, which is available to authorized users.

Additional file 1: Figure S1. Increased levels of apoptosis in lymphocytes from elderly donors. Gating strategy of flow cytometry analysis of death and apoptosis rates from mock or HIV-1 NL4-3 reporter virus infected GFP+ or GFPâ cells. Figure S2. Expression of activation markers and viral LTR activity in HIV-1 infected PBMC cultures from young and elderly individuals. (A, B) Representative primary data and statistical evaluations of the expression levels of (A) CD69 and (B) CD25 on X4 or R5 HIV-1 NL4-3 reporter virus infected GFP+ or GFPâ cells from young (Y) and elderly (O) blood donors. (C) GFP expression levels in PBMC cultures from young and elderly donors infected with X4 or R5 HIV-1 NL4-3 reporter constructs. Each symbol represents the result obtained for one individual PBMC donor from the young (blue) or elderly (red) groups.

Mit der steigenden Automatisierung von Fahrerassistenzsystemen wachsen auch die Anforderungen an die eingesetzten Verfahren zur Umfeldmodellierung. Soll sich ein Fahrzeug weitgehend selbststandig in einem vorab unbekannten und undefinierten Umfeld bewegen, so ist eine genaue Kenntnis der Aufenthaltsorte von statischen sowie dynamischen Objekten von hoher Relevanz, um Assistenzfunktionen, wie Kollisionsvermeidung oder Pfadplanung, durchfuhren zu konnen. Die Problematik der Umfeldmodellierung ist in der Robotik seit vielen Jahren ein bekanntes Problem und gut untersucht [7]. Demnach ist es bereits eine hochkomplexe Aufgabe, wenn ein autonomer Roboter in einem gut strukturierten Gebaude interagiert, die Zeit hat Messungen in ein Umfeldmodell zu integrieren und in der Lage ist, seine Bewegung einzustellen, um Messungen verwerten [5].

International audience; CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

Gamma-aminobutyric acid (GABA) is the first transmitter which provides synaptic input to newly generated neurons. In the first 2-3 weeks after mitosis, young neurons show an elevated intracellular chloride concentration due to the expression of the NKCC1 Cl- importer. Hence, GABAergic transmission provides depolarization to the newborn cells, which is known to be crucial for activity-dependent cell survival, development and functional maturation. However, it is still unknown whether activation of GABAergic synapses can evoke action potential (AP) firing in newly generated granule cells of the adult hippocampus to induce these trophic effects. In order to address this question, young neurons of the adult brain were fluorescently labeled using either retrovirus-based GFP expression or transgenic mice expressing the red fluorescent protein DsRed under the control of the doublecortin (DCX)-promoter. Electrophysiological recordings were performed on acute hippocampal brain slices. Gramicidin perforated-patch recordings revealed a reversal potential of GABAergic synaptic currents substantially more positive in 2-3 week old DCX-expressing neurons (~-35 mV) as compared to mature granule cells (~-75 mV). In both perforated-patch and whole-cell configuration, GABAergic synaptic currents are indeed able to excite AP firing and to modulate glutamatergic subthreshold inputs. Due to the high input resistance and the slow membrane time constant of young granule cells, low GABAergic synaptic inputs result in a long lasting depolarization, which provides the basis for an efficient temporal integration of excitatory postsynaptic potentials with an enhanced firing probability for ~200 ms. Thereby, GABAergic synaptic currents boost AP firing in young granule cells within a conductance window between ~0.5 and 3.5 nS. Larger GABAergic inputs however effectively block AP firing via shunting inhibition, which might be important to protect the young cells from over excitation. Synaptic GABAergic transmission was fully blocked by 10 µM gabazine, whereas a half maximal inhibitory concentration (0.2 µM) increased AP firing at high stimulation intensities, showing that both AP generation and shunting inhibition are mediated by GABAA receptor mediated chloride conductances. Taken together, this study shows that GABAergic synaptic inputs in newly generated young granule cells can dynamically support either AP firing or shunting inhibition dependent on hippocampal network activity.

The first consecutive series of 250 implantations of an uncemented, proximally anchored straight femoral shaft prosthesis in 236 patients is included in this prospective follow-up study. Average time of follow-up evaluation was 11.8 years (range 10.6 - 13.7 years). At follow-up, 41 patients with 44 hips had died and three could not be located. Eight hips were revised, two for infection, one for recurrent dislocation, two for rapid subsidence due to component undersizing and one for aseptic loosening of a varus-malaligned stem; two radiologically well-fixed stems were revised during acetabular revision. Survival estimate showed an overall survival of 96.6% after 14 years (confidence limits: 98.4% (upper) and 92.8% (lower)). The median Harris hip score at time of follow-up was 81.4 points; clinical results were compromised by high loosening rates (68.8%) of the threaded cup, which had been used in 165 of the 250 cases. Radiologically, tiny reactive lines (< 2mm) were frequently present in the distal zones of the femoral shaft, but could be found in the proximal anchoring zone in only one case. In conclusion, the long-term follow-up results with this femoral component are encouraging and are comparable to those of modern techniques of cementing in primary total hip arthroplasty.

SummaryMost simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon-α. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV-1 group O.

Background Increased cellular iron levels are associated with high mortality in HIV-1 infection. Moreover iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains. Results Surface Transferrin receptor (TfR) levels are unaffected by Nef proteins of HIV-1 and its simian precursors but elevated in cells expressing Nefs from most other primate lentiviruses due to reduced TfR internalization. The SIV Nef-mediated reduction of TfR endocytosis is dependent on an N-terminal AP2 binding motif that is not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis leads to the reduction of Transferrin uptake and intracellular iron concentration and is accompanied by attenuated lentiviral replication in macrophages. Conclusion Inhibition of Transferrin and thereby iron uptake by SIV Nef might limit viral replication in myeloid cells. Furthermore, this new SIV Nef function could represent a virus-host adaptation that evolved in natural SIV-infected monkeys.

This contribution investigates algorithms for ego- motion estimation from environmental features. Various formu- lations for solving the underlying procrustes problem exist. It is analytically shown that in the 2-D case this can be performed more efficiently compared to common implementations based on matrix decompositions. Furthermore, analytic error propa- gation is performed to second order which reveals a multiplica- tive estimator bias. A novel bias-corrected solution is proposed and evaluated in Monte Carlo simulations. Propagation of the derived error model to a representation used in the recursive trajectory reconstruction is presented and verified.

Nef is a multifunctional protein encoded by all primate lentiviruses that modulates cell surface expression of a variety of cellular receptors and increases the infectivity of progeny virons. Here, we describe the use of bicistronic HIV-1 constructs that coexpress Nef and fluorescent proteins via an internal ribosome entry site to quantify Nef-mediated receptor modulation in virally infected cells. We also report how such proviral constructs and indicator cell lines can be used to quantify the effect of Nef on virion infectivity.

A new quantitative tissue differentiation theory which relates the local tissue formation in a fracture gap to the local stress and strain is presented. Our hypothesis proposes that the amounts of strain and hydrostatic pressure along existing calcified surfaces in the fracture callus determine the differentiation of the callus tissue. The study compares the local strains and stresses in the callus as calculated from a finite element model with histological findings from an animal fracture model. The hypothesis predicts intramembranous bone formation for strains smaller approximately +/- 5% and hydrostatic pressures smaller than +/- 0.15 MPa. Endochondral ossification is associated with compressive pressures larger than about -0.15 MPa and strains smaller than +/- 15%. All other conditions seemed to lead to connective tissue or fibrous cartilage. The hypothesis enables a better understanding of the complex tissue differentiation seen in histological images and the mechanical conditions for healing delayed healing or nonunions.