Proteolytic release of transmembrane proteins from the cell surface, the so called ectodomain shedding, is a key process in inflammation. Inactive rhomboid 2 (iRhom2) plays a crucial role in this ...context, in that it guides maturation and function of the sheddase ADAM17 (a disintegrin and metalloproteinase 17) in immune cells, and, ultimately, its ability to release inflammatory mediators such as tumor necrosis factor α (TNFα). Yet, the macrophage sheddome of iRhom2/ADAM17, which is the collection of substrates that are released by the proteolytic complex, is only partly known. In this study, we applied high-resolution proteomics to murine and human iRhom2-deficient macrophages for a systematic identification of substrates, and therefore functions, of the iRhom2/ADAM17 proteolytic complex. We found that iRhom2 loss suppressed the release of a group of transmembrane proteins, including known (e.g. CSF1R) and putative novel ADAM17 substrates. In the latter group, shedding of major histocompatibility complex class I molecules (MHC-I) was consistently reduced in both murine and human macrophages when iRhom2 was ablated. Intriguingly, it emerged that in addition to its shedding, iRhom2 could also control surface expression of MHC-I by an undefined mechanism. We have demonstrated the biological significance of this process by using an in vitro model of CD8
+
T-cell (CTL) activation. In this model, iRhom2 loss and consequent reduction of MHC-I expression on the cell surface of an Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line dampened activation of autologous CTLs and their cell-mediated cytotoxicity. Taken together, this study uncovers a new role for iRhom2 in controlling cell surface levels of MHC-I by a dual mechanism that involves regulation of their surface expression and ectodomain shedding.
ESPRESSO at VLT Pepe, F; Cristiani, S; Rebolo, R ...
Astronomy & astrophysics,
01/2021, Letnik:
645
Journal Article
Recenzirano
Odprti dostop
Context. ESPRESSO is the new high-resolution spectrograph of ESO’s Very Large Telescope (VLT). It was designed for ultra-high radial-velocity (RV) precision and extreme spectral fidelity with the aim ...of performing exoplanet research and fundamental astrophysical experiments with unprecedented precision and accuracy. It is able to observe with any of the four Unit Telescopes (UTs) of the VLT at a spectral resolving power of 140 000 or 190 000 over the 378.2 to 788.7 nm wavelength range; it can also observe with all four UTs together, turning the VLT into a 16 m diameter equivalent telescope in terms of collecting area while still providing a resolving power of 70 000. Aims. We provide a general description of the ESPRESSO instrument, report on its on-sky performance, and present our Guaranteed Time Observation (GTO) program along with its first results. Methods. ESPRESSO was installed on the Paranal Observatory in fall 2017. Commissioning (on-sky testing) was conducted between December 2017 and September 2018. The instrument saw its official start of operations on October 1, 2018, but improvements to the instrument and recommissioning runs were conducted until July 2019. Results. The measured overall optical throughput of ESPRESSO at 550 nm and a seeing of 0.65″ exceeds the 10% mark under nominal astroclimatic conditions. We demonstrate an RV precision of better than 25 cm s−1 during a single night and 50 cm s−1 over several months. These values being limited by photon noise and stellar jitter shows that the performance is compatible with an instrumental precision of 10 cm s−1. No difference has been measured across the UTs, neither in throughput nor RV precision. Conclusions. The combination of the large collecting telescope area with the efficiency and the exquisite spectral fidelity of ESPRESSO opens a new parameter space in RV measurements, the study of planetary atmospheres, fundamental constants, stellar characterization, and many other fields.
Active cancer and ongoing antineoplastic treatments are major factors for severe COVID-19 and death, reasons why the SARS-CoV-2 vaccination remains a priority in cancer patients (CPs). However, ...immunocompromised patients were excluded from major studies on mRNA vaccines, and could have a decreased response to vaccination, as recently demonstrated in solid organ transplant recipients. Herein, we aimed to assess the proportion of antibody response 4 weeks after the first injection of the BNT162b2 (Pfizer-BioNTech) vaccine in CPs and health care workers (HCWs) as the control population.
Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism ...involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.
ESPRESSO at VLT Pepe, F.; Cristiani, S.; Rebolo, R. ...
Astronomy and astrophysics (Berlin),
01/2021, Letnik:
645
Journal Article
Recenzirano
Context.
ESPRESSO is the new high-resolution spectrograph of ESO’s Very Large Telescope (VLT). It was designed for ultra-high radial-velocity (RV) precision and extreme spectral fidelity with the aim ...of performing exoplanet research and fundamental astrophysical experiments with unprecedented precision and accuracy. It is able to observe with any of the four Unit Telescopes (UTs) of the VLT at a spectral resolving power of 140 000 or 190 000 over the 378.2 to 788.7 nm wavelength range; it can also observe with all four UTs together, turning the VLT into a 16 m diameter equivalent telescope in terms of collecting area while still providing a resolving power of 70 000.
Aims.
We provide a general description of the ESPRESSO instrument, report on its on-sky performance, and present our Guaranteed Time Observation (GTO) program along with its first results.
Methods.
ESPRESSO was installed on the Paranal Observatory in fall 2017. Commissioning (on-sky testing) was conducted between December 2017 and September 2018. The instrument saw its official start of operations on October 1, 2018, but improvements to the instrument and recommissioning runs were conducted until July 2019.
Results.
The measured overall optical throughput of ESPRESSO at 550 nm and a seeing of 0.65″ exceeds the 10% mark under nominal astroclimatic conditions. We demonstrate an RV precision of better than 25 cm s
−1
during a single night and 50 cm s
−1
over several months. These values being limited by photon noise and stellar jitter shows that the performance is compatible with an instrumental precision of 10 cm s
−1
. No difference has been measured across the UTs, neither in throughput nor RV precision.
Conclusions.
The combination of the large collecting telescope area with the efficiency and the exquisite spectral fidelity of ESPRESSO opens a new parameter space in RV measurements, the study of planetary atmospheres, fundamental constants, stellar characterization, and many other fields.
Genetic landscape of indolent and aggressive Kaposi sarcomas Malouf, G.G.; Lu, X.; Mouawad, R. ...
Journal of the European Academy of Dermatology and Venereology,
December 2022, 2022-Dec, 2022-12-00, 20221201, 2022-12, Letnik:
36, Številka:
12
Journal Article
Recenzirano
Background
Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic ...basis of this difference remains unknown.
Objectives
To explore the tumour mutational burden in indolent and aggressive KS.
Methods
We performed whole‐exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS.
Results
Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy‐number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS.
Conclusions
These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.
Background: Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancers, especially colorectal cancer (CRC), and seems to reflect more aggressive histological and clinical ...behaviors. The aim of this study was to evaluate EGFR immunohistochemical reactivity in CRC biopsies, and to analyze its relationship with various histological and clinical characteristics and survival. Patients and methods: A composite EGFR score, obtained by multiplying the grade (% positive cells) by the intensity of labeling (0–9) was used to define patients with low or high EGFR expression whose clinicopathological features were then compared. Univariate tests and multivariate Cox proportional hazards model were applied for data analysis. Results: Tissue sections from 150 CRC patients with a median follow-up of 40 months were examined. Median patient age at diagnosis was 70 years (range 38–89 years). EGFR reactivity was positive for 143 patients (97%) and high for 118 (80%). According to multivariate analysis, EGFR overexpression was significantly associated with tumor stage, with a higher percentage of EGFR overexpression in T3 than T4 (P=0.003) and not with overall survival. Conclusions: EGFR was overexpressed in this CRC patient population and was significantly associated with TNM (tumor–node–metastasis) stage T3. In the context of a new therapeutic strategy using EGFR-targeted therapies, although EGFR remains a controversial prognostic factor, this expression–stage association may play a crucial role in a decision to initiate an adjuvant treatment.
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