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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 18F-FDG-PET/CT status, higher risk and lower response to PRRT.MethodsWhole 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 semi-automated miR-protein protocol was applied in PanNET FFPE specimens (n=9). In vitro functional experiments were performed in PanNET models.ResultsWhile 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:18F-FDG-PET/CT positive PanNETs with worse prognosis after PRRT (p-value:68Gallium-DOTATOC captation values (p-value:SSTR2 when ectopically expressed in PanNET cells (p-value:Conclusionshsa-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.

Planet formation imprints signatures on the physical structures of disks. In this paper, we present high-resolution ($\sim$50 mas, 8 au) Atacama Large Millimeter/submillimeter Array (ALMA) observations of 1.3 mm dust continuum and CO line emission toward the disk around the M3.5 star 2MASS J04124068+2438157. The dust disk consists only of two narrow rings at radial distances of 0.47 and 0.78 arcsec ($\sim$70 and 116 au), with Gaussian $\sigma$ widths of 5.6 and 8.5 au, respectively. The width of the outer ring is smaller than the estimated pressure scale height by $\sim25\%$, suggesting dust trapping in a radial pressure bump. The dust disk size, set by the location of the outermost ring, is significantly larger (by $3\sigma$) than other disks with similar millimeter luminosity, which can be explained by an early formation of local pressure bump to stop radial drift of millimeter dust grains. After considering the disk's physical structure and accretion properties, we prefer planet--disk interaction over dead zone or photoevaporation models to explain the observed dust disk morphology. We carry out high-contrast imaging at $L'$ band using Keck/NIRC2 to search for potential young planets, but do not identify any source above $5\sigma$. Within the dust gap between the two rings, we reach a contrast level of $\sim$7 mag, constraining the possible planet below $\sim$2--4 $M_{\rm Jup}$. Analyses of the gap/ring properties suggest a $\sim$Saturn mass planet at $\sim$90 au is likely responsible for the formation of the outer ring, which can be potentially revealed with JWST., Comment: 15 pages, 5 figures. Accepted for publication in ApJ

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 .

Sections from case D6, exhibiting low- (left) and high-grade (right) components, immunolabelled with antibodies against SNAI2/SLUG (A), TWIST1(B) and ZEB1 (C). The photograph show a significant increase of immunolabelled nuclei in the more cellular high-grade area.

The imaging gallery demonstrates that the number of EZH2 immunolabelled nuclei parallels those decorated by Ki-67 in both FS-DFSP (left) and DFSP (right) cases.

Top 50 upregulated and downregulated genes in FS-DFSP vs DFSP and pathway analyses.

Principal Component Analysis of DFSP and FS-DFSP gene expression profiles.

Clinical/pathologic characteristics of the patients from whom the tissue samples molecularly profiled were derived; bold/underlined type indicates the tumor tissue from which the sample for the molecular analysis was derived.

Additional fusion genes identified in FS-DFSP.

Supplemental methodological information

Expression analysis (qRT-PCR) of H19, HOTAIR and EZH2 in DFSP and FS-DFSP samples. Statistical p values (unpaired Student's t test) are indicated.

Purpose: To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology.Experimental design: Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis.Results: All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer–mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected.Conclusions: All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM. Clin Cancer Res; 22(4); 837–46. ©2015 AACR.

Supplementary Table 1. Supervised analysis highlighted the differential expression of 250 genes, with a p value

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Supplementary Figure 1 from Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells

Supplementary Figure 1 from Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia

Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G0-G1 phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3β. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth. [Cancer Res 2009;69(8):3520–28]

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Supplementary Figure 1 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 3 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells

Supplementary Table 1 from Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

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.

Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) is the commonest subtype of PTCL. NF–kB related molecules have been found to be variably expressed in PTCL/NOS, suggesting a potential involvement of the NF–kB system in their pathogenesis. However, the actual contribution of NF–kB molecular programs to the PTCL/NOS landscape has not been investigated yet. In this study, we assessed in a large series of PTCL/NOS, the activation status of NF–kB programs and investigated the prognostic impact of such NF–kB expression. Moreover, we explored the possible role of NF–kB inhibitors. We studied the gene expression profiles of 180 PTCL cases and tested two different drugs, the IKK inhibitor BMS-345541 and the proteasome inhibitor Bortezomib, in four PTCL cell lines. We found that most cases (84%) presented with some degree of NF–kB activation, based on the expression of REL and RELA. Functionally, the latter was strictly related with TCR signaling activation, while REL was at least partially TCR independent. We also identified genes related with NF–kB activation in this setting that were mainly involved in cell proliferation and apoptosis inhibition. Further, by reverse engineering we defined the transcriptional network of both REL and RELA in PTCLs that only partially overlapped. On the clinical ground, we found that RELA expression was related to a significantly poorer overall survival, with similar trends for REL. However, most remarkably, when all the three genes were considered together, cases with at least one gene over-expressed, showed a dramatically inferior overall survival (28.67 vs. 56.018 months; p = 0.004). Finally, we showed that NF–kB pharmacological inhibition was associated with cell cycle arrest and cell death in NF–kB positive PTCL cells. In conclusion, we extensively explored NF–kB activation in PTCL/NOS, documenting its negative prognostic role. Further, we showed that NF–kB inhibition might represent a rational therapeutic approach in selected cases.

AimsTo assess survival predictivity of baseline blood cell differential count (BCDC) discretization methods in acutely ill adults visiting the emergency room over one-year.MethodsRetrospective cohort study on one-year survival of adults reporting to the emergency room of the A. Manzoni Hospital (Italy) during 2020. Automated BCDC analysis performed at baseline, assessed hemoglobin, red cell mean volume and distribution width (RDW), platelet distribution width (PDW), platelet-hematocrit, absolute red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets. Discretization cutoffs were defined by: Benchmark laboratory reference values and Tailored (maximally selected rank statistics for linear and sigmoid-shaped distributed variables; optimal-equal hazard ratio (HR) method for U-shaped distributed variables. Explanatory variables (age, gender, inward admission) were analyzed using Cox multivariable regression. Receiver operating characteristic curves used the sum of Cox-significant variables in each method.ResultsOf 11052 patients (median age 67 years, interquartile range (IQR) 51–81, 48% female), 59% (n=6489) were discharged and 41% (n=4563) were admitted. After a 306-day median follow up (IQR 208–417 days), 9455 (86%) patients were alive and 1597 (14%) deceased. Increased HRs were associated with age > 73 years (HR=4.29 CI 3.78–4.87), and hospital admission (HR=2.05, CI 1.83–2.29). Age, sex, hemoglobin, mean corpuscular volume, RDW, PDW, neutrophils, lymphocytes and eosinophils were significant in overall. Benchmark included basophils and platelet count (area under the ROC curve (AUROC) 0.78). Tailored included monocyte counts and PCT (AUROC of 0.82).ConclusionsTailored discretization of BCDC provided meaningful insight regarding acute patient survival.Key messagesWhat is already known on this topicInformation on survival predictivity of BCDC is scarce, particularly in acutely ill patients considering that reference values are based on the general population.What this study addsLaboratory reference interval values predicting survival were hemoglobin, RDW, MCV, neutrophil, lymphocyte, eosinophil, and basophils counts, PLT, and PDW, independently of sex, age, and acute inward admission. Survival predictivity was improved by discretization of hemoglobin, RDW, MCV, neutrophil, lymphocyte, eosinophil, and monocyte counts, and PDW, according to the maximally selected rank statistics and optimal-equal HR method.How this study might affect research, practice, or policyBaseline BCDC discretized by tailored methods may be a useful biomarker for hazard warning in acute illness.

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 sub-millimeter 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 Letter focuses on CX Tau, a ${\sim}0.4\,M_\odot$ star with an extended gas emission and a compact and apparently structureless dust disk, with an average millimeter flux when compared to Class II sources in Taurus. We present Karl G. Jansky Very Large Array (VLA) observations in 4 bands (between 9.0 mm and 6.0 cm) and combine them with archival data from the Atacama Large Millimeter/submillimeter Array (ALMA), the Submillimeter Array (SMA) and the Plateau de Bure Interferometer (PdBI). Such a multiwavelength approach allows 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. 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 strong variability of the free-free emission with timescales shorter than a month. Another possible interpretation is the presence of anomalous microwave emission from spinning dust grains., Comment: Accepted for publication in A&A Letters; 13 pages, 13 figures, 1 table

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.

The present work is aimed at presenting the data, methods and criteria that are being used for the assessment of ecosystem collapse risk in Italy.

Hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children (< 3 years), is mainly related to Shiga toxins (Stx)-producing Escherichia coli (STEC) infections. STEC are confined to the gut resulting in hemorrhagic colitis, whereas Stx are delivered in blood to target kidney and brain, with unclear mechanisms, triggering HUS in 5 to 15% of infected children. Stx were found on circulating cells, free in sera (soluble Stx) or in blood cell-derived microvesicles (particulate Stx), whereby the relationship between these forms of circulating toxins is unclear. Here, we have examined 2,846 children with bloody diarrhea and found evidence of STEC infection in 5%. Twenty patients were enrolled to study the natural course of STEC infections before the onset of HUS. In patients, Stx were found to be associated to circulating cells and/or free and functionally active in sera. In most children, Stx were bound to neutrophils when high amounts of toxins were found in feces. Time-course analysis showed that Stx increased transiently in patients' sera while the decrease of toxin amount on leukocytes was observed. Notably, patients who recovered (85%) displayed different settings than those who developed HUS (15%). The distinctive feature of the latter group was the presence in blood of particulate Stx2 (Stx2 sedimented at g-forces corresponding to 1 μm microvesicles) the day before diagnosis of HUS, during the release phase of toxins from circulating cells. This observation strongly suggests the involvement of blood cell-derived particulate Stx2 in the transition from hemorrhagic colitis to HUS.

Class III stars are those in star forming regions without large non-photospheric infrared emission, suggesting recent dispersal of their protoplanetary disks. We observed 30 class III stars in the 1-3 Myr Lupus region with ALMA at ${\sim}856��$m, resulting in 4 detections that we attribute to circumstellar dust. Inferred dust masses are $0.036{-}0.093M_\oplus$, ${\sim}1$ order of magnitude lower than any previous measurements; one disk is resolved with radius ${\sim}80$ au. Two class II sources in the field of view were also detected, and 11 other sources, consistent with sub-mm galaxy number counts. Stacking non-detections yields a marginal detection with mean dust mass ${\sim}0.0048M_\oplus$. We searched for gas emission from the CO J=3-2 line, and present its detection to NO Lup inferring a gas mass ($4.9 {\pm} 1.1$) ${\times}10^{-5} M_\oplus$ and gas-to-dust ratio $1.0{\pm}0.4$. Combining our survey with class II sources shows a gap in the disk mass distribution from $0.09{-}2M_\oplus$ for ${>}0.7M_\odot$ Lupus stars, evidence of rapid dispersal of mm-sized dust from protoplanetary disks. The class III disk mass distribution is consistent with a population model of planetesimal belts that go on to replenish the debris disks seen around main sequence stars. This suggests that planetesimal belt formation does not require long-lived protoplanetary disks, i.e., planetesimals form within ${\sim}$2 Myr. While all 4 class III disks are consistent with collisional replenishment, for two the gas and/or mid-IR emission could indicate primordial circumstellar material in the final stages of protoplanetary disk dispersal. Two class III stars without sub-mm detections exhibit hot emission that could arise from ongoing planet formation processes inside ${\sim}1$ au., 30 pages, 20 figures. This is a pre-copyedited, author-produced PDF of an article accepted for publication in MNRAS following peer review

Large surveys of star-forming regions have unveiled power-law correlations between the stellar mass and the disc parameters, such as the disc mass $M_{\mathrm{d}} \propto {M_{\star}}^{\lambda_{\mathrm{m}}}$ and the accretion rate $\dot M \propto {M_{\star}}^{\lambda_{\mathrm{acc}}}$. 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, $\lambda_{\mathrm{m}}$ = $\lambda_{\mathrm{acc}}$, and that this limit is uniquely determined by the initial slopes $\lambda_{\mathrm{m}, 0}$ and $\lambda_{\mathrm{acc}, 0}$. We recover the increasing trend claimed from the observations when the difference in the initial values, $\delta_0 = \lambda_{\mathrm{m}, 0} - \lambda_{\mathrm{acc}, 0}$, is larger than $1/2$; moreover, we find that this increasing trend is a consequence of a positive correlation between the viscous timescale 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 $\lambda_{\mathrm{m}, 0} \in [1.2, 2.1]$, $\lambda_{\mathrm{acc}, 0} \in [0.7, 1.5]$., Comment: Accepted for publication in MNRAS. 14 pages, 8 figures

Dippers are a common class of young variable star exhibiting day-long dimmings with depths of up to several tens of percent. A standard explanation is that dippers host nearly edge-on (70 deg) protoplanetary discs that allow close-in (< 1 au) dust lifted slightly out of the midplane 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 0-75 deg, above which the occurrence rate declines (likely an observational selection effect due to optically thick disc midplanes 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., Accepted to MNRAS (19 pages, 7 figures, 2 tables)

The distributions and abundances of molecules in protoplanetary disks are powerful tracers of the physical and chemical disk structures. The abundance ratios of HCN and its isomer HNC are known to be sensitive to gas temperature. Their line ratios might therefore offer a unique opportunity to probe the properties of the emitting gas. Using the 2D thermochemical code DALI, we ran a set of disk models accounting for different stellar and disk properties, with an updated chemical network for the nitrogen chemistry. These modeling results were then compared with observations, including new ALMA observations of HNC $J=3-2$ for the TW Hya disk and HNC $J=1-0$ for 29 disks in Lupus. Similar to CN, HCN and HNC have brighter line emission in models with larger disk flaring angles and higher UV fluxes. HNC and HCN are predicted to be abundant in the warm surface layer and outer midplane region, which results in ring-shaped emission patterns. However, the precise emitting regions and emission morphology depend on the probed transition, as well as on other parameters such as C and O abundances. The modeled HNC-to-HCN line intensity ratio increases from $, accepted for publication in A&A

The DSHARP survey evidenced the ubiquity of substructure in the mm dust distribution of large, bright protoplanetary discs. Intriguingly, these datasets have yet higher resolution information that is not recovered in a CLEAN image. We first show that the intrinsic performance of the CLEAN algorithm is resolution-limited. Then analyzing all 20 DSHARP sources using the 1D, super-resolution code Frankenstein (frank), we accurately fit the 1D visibilities to a mean factor of 4.3 longer baseline than the Fourier transform of the CLEAN images and a factor of 3.0 longer baseline than the transform of the CLEAN component models. This yields a higher resolution brightness profile for each source, identifying new substructure interior to 30 au in multiple discs; resolving known gaps to be deeper, wider, and more structured; and known rings to be narrower and brighter. Across the survey, high contrast gaps are an average 14% wider and 44% deeper in the frank profiles relative to CLEAN, and high contrast rings are an average 26% narrower. Categorizing the frank brightness profiles into trends, we find that the relative scarcity of features interior to 30 au in the survey's CLEAN images is an artifact of resolving power, rather than an intrinsic rarity of inner disc (or compact disc) substructure. Finally the rings in the frank profiles are narrower than the previously inferred deconvolved widths, indicating smaller alpha / St ratios in the local gas disc., Comment: Revised version, accepted to MNRAS. Changes: added CLEAN .model profiles to Sec.3 and 4, quantified gaps/rings in frank profiles in Sec.5 and Table 3, expanded analysis of alpha/St in Sec.5.3.1. All frank fits are now available at https://zenodo.org/record/5587841

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 characterise the discs multi-wavelength 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 millimeter 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% smaller than when observed at 0.9 mm, in tension with models of dust evolution which 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}>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., MNRAS Accepted. 20 pages, 12 figures, 5 tables. Detailed fit results in Appendix E (27 pages, 78 figures), available as supplementary material. Machine-readable version of Table 1, Table 2, and Table 3 available at https://zenodo.org/record/4756381

We present a ground robot tailored for agricultural applications. The general design and logical architecture concepts are presented, as well as emphasizing the aspects that make the platform particularly suited to operate in “all-terrains”. We also present the implementation of the localization and navigation algorithms designed to autonomously operate both outside and inside the rows of an orchard. Experimental results are shown in the attached video., https://youtu.be/PovNTLooZCo

Background Scabies or sarcoptic mange is an infestation of the skin caused by the mite Sarcoptes scabiei. Transmission from animals to humans occurs through close contact. The most common symptoms are papules, erythema, excoriations, hyperkeratosis, and hypotrichosis. In the province of Ferrara (Emilia Romagna, Italy) mange is endemic in wild animals, mostly in foxes, which can act as vectors for domestic animals and humans. Methods From 2012 to 2020, 564 foxes were surveyed within the Wildlife Health Surveillance Re-gional Program, including microscopic examination in cases of skin lesions referable to scabies. In 2018, a domestic dog (10-year border collie, male), frequenting an uncultivated area colonized by foxes and located in the outskirts of Ferrara, showed scabby lesions mainly on the nose, around the eyes and on the back. Results 11 out of 564 foxes resulted positive (1,95%), 6 cases out of 38 being in 2018 (15,8%). The parasite was detected by skin biopsy and direct microscopic examination in the domestic dog. The parasite was transmitted by the dog to the owner and the other two family members. Conclusions The increased density of dogs and foxes in the Ferrara province, and the attitude of foxes to live near to human settlements, increase the risk of contacts between foxes, domestic animals and humans, even though stray dogs are uncommon. This case illustrates the interdependencies between animal health, human health and environment, a synergy that can enable exacerbation of diseases of zoonotic origin as highlighted by the One Health concept. It is therefore important to increase the investigation on paths as well as vectors of diseases and to find collaborative, multi-sectorial and transversal approaches to ensure quality health outcomes. The control of the disease requires an appropriate monitoring of dogs' health being skin lesions in both, humans and animals, very similar to allergic dermatitis, which can delay the proper diagnosis of the disease. Key messages Sarcoptic mange is a zoonosis still present in Emilia Romagna, Italy. The One Health approach is key to control the cycle of the zoonotic sarcoptic mange.

We present an autonomous ground robotic platform for agriculture application. The design is specifically targeted for small/medium farms with orchards and in this paper we propose a new vehicle concept as well as the sensor suite and software architecture to accomplish the implementation of the navigation algorithm designed to autonomously operate within the rows of an orchard. In this context, we also show how to exploit the structure of the orchard to optimize the Hough Transform algorithm to detect tree rows. Simulations and experimental results are presented.

We present a ground robotic platform suited to agriculture applications. The design is specifically targeted for small/medium farms and it is characterized by marked features in terms of flexibility, reconfigurability and robustness.We present the tracked vehicle design concept as well as the mechanical model by emphasizing some aspects that make the platform particularly suited to operate in "all-Terrains". We also present experimental results to validate the model.

Class III stars are those in star forming regions without large non-photospheric infrared emission, suggesting recent dispersal of their protoplanetary discs. We observed 30 class III stars in the 1–3 Myr Lupus region with ALMA at ∼856μm, resulting in four detections that we attribute to circumstellar dust. Inferred dust masses are 0.036–0.093M⊕, ∼1 order of magnitude lower than any previous measurements; one disc is resolved with radius ∼80 au. Two class II sources in the field of view were also detected, and 11 other sources, consistent with sub-mm galaxy number counts. Stacking non-detections yields a marginal detection with mean dust mass ∼0.0048M⊕. We searched for gas emission from the CO J = 3–2 line, and present its detection to NO Lup inferring a gas mass (4.9 ± 1.1) × 10−5 M⊕ and gas-to-dust ratio 1.0 ± 0.4. Combining our survey with class II sources shows a gap in the disc mass distribution from 0.09–2M⊕ for ${\gt}0.7\, \mathrm{M}_\odot$ Lupus stars, evidence of rapid dispersal of mm-sized dust from protoplanetary discs. The class III disc mass distribution is consistent with a population model of planetesimal belts that go on to replenish the debris discs seen around main sequence stars. This suggests that planetesimal belt formation does not require long-lived protoplanetary discs, i.e. planetesimals form within ∼2 Myr. While all four class III discs are consistent with collisional replenishment, for two the gas and/or mid-IR emission could indicate primordial circumstellar material in the final stages of protoplanetary disc dispersal. Two class III stars without sub-mm detections exhibit hot emission that could arise from ongoing planet formation processes inside ∼1 au.

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 onto 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 S-Z detection (~3.3$\sigma$) 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 emphasise that detecting an SZ signal is more easily achieved in the visibility plane than in the (inferred) images. We also confirm a marginal detection (3.2$\sigma$) of a potential SZ dip on smaller scales (, Comment: 13 pages, 16 figures. Accepted for publication by MNRAS

Simple Summary Patients with polycythemia vera, a myeloproliferative neoplasm, are at increased risk of thrombosis and progression to myelofibrosis. However, no disease-specific risk factors have been identified so far. Extracellular vesicles, released from a broad variety of cells, are receiving increasing attention for their effects on cell-to-cell communication. In addition, they play a role in cancer and thrombosis. Interestingly, circulating microbial components/microbes have been recently indicated as potential modifiers of inflammation and coagulation. Here, we identified a signature of thrombosis history and marrow fibrosis by analyzing the phenotype and the microbial DNA cargo of the circulating extracellular vesicles after isolation from the plasma of patients with polycythemia vera. These data may support the role of extracellular vesicles as liquid biomarkers of aggressive disease, thus contributing to refining the prognosis of polycythemia vera. Abstract Polycythemia vera is a myeloproliferative neoplasm with increased risk of thrombosis and progression to myelofibrosis. However, no disease-specific risk factors have been identified so far. Circulating extracellular vesicles (EVs) are mostly of megakaryocyte (MK-EVs) and platelet (PLT-EVs) origin and, along with phosphatidylethanolamine (PE)-EVs, play a role in cancer and thrombosis. Interestingly, circulating microbial components/microbes have been recently indicated as potential modifiers of inflammation and coagulation. Here, we investigated phenotype and microbial DNA cargo of EVs after isolation from the plasma of 38 patients with polycythemia vera. Increased proportion of MK-EVs and reduced proportion of PLT-EVs identify patients with thrombosis history. Interestingly, EVs from patients with thrombosis history were depleted in Staphylococcus DNA but enriched in DNA from Actinobacteria members as well as Anaerococcus. In addition, patients with thrombosis history had also lower levels of lipopolysaccharide-associated EVs. In regard to fibrosis, along with increased proportion of PE-EVs, the EVs of patients with marrow fibrosis were enriched in DNA from Collinsella and Flavobacterium. Here, we identified a polycythemia-vera-specific host/microbial EV-based signature associated to thrombosis history and marrow fibrosis. These data may contribute to refining PV prognosis and to identifying novel druggable targets.

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target. Mol Cancer Res; 14(9); 820–9. ©2016 AACR.