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Since the accident at the Chornobyl Nuclear Power Plant in 1986, there have been few studies published on medium and large mammals inhabiting the area from which the human population was removed (now referred to as the Chornobyl Exclusion Zone, CEZ). The dataset presented in this paper describes a motion-activated camera trap study (n=21 cameras) conducted from September 2016 to September 2017 in the Red Forest located within the Chornobyl Exclusion Zone. The Red Forest, which is likely the most anthropogenically contaminated radioactive terrestrial ecosystem on earth, suffered a severe wildfire in July 2016. The motion-activated trap cameras were therefore in place as the Red Forest recovered from the wildfire. A total of 45 859 images were captured, and of these 19 391 contained identifiable species or organism types (e.g. insects). A total of 14 mammal species were positively identified together with 23 species of birds (though birds were not a focus of the study). Weighted absorbed radiation dose rates were estimated for mammals across the different camera trap locations; the number of species observed did not vary with estimated dose rate. We also observed no relationship between estimated weighted absorbed radiation dose rates and the number of triggering events for the four main species observed during the study (brown hare, Eurasian elk, red deer, roe deer). The data presented will be of value to those studying wildlife within the CEZ from the perspectives of the potential effects of radiation on wildlife and also rewilding in this large, abandoned area. They may also have value in any future studies investigating the impacts of the recent Russian military action in the CEZ. The data and supporting documentation are freely available from the Environmental Information Data Centre (EIDC) under the terms and conditions of a Creative Commons Attribution (CC BY) license: https://doi.org/10.5285/bf82cec2-5f8a-407c-bf74-f8689ca35e83 (Barnett et al., 2022a).

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L– cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression promoted NKT expansion and limited exhaustion following serial tumor challenge and was sufficient to induce a central memory–like transcriptional program in NKTs. In mice, NKTs expressing a GD2-specific chimeric-antigen receptor (CAR) with LEF1 demonstrated superior control of neuroblastoma xenograft tumors compared with control CAR-NKTs. These results identify LEF1 as a transcriptional activator of the NKT central memory program and advance development of NKT cell–based immunotherapy. See related Spotlight by Van Kaer, p. 144

Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice. PIDO expressing murine islets maintain robust dynamic insulin secretion in vitro and when transplanted in allogeneic hyperglycemic murine recipients reverse pre-existing streptozotocin-induced and autoimmune diabetes in the absence of pharmacological immunosuppression for more than 50 and 8 weeks, respectively, and is dependent on host CD4 competence. Additionally, PIDO expression in allografts preserves endocrine functional viability of islets and promotes a localized tolerogenic milieu characterized by the suppression of host CD8 T cell and phagocyte recruitment and accumulation of FOXP3

Research into anti-icing surfaces often conflates the two separate problems of ice accumulation: water adhesion and ice adhesion. The body feathers of perpetually ice-free penguins are very good natural examples of anti-icing surfaces, which use two different mitigation strategies for the two disparate problems. Herein, we mimic the form of the feather's wire-like structure, which is decorated with superimposed nanogrooves by laser micromachining fine woven wire cloths. Post-processing techniques also allow us to isolate the role of surface chemistry by creating both hydrophilic and hydrophobic versions of the synthetic anti-icing surfaces. Our results show that water-shedding and ice-shedding characteristics are indeed derived from different physical functions of the hierarchical structure. The microstructure of the woven wire cloth leads to facile interfacial cracking and therefore extremely low ice adhesion strengths; the superimposed laser-induced periodic surface structures with hydrophobic surface chemistry lead to water shedding. Our work shows that by first taking a fracture mechanics approach to designing the ice-shedding function, a robust anti-icing surface can be engineered by separately designing the water-shedding functions.

International audience; Background: Reproductive effects of ionizing radiation in organisms have been observed under laboratory and field conditions. Such assessments often rely on associations between exposure and effects, and thus lacking a detailed mechanistic understanding of causality between effects occurring at different levels of biological organization. The Adverse Outcome Pathway (AOP), a conceptual knowledge framework to capture, organize, evaluate and visualize the scientific knowledge of relevant toxicological effects, has the potential to evaluate the causal relationships between molecular, cellular, individual, and population effects. This paper presents the first development of a set of consensus AOPs for reproductive effects of ionizing radiation in wildlife. This work was performed by a group of experts formed during a workshop organized jointly by the Multidisciplinary European Low Dose Initiative (MELODI) and the European Radioecology Alliance(ALLIANCE) associations to present the AOP approach and tools. The work presents a series of taxon-specific case studies that were used to identify relevant empirical evidence, identify common AOP components and propose a set of consensus AOPs that could be organized into an AOP network with broader taxonomic applicability.Conclusion: Expert consultation led to the identification of key biological events and description of causal linkages between ionizing radiation, reproductive impairment and reduction in population fitness. The study characterized the knowledge domain of taxon-specific AOPs, identified knowledge gaps pertinent to reproductive-relevant AOP development and reflected on how AOPs could assist applications in radiation (radioecological) research, environmental health assessment, and radiological protection. Future advancement and consolidation of the AOPs is planned to include structured weight of evidence considerations, formalized review and critical assessment of the empirical evidence prior to formal submission and review by the OECD sponsored AOP development program.

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L– cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression promoted NKT expansion and limited exhaustion following serial tumor challenge and was sufficient to induce a central memory–like transcriptional program in NKTs. In mice, NKTs expressing a GD2-specific chimeric-antigen receptor (CAR) with LEF1 demonstrated superior control of neuroblastoma xenograft tumors compared with control CAR-NKTs. These results identify LEF1 as a transcriptional activator of the NKT central memory program and advance development of NKT cell–based immunotherapy.See related Spotlight by Van Kaer, p. 144

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Purpose: Adoptive transfer of Epstein–Barr virus (EBV)–specific and cytomegalovirus (CMV)-specific cytotoxic T cells (CTL) genetically modified to express a chimeric antigen receptor (CAR) induces objective tumor responses in clinical trials. In vivo expansion and persistence of these cells are crucial to achieve sustained clinical responses. We aimed to develop an off-the-shelf whole-cell vaccine to boost CAR-redirected virus-specific CTLs in vivo after adoptive transfer. As proof of principle, we validated our vaccine approach by boosting CMV-specific CTLs (CMV-CTLs) engineered with a CAR that targets the GD2 antigen.Experimental Design: We generated the whole-cell vaccine by engineering the K562 cell line to express the CMV-pp65 protein and the immune stimulatory molecules CD40L and OX40L. Single-cell–derived clones were used to stimulate CMV-CTLs in vitro and in vivo in a xenograft model. We also assessed whether the in vivo boosting of CAR-redirected CMV-CTLs with the whole-cell vaccine enhances the antitumor responses. Finally, we addressed potential safety concerns by including the inducible safety switch caspase9 (iC9) gene in the whole-cell vaccine.Results: We found that K562-expressing CMV-pp65, CD40L, and OX40L effectively stimulate CMV-specific responses in vitro by promoting antigen cross-presentation to professional antigen-presenting cells (APCs). Vaccination also enhances antitumor effects of CAR-redirected CMV-CTLs in xenograft tumor models. Activation of the iC9 gene successfully induces growth arrest of engineered K562 implanted in mice.Conclusions: Vaccination with a whole-cell vaccine obtained from K562 engineered to express CMV-pp65, CD40L, OX40L and iC9 can safely enhance the antitumor effects of CAR-redirected CMV-CTLs. Clin Cancer Res; 21(13); 2952–62. ©2015 AACR.

This study profiles ceramides extracted from visceral and subcutaneous adipose tissue of human subjects by liquid chromatography-mass spectrometry to determine a correlation with status of diabetes and gender.Samples of visceral and abdominal wall subcutaneous adipose tissue (n = 36 and n = 31, respectively) were taken during laparoscopic surgery from 36 patients (14 nondiabetic, 22 diabetic and prediabetic) undergoing bariatric surgery with a body mass index (BMI)35 kg/mAfter logarithm 2 conversion, paired analysis of visceral to subcutaneous tissue showed differential accumulation of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in visceral tissue of prediabetic/diabetic female subjects, but not in males. Within-tissue analysis showed higher mean levels of ceramide species linked to insulin resistance, such as Cer(d18:1/18:0) and Cer(d18:1/16:0), in visceral tissue of prediabetic/diabetic patients compared with nondiabetic subjects and higher content of Cer(d18:1/14:0) in subcutaneous tissue of insulin-resistant female patients compared with prediabetic/diabetic males. Statistically significant differences in mean levels of ceramide species between insulin-resistant African American and insulin-resistant Caucasian patients were not evident in visceral or subcutaneous tissue.Analysis of ceramides is important for developing a better understanding of biological processes underlying type 2 diabetes, metabolic syndrome, and obesity. Knowledge of the accumulated ceramides/dihydroceramides may reflect on the prelipolytic state that leads the lipotoxic phase of insulin resistance and may shed light on the predisposition to insulin resistance by gender.目的: 采用液相色谱-质谱分析从受试者内脏和皮下脂肪组织中提取的神经酰胺, 以确定神经酰胺与糖尿病状态和性别的相关性。 方法: 在腹腔镜手术中采集36例内脏和31例腹壁皮下脂肪组织标本, 这些标本来自36位患者, 其中14位非糖尿病, 22例糖尿病及糖尿病前期患者, 体重指数35 kg/m

Since the accident at the Chornobyl nuclear power plant in 1986 there have been few studies published on medium/large mammals inhabiting the area from which the human population was removed (now referred to as the Chornobyl Exclusion Zone). The dataset presented in this paper describes a motion activated camera trap study (n=21 cameras) conducted from September 2016–September 2017 in the Red Forest located within the Chornobyl Exclusion Zone. The Red Forest, which is likely the most anthropogenically contaminated radioactive terrestrial ecosystem on earth, suffered a severe wildfire in July 2016. The motion activated trap cameras were therefore in place as the Red Forest recovered from the wildfire. A total of 45859 images were captured and of these 19391 contained identifiable species or organism types (e.g. insects). A total of 14 mammal species were positively identified together with 23 species of birds (though birds were not a focus of the study). Weighted absorbed radiation dose rate rates were estimated for mammals across the different camera trap locations; the number of species observed did not vary with estimated dose rate. We also observed no relationship between estimated weighted absorbed radiation dose rates and the number of triggering events for the four main species observed during the study (Brown hare, Eurasian elk, Red deer, Roe deer). The data presented will be of value to those studying wildlife within the CEZ both from the perspectives of the potential effects of radiation on wildlife and also rewilding in this large, abandoned area. They may also have value in any future studies investigating the impacts of the recent Russian military action in the CEZ. The data and supporting documentation are freely available from the Environmental Information Data Centre (EIDC) under the terms and conditions of a Creative Commons Attribution (CC BY) licence: https://doi.org/10.5285/bf82cec2-5f8a-407c-bf74-f8689ca35e83 (Barnett et al. 2022a).

Objective To describe the prevalence of postoperative bacteriuria, clinical course of subclinical bacteriuria in the absence of antimicrobial intervention, clinical signs of bacteriuria that trigger antimicrobial treatment, and outcomes for dogs with subclinical bacteriuria following surgical decompression of acute intervertebral disc herniation (IVDH) Hansen type I. Animals Twenty client-owned dogs undergoing hemilaminectomy for acute (≤ 6 days) IVDH Hansen type I affecting the thoracolumbar spinal cord segments between August 2018 and January 2019. Procedures In this prospective study, dogs were serially evaluated at presentation, hospital discharge, 2 weeks postoperatively, and between 4 and 6 weeks postoperatively. Dogs were monitored for clinical signs of bacteriuria, underwent laboratory monitoring (CBC, biochemical analyses, urinalysis, urine bacterial culture), and were scored for neurologic and urinary status. In the absence of clinical signs, bacteriuria was not treated with antimicrobials. Results Four of the 18 dogs developed bacteriuria without clinical signs 4 days to 4 to 6 weeks after surgery. In all 4 dogs, bacteriuria resulted in lower urinary tract signs 13 to 26 weeks postoperatively. No dogs had evidence of systemic illness despite delaying antimicrobial treatment until clinical signs developed. New-onset incontinence was the only clinical sign in 3 dogs. All bacterial isolates had wide antimicrobial susceptibility. Bacteriuria and clinical signs resolved with beta-lactam antimicrobial treatment. Clinical Relevance Postoperative bacteriuria occurs in some dogs with IVDH Hansen type I and, when present, may lead to clinical signs over time. Clinical signs of bacteriuria may be limited to new-onset urinary incontinence, inappropriate urination, or both. Delaying antimicrobial treatment until clinical signs of bacteriuria developed did not result in adverse consequences or systemic illness.

The Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP), representing approximately USD 13.5 trillion of the global GDP, is one of the largest free-trade agreements in the...

CASE DESCRIPTION A 3-year-old 17.5-kg (38.5-lb) mixed-breed dog was referred for evaluation because of nasal discharge, sneezing, and signs of nasal congestion of approximately 9 months’ duration. A diagnosis of nasopharyngeal stenosis (NPS) was made prior to referral. CLINICAL FINDINGS Sneezing, bilateral mucopurulent nasal discharge, reduced nasal airflow, stertor, and increased inspiratory effort were noted on physical examination. Results of serum biochemical analysis were within respective reference ranges. Review of CT images of the skull revealed findings consistent with severe bilateral partial osseous choanal atresia and NPS. Retrograde rhinoscopy confirmed membranous NPS. TREATMENT AND OUTCOME A ventral rhinotomy was performed; communication between the pharynx and nasal passageway was reestablished by surgical debridement of the caudal border of the palatine bone and vomerine crest and groove, followed by dissection of the membranous NPS and reconstruction of the caudal part of the nasopharynx. A covered nasopharyngeal stent was placed in the newly established nasopharynx. The dog recovered uneventfully but was presented 3 weeks later with recurrent signs; diagnostic findings were consistent with stenosis rostral to the stent. The stenosis was treated with balloon dilation, and a second covered stent was placed rostral to and overlapping the first stent, spanning the stenotic region. Eleven months after this procedure, the dog was doing well. CLINICAL RELEVANCE Results for this patient suggested that ventral rhinotomy and covered nasopharyngeal stent placement can be used successfully for the management of osseous choanal atresia in dogs; however, careful attention to preoperative planning and potential complications is necessary. (J Am Vet Med Assoc 2021;259:190–196)

BACKGROUND The perioperative period is a data-rich environment with potential for innovation through digital health tools and predictive analytics (e.g., to optimize patients’ health with targeted pre-habilitation). While some risk factors for postoperative pain following pediatric surgery are already known, the systematic use of pre-operative information to guide personalized interventions are not yet widespread in clinical practice. OBJECTIVE Our long-term goal is to reduce the incidence of persistent post-surgical pain and long-term opioid use in children by developing personalized pain risk prediction models that can guide clinicians and families to identify targeted pre-habilitation strategies. To develop such a system, our first step was to use patient-oriented research methodology, leveraging parental/caregiver and clinician expertise, to identify risk factors, outcomes, and relevant experience measures, as well as data collection tools for a future data collection and risk modeling study. METHODS We conducted virtual focus groups with participants recruited at a tertiary pediatric hospital; each session lasted approximately one hour and was composed of clinicians and/or family members (people with lived surgical experience and parents of children who had recently undergone a procedure requiring anesthesia). Data were analyzed thematically to identify potential risk factors for pain, as well as relevant patient-reported experience and outcome measures (PREMs and PROMs) that can be used to evaluate the progress of postoperative recovery at home. This guidance was combined with a targeted literature review to select tools to collect risk factors and outcomes information for implementation in a future study. RESULTS Twenty-two participants (12 clinicians and 10 family members) attended 10 focus group sessions; participants included 12/22 (55%) persons identifying as female, and 12/22 (55%) were under 50 years of age. Thematic analysis identified five key domains: 1) demographic risk factors (e.g., age, sex, weight), 2) clinical characteristics (e.g., length of hospital stay, procedure type, medications, pre-existing conditions), 3) psychosocial factors (e.g., anxiety, depression, medical phobias), 4) PREMs (e.g., patient and family satisfaction with care), and 5) PROMs (e.g., nausea and vomiting, functional recovery, return to normal activities of daily living). Participants further suggested desirable functional requirements (e.g., use of standardized and validated tools, longitudinal data collection) and delivery modes (e.g., primarily electronic, parent proxy and self-report) for tools that can be used to capture these metrics, both in hospital and following discharge. Established PREMs/PROMs questionnaires, pain catastrophizing scales, and substance use questionnaires for adolescents were subsequently selected for our proposed data collection platform. CONCLUSIONS This study established five key data domains for identifying pain risk factors and evaluating postoperative recovery at home, as well as the functional requirements and delivery modes of selected tools with which to capture these metrics both in hospital and after discharge. These tools have been implemented to generate data for the development of personalized pain risk prediction models.

Background The perioperative period is a data-rich environment with potential for innovation through digital health tools and predictive analytics to optimize patients’ health with targeted prehabilitation. Although some risk factors for postoperative pain following pediatric surgery are already known, the systematic use of preoperative information to guide personalized interventions is not yet widespread in clinical practice. Objective Our long-term goal is to reduce the incidence of persistent postsurgical pain (PPSP) and long-term opioid use in children by developing personalized pain risk prediction models that can guide clinicians and families to identify targeted prehabilitation strategies. To develop such a system, our first objective was to identify risk factors, outcomes, and relevant experience measures, as well as data collection tools, for a future data collection and risk modeling study. Methods This study used a patient-oriented research methodology, leveraging parental/caregiver and clinician expertise. We conducted virtual focus groups with participants recruited at a tertiary pediatric hospital; each session lasted approximately 1 hour and was composed of clinicians or family members (people with lived surgical experience and parents of children who had recently undergone a procedure requiring general anesthesia) or both. Data were analyzed thematically to identify potential risk factors for pain, as well as relevant patient-reported experience and outcome measures (PREMs and PROMs, respectively) that can be used to evaluate the progress of postoperative recovery at home. This guidance was combined with a targeted literature review to select tools to collect risk factor and outcome information for implementation in a future study. Results In total, 22 participants (n=12, 55%, clinicians and n=10, 45%, family members) attended 10 focus group sessions; participants included 12 (55%) of 22 persons identifying as female, and 12 (55%) were under 50 years of age. Thematic analysis identified 5 key domains: (1) demographic risk factors, including both child and family characteristics; (2) psychosocial risk factors, including anxiety, depression, and medical phobias; (3) clinical risk factors, including length of hospital stay, procedure type, medications, and pre-existing conditions; (4) PREMs, including patient and family satisfaction with care; and (5) PROMs, including nausea and vomiting, functional recovery, and return to normal activities of daily living. Participants further suggested desirable functional requirements, including use of standardized and validated tools, and longitudinal data collection, as well as delivery modes, including electronic, parent proxy, and self-reporting, that can be used to capture these metrics, both in the hospital and following discharge. Established PREM/PROM questionnaires, pain-catastrophizing scales (PCSs), and substance use questionnaires for adolescents were subsequently selected for our proposed data collection platform. Conclusions This study established 5 key data domains for identifying pain risk factors and evaluating postoperative recovery at home, as well as the functional requirements and delivery modes of selected tools with which to capture these metrics both in the hospital and after discharge. These tools have been implemented to generate data for the development of personalized pain risk prediction models.

The adhesion of ice to external surfaces is an important challenge in many industries. This has sparked much research into fabricating surfaces with low ice adhesion strengths. Our novel approach to designing ice-shedding surfaces leverages the dynamics of water solidification to induce beneficial stress concentrations throughout the iced interface. We have chosen a bare woven metal wire cloth substrate to demonstrate these principles. The pore geometries of the wire cloths lead to stress concentrations upon freezing and expansion of the water/ice, while their microstructural topography allows for facile crack opening. We have discovered that by leveraging knowledge of the underlying physical processes involved in ice formation and delamination, we can engineer a robust metal surface to have an extremely low ice adhesion strength (12.5 kPa) without using chemical coatings.

Initially associated with cancer diagnosis and therapy, the sigma 2 receptor (σ

The Indian leafwing butterfly Kallima paralekta (Horsfield, 1829) (Nymphalidae) is an Asian forest-dwelling, leaf-mimic. Genome skimming by Illumina sequencing permitted assembly of a complete circ...

Rationale: Studies suggest that reduced cerebral perfusion may contribute to delirium development in the intensive care unit (ICU). However, evidence is limited because of factors including small s...

Predictions of radionuclide dose rates to freshwater organisms can be used to evaluate the radiological environmental impacts of releases from uranium mining and milling projects. These predictions help inform decisions on the implementation of mitigation measures. The objective of this study was to identify how dose rate modelling could be improved to reduce uncertainty in predictions to non-human biota. For this purpose, we modelled the activity concentrations of 210Pb, 210Po, 226Ra, 230Th, and 238U downstream of uranium mines and mills in northern Saskatchewan, Canada, together with associated weighted absorbed dose rates for a freshwater food chain using measured activity concentrations in water and sediments. Differences in predictions of radionuclide activity concentrations occurred mainly from the different default partition coefficient and concentration ratio values from one model to another and including all or only some 238U decay daughters in the dose rate assessments. Consequently, we recommend a standardized best-practice approach to calculate weighted absorbed dose rates to freshwater biota whether a facility is at the planning, operating or decommissioned stage. At the initial planning stage, the best-practice approach recommend using conservative site-specific baseline activity concentrations in water, sediments and organisms and predict conservative incremental activity concentrations in these media by selecting concentration ratios based on species similarity and similar water quality conditions to reduce the uncertainty in dose rate calculations. At the operating and decommissioned stages, the best-practice approach recommends relying on measured activity concentrations in water, sediment, fish tissue and whole-body of small organisms to further reduce uncertainty in dose rate estimates. This approach would allow for more realistic but still conservative dose assessments when evaluating impacts from uranium mining projects and making decision on adequate controls of releases.

This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.