A dual defensive role of CIITA against retroviral infections

We describe how CIITA exerts a dual role against retroviral infection. The first, classical role is the upregulation of MHC class II expression and thus the capacity to present viral antigens to CD4+ T cells. The other, evolutionary new and fundamental role is to inhibit viral replication by blocking specifically the function of the viral transactivators. HIV-1 Tat is inhibited through the competition for cyclin T1 of the P-TEFb complex, whereas HTLV-2 Tax-2 is inhibited through a concerted action which may increase the binding affinity of the CIITA-NFY complex for Tax-2, displacing it from the viral LTR promoter. As expected, two distint sequences in the N-term region of CIITA mediate the inhibitory action on Tat and Tax-2, respectively. Of note, Tax-1 from HTLV-1 seems also to be inhibited by the same sequence that inhibits HTLV-2 Tax-2. Interestingly, only those CIITA fragments containing the minimal inhibitory domains that localize into the nucleus could exert an effective suppressive action. Taken together, our results indicate that CIITA is an extant molecular tool endowed with distinct evolving functions against retroviruses. These distinct properties of CIITA will shed new light on the molecular mechanisms of adaptive coevolution of hosts and pathogens and may be exploited to envisage novel therapeutic strategies aimed at counteracting retroviral infections

Therapy-induced antitumor vaccination in neuroblastomas by the combined targeting of IL-2 and TNF alpha

L19-IL2 and L19TNF are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNF. Because of the tumor targeting properties of L19, IL-2 and TNF concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNF in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNF, alone or in combination protocols. Seventy percent of Neuro2A- and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNF, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4+ T helper cells and CD8+ CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4+ and CD8+ T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNF efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4+ and CD8+ T cells

GIADA performance during Rosetta mission scientific operations at comet 67P

The Grain Impact Analyser and Dust Accumulator (GIADA) instrument onboard Rosetta studied the dust environment of comet 67P/Churyumov–Gerasimenko from 3.7 au inbound, through perihelion, to 3.8 au outbound, measuring the dust flow and the dynamic properties of individual particles. GIADA is composed of three subsystems: 1) Grain Detection System (GDS); 2) Impact Sensor (IS); and 3) Micro-Balances System (MBS). Monitoring the subsystems’ performance during operations is an important element for the correct calibration of scientific measurements. In this paper, we analyse the GIADA inflight calibration data obtained by internal calibration devices for the three subsystems during the period from 1 August 2014 to 31 October 2015. The calibration data testify a nominal behaviour of the instrument during these fifteen months of mission; the only exception is a minor loss of sensitivity for one of the two GDS receivers, attributed to dust contamination

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of endocrine disruptor effects on trout

We demonstrate how mechanistic modeling can be used to predict whether and how biological responses to chemicals at (sub)organismal levels in model species (i.e., what we typically measure) translate into impacts on ecosystem service delivery (i.e., what we care about). We consider a hypothetical case study of two species of trout, brown trout (Salmo trutta; BT) and greenback cutthroat trout (Oncorhynchus clarkii stomias; GCT). These hypothetical populations live in a high-altitude river system and are exposed to human-derived estrogen (17α‑ethinyl estradiol, EE2), which is the bioactive estrogen in many contraceptives. We use the individual based model in STREAM to explore how seasonally varying concentrations of EE2 could influence male spawning and sperm quality. Resulting impacts on trout recruitment and the consequences of such for anglers and for the continued viability of populations of GCT (the state fish of Colorado) are explored. in STREAM incorporates seasonally varying river flow and temperature, fishing pressure, the influence of EE2 on species-specific demography, and inter-specific competition. The model facilitates quantitative exploration of the relative importance of endocrine disruption and inter-species competition on trout population dynamics. Simulations predicted constant EE2 loading to have more impacts on GCT than BT. However, increasing removal of BT by anglers can enhance the persistence of GCT and offset some of the negative effects of EE2. We demonstrate how models that quantitatively link impacts of chemicals and other stressors on individual survival, growth, and reproduction to consequences for populations and ecosystem service delivery, can be coupled with ecosystem service valuation. The approach facilitates interpretation of toxicity data in an ecological context and gives beneficiaries of ecosystem services amore explicit role in management decisions. Although challenges remain, this type of approach may be particularly helpful for site-specific risk assessments and those in which trade offs and synergies among ecosystem services need to be considered

Comet 67P/Churyumov-Gerasimenko preserved the pebbles that formed planetesimals

Solar System formation models predict that the building-blocks of planetesimals were mm- to cm-sized pebbles, aggregates of ices and non-volatile materials, consistent with the compact particles ejected by comet 67P/Churyumov-Gerasimenko (67P hereafter) and detected by GIADA (Grain Impact Analyzer and Dust Accumulator) on-board the Rosetta spacecraft. Planetesimals were formed by the gentle gravitational accretion of pebbles, so that they have an internal macroporosity of 40%. We measure the average dust bulk density ${\rho}D = 795 _{-65}^{+840} kg m^{-3}$ that, coupled to the 67P nucleus bulk density, provides the average dust-to-ices mass ratio δ = 8.5. We find that the measured densities of the 67P pebbles are consistent with a mixture of (15 ± 6)% of ices, (5 ± 2)% of Fe-sulfides, (28 ± 5)% of silicates, and (52 ± 12)% of hydrocarbons, in average volume abundances. This composition matches both the solar and CI-chondritic chemical abundances, thus showing that GIADA has sampled the typical non-volatile composition of the pebbles that formed all planetesimals. The GIADA data do not constrain the abundance of amorphous silicates vs. crystalline Mg,Fe- olivines and pyroxenes. We find that the pebbles have a microporosity of (52 ± 8)% (internal volume filling factor φP = 0.48±0.08), implying an average porosity for the 67P nucleus of (71 ± 8)%, lower than previously estimated

Optimal MHC-II-restricted tumor antigen presentation to CD4+ T helper cells: the key issue for development of anti-tumor vaccines

Present immunoprevention and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus newly conceived anti-tumor vaccination strategies are urgently needed. In this review we will focus on ways to provide optimal MHC class II-restricted tumor antigen presentation to CD4+ T helper cells as a crucial parameter to get optimal and protective adaptive immune response against tumor. Through the description of successful preventive or therapeutic experimental approaches to vaccinate the host against the tumor we will show that optimal activation of MHC class II-restricted tumor specific CD4+ T helper cells can be achieved in various ways. Interestingly, the success in tumor eradication and/or growth arrest generated by classical therapies such as radiotherapy and chemotherapy in some instances can be re-interpreted on the basis of an adaptive immune response induced by providing suitable access of tumor-associated antigens to MHC class II molecules. Therefore, focussing on strategies to generate better and suitable MHC class II–restricted activation of tumor specific CD4+ T helper cells may have an important impact on fighting and defeating cancer

Metal-catalyst-free gas-phase synthesis of long-chain hydrocarbons

Development of sustainable processes for hydrocarbons synthesis is a fundamental challenge in chemistry since these are of unquestionable importance for the production of many essential synthetic chemicals, materials and carbon-based fuels. Current industrial processes rely on non-abundant metal catalysts, temperatures of hundreds of Celsius and pressures of tens of bars. We propose an alternative gas phase process under mild reaction conditions using only atomic carbon, molecular hydrogen and an inert carrier gas. We demonstrate that the presence of CH2 and H radicals leads to efficient C-C chain growth, producing micron-length fibres of unbranched alkanes with an average length distribution between C23-C33. Ab-initio calculations uncover a thermodynamically favourable methylene coupling process on the surface of carbonaceous nanoparticles, which is kinematically facilitated by a trap-and-release mechanism of the reactants and nanoparticles that is confirmed by a steady incompressible flow simulation. This work could lead to future alternative sustainable synthetic routes to critical alkane-based chemicals or fuels

GIADA: its status after the Rosetta cruise phase and on-ground activity in support of the encounter with comet 67P/Churyumov-Gerasimenko

GIADA (Grain Impact Analyser and Dust Accumulator) on-board the Rosetta mission to comet 67P/Churyumov-Gerasimenko was designed to study the physical and dynamical properties of dust particles ejected by the comet during the encounter. In this paper we report the results of the analysis of data collected by GIADA during the past seven years of the cruise phase. During this period the GIADA detection subsystems were switched on for periodic in-flight payload checkouts to monitor their state of-health including potential changes in its performance that could affect its data collection. Only slight variations in sensitivity and dynamical range were identified that will not affect the GIADA measurement capability during the Rosetta comet encounter and rendezvous phase. The GIADA microbalance system detected the presence of low-volatility material over a period of about 169 days when the GIADA cover remained partially opened. It is highly probable that this material originated from the spacecraft itself, as a spacecraft’s outgassing was observed by the ROSINA mass spectrometer (on-board Rosetta) during the cruise phase. The identification of the low-volatility mass deposited on the microbalances as self-contamination will allow us to evaluate the mass rate background to be subtracted from the GIADA science data. These results obtained from GIADA cruise data analysis coupled with laboratory calibration data obtained from measurements using the GIADA spare model for selected cometary dust analogs will be the basis for the interpretation of the GIADA scientific data

Somatosensory and auditory deviance detection for outcome prediction during postanoxic coma.

Prominent research in patients with disorders of consciousness investigated the electrophysiological correlates of auditory deviance detection as a marker of consciousness recovery. Here, we extend previous studies by investigating whether somatosensory deviance detection provides an added value for outcome prediction in postanoxic comatose patients. Electroencephalography responses to frequent and rare stimuli were obtained from 66 patients on the first and second day after coma onset. Multivariate decoding analysis revealed an above chance-level auditory discrimination in 25 patients on the first day and in 31 patients on the second day. Tactile discrimination was significant in 16 patients on the first day and in 23 patients on the second day. Single-day sensory discrimination was unrelated to patients' outcome in both modalities. However, improvement of auditory discrimination from first to the second day was predictive of good outcome with a positive predictive power (PPV) of 0.73 (CI = 0.52-0.88). Analyses considering the improvement of tactile, auditory and tactile, or either auditory or tactile discrimination showed no significant prediction of good outcome (PPVs = 0.58-0.68). Our results show that in the acute phase of coma deviance detection is largely preserved for both auditory and tactile modalities. However, we found no evidence for an added value of somatosensory to auditory deviance detection function for coma-outcome prediction

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions