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The Cherenkov Telescope Array Observatory (CTAO) is a next-generation facility comprised of ground-based Imaging Atmospheric Cherenkov Telescopes (IACTs). The observatory, currently under construction, will include more than 70 telescopes at two locations: in the northern hemisphere, CTAO-North at the Observatorio del Roque de Los Muchachos (ORM), La Palma, Canary Islands, Spain, and in the southern hemisphere, CTAO-South at a site belonging to the European Southern Observatory (ESO), Cerro Paranal, Chile. IACTs indirectly detect high-energy cosmic photons in an energy range from tens of GeV to several hundreds of TeV by measuring Cherenkov light emitted by atmospheric showers of secondary particles, produced through interactions between incident photons and nuclei of atmospheric gasses in the upper layers. The size of the CTAO will improve the detection sensitivity in the designed energy range by about an order of magnitude with respect to present experiments and aim at improved energy and angular resolution, as well as greatly reduced systematic uncertainties. The key to achieving improvements in accuracy on the absolute energy and flux scales is the precise monitoring of the atmospheric properties for the Cherenkov light, which can be obtained with a specifically designed LIDAR. The Barcelona Raman LIDAR (BRL) prototype is the official CTAO-North Pathfinder and was deployed at ORM for extensive tests between February 2021 and May 2022. We report the BRL’s prospects for the CTAO-North, emphasizing the technical implementation and the preliminary data taken during its deployment period.

Background Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Acipenserids (sturgeons) live in large rivers and lakes in North America and Eurasia, where many species and populations are considered imperiled. One of the most pervasive threats across the global range of sturgeon is water resource development (e.g., hydropower dams, water intakes for irrigation, industrial use, or human consumption). We report on the outcome of a literature review focused on interactions between sturgeon and water resource development. We focused on the persistent issue of dam passage (both upstream and downstream), impingement, and entrainment, which are all relevant issues for both existing and planned facilities. We discuss aspects of sturgeon sensory physiology, and how knowledge of sensory physiology can be used for behavioural guidance. We also consider how the swimming ability and style of sturgeon is relevant for passage. Most of the literature emanated from research on just a few species (especially lake sturgeon, white sturgeon, green sturgeon, and shortnose sturgeon). Although there are several examples of apparent “success stories” (e.g., successful upstream fish passage, efforts to reduce impingement and entrainment), there are also many failures, and such examples are likely under-reported. Without significant investments in solutions-oriented research related to sturgeon-water resource development interactions, we submit that fish passage, entrainment and impingement problems for acipenserids will remain. There is a need for research that spans life-stages, compares different species, and considers how passage, entrainment, and impingement influence demography. Further, there is a need for investment into evidence-based implementation of mitigation infrastructure and management strategies to ensure conservation needs of sturgeons are adequately considered.

The origin of bimodal (mafic–felsic) rock suites is a fundamental question in volcanology. Here we use major and trace elements, high-resolution Sr, Nd and Pb isotope analyses, experimental petrology and thermodynamic modelling to investigate bimodal magmatism at the iconic Carlingford Igneous Centre, Ireland. We show that early microgranites are the result of extensive assimilation of trace element-enriched partial melts of local metasiltstones into mafic parent magmas. Melting experiments reveal the crust is very fusible, but thermodynamic modelling indicates repeated heating events rapidly lower its melt-production capacity. Granite generation ceased once enriched partial melts could no longer form and subsequent magmatism incorporated less fertile restite compositions only, producing mafic intrusions and a pronounced compositional gap. Considering the frequency of bimodal magma suites in the North Atlantic Igneous Province, and the ubiquity of suitable crustal compositions, we propose ‘progressively inhibited crustal assimilation’ (PICA) as a major cause of bimodality in continental volcanism. The origin of bimodal (mafic–felsic) rock suites is a fundamental question in volcanology. Here, the authors present a new model for magmatic differentiation in continental igneous provinces and explain how large volumes of granitic magma can be produced in otherwise basaltic systems.

The Cherenkov Telescope Array Observatory (CTAO), currently under construction, is the next-generation very-high-energy gamma-ray observatory, providing the coverage for photons in the energy range 20GeV to 300TeV. CTAO will increase detection sensitivity in the 100 GeV to 10TeV range by a factor of 5 — 10 with respect to present experiments. CTAO retrieves the properties of very-high-energy gamma-rays by measuring Cherenkov light emitted by atmospheric showers of secondary particles that incident gamma rays produce in upper layers of the atmosphere. The key for reaching the required energy measurement accuracy is a precise knowledge of the atmospheric transmittance for Cherenkov light, which can be obtained using a dedicated Raman LIDAR. The device should operate at 355nm (near the maximum of Cherenkov light spectrum) and have the capability of taking data at specific azimuth and zenith angles up to distances of 30 km, so that atmospheric transmission along all possible air-shower directions can be determined. The Barcelona Raman LIDAR (BRL) is the official CTAO Pathfinder prototype, developed for atmospheric characterization of the Northern CTAO Site at the Observatorio del Roque de los Muchachos (ORM) on the Canary island of La Palma. BRL was deployed at ORM for extensive on-field tests between February 2021 and May 2022. We report on the commissioning results, including the remote operation capabilities of the system and its contribution to the understanding of atmospheric phenomena during its deployment period. In particular, we report on the properties of the volcanic plume from the eruption of the Cumbre Vieja volcano on 22 September 2021.

Aim: To establish the histological and immunohistochemical parameters that are helpful in recognising temporal arteritis in patients who have been treated with steroids before biopsy, and to analyse the clinical features and correlate them with the histological findings. Methods: A retrospective review of charts of 35 patients treated with steroids before obtaining temporal artery biopsy specimens, spanning a 11-year period from 1995 to 2005. The study was conducted at the Ophthalmic Pathology Laboratory, Cullen Eye Institute, Houston, Texas, USA. The clinical features were evaluated and correlated with the histopathological findings. Each case was evaluated with respect to age, sex, race, clinical findings, erythrocyte sedimentation rate, corticosteroid dosage (oral versus intravenous) and the duration of treatment. The time interval between obtaining the biopsy specimen and the onset of steroid treatment was carefully recorded for each patient. In selected cases, histiocytic markers (CD-68 and HAM-56) were used to identify the presence of epithelioid histiocytes, which characterises a granulomatous inflammation. Other immunohistochemical studies (CD3, CD20, CD4, CD8, CD45RO, CD45RA and S-100 protein) were performed in selected cases to characterise the inflammatory cells. Results: The three most reliable histopathological parameters of corticosteroid-treated temporal arteritis are the following: (1) complete or incomplete mantle of lymphocytes and epithelioid histiocytes located between the outer muscular layer and the adventitia; (2) large circumferential defects in the elastic lamina (best seen with the Movat’s pentachrome); and (3) absent or few small multinucleated giant cells. In some cases the main artery appears normal, whereas the primary branches show evidence of a healing arteritis. The histological findings vary according to the duration of treatment before obtaining the biopsy specimen. Conclusion: Striking histological differences can be recognised objectively between patients with active (untreated) giant cell arteritis and patients who have been treated with corticosteroids. The earliest histopathological changes were detected by the end of the first week after steroid treatment (usually after day 4 to the end of the first week). The histological findings were more difficult to recognise at 2–3 months after steroid treatment. Ophthalmic and general pathologists should be able to recognise this entity on the basis of the histological findings including the special stains and results of immunohistochemical studies (CD-68 and HAM-56).

BackgroundOur group has previously shown that Adoptive Cellular Therapy (ACT) is efficacious against CNS malignancies including medulloblastoma, brain stem glioma, and glioblastoma. Here, we used GeoMx Digital Spatial profiling platform to perform in situ characterization and spatial distribution of the glioma microenvironment in tumor-bearing mice after ACT. Our goal is to elucidate the underlying cell dynamics occurring within the tumor microenvironment and determine what immune cells and gene signatures are playing a major role in overcoming treatment resistance. This method enabled us to define differences in antigen processing and cross presentation gene signatures in the ACT-treated tumors compared to untreated tumors. We also observed differences in gene expression within T cell subsets in the treated versus untreated tumors including changes in gene expression of regulatory T cell (Treg) associated genes, such as Runx1 and TGF-β. We also found a significant increase in Batf3 expression associated with therapy.Materials and MethodsTo characterize the cellular dynamics behind the efficacy of this therapy, we performed in situ GeoMx Digital Spatial Profiling (DSP) and whole genome transcriptomics (RNA) of murine glioma KR-158B-luciferase tumors after adoptive cellular therapy. C57/BL6 mice were orthotopically implanted with KR158B-luciferase cells and subsequently treated with ACT. Histological slides of brain sections were sent to be stained for CD45, CD3, GFP (marks hematopoietic stem cell-derived cells) and nuclei, and processed following GeoMx DSP workflow for RNA. Gene set enrichment analysis (GSEA) was performed to determine differentially expressed gene signatures in treated vs control mice. Gene expression clustering profiles were conducted using a Principal Component Analysis (PCA), and relative gene expression differences were analyzed by unpaired t-tests.ResultsOur data shows differentially expressed antigen processing and cross presentation gene signatures in the ACT-treated compared to untreated tumors by GSEA analysis. We also observed that tumors treated with ACT cluster separately from control tumors in PCA analysis and they have several differentially expressed genes. Furthermore, we found downregulation of genes associated with the suppressive properties of regulatory T cells (Runx1 and TGF-β), and upregulation of dendritic cell characteristic genes (Batf3) in ACT-treated tumors vs control.ConclusionsThese findings provide insights into the immune cell dynamics and specific genes and gene signatures that are differentially expressed within the tumor microenvironment after treatment. This could help improve current adoptive cellular therapies to treat brain tumors.Disclosure Information L. Falceto Font: None. C. Francis: None. D. Jin: None. B. DiVita Dean: None. A. Reid: None. K. Long-James: None. L. Deleyrolle: None. C. Flores: None.

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

Rationale Considerable evidence indicates that brain ethanol metabolism mediated by catalase is involved in modulating some of the behavioral and physiological effects of this drug, which suggests that the first metabolite of ethanol, acetaldehyde, may have central actions. Previous results have shown that acetaldehyde administered into the lateral ventricles produced anxiolysis in a novel open arena in rats. Objectives The present studies investigate the effects of centrally formed acetaldehyde on ethanol-induced anxiolysis. Materials and methods The effects of the catalase inhibitor sodium azide (SA; 0 or 10 mg/kg, IP) on ethanol-induced anxiolysis (0.0, 0.5, or 1.0 g/kg, IP) were evaluated in CD1 mice in two anxiety paradigms, the elevated plus maze and the dark/light box. Additional studies assessed the effect of the noncompetitive catalase inhibitor 3-amino-1,2,4-triazole (AT; 0.5 g/kg, IP) and the acetaldehyde inactivation agent d -penicillamine (50 mg/kg, IP) on the plus maze. Results SA reduced the anxiolytic effects of ethanol on several parameters evaluated in the elevated plus maze and in the dark/light box. In the plus maze, AT completely blocked and d -penicillamine significantly reduced the anxiolytic properties of ethanol. Conclusions Thus, when cerebral metabolism of ethanol into acetaldehyde is blocked by catalase inhibitors, or acetaldehyde is inactivated, there is a suppressive effect on the anxiolytic actions of ethanol. These data provide further support for the idea that centrally formed or administered acetaldehyde can contribute to some of the psychopharmacological actions of ethanol, including its anxiolytic properties.

The tumor microenvironment plays a crucial role in determining response to treatment. This involves a series of interconnected changes in the cellular landscape, spatial organization, and extracellular matrix composition. However, assessing these alterations simultaneously is challenging from a spatial perspective, due to the limitations of current high-dimensional imaging techniques and the extent of intratumoral heterogeneity over large lesion areas. In this study, we introduce a spatial proteomic workflow termed Hyperplexed Immunofluorescence Imaging (HIFI) that overcomes these limitations. HIFI allows for the simultaneous analysis of > 45 markers in fragile tissue sections at high magnification, using a cost-effective high-throughput workflow. We integrate HIFI with machine learning feature detection, graph-based network analysis, and cluster-based neighborhood analysis to analyze the microenvironment response to radiation therapy in a preclinical model of glioblastoma, and compare this response to a mouse model of breast-to-brain metastasis. Here we show that glioblastomas undergo extensive spatial reorganization of immune cell populations and structural architecture in response to treatment, while brain metastases show no comparable reorganization. Our integrated spatial analyses reveal highly divergent responses to radiation therapy between brain tumor models, despite equivalent radiotherapy benefit. Improved imaging techniques are required to help advance our understanding of the complex role of the tumour microenvironment (TME). Here, the authors develop a high-throughput, highly multiplexed tissue visualisation workflow and demonstrate its utility by characterising the response of the TME to radiotherapy in preclinical models of glioblastoma.