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IntroductionTheileria orientalis Ikeda genotype is an emerging cattle disease in the US. Since 2017, when T. orientalis Ikeda was discovered in beef cattle in two counties in Virginia, cattle infections have risen to include ~67% of Virginia counties and 14 states. Consistent with New Zealand studies, many infected herds in Virginia were >90% positive upon initial testing without overt evidence of infection. Central bull tests present a unique opportunity to study the effects of T. orientalis Ikeda infections, as bulls from multiple source herds are consolidated. The objective of this study was to determine if infection with T. orientalis Ikeda affected the average daily gain (ADG), adjusted yearling weight (AYW) and breeding soundness of bulls at two test stations in Virginia over a period of years.Materials and methodsThe bulls were fed and housed similarly to compare their growth performance and breeding soundness. For T. orientalis Ikeda testing, DNA was extracted from whole blood for quantitative polymerase chain reaction.ResultsThe number of bulls infected with T. orientalis Ikeda at initial delivery to the stations increased significantly over the years studied. Multivariable linear regression models, using Angus bulls from Virginia test stations, indicated no significant effect on ADG or AYW in bulls that became test positive during the test or were positive for the duration, compared to Angus bulls that were negative for the duration. At LOC A, the odds of passing a breeding soundness exam (BSE) were not significantly different for bulls that turned positive during the test or were positive for the duration, compared to bulls that were negative for the duration of the test. At LOC B, bulls that became positive during the test were 2.4 times more likely (95% CI: 1.165–4.995, p = 0.016) to pass their BSE compared to bulls that remained negative throughout the test.DiscussionWe do not suppose that an obscured infection of T. orientalis Ikeda is protective for bulls to pass a BSE. However, this study demonstrates an obscured infection of T. orientalis Ikeda does not negatively affect weight gain or achievement of a satisfactory BSE rating at the central bull test stations in Virginia.

Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.

Purpose: The etiopathogenesis of coronal nonsyndromic craniosynostosis (cNCS), a congenital condition defined by premature fusion of 1 or both coronal sutures, remains largely unknown. Methods: We conducted the largest genome-wide association study of cNCS followed by replication, fine mapping, and functional validation of the most significant region using zebrafish animal model. Results: Genome-wide association study identified 6 independent genome-wide-significant risk alleles, 4 on chromosome 7q21.3 SEM1-DLX5-DLX6 locus, and their combination conferred over 7-fold increased risk of cNCS. The top variants were replicated in an independent cohort and showed pleiotropic effects on brain and facial morphology and bone mineral density. Fine mapping of 7q21.3 identified a craniofacial transcriptional enhancer (eDlx36) within the linkage region of the top variant (rs4727341; odds ratio [95% confidence interval], 0.48[0.39-0.59]; P = 1.2E−12) that was located in SEM1 intron and enriched in 4 rare risk variants. In zebrafish, the activity of the transfected human eDlx36 enhancer was observed in the frontonasal prominence and calvaria during skull development and was reduced when the 4 rare risk variants were introduced into the sequence. Conclusion: Our findings support a polygenic nature of cNCS risk and functional role of craniofacial enhancers in cNCS susceptibility with potential broader implications for bone health.

The threats that affect a species often vary within its geographic range. Wood Turtles (Glyptemys insculpta (Le Conte, 1830), formerly Clemmys insculpta (Le Conte, 1830)) are a species of concern due to widespread decline from anthropogenic threats. We studied two populations of Wood Turtles from June to September 2019 and 2020 to evaluate how landscape features and vegetative structure influenced space and habitat use and to identify potential risks in the remote, northern parts of its range. We hypothesized that space use would vary due to regional, landscape, and sex-specific differences. Turtles at the conifer-dominated site with higher road density had significantly smaller home ranges than the site with expansive and contiguous floodplains (7.25 [+ or -] 1.92 ha and 26.28 [+ or -] 6.77 ha, respectively). Females moved farther away from rivers than males (136.00 [+ or -] 23.68 m and 69.18 [+ or -] 34.81 m, respectively) and made the longest single-event movements. However, movements by males were significantly longer (34.65 [+ or -] 1.91 m) than females (23.99 [+ or -] 1.03 m) and followed rivers. At finer spatial scales, we found that turtles selected activity areas with complex vegetative structure and a more open canopy. Our study indicates that populations in contiguous forest could be critical to the conservation of Wood Turtles and we discuss management recommendations to reduce potential mortality risks in the northern part of its range. Key words: Wood Turtle, Glyptemys insculpta, habitat selection, home range, microhabitat, endangered species, habitat fragmentation, Introduction Population- and individual-level responses to landscape and microhabitat features can differ due to differences in climate, geomorphology, anthropogenic factors, food availability, and habitat availability (Andreassen et al. 1998; Mcloughlin [...]

BACKGROUND. Oxidized apolipoprotein B (oxLDL) and oxidized ApoA-I (oxHDL) are proatherogenic. Their prognostic value for assessing high-risk plaques by coronary computed tomography angiography (CCTA) is missing.METHODS. In a prospective, observational study, 306 participants with cardiovascular disease (CVD) had extensive lipoprotein profiling. Proteomics analysis was performed on isolated oxHDL, and atherosclerotic plaque assessment was accomplished by quantitative CCTA.RESULTS. Patients were predominantly White, overweight men (58.5%) on statin therapy (43.5%). Increase in LDL-C, ApoB, small dense LDL-C (P < 0.001 for all), triglycerides (P = 0.03), and lower HDL function were observed in the high oxLDL group. High oxLDL associated with necrotic burden (NB; β = 0.20; P < 0.0001) and fibrofatty burden (FFB; β = 0.15; P = 0.001) after multivariate adjustment. Low oxHDL had a significant reverse association with these plaque characteristics. Plasma oxHDL levels better predicted NB and FFB after adjustment (OR, 2.22; 95% CI, 1.27–3.88, and OR, 2.80; 95% CI, 1.71–4.58) compared with oxLDL and HDL-C. Interestingly, oxHDL associated with fibrous burden (FB) change over 3.3 years (β = 0.535; P = 0.033) when compared with oxLDL. Combined Met136 mono-oxidation and Trp132 dioxidation of HDL showed evident association with coronary artery calcium score (r = 0.786; P < 0.001) and FB (r = 0.539; P = 0.012) in high oxHDL, whereas Met136 mono-oxidation significantly associated with vulnerable plaque in low oxHDL.CONCLUSION. Our findings suggest that the investigated oxidized lipids are associated with high-risk coronary plaque features and progression over time in patients with CVD.TRIAL REGISTRATION. ClinicalTrials.gov NCT01621594.FUNDING. National Heart, Lung, and Blood Institute at the NIH Intramural Research Program.

BackgroundAdvances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown.MethodsWe screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH.ResultsWe confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI.ConclusionsOur findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.

Precise discrimination of tumor from normal tissues remains a major roadblock for therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Here, we perform a comprehensive in silico screen to identify multi-antigen signatures that improve tumor discrimination by CAR T cells engineered to integrate multiple antigen inputs via Boolean logic, e.g., AND and NOT. We screen >2.5 million dual antigens and ∼60 million triple antigens across 33 tumor types and 34 normal tissues. We find that dual antigens significantly outperform the best single clinically investigated CAR targets and confirm key predictions experimentally. Further, we identify antigen triplets that are predicted to show close to ideal tumor-versus-normal tissue discrimination for several tumor types. This work demonstrates the potential of 2- to 3-antigen Boolean logic gates for improving tumor discrimination by CAR T cell therapies. Our predictions are available on an interactive web server resource (antigen.princeton.edu).

Objective: To explore the correlation between eating habits of university students and academic achievement. Participants: 577 undergraduate students at a university in the United States. Methods: Students were invited to participate in an anonymous online survey that asked questions concerning health-related behaviors; participants were asked to report their current grade point average (GPA). Statistical analyses were performed using the JMP software program; a standard least squares regression was used to test whether self-reported current GPA was related to different types and rates of weekly food and drink consumption. Results: Self-reported GPA did not change along with weekly rates of milk, vegetables, green salad, fruit juice, or fresh fruit consumption. Breakfast consumption had a positive effect on self-reported GPA, while fast food consumption had a negative effect. Conclusion: Healthy eating habits have a positive effect on students' academic performance. However, other factors, such as sleep habits, may be more important.

Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPR-associated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Abstract Phoenixin (PNX) is a highly conserved, novel hormone with diverse functions, including hypothalamic control of reproduction, appetite modulation, and regulation of energy metabolism and inflammation. While some functions appear conserved across vertebrates, additional research is required to fully characterize these complex pleiotropic effects. For instance, very little is known about transcriptome level changes associated with PNX exposure, including responses in the hypothalamic–pituitary–gonadal (HPG) axis, which is critical in vertebrate reproduction. In addition, the PNX system may be especially complex in fish, where an additional receptor is likely present in some species. The purpose of this study was to assess hypothalamic and ovarian transcriptomes after PNX-14 administration in female vitellogenic green-spotted puffer (Dichotomyctere nigroviridis). Steroid-related changes were also assessed in the liver and blood plasma. Hypothalamic responses included pro-inflammatory signals such as interleukin 1β, possibly related to gut–brain axis functions, as well as suppression of cell proliferation. Ovarian responses were more widely downregulated across all identified pathways, which may reflect progression to a less transcriptionally active state in oocytes. Both organs shared regulation in transforming growth factor-β and extracellular matrix remodeling (periostin) pathways. Reproductive processes were in general downregulated, but both inhibiting (bone morphogenetic protein 15 and follistatin) and promoting (17-hydroxyprogesterone) factors for oocyte maturation were identified. Select genes involved in reproduction (vitellogenins, estrogen receptors) in the liver were unresponsive to PNX-14 and higher doses may be needed to induce reproductive effects in D. nigroviridis. These results reinforce the complexity of PNX actions in diverse tissues and highlight important roles for this hormone in regulating the immune response, energy metabolism, and cell growth.

Introduction: Theileria orientalis Ikeda genotype is an emerging cattle disease in the US. Since 2017, when T. orientalis Ikeda was discovered in beef cattle in two counties in Virginia, cattle infections have risen to include ~67% of Virginia counties and 14 states. Consistent with New Zealand studies, many infected herds in Virginia were >90% positive upon initial testing without overt evidence of infection. Central bull tests present a unique opportunity to study the effects of T. orientalis Ikeda infections, as bulls from multiple source herds are consolidated. The objective of this study was to determine if infection with T. orientalis Ikeda affected the average daily gain (ADG), adjusted yearling weight (AYW) and breeding soundness of bulls at two test stations in Virginia over a period of years. Materials and methods: The bulls were fed and housed similarly to compare their growth performance and breeding soundness. For T. orientalis Ikeda testing, DNA was extracted from whole blood for quantitative polymerase chain reaction. Results: The number of bulls infected with T. orientalis Ikeda at initial delivery to the stations increased significantly over the years studied. Multivariable linear regression models, using Angus bulls from Virginia test stations, indicated no significant effect on ADG or AYW in bulls that became test positive during the test or were positive for the duration, compared to Angus bulls that were negative for the duration. At LOC A, the odds of passing a breeding soundness exam (BSE) were not significantly different for bulls that turned positive during the test or were positive for the duration, compared to bulls that were negative for the duration of the test. At LOC B, bulls that became positive during the test were 2.4 times more likely (95% CI: 1.165-4.995, p = 0.016) to pass their BSE compared to bulls that remained negative throughout the test. Discussion: We do not suppose that an obscured infection of T. orientalis Ikeda is protective for bulls to pass a BSE. However, this study demonstrates an obscured infection of T. orientalis Ikeda does not negatively affect weight gain or achievement of a satisfactory BSE rating at the central bull test stations in Virginia. [ABSTRACT FROM AUTHOR]

Gold nanoparticles (AuNPs) have great potential as biosensors for glucose detection due to their high sensitivity, as well as their extraordinary physical and chemical properties that improve compatibility with different biorecognition molecules, such as glucose oxidase (GOx). In this work the D-glucose quantification was determined by using the traditional technique based on biochemical reaction of GOx and AuNPs functionalized with polyvinylpirrolidone (PVP) polymer and the enzyme. The AuNPs-PVP-GOx nanocomplexes were characterized by ultraviolet-visible (UV-Visible), Infrared (FTIR), and Raman spectroscopies, as well as scanning electron microscopy (SEM), Z potential, dynamic light scattering (DLS), and thermogravimetry analysis (TGA). In general, these techniques showed significant differences after each functionalization stage with PVP and GOx, for instance it was observed: the presence of different functional groups, an increase of hydrodynamic diameter from 48.60 to 198.77 nm, a shift of the band absorption to larger wavelength, a change in the surface potential and weight loss, and in the morphology of the nanocomplex, which confirm the functionalization. In addition, the enzymatic activity of the AuNPs-PVP-GOx was confirmed through the detection of triiodide ions by UV-Visible spectrophotometry, coming from the oxidation reaction of iodide ions in the presence of H2O2. Furthermore, the nanocomplex synthesized by passive adsorption was evaluated as a possible biosensor for the quantification of D-glucose using a colorimetric assay, obtaining greater sensitivity than the traditional method. These findings indicate that PVP can be used as a linkage medium between AuNPs and GOx, which in turn can be used as a biosensor for the detection of D-glucose at low concentrations in biological fluids. [ABSTRACT FROM AUTHOR]

The primary cilium is a cellular sensory organelle found in most cells in our body. This includes adipocyte progenitor cells in our adipose tissue, a complex organ involved in energy storage, endocrine signaling, and thermogenesis. Numerous studies have shown that the primary cilium plays a critical role in directing the cell fate of adipocyte progenitor cells in multiple adipose tissue types. Accordingly, diseases with dysfunctional cilia called ciliopathies have a broad range of clinical manifestations, including obesity and diabetes. This review summarizes our current understanding of how the primary cilium regulates adipocyte progenitor cell fate in multiple contexts and illustrates the importance of the primary cilium in regulating energy storage and adipose tissue function.

This study illustrates the benefits of public-private partnerships in creating public corporations to build sport venues. In addition to potential returns, public officials' understanding of the potential structures of these authorities is equally important. Additionally, as the scope of public-private partnerships broadens, it is essential for administrators of secondary and higher level education to recognize the benefits of and understand the structure of these partnerships. This study presents the structures of four authorities and the details of the sport-related partnerships they entered. The authorities include the Gateway Economic Development Corporation of Greater Cleveland, Indianapolis Capital Improvement Board, Frisco Economic Development Corporation, and Detroit Downtown Development Authority. In each instance, individual outcomes were analyzed. This paper illustrates the range of responsibilities that could be assigned to authorities and the potential for benefits to be generated for teams, cities, universities, and school districts. The results from each partnership reflect the structure of the public authority. To protect the public's interest, the legislation creating a new public corporation must clearly outline its objectives, structure, and responsibilities. But when cities, universities, and school districts utilize authorities for sport-related development projects, the opportunities for achieving public policy goals are more expansive than many realize.

The assessment of dietary patterns comprehensively represents the totality of the diet, an important risk factor for many chronic diseases. This study aimed to characterise and compare four dietary pattern indices in middle-aged Australian adults. In 3458 participants (55% female) from the Busselton Healthy Ageing Study (Phase Two), a validated food frequency questionnaire was used to capture dietary data between 2016 and 2022. Four dietary patterns [Australian Dietary Guideline Index 2013 (DGI-2013); the Mediterranean Diet Index (MedDiet); the Literature-based Mediterranean Diet Index (Lit-MedDiet); and the EAT-Lancet Index], were calculated and compared by measuring total and sub-component scores, and concordance (𝜌c). Cross-sectional associations between the dietary indices and demographic, lifestyle, and medical conditions were modelled with linear regression and restricted cubic splines. Participants had the highest standardised scores for the DGI-2013 followed by the EAT-Lancet Index and the MedDiet, with the lowest standardised scores observed for the Lit-MedDiet. The DGI-2013 had the lowest agreement with the other scores (𝜌c ≤ 0.47). These findings indicate that the diets included in this Australian cohort align more closely with the Australian Dietary Guidelines than with the other international dietary patterns, likely due to the wide variation of individual food group weightings in the construction of these indices.

Patients with hypertension or obesity can develop glomerular dysfunction characterized by injury and depletion of podocytes. To better understand the molecular processes involved, young mice were treated with either deoxycorticosterone acetate (DOCA) or fed a high-fat diet (HFD) to induce hypertension or obesity, respectively. The transcriptional changes associated with these phenotypes were measured by unbiased bulk mRNA sequencing of isolated podocytes from experimental models and their respective controls. Key findings were validated by immunostaining. In addition to a decrease in canonical proteins and reduced podocyte number, podocytes from both hypertensive and obese mice exhibited a sterile inflammatory phenotype characterized by increases in NLR family pyrin domain containing 3 (NLRP3) inflammasome, protein cell death-1, and Toll-like receptor pathways. Finally, although the mice were young, podocytes in both models exhibited increased expression of senescence and aging genes, including genes consistent with a senescence-associated secretory phenotype. However, there were differences between the hypertension- and obesity-associated senescence phenotypes. Both show stress-induced podocyte senescence characterized by increased p21 and p53. Moreover, in hypertensive mice, this is superimposed upon age-associated podocyte senescence characterized by increased p16 and p19. These results suggest that senescence, aging, and inflammation are critical aspects of the podocyte phenotype in experimental hypertension and obesity in mice. NEW & NOTEWORTHY: Hypertension and obesity can lead to glomerular dysfunction in patients, causing podocyte injury and depletion. Here, young mice given deoxycorticosterone acetate or a high-fat diet to induce hypertension or obesity, respectively. mRNA sequencing of isolated podocytes showed transcriptional changes consistent with senescence, a senescent-associated secretory phenotype, and aging, which was confirmed by immunostaining. Ongoing studies are determining the mechanistic roles of the accelerated aging podocyte phenotype in experimental hypertension and obesity. [ABSTRACT FROM AUTHOR]

Abstract Background Advances in antiretroviral therapies have greatly improved the survival of people living with human immunodeficiency virus (HIV) infection (PLWH); yet, PLWH have a higher risk of cardiovascular disease than those without HIV. While numerous genetic loci have been linked to cardiometabolic risk in the general population, genetic predictors of the excessive risk in PLWH are largely unknown. Methods We screened for common and HIV-specific genetic variants associated with variation in lipid levels in 6284 PLWH (3095 European Americans [EA] and 3189 African Americans [AA]), from the Centers for AIDS Research Network of Integrated Clinical Systems cohort. Genetic hits found exclusively in the PLWH cohort were tested for association with other traits. We then assessed the predictive value of a series of polygenic risk scores (PRS) recapitulating the genetic burden for lipid levels, type 2 diabetes (T2D), and myocardial infarction (MI) in EA and AA PLWH. Results We confirmed the impact of previously reported lipid-related susceptibility loci in PLWH. Furthermore, we identified PLWH-specific variants in genes involved in immune cell regulation and previously linked to HIV control, body composition, smoking, and alcohol consumption. Moreover, PLWH at the top of European-based PRS for T2D distribution demonstrated a > 2-fold increased risk of T2D compared to the remaining 95% in EA PLWH but to a much lesser degree in AA. Importantly, while PRS for MI was not predictive of MI risk in AA PLWH, multiethnic PRS significantly improved risk stratification for T2D and MI. Conclusions Our findings suggest that genetic loci involved in the regulation of the immune system and predisposition to risky behaviors contribute to dyslipidemia in the presence of HIV infection. Moreover, we demonstrate the utility of the European-based and multiethnic PRS for stratification of PLWH at a high risk of cardiometabolic diseases who may benefit from preventive therapies.