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BackgroundNewer 3D culturing approaches are a promising way to better mimic the in vivo tumor microenvironment and to study the interactions between the heterogeneous cell populations of glioblastoma multiforme. Like many other tumors, glioblastoma uses extracellular vesicles as an intercellular communication system to prepare surrounding tissue for invasive tumor growth. However, little is known about the effects of 3D culture on extracellular vesicles. The aim of this study was to comprehensively characterize extracellular vesicles in 3D organoid models and compare them to conventional 2D cell culture systems.MethodsPrimary glioblastoma cells were cultured as 2D and 3D organoid models. Extracellular vesicles were obtained by precipitation and immunoaffinity, with the latter allowing targeted isolation of the CD9/CD63/CD81 vesicle subpopulation. Comprehensive vesicle characterization was performed and miRNA expression profiles were generated by smallRNA-sequencing. In silico analysis of differentially regulated miRNAs was performed to identify mRNA targets and corresponding signaling pathways. The tumor cell media and extracellular vesicle proteome were analyzed by high-resolution mass spectrometry.ResultsWe observed an increased concentration of extracellular vesicles in 3D organoid cultures. Differential gene expression analysis further revealed the regulation of twelve miRNAs in 3D tumor organoid cultures (with nine miRNAs down and three miRNAs upregulated). MiR-23a-3p, known to be involved in glioblastoma invasion, was significantly increased in 3D. MiR-7-5p, which counteracts glioblastoma malignancy, was significantly decreased. Moreover, we identified four miRNAs (miR-323a-3p, miR-382-5p, miR-370-3p, miR-134-5p) located within the DLK1-DIO3 domain, a cancer-associated genomic region, suggesting a possible importance of this region in glioblastoma progression. Overrepresentation analysis identified alterations of extracellular vesicle cargo in 3D organoids, including representation of several miRNA targets and proteins primarily implicated in the immune response.ConclusionOur results show that 3D glioblastoma organoid models secrete extracellular vesicles with an altered cargo compared to corresponding conventional 2D cultures. Extracellular vesicles from 3D cultures were found to contain signaling molecules associated with the immune regulatory signaling pathways and as such could potentially change the surrounding microenvironment towards tumor progression and immunosuppressive conditions. These findings suggest the use of 3D glioblastoma models for further clinical biomarker studies as well as investigation of new therapeutic options.

Transmission lines (TLs) are excellent examples of quantum simulators of quantum fields. By appropriately driving-specific circuit elements, these devices can reproduce relativistic and quantum phenomena such as particle creation due to the nonadiabatic stimulation of the quantum vacuum. We investigate particle creation in left-handed TLs induced by the modulation of the Josephson energy in superconducting quantum interference devices. Our results show that, as a consequence of the peculiar dispersion relations present in these systems, particle production occurs with much more favorable conditions with respect to the usual right-handed TLs.

Folded-optics-based quartz-enhanced photoacoustic and photothermal hybrid spectroscopy (FO-QEPA-PTS) is reported for the first time. In FO-QEPA-PTS, the detection of the photoacoustic and photothermal hybrid signal is achieved through the use of a custom quartz tuning fork (QTF), thereby mitigating the issue of resonant frequency mismatch typically encountered in quartz-enhanced photoacoustic-photothermal spectroscopy employing multiple QTFs. A multi-laser beam, created by a multi-pass cell (MPC) with a designed single-line spot pattern, partially strikes the inner edge of the QTF and partially passes through the prong of the QTF, thereby generating photoacoustic and photothermal hybrid signals. To assess the performance of FO-QEPA-PTS, 1 % acetylene is selected as the analyte gas and the 2f signals produced by the photoacoustic, the photothermal, and their hybrid effects are measured. Comparative analysis against QEPAS and QEPTS reveals signal gain factors of ∼ 79 and ∼ 14, respectively, when these laser beams created by MPC excite the QTF operating at fundamental resonance mode in phase. In the FO-QEPA-PTS signal, the proportions of the photoacoustic and the photothermal effects induced by the multiple beams are ∼7 % and 93 %, respectively.

Abstract TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing. We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages. In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.

Abstract Purpose Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP. Materials and methods All patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine (groupPROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0). Results Thromboembolic events were recorded after 10 PHP procedures (5%) in groupPROTAMINE, six of which (3%) were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine. Conclusion Our retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated.

Abstract Background Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It’s capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. Materials and methods 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. Results PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. Conclusion A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.

Background: Despite multimodality therapies, the prognosis of patients with malignant brain tumors remains extremely poor. One of the major obstacles that hinders development of effective therapies is the limited availability of clinically relevant and biologically accurate (CRBA) mouse models. Methods: We have developed a freehand surgical technique that allows for rapid and safe injection of fresh human brain tumor specimens directly into the matching locations (cerebrum, cerebellum, or brainstem) in the brains of SCID mice. Results: Using this technique, we successfully developed 188 PDOX models from 408 brain tumor patient samples (both high-and low-grade) with a success rate of 72.3% in high-grade glioma, 64.2% in medulloblastoma, 50% in ATRT, 33.8% in ependymoma, and 11.6% in low-grade gliomas. Detailed characterization confirmed their replication of the histopathological and genetic abnormalities of the original patient tumors. Conclusions: The protocol is easy to follow, without a sterotactic frame, in order to generate large cohorts of tumor-bearing mice to meet the needs of biological studies and preclinical drug testing.

Abstract Background To report the technique and outcome of ultrasound-guided percutaneous access to the superior mesenteric vein (SMV) for balloon-assisted portal vein recanalization–transjugular intrahepatic portosystemic shunt (PVR-TIPS) in a patient with chronic portal venous and splenic vein occlusion. Case presentation A 51-year-old, non-cirrhotic patient with severe portal hypertension was admitted for PVR-TIPS. Neither splenic nor hepatic access was feasible due to chronic portal and splenic vein occlusion. Percutaneous ultrasound-guided direct puncture of the SMV was performed to obtain access for balloon-assisted PVR-TIPS. The transmesenteric approach in combination with a balloon puncture technique for PVR-TIPS was successful, and no immediate complications were observed post-procedure. The subsequent follow-up exams showed patent TIPS and SMV without signs of intraabdominal hemorrhage. Conclusion Percutaneous ultrasound-guided superior mesenteric vein access for balloon-assisted PVR-TIPS is a feasible option in cases where hepatic or splenic access is not.

Abstract Background Animal diseases are a danger to livestock, businesses, and public health. This is why the public and private sectors in Africa have invested immensely in the manufacture and distribution of veterinary drugs. However, veterinary drug supply chain actors still suffer losses as a result of expiration. Besides, the way expired products are managed might pose risks to human, animal, and environmental health. This study investigated the prevalence, management of, and factors associated with the expiry of veterinary medicines in supply outlets in Central Uganda. Methods A cross-sectional study was conducted among owners and caretakers of veterinary drug supply outlets. Data were collected using self-administered, semi-structured questionnaires. The level of expiry was computed as “acceptable” (for levels reported as ≤ 5%) and “unacceptable” (for levels reported as ˃5%). Logistic regression was used to assess associations between the level of drug expiry and predictor variables. Results A total of 168 owners/caretakers of veterinary drug supply outlets were included in this study. The majority (148/168, 88.1%) of respondents reported having experienced expiries in their outlets. Unacceptable levels of expiry were reported in 38/168 (22.6%) of the outlets. Retail outlets accounted for the majority (34/38, 89.5%) of the unacceptable levels. Powdered drugs accounted for most expiries (106/148, 71.6%). Most expiries were for drugs supplied to outlets on credit (58/124, 46.8%) and those used to treat rare diseases (26/124, 21%). Major reasons for expiry included irrational prescription, inaccurate forecasts, overstocking, dry seasons, and stocking without considering stock-at-hand. Methods of disposal of expired drugs included throwing at pits (74/168, 44.1%); returning drugs to suppliers (51/168, 30.4%); and incineration (33/168, 19.6%). Factors associated with acceptable levels of expiry included the caretaker being female [adjusted OR = 2.9, 95% CI = 1.22–5.08]; having a procurement policy [adjusted OR = 3.9, 95% CI = 1.29–4.81] and practicing first expiry, first out [adjusted OR = 6.07, 95% CI = 4.71–8.70]. Conclusions Veterinary drug expiries are common in Uganda, and environmentally unfriendly methods of disposal are widely used. Acquisition and use of inventory tracking technologies that support First-Expiry-First-Out principles as well as proper disposal of expired medicines are recommended.

Abstract Glioblastoma (GB) IDH-wildtype is the most malignant primary brain tumor. It is particularly resistant to current immunotherapies. Translocator protein 18 kDa (TSPO) is upregulated in GB and correlates with malignancy and poor prognosis, but also with increased immune infiltration. Here, we studied the role of TSPO in the regulation of immune resistance of human GB cells. The role of TSPO in tumor immune resistance was experimentally determined in primary brain tumor initiating cells (BTICs) and cell lines through genetic manipulation of TSPO expression and subsequent cocultures with antigen specific cytotoxic T cells and autologous tumor-infiltrating T cells. Death inducing intrinsic and extrinsic apoptotic pathways affected by TSPO were investigated. TSPO-regulated genes mediating apoptosis resistance in BTICs were identified through gene expression analysis and subsequent functional analyses. TSPO transcription in primary GB cells correlated with CD8+ T cell infiltration, cytotoxic activity of T cell infiltrate, expression of TNFR and IFNGR and with the activity of their downstream signalling pathways, as well as with the expression of TRAIL receptors. Coculture of BTICs with tumor reactive cytotoxic T cells or with T cell-derived factors induced TSPO up-regulation through T cell derived TNFα and IFNγ. Silencing of TSPO sensitized BTICs against T cell-mediated cytotoxicity. TSPO selectively protected BTICs against TRAIL-induced apoptosis by regulating apoptosis pathways. TSPO also regulated the expression of multiple genes associated with resistance against apoptosis. We conclude that TSPO expression in GB is induced through T cell-derived cytokines TNFα and IFNγ and that TSPO expression protects GB cells against cytotoxic T cell attack through TRAIL. Our data thereby provide an indication that therapeutic targeting of TSPO may be a suitable approach to sensitize GB to immune cell-mediated cytotoxicity by circumventing tumor intrinsic TRAIL resistance.

Abstract Background Photon-counting detector computed tomography (PCD-CT) has the potential to provide superior image quality compared to energy-integrating detector computed tomography (EID-CT). We compared the two systems for elbow imaging in off-center arm positioning, 90° flexion, and cast fixation in a simulated post-trauma setting. Methods The institutional review board approved the study protocol. In a cadaver study, an olecranon fracture was artificially created in ten whole arm specimens. Two different scanning positions were evaluated: (a) arm overhead; and (b) arm on top of the abdomen of a whole-body phantom. The ultra-high resolution mode with three dose protocols and two reconstruction kernels was applied. Two blinded radiologists independently evaluated fracture and trabecular bone delineation. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and cortical sharpness measurements were performed. Cohen κ correlations, Mann-Whitney U and Wilcoxon signed rank tests were used. A p value lower than 0.05 was considered statistically significant. Results Dose-equivalent PCD-CT scans were rated better for fracture and trabecular bone evaluation (p < 0.001). SNR, CNR, and cortical sharpness were higher for all diagnostic (Br76) PCD-CT images (p < 0.001). The arm position had less effect on image quality in the PCD-CT compared to the EID-CT. The use of a sharp bone kernel (Br89) improved image quality ratings for PCD-CT. In the low-dose scan mode, PCD-CT resulted in more diagnostic scans (75%) compared to EID-CT (19%). Conclusions PCD-CT provided superior objective and subjective image quality for fracture and trabecular bone structures delineation of the elbow compared to EID-CT in a typical post-trauma setting. Key points • Photon-counting detector computed tomography (PCD-CT) preserved high image quality in elbow imaging with off-center positions. • PCD-CT was advantageous for bone evaluation in trauma elbows. • PCD-CT ultra-high-resolution mode and very sharp reconstruction kernels facilitated higher image quality.

Abstract The Identification of Relevant Attributes for Liver Cancer Therapies (IRALCT) project is intended to provide new insights into the relevant utility attributes regarding therapy choices for malignant primary and secondary liver tumors from the perspective of those who are involved in the decision-making process. It addresses the potential value of taking patients’ expectations and preferences into account during the decision-making and, when possible, adapting therapies according to these preferences. Specifically, it is intended to identify the relevant clinical attributes that influence the patients’, medical laymen’s, and medical professionals’ decisions and compare the three groups’ preferences. We conducted maximum difference (MaxDiff) scaling among 261 participants (75 physicians, 97 patients with hepatic malignancies, and 89 medical laymen) to rank the importance of 14 attributes previously identified through a literature review. We evaluated the MaxDiff data using count analysis and hierarchical Bayes estimation (HB). Physicians, patients, and medical laymen assessed the same 7 attributes as the most important: probability (certainty) of a complete removal of the tumor, probability of reoccurrence of the disease, pathological evidence of tumor removal, possible complications during the medical intervention, welfare after the medical intervention, duration and intensity of the pain, and degree of difficulty of the medical intervention. The cumulative relative importance of these 7 attributes was 88.3%. Our results show that the physicians’, patients’, and medical laymen’s preferences were very similar and stable. Trial registration DRKS-ID of the study: DRKS00013304, Date of Registration in DRKS: 2017/11/16.

While recurrence is frequent in ependymoma, the underlying molecular mechanisms remain to be explored. Here, the authors investigate epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses over 13 years and identify distinct patterns of DNA methylation.

Abstract Background To evaluate effectivity of a 3D-motion correction algorithm in C-Arm CTs (CACT) with limited image quality (IQ) during transarterial chemoembolization (TACE). Methods From 1/2015–5/2021, 644 CACTs were performed in patients during TACE. Of these, 27 CACTs in 26 patients (18 m, 8f; 69.7 years ± 10.7 SD) of limited IQ were included. Post-processing of the original raw-data sets (CACTOrg) included application of a 3D-motion correction algorithm and bone segmentation (CACTMC_no_bone). Four radiologists (R1-4) compared the images by choosing their preferred dataset and recommending repeat acquisition in case of severe IQ-impairment. R1,2 performed additional grading of intrahepatic vessel visualization, presence/extent of movement artifacts, and overall IQ. Results R1,2 demonstrated excellent interobserver agreement for overall IQ (ICC 0.79,p

Abstract Historically, wildfire and tribal burning practices played important roles in shaping ecosystems throughout the Klamath Siskiyou Bioregion of northern California and southern Oregon. Over the past several decades, there has been increased interest in the application of fire for forest management through the implementation of prescribed fires within habitats that are used by a diversity of migrant and resident land birds. While many bird species may benefit from habitat enhancements associated with wildfires, cultural burning, and prescribed fire, individuals may face direct or indirect harm. In this study, we analyzed the timing of breeding and molting in 11 species of culturally significant land birds across five ecologically distinct regions of northern California and southern Oregon to explore the potential timeframes that these bird species may be vulnerable to wildland fires (wildfire, prescribed fire, or cultural burning). We estimated that these selected species adhered to a breeding season from April 21 to August 23 and a molting season from June 30 to October 7 based on bird capture data collected between 1992 and 2014. Within these date ranges, we found that breeding and molting seasons of resident and migratory bird species varied temporally and spatially throughout our study region. Given this variability, spring fires that occur prior to April 21 and fall fires that occur after October 7 may reduce the potential for direct and indirect negative impacts on these culturally significant birds across the region. This timing corresponds with some Indigenous ecocultural burning practices that are aligned with traditionally observed environmental cues relating to patterns of biological phenology, weather, and astronomy. We detail the timing of breeding and molting seasons more specific to regions and species, and estimate 75%, 50%, and 25% quartiles for each season to allow for greater flexibility in planning the timing of prescribed fires and cultural burning, or regarding the potential implications of wildfires. The results of our study may serve as an additional resource for tribal members and cultural practitioners (when examined within the context of Indigenous Traditional Ecological Knowledge) and forest and wildland fire managers to promote stable populations of culturally significant bird species within fire‐dependent forest systems.

We present a quantum heat engine based on a cavity with two oscillating mirrors that confine a quantum field. The engine performs an Otto cycle during which the walls and a field mode, together representing the working substance of the engine, interact via a nonlinear Hamiltonian. Resonances between the frequencies of the cavity mode and the walls allow one to transfer heat from the hot and the cold bath by exploiting the conversion between phononic and photonic excitations. We study the time evolution of the system and show that net work can be extracted after a full cycle. We evaluate the efficiency of the process.

Phosphorus (P) is a major limiting factor for legume and symbiotic nitrogen fixation (SNF). Although overall adaptations of legumes to P supplementation have been extensively studied in connection with inorganic P, little information is currently available regarding nodulation or SNF responses to organic P (Po) in hydroponics. We investigated the mineral and carbon metabolism of Po-induced nodules of two contrasting faba bean varieties grown hydroponically under inorganic P (Pi), viz., in P-deficient (2 µM KH2PO4, −Pi), sufficient-P (200 µM KH2PO4, +Pi), and phytic acid (200 µM, Po) conditions, and were inoculated with Rhizobium leguminosarum bv. viciae 3841 and grown for 30 days. The results consistently reveal similar growth and biomass partitioning patterns between +Pi and Po, with both varying substantially from −Pi. In comparison, +Pi and Po observed equivalent accumulations of overall elemental P concentrations, with both increasing by 114 and 119%, respectively, relative to −Pi. A principal component analysis on metabolites showed a clear separation of the −Pi treatment from the others, with +Pi and Po correlating closely together, highlighting the nonsignificant differences between them. Additionally, the δ15N abundance of shoots, roots, and nodules was not significantly different between treatments and varieties and exhibited negative δ15N signatures for all tissues. Our study provides a novel perspective on mineral and carbon metabolism and their regulation of the growth, functioning, and reprogramming of nodules upon phytate supply.

Abstract Background The aim of this animal study was to compare the fluoroscopic image quality (IQ) and radiation dose between a tantalum (Ta)-specific contrast-to-noise ratio-driven exposure control (Ta-CEC) and a detector dose-driven exposure control (DEC) in abdominal angiography. Methods Nine angiography scenarios were created in seven anaesthetised pigs using Ta-based embolisation material during percutaneous liver and kidney intervention. Fluoroscopic images were acquired using three DEC protocols with different dose levels and Ta-CEC protocols with different IQ levels, sampled in small steps. Polymethyl-methacrylate and aluminium plates were used to simulate attenuation of three water equivalent thicknesses (WET). Three blinded readers evaluated the IQ of DEC and dose equivalent Ta images and selected the Ta-IQ equivalent image corresponding to the DEC image. Results Interobserver agreement for the IQ assessment was 0.43 for DEC, 0.56 for Ta-CEC and for the assessment of incident air kerma at the interventional reference point (K a,r) for the Ta-IQ equivalent image 0.73. The average IQ of the dose equivalent Ta images was superior compared to the DEC images (p < 0.001) and also for every WET (26, 31, or 36 cm) and dose level (p ≤ 0.022). The average K a,r for the Ta-IQ equivalent images was 59 ± 16% (mean ± standard deviation) lower compared to the DEC images (p < 0.001). Conclusions Compared to DEC, Ta-CEC significantly improved the fluoroscopic depiction of Ta, while maintaining the K a,r. Alternatively, the K a,r can be significantly reduced by using Ta-CEC instead of DEC, while maintaining equivalent IQ.

Unreplicated field trials and genomic prediction are both used to enhance the efficiency in early selection stages of a hybrid maize breeding program. No results are available on the optimal experimental design when combining both approaches. Our objectives were to investigate the effect of the training set design on the accuracy of genomic prediction in unreplicated maize test crosses. We carried out a cross validation study on basis of an experimental data set consisting of 1436 hybrids evaluated for yield and moisture for which genotyping information of 461 SNP markers were available. Training set designs of different size, implementing within environment prediction, within year prediction, across year prediction, and combinations of data sources across years and environments were compared with respect to their prediction accuracy. Across year prediction did not reach prediction accuracies that are useful for genomic selection. Within year prediction across environments provided useful correlations between observed and predicted breeding values. The prediction accuracies did not improve when adding to the training set data from previous years. We conclude that using all data available from unreplicated tests of the current breeding cycle provides a good accuracy of predicting test crosses, whereas adding data from previous breeding cycles, in which the genotypes are less related to the tested material, has only limited value for increasing the prediction accuracy.

The quantum approximate optimization algorithm (QAOA) is suggested as a promising application on early quantum computers. Here a quantum-inspired classical algorithm, the mean-field approximate optimization algorithm (mean-field AOA), is developed by replacement of the quantum evolution of the QAOA with classical spin dynamics through the mean-field approximation. Because of the alternating structure of the QAOA, this classical dynamics can be found exactly for any number of QAOA layers. We benchmark its performance against the QAOA on the Sherrington-Kirkpatrick model and the partition problem, and find that the mean-field AOA outperforms the QAOA in both cases for most instances. Our algorithm can thus serve as a tool to delineate optimization problems that can be solved classically from those that cannot, i.e., we believe that it will help to identify instances where a true quantum advantage can be expected from the QAOA. To quantify quantum fluctuations around the mean-field trajectories, we solve an effective scattering problem in time, which is characterized by a spectrum of time-dependent Lyapunov exponents. These provide an indicator for the hardness of a given optimization problem relative to the mean-field AOA.

Conventional 2D cultures are commonly used in cancer research though they come with limitations such as the lack of microenvironment or reduced cell heterogeneity. In this study, we investigated in what respect a scaffold-based (Matrigel™) 3D culture technique can ameliorate the limitations of 2D cultures. NGS-based bulk and single-cell sequencing of matched pairs of 2D and 3D models showed an altered transcription of key immune regulatory genes in around 36% of 3D models, indicating the reoccurrence of an immune suppressive phenotype. Changes included the presentation of different HLA surface molecules as well as cellular stressors. We also investigated the 3D tumor organoids in a co-culture setting with tumor-infiltrating lymphocytes (TILs). Of note, lymphocyte-mediated cell killing appeared less effective in clearing 3D models than their 2D counterparts. IFN-γ release, as well as live cell staining and proliferation analysis, pointed toward an elevated resistance of 3D models. In conclusion, we found that the scaffold-based (Matrigel™) 3D culture technique affects the transcriptional profile in a subset of GBM models. Thus, these models allow for depicting clinically relevant aspects of tumor-immune interaction, with the potential to explore immunotherapeutic approaches in an easily accessible in vitro system.

Abstract To evaluate mosaic perfusion patterns and vascular lesions in patients with chronic thromboembolic pulmonary hypertension (CTEPH) using C-Arm computed tomography (CACT) compared to computed tomography pulmonary angiography (CTPA). We included 41 patients (18 female; mean age 59.9 ± 18.3 years) with confirmed CTEPH who underwent CACT and CTPA within 21 days (average 5.3 ± 5.2). Two readers (R1; R2) independently evaluated datasets from both imaging techniques for mosaic perfusion patterns and presence of CTEPH-typical vascular lesions. The number of pulmonary arterial segments with typical findings was evaluated and the percentage of affected segments was calculated and categorized: 0.87) and the percentage of affected segments (ICC > 0.76) and good for the perceptibility of mosaic perfusion (ICC > 0.6) and attribution of the pattern of mosaic perfusion (ICC > 0.6) for both readers on CACT and CTPA. Inter-modality agreement was excellent for the perceptibility of mosaic perfusion (ICC = 1), the present perfusion pattern (ICC = 1) and central vascular lesions (ICC = 1). However, inter-modality agreement for the percentage of affected segments was fair (ICC = 0.50), with a greater proportion of identified affected segments on CACTcons. CACT demonstrates a high agreement with CTPA regarding the detection of mosaic perfusion. CACT detects a higher number of peripheral vascular lesions compared to CTPA.

The surface water systems of Ghana serve as a major source of drinking water, besides other multi-purpose benefit of hydro-electrical power generation and transportation. Thus, the dependence and benefits from such resources are of national interest. For instance, the Pra river of the South-Western surface water system of Ghana was a major consideration for a projected 5 billion m3 water demand in the year 2020 and “African Water Vision 2025”. In recent times, the colour state of the Pra river and similar surface water bodies of the Offin and Oda rivers has attracted intense public discussion. The prime issue relates to incessant illegal artisanal gold/diamond mining on or along these rivers. In order to assess the state of these rivers, water samples were taken, and analysed at the Council of Scientific and Industrial Research Laboratory (CSIR, Accra-Ghana) to investigate their physico-chemical quality. The research objective was to assess the extent of their water pollution by measuring physico-chemical parameters of turbidity, colour, pH and content of selected metals. A total of 18 preserved bottled samples [(5 from Offin river and 2 boreholes), 5 from Oda river and 5 from Pra river and 1 borehole)] were analysed, and results compared with portable water standards as defined by the WHO and CSIR (GS-175-1) of Ghana.Results on turbidity, colour, mercury and iron from the river and water samples generally exceed WHO or GS-175-1 limit. The Pra river recorded the most alarming result; range for turbidity (2,010 to 2,745 NTU), colour (3,000 to 4,500 Hz), total suspended solutes (2,240 to 2,570 mg/L) and total dissolved solutes (97.80–99.60 mg/L, excluding 319.00 to 25,440 mg/L). The Oda river shows lowest parameter values among the three rivers, as the areas have been dormant from illegal gold mining for 5 years. Current data suggests polluted river bodies and boreholes, and that none of these water resources meets the portable water consumption criteria unless treated prior to usage. As the current state of the water bodies may incur higher cost of water treatment or purification, an integrated water governance under Ghana's Ministry of Water Resource, Work and Housing, and the Minerals Commission and Environmental Protection Agency are recommended for the management of these valuable water resources.

The problem of a traditional waveguide plasmonic resonator sensor is that part of the near-field intensity enhanced area is confined in the waveguide dielectric layer, which decreases the interaction effect between light and analyte. In order to solve this problem, a novel mid-infrared (MIR) chalcogenide (ChG) slot waveguide plasmonic resonator (SWGPR) sensor embedded with Au nanorods was proposed, where Au nanorods were used as antenna for enhancing mode coupling with the waveguide through resonance at the absorption wavelength of the analyte. The antenna parameters were optimized to make the resonance wavelength align with the absorption wavelength of the analyte. The proposed waveguide structure provides a sufficient sensing area and increases the electric field enhancement factor to > 6400. Polymethyl methacrylate (PMMA) and styrene were adopted as the analyte for sensing performance evaluation. The normalized absorption reaches 23.31 when the maximum extinction coefficient of PMMA is 0.08, which is at least 7 times higher than other silicon-on-insulator (SOI) waveguide plasmonic resonator sensors. The proposed waveguide structure provides a new idea for the design of other waveguide plasmonic resonator sensors with high sensing performance and has the potential for biochemical sensing.

Abstract Optical fibers, stretched between anchors attached to the Earth and buried in boreholes and shallow trenches, offer an inexpensive and robust means to observe Earth strain. We have deployed several optical fiber strainmeters (OFSs) in boreholes, where thermal stability helps mitigate the noise from temperature changes. We have also constructed horizontal OFSs in 1‐m‐deep trenches of lengths 221 and 174 m. In these, a second optical fiber having a contrasting temperature coefficient provides a means to separate true strain from thermal noise. Signals in the seismic band from the horizontal strainmeters agree well with records from collocated seismometers, and the predominant ambient noise recorded by both techniques are consistent. Solid Earth strain tides with amplitude of 30 nε (nanostrain) are observed in these horizontal OFSs that agree well with those observed by collocated vacuum laser strainmeters. Noise at periods of a few days amounts to 50 nε. The two horizontal strainmeters show drift rates of up to 1 µε per month, and occasional false signals (evident from comparisons with the vacuum laser strainmeters) can accumulate occasionally to the order of 50 nε over times from hours to weeks. Results to date indicate that this technology on land could detect slow‐slip events of amplitude 100 nε and higher.

Portable or even on-chip detection of methane (CH4) is significant for environmental protection and production safety. However, optical sensing systems are usually based on discrete optical elements, which makes them unsuitable for the occasions with high portability requirement. In this work, we report on-chip silicon-on-insulator (SOI) waveguide CH4 sensors at 3.291 μm based on two measurement schemes including direct absorption spectroscopy (DAS) and wavelength modulation spectroscopy (WMS). In order to suppress noise, Kalman filter was adopted in signal processing. By optimizing the waveguide cross-section structure, an etch depth of 220 nm was selected with an experimentally high power confinement factor (PCF) of 23% and a low loss of only 0.71 dB/cm. A limit of detection (LoD) of 155 parts-per-million (ppm) by DAS and 78 ppm by WMS at an averaging time of 0.2 s were obtained for a 2 cm-long waveguide sensor. Compared to the chalcogenide (ChG) waveguide CH4 sensors at the same wavelength, the reported sensor reveals the minimum waveguide loss and the lowest LoD. Therefore the SOI waveguide sensor has the potential of on-chip gas sensing in the mid-infrared (MIR) waveband.

Background: Oral-functioning impairment can negatively affect the quality of life (QoL) of head and neck cancer (HNC) patients after receiving radiotherapy (RT). Assessment of patient-reported oral functioning throughout treatment can improve patient care. This scoping review aims to propose a definition for oral functioning for HNC patients and to map out the available questionnaires measuring patient-reported oral functioning in RT-treated HNC patients. Methods: A literature search in relevant databases was performed. Each questionnaire was scored on the domains validity, reliability, and responsiveness. Furthermore, the items from the questionnaires were analyzed to define the common denominators for oral functioning in HNC patients. Results: Of the 6434 articles assessed, 16 met the inclusion criteria and employed 16 distinct instruments to evaluate QoL. No questionnaire covered all oral-health-related QoL items nor assessed all aspects of validity, reliability, and responsiveness. Chewing, speaking, and swallowing were the common denominators for oral functioning. Conclusions: Based on the included studies, we suggest using the VHNSS 2.0 questionnaire to assess oral functioning in HNC patients. Furthermore, we suggest to more clearly define oral functioning in HNC patients by focusing on masticatory function (chewing and grinding), mouth opening, swallowing, speaking, and salivation.

Drosophila’s dorsal clock neurons (DNs) consist of four clusters (DN1as, DN1ps, DN2s, and DN3s) that largely differ in size. While the DN1as and the DN2s encompass only two neurons, the DN1ps consist of ∼15 neurons, and the DN3s comprise ∼40 neurons per brain hemisphere. In comparison to the well-characterized lateral clock neurons (LNs), the neuroanatomy and function of the DNs are still not clear. Over the past decade, numerous studies have addressed their role in the fly’s circadian system, leading to several sometimes divergent results. Nonetheless, these studies agreed that the DNs are important to fine-tune activity under light and temperature cycles and play essential roles in linking the output from the LNs to downstream neurons that control sleep and metabolism. Here, we used the Flybow system, specific split-GAL4 lines, trans-Tango, and the recently published fly connectome (called hemibrain) to describe the morphology of the DNs in greater detail, including their synaptic connections to other clock and non-clock neurons. We show that some DN groups are largely heterogenous. While certain DNs are strongly connected with the LNs, others are mainly output neurons that signal to circuits downstream of the clock. Among the latter are mushroom body neurons, central complex neurons, tubercle bulb neurons, neurosecretory cells in the pars intercerebralis, and other still unidentified partners. This heterogeneity of the DNs may explain some of the conflicting results previously found about their functionality. Most importantly, we identify two putative novel communication centers of the clock network: one fiber bundle in the superior lateral protocerebrum running toward the anterior optic tubercle and one fiber hub in the posterior lateral protocerebrum. Both are invaded by several DNs and LNs and might play an instrumental role in the clock network.

Clinical outcomes in patients with WHO grade II/III astrocytoma, oligodendroglioma or secondary glioblastoma remain poor. Isocitrate dehydrogenase 1 (IDH1) is mutated in > 70% of these tumors, making it an attractive therapeutic target. To determine the efficacy of our newly developed mutant IDH1 inhibitor, SYC-435 (1-hydroxypyridin-2-one), we treated orthotopic glioma xenograft model (IC-BT142AOA) carrying R132H mutation and our newly established orthotopic patient-derived xenograft (PDX) model of recurrent anaplastic oligoastrocytoma (IC-V0914AOA) bearing R132C mutation. In addition to suppressing IDH1 mutant cell proliferation in vitro, SYC-435 (15 mg/kg, daily x 28 days) synergistically prolonged animal survival times with standard therapies (Temozolomide + fractionated radiation) mediated by reduction of H3K4/H3K9 methylation and expression of mitochondrial DNA (mtDNA)-encoded molecules. Furthermore, RNA-seq of the remnant tumors identified genes (MYO1F, CTC1 and BCL9) and pathways (base excision repair, TCA cycle II, sirtuin signaling, protein kinase A, eukaryotic initiation factor 2 and α-adrenergic signaling) as mediators of therapy resistance. Our data demonstrated the efficacy SYC-435 in targeting IDH1 mutant gliomas when combined with standard therapy and identified a novel set of genes that should be prioritized for future studies to overcome SYC-435 resistance.

Abstract High intracranial pressure (ICP) can impede cerebral blood flow resulting in secondary injury or death following severe stroke. Compensatory mechanisms include reduced cerebral blood and cerebrospinal fluid volumes, but these often fail to prevent raised ICP. Serendipitous observations in intracerebral hemorrhage (ICH) suggest that neurons far removed from a hematoma may shrink as an ICP compliance mechanism. Here, we sought to critically test this observation. We tracked the timing of distal tissue shrinkage (e.g. CA1) after collagenase-induced striatal ICH in rat; cell volume and density alterations (42% volume reduction, 34% density increase; p

In SF6 insulated high-voltage gas power systems, H2O is the most problematic impurity which not only decreases insulation performance but also creates an acidic atmosphere that promotes corrosion. Corrosion damages electrical equipment and leads to leaks, which pose serious safety hazards to people and the environment. A QEPAS-based sensor system for the sub-ppm level H2O detection in SF6 buffer gas was developed by use of a near-infrared commercial DFB diode laser. Since the specific physical constants of SF6 are strongly different from that of N2 or air, the resonant frequency and Q-factor of the bare quartz tuning fork (QTF) had changed to 32,763 Hz and 4173, respectively. The optimal vertical detection position was 1.2 mm far from the QTF opening. After the experimental optimization of acoustic micro-resonator (AmR) parameters, gas pressures, and modulation depths, a detection limit of 0.49 ppm was achieved for an averaging time of 1 s, which provided a powerful prevention tool for the safety monitoring in power systems.

In this invited paper, a compact dense-pattern multipass cell-based near-infrared sensor system was demonstrated for detection of parts-per-billion in volume (ppbv)-level methane (CH4) and ethane (C2H6). The dimension size of the fabricated gas cell is 18.5 × 8 × 9 cm3 with an absorption path length of 9.39 m. CH4 measurement was realized within a spectral range of 6,046–6,048 cm−1 and an absorption line of 6,046.95 cm−1. The spectral range for C2H6 detection is 5,951–5,953 cm−1 with an absorption line of 5,951.73 cm−1. Allan deviation analysis was used for evaluating the dual-gas sensing performance, and a detection limit of 78 ppbv for CH4 and 190 ppbv for C2H6 were achieved, respectively, with an averaging time of 0.8 s. Furthermore, CH4 measurement in the indoor and outdoor atmosphere was both performed to verify the field sensing capability of the sensor system. Compared with two separate sensor systems for CH4/C2H6 sensing, the proposed dual-gas sensor system using two near-infrared lasers and one multipass cell has the advantages of low-cost, compact-size without decreasing the selectivity and sensitivity.

Background/Aims There is a lack of data on long-term morbidity, particularly dysphagia, following endoscopic variceal band ligation (EVL). The aim of this study are to assess the incidence of dysphagia and variables associated with this complication after EVL. Methods We identified individuals who completed at least one session of EVL as their sole treatment for varices from August 2012 to December 2017. Included patients achieved “complete eradication” of varices not requiring further therapy. Patients ≥90 days from their last EVL session completed a modified version of the Mayo Clinic Dysphagia Questionnaire. Individuals with dysphagia were invited to undergo a barium esophagram. Patients with pre-EVL dysphagia were excluded. Results Of the patients, 68 possessed inclusion criteria, nine (13.2%) died and 20 (29.4%) were lost to follow up. For the remaining 39 (57.4%) patients, 23 were males, mean age of 61.7±8.6 years. The most common etiology of liver disease was hepatitis C virus (n=18; 46.2%). The median number of banding sessions was 2.0 (interquartile range [IQR], 1.0–4.0) with a median of 9.0 bands placed (IQR, 3.0–14.0). Twelve patients (30.8%) developed new-onset dysphagia post-EVL. In univariate analysis, pre-EVL MELD score and non-emergent initial banding were associated with long-term dysphagia. In a regression model adjusted for age, sex, number of bands, and use of acid suppression after EVL, no factor was independently associated with dysphagia (all p>0.05). No strictures were identified on subsequent esophageal evaluation. Conclusions Approximately 30% of patients developed new-onset, chronic dysphagia post-EVL. Incident dysphagia was associated with a non-emergent initial banding session. The mechanism for dysphagia remains unknown.

Abstract Diffuse invasion is the primary cause of treatment failure of glioblastoma (GBM). Previous studies on GBM invasion have long been forced to use the resected tumor mass cells. Here, a strategy to reliably isolate matching pairs of invasive (GBMINV) and tumor core (GBMTC) cells from the brains of 6 highly invasive patient‐derived orthotopic models is described. Direct comparison of these GBMINV and GBMTC cells reveals a significantly elevated invasion capacity in GBMINV cells, detects 23/768 miRNAs over‐expressed in the GBMINV cells (miRNAINV) and 22/768 in the GBMTC cells (miRNATC), respectively. Silencing the top 3 miRNAsINV (miR‐126, miR‐369‐5p, miR‐487b) successfully blocks invasion of GBMINV cells in vitro and in mouse brains. Integrated analysis with mRNA expression identifies miRNAINV target genes and discovers KCNA1 as the sole common computational target gene of which 3 inhibitors significantly suppress invasion in vitro. Furthermore, in vivo treatment with 4‐aminopyridine (4‐AP) effectively eliminates GBM invasion and significantly prolongs animal survival times (P = 0.035). The results highlight the power of spatial dissection of functionally accurate GBMINV and GBMTC cells in identifying novel drivers of GBM invasion and provide strong rationale to support the use of biologically accurate starting materials in understanding cancer invasion and metastasis.

Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage-specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3 (optoα1AR) and cAMP (optoß2AR), or Ca2+-permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+ imaging in Hcn4BAC-CatCh2/Myh6-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks.

Background & Aims: Hepatic enzymes play a major role in the metabolic elimination of cortisol, and reduced rates of cortisol clearance have been consistently observed in patients with chronic liver disease. It is less clear whether there are concomitant abnormalities of adrenocortical function in patients with cirrhosis. In the present study, we sought to assess adrenocortical function in patients with cirrhosis using measures of free cortisol appearance and elimination rates that are independent of serum concentrations of cortisol binding proteins. Methods: Post hoc analysis used computer-assisted numerical and modelling methods with serial total and free cortisol concentration data to obtain rates of free cortisol appearance and elimination. Rate parameters were obtained in 114 patients with chronic liver disease, including Child-Pugh (CP) ≤8 (n = 53) and CP >8 (n = 61). Results: Maximal cortisol secretion rate (CSRmax) was significantly decreased (p = 0.01) in patients with cirrhosis with CP >8 (0.28 nM/s; 95% CI 0.24–0.34) compared with those with CP ≤8 (0.39 nM/s; 95% CI 0.33–0.46), and CSRmax was negatively correlated with CP score (r = −0.19, p = 0.01). Free cortisol elimination rate was significantly (p = 0.04) decreased in the CP >8 group (0.16 ± 0.20 min−1) compared with that in the CP ≤8 group (0.21 ± 0.21 min−1), and free cortisol elimination rates were negatively correlated with CP score (r = −0.23, p = 0.01). A significant correlation between CSRmax and free cortisol elimination rate (r = 0.88, p

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

Abstract The study of primary glucagon-secreting α-cells is hampered by their low abundance and scattered distribution in rodent pancreatic islets. We have designed a double-stranded adeno-associated virus containing a rat proglucagon promoter (700 bp) driving enhanced green fluorescent protein (AAV GCG-EGFP), to specifically identify α-cells. The administration of AAV GCG-EGFP by intraperitoneal or intraductal injection led to EGFP expression selectively in the α-cell population. AAV GCG-EGFP delivery to mice followed by islet isolation, dispersion and separation by FACS for EGFP resulted in an 86% pure population of α-cells. Furthermore, the administration of AAV GCG-EGFP at various doses to adult wild type mice did not significantly alter body weight, blood glucose, plasma insulin or glucagon levels, glucose tolerance or arginine tolerance. In vitro experiments in transgene positive α-cells demonstrated that EGFP expression did not alter the intracellular Ca2+ pattern in response to glucose or adrenaline. This approach may be useful for studying purified primary α-cells and for the in vivo delivery of other genes selectively to α-cells to further probe their function or to manipulate them for therapeutic purposes.