Durability of Running Economy: Differences between Quantification Methods and Performance Status in Male Runners.

INTRODUCTION: Running economy (RE) deteriorates during prolonged running, although the effect of measuring energy cost (EC) or oxygen cost (OC) on the magnitude of these changes has not been investigated. Similarly, it is unknown if runners' performance level may influence the deterioration of RE during prolonged running. The aims of this study were to compare changes in EC and OC measurements of RE during a prolonged run in a large cohort of well-trained male runners, and to compare changes between runners of high and low performance standard. METHODS: Forty-four male runners (maximal oxygen uptake (V̇O2max) 62.4 ml·kg-1·min-1; 10 km time 35:50 ± 4:40 mm:ss) completed an incremental test determining lactate threshold 1 (LT1) and V̇O2max, and on a separate occasion, a 90 min run at LT1. Respiratory gases were collected at 15 min intervals. Subsequently, sub-groups of high- (HP, 10 km 31:20 ± 01:00 mm:ss) and low-performing (LP, 10 km 41:50 ± 01:20 mm:ss) runners were compared. RESULTS: RE deterioration was only fractionally larger when expressed as OC than EC (0.1% greater from 30-90 min; p < 0.001), perhaps due to the small change in RER (-0.01) in this study. For the HP group increases were lower than LP after 90 min in both EC (+2.3 vs +4.3%; p < 0.01) and OC (+2.4 vs +4.5%; p < 0.01). Similarly, at standardized distances, changes were lower for HP vs LP e.g. at 16.7 km +1.0 vs +3.2% for EC (p < 0.01), and + 1.2 vs +3.4% for OC (p < 0.001). CONCLUSIONS: The deterioration of RE was dependent on athlete's performance level, with HP runners displaying superior RE durability. The use of EC or OC had only a fractional influence on RE durability, although this may gain importance with larger shifts in substrate metabolism.

Historical Structural Racism in the Built Environment and Physical Health among Residents of Allegheny County, Pennsylvania.

Historical structural racism in the built environment contributes to health inequities, yet to date, research has almost exclusively focused on racist policy of redlining. We expand upon this conceptualization of historical structural racism by examining the potential associations of probable blockbusting, urban renewal, and proximity to displacement from freeway construction, along with redlining, to multiple contemporary health measures. Analyses linked historical structural racism, measured continuously at the census-tract level using archival data sources, to present-day residents' physical health measures drawn from publicly accessible records for Allegheny County, Pennsylvania. Outcome measures included average life expectancy and the percentage of residents reporting hypertension, stroke, coronary heart disease, smoking, insufficient sleep, sedentary behavior, and no health insurance coverage. Multiple regression analyses were conducted to examine separate and additive associations between structural racism and physical health measures. Redlining, probable blockbusting, and urban renewal were associated with shorter life expectancy and a higher prevalence of cardiovascular conditions, risky health behaviors, and residents lacking health insurance coverage. Probable blockbusting and urban renewal had the most consistent correlations with all 8 health measures, while freeway displacement was not reliably associated with health. Additive models explained a greater proportion of variance in health than any individual structural racism measure alone. Moreover, probable blockbusting and urban renewal accounted for relatively more variance in health compared to redlining, suggesting that research should consider these other measures in addition to redlining. These preliminary correlational findings underscore the importance of considering multiple aspects of historical structural racism in relation to current health inequities and serve as a starting point for additional research.

Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival.

BACKGROUND: Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells. METHODS AND RESULTS: The cytotoxic effects of metformin with or without the presence of SBI0206965 (AMPK inhibitor) on LNCaP cells were determined using MTT and trypan blue exclusion assays. Seahorse XP extracellular analysis, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), and 2,7- and Dichlorofluoresin diacetate (DCFDA) assay were used to assess the effects of metformin on cellular bioenergetics, redox status, and redox-related metabolites. mRNA expression and protein concentration of redox-related enzymes were measured using Real Time-qPCR and ELISA assay, respectively. Independently of AMP-activated protein kinase, metformin exhibited a dose- and time-dependent inhibition of LNCaP cell survival, a response mitigated by glutathione or N-acetylcysteine (ROS scavengers) treatment. Notably, these findings were concomitant with a decline in ATP levels and the inhibition of oxidative phosphorylation. The results further indicated metformin's induction of reactive oxygen species, which significantly decreased glutathione levels and the ratio of reduced to oxidized glutathione, as well as the transsulfuration metabolite, cystathionine. Consistent with an induction of oxidative stress condition, metformin increased mRNA levels of the master redox transcription factor Nrf-2 (nuclear factor erythroid-derived 2-like), as well as transsulfuration enzymes cystathionine beta-synthase and cystathionase and GSH synthesis enzymes γ-glutamylcysteine synthetase and glutathione synthetase. CONCLUSION: Our findings highlight multiple mechanisms by which metformin-induced formation of reactive oxygen species may contribute to its efficacy in prostate cancer treatment, including promotion of oxidative stress, Nrf2 activation, and modulation of redox-related pathways, leading to its anti-survival action.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (µ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Age and number of lesions predict chalazion recurrence.

PURPOSE: Periocular lesions in pediatric patients usually require general anesthesia for surgical intervention. The US Food and Drug Administration (FDA) warns against multiple exposures to anesthesia in children younger than 3 years due to the increased risk of learning disabilities in this population. This study aimed to evaluate risk factors associated with chalazion recurrence after surgery. METHODS: A retrospective chart review over a five-year period identified 649 patients at our institution undergoing surgical intervention for chalazion. The primary outcomes examined were as follows: (1) return to the operating room for additional surgical intervention and (2) recurrence of chalazion during convalescence from surgery and follow-up. RESULTS: Fewer than one-third of patients suffered a recurrence after surgery. Multivariate logistic regression found younger age (p = 0.01), female sex (p = 0.01), and a greater number of chalazia drained (p < 0.001) were significantly correlated with recurrence of chalazia after surgery. CONCLUSIONS: Patients presenting at a younger age and with a greater number of chalazion were statistically more likely to have a recurrence of chalazion after surgery. Given recurrence is more likely in younger children, reconciling this with the risk-benefit ratio with regard to FDA guidelines on anesthesia in children under three years is a critical consideration for ophthalmologists.

The Role of Musculoskeletal Training During Return to Performance Following Relative Energy Deficiency in Sport.

BACKGROUND: Relative energy deficiency in sport (REDs) is a condition that is associated with negative health and performance outcomes in athletes. Insufficient energy intake relative to exercise energy expenditure, resulting in low energy availability, is the underlying cause, which triggers numerous adverse physiological consequences including several associated with musculoskeletal (MSK) health and neuromuscular performance. PURPOSE: This commentary aims to (1) discuss the health and performance implications of REDs on the skeletal and neuromuscular systems and (2) examine the role that MSK training (ie, strength and plyometric training) during treatment and return to performance following REDs might have on health and performance in athletes, with practical guidelines provided. CONCLUSIONS: REDs is associated with decreases in markers of bone health, lean body mass, maximal and explosive strength, and muscle work capacity. Restoration of optimal energy availability, mainly through an increase in energy intake, is the primary goal during the initial treatment of REDs with a return to performance managed by a multidisciplinary team of specialists. MSK training is an effective nonpharmacological component of treatment for REDs, which offers multiple long-term health and performance benefits, assuming the energy needs of athletes are met as part of their recovery. Supervised, prescribed, and gradually progressive MSK training should include a combination of resistance training and high-impact plyometric-based exercise to promote MSK adaptations, with an initial focus on achieving movement competency. Progressing MSK training exercises to higher intensities will have the greatest effects on bone health and strength performance in the long term.

Exploring melanoma shifts: a two-decade analysis in New Zealand.

AIMS: New Zealand melanoma incidence rates are amongst the highest in the world. The study aims to provide information on the incidence of cutaneous melanoma in New Zealand from 2000 to 2022. METHODS: De-identified data were extracted from the New Zealand Cancer Registry using the ICD-10 code for malignant melanoma (C34) and melanoma in situ (MIS) (D03) from 2000 to 2022. Statistical analysis was performed to calculate melanoma incidence rates. RESULTS: Invasive melanoma (IM) incidence rates demonstrated an increasing trend from 2000 to 2008 (+1.10 per 100,000 person-years per year), followed by an inflection point at 2008 and then a decreasing trend from 2008 to 2022 (-0.28 per 100,000 person-years per year), which was not statistically different from zero/no change. MIS incidence increased from 30.3 to 72.1 per 100,000 person-years between 2000 and 2022. CONCLUSIONS: The incidence of IM in New Zealand has plateaued in the last decade and was associated with an increase in MIS incidence over the same period. While this trend is encouraging, further research is required to investigate whether there is an actual decline in IM incidence.

A single-nucleus transcriptomic atlas of medium spiny neurons in the rat nucleus accumbens.

Neural processing of rewarding stimuli involves several distinct regions, including the nucleus accumbens (NAc). The majority of NAc neurons are GABAergic projection neurons known as medium spiny neurons (MSNs). MSNs are broadly defined by dopamine receptor expression, but evidence suggests that a wider array of subtypes exist. To study MSN heterogeneity, we analyzed single-nucleus RNA sequencing data from the largest available rat NAc dataset. Analysis of 48,040 NAc MSN nuclei identified major populations belonging to the striosome and matrix compartments. Integration with mouse and human data indicated consistency across species and disease-relevance scoring using genome-wide association study results revealed potentially differential roles for MSN populations in substance use disorders. Additional high-resolution clustering identified 34 transcriptomically distinct subtypes of MSNs definable by a limited number of marker genes. Together, these data demonstrate the diversity of MSNs in the NAc and provide a basis for more targeted genetic manipulation of specific populations.

Juvenile social play predicts adult reproductive success in male bottlenose dolphins.

For over a century, the evolution of animal play has sparked scientific curiosity. The prevalence of social play in juvenile mammals suggests that play is a beneficial behavior, potentially contributing to individual fitness. Yet evidence from wild animals supporting the long-hypothesized link between juvenile social play, adult behavior, and fitness remains limited. In Western Australia, adult male bottlenose dolphins (Tursiops aduncus) form multilevel alliances that are crucial for their reproductive success. A key adult mating behavior involves allied males using joint action to herd individual females. Juveniles of both sexes invest significant time in play that resembles adult herding-taking turns in mature male (actor) and female (receiver) roles. Using a 32-y dataset of individual-level association patterns, paternity success, and behavioral observations, we show that juvenile males with stronger social bonds are significantly more likely to engage in joint action when play-herding in actor roles. Juvenile males also monopolized the actor role and produced an adult male herding vocalization ("pops") when playing with females. Notably, males who spent more time playing in the actor role as juveniles achieved more paternities as adults. These findings not only reveal that play behavior provides male dolphins with mating skill practice years before they sexually mature but also demonstrate in a wild animal population that juvenile social play predicts adult reproductive success.

A multidomain lifestyle intervention to maintain optimal cognitive functioning in Dutch older adults-study design and baseline characteristics of the FINGER-NL randomized controlled trial.

BACKGROUND: Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in older people without dementia is mixed. Embedded in the World-Wide FINGERS initiative, FINGER-NL aims to investigate the effectiveness of a 2-year multidomain lifestyle intervention on cognitive functioning in older Dutch at risk individuals. METHODS: Multi-center, randomized, controlled, multidomain lifestyle intervention trial with a duration of 24 months. 1210 adults between 60-79 years old with presence of ≥ 2 modifiable risk factors and ≥ 1 non-modifiable risk factor for cognitive decline were recruited between January 2022 and May 2023 via the Dutch Brain Research Registry and across five study sites in the Netherlands. Participants were randomized to either a high-intensity or a low-intensity intervention group. The multidomain intervention comprises a combination of 7 lifestyle components (physical activity, cognitive training, cardiovascular risk factor management, nutritional counseling, sleep counseling, stress management, and social activities) and 1 nutritional product (Souvenaid®) that could help maintain cognitive functioning. The high-intensity intervention group receives a personalized, supervised and hybrid intervention consisting of group meetings (on-site and online) and individual sessions guided by a trained lifestyle coach, and access to a digital intervention platform that provides custom-made training materials and selected lifestyle apps. The low-intensity intervention group receives bi-monthly online lifestyle-related health advice via the digital intervention platform. Primary outcome is 2-year change on a cognitive composite score covering processing speed, executive function, and memory. RESULTS: Within 17 months, participant recruitment has been successfully completed (N = 1210; mean age: 67.7 years (SD: 4.6); 64% female). Modifiable risk factors commonly present at baseline were physical inactivity (89%), low mental/cognitive activity (50%), low social engagement (39%), hypertension (39%) and high alcohol consumption (39%). The mean body mass index of participants was 28.3 (SD: 4.2) and the total serum cholesterol was 5.4 mmol/L (SD: 1.2). CONCLUSIONS: Baseline lifestyle and clinical measurements showed successful recruitment of participants with sufficient potential for prevention. Results of FINGER-NL will provide further insight into the efficacy of a multidomain lifestyle intervention to prevent cognitive decline in older adults. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT05256199)/2022-01-11.

The carcass characteristics and quality of meat from lambs grazing perennial wheat with different companion legumes (clover, serradella, lucerne) or a mineral supplement.

This study compared carcasses as well as the quality and mineral concentration of meat from lambs extensively grazing perennial wheat with clover (PW + C), serradella (PW + S), lucerne (PW + L), or a mineral salt supplement (PW + Min). A split-plot design was used, wherein 3 crossbred ewe lambs (n = 72 in total) (sub-plots) grazed each of 4 forage types (plots), that were replicated across 6 locations (blocks). The feeding study concluded after 96 d, when all the lambs were slaughtered. The left longissimus lumborum muscles (LL) were collected and wet aged for either 5 or 56 d post-mortem. Lambs grazing PW + Min were found to produce carcasses with lower dressing percentage values to those grazing the other forage types (P = 0.037). The LL of lambs grazing PW + L had the lowest crude protein values (P = 0.015). Forage type by ageing period interactions did not affect meat quality. The 56 d ageing period resulted in higher purge loss (P < 0.001) and TVB-N values (P < 0.001) and a decline in shear force (P < 0.001) compared to the 5 d ageing period. The other carcass and meat quality parameters were not affected by forage type; including hot carcass weight, pH decline parameters, eye muscle area, cooking loss, intramuscular fat, sarcomere length, colour stability, and concentrations of calcium, iron, magnesium, sodium, and zinc in the LL. These findings confirm that perennial cereal production systems, that include legume forages with contrasting protein, energy, and micronutrient profiles, can deliver comparable lamb carcasses and meat quality.

Mercury biomagnification in the food chain of a piscivorous turtle species (Testudines: Chelidae: Chelus fimbriata) in the Central Amazon, Brazil.

Due to their natural history and ecological attributes, turtles are excellent organisms for studies of heavy metal contamination. Turtles have a large geographical distribution, occupy different aquatic habitats, and occupy various trophic levels. The present study investigated mercury bioaccumulation in the carnivorous chelonian Chelus fimbriata (Matamata turtle) and Hg biomagnification in relation to its aquatic food chain in the middle Rio Negro, AM-Brazil. Tissue samples of muscle, carapace and claws were collected from 26 C. fimbriata individuals, as well as collections of autotrophic energy sources found in the turtle's aquatic habitat area. The samples were collected in February-March/2014 and analyzed for THg concentrations and carbon (δ13C) and nitrogen (δ15N) stable isotopes. The highest THg levels were found in claws (3780 ng.g-1), carapace (3622 ng.g-1) and muscle (403 ng.g-1), which were found to be significantly different [F(2.73) = 49.02 p < 0.01]. However, THg concentrations in muscle tissue were below the consumption threshold indicated by the WHO and Brazilian Health Ministry. The average δ13C and δ15N values in Matamata samples were -31.7‰ and 11.9‰, respectively. The principal energy source sustaining the food chain of C. fimbriata was found to be terrestrial shrubs, with smaller contributions from emergent aquatic herbaceous plants and algae, while δ15N values showed its trophic position to be two levels above the autotrophic energy sources. There was a positive correlation between THg and turtle size, while a significant relationship was found between THg and δ15N, showing strong biomagnification in the food chain of C. fimbriata: y = 0.21x + 0.46; r2 = 0.45; p < 0.001, for which the slope presented a value of 0.21.

US Hospital Service Availability and New 340B Program Participation.

Importance: The US 340B Drug Pricing Program enables eligible hospitals to receive substantial discounts on outpatient drugs to improve hospitals' financial sustainability and maintain access to care for patients who have low income and/or are uninsured. However, it is unclear whether hospitals use program savings to subsidize access as intended. Objective: To evaluate whether the 340B program is associated with improvements in access to hospital-based services and to test whether the association varies by hospital ownership. Design, Setting, and Participants: Difference-in-differences and cohort analysis from 2010 to 2019. Never and newly participating 340B general, acute, nonfederal hospitals in the US using data from the American Hospital Association's Annual Survey of Hospitals merged with hospital and market characteristics. Data were analyzed from January 1, 2023, to January 31, 2024. Exposures: New enrollment in 340B between 2012 and 2018. Main Outcomes and Measures: Total number of unprofitable service lines, ie, substance use, psychiatric (inpatient and outpatient), burn clinic, and obstetrics services; and profitable services, ie, cardiac surgery and orthopedic, oncologic, neurologic, and neonatal intensive services. Results: The study sample comprised a total of 2152 hospitals, 1074 newly participating and 1078 not participating in the 340B program. Participating hospitals were more likely than nonparticipating hospitals to be critical access and teaching hospitals, have higher Medicaid shares, and be located in rural areas and in Medicaid expansion states. At public hospitals, participation in the 340B program was associated with a significant increase in total unprofitable services (0.21; 95% CI, 0.04 to 0.38; P = .02) and marginal increases in substance use (5.4 percentage points [pp]; 95% CI, -0.8 pp to 11.6 pp; P = .09) and inpatient psychiatric (6.5 pp; 95% CI, -0.7 pp to 13.7 pp; P = .09) services. Among nonprofit hospitals, there was no significant association between 340B and service offerings (profitable and unprofitable) except for an increase in oncologic services (2.5 pp; 95% CI, 0.0 pp to 5.0 pp; P = .05). Conclusions and Relevance: The finding of the cohort study indicate that participation in the 340B program was associated with an increase in unprofitable services among newly participating public hospitals. Nonprofit hospitals were largely unaffected. These findings suggest that public hospitals responded to 340B savings by improving patient access, whereas nonprofits did not. This heterogeneous response should be considered when evaluating the eligibility criteria for the 340B program and how it affects social welfare.

Delayed Sternal Closure vs Emergency Sternal Reopening in Adults with Congenital Heart Disease.

BACKGROUND: Limited data exist regarding outcomes of delayed sternal closure (DSC) in adults with congenital heart disease (ACHD). METHODS: We reviewed 159 ACHD patients undergoing cardiac surgery 1993-2023, who required DSC (open sternum at the end of operation, n=112) or ESR (sternum emergently reopened, n=47). Regression models were performed to determine factors associated with outcomes. RESULTS: Of 112 patients undergoing DSC, 87 patients (77.6%) underwent DSC ≤4 days, and 25 patients (22.3%) >4 days. The most common operations were valve (n=35, 31.2%), aortic (n=33, 29.4%), and right ventricular outflow tract procedures (n=23, 20.5%). Median time to chest closure was 2 days (interquartile range 1, 5). Apart from gender, baseline characteristics were similar between DSC groups. A stepwise increase in early mortality was observed from DSC≤4 days to DSC>4 days (6.8% vs 32%), as well as incidence of early complications, except sternal infection. Risk factors associated with early mortality were age (p=0.02), DSC >4 days (p<0.001), hemodynamic indication (p=0.03), and single ventricle (p=0.02). On multivariable analysis, lower ejection fraction (p=0.04), hemodynamic indication (p=0.02), single ventricle (p=0.004), and diabetes mellitus (p=0.03) were predictors of prolonged time to chest closure. Amongst hospital survivors, there was no difference in late survival between patients undergoing DSC ≤4 days vs >4 days (p=0.48). CONCLUSIONS: Brief duration of DSC in ACHD patients is associated with low morbidity and mortality. Higher early mortality and complications were observed among patients who did not achieve chest closure within 4 days.

Temperature, humidity, and ionisation effect of iodine oxoacid nucleation.

Iodine oxoacids are recognised for their significant contribution to the formation of new particles in marine and polar atmospheres. Nevertheless, to incorporate the iodine oxoacid nucleation mechanism into global simulations, it is essential to comprehend how this mechanism varies under various atmospheric conditions. In this study, we combined measurements from the CLOUD (Cosmic Leaving OUtdoor Droplets) chamber at CERN and simulations with a kinetic model to investigate the impact of temperature, ionisation, and humidity on iodine oxoacid nucleation. Our findings reveal that ion-induced particle formation rates remain largely unaffected by changes in temperature. However, neutral particle formation rates experience a significant increase when the temperature drops from +10 °C to -10 °C. Running the kinetic model with varying ionisation rates demonstrates that the particle formation rate only increases with a higher ionisation rate when the iodic acid concentration exceeds 1.5 × 107 cm-3, a concentration rarely reached in pristine marine atmospheres. Consequently, our simulations suggest that, despite higher ionisation rates, the charged cluster nucleation pathway of iodic acid is unlikely to be enhanced in the upper troposphere by higher ionisation rates. Instead, the neutral nucleation channel is likely to be the dominant channel in that region. Notably, the iodine oxoacid nucleation mechanism remains unaffected by changes in relative humidity from 2% to 80%. However, under unrealistically dry conditions (below 0.008% RH at +10 °C), iodine oxides (I2O4 and I2O5) significantly enhance formation rates. Therefore, we conclude that iodine oxoacid nucleation is the dominant nucleation mechanism for iodine nucleation in the marine and polar boundary layer atmosphere.

In pop pursuit: social bond strength predicts vocal synchrony during cooperative mate guarding in bottlenose dolphins.

Vocal communication is an emblematic feature of group-living animals, used to share information and strengthen social bonds. Vocalizations are also used to coordinate group-level behaviours in many taxa, but little is known of the factors that may influence vocal behaviour during cooperative acts. Allied male Indo-Pacific bottlenose dolphins (Tursiops aduncus) use the 'pop' vocalization as a coercive signal when working together to herd single oestrous females. Using long-term association and acoustic data, we examined the influence of social and non-social factors on pop use by allied male dolphins in this context. Neither pop rate nor pop bout duration were influenced by any of the factors examined. However, allied males with stronger social bonds engaged in higher rates of vocal synchrony; whereby they actively matched the timing of their pop production. Hence, social bond strength influenced pop use in a cooperative context, suggesting dual functions of pop use: to induce the female to remain close, and to promote social bond maintenance and cooperation among males. This article is part of the theme issue 'The power of sound: unravelling how acoustic communication shapes group dynamics'.

Enzymatic depletion of circulating glutamine is immunosuppressive in cancers.

Although glutamine addiction in cancer cells is extensively reported, there is controversy on the impact of glutamine metabolism on the immune cells within the tumor microenvironment (TME). To address the role of extracellular glutamine, we enzymatically depleted circulating glutamine using PEGylated Helicobacter pylori gamma-glutamyl transferase (PEG-GGT) in syngeneic mouse models of breast and colon cancers. PEG-GGT treatment inhibits growth of cancer cells in vitro, but in vivo it increases myeloid-derived suppressor cells (MDSCs) and has no significant impact on tumor growth. By deriving a glutamine depletion signature, we analyze diverse human cancers within the TCGA and illustrate that glutamine depletion is not associated with favorable clinical outcomes and correlates with accumulation of MDSC. Broadly, our results help clarify the integrated impact of glutamine depletion within the TME and advance PEG-GGT as an enzymatic tool for the systemic and selective depletion (no asparaginase activity) of circulating glutamine in live animals.

Parameterization of H2SO4 and organic contributions to volatile PM in aircraft plumes at ground idle.

Volatile Particulate Matter (vPM) emissions are challenging to measure and quantify, since they are not present in the condensed form at the engine exit plane and they evolve to first form in the aircraft plume and then continue to grow and change as they mix and dilute in the ambient atmosphere. To better understand the issues associated with the initial formation and growth of vPM, a modeling study has been undertaken to examine several key parameters that affect the formation and properties of the vPM that is created in the initial cooling and dilution of the aircraft exhaust. A modeling tool (Aerosol Dynamic Simulation Code, ADSC) that was developed and enhanced over a series of past research projects supported by NASA, DoD's SERDP/ESTCP, and FAA (Wong et al. 2010, 2014, 2015) was used to perform a parametric analysis of vPM. The parameters of fuel sulfur content (FSC), emitted condensable hydrocarbon (HC) concentrations, and the species profile of the HCs were used to construct a computational matrix that framed a wide range of expected parameter values. This computational matrix was executed for two representative commercial aircraft engines at ground idle and results were obtained for distances of 250 m and 1000 m downstream. From prior results, the most significant vPM emissions occur at the lowest power settings, so an engine power condition of 7% rated thrust was used. A primary goal of the parametric study is to develop an updated vPM modeling methodology and also to help interpret data collected in experimental campaigns. The parameterization proposed here allows the vPM emission composition and particle numbers to be estimated in greater detail than current methods. The aim is to provide additional understanding on how the vPM properties vary with fuel and engine parameters to increase the utility of vPM predictions.Implications: Volatile ParticulateMatter (vPM) is an important contribution to the total PM emitted by aviationengines. While vPM is not currently a part of engine emissions certificationregulations, vPM is used in aviation environmental impact assessments and forair quality modeling in and around airports. Current methods in use, such asFOA (Wayson et al. 2009), were developed before many recent advances inexperimental data acquisition and in understanding of vPM processes. Theparameterization proposed here allows the vPM emission composition and particlenumbers to be estimated in greater detail than current methods. These estimatescan be used to develop inventories and provide a better estimate of total PMemission for most aviation engines. Its use in international regulatory toolscan inform possible future regulatory actions regarding vPM.