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Rhinoviruses (RVs) and coronaviruses (CoVs) upregulate host cell metabolic pathways such as glycolysis to meet their bioenergetic demands for rapid multiplication. Using the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), we assessed the dose-dependent inhibition of viral replication of minor- and major-receptor group RVs in epithelial cells. 2-DG disrupted RV infection cycle by inhibiting template negative-strand as well as genomic positive-strand RNA synthesis, resulting in less progeny virus and RV-mediated cell death. Assessment of 2-DG’s intracellular kinetics revealed that after a short-exposure to 2-DG, the active intermediate, 2-DG6P, is stored intracellularly for several hours. Finally, we confirmed the antiviral effect of 2-DG on pandemic SARS-CoV-2 and showed for the first time that 2-DG also reduces replication of endemic human coronaviruses (HCoVs). These results provide further evidence that 2-DG could be utilized as a broad-spectrum antiviral.HIGHLIGHTS2-DG inhibits replication of minor- and major-group rhinoviruses in epithelial cells including human nasal epithelial cell.2-DG disrupts rhinovirus infection cycle and reduces rhinovirus-mediated cell death in vitro.2-DG treatment attenuates viral load of endemic coronaviruses in vitro.

Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by inter-species differences between human and mouse, as well as inter-person germline and somatic variation. Here we develop an autologous system that models the TME in individual patients. With patient-derived bone marrow, we engrafted a patient’s hematopoietic system in MISTRG6 mice followed by patient-derived xenograft (PDX) tissue, providing a genetically matched autologous model. We used this system to prospectively study tumor-immune interactions in solid tumor patients. Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent VEGF-A signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth, demonstrating the utility of the autologous PDX system for pre-clinical testing.

We report on an 11-year-old girl with cystic fibrosis who presented with thoracic pain and an extensive subcutaneous emphysema and subsequently developed progressive respiratory distress. The chest computed tomography revealed a huge pneumomediastinum. Due to the development of severe respiratory failure, urgent needle thoracocentesis was necessary that resulted in only temporary improvement. Therefore, under general anesthesia two mediastinal drains were introduced. Using active suction, the size of the pneumomediastinum decreased gradually and the drains were removed after 3 weeks. Here, we describe an extremely rare situation, when acute surgical intervention was necessary in a child with spontaneous pneumomediastinum.

The immune milieu within tumors, consisting of diverse cell types including adaptive immune cells as well as macrophages, dendritic cells, natural killer and other innate immune cells, is critical to determining cancer outcome. However, the immune tumor microenvironment (TME) has been challenging to model, owing to inherent inter-species differences. While humanized mice can support human immune cells, the hematopoietic stem and progenitor cells (HSPCs) used for transplantation have been largely limited to fetal or neonatal stem cell sources, necessitating allogeneic experiments with limited applicability. We sought to develop a method to pre-clinically model an individual adult cancer patient, capturing the unique features of an individual such as germline genetic determinants of immune function and somatic tumor heterogeneity, and creating an autologous system. MISTRG6 may be engrafted with low numbers of HSPCs. When engrafted with equivalent numbers of CD34+ cells from human fetal liver (FL), neonatal cord blood (CB), adult mobilized peripheral blood (MPB), or adult bone marrow (BM), MISTRG6 mice harbored greatly increased human hematopoietic cells as a proportion of total hematopoietic cells in peripheral blood compared with NOD-scid-gamma (NSG) and MISTRG mice (p MISTRG6 allows efficient engraftment of patient derived HSPCs. We sought to apply this improved engraftment prospectively to model individual patients’ TME through collection of BM-derived CD34+ cells from patients under active treatment along with tumor tissue from the same patient. At two cancer centers, we enrolled patients with melanoma, NSCLC, PDAC, and HNSCC to provide BM aspirate, peripheral blood, and tumor tissue. CD34+ cells were isolated from BM aspirates and tumor tissue was utilized to generate PDXs. Overall, 71 patients were enrolled, 46 melanoma, 19 NSCLC, 4 PDAC, 2 HNSCC, ages 22-85, 39% females. These yielded autologous, immune-reconstituted MISTRG6 hosts from 14 melanoma, 5 NSCLC, 2 PDAC, and 1 HNSCC patients. Autologously engrafted MISTRG6 mice displayed the gamut of human immune cells of adaptive and innate types in PB at 7 weeks of age. Notably, this included CD33+ myeloid cells such as CD14+CD16− classical, CD14+CD16+ intermediate, and CD14−CD16+ non-classical monocytes. Moreover, human dendritic cells (DCs), key innate immune cells for initiation of anti-tumor responses were readily detected by flow cytometry in spleens of autologously-engrafted mice, including cDC1, cDC2, and pDC cells. MISTRG6 mice bearing a patient’s hematopoietic cells support autologous PDX growth. Having achieved successful engraftment of patient hematopoietic systems in MISTRG6 hosts, we next subcutaneously introduced the patient’s matched PDX tumor tissue to generate autologously engrafted PDX mice. For most patients, tumors grown in autologous HSPC-engrafted hosts were significantly larger than in non-engrafted hosts. Multicolor immunofluorescence staining of PDX tumors demonstrated that human immune cells, including CD3+ T cells, CD14+ and HLA-DR+ myeloid cells, penetrated deeply into the tumor and co-localized with tumor cells as well as with other engrafted immune cells. Indeed, HLA-DR+CD14+macrophages and HLA-DR+CD14(-) dendritic cells were present, and direct physical interaction between T cells and macrophages was evident. Using whole-exome sequencing, we found that 225 somatic changes were shared between patient Mel738’s surgical resection sample, two PDX tumors from non-engrafted mice lacking human immune cells, and two PDX tumors from mice with autologous engraftment. 5 additional changes were shared among the tumor samples and absent from the cell line, with 36 additional mutations being specific to the cell line. These data underscore the capacity of the autologous PDX method to recapitulate the somatic heterogeneity that the patient tumor possesses. Autologous MISTRG6 mice display diverse human immune cell populations and recapitulate an immunosuppressive TME. To fully characterize the autologous MISTRG6 model and investigate mechanisms by which autologous human immune cells enhance tumor growth, we performed single cell transcriptomics on hCD45+-enriched cells from blood and tumor isolated from autologous mice. This revealed 16 distinct cell subtypes, including 3 myeloid, 2 NK cell, 2 CD8 T cell, 3 CD4 T cell, 2 cycling lymphocyte, 1 B cell, and 3 melanoma cell clusters. Subclustering of myeloid cells revealed 9 distinct clusters including 4 monocyte, 4 macrophage, and 1 DC cluster. Comparing CD8 T cells present in blood versus tumor revealed that the most differentially expressed genes (DEGs) found in blood were characteristic of naïve T cells, while genes present in the TME were consistent with activated T cell phenotypes. In addition, sub-clustering revealed 3 distinct CD8 T cell types that included two activated-like populations, with one of these populations also expressing an activated/exhausted program typified by expression of PDCD1, LAG3, and GZMA. Naïve-like T cells were most highly represented in the blood, while activated and activated/exhausted-like genes were more present in the TME. Inhibiting the actions of human VEGF-A blocks the enhanced tumor growth in autologously engrafted mice. Notably, IPA Upstream Regulator Analysis identified VEGFA, a central player in tumor growth and vascularization, as a key upstream inducer of genes in the TME (FDR p= 5.65 × 10−13). Indeed, expression VEGFA itself was nearly absent in blood but induced in the TME, especially in macrophages and VEGFA targets were highly represented among the DEGs between tumor and blood.To test the relevance of VEGF-A in the TME, we selectively blocked human VEGF-A by treating autologous mice humanized from Mel2 with the anti-hVEGF-A antibody bevacizumab that has high affinity for human VEGF-A yet low affinity for mouse VEGF-A. PDXs grown in untreated autologously engrafted MISTRG6 mice grew significantly larger than those in non-engrafted littermate control hosts (p Future Directions: Thus, these in silico and in vivo results suggest that human VEGF-A production in the autologous TME enhances tumor growth in MISTRG6 PDX models and underscores the utility of the MISTRG6 system for pre-clinical testing of drugs that act on human immune components of the TME. By engrafting mice with bone marrow derived stem cells followed by implantation of tumor derived from the same donor, we have demonstrated that autologous MISTRG6 models recapitulate important features of the human TME, including sufficient immunosuppression to prevent tumor clearance, presence of activated/exhausted T cells, and innate immune cells including DCs, monocytes, NK cells, and macrophages, the latter especially relevant to the production of VEGF-A. Citation Format: Michael Chiorazzi, Jan Martinek, Bradley Krasnick, Yunjiang Zheng, Keenan Robbins, Rihao Qu, Gabriel Kaufmann, Zachary Skidmore, Laura Henze, Frederic Brösecke, Adam Adonyi, Jun Zhao, Liang Shan, Esen Sefik, Jacqueline Mudd, Ye Bi, S Peter Goedegebuure, Malachi Griffith, Obi Griffith, Abimbola Oyedeji, Sofia Fertuzinhos, Roland Garcia-Milian, Daniel Boffa, Frank Detterbeck, Andrew Dhanasopon, Justin Blasberg, Benjamin Judson, Scott Gettinger, Katerina Politi, Yuval Kluger, A Karolina Palucka, Ryan Fields, Richard A. Flavell. Autologous humanized PDX modeling for immuno-oncology recapitulates the human tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr NG11.

This study is part of a longitudinal, multiphase study on development of literacy mentoring practices particularly with regard to the cooperating teacher. This paper reports on the findings from the first year of the study during which cooperating teachers (CT) participated in a master's program focused on coaching and mentoring while mentoring preservice teachers completing their elementary education degree inside a literacy specialization cohort. Drawing on observational and interview data and employing an activity theory framework, we examine the ways the CTs' involvement in a community of peers and faculty who met regularly in courses was instrumental their appropriation of a model of mentoring known as coaching with CARE. Analysis indicated that coursework, particularly two courses taken during the first year, offered multiple spaces that functioned as ways for participants to work through tensions that arose as the CTs moved across activity systems (from their coaching community at the university to their individual schools situated within area school districts). Specifically, these spaces afforded opportunities to work through understandings of the underlying theories and concepts related to reflective coaching, to share their experiences and beginning enactments of the coaching model, and to coach one another as they interacted around videotaped coaching conferences.

In this study, the complete genome of a novel picornavirus called harrier picornavirus 1 (HaPV-1) strain harrier/MR-01/HUN/2014 (KY488458) was sequenced and analysed from a cloacal sample of a threatened, carnivorous wild bird, western marsh harrier (Circus aeruginosus). HaPV-1 was detectable from 2 of the 3 samples from harriers. HaPV-1 is phylogenetically related to megriviruses (genus Megrivirus) from domestic chicken, turkey and duck, showing a similar genome organization pattern; it also has an avian picornavirus-like "Unit A" motif in the 3' UTR. Unlike the type-IV internal ribosomal entry site (IRES) of megriviruses, HaPV-1 is predicted to contain a type-II-like IRES, suggesting modular exchange of IRES elements between picornavirus genomes.

A substantial body of research has collectively concluded that encouraging students to draw flexibly on multiple aspects of their linguistic repertoires is positively associated with developing bilingualism, metalinguistic awareness, and academic skills. However, most bilingual education programs—including transitional and dual-language—limit, discourage, and/or stigmatize such practices. This study examines literature discussion in a fifth-grade bilingual education classroom, in which the teacher valued, supported, and facilitated hybrid language practices. The findings illuminate the ways in which the teacher and students flexibly used their linguistic and cultural resources to understand the text content and language.

Handling major hypersensitivity reactions (e.g. celiac disease) triggered by proteins of wheat and other cereals is a challenging task for healthcare systems, legislative forces and the related fields of food analysis as well. In spite of the fact that there are available official threshold levels for labelling the absence of gluten, which is considered to be the toxic protein fraction of wheat, barley and rye, validation of the analytical methodology supporting regulatory requirements is currently problematic. The main limiting factors of method validation are the lack of reference methods and reference materials. The objective of this study was to provide a solution to this problem. An incurred reference material in a model food matrix was developed and studied by commercially available ELISA test kits as a part of the activity of the Food Allergen Working Group within the FP6 funded EU project MoniQA. After successful completion of the reference material development process, the incurred material was used as a basis of a comparative study examining the performance and applicability of seven commercially available ELISA kits designed for quantification of gluten/gliadin. In certain cases the obtained data showed discrepancies from the expected gliadin content that may carry both a food safety and an economic relevance. The evaluation of the effects of heat treatment on the analytical results is also presented, highlighting the fact that the food processing steps may have a considerable impact on the analytical data, thus should be carefully handled during method development and validation.

A gyermekkori asztma, allergiás rhinitis és atópiás dermatitis prevalenciája világszerte folyamatosan emelkedett az elmúlt évtizedekben. A legfrissebb közlések az emelkedő tendencia megváltozásáról, plató kialakulásáról vagy csökkenésről számolnak be. A szerzők 2003 után 2006-ban is meghatározták az asztma és asztmatünetek prevalenciáját Baranya megyei iskolás gyermekek körében, hogy regisztrálják az esetleges változásokat. Vizsgálati anyag, módszer: Munkájukhoz az ISAAC (International Study for Asthma and Allergies in Childhood) III. fázisú protokoll magyar nyelvre fordított kérdőívét használták. 2006 februárjában 16 általános iskolában (6 nagyvárosi és 10 kisvárosi, falusi) 2404 (1124 fiú, 1280 lány) 6–7 és 13–14 éves gyermek adatait gyűjtötték össze, és értékelték, illetőleg az adatokat a 2003-ban végzett ISAAC I. fázisú protokoll szerinti felmérés eredményeihez viszonyították. Eredmények: A valaha előfordult asztmás nehézlégzés és az orvos által megállapított asztma prevalenciája nem változott szignifikánsan (2006-ban 20,2% és 6,7%, 2003-ban 19,8% és 8,2%), míg a legutóbbi 12 hónapban előforduló asztmás nehézlégzés aránya szignifikánsan emelkedett (2006-ban 9,6% és 2003-ban 6,8%). A várakozásnak megfelelően, 2006-ban éppúgy, mint 2003-ban, a fiúk és a 6–7 évesek körében szignifikánsan magasabb volt a prevalencia, mint a lányok és a 13–14 évesek körében. 2006-ban és 2003-ban nem volt szignifikáns különbség a nagyvárosi és a kisebb települések iskolás gyermekeinek asztma- és asztmatüneti prevalenciájában. Következtetés: Baranya megyében az iskolás gyermekek körében a legutóbbi 12 hónapban előforduló asztmás nehézlégzés prevalenciája szignifikánsan emelkedett a vizsgált periódusban, a valaha előforduló asztmás nehézlégzés és az orvos által megállapított asztma prevalenciája nem változott.

This work presents a methodology for incorporating heat integration in batch process scheduling. The formerly introduced S-graph approach [AIChE J. 48 (2002) 2557–2570] for solving multipurpose scheduling problems is proved to be appropriate for the representation of both scheduling problems and the corresponding heat exchanger network synthesis problem. The proposed procedure is based on the branch-andbound framework, where two optimisation problems, the scheduling and the heat integration one, are considered simultaneously instead of consecutively. This method is primarily based on combinatorics and combinatorial algorithms. Solution of several examples illustrates the efficiency of the proposed approach and the benefits of considering heat exchanger network synthesis while scheduling batch processes. � 2003 Elsevier Ltd. All rights reserved.