Proteomics of Human Dendritic Cell Subsets Reveals Subset-Specific Surface Markers and Differential Inflammasome Function.

Dendritic cells (DCs) play a key role in orchestrating adaptive immune responses. In human blood, three distinct subsets exist: plasmacytoid DCs (pDCs) and BDCA3+ and CD1c+ myeloid DCs. In addition, a DC-like CD16+ monocyte has been reported. Although RNA-expression profiles have been previously compared, protein expression data may provide a different picture. Here, we exploited label-free quantitative mass spectrometry to compare and identify differences in primary human DC subset proteins. Moreover, we integrated these proteomic data with existing mRNA data to derive robust cell-specific expression signatures with more than 400 differentially expressed proteins between subsets, forming a solid basis for investigation of subset-specific functions. We illustrated this by extracting subset identification markers and by demonstrating that pDCs lack caspase-1 and only express low levels of other inflammasome-related proteins. In accordance, pDCs were incapable of interleukin (IL)-1ß secretion in response to ATP

Support for a synaptic chain model of neuronal sequence generation

In songbirds, the remarkable temporal precision of song is generated by a sparse sequence of bursts in the premotor nucleus HVC. To distinguish between two possible classes of models of neural sequence generation, we carried out intracellular recordings of HVC neurons in singing zebra finches (Taeniopygia guttata). We found that the subthreshold membrane potential is characterized by a large, rapid depolarization 5–10 ms before burst onset, consistent with a synaptically connected chain of neurons in HVC. We found no evidence for the slow membrane potential modulation predicted by models in which burst timing is controlled by subthreshold dynamics. Furthermore, bursts ride on an underlying depolarization of ~10-ms duration, probably the result of a regenerative calcium spike within HVC neurons that could facilitate the propagation of activity through a chain network with high temporal precision. Our results provide insight into the fundamental mechanisms by which neural circuits can generate complex sequential behaviours.National Institutes of Health (U.S.) (Grant MH067105)National Institutes of Health (U.S.) (Grant DC009280)National Science Foundation (U.S.) (IOS-0827731)Alfred P. Sloan Foundation (Research Fellowship

The Link Between Shocks, Turbulence and Magnetic Reconnection in Collisionless Plasmas

Global hybrid (electron fluid, kinetic ions) and fully kinetic simulations of the magnetosphere have been used to show surprising interconnection between shocks, turbulence and magnetic reconnection. In particular collisionless shocks with their reflected ions that can get upstream before retransmission can generate previously unforeseen phenomena in the post shocked flows: (i) formation of reconnecting current sheets and magnetic islands with sizes up to tens of ion inertial length. (ii) Generation of large scale low frequency electromagnetic waves that are compressed and amplified as they cross the shock. These \u27wavefronts\u27 maintain their integrity for tens of ion cyclotron times but eventually disrupt and dissipate their energy. (iii) Rippling of the shock front, which can in turn lead to formation of fast collimated jets extending to hundreds of ion inertial lengths downstream of the shock. The jets, which have high dynamical pressure, \u27stir\u27 the downstream region, creating large scale disturbances such as vortices, sunward flows, and can trigger flux ropes along the magnetopause. This phenomenology closes the loop between shocks, turbulence and magnetic reconnection in ways previously unrealized. These interconnections appear generic for the collisionless plasmas typical of space, and are expected even at planar shocks, although they will also occur at curved shocks as occur at planets or around ejecta

Homo-PROTACs:bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation

E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for 'proteolysis-targeting chimeras'). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.Targeting the ubiquitin proteasome system to modulate protein homeostasis using small molecules has promising therapeutic potential. Here the authors describe Homo-PROTACS: small molecules that can induce the homo-dimerization of E3 ubiquitin ligases and cause their proteasome-dependent degradation

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Biomarker-Based HIV Incidence in a Community Sample of Men Who Have Sex with Men in Paris, France

BACKGROUND: Population-based estimates of HIV incidence in France have revealed that men who have sex with men (MSM) are the most affected population and contribute to nearly half of new infections each year. We sought to estimate HIV incidence among sexually active MSM in Paris gay community social venues. METHODOLOGY/ PRINCIPAL FINDINGS: A cross-sectional survey was conducted in 2009 in a sample of commercial venues such as bars, saunas and backrooms. We collected a behavioural questionnaire and blood sample. Specimens were tested for HIV infection and positive specimens then tested for recent infection by the enzyme immunoassay for recent HIV-1 infection (EIA-RI). We assessed the presence of antiretroviral therapy among infected individuals to rule out treated patients in the algorithm that determined recent infection. Biomarker-based cross-sectional incidence estimates were calculated. We enrolled 886 MSM participants among which 157 (18%) tested HIV positive. In positive individuals who knew they were infected, 75% of EIA-RI positive results were due to ART. Of 157 HIV positive specimens, 15 were deemed to be recently infected. The overall HIV incidence was estimated at 3.8% person-years (py) [95%CI: 1.5-6.2]. Although differences were not significant, incidence was estimated to be 3.5% py [0.1-6.1] in men having had a negative HIV test in previous year and 4.8% py [0.1-10.6] in men having had their last HIV test more than one year before the survey, or never tested. Incidence was estimated at 4.1% py [0-8.3] in men under 35 years and 2.5% py [0-5.4] in older men. CONCLUSIONS/ SIGNIFICANCE: This is the first community-based survey to estimate HIV incidence among MSM in France. It includes ART detection and reveals a high level of HIV transmission in sexually active individuals, despite a high uptake of HIV testing. These data call for effective prevention programs targeting MSM engaged in high-risk behaviours

Effectiveness of Transmitted Drug Resistance Testing Before Initiation of Antiretroviral Therapy in HIV-Positive Individuals

BACKGROUND For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS We included individuals from the HIV-CAUSAL Collaboration who enrolled <6 months of HIV diagnosis between 2006 and 2015, were ART-naive, and had measured CD4 count and HIV-RNA. Follow-up started at the date when all inclusion criteria were first met (baseline). We compared 2 strategies: (1) TDR testing within 3 months of baseline versus (2) no TDR testing. We used inverse probability weighting to estimate the 5-year proportion and hazard ratios (HRs) of virological suppression (confirmed HIV-RNA <50 copies/mL), and of AIDS or death under both strategies. RESULTS Of 25,672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17,189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). CONCLUSIONS TDR prevalence was low. Although TDR testing improved virological response, we found no evidence that it reduced the incidence of AIDS or death in first 5 years after diagnosis

On the possibility of a terahertz light emitting diode based on a dressed quantum well

We consider theoretically the realization of a tunable terahertz light emitting diode from a quantum well with dressed electrons placed in a highly doped p-n junction. In the considered system the strong resonant dressing field forms dynamic Stark gaps in the valence and conduction bands and the electric field inside the p-n junction makes the QW asymmetric. It is shown that the electrons transiting through the light induced Stark gaps in the conduction band emit photons with energy directly proportional to the dressing field. This scheme is tunable, compact, and shows a fair efficiency.Comment: 6 pages, 5 figure

Characterization of Synaptically Connected Nuclei in a Potential Sensorimotor Feedback Pathway in the Zebra Finch Song System

Birdsong is a learned behavior that is controlled by a group of identified nuclei, known collectively as the song system. The cortical nucleus HVC (used as a proper name) is a focal point of many investigations as it is necessary for song production, song learning, and receives selective auditory information. HVC receives input from several sources including the cortical area MMAN (medial magnocellular nucleus of the nidopallium). The MMAN to HVC connection is particularly interesting as it provides potential sensorimotor feedback to HVC. To begin to understand the role of this connection, we investigated the physiological relation between MMAN and HVC activity with simultaneous multiunit extracellular recordings from these two nuclei in urethane anesthetized zebra finches. As previously reported, we found similar timing in spontaneous bursts of activity in MMAN and HVC. Like HVC, MMAN responds to auditory playback of the bird's own song (BOS), but had little response to reversed BOS or conspecific song. Stimulation of MMAN resulted in evoked activity in HVC, indicating functional excitation from MMAN to HVC. However, inactivation of MMAN resulted in no consistent change in auditory responses in HVC. Taken together, these results indicate that MMAN provides functional excitatory input to HVC but does not provide significant auditory input to HVC in anesthetized animals. We hypothesize that MMAN may play a role in motor reinforcement or coordination, or may provide modulatory input to the song system about the internal state of the animal as it receives input from the hypothalamus

A randomised, controlled crossover comparison of the C-MAC videolaryngoscope with direct laryngoscopy in 150 patients during routine induction of anaesthesia

<p>Abstract</p> <p>Background</p> <p>The C-MAC^®(Karl Storz, Tuttlingen, Germany) has recently been introduced as a new device for videolaryngoscopy guided intubation. The purpose of the present study was to compare for the first time the C-MAC with conventional direct laryngoscopy in 150 patients during routine induction of anaesthesia.</p> <p>Methods</p> <p>After approval of the institutional review board and written informed consent, 150 patients (ASA I-III) with general anaesthesia were enrolled. Computer-based open crossover randomisation was used to determine the sequence of the three laryngoscopies: Conventional direct laryngoscopy (HEINE Macintosh classic, Herrsching, Germany; blade sizes 3 or 4; <it>DL </it>group), C-MAC size 3 (<it>C-MAC3 </it>group) and C-MAC size 4 (<it>C-MAC4 </it>group) videolaryngoscopy, respectively. After 50 patients, laryngoscopy technique in the C-MAC4 group was changed to the straight blade technique described by Miller (C-MAC4/SBT).</p> <p>Results</p> <p>Including all 150 patients (70 male, aged (median [range]) 53 [20-82] years, 80 [48-179] kg), there was no difference of glottic view between DL, C-MAC3, C-MAC4, and C-MAC4/SBT groups; however, worst glottic view (C/L 4) was only seen with DL, but not with C-MAC videolaryngoscopy. In the subgroup of patients that had suboptimal glottic view with DL (C/L≥2a; n = 24), glottic view was improved in the C-MAC4/SBT group; C/L class improved by three classes in 5 patients, by two classes in 2 patients, by one class in 8 patients, remained unchanged in 8 patients, or decreased by two classes in 1 patient. The median (range) time taken for tracheal intubation in the DL, C-MAC3, C-MAC4 and C-MAC4/SBT groups was 8 sec (2-91 sec; n = 44), 10 sec (2-60 sec; n = 37), 8 sec (5-80 sec; n = 18) and 12 sec (2-70 sec; n = 51), respectively.</p> <p>Conclusions</p> <p>Combining the benefits of conventional direct laryngoscopy and videolaryngoscopy in one device, the C-MAC may serve as a standard intubation device for both routine airway management and educational purposes. However, in patients with suboptimal glottic view (C/L≥2a), the C-MAC size 4 with straight blade technique may reduce the number of C/L 3 or C/L 4 views, and therefore facilitate intubation. Further studies on patients with difficult airway should be performed to confirm these findings.</p