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Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RTCTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards Frontiers autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. [ABSTRACT FROM AUTHOR]

The conversion of chemical structures into computer-readable descriptors, able to capture key structural aspects, is of pivotal importance in the field of cheminformatics and computer-aided drug design. Molecular fingerprints represent a widely employed class of descriptors; however, their generation process is time-consuming for large databases and is susceptible to bias. Therefore, descriptors able to accurately detect predefined structural fragments and devoid of lengthy generation procedures would be highly desirable. To meet additional needs, such descriptors should also be interpretable by medicinal chemists, and suitable for indexing databases with trillions of compounds. To this end, we developed—as integral part of EXSCALATE, Dompé's end-to-end drug discovery platform—the DompeKeys (DK), a new substructure-based descriptor set, which encodes the chemical features that characterize compounds of pharmaceutical interest. DK represent an exhaustive collection of curated SMARTS strings, defining chemical features at different levels of complexity, from specific functional groups and structural patterns to simpler pharmacophoric points, corresponding to a network of hierarchically interconnected substructures. Because of their extended and hierarchical structure, DK can be used, with good performance, in different kinds of applications. In particular, we demonstrate how they are very well suited for effective mapping of chemical space, as well as substructure search and virtual screening. Notably, the incorporation of DK yields highly performing machine learning models for the prediction of both compounds' activity and metabolic reaction occurrence. The protocol to generate the DK is freely available at https://dompekeys.exscalate.eu and is fully integrated with the Molecular Anatomy protocol for the generation and analysis of hierarchically interconnected molecular scaffolds and frameworks, thus providing a comprehensive and flexible tool for drug design applications. [ABSTRACT FROM AUTHOR]

Most of the time, the deep analysis of a biological sample requires the acquisition of images at different time points, using different modalities and/or different stainings. This information gives morphological, functional, and physiological insights, but the acquired images must be aligned to be able to proceed with the co-localisation analysis. Practically speaking, according to Aristotle's principle, "The whole is greater than the sum of its parts", multi-modal image registration is a challenging task that involves fusing complementary signals. In the past few years, several methods for image registration have been described in the literature, but unfortunately, there is not one method that works for all applications. In addition, there is currently no user-friendly solution for aligning images that does not require any computer skills. In this work, DS4H Image Alignment (DS4H-IA), an open-source ImageJ/Fiji plugin for aligning multimodality, immunohistochemistry (IHC), and/or immunofluorescence (IF) 2D microscopy images, designed with the goal of being extremely easy to use, is described. All of the available solutions for aligning 2D microscopy images have also been revised. The DS4H-IA source code; standalone applications for MAC, Linux, and Windows; video tutorials; manual documentation; and sample datasets are publicly available. [ABSTRACT FROM AUTHOR]

Typical hemolytic uremic syndrome (HUS) is mainly caused by Shiga toxin-producing Escherichia coli (STEC) releasing Shiga toxin 2 (Stx2). Two different structures of this AB5 toxin have been described: uncleaved, with intact B and A chains, and cleaved, with intact B and a nicked A chain consisting of two fragments, A1 and A2, connected by a disulfide bond. Despite having the same toxic effect on sensitive cells, the two forms differ in their binding properties for circulating cells, serum components and complement factors, thus contributing to the pathogenesis of HUS differently. The outcome of STEC infections and the development of HUS could be influenced by the relative amounts of uncleaved or cleaved Stx2 circulating in patients' blood. Cleaved Stx2 was identified and quantified for the first time in four out of eight STEC-infected patients' sera by a method based on the inhibition of cell-free translation. Cleaved Stx2 was present in the sera of patients with toxins bound to neutrophils and in two out of three patients developing HUS, suggesting its involvement in HUS pathogenesis, although in association with other bacterial or host factors. [ABSTRACT FROM AUTHOR]

Protoplanetary disks emit radiation across a broad range of wavelengths, requiring a multiwavelength approach to fully understand their physical mechanisms and how they form planets. Observations at submillimeter to centimeter wavelengths can provide insights into the thermal emission from dust, free-free emission from ionized gas, and possible gyro-synchrotron emission from the stellar magnetosphere. This work is focused on CX Tau, a ~0.4 M⊙ star with an extended gas emission and a compact and apparently structureless dust disk, with an average millimeter flux compared to Class II sources in Taurus. We present observations from the Karl G. Jansky Very Large Array across four bands (between 9.0 mm and 6.0 cm) and combine them with archival data from the Atacama Large Millimeter/submillimeter Array, the Submillimeter Array, and the Plateau de Bure Interferometer. This multiwavelength approach allows us to separate the dust continuum from other emissions. After isolating the dust thermal emission, we derived an upper limit of the dust disk extent at 1.3 cm, which is consistent with theoretical predictions of a radial drift-dominated disk. The centimeter data show a peculiar behavior: deep observations at 6.0 cm did not detect the source, while at 1.3 cm, the flux density is anomalously higher than adjacent bands. Intraband spectral indices suggest a dominant contribution from free-free emission, whereas gyro-synchrotron emission is excluded. To explain these observations, we propose a strong variability among the free-free emission with timescales shorter than a month. Another possible interpretation is the presence of anomalous microwave emission from spinning dust grains. [ABSTRACT FROM AUTHOR]

Purpose: The aims of our retrospective study investigated the role of immune system in glioblastoma (GBM), which is the most aggressive primary brain tumor in adults characterized by a poor prognosis. The recurrence rate remains high, probably due to "immune-desert" tumor microenvironment (TME) making GBM hidden from the anti-tumoral immune clearance. Considering this, we aimed to create a panel of prognostic markers from blood and tumor tissue correlating with overall survival (OS) and progression-free survival (PFS). Methods: Firstly, we analyzed the inflammatory markers NLR and PLR as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively, collected at different time points in the peripheral blood of 95 patients. Furthermore, in 31 patients of the same cohort, we analyzed the formalin-fixed paraffin embedded samples to further compare the impact of circulating and inflammatory markers within the TME. Results: Patients aged < 60 years and with methylated MGMT showed better OS. While, pre-chemotherapy Systemic Inflammatory Index (SII) < 480 was related to a better OS and PFS, we observed that only CD68+macrophage and CD66b+neutrophils expressed in vascular/perivascular area (V) showed a statistically significant prognostic role in median OS and PFS. Conclusions: Thus, we underscored a role of SII as predictive value of response to STUPP protocol. Regarding the TME-related markers, we suggested to take into consideration for future studies with new immunotherapy combinations, each component relating to expression of immune infiltrating subsets. [ABSTRACT FROM AUTHOR]

Introduction: Three-dimensional (3D) multicellular spheroids are fundamental in vitro tools for studying in vivo tissues. Volume is the main feature used for evaluating the drug/treatment effects, but several other features can be estimated even from a simple 2D image. For high-content screening analysis, the bottleneck is the segmentation stage, which is essential for detecting the spheroids in the images and then proceeding to the feature extraction stage for performing morphotypic analysis. Problem: Today, several tools are available for extracting morphological features from spheroid images, but all of them have pros and cons and there is no general validated solution. Thanks to new deep learning models, it is possible to standardize the process and adapt the analysis to big data. Novelty: Starting from the first version of AnaSP, an open-source software suitable for estimating several morphological features of 3D spheroids, we implemented a new module for automatically segmenting 2D brightfield images of spheroids by exploiting convolutional neural networks. Results: Several deep learning segmentation models (i.e., VVG16, VGG19, ResNet18, ResNet50) have been trained and compared. All of them obtained very interesting results and ResNet18 ranked as the best-performing. Conclusions: A network based on an 18-layer deep residual architecture (ResNet-18) has been integrated into AnaSP, releasing AnaSP 2.0, a version of the tool optimized for high-content screening analysis. The source code, standalone versions, user manual, sample images, video tutorial, and further documentation are freely available at: https://sourceforge.net/p/anasp. [ABSTRACT FROM AUTHOR]

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are rare diseases encompassing pancreatic (PanNETs) and ileal NETs (SINETs), characterized by heterogeneous somatostatin receptors (SSTRs) expression. Treatments for inoperable GEP-NETs are limited, and SSTR-targeted Peptide Receptor Radionuclide Therapy (PRRT) achieves variable responses. Prognostic biomarkers for the management of GEP-NET patients are required. 18F-FDG uptake is a prognostic indicator of aggressiveness in GEP-NETs. This study aims to identify circulating and measurable prognostic miRNAs associated with 18FFDG-PET/CT status, higher risk and lower response to PRRT. Methods: Whole miRNOme NGS profiling was conducted on plasma samples obtained from well-differentiated advanced, metastatic, inoperable G1, G2 and G3 GEP-NET patients enrolled in the non-randomized LUX (NCT02736500) and LUNET (NCT02489604) clinical trials prior to PRRT (screening set, n= 24). Differential expression analysis was performed between 18F-FDG positive (n=12) and negative (n=12) patients. Validation was conducted by Real Time quantitative PCR in two distinct well-differentiated GEP-NET validation cohorts, considering the primary site of origin (PanNETs n=38 and SINETs n=30). The Cox regression was applied to assess independent clinical parameters and imaging for progression-free survival (PFS) in PanNETs. In situ RNA hybridization combined with immunohistochemistry was performed to simultaneously detect miR and protein expression in the same tissue specimens. This novel semiautomated miR-protein protocol was applied in PanNET FFPE specimens (n=9). In vitro functional experiments were performed in PanNET models. Results: While no miRNAs emerged to be deregulated in SINETs, hsa-miR-5096, hsa-let-7i-3p and hsa-miR-4311 were found to correlate with 18F-FDG-PET/CT in PanNETs (p-value:<0.005). Statistical analysis has shown that, hsa-miR-5096 can predict 6-month PFS (p-value:<0.001) and 12-month Overall Survival upon PRRT treatment (p-value:<0.05), as well as identify 18F-FDG-PET/CT positive PanNETs with worse prognosis after PRRT (p-value:<0.005). In addition, hsamiR-5096 inversely correlated with both SSTR2 expression in PanNET tissue and with the 68Gallium-DOTATOC captation values (p-value:<0.05), and accordingly it was able to decrease SSTR2 when ectopically expressed in PanNET cells (pvalue:< 0.01). Conclusions: hsa-miR-5096 well performs as a biomarker for 18F-FDG-PET/CT and as independent predictor of PFS. Moreover, exosome-mediated delivery of hsa-miR-5096 may promote SSTR2 heterogeneity and thus resistance to PRRT. [ABSTRACT FROM AUTHOR]

Introduction: Extracellular vesicles (EVs) and particles (EPs) represent reliable biomarkers for disease detection. Their role in the inflammatory microenvironment of severe COVID-19 patients is not well determined. Here, we characterized the immunophenotype, the lipidomic cargo and the functional activity of circulating EPs from severe COVID-19 patients (Co-19-EPs) and healthy controls (HC-EPs) correlating the data with the clinical parameters including the partial pressure of oxygen to fraction of inspired oxygen ratio (PaO2/FiO2) and the sequential organ failure assessment (SOFA) score. Methods: Peripheral blood (PB) was collected from COVID-19 patients (n=10) and HC (n=10). EPs were purified from platelet-poor plasma by size exclusion chromatography (SEC) and ultrafiltration. Plasma cytokines and EPs were characterized by multiplex bead-based assay. Quantitative lipidomic profiling of EPs was performed by liquid chromatography/mass spectrometry combined with quadrupole time-of-flight (LC/MS Q-TOF). Innate lymphoid cells (ILC) were characterized by flow cytometry after co-cultures with HC-EPs or Co-19-EPs. Results: We observed that EPs from severe COVID-19 patients: 1) display an altered surface signature as assessed by multiplex protein analysis; 2) are characterized by distinct lipidomic profiling; 3) show correlations between lipidomic profiling and disease aggressiveness scores; 4) fail to dampen type 2 innate lymphoid cells (ILC2) cytokine secretion. As a consequence, ILC2 from severe COVID-19 patients show a more activated phenotype due to the presence of Co-19-EPs. Discussion: In summary, these data highlight that abnormal circulating EPs promote ILC2-driven inflammatory signals in severe COVID-19 patients and support further exploration to unravel the role of EPs (and EVs) in COVID-19 pathogenesis. [ABSTRACT FROM AUTHOR]

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG_AUCCD45: 241.52 ± 152.16 vs. 766.63 +/- 283.52 (mg*day)/ml, p = 1.46e-5). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG_AUCCD3: 335.83 ± 208.15 vs. 903.54 ± 378.78 (mg*day)/ml, p = 1.92e-4; ATLG_AUCCD4: 317.75 ± 170.70 vs. 910.54 ± 353.35 (mg*day)/ml, p = 3.78e-5. Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e-5). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention. [ABSTRACT FROM AUTHOR]

The 1.33-mm survey of protoplanetary discs in the Taurus molecular cloud found annular gaps and rings to be common in extended sources (≳ 55 au), when their 1D visibility distributions were fit parametrically. We first demonstrate the advantages and limitations of non-parametric visibility fits for data at the survey's 0.12-arcsec resolution. Then we use the non-parametric model in Frankenstein (frank) to identify new substructure in three compact and seven extended sources. Among the new features, we identify three trends: a higher occurrence rate of substructure in the survey's compact discs than previously seen, underresolved (potentially azimuthally asymmetric) substructure in the innermost disc of extended sources, and a 'shoulder' on the trailing edge of a ring in discs with strong depletion at small radii. Noting the shoulder morphology is present in multiple discs observed at higher resolution, we postulate it is tracing a common physical mechanism. We further demonstrate how a superresolution frank brightness profile is useful in motivating an accurate parametric model, using the highly structured source DL Tau in which frank finds two new rings. Finally, we show that sparse (u, v) plane sampling may be masking the presence of substructure in several additional compact survey sources. [ABSTRACT FROM AUTHOR]

Large surveys of star-forming regions have unveiled power-law correlations between the stellar mass and the disc parameters, such as the disc mass |$M_{\mathrm{d}} \!-\! {M_{\star }}$| and the accretion rate |$\dot{M} \!-\! {M_{\star }}$|⁠. The observed slopes appear to be increasing with time, but the reason behind the establishment of these correlations and their subsequent evolution is still uncertain. We conduct a theoretical analysis of the impact of viscous evolution on power-law initial conditions for a population of protoplanetary discs. We find that, for evolved populations, viscous evolution enforces the two correlations to have the same slope, λ m =  λ acc, and that this limit is uniquely determined by the initial slopes λ m, 0 and λ acc, 0. We recover the increasing trend claimed from the observations when the difference in the initial values, δ 0 = λ m, 0− λ acc, 0, is larger than 1/2; moreover, we find that this increasing trend is a consequence of a positive correlation between the viscous time-scale and the stellar mass. We also present the results of disc population synthesis numerical simulations, that allow us to introduce a spread and analyse the effect of sampling, which show a good agreement with our analytical predictions. Finally, we perform a preliminary comparison of our numerical results with observational data, which allows us to constrain the parameter space of the initial conditions to λ m, 0 ∈ [1.2, 2.1], λ acc, 0 ∈ [0.7, 1.5]. [ABSTRACT FROM AUTHOR]

Advanced therapy medical products (ATMPs) are rapidly growing as innovative medicines for the treatment of several diseases. Hence, the role of quality analytical tests to ensure consistent product safety and quality has become highly relevant. Several clinical trials involving dendritic cell (DC)-based vaccines for cancer treatment are ongoing at our institute. The DC-based vaccine is prepared via CD14+ monocyte differentiation. A fresh dose of 10 million DCs is administered to the patient, while the remaining DCs are aliquoted, frozen, and stored in nitrogen vapor for subsequent treatment doses. To evaluate the maintenance of quality parameters and to establish a shelf life of frozen vaccine aliquots, a stability program was developed. Several parameters of the DC final product at 0, 6, 12, 18, and 24 months were evaluated. Our results reveal that after 24 months of storage in nitrogen vapor, the cell viability is in a range between 82% and 99%, the expression of maturation markers remains inside the criteria for batch release, the sterility tests are compliant, and the cell costimulatory capacity unchanged. Thus, the data collected demonstrate that freezing and thawing do not perturb the DC vaccine product maintaining over time its functional and quality characteristics. [ABSTRACT FROM AUTHOR]

In the last few years, steps forward in the knowledge of the biology of soft tissue sarcomas (STS) have led to the development of new therapeutic strategies, including immunotherapy. This review outlines the recent findings on immunological features and provides a synopsis of the results of clinical trials with different immunotherapy approaches in STS, discussing criticisms, and how the efficacy of immunotherapy could be improved. The heterogeneity of STS has limited generalized approaches of immunotherapy in the disease. Clinical decisions should encompass a comprehensive characterization of the tumor microenvironment (TME), marked by intra-histotype diversity. Profiling of immune cells, checkpoint molecules, and antigen target/HLA expression is deemed to reshape the classical histotype classification for a selection of the most appropriate immune-based treatment. In a synergistic view, tumor-directed treatments, designed on the genetic and epigenetic histotype make-up, should be monitored for their immunomodulant effect and applied to ensure or amplify immunotherapy response. In light of the dynamic nature of the TME, this immunomonitoring should be conducted at baseline and during treatment, for improved therapeutic decisions and rational sequence of treatment combination, pursuing an immunological marker approach by histotype guidance. [ABSTRACT FROM AUTHOR]

Aims: In patients undergoing cardiac implantable electronic device (CIED) intervention, routine pre-procedure antibiotic prophylaxis is recommended. A more powerful antibiotic protocol has been suggested in patients at high risk of infection. Stratification of individual infective risk could guide the prophylaxis before CIED procedure.Methods and Results: Patients undergoing CIED surgery were stratified according to the Shariff score in low and high infective risk. Patients in the 'low-risk' group were treated with only two antibiotic administrations while patients in the 'high-risk' group were treated with a prolonged 9-day protocol, according to renal function and allergies. We followed-up patients for 250 days with clinical outpatient visit and electronic control of the CIED. As primary endpoint, we evaluated CIED-related infections. A total of 937 consecutive patients were enrolled, of whom 735 were stratified in the 'low-risk' group and 202 in the 'high-risk' group. Despite different risk profiles, CIED-related infection rate at 250 days was similar in the two groups (8/735 in 'low risk' vs. 4/202 in 'high risk', P = 0.32). At multivariate analysis, active neoplasia, haematoma, and reintervention were independently associated with CIED-related infection (HR 5.54, 10.77, and 12.15, respectively).Conclusion: In a large cohort of patients undergoing CIED procedure, an antibiotic prophylaxis based on individual stratification of infective risk resulted in similar rate of infection between groups at high and low risk of CIED-related infection. [ABSTRACT FROM AUTHOR]

Polycythemia Vera (PV) is a myeloproliferative neoplasm with increased risk of thrombosis and progression to myelofibrosis. Chronic inflammation is commonly observed in myeloproliferative neoplasms including PV. The inflammatory network includes the extracellular vesicles (EVs), which play a role in cell-cell communication. Recent evidence points to circulating microbial components/microbes as potential players in hemopoiesis regulation. To address the role of EVs in PV, here we investigated phenotype and microbial DNA cargo of circulating EVs through multidimensional analysis. Peripheral blood and feces were collected from PV patients (n=38) and healthy donors (n=30). Circulating megakaryocyte (MK)- and platelet (PLT)-derived EVs were analyzed by flow cytometry. After microbial DNA extraction from feces and isolated EVs, the 16S rDNA V3-V4 region was sequenced. We found that the proportion of circulating MK-derived EVs was significantly decreased in PV patients as compared with the healthy donors. By contrast, the proportion of the PLT-derived EVs was increased. Interestingly, PV was also associated with a microbial DNA signature of the isolated EVs with higher diversity and distinct microbial composition than the healthy counterparts. Of note, increased proportion of isolated lipopolysaccharide-associated EVs has been demonstrated in PV patients. Conversely, the gut microbiome profile failed to identify a distinct layout between PV patients and healthy donors. In conclusion, PV is associated with circulating EVs harbouring abnormal phenotype and dysbiosis signature with a potential role in the (inflammatory) pathogenesis of the disease. [ABSTRACT FROM AUTHOR]

We present the first ALMA survey of protoplanetary discs at 3 mm, targeting 36 young stellar objects in the Lupus star-forming region with deep observations (sensitivity 20–50  |$\mu$| Jy beam−1) at ∼0.35 arcsec resolution (∼50 au). Building on previous ALMA surveys at 0.89 and 1.3 mm that observed the complete sample of Class II discs in Lupus at a comparable resolution, we aim to assess the level of grain growth in the relatively young Lupus region. We measure 3 mm integrated fluxes, from which we derive disc-averaged 1–3 mm spectral indices. We find that the mean spectral index of the observed Lupus discs is |$\alpha _\mathrm{1-3\, mm}=2.23\pm 0.06$|⁠ , in all cases |$\alpha _\mathrm{1-3\, mm}\lt 3.0$|⁠ , with a tendency for larger spectral indices in the brightest discs and in transition discs. Furthermore, we find that the distribution of spectral indices in Lupus discs is statistically indistinguishable from that of the Taurus and Ophiuchus star-forming regions. Assuming the emission is optically thin, the low values |$\alpha _\mathrm{1-3\, mm}\le 2.5$| measured for most discs can be interpreted with the presence of grains larger than 1 mm. The observations of the faint discs in the sample can be explained without invoking the presence of large grains, namely through a mixture of optically thin and optically thick emission from small grains. However, the bright (and typically large) discs do inescapably require the presence of millimetre-sized grains in order to have realistic masses. Based on a disc mass argument, our results challenge previous claims that the presence of optically thick substructures may be a universal explanation for the empirical millimetre size-luminosity correlation observed at 0.89 mm. [ABSTRACT FROM AUTHOR]

We analyse spatially resolved ALMA observations at 0.9, 1.3, and 3.1 mm for the 26 brightest protoplanetary discs in the Lupus star-forming region. We characterize the discs multiwavelength brightness profiles by fitting the interferometric visibilities in a homogeneous way, obtaining effective disc sizes at the three wavelengths, spectral index profiles, and optical depth estimates. We report three fundamental discoveries: first, the millimetre continuum size–luminosity relation already observed at 0.9 mm is also present at 1.3 mm with an identical slope, and at 3.1 mm with a steeper slope, confirming that emission at longer wavelengths becomes increasingly optically thin. Second, when observed at 3.1 mm the discs appear to be only 9 per cent smaller than when observed at 0.9 mm, in tension with models of dust evolution that predict a starker difference. Third, by forward modelling the sample of measurements with a simple parametric disc model, we find that the presence of large grains (⁠|$a_\mathrm{max}\gt 1\,$| mm) throughout the discs is the most favoured explanation for all discs as it reproduces simultaneously their spectral indices, optical depth, luminosity, and radial extent in the 0.9–1.3 mm wavelength range. We also find that the observations can be alternatively interpreted with the discs being dominated by optically thick, unresolved, substructures made of mm-sized grains with a high scattering albedo. [ABSTRACT FROM AUTHOR]

Vineyard and olive farming are deeply rooted in the economy, culture, and even the welfare of Mediterranean countries. Although numerous approaches and methods were developed to valorize their agricultural residues, several challenges remain to overcome moving towards the Circular Economy (CE). Conventional treatments of winery and olive mill wastes are becoming increasingly expensive, demanding significant amounts of effort, resources, and energy for safe waste discharge. Therefore, the need to recycle, reuse, and recover energy and valuable biocompounds from the wastes of these two sectors become apparent. In the context of increasing waste production, climate change, coupled with dramatic rises in demand from a much larger global population and customers, CE offers the prospect of a better future. Microbes are able to produce diverse biosurfactants (BS) containing both hydrophilic and hydrophobic moieties that could interact with surfaces, lower surface and interfacial tensions, form micelles, and emulsify immiscible substances. Among several BS classes, rhamnolipids are glycolipids produced by some gram-negative bacteria with various potential applications in numerous fields, including bioremediation of contaminated soils. In contrast to several biosurfactants, this particular class of glycolipids is among the economically competitive biomolecules with its synthetic equivalents. For that, we highlighted the main opportunities, the challenges, and the future aspects towards the production of this particular type of glycolipids using winery and olive oil wastes. Therefore, we proposed the critical points that should be assumed through the path of successful strategies for rhamnolipid production using these two potential agricultural residues. This review might help at boosting the current attempts to find novel CE models. [ABSTRACT FROM AUTHOR]

To determine the origin of the spiral structure observed in the dust continuum emission of Elias 2–27 we analyze multiwavelength continuum ALMA data with a resolution of ∼0.″2 (∼23 au) at 0.89, 1.3, and 3.3 mm. We also study the kinematics of the disk with 13CO and C18O ALMA observations in the J = 3–2 transition. The spiral arm morphology is recovered at all wavelengths in the dust continuum observations, where we measure contrast and spectral index variations along the spiral arms and detect subtle dust-trapping signatures. We determine that the emission from the midplane is cold and interpret the optical depth results as signatures of a disk mass higher than previous constraints. From the gas data, we search for deviations from Keplerian motion and trace the morphology of the emitting surfaces and the velocity profiles. We find an azimuthally varying emission layer height in the system, large-scale emission surrounding the disk, and strong perturbations in the channel maps, colocated with the spirals. Additionally, we develop multigrain dust and gas hydrodynamical simulations of a gravitationally unstable disk and compare them to the observations. Given the large-scale emission and highly perturbed gas structure, together with the comparison of continuum observations to theoretical predictions, we propose infall-triggered gravitational instabilities as the origin for the observed spiral structure. [ABSTRACT FROM AUTHOR]

Within the circular economy framework, our study aims to assess the rhamnolipid production from winery and olive oil residues as low-cost carbon sources by nonpathogenic strains. After evaluating various agricultural residues from those two sectors, Burkholderia thailandensis E264 was found to use the raw soluble fraction of nonfermented (white) grape marcs (NF), as the sole carbon and energy source, and simultaneously, reducing the surface tension to around 35 mN/m. Interestingly, this strain showed a rhamnolipid production up to 1070 mg/L (13.37 mg/g of NF), with a higher purity, on those grape marcs, predominately Rha-Rha C14-C14, in MSM medium. On olive oil residues, the rhamnolipid yield of using olive mill pomace (OMP) at 2% (w/v) was around 300 mg/L (15 mg/g of OMP) with a similar CMC of 500 mg/L. To the best of our knowledge, our study indicated for the first time that a nonpathogenic bacterium is able to produce long-chain rhamnolipids in MSM medium supplemented with winery residues, as sole carbon and energy source. Key points: • Winery and olive oil residues are used for producing long-chain rhamnolipids (RLs). • Both higher RL yields and purity were obtained on nonfermented grape marcs as substrates. • Long-chain RLs revealed stabilities over a wide range of pH, temperatures, and salinities [ABSTRACT FROM AUTHOR]

Recent observations have revealed that most proto-planetary discs show a pattern of bright rings and dark gaps. However, most of the high-resolution observations have focused only on the continuum emission. In this paper, we present high-resolution ALMA band 7 (0.89 mm) observations of the disc around the star CI Tau in the 12CO & 13CO J  = 3–2 and CS J  = 7–6 emission lines. Our recent work demonstrated that the disc around CI Tau contains three gaps and rings in continuum emission, and we look for their counterparts in the gas emission. While we find no counterpart of the third gap and ring in 13CO, the disc has a gap in emission at the location of the second continuum ring (rather than gap). We demonstrate that this is mostly an artefact of the continuum subtraction, although a residual gap still remains after accounting for this effect. Through radiative transfer modelling, we propose this is due to the inner disc shadowing the outer parts of the disc and making them colder. This raises a note of caution in mapping high-resolution gas emission lines observations to the gas surface density – while possible, this needs to be done carefully. In contrast to 13CO, CS emission shows instead a ring morphology, most likely due to chemical effects. Finally, we note that 12CO is heavily absorbed by the foreground preventing any morphological study using this line. [ABSTRACT FROM AUTHOR]

We observed the K7 class III star NO Lup in an ALMA survey of the 1–3 Myr Lupus association and detected circumstellar dust and CO gas. Here we show that the J = 3–2 CO emission is both spectrally and spatially resolved, with a broad velocity width ∼19 km s−1 for its resolved size ∼1 arcsec (∼130 au). We model the gas emission as a Keplerian disc, finding consistency, but only with a central mass of ∼11M⊙, which is implausible given its spectral type and X-Shooter spectrum. A good fit to the data can also be found by modelling the CO emission as outflowing gas with a radial velocity ∼22 km s−1. We interpret NO Lup's CO emission as the first imaged class III circumstellar disc with outflowing gas. We conclude that the CO is continually replenished, but cannot say if this is from the breakup of icy planetesimals or from the last remnants of the protoplanetary disc. We suggest further work to explore the origin of this CO, and its higher than expected velocity in comparison to photoevaporative models. [ABSTRACT FROM AUTHOR]

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system. Conventional co-culture systems often lack physiological complexity of the tumor microenvironment. Here, the authors report an organotypic skin melanoma culture and use this model to investigate the tumor induced suppression on dendritic cells. [ABSTRACT FROM AUTHOR]

We utilize ALMA archival data to estimate the dust disk size of 152 protoplanetary disks in Lupus (1–3 Myr), Chamaeleon I (2–3 Myr), and Upper-Sco (5–11 Myr). We combine our sample with 47 disks from Tau/Aur and Oph whose dust disk radii were estimated, as here, through fitting radial profile models to visibility data. We use these 199 homogeneously derived disk sizes to identify empirical disk–disk and disk–host property relations as well as to search for evolutionary trends. In agreement with previous studies, we find that dust disk sizes and millimeter luminosities are correlated, but show for the first time that the relationship is not universal between regions. We find that disks in the 2–3 Myr old Cha I are not smaller than disks in other regions of similar age, and confirm the Barenfeld et al. finding that the 5–10 Myr USco disks are smaller than disks belonging to younger regions. Finally, we find that the outer edge of the solar system, as defined by the Kuiper Belt, is consistent with a population of dust disk sizes which have not experienced significant truncation. [ABSTRACT FROM AUTHOR]

Dippers are a common class of young variable star exhibiting day-long dimmings with depths of up to several tens of per cent. A standard explanation is that dippers host nearly edge-on (i d ≈ 70°) protoplanetary discs that allow close-in (<1 au) dust lifted slightly out of the mid-plane to partially occult the star. The identification of a face-on dipper disc and growing evidence of inner disc misalignments brings this scenario into question. Thus, we uniformly (re)derive the inclinations of 24 dipper discs resolved with (sub-)mm interferometry from ALMA. We find that dipper disc inclinations are consistent with an isotropic distribution over i d ≈ 0−75°, above which the occurrence rate declines (likely an observational selection effect due to optically thick disc mid-planes blocking their host stars). These findings indicate that the dipper phenomenon is unrelated to the outer (>10 au) disc resolved by ALMA and that inner disc misalignments may be common during the protoplanetary phase. More than one mechanism may contribute to the dipper phenomenon, including accretion-driven warps and 'broken' discs caused by inclined (sub-)stellar or planetary companions. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/anti-inflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response. [ABSTRACT FROM AUTHOR]

The Sunyaev–Zel'dovich (SZ) effect can potentially be used to investigate the heating of the circumgalactic medium and subsequent suppression of cold gas accretion on to the host galaxy caused by quasar feedback. We use a deep ALMA observation of HE0515-4414 in band 4, the most luminous quasar known at the peak of cosmic star formation (z  = 1.7), to search for the SZ signal tracing the heating of the galaxy's halo. ALMA's sensitivity to a broad range of spatial scales enables us to disentangle emitting compact sources from the negative, extended SZ signal. We obtain a marginal SZ detection (∼3.3σ) on scales of about 300 kpc (30–40 arcsec), at the 0.2 mJy level, 0.5 mJy after applying a correction factor for primary beam attenuation and flux that is resolved out by the array. We show that our result is consistent with a simulated ALMA observation of a similar quasar in the fable cosmological simulations. We emphasize that detecting an SZ signal is more easily achieved in the visibility plane than in the (inferred) images. We also confirm a marginal detection (3.2σ) of a potential SZ dip on smaller scales (<100 kpc) already claimed by other authors, possibly highlighting the complex structure of the halo heating. Finally, we use SZ maps from the fable cosmological simulations, convolved with ALMA simulations, to illustrate that band 3 observations are much more effective in detecting the SZ signal with higher significance, and discuss the optimal observing strategy. [ABSTRACT FROM AUTHOR]

We present Atacama Large Millimeter/submillimeter Array (ALMA) observations of eight highly excited CO (⁠|${\rm J_{\rm up}}$|  > 8) lines and continuum emission in two z  ∼ 6 quasars: SDSS J231038.88+185519.7 (hereafter J2310), for which CO(8–7), CO(9–8), and CO(17–16) lines have been observed, and ULAS J131911.29+095951.4 (J1319), observed in the CO(14–13), CO(17–16), and CO(19–18) lines. The continuum emission of both quasars arises from a compact region (<0.9 kpc). By assuming a modified blackbody law, we estimate dust masses of log(M dust/M⊙) = 8.75 ± 0.07 and log(M dust/M⊙) = 8.8 ± 0.2 and dust temperatures of T dust = 76 ± 3 K and |$T_{\rm dust}=66^{+15}_{-10}\,{\rm K}$|⁠ , respectively, for J2310 and J1319. Only CO(8–7) and CO(9–8) in J2310 are detected, while 3σ upper limits on luminosities are reported for the other lines of both quasars. The CO line luminosities and upper limits measured in J2310 and J1319 are consistent with those observed in local active galactic nuclei and starburst galaxies, and other z  ∼ 6 quasars, except for SDSS J1148+5251 (J1148), the only quasar at z  = 6.4 with a previous CO(17–16) line detection. By computing the CO spectral line energy distributions normalized to the CO(6–5) line and far-infrared luminosities for J2310, J1319, and J1148, we conclude that different gas heating mechanisms (X-ray radiation and/or shocks) may explain the different CO luminosities observed in these z  ∼ 6 quasar. Future |${\rm J_{\rm up}}$|  > 8 CO observations will be crucial to understand the processes responsible for molecular gas excitation in luminous high- z quasars. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies. [ABSTRACT FROM AUTHOR]

ALMA has observed a plethora of ring-like structures in planet-forming discs at distances of 10–100 au from their host star. Although several mechanisms have been invoked to explain the origin of such rings, a common explanation is that they trace new-born planets. Under the planetary hypothesis, a natural question is how to reconcile the apparently high frequency of gap-carving planets at 10–100 au with the paucity of Jupiter-mass planets observed around main-sequence stars at those separations. Here, we provide an analysis of the new-born planet population emerging from observations of gaps in discs, under the assumption that the observed gaps are due to planets. We use a simple estimate of the planet mass based on the gap morphology, and apply it to a sample of gaps recently obtained by us in a survey of Taurus with ALMA. We also include additional data from recent published surveys, thus analysing the largest gap sample to date, for a total of 48 gaps. The properties of the purported planets occupy a distinctively different region of parameter space with respect to the known exo-planet population, currently not accessible through planet finding methods. Thus, no discrepancy in the mass and radius distribution of the two populations can be claimed at this stage. We show that the mass of the inferred planets conforms to the theoretically expected trend for the minimum planet mass needed to carve a dust gap. Finally, we estimate the separation and mass of the putative planets after accounting for migration and accretion, for a range of evolutionary times, finding a good match with the distribution of cold Jupiters. [ABSTRACT FROM AUTHOR]

Recent observations show that rings and gaps are ubiquitous in protoplanetary discs. These features are often interpreted as being due to the presence of planets; however, the effect of planetary migration on the observed morphology has not been investigated hitherto. In this work, we investigate whether multiwavelength mm/submm observations can detect signatures of planet migration, using 2D dusty hydrodynamic simulations to model the structures generated by migrating planets and synthesizing ALMA continuum observations at |$\rm 850\, \hbox{$\mu $m}$| and |$\rm 3\, mm$|⁠. We identify three possible morphologies for a migrating planet: a slowly migrating planet is associated with a single ring outside the planet's orbit, a rapidly migrating planet is associated with a single ring inside the planet's orbit while a planet migrating at intermediate speed generates one ring on each side of the planet's orbit. We argue that multiwavelength data can distinguish multiple rings produced by a migrating planet from other scenarios for creating multiple rings, such as multiple planets or discs with low viscosity. The signature of migration is that the outer ring has a lower spectral index, due to larger dust grains being trapped there. Of the recent ALMA observations revealing protoplanetary discs with multiple rings and gaps, we suggest that Elias 24 is the best candidate for a planet migrating in the intermediate speed regime. [ABSTRACT FROM AUTHOR]

The large majority of protoplanetary disks have very compact continuum emission (≲15 AU) at millimeter wavelengths. However, high angular resolution observations that resolve these small disks are still lacking, due to their intrinsically fainter emission compared with large bright disks. In this Letter we present 1.3 mm ALMA data of the faint disk (∼10 mJy) orbiting the TTauri star CX Tau at a resolution of ∼40 mas, ∼5 AU in diameter. The millimeter dust disk is compact, with a 68% enclosing flux radius of 14 AU, and the intensity profile exhibits a sharp drop between 10 and 20 AU, and a shallow tail between 20 and 40 AU. No clear signatures of substructure in the dust continuum are observed, down to the same sensitivity level of the DSHARP large program. However, the angular resolution does not allow us to detect substructures on the scale of the disk aspect ratio in the inner regions. The radial intensity profile closely resembles the inner regions of more extended disks imaged at the same resolution in DSHARP, but with no rings present in the outer disk. No inner cavity is detected, even though the disk has been classified as a transition disk from the spectral energy distribution in the near-infrared. The emission of 12CO is much more extended, with a 68% enclosing flux radius of 75 AU. The large difference of the millimeter dust and gas extents (> 5) strongly points to radial drift, and closely matches the predictions of theoretical models. [ABSTRACT FROM AUTHOR]

The article focuses on a study which aims to investigate the profile of microvesicles (MV) in myelofibrosis (MF) and essential thrombocythaemia (ET) whether MV proportions could be related to severity of MF as well as the role of inflammation on MV frequency in MF. Information about the effects of ruxolitinib on MVs in MF and the frequency of circulating megakaryocyte- and platelet-MVs is presented.

A correlation between proto-planetary disc radii and sub-mm fluxes has been recently reported. In this letter, we show that the correlation is a sensitive probe of grain growth processes. Using models of grain growth and drift, we have shown in a companion paper that the observed disc radii trace where the dust grains are large enough to have a significant sub-mm opacity. We show that the observed correlation emerges naturally if the maximum grain size is set by radial drift, implying relatively low values of the viscous α parameter ≲0.001. In this case, the relation has an almost universal normalization, while if the grain size is set by fragmentation the flux at a given radius depends on the dust-to-gas ratio. We highlight two observational consequences of the fact that radial drift limits the grain size. The first is that the dust masses measured from the sub-mm could be overestimated by a factor of a few. The second is that the correlation should be present also at longer wavelengths (e.g. 3mm), with a normalization factor that scales as the square of the observing frequency as in the optically thick case. [ABSTRACT FROM AUTHOR]

Context. The cyanide radical CN is abundant in protoplanetary disks, with line fluxes often comparable to those of 13CO. It is known to be sensitive to UV irradiation of the upper disk atmosphere, with models predicting ring-shaped emission. Aims. We seek to characterize the CN emission from 94 Class-II disks in the Lupus star-forming region, compare it to observations in other regions, and interpret our observations with a grid of models. The CN emission morphology is discussed for two primordial disks, Sz 71 and Sz 98, and is modeled in more detail. Methods. ALMA observed CN N = 3−2 in Lupus disks down to sensitivities better than previous surveys. Models constructed with the physico-chemical code DALI are used to study the integrated fluxes of the disks and resolved emission of CN in disks without (dust) substructures. Results. CN N = 3−2 is bright, and detected in 38% of sources, but its disk-integrated flux is not strongly correlated to either 13CO or continuum flux. Compared to pre-ALMA single-dish surveys, no significant difference in the CN flux distributions in Lupus and Taurus–Auriga is found, although ρ Ophiuchus disks may be fainter on average. We find ring-shaped CN emission with peak radii of ~50 AU in two resolved disks. Conclusions. A large fraction of sources are faint in CN; only exponential gas surface density cutoffs at Rc ≤ 15 AU can reconcile observations with models. This is the first observational evidence of such a compact gas disk population in Lupus. Absolute intensities and the emission morphology of CN are reproduced by DALI models without the need for any continuum substructure; they are unrelated to the CO snowline location. The observations presented here, together with the modeling of these rings, provide a new probe of the structure and conditions in disks, and particularly their incident UV radiation field, if disk size is determined from the data. [ABSTRACT FROM AUTHOR]

Context. A good constraint of when the growth of dust grains from sub-micrometer to millimeter sizes occurs, is crucial for planet formation models. This provides the first step towards the production of pebbles and planetesimals in protoplanetary disks. Currently, it is well established that Class II objects have large dust grains. However, it is not clear when in the star formation process this grain growth occurs. Aims. We use multi-wavelength millimeter observations of a Class I protostar to obtain the spectral index of the observed flux densities αmm of the unresolved disk and the surrounding envelope. Our goal is to compare our observational results with visibility modeling at both, 1.3 and 2.7 mm simultaneously. Methods. We present data from NOEMA at 2.7 mm and SMA at 1.3 mm of the Class I protostar, Per-emb-50. We model the dust emission with a variety of parametric and radiative-transfer models to deduce the grain size from the observed emission spectral index. Results. We find a spectral index in the envelope of Per-emb-50 of αenv = 3.3 ± 0.3, similar to the typical ISM values. The radiative-transfer modeling of the source confirms this value of αenv with the presence of dust with a amax ≤ 100 μm. Additionally, we explore the backwarming effect, where we find that the envelope structure affects the millimeter emission of the disk. Conclusions. Our results reveal grains with a maximum size no larger than 100 μm in the inner envelope of the Class I protostar Per-emb-50, providing an interesting case to test the universality of millimeter grain growth expected in these sources. [ABSTRACT FROM AUTHOR]

The synthesis of a new dithiolethione-cysteine ethyl ester hybrid, ACS94, its metabolites, and its effect on GSH levels in rat tissues and on the concentration of circulating H2S is described. ACS94 rapidly enters the cells, where it is metabolised to cysteine and the dithiolethione moiety ACS48. Experiments performed through the oral administration of ACS94 to healthy rats showed that it is capable of increasing the GSH levels in most of the analysed organs and the concentration of circulating H2S. Although the increase in GSH concentration was similar to that obtained by ACS48 and N-acetylcysteine ethyl ester, the H2S increase was long-lasting and more evident with respect to the parent molecules. Moreover, a decrease of homocysteine in several rat organs and in plasma was noted. This effect may represent a potential therapeutic use of ACS94, as hyperhomocysteinaemia is considered a risk factor for cardiovascular diseases. Lastly, ACS94 was more efficient than N-acetylcysteine in protecting the liver and kidneys against acute acetaminophen toxicity. [ABSTRACT FROM AUTHOR]

Context. Spiral arms, rings and large scale asymmetries are structures observed in high resolution observations of protoplanetary disks, and it appears that some of the disks showing spiral arms in scattered light also show asymmetries in millimeter-sized dust. HD 135344B is one such disk. Planets are invoked as the origin of these structures, but no planet has been observed so far and upper limits are becoming more stringent with time. Aims. We want to investigate the nature of the asymmetric structure in the HD 135344B disk in order to understand the origin of the spirals and of the asymmetry seen in this disk. Ultimately, we aim to understand whether or not one or more planets are needed to explain such structures. Methods. We present new ALMA sub-0.1′′ resolution observations at optically thin wavelengths (λ = 2.8 and 1.9 mm) of the HD 135344B disk. The high spatial resolution allows us to unambiguously characterize the mm-dust morphology of the disk. The low optical depth of continuum emission probes the bulk of the dust content of the vortex. Moreover, we have combined the new observations with archival data at shorter wavelengths to perform a multi-wavelength analysis and to obtain information about the dust distribution and properties inside the observed asymmetry. Results. We resolve the asymmetric disk into a symmetric ring + asymmetric crescent, and observe that (1) the spectral index strongly decreases at the centre of the vortex, consistent with the presence of large grains; (2) for the first time, an azimuthal shift of the peak of the vortex with wavelength is observed; (3) the azimuthal width of the vortex decreases at longer wavelengths, as expected for dust traps. These features allow confirming the nature of the asymmetry as a vortex. Finally, under the assumption of optically thin emission, a lower limit to the total mass of the vortex is 0.3MJupiter. Considering the uncertainties involved in this estimate, it is possible that the actual mass of the vortex is higher and possibly within the required values (~4 MJupiter) to launch spiral arms similar to those observed in scattered light. If this is the case, then explaining the morphology does not require an outer planet. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma (MpM), arising in the setting of local inflammation, is a rare aggressive tumour with a poor prognosis and limited therapeutic options. The three major MpM histological variants, epithelioid (E-MpMs), biphasic, and sarcomatoid MpMs (S-MpMs), are characterised by an increased aggressiveness and enhanced levels of EZH2 expression. To investigate the MpM immune contexture along the spectrum of MpM histotypes, an extended in situ analysis was performed on a series of 14 cases. Tumour-infiltrating immune cells and their functionality were assessed by immunohistochemistry, immunofluorescence, qRT-PCR, and flow cytometry analysis. MpMs are featured by a complex immune landscape modulated along the spectrum of MpM variants. Tumour-infiltrating T cells and evidence for pre-existing antitumour immunity are mainly confined to E-MpMs. However, Th1-related immunological features are progressively impaired in the more aggressive forms of E-MpMs and completely lost in S-MpM. Concomitantly, E-MpMs show also signs of active immune suppression, such as the occurrence of Tregs and Bregs and the expression of the immune checkpoint inhibitory molecules PD1 and PDL1. This study enriches the rising rationale for immunotherapy in MpM and points to the E-MpMs as the most immune-sensitive MpM histotypes, but it also suggests that synergistic interventions aimed at modifying the tumour microenvironment (TME) should be considered to make immunotherapy beneficial for these patients. [ABSTRACT FROM AUTHOR]

We present GALARIO, a computational library that exploits the power of modern graphical processing units (GPUs) to accelerate the analysis of observations from radio interferometers like Atacama Large Millimeter and sub-millimeter Array or the Karl G. Jansky Very Large Array. GALARIO speeds up the computation of synthetic visibilities from a generic 2D model image or a radial brightness profile (for axisymmetric sources). On a GPU, GALARIO is 150 faster than standard PYTHON and 10 times faster than serial C++ code on a CPU. Highly modular, easy to use, and to adopt in existing code,GALARIOcomes as two compiled libraries, one for Nvidia GPUs and one for multicore CPUs, where both have the same functions with identical interfaces. GALARIO comes with PYTHON bindings but can also be directly used in C or C++. The versatility and the speed of GALARIO open new analysis pathways that otherwise would be prohibitively time consuming, e.g. fitting high-resolution observations of large number of objects, or entire spectral cubes of molecular gas emission. It is a general tool that can be applied to any field that uses radio interferometer observations. The source code is available online at http://github.com/mtazzari/galario under the open source GNU Lesser General Public License v3. [ABSTRACT FROM AUTHOR]

We present Atacama Large Millimeter/sub-millimeter Array (ALMA) Cycle 2 observations of the 1.3-mm dust continuum emission of the protoplanetary disc surrounding the T Tauri star Elias 24 with an angular resolution of ~0.2 arcsec (~28 au). The dust continuum emission map reveals a dark ring at a radial distance of 0.47 arcsec (~65 au) from the central star, surrounded by a bright ring at 0.58 arcsec (~81 au). In the outer disc, the radial intensity profile shows two inflection points at 0.71 and 0.87 arcsec (~99 and 121 au, respectively). We perform global three-dimensional smoothed particle hydrodynamic gas/dust simulations of discs hosting a migrating and accreting planet. Combining the dust density maps of small and large grains with three-dimensional radiative transfer calculations, we produce synthetic ALMA observations of a variety of disc models in order to reproduce the gap- and ring-like features observed in Elias 24. We find that the dust emission across the disc is consistent with the presence of an embedded planet with a mass of ~0.7MJ at an orbital radius of ~ 60 au. Our model suggests that the two inflection points in the radial intensity profile are due to the inward radial motion of large dust grains from the outer disc. The surface brightness map of our disc model provides a reasonable match to the gap- and ring-like structures observed in Elias 24, with an average discrepancy of ~5 per cent of the observed fluxes around the gap region. [ABSTRACT FROM AUTHOR]

B Introduction: b Immune effector cell-associated neurotoxicity syndrome (ICANS) is a life-threatening adverse effect of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that usually occurs within 5-7 days after cell infusion. Predicting ICANS by means of plasma CAR-T cell derived extracellular vesicles in patients undergoing infusion of anti-CD19 CAR-T cells Twenty out of 71 patients (28%) had ICANS of any grade: 5 patients (7%) ICANS grade 1, 7 patients (10%) ICANS grade 2 and 8 patients (11%) ICANS grade >=3 (3 patients ICANS grade 3, 3 patients ICANS grade 4 and 2 patients ICANS grade 5 with diffuse cerebral edema). [Extracted from the article]

Aims: The aim of this work is to constrain properties of the disk around the archetype FU Orionis object, FU Ori, with as good as ~25 au resolution. Methods. We resolved FU Ori at 29-37 GHz using the Karl G. Jansky Very Large Array (JVLA) in the A-array configuration, which provided the highest possible angular resolution to date at this frequency band (~007). We also performed complementary JVLA 8-10 GHz observations, Submillimeter Array (SMA) 224 GHz and 272 GHz observations, and compared these with archival Atacama Large Millimeter Array (ALMA) 346 GHz observations to obtain the spectral energy distributions (SEDs). Results: Our 8-10 GHz observations do not find evidence for the presence of thermal radio jets, and constrain the radio jet/wind flux to at least 90 times lower than the expected value from the previously reported bolometric luminosity-radio luminosity correlation. The emission at frequencies higher than 29 GHz may be dominated by the two spatially unresolved sources, which are located immediately around FU Ori and its companion FU Ori S, respectively. Their deconvolved radii at 33 GHz are only a few au, which is two orders of magnitude smaller in linear scale than the gaseous disk revealed by the previous Subaru-HiCIAO 1.6 µm coronagraphic polarization imaging observations. We are struck by the fact that these two spatially compact sources contribute to over 50% of the observed fluxes at 224 GHz, 272 GHz, and 346 GHz. The 8-346 GHz SEDs of FU Ori and FU Ori S cannot be fit by constant spectral indices (over frequency), although we cannot rule out that it is due to the time variability of their (sub)millimeter fluxes. Conclusions: The more sophisticated models for SEDs considering the details of the observed spectral indices in the millimeter bands suggest that the >29 GHz emission is contributed by a combination of free-free emission from ionized gas and thermal emission from optically thick and optically thin dust components. We hypothesize that dust in the innermost parts of the disks (≤0.1 au) has been sublimated, and thus the disks are no longer well shielded against the ionizing photons. The estimated overall gas and dust mass based on SED modeling, can be as high as a fraction of a solar mass, which is adequate for developing disk gravitational instability. Our present explanation for the observational data is that the massive inflow of gas and dust due to disk gravitational instability or interaction with a companion/intruder, was piled up at the few-au scale due to the development of a deadzone with negligible ionization. The piled up material subsequently triggered the thermal instability and the magnetorotational instability when the ionization fraction in the inner sub-au scale region exceeded a threshold value, leading to the high protostellar accretion rate. [ABSTRACT FROM AUTHOR]

Background: The study of lipid metabolism in stem cell physiology has recently raised great interest. The role of lipids goes beyond the mere structural involvement in assembling extra- and intra-cellular compartments. Nevertheless, we are still far from understanding the impact of membrane lipidomics in stemness maintenance and differentiation patterns. In the last years, it has been reported how in vitro cell culturing can modify membrane lipidomics. The aim of the present work was to study the membrane fatty acid profile of mesenchymal stromal cells (MSCs) derived from human fetal membranes (hFM-MSCs) and to correlate this to specific biological properties by using chemically defined tailored lipid supplements (Refeed®). Methods: Freshly isolated hFM-MSCs were characterized for their membrane fatty acid composition. hFM-MSCs were cultivated in vitro following a classical protocol and their membrane fatty acid profile at different passages was compared to the profile in vivo. A tailored Refeed® lipid supplement was developed with the aim of reducing the differences created by the in vitro cultivation and was tested on cultured hFM-MSCs. Cell morphology, viability, proliferation, angiogenic differentiation, and immunomodulatory properties after in vitro exposure to the tailored Refeed® lipid supplement were investigated. Results: A significant modification of hFM-MSC membrane fatty acid composition occurred during in vitro culture. Using a tailored lipid supplement, the fatty acid composition of cultured cells remained more similar to their in vivo counterparts, being characterized by a higher polyunsaturated and omega-6 fatty acid content. These changes in membrane composition had no effect on cell morphology and viability, but were linked with increased cell proliferation rate, angiogenic differentiation, and immunomodulatory properties. In particular, Refeed®-supplemented hFM-MSCs showed greater ability to express fully functional cell membrane molecules. Conclusions: Culturing hFM-MSCs alters their fatty acid composition. A tailored lipid supplement is able to improve in vitro hFM-MSC functional properties by recreating a membrane environment more similar to the physiological counterpart. This approach should be considered in cell therapy applications in order to maintain a higher cell quality during in vitro passaging and to influence the outcome of cell-based therapeutic approaches when cells are administered to patients. [ABSTRACT FROM AUTHOR]

Electrospray Ionization and collision induced dissociation tandem mass spectrometry are usually employed to obtain compound identification through a mass spectra match. Different algorithms have been developed for this purpose (for example the NIST match algorithm). These approaches compare the tandem mass spectra of the unknown analyte with the tandem mass spectra spectra of known compounds inserted in a database. The compounds are usually identified on the basis of spectral match value associated with a probability of recognition. However, this approach is not usually applied to multiple reaction monitoring transition spectra achieved bymeans of triple quadrupole apparatus, mainly due to the lack of a transition spectra database. The Surface Activated Chemical Ionization-Electrospray-NIST Bayesian model database search (SANIST) platform has been recently developed for new potential metabolite biomarker discovery, to confirm their identity and to use themfor clinical and diagnostic applications. Here, we present an improved version of the SANIST platform that extends its application to forensic, pharmaceutical, and food analysis studies, where the compound identification rules are strict. The European Union (EU) has set directives for compound identification (EU directive 2002/657/EC). We have applied the SANIST method to identification of 11-nor-9-carboxytetrahydro-cannabinol in urine samples (an example of a forensic application), circulating levels of the immunosuppressive drug tacrolimus in blood (an example of a pharmaceutical application) and glyphosate in fruit juice (an example of a food analysis application) that meet the EU directive requirements. [ABSTRACT FROM AUTHOR]