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[This corrects the article DOI: 10.3389/fimmu.2019.00316.].

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro. Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis. Highlights - Patient with atypical primary immunodeficiency - Clinical manifestations: pyogenic bacterial infections, high IgE level, and persistent EBV viremia - Next-generation sequencing reveals two homozygous mutations in MYD88 and CARD9 genes leading to complete absence of proteins - Monocytes/macrophages function and DC differentiation were severely compromised - NGS has a key role to determine the correct diagnosis in atypical primary immunodeficiency leading to reconsider the individualized treatment.

BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-gamma modulation of PD-L1/PD-L2 in MET-amplified tumours.METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-gamma were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-gamma stimulation, and after anti-MET therapy.RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-gamma treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/STAT1, signal transducers downstream of the Interferon-gamma receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-gamma induced PD-L1 expression.CONCLUSIONS: These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-gamma. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.

This work uses a network of GPS stations over Europe from which a homogenized integrated water vapor (IWV) dataset has been retrieved, completed with colocated temperature and precipitation measurements over specific stations to (i) estimate the biases of six regional climate models over Europe in terms of humidity; (ii) understand their origins; and (iii) finally assess the impact of these biases on the frequency of occurrence of precipitation. The evaluated simulations have been performed in the framework of HYMEX/Med-CORDEX programs and cover the Mediterranean area and part of Europe at horizontal resolutions of 50 to 12 km. The analysis shows that models tend to overestimate the low values of IWV and the use of the nudging technique reduces the differences between GPS and simulated IWV. Results suggest that physics of models mostly explain the mean biases, while dynamics affects the variability. The land surface–atmosphere exchanges affect the estimation of IWV over most part of Europe, especially in summer. The limitations of the models to represent these processes explain part of their biases in IWV. However, models correctly simulate the dependance between IWV and temperature, and specifically the deviation that this relationship experiences regarding the Clausius–Clapeyron law after a critical value of temperature (Tbreak). The high spatial variability of Tbreak indicates that it has a strong dependence on local processes which drive the local humidity sources. This explains why the maximum values of IWV are not necessarily observed over warmer areas, which are often dry areas. Finally, it is shown over the SIRTA observatory (near Paris) that the frequency of occurrence of light precipitation is strongly conditioned by the biases in IWV and by the precision of the models to reproduce the distribution of IWV as a function of the temperature. The results of the models indicate that a similar dependence occurs in other areas of Europe, especially where precipitation has a predominantly convective character. According to the observations, for each range of temperature, there is a critical value of IWV from which precipitation starts to increase. The critical values and the probability of exceeding them are simulated with a bias that depends on the model. Those models, which generally present light precipitation too often, show lower critical values and higher probability of exceeding them. This work is a contribution to the HyMeX program (HYdrological cycle in The Mediterranean EXperiment) through INSU-MISTRALS support and the MEDCORDEX program (Coordinated Regional climate Downscaling EXperiment–Mediterranean region). This research has received funding from the French National Research Agency (ANR) project REMEMBER (grant ANR-12-SENV-001) and is a contribution to the VEGA project through LEFE/INSU support, to the EECLAT project through LEFE-INSU and CNES supports and to the GNSS4SWEC COST action ES1206 through EU support. It was supported by the IPSL group for regional climate and environmental studies, with granted access to the HPC resources of GENCI/IDRIS (under allocation i2011010227), by SIRTA Working Group “Climate studies” and by the national infrastructure ACTRIS-FR, identified on the French road map for Research Infrastructures, published by the Ministry of Research. The SIRTA-ReOBS effort also benefited from the support of the L-IPSL funded by ANR under the “Programme d'Investissements d'Avenir” (grant ANR-10-LABX-0018) and by the EUCLIPSE project funded by the European Commission under the Seventh Framework Program (grant no. 244067).

Lam et al. characterize a novel hematological/autoinflammatory disorder due to a de novo recurrent missense mutation of CDC42. The authors use in silico, in vitro, and in vivo analyses to correlate the molecular mechanisms altering CDC42 function to the observed phenotype., Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival., Graphical Abstract

Renal denervation (RDN) is a device-based procedure historically studied in the treatment of resistant hypertension. Studies conducted over the years have produced conflicting results and its application in routine antihypertensive treatment is still debated. Recent trials using different devices have shown promising results in the treatment of patients with hypertension at low-moderate cardiovascular risk. Although long-term results are still needed to confirm the efficacy and safety of the procedure, there is reason at the moment to consider an application of RDN in the treatment of selected patients with hypertension, other than the application for resistant hypertension. The following is a state-of-the-art review of current studies and an analysis of the characteristics of hypertensive patients that could benefit from RDN.

The local contribution of clouds to the surface energy balance and temperature variability is an important topic in order to apprehend how this intake affects local climate variability and extreme events, how this contribution varies from one place to another, and how it evolves in a warming climate. The scope of this study is to understand how clouds impact temperature variability, to quantify their contribution, and to compare their effects to other surface processes. To do so, we develop a method to estimate the different terms that control temperature variability at the surface (∂T2m /∂t) by using this equation: ∂T2m /∂t=R+HA+HG+Adv where R is the radiation that is separated into the cloud term (Rcloud) and the clear sky one (RCS), HA the atmospheric heat exchange, HG the ground heat exchange, and Adv the advection. These terms are estimated hourly, almost only using direct measurements from SIRTA-ReOBS dataset (an hourly long-term multi-variables dataset retrieved from SIRTA, an observatory located in a semi-urban area 20-km South-West of Paris; Chiriaco et al., 2019) for a five-years period. The method gives good results for the hourly temperature variability, with a 0.8 correlation coefficient and a weak residual term between left part (directly measured) and right part of the equation.A bagged decision trees analysis of this equation shows that RCS dominates temperature variability during daytime and is mainly modulated by cloud radiative effect (Rcloud). During nighttime, the bagged decision trees analysis determines that Rcloud is the term controlling temperature changes. When a diurnal cycle analysis (split into seasons) is performed for each term, HA becomes an important negative modulator in the late afternoon, chiefly in spring and summer, when evaporation and thermal conduction are increased. In contrast, HG and Adv terms do not play an essential role on temperature variability at this temporal scale and their contribution is barely considerable in the one-hour variability, but still they remain necessary in order to obtain the best coefficient estimator between the directly measured observations and the method estimated. All terms except advection have a marked monthly-hourly cycle.Next steps consist in characterize the types of clouds and study their physical properties corresponding to the cases where Rcloud is significant, using the Lidar profiles also available in the SIRTA-ReOBS dataset.

INTRODUCTION AND OBJECTIVE:The goal of genital female-to-male (FTM) gender affirming surgery is to create an aesthetically acceptable phallus to allow voiding while standing and penetrative sexual ...

Clouds and aerosols play an important role in the Earth’s energy budget through a complex interaction with solar, atmospheric, and terrestrial radiation, and air humidity. Optically thick clouds efficiently reflect the incoming solar radiation and, globally, clouds are responsible for about two thirds of the planetary albedo. Thin cirrus trap the outgoing longwave radiation and keep the planet warm. Aerosols scatter or absorb sunlight depending on their size and shape and interact with clouds in various ways.Due to the importance of clouds and aerosols for the Earth’s energy budget, global satellite observations of their properties are essential for climate studies, for constraining climate models, and for evaluating cloud parameterizations. Active sounding from space by lidars and radars is advantageous since it provides the vertically resolved information. This has been proven by CALIOP lidar which has been observing the Earth’s atmosphere since 2006. Another instrument of this kind, CATS lidar on-board ISS provided measurements for over 33 months starting from the beginning of 2015. The ALADIN lidar on-board ADM/Aeolus has been measuring horizontal winds and aerosols/clouds since August 2018. More lidars are planned – in 2021, the ATLID/EarthCare lidar will be launched and other space-borne lidars are currently in the development phase.Needless to say that the quality of the retrieved data strongly depends on the quality of the calibration of the lidar system and its components. Besides “classical” calibration methods (laboratory calibration, calibration in space using on-board sources and/or known external sources and calibration through collocation, which involves comparisons with ground-based station-, balloon-, and aircraft measurements), one can also make use of a vicarious calibration, where the sites with known properties are used. In this work, we use the whole atmosphere for quality control of the space-borne lidar system, which includes the laser, the sending optics, the receiver with its telescope, and the detection system.We describe the quality control approach based on a set of several indicators, which characterize the behavior of the lidar system on a day-to-day basis using the L1 (and even L2) data as an input. With the help of this set one can trace:(a) the stability of the detection chain for the lidar channels (Rayleigh, Mie);(b) the drift of crosstalk coefficients;(c) the stability of day- and nighttime stratospheric noise;(d) the stability of the radiation detection for all atmospheric scenarios and over the whole globe using a clustering algorithm applied to the scattering ratio (SR) histograms.We demonstrate the results using the L1B and L2A data flow of Aeolus obtained from the first days of its operation and up to now, compare them with the results obtained for CALIOP, and discuss the applications of the approach.

Background and Purpose: Early life microbiota plays a crucial role in human health by acting as a barrier from pathogens' invasion and maintaining the intestinal immune homoeostasis. Altered fecal microbiota (FM) ecology was reported in newborns affected by intestinal ischemia. Our purpose was to describe, in these patients, the FM, the mucosal microbiota (MM) and the mucosal immunity. Methods: Fourteen newborns underwent intestinal resection because of intestinal ischemia. FM and MM were determined through targeted-metagenomics, diversity assignment and Kruskal-Wallis analyses of Operational taxonomic units (OTUs). The mucosal immune cells were analyzed through cytofluorimetry. Results and Conclusion: Based on the severity intestinal injueris we identified two groups: extensive (EII) and focal intestinal ischemia (FII). FM and MM varied in EII and FII groups, showing in the EII group the predominance of Proteobacteria and Enterobacteriaceae and the reduction of Bacteroidetes and Verrucomicrobia for both microbiota. The MM was characterized by a statistically significant reduction of Bacteroides, Lachnospiraceae and Ruminococcaceae and by a higher diversity in the EII compared to FII group. FM showed a prevalence of Proteobacteria, while the Shannon index was lower in the EII compared to FII group. An overall increment in B- and T-lymphocytes and Natural killer (NK) T-like cells was found for EII mucosal samples associated to an increment of TNF-α and INF-γ expressing cells, compared to FII group. FM and MM carry specific signatures of intestinal ischemic lesions. Further research may be crucial to address the role of specific taxa in EII, expecially with reference to inflammation grade and ischemia extension.

X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T− B+ NK− phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RGR222C) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4+ T cell counts, a decreased frequency of naïve CD4+ and CD8+ T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4+CD45RO+ T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3+ cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA+ terminally differentiated EM (EMRA) CD4+ T cells. Of note, patient’s NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56bright cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation.

In this thesis we investigate different phases of matter in systems driven out of equilibrium. In particular, we focus on current driven metal insulator transitions and on the physics of negative conductivity in photoexcited metals. We present a new mechanism by which a modest applied electric field can destabilize a correlated insulating phase at finite temperature, without directly exciting carriers across the gap. We investigate the consequences of a metal insulator phase interface, and show that the large difference in Seebeck coefficients leads to a substantial heat generation or removal at the interface depending on the direction of the applied electric current; our findings explain the key features of recent interesting experiments in Calcium Ruthenate. We also analyze a model of a metal coupled to a strongly photoexcited phonon mode and show that under general conditions the system exhibits a negative conductivity, even long after the removal of the pump; we study the phenomenological consequences of such state and find that it leads to a novel and purely non-equilibrium collective mode coupling charge and entropy. The resonance of this mode with probe radiation induces an enhancement of the optical reflectivity and can explain the experimental reports of the non-equilibrium state in photoexcited fullerides.

Current-driven insulator-metal transitions are in many cases driven by Joule heating proportional to the square of the applied current. Recent nano-imaging experiments in Ca$_2$RuO$_4$ reveal a metal-insulator phase boundary that depends on the direction of an applied current, suggesting an important non-heating effect. Motivated by these results, we study the effects of an electric current in a system containing interfaces between metallic and insulating phases. Derivation of a heat balance equation from general macroscopic Onsager transport theory, reveals a heating term proportional to the product of the current across the interface and the discontinuity in the Seebeck coefficient, so that heat can either be generated or removed at an interface, depending on the direction of the current relative to the change in material properties. For parameters appropriate to Ca$_2$RuO$_4$, this heating can be comparable to or larger than Joule heating. A simplified model of the relevant experimental geometry is shown to provide results consistent with the experiments. Extension of the results to other inhomogeneous metal-insulator transition systems is discussed., Comment: 11 pages, 2 figures

Perinatally HIV-infected children (PHIV), despite successful antiretroviral therapy, present suboptimal responses to vaccinations compared to healthy-controls (HC). Here we investigated phenotypic and transcriptional signatures of H1N1-specific B-cells (H1N1-Sp) in PHIV, differentially responding to trivalent-influenza-vaccine (TIV), and HC. Patients were categorized in responders (R) and non-responders (NR) according to hemagglutination-inhibition-assay at baseline and 21 days after TIV. No differences in H1N1-Sp frequencies were found between groups. H1N1-Sp transcriptional analysis revealed a distinct signature between PHIV and HC. NR presented higher PIK3C2B and NOD2 expression compared to R, confirmed by downregulation of PIK3C2B in resting-memory of R after H1N1 in-vitro stimulation. In conclusion this study confirms that qualitative rather than quantitative analyses are needed to characterize immune responses in PHIV. These results further suggest that higher PIK3C2B in H1N1-Sp of NR is associated with lower H1N1 immunogenicity and may be targeted by future modulating strategies to improve TIV responses in PHIV.

Collagenase clostridium histiolyticum (CCH), administered as an intra-lesional injection, is the first licensed, non-surgical treatment for Peyronie’s Disease. Its safety and efficacy have been widely demonstrated in the literature, which includes several large, randomised controlled trials. Each treatment cycle described in these trials involved two injections of CCH at six-weekly intervals, combined with physician modeling. A modified protocol has been developed in London, wherein only a single injection is given in each cycle, and physician modeling is replaced by manual stretching and the use of a vacuum pump by the patient at home. Further refinements are currently underway. While the response to treatment with CCH is difficult to predict, several factors have been identified that influence the likelihood of success. Thorough clinical assessment and careful patient counseling are also imperative to optimize this.

Machine Learning application on clinical data in order to support diagnosis and prognostic evaluation arouses growing interest in scientific community. However, choice of right algorithm to use was fundamental to perform reliable and robust classification. Our study aimed to explore if different kinds of Machine Learning technique could be effective to support early diagnosis of Multiple Sclerosis and which of them presented best performance in distinguishing Multiple Sclerosis patients from control subjects. We selected following algorithms: Random Forest, Support Vector Machine, Naïve-Bayes, K-nearest-neighbor and Artificial Neural Network. We applied the Independent Component Analysis to resting-state functional-MRI sequence to identify brain networks. We found 15 networks, from which we extracted the mean signals used into classification. We performed feature selection tasks in all algorithms to obtain the most important variables. We showed that best discriminant network between controls and early Multiple Sclerosis, was the sensori-motor I, according to early manifestation of motor/sensorial deficits in Multiple Sclerosis. Moreover, in classification performance, Random Forest and Support Vector Machine showed same 5-fold cross-validation accuracies (85.7%) using only this network, resulting to be best approaches. We believe that these findings could represent encouraging step toward the translation to clinical diagnosis and prognosis.