Rab8 binding to immune cell-specific adaptor LAX facilitates formation of trans-Golgi network-proximal CTLA-4 vesicles for surface expression.

Despite playing a central role in tolerance, little is known regarding the mechanism by which intracellular CTLA-4 is shuttled from the trans-Golgi network to the surfaces of T cells. In this context, Ras-related GTPase Rab8 plays an important role in the intracellular transport, while we have previously shown that CTLA-4 binds to the immune cell adaptor TRIM in T cells. In this study, we demonstrate that CTLA-4 forms a multimeric complex comprised of TRIM and related LAX that in turn binds to GTP bound Rab8 for post-Golgi transport to the cell surface. LAX bound via its N terminus to active GTP-Rab8, as well as the cytoplasmic tail of CTLA-4. TRIM required LAX for binding to Rab8 in a complex. Wild-type LAX or its N terminus (residues 1 to 77) increased CTLA-4 surface expression, whereas small interfering RNAs of Rab8 or LAX or disruption of LAX/Rab8 binding reduced numbers of CTLA-4-containing vesicles and its coreceptor surface expression. LAX also promoted the polarization of CTLA-4 and the reorientation of the microtubule-organizing center to the site of T-cell receptor engagement. Our results identify a novel CTLA-4/TRIM/LAX/Rab8 effector complex in the transport of CTLA-4 to the surfaces of T cells

Synaptic Cleft Segmentation in Non-Isotropic Volume Electron Microscopy of the Complete Drosophila Brain

Neural circuit reconstruction at single synapse resolution is increasingly recognized as crucially important to decipher the function of biological nervous systems. Volume electron microscopy in serial transmission or scanning mode has been demonstrated to provide the necessary resolution to segment or trace all neurites and to annotate all synaptic connections. Automatic annotation of synaptic connections has been done successfully in near isotropic electron microscopy of vertebrate model organisms. Results on non-isotropic data in insect models, however, are not yet on par with human annotation. We designed a new 3D-U-Net architecture to optimally represent isotropic fields of view in non-isotropic data. We used regression on a signed distance transform of manually annotated synaptic clefts of the CREMI challenge dataset to train this model and observed significant improvement over the state of the art. We developed open source software for optimized parallel prediction on very large volumetric datasets and applied our model to predict synaptic clefts in a 50 tera-voxels dataset of the complete Drosophila brain. Our model generalizes well to areas far away from where training data was available

Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

2015 Update on Acute Adverse Reactions to Gadolinium based Contrast Agents in Cardiovascular MR. Large Multi-National and Multi-Ethnical Population Experience With 37788 Patients From the EuroCMR Registry

Objectives: Specifically we aim to demonstrate that the results of our earlier safety data hold true in this much larger multi-national and multi-ethnical population. Background: We sought to re-evaluate the frequency, manifestations, and severity of acute adverse reactions associated with administration of several gadolinium- based contrast agents during routine CMR on a European level. Methods: Multi-centre, multi-national, and multi-ethnical registry with consecutive enrolment of patients in 57 European centres. Results: During the current observation 37788 doses of Gadolinium based contrast agent were administered to 37788 patients. The mean dose was 24.7 ml (range 5–80 ml), which is equivalent to 0.123 mmol/kg (range 0.01 - 0.3 mmol/kg). Forty-five acute adverse reactions due to contrast administration occurred (0.12 %). Most reactions were classified as mild (43 of 45) according to the American College of Radiology definition. The most frequent complaints following contrast administration were rashes and hives (15 of 45), followed by nausea (10 of 45) and flushes (10 of 45). The event rate ranged from 0.05 % (linear non-ionic agent gadodiamide) to 0.42 % (linear ionic agent gadobenate dimeglumine). Interestingly, we also found different event rates between the three main indications for CMR ranging from 0.05 % (risk stratification in suspected CAD) to 0.22 % (viability in known CAD). Conclusions: The current data indicate that the results of the earlier safety data hold true in this much larger multi-national and multi-ethnical population. Thus, the “off-label” use of Gadolinium based contrast in cardiovascular MR should be regarded as safe concerning the frequency, manifestation and severity of acute events

"First pain" in humans: convergent and specific forebrain responses

<p>Abstract</p> <p>Background</p> <p>Brief heat stimuli that excite nociceptors innervated by finely myelinated (Aδ) fibers evoke an initial, sharp, well-localized pain ("first pain") that is distinguishable from the delayed, less intense, more prolonged dull pain attributed to nociceptors innervated by unmyelinated (C) fibers ("second pain"). In the present study, we address the question of whether a brief, noxious heat stimulus that excites cutaneous Aδ fibers activates a distinct set of forebrain structures preferentially in addition to those with similar responses to converging input from C fibers. Heat stimuli at two temperatures were applied to the dorsum of the left hand of healthy volunteers in a functional brain imaging (fMRI) paradigm and responses analyzed in a set of volumes of interest (VOI).</p> <p>Results</p> <p>Brief 41°C stimuli were painless and evoked only C fiber responses, but 51°C stimuli were at pain threshold and preferentially evoked Aδ fiber responses. Most VOI responded to both intensities of stimulation. However, within volumes of interest, a contrast analysis and comparison of BOLD response latencies showed that the bilateral anterior insulae, the contralateral hippocampus, and the ipsilateral posterior insula were preferentially activated by painful heat stimulation that excited Aδ fibers.</p> <p>Conclusions</p> <p>These findings show that two sets of forebrain structures mediate the initial sharp pain evoked by brief cutaneous heat stimulation: those responding preferentially to the brief stimulation of Aδ heat nociceptors and those with similar responses to converging inputs from the painless stimulation of C fibers. Our results suggest a unique and specific physiological basis, at the forebrain level, for the "first pain" sensation that has long been attributed to Aδ fiber stimulation and support the concept that both specific and convergent mechanisms act concurrently to mediate pain.</p

Dielectric and thermal relaxation in the energy landscape

We derive an energy landscape interpretation of dielectric relaxation times in undercooled liquids, comparing it to the traditional Debye and Gemant-DiMarzio-Bishop pictures. The interaction between different local structural rearrangements in the energy landscape explains qualitatively the recently observed splitting of the flow process into an initial and a final stage. The initial mechanical relaxation stage is attributed to hopping processes, the final thermal or structural relaxation stage to the decay of the local double-well potentials. The energy landscape concept provides an explanation for the equality of thermal and dielectric relaxation times. The equality itself is once more demonstrated on the basis of literature data for salol.Comment: 7 pages, 3 figures, 41 references, Workshop Disordered Systems, Molveno 2006, submitted to Philosophical Magazin

Quantum phase transition to unconventional multi-orbital superfluidity in optical lattices

Orbital physics plays a significant role for a vast number of important phenomena in complex condensed matter systems such as high-T$_c$ superconductivity and unconventional magnetism. In contrast, phenomena in superfluids -- especially in ultracold quantum gases -- are commonly well described by the lowest orbital and a real order parameter. Here, we report on the observation of a novel multi-orbital superfluid phase with a {\it complex} order parameter in binary spin mixtures. In this unconventional superfluid, the local phase angle of the complex order parameter is continuously twisted between neighboring lattice sites. The nature of this twisted superfluid quantum phase is an interaction-induced admixture of the p-orbital favored by the graphene-like band structure of the hexagonal optical lattice used in the experiment. We observe a second-order quantum phase transition between the normal superfluid (NSF) and the twisted superfluid phase (TSF) which is accompanied by a symmetry breaking in momentum space. The experimental results are consistent with calculated phase diagrams and reveal fundamentally new aspects of orbital superfluidity in quantum gas mixtures. Our studies might bridge the gap between conventional superfluidity and complex phenomena of orbital physics.Comment: 5 pages, 4 figure

SPECULOOS exoplanet search and its prototype on TRAPPIST

One of the most significant goals of modern science is establishing whether life exists around other suns. The most direct path towards its achievement is the detection and atmospheric characterization of terrestrial exoplanets with potentially habitable surface conditions. The nearest ultracool dwarfs (UCDs), i.e. very-low-mass stars and brown dwarfs with effective temperatures lower than 2700 K, represent a unique opportunity to reach this goal within the next decade. The potential of the transit method for detecting potentially habitable Earth-sized planets around these objects is drastically increased compared to Earth-Sun analogs. Furthermore, only a terrestrial planet transiting a nearby UCD would be amenable for a thorough atmospheric characterization, including the search for possible biosignatures, with near-future facilities such as the James Webb Space Telescope. In this chapter, we first describe the physical properties of UCDs as well as the unique potential they offer for the detection of potentially habitable Earth-sized planets suitable for atmospheric characterization. Then, we present the SPECULOOS ground-based transit survey, that will search for Earth-sized planets transiting the nearest UCDs, as well as its prototype survey on the TRAPPIST telescopes. We conclude by discussing the prospects offered by the recent detection by this prototype survey of a system of seven temperate Earth-sized planets transiting a nearby UCD, TRAPPIST-1.Comment: Submitted as a chapter in the "Handbook of Exoplanets" (editors: H. Deeg & J.A. Belmonte; Section Editor: N. Narita). 16 pages, 4 figure

Creating, moving and merging Dirac points with a Fermi gas in a tunable honeycomb lattice

Dirac points lie at the heart of many fascinating phenomena in condensed matter physics, from massless electrons in graphene to the emergence of conducting edge states in topological insulators [1, 2]. At a Dirac point, two energy bands intersect linearly and the particles behave as relativistic Dirac fermions. In solids, the rigid structure of the material sets the mass and velocity of the particles, as well as their interactions. A different, highly flexible approach is to create model systems using fermionic atoms trapped in the periodic potential of interfering laser beams, a method which so far has only been applied to explore simple lattice structures [3, 4]. Here we report on the creation of Dirac points with adjustable properties in a tunable honeycomb optical lattice. Using momentum-resolved interband transitions, we observe a minimum band gap inside the Brillouin zone at the position of the Dirac points. We exploit the unique tunability of our lattice potential to adjust the effective mass of the Dirac fermions by breaking inversion symmetry. Moreover, changing the lattice anisotropy allows us to move the position of the Dirac points inside the Brillouin zone. When increasing the anisotropy beyond a critical limit, the two Dirac points merge and annihilate each other - a situation which has recently attracted considerable theoretical interest [5-9], but seems extremely challenging to observe in solids [10]. We map out this topological transition in lattice parameter space and find excellent agreement with ab initio calculations. Our results not only pave the way to model materials where the topology of the band structure plays a crucial role, but also provide an avenue to explore many-body phases resulting from the interplay of complex lattice geometries with interactions [11, 12]

A Systematic Review of Online Sex Addiction and Clinical Treatments Using CONSORT Evaluation

Researchers have suggested that the advances of the Internet over the past two decades have gradually eliminated traditional offline methods of obtaining sexual material. Additionally, research on cybersex and/or online sex addictions has increased alongside the development of online technology. The present study extended the findings from Griffiths’ (2012) systematic empirical review of online sex addiction by additionally investigating empirical studies that implemented and/or documented clinical treatments for online sex addiction in adults. A total of nine studies were identified and then each underwent a CONSORT evaluation. The main findings of the present review provide some evidence to suggest that some treatments (both psychological and/or pharmacological) provide positive outcomes among those experiencing difficulties with online sex addiction. Similar to Griffiths’ original review, this study recommends that further research is warranted to establish the efficacy of empirically driven treatments for online sex addiction