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Nitro group containing xenobiotics include drugs, cancer chemotherapeutic agents, carcinogens (e.g., nitroarenes and aristolochic acid) and explosives. The nitro group undergoes a six-electron reduction to form sequentially the nitroso

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex–disparate GVHD model of lethally irradiated BALB/c mice given T cell–depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ–transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

Strut-and-tie modelling has proved a very useful method in the analysis and design of non-flexural components of reinforced concrete members. Examples of design codes encompassing the strut-and-tie model (STM) provisions include Eurocode 2 (EC2), the fib Model Code 2010 (MC2010), the Canadian Standard (CSA A23.3-04), the American bridge design specifications (AASHTO LRFD 2020), the American Standard (ACI 318-14 and -19) and the Australian Standard (AS 3600:2018). Nevertheless, the application of different assumptions, model types and methodologies means that the strength acceptance criteria for struts, nodes and bearings vary within the literature and design codes. Unifying the STM design criteria is thus encouraged, to facilitate worldwide use of the STM in the design of non-flexural components, particularly for places such as Hong Kong that have not yet developed the localised design criteria for the STM. In this paper, the proposals set out in the literature and the provisions in the above-stated design codes are reviewed and compared with each other. Calibrating with the existing literature and design provisions, unified STM design criteria for struts, nodes and bearings with localisation are proposed for application in Hong Kong. The proposed design criteria are then applied to the STM design of a cantilever deep beam.

1-Nitropyrene (1-NP) and 1,8-dinitropyrene (1,8-DNP) are diesel exhaust constituents and are classified by the International Agency for Research on Cancer as probable (Group 2A) or possible (Group 2B) human carcinogens. These nitroarenes undergo metabolic activation by nitroreduction to result in the formation of DNA adducts. Human aldo-keto reductases (AKRs) 1C1-1C3 catalyze the nitroreduction of 3-nitrobenzanthrone (3-nitro-7

Natural Killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus infected cells, limiting their antitumor and antiviral activity. Here, we find that single-chain mouse NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activity to a greater extent than NKR blocking antibodies alone in vitro. We also uncovered crosstalk between mouse NKG2A and Ly49 that collectively inhibit NK cell activation, such that CD45-NKG2A and CD45-Ly49 bispecific molecules show synergistic effects in their ability to enhance NK cell activation. The basis of the activity enhancement by CD45 ligation may reflect greater antagonism of inhibitory signaling from engagement of MHC I on target cells, combined with other mechanisms, including avidity effects, tonic signaling, antagonism of weak inhibition from engagement of MHC I on non-target cells and possibly CD45 segregation within the NK cell-target cell synapse. These engineered ligands uncover a mechanism for enhancing the activity of mouse NK and T cells that merits evaluation in the context of human NKR antagonist cancer immunotherapies.

STUDY QUESTION Do spermatogonia, including spermatogonial stem cells (SSCs), undergo metabolic changes during prepubertal development? SUMMARY ANSWER Here, we show that the metabolic phenotype of prepubertal human spermatogonia is distinct from that of adult spermatogonia and that SSC development is characterized by distinct metabolic transitions from oxidative phosphorylation (OXPHOS) to anaerobic metabolism. WHAT IS KNOWN ALREADY Maintenance of both mouse and human adult SSCs relies on glycolysis, while embryonic SSC precursors, primordial germ cells (PGCs), exhibit an elevated dependence on OXPHOS. Neonatal porcine SSC precursors reportedly initiate a transition to an adult SSC metabolic phenotype at 2 months of development. However, when and if such a metabolic transition occurs in humans is ambiguous. STUDY DESIGN, SIZE, DURATION To address our research questions: (i) we performed a meta-analysis of publicly available and newly generated (current study) single-cell RNA sequencing (scRNA-Seq) datasets in order to establish a roadmap of SSC metabolic development from embryonic stages (embryonic week 6) to adulthood in humans (25 years of age) with a total of ten groups; (ii) in parallel, we analyzed single-cell RNA sequencing datasets of isolated pup (n = 3) and adult (n = 2) murine spermatogonia to determine whether a similar metabolic switch occurs; and (iii) we characterized the mechanisms that regulate these metabolic transitions during SSC maturation by conducting quantitative proteomic analysis using two different ages of prepubertal pig spermatogonia as a model, each with four independently collected cell populations. PARTICIPANTS/MATERIALS, SETTING, METHODS Single testicular cells collected from 1-year, 2-year and 7-year-old human males and sorted spermatogonia isolated from 6- to 8-day (n = 3) and 4-month (n = 2) old mice were subjected to scRNA-Seq. The human sequences were individually processed and then merged with the publicly available datasets for a meta-analysis using Seurat V4 package. We then performed a pairwise differential gene expression analysis between groups of age, followed by pathways enrichment analysis using gene set enrichment analysis (cutoff of false discovery rate < 0.05). The sequences from mice were subjected to a similar workflow as described for humans. Early (1-week-old) and late (8-week-old) prepubertal pig spermatogonia were analyzed to reveal underlying cellular mechanisms of the metabolic shift using immunohistochemistry, western blot, qRT-PCR, quantitative proteomics, and culture experiments. MAIN RESULTS AND THE ROLE OF CHANCE Human PGCs and prepubertal human spermatogonia show an enrichment of OXPHOS-associated genes, which is downregulated at the onset of puberty (P LARGE SCALE DATA New single-cell RNA sequencing datasets obtained from this study are freely available through NCBI GEO with accession number GSE196819. LIMITATIONS, REASONS FOR CAUTION Human prepubertal tissue samples are scarce, which led to the investigation of a low number of samples per age. Gene enrichment analysis gives only an indication about the functional state of the cells. Due to limited numbers of prepubertal human spermatogonia, porcine spermatogonia were used for further proteomic and in vitro analyses. WIDER IMPLICATIONS OF THE FINDINGS We show that prepubertal human spermatogonia exhibit high OXHPOS and switch to an adult-like metabolism only after 11 years of age. Prepubescent cancer survivors often suffer from infertility in adulthood. SSC transplantation could provide a powerful tool for the treatment of infertility; however, it requires high cell numbers. This work provides key insight into the dynamic metabolic requirements of human SSCs across development that would be critical in establishing ex vivo systems to support expansion and sustained function of SSCs toward clinical use. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the NIH/NICHD R01 HD091068 and NIH/ORIP R01 OD016575 to I.D. K.E.O. was supported by R01 HD100197. S.K.M. was supported by T32 HD087194 and F31 HD101323. The authors declare no conflict of interest.

Planetary debris disks around other stars are analogous to the Asteroid and Kuiper belts in the Solar System. Their structure reveals the configuration of small bodies and provides hints for the presence of planets. The nearby star Fomalhaut hosts one of the most prominent debris disks, resolved by HST, Spitzer, Herschel, and ALMA. Images of this system at mid-infrared wavelengths using JWST/MIRI not only show the narrow Kuiper-Belt-analog outer ring, but also that (1) what was thought from indirect evidence to be an asteroid-analog structure is instead broad, extending outward into the outer system; (2) there is an intermediate belt, probably shepherded by an unseen planet. The newly discovered belt is demarcated by an inner gap, located at ~ 78 au, and it is misaligned relative to the outer belt. The previously known collisionally generated dust cloud, Fomalhaut b, could have originated from this belt, suggesting increased dynamical stirring and collision rates there. We also discovered a large dust cloud within the outer ring, possible evidence of another dust-creating collision. Taken together with previous observations, Fomalhaut appears to be the site of a complex and possibly dynamically active planetary system., Comment: 17 Figures, 3 tables; includes Supplementary Information package; Published in Nature Astronomy

ImportanceDiagnostic information from administrative claims and electronic health record (EHR) data may serve as an important resource for surveillance of vision and eye health, but the accuracy and validity of these sources are unknown.ObjectiveTo estimate the accuracy of diagnosis codes in administrative claims and EHRs compared to retrospective medical record review.Design, Setting, and ParticipantsThis cross-sectional study compared the presence and prevalence of eye disorders based on diagnostic codes in EHR and claims records vs clinical medical record review at University of Washington–affiliated ophthalmology or optometry clinics from May 2018 to April 2020. Patients 16 years and older with an eye examination in the previous 2 years were included, oversampled for diagnosed major eye diseases and visual acuity loss.ExposuresPatients were assigned to vision and eye health condition categories based on diagnosis codes present in their billing claims history and EHR using the diagnostic case definitions of the US Centers for Disease Control and Prevention Vision and Eye Health Surveillance System (VEHSS) as well as clinical assessment based on retrospective medical record review.Main Outcome and MeasuresAccuracy was measured as area under the receiver operating characteristic curve (AUC) of claims and EHR-based diagnostic coding vs retrospective review of clinical assessments and treatment plans.ResultsAmong 669 participants (mean [range] age, 66.1 [16-99] years; 357 [53.4%] female), identification of diseases in billing claims and EHR data using VEHSS case definitions was accurate for diabetic retinopathy (claims AUC, 0.94; 95% CI, 0.91-0.98; EHR AUC, 0.97; 95% CI, 0.95-0.99), glaucoma (claims AUC, 0.90; 95% CI, 0.88-0.93; EHR AUC, 0.93; 95% CI, 0.90-0.95), age-related macular degeneration (claims AUC, 0.87; 95% CI, 0.83-0.92; EHR AUC, 0.96; 95% CI, 0.94-0.98), and cataracts (claims AUC, 0.82; 95% CI, 0.79-0.86; EHR AUC, 0.91; 95% CI, 0.89-0.93). However, several condition categories showed low validity with AUCs below 0.7, including diagnosed disorders of refraction and accommodation (claims AUC, 0.54; 95% CI, 0.49-0.60; EHR AUC, 0.61; 95% CI, 0.56-0.67), diagnosed blindness and low vision (claims AUC, 0.56; 95% CI, 0.53-0.58; EHR AUC, 0.57; 95% CI, 0.54-0.59), and orbital and external diseases (claims AUC, 0.63; 95% CI, 0.57-0.69; EHR AUC, 0.65; 95% CI, 0.59-0.70).Conclusion and RelevanceIn this cross-sectional study of current and recent ophthalmology patients with high rates of eye disorders and vision loss, identification of major vision-threatening eye disorders based on diagnosis codes in claims and EHR records was accurate. However, vision loss, refractive error, and other broadly defined or lower-risk disorder categories were less accurately identified by diagnosis codes in claims and EHR data.

Building inspection and maintenance are becoming increasingly essential means by which to consider the deterioration problems of old, reinforced concrete (RC) buildings. While such inspection work can be conducted with the aid of computer vision-based technology, this technology remains challenged, since real-world structural defects and environmental conditions are varied and complex. In recent years, object detection algorithms have improved to achieve greater speed and accuracy with the help of deep learning. In this paper, an advanced object detector, YOLOv5s, was successfully applied to the recognition of common structural defects including cracks, delamination, exposed reinforcement, rust stains, spalling, tile cracks, tile delamination, and tile loss. Compared with the other advanced object detectors of YOLO (i.e., YOLOv5m, YOLOv5l, YOLOv5x, YOLOv4, and YOLOv3) based on the built data set, the YOLOv5s algorithm shows an obvious advantage for defect detection, achieving 64.5% and 67.0% mean average precision (mAP) for training and testing, respectively. It also takes less than 0.1 seconds to detect a defect on an image. The lightweight and high detection performance of the YOLOv5s algorithm shows great promise for potential deployment on an onboard inspection device, such as an unmanned aerial vehicle (UAV) or a robot, to achieve real-time structural inspection.

Exposure to trichloroethylene (TCE), an industrial solvent, is associated with several adverse pregnancy outcomes in humans and decreased fetal weight in rats. However, effects of TCE on energy metabolites in amniotic fluid, which have associations with pregnancy outcomes, has not been published previously. In the current exploratory study, timed-pregnant Wistar rats were exposed to 480 mg TCE/kg/day via vanilla wafer or to vehicle (wafer) alone from gestational day (GD) 6 to 16. Amniotic fluid collected on GD 16 was analyzed for metabolites important in energy metabolism using short chain fatty acid and tricarboxylic acid plus platforms (N= 4 samples/sex/treatment). TCE decreased concentrations of the following metabolites in amniotic fluid for both fetal sexes: 6-phosphogluconate, guanosine diphosphate, adenosine diphosphate, adenosine triphosphate, and flavin adenine dinucleotide. TCE decreased fructose 1,6-bisphosphate and guanosine triphosphate concentrations in amniotic fluid of male but not female fetuses. Moreover, TCE decreased uridine diphosphate-D-glucuronate concentrations, and increased arginine and phosphocreatine concentrations, in amniotic fluid of female fetuses only. No metabolites were increased in amniotic fluid of male fetuses. Pathway analysis suggested that TCE altered folate biosynthesis and pentose phosphate pathway in both sexes. Using metabolite ratios to investigate changes within specific pathways, some ratio alterations, including those in arginine metabolism and phenylalanine metabolism, were detected in females only. Ratio analysis also suggested enzymes, including gluconokinase, as potential TCE targets. Together, results from this exploratory study suggest that TCE differentially modified energy metabolites in amniotic fluid based on sex. These findings may inform future studies of TCE reproductive toxicity.

To explore Tuberculosis (TB) health promotion and education in universities, and to provide a feasible reference method and specific implementation measures for improving health education among university students. We collected a total of 811 respondents, using a uniform questionnaire online survey questionnaire network. The completed questionnaires were double-entered using EpiData3.1, the database was established, and the analysis was performed by Excel2016 and SPSS 22 software. The total awareness rate of the 8 core information on tuberculosis prevention and control was 74.2 %. Among them, “the state provides free anti-tuberculosis drugs and major tests for infectious tuberculosis patients” with the lowest awareness rate of 49.2 %; followed by the awareness rate of “should care about tuberculosis patients and should not discriminate against tuberculosis patients”, for 63.8 %. The channels for college students to acquire knowledge about tuberculosis prevention were “newspapers and magazines”, accounted for 50.3 percent; “broadcasting, television and video” accounted for 52.4 %; “wall advertising, bulletin boards, slogans” accounted for 44.6 %; “School Health Education” accounted for 38.5 % of “school propaganda columns or publicity panels” accounted for 34.9 %. The favourite way for college students to promote was “watching TV” 40.3 %.

Measurements of visceral adipose tissue cross-sectional area and radiation attenuation from computed tomography (CT) scans provide useful information about risk and mortality. However, scan protocols vary, encompassing differing vertebra levels and utilizing differing phases of contrast enhancement. Furthermore, fat measurements have been extracted from CT using different Hounsfield Unit (HU) ranges. To our knowledge, there have been no large studies of healthy cohorts that reported reference values for visceral fat area and radiation attenuation at multiple vertebra levels, for different contrast phases, and using different fat HU ranges. Two-phase CT scans from 1,677 healthy, adult kidney donors (age 18–65) between 1999 and 2017, previously studied to determine healthy reference values for skeletal muscle measures, were utilized. Visceral adipose tissue cross-sectional area (VFA) and radiation attenuation (VFRA) measures were quantified using axial slices at T10 through L4 vertebra levels. T-tests were used to compare males and females, while paired t-tests were conducted to determine the effect (magnitude and direction) of (a) contrast enhancement and (b) different fat HU ranges on each fat measure at each vertebra level. We report the means, standard deviations, and effect sizes of contrast enhancement and fat HU range. Male and female VFA and VFRA were significantly different at all vertebra levels in both contrast and non-contrast scans. Peak VFA was observed at L4 in females and L2 in males, while peak VFRA was observed at L1 in both females and males. In general, non-contrast scans showed significantly greater VFA and VFRA compared to contrast scans. The average paired difference due to contrast ranged from 1.6 to − 8% (VFA) and 3.2 to − 3.0% (VFRA) of the non-contrast value. HU range showed much greater differences in VFA and VFRA than contrast. The average paired differences due to HU range ranged from − 5.3 to 22.2% (VFA) and − 5.9 to 13.6% (VFRA) in non-contrast scans, and − 4.4 to 20.2% (VFA) and − 4.1 to 12.6% (VFRA) in contrast scans. The − 190 to − 30 HU range showed the largest differences in both VFA (10.8% to 22.2%) and VFRA (7.6% to 13.6%) compared to the reference range (− 205 to − 51 HU). Incidentally, we found that differences in lung inflation result in very large differences in visceral fat measures, particularly in the thoracic region. We assessed the independent effects of contrast presence and fat HU ranges on visceral fat cross-sectional area and mean radiation attenuation, finding significant differences particularly between different fat HU ranges. These results demonstrate that CT measurements of visceral fat area and radiation attenuation are strongly dependent upon contrast presence, fat HU range, sex, breath cycle, and vertebra level of measurement. We quantified contrast and non-contrast reference values separately for males and females, using different fat HU ranges, for lumbar and thoracic CT visceral fat measures at multiple vertebra levels in a healthy adult US population.

BackgroundHematopoietic stem cells are cells that differentiate into all blood cell types. Although the placenta secretes hormones, proteins and other factors important for maternal and fetal health, cross-talk between placental cells and hematopoietic stem cells is poorly understood. Moreover, toxicant impacts on placental-hematopoietic stem cell communication is understudied. The goals of this study were to determine if factors secreted from placental cells alter transcriptomic responses in hematopoietic stem cells and if monoethylhexyl phthalate (MEHP), the bioactive metabolite of the pollutant diethylhexyl phthalate, modifies these effects.MethodsWe used K-562 and BeWo cells asin vitromodels of hematopoietic stem cells and placental syncytiotrophoblasts, respectively. We treated K-562 cells with medium conditioned by incubation with BeWo cells, medium conditioned with BeWo cells treated with 10 μM MEHP for 24 hours, or controls treated with unconditioned medium. We extracted K-562 cell RNA, performed RNA sequencing, then conducted differential gene expression and pathway analysis by treatment group.ResultsRelative to controls, K-562 cells treated with BeWo cell conditioned medium differentially expressed 173 genes (FDR2.0), including 2.4 fold upregulatation ofTPM4and 3.3 fold upregulatation ofS1PR3. Upregulated genes were enriched for pathways including stem cell maintenance, cell proliferation and immune processes. Downregulated genes were enriched for terms involved in protein translation and transcriptional regulation. MEHP treatment differentially expressed eight genes (FDRPLIN2, fold-change: 1.4;CPT1A, fold-change: 1.4).ConclusionK-562 cells, a model of hematopoietic stem cells, are responsive to media conditioned by placental cells, potentially impacting pathways like stem cell maintenance and proliferation.

BACKGROUND Self-reported questions on blindness and vision problems are collected in many national surveys. Recently released surveillance estimates on the prevalence of vision loss used self-reported data to predict variation in the prevalence of objectively measured acuity loss among population groups for whom examination data are not available. However, the validity of self-reported measures to predict prevalence and disparities in visual acuity has not been established. OBJECTIVE This study aimed to estimate the diagnostic accuracy of self-reported vision loss measures compared to best-corrected visual acuity (BCVA), inform the design and selection of questions for future data collection, and identify the concordance between self-reported vision and measured acuity at the population level to support ongoing surveillance efforts. METHODS We calculated accuracy and correlation between self-reported visual function versus BCVA at the individual and population level among patients from the University of Washington ophthalmology or optometry clinics with a prior eye examination, randomly oversampled for visual acuity loss or diagnosed eye diseases. Self-reported visual function was collected via telephone survey. BCVA was determined based on retrospective chart review. Diagnostic accuracy of questions at the person level was measured based on the area under the receiver operator curve (AUC), whereas population-level accuracy was determined based on correlation. RESULTS The survey question, “Are you blind or do you have serious difficulty seeing, even when wearing glasses?” had the highest accuracy for identifying patients with blindness (BCVA ≤20/200; AUC=0.797). The highest accuracy for detecting any vision loss (BCVA CONCLUSIONS Although survey questions are not considered to be sufficiently accurate to be used as a diagnostic test at the individual level, we did find relatively high levels of accuracy for some questions. At the population level, we found that the relative prevalence of the 2 most accurate survey questions were highly correlated with the prevalence of measured visual acuity loss among nearly all demographic groups. The results of this study suggest that self-reported vision questions fielded in national surveys are likely to yield an accurate and stable signal of vision loss across different population groups, although the actual measure of prevalence from these questions is not directly analogous to that of BCVA.