A human cadaveric model for venous air embolism tool development.

Purpose: A human cadaveric model combining standard lung protective mechanical ventilation and modified cardiac bypass techniques was developed to allow investigation into automated modes of detection of venous air emboli (VAE) prior to in vivo human or animal investigations. Methods: In this study, in order to create an artificial cardiopulmonary circuit in a cadaver that could mimic VAE physiology, the direction of flow was reversed from conventional cardiac bypass. Saline was circulated in isolation through the heart and lungs as opposed to the peripheral organs by placing the venous cannula into the aorta and the arterial cannula into the inferior vena cava with selective ligation of other vessels. Results: Mechanical ventilation and this reversed cardiac bypass scheme allowed preliminary detection of VAE independently but not in concert in our current simulation scheme due to pulmonary edema in the cadaver. A limited dissection approach was used initially followed by a radical exposure of the great vessels, and both proved feasible in terms of air signal detection. We used electrical impendence as a preliminary tool to validate detection in this cadaveric model however we theorize that it would work for echocardiographic, intravenous ultrasound or other novel modalities as well. Conclusion: A cadaveric model allows monitoring technology development with reduced use of animal and conventional human testing.

Amplification and Quantitation of Telomeric Extrachromosomal Circles.

Telomeres are structures that cap the ends of linear chromosomes and play critical roles in maintaining genome integrity and establishing the replicative lifespan of cells. In stem and cancer cells, telomeres are actively elongated by either telomerase or the alternative lengthening of telomeres (ALT) pathway. This pathway is characterized by several hallmark features, including extrachromosomal C-rich circular DNAs that can be probed to assess ALT activity. These so-called C-circles are the product of ALT-associated DNA damage repair processes and simultaneously serve as potential templates for iterative telomere extension. This bifunctional nature makes C-circles highly sensitive and specific markers of ALT. Here, we describe a C-circle assay, adapted from previous reports, that enables the quantitation of C-circle abundance in mammalian cells subjected to a wide range of experimental perturbations. This protocol combines the Quick C-circle Preparation (QCP) method for DNA isolation with fluorometry-based DNA quantification, rolling circle amplification (RCA), and detection of C-circles using quantitative PCR. Moreover, the inclusion of internal standards with well-characterized telomere maintenance mechanisms (TMMs) allows for the reliable benchmarking of cells with unknown TMM status. Overall, our work builds upon existing protocols to create a generalizable workflow for in vitro C-circle quantitation and ascertainment of TMM identity.

Humid tropical vertebrates are at lower risk of extinction and population decline in forests with higher structural integrity.

Reducing deforestation underpins global biodiversity conservation efforts. However, this focus on retaining forest cover overlooks the multitude of anthropogenic pressures that can degrade forest quality and imperil biodiversity. We use remotely sensed indices of tropical rainforest structural condition and associated human pressures to quantify the relative importance of forest cover, structural condition and integrity (the cumulative effect of condition and pressures) on vertebrate species extinction risk and population trends across the global humid tropics. We found that tropical rainforests of high integrity (structurally intact and under low pressures) were associated with lower likelihood of species being threatened and having declining populations, compared with forest cover alone (without consideration of condition and pressures). Further, species were more likely to be threatened or have declining populations if their geographic ranges contained high proportions of degraded forest than if their ranges contained lower proportions of forest cover but of high quality. Our work suggests that biodiversity conservation policies to preserve forest integrity are now urgently required alongside ongoing efforts to halt deforestation in the hyperdiverse humid tropics.

Morning Exercise Reduces Abdominal Fat and Blood Pressure in Women; Evening Exercise Increases Muscular Performance in Women and Lowers Blood Pressure in Men.

The ideal exercise time of day (ETOD) remains elusive regarding simultaneous effects on health and performance outcomes, especially in women. Purpose: Given known sex differences in response to exercise training, this study quantified health and performance outcomes in separate cohorts of women and men adhering to different ETOD. Methods: Thirty exercise-trained women (BMI = 24 ± 3 kg/m2; 42 ± 8 years) and twenty-six men (BMI = 25.5 ± 3 kg/m2; 45 ± 8 years) were randomized to multimodal ETOD in the morning (0600-0800 h, AM) or evening (1830-2030 h, PM) for 12 weeks and analyzed as separate cohorts. Baseline (week 0) and post (week 12) muscular strength (1-RM bench/leg press), endurance (sit-ups/push-ups) and power (squat jumps, SJ; bench throws, BT), body composition (iDXA; fat mass, FM; abdominal fat, Abfat), systolic/diastolic blood pressure (BP), respiratory exchange ratio (RER), profile of mood states (POMS), and dietary intake were assessed. Results: Twenty-seven women and twenty men completed the 12-week intervention. No differences at baseline existed between groups (AM vs PM) for both women and men cohorts. In women, significant interactions (p < 0.05) existed for 1RM bench (8 ± 2 vs 12 ± 2, ∆kg), pushups (9 ± 1 vs 13 ± 2, ∆reps), BT (10 ± 6 vs 45 ± 28, ∆watts), SJ (135 ± 6 vs 39 ± 8, ∆watts), fat mass (-1.0 ± 0.2 vs -0.3 ± 0.2, ∆kg), Abfat (-2.6 ± 0.3 vs -0.9 ± 0.5, ∆kg), diastolic (-10 ± 1 vs-5 ± 5, ∆mmHg) and systolic (-12.5 ± 2.7 vs 2.3 ± 3, mmHg) BP, AM vs PM, respectively. In men, significant interactions (p < 0.05) existed for systolic BP (-3.5 ± 2.6 vs -14.9 ± 5.1, ∆mmHg), RER (-0.01 ± 0.01 vs -0.06 ± 0.01, ∆VCO2/VO2), and fatigue (-0.8 ± 2 vs -5.9 ± 2, ∆mm), AM vs PM, respectively. Macronutrient intake was similar among AM and PM groups. Conclusion: Morning exercise (AM) reduced abdominal fat and blood pressure and evening exercise (PM) enhanced muscular performance in the women cohort. In the men cohort, PM increased fat oxidation and reduced systolic BP and fatigue. Thus, ETOD may be important to optimize individual exercise-induced health and performance outcomes in physically active individuals and may be independent of macronutrient intake.

Informing conservation decisions to target private lands of highest ecological value and risk of loss.

Natural habitats on private lands are potentially important components of national biodiversity conservation strategies, yet they are being rapidly lost to development. Conservation easements and other means of protecting these habitats have expanded in use and will be most effective if they target private lands of highest biodiversity value and risk of loss. We developed a Biodiversity Conservation Priority Index (BCPI) based on ecological value and risk of habitat loss for remaining areas of natural vegetation cover (NVC) in the northwestern United States and addressed two questions: (1) Which remaining NVC on private lands is the highest priority for biodiversity conservation based on ecological value and risk of development? And (2) are conservation easements in NVC placed preferentially in locations of high biodiversity conservation priority? Drawing on the concept of ecological integrity, we integrated five metrics of ecological structure, function, and composition to quantify ecological value of NVC. These included net primary productivity, species richness, ecosystem type representation, imperiled species range rarity, and connectivity among "Greater Wildland Ecosystems." Risk of habitat loss was derived from analysis of biophysical and sociodemographic predictors of NVC loss. Ecological value and risk of loss were combined into the BCPI. We then analyzed spatial patterns of BCPI to identify the NVC highest in biodiversity conservation priority and examined the relationship between BCPI and conservation easement status. We found that BCPI varied spatially across the study area and was highest in western and southern portions of the study area. High BCPI was associated with suburban and rural development, roads, urban proximity, valley bottom landforms, and low intensity of current development. Existing conservation easements were distributed more towards lower BCPI values than unprotected NVC at both the study area and region scales. The BCPI can be used to better inform land use decision making at local, regional, and potentially national scales in order to better achieve biodiversity goals.

Telomerase in Cancer: Function, Regulation, and Clinical Translation.

During the process of malignant transformation, cells undergo a series of genetic, epigenetic, and phenotypic alterations, including the acquisition and propagation of genomic aberrations that impart survival and proliferative advantages. These changes are mediated in part by the induction of replicative immortality that is accompanied by active telomere elongation. Indeed, telomeres undergo dynamic changes to their lengths and higher-order structures throughout tumor formation and progression, processes overseen in most cancers by telomerase. Telomerase is a multimeric enzyme whose function is exquisitely regulated through diverse transcriptional, post-transcriptional, and post-translational mechanisms to facilitate telomere extension. In turn, telomerase function depends not only on its core components, but also on a suite of binding partners, transcription factors, and intra- and extracellular signaling effectors. Additionally, telomerase exhibits telomere-independent regulation of cancer cell growth by participating directly in cellular metabolism, signal transduction, and the regulation of gene expression in ways that are critical for tumorigenesis. In this review, we summarize the complex mechanisms underlying telomere maintenance, with a particular focus on both the telomeric and extratelomeric functions of telomerase. We also explore the clinical utility of telomeres and telomerase in the diagnosis, prognosis, and development of targeted therapies for primary, metastatic, and recurrent cancers.

The role of RNA processing and regulation in metastatic dormancy.

Tumor dormancy is a major contributor to the lethality of metastatic disease, especially for cancer patients who develop metastases years-to-decades after initial diagnosis. Indeed, tumor cells can disseminate during early disease stages and persist in new microenvironments at distal sites for months, years, or even decades before initiating metastatic outgrowth. This delay between primary tumor remission and metastatic relapse is known as "dormancy," during which disseminated tumor cells (DTCs) acquire quiescent states in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) signals. Maintaining dormancy-associated phenotypes requires DTCs to activate transcriptional, translational, and post-translational mechanisms that engender cellular plasticity. RNA processing is emerging as an essential facet of cellular plasticity, particularly with respect to the initiation, maintenance, and reversal of dormancy-associated phenotypes. Moreover, dysregulated RNA processing, particularly that associated with alternative RNA splicing and expression of noncoding RNAs (ncRNAs), can occur in DTCs to mediate intrinsic and extrinsic metastatic dormancy. Here we review the pathophysiological impact of alternative RNA splicing and ncRNAs in promoting metastatic dormancy and disease recurrence in human cancers.

Early Outcomes of Scapholunate Injuries With Concomitant Distal Radius Fractures.

Background: There is limited literature regarding the treatment of concomitant scapholunate ligament (SL) injuries in acute distal radius fractures (DRFs). We hypothesized that surgical treatment of SL injuries in adult patients with DRFs leads to improved functional outcomes. Methods: A retrospective review was made of 42 adult patients who underwent surgical treatment of a DRF with a SL injury between 2005 and 2013. In all, 39 of the 42 patients sustained an intra-articular DRF (AO B or C). SL injury was diagnosed by SL diastasis > 3 mm on posteroanterior (PA) radiographs, magnetic resonance imaging, or with wrist arthroscopy. Patients were divided into 3 groups: 23 had a SL repair and were treated within 21 days of injury (acute), 8 underwent SL repair greater than 21 days from injury (subacute/chronic), and 11 did not undergo repair (non-operative). Median overall time to clinical follow-up was 5.1 years. Mayo Wrist Scores (MWS) and Disabilities of the Arm, Shoulder and Hand (DASH) scores were used to evaluate functional outcome. Results: Clinical outcomes measured by the MWS at final follow-up (6 months-12 years) showed no significant differences between the 3 groups. Of patients treated acutely, 17.3% had good to excellent MWS. MWS at 1-year follow-up was 68.4, 70, and 64 in the acute, subacute/chronic, and non-operative groups, respectively. DASH scores were 16.7, 14.3, and 11.8 in the acute, subacute/chronic, and nonoperative groups, respectively, at a mean of 7.8 years. Conclusions: At mid-term follow-up, all 3 treatment groups had similar DASH scores to the general population. There were no statistical functional differences between any of the groups based upon MWS or DASH scores.

SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling.

The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

Multispectral high resolution sensor fusion for smoothing and gap-filling in the cloud.

Remote sensing optical sensors onboard operational satellites cannot have high spectral, spatial and temporal resolutions simultaneously. In addition, clouds and aerosols can adversely affect the signal contaminating the land surface observations. We present a HIghly Scalable Temporal Adaptive Reflectance Fusion Model (HISTARFM) algorithm to combine multispectral images of different sensors to reduce noise and produce monthly gap free high resolution (30 m) observations over land. Our approach uses images from the Landsat (30 m spatial resolution and 16 day revisit cycle) and the MODIS missions, both from Terra and Aqua platforms (500 m spatial resolution and daily revisit cycle). We implement a bias-aware Kalman filter method in the Google Earth Engine (GEE) platform to obtain fused images at the Landsat spatial-resolution. The added bias correction in the Kalman filter estimates accounts for the fact that both model and observation errors are temporally auto-correlated and may have a non-zero mean. This approach also enables reliable estimation of the uncertainty associated with the final reflectance estimates, allowing for error propagation analyses in higher level remote sensing products. Quantitative and qualitative evaluations of the generated products through comparison with other state-of-the-art methods confirm the validity of the approach, and open the door to operational applications at enhanced spatio-temporal resolutions at broad continental scales.

Epigenetic plasticity in metastatic dormancy: mechanisms and therapeutic implications.

The overwhelming majority of cancer-associated morbidity and mortality can be ascribed to metastasis. Metastatic disease frequently presents in a delayed fashion following initial diagnosis and treatment, requiring that disseminated cancer cells (DCCs) spread early in tumor progression and persist in a dormant state at metastatic sites. To accomplish this feat, DCCs exhibit substantial phenotypic plasticity that is mediated by the epigenetic regulation of dormancy programs in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) cues. The epigenome is a dynamic landscape that encompasses transcriptional regulation via alteration of chromatin architecture, posttranscriptional RNA processing, and the diverse functions carried out by noncoding RNAs. Signals converging on DCCs are transduced through epigenetic effectors. Conversely, epigenetic regulation of gene expression controls the crosstalk between DCCs and cells of the metastatic niche, a phenomenon that is essential for the institution of dormant phenotypes. Importantly, epigenetic effectors can be targeted therapeutically, and the development of novel epigenetic therapies may provide new inroads to combating recurrent metastatic disease. Here we provide an overview of the dynamics of metastatic dormancy and summarize our current understanding of the intersections between dormancy and the epigenome, both mechanistically and therapeutically.

SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness.

Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.

Stem cells, immortality, and the evolution of metastatic properties in breast cancer: telomere maintenance mechanisms and metastatic evolution.

Breast cancer is the most significant cause of cancer-related death in women around the world. The vast majority of breast cancer-associated mortality stems from metastasis, which remains an incurable disease state. Metastasis results from evolution of clones that possess the insidious properties required for dissemination and colonization of distant organs. These clonal populations are descended from breast cancer stem cells (CSCs), which are also responsible for their prolonged maintenance and continued evolution. Telomeres impose a lifespan on cells that can be extended when they are actively elongated, as occurs in CSCs. Thus, changes in telomere structure serve to promote the survival of CSCs and subsequent metastatic evolution. The selection of telomere maintenance mechanism (TMM) has important consequences not only for CSC survival and evolution, but also for their coordination of various signaling pathways that choreograph the metastatic cascade. Targeting the telomere maintenance machinery may therefore provide a boon to the treatment of metastatic breast cancer. Here we review the two major TMMs and the roles they play in the development of stem and metastatic breast cancer cells. We also highlight current and future approaches to targeting these mechanisms in clinical settings to alleviate metastatic breast cancers.

A non-natural nucleotide uses a specific pocket to selectively inhibit telomerase activity.

Telomerase, a unique reverse transcriptase that specifically extends the ends of linear chromosomes, is up-regulated in the vast majority of cancer cells. Here, we show that an indole nucleotide analog, 5-methylcarboxyl-indolyl-2'-deoxyriboside 5'-triphosphate (5-MeCITP), functions as an inhibitor of telomerase activity. The crystal structure of 5-MeCITP bound to the Tribolium castaneum telomerase reverse transcriptase reveals an atypical interaction, in which the nucleobase is flipped in the active site. In this orientation, the methoxy group of 5-MeCITP extends out of the canonical active site to interact with a telomerase-specific hydrophobic pocket formed by motifs 1 and 2 in the fingers domain and T-motif in the RNA-binding domain of the telomerase reverse transcriptase. In vitro data show that 5-MeCITP inhibits telomerase with a similar potency as the clinically administered nucleoside analog reverse transcriptase inhibitor azidothymidine (AZT). In addition, cell-based studies show that treatment with the cell-permeable nucleoside counterpart of 5-MeCITP leads to telomere shortening in telomerase-positive cancer cells, while resulting in significantly lower cytotoxic effects in telomerase-negative cell lines when compared with AZT treatment.

Determination of Fucose Concentration in a Lectin-Based Displacement Microfluidic Assay.

We compare three different methods to quantify the monosaccharide fucose in solutions using the displacement of a large glycoprotein, lactoferrin. Two microfluidic analysis methods, namely fluorescence detection of (labeled) lactoferrin as it is displaced by unlabeled fucose and the displacement of (unlabeled) lactoferrin in SPR, provide fast responses and continuous data during the experiment, theoretically providing significant information regarding the interaction kinetics between the saccharide groups and binding sites. For comparison, we also performed a static displacement ELISA. The stationary binding site in all cases was immobilized S2-AAL, a monovalent polypeptide based on Aleuria aurantia lectin. Although all three assays showed a similar dynamic range, the microfluidic assays with fluorescent or SPR detection show an advantage in short analysis times. Furthermore, the microfluidic displacement assays provide a possibility to develop a one-step analytical platform.

Patterns of rangeland productivity and land ownership: Implications for conservation and management.

Rangelands cover 40-50% of the Earth's terrestrial surface. While often characterized by limited, yet variable resource availability, rangelands are vital for humans, providing numerous ecosystem goods and services. In the conterminous United States (CONUS), the dominant component of rangeland conservation is a network of public rangelands, concentrated in the west. Public rangelands are interspersed with private and tribal rangelands resulting in a complex mosaic of land tenure and management priorities. We quantify ownership patterns of rangeland production at multiple scales across CONUS and find that both total production and average productivity of private rangelands is more than twice that of public and tribal rangelands. At finer scales, private rangelands are consistently more productive than their public counterparts. We also demonstrate an inverse relationship between public rangeland acreage and productivity. While conserving acreage is crucial to rangeland conservation, just as critical are broad-scale ecological patterns and processes that sustain ecosystem services. Across CONUS, ownership regimes capture distinct elements of these patterns and services, demonstrated through disparate production dynamics. As ownership determines the range of feasible conservation actions, and the technical and financial resources available to implement them, understanding ownership-production dynamics is critical for effective and sustained conservation of rangeland ecosystem services.

Patterning Highly Conducting Conjugated Polymer Electrodes for Soft and Flexible Microelectrochemical Devices.

There is a need for soft actuators in various biomedical applications to manipulate delicate objects such as cells and tissues. Soft actuators are able to adapt to any shape and limit the stress applied to delicate objects. Conjugated polymer (CP) actuators, especially in the so-called trilayer configuration, are interesting candidates for driving such micromanipulators. However, challenges involved in patterning the electrodes in a trilayer with individual contact have prevented further development of soft micromanipulators based on CP actuators. To allow such patterning, two printing-based patterning techniques have been developed. First, an oxidant layer is printed using either syringe-based printing or microcontact printing, followed by vapor-phase polymerization of the CP. Submillimeter patterns with electronic conductivities of 800 S·cm-1 are obtained. Next, laser ablation is used to cleanly cut the final device structures including the printed patterns, resulting in fingers with individually controllable digits and miniaturized hands. The methods presented in this paper will enable integration of patterned electrically active CP layers in many types of complex three-dimensional structures.

Estimating large carnivore populations at global scale based on spatial predictions of density and distribution - Application to the jaguar (Panthera onca).

Broad scale population estimates of declining species are desired for conservation efforts. However, for many secretive species including large carnivores, such estimates are often difficult. Based on published density estimates obtained through camera trapping, presence/absence data, and globally available predictive variables derived from satellite imagery, we modelled density and occurrence of a large carnivore, the jaguar, across the species' entire range. We then combined these models in a hierarchical framework to estimate the total population. Our models indicate that potential jaguar density is best predicted by measures of primary productivity, with the highest densities in the most productive tropical habitats and a clear declining gradient with distance from the equator. Jaguar distribution, in contrast, is determined by the combined effects of human impacts and environmental factors: probability of jaguar occurrence increased with forest cover, mean temperature, and annual precipitation and declined with increases in human foot print index and human density. Probability of occurrence was also significantly higher for protected areas than outside of them. We estimated the world's jaguar population at 173,000 (95% CI: 138,000-208,000) individuals, mostly concentrated in the Amazon Basin; elsewhere, populations tend to be small and fragmented. The high number of jaguars results from the large total area still occupied (almost 9 million km2) and low human densities (< 1 person/km2) coinciding with high primary productivity in the core area of jaguar range. Our results show the importance of protected areas for jaguar persistence. We conclude that combining modelling of density and distribution can reveal ecological patterns and processes at global scales, can provide robust estimates for use in species assessments, and can guide broad-scale conservation actions.

Exercise performance and physiological responses: the potential role of redox imbalance.

Increases in oxidative stress or decreases in antioxidant capacity, or redox imbalance, are known to alter physiological function and has been suggested to influence performance. To date, no study has sought to manipulate this balance in the same participants and observe the impact on physiological function and performance. Using a single-blind, placebo-controlled, and counterbalanced design, this study examined the effects of increasing free radicals, via hyperoxic exposure (FiO2 = 1.0), and/or increasing antioxidant capacity, through consuming an antioxidant cocktail (AOC; vitamin-C, vitamin-E, α-lipoic acid), on 5-kilometer (km) cycling time-trial performance, and the physiological and fatigue responses in healthy college-aged males. Hyperoxic exposure prior to the 5 km TT had no effect on performance, fatigue, or the physiological responses to exercise. The AOC significantly reduced average power output (222 ± 11 vs. 214 ± 12 W), increased 5 km time (516 ± 17 vs. 533 ± 18 sec), suppressed ventilation (VE; 116 ± 5 vs. 109 ± 13 L/min), despite similar oxygen consumption (VO2; 43.1 ± 0.8 vs. 44.9 ± 0.2 mL/kg per min), decreased VE/VO2 (35.9 ± 2.0 vs. 32.3 ± 1.5 L/min), reduced economy (VO2/W; 0.20 ± 0.01 vs. 0.22 ± 0.01), increased blood lactate (10 ± 0.7 vs. 11 ± 0.7 mmol), and perception of fatigue (RPE; 7.39 ± 0.4 vs. 7.60 ± 0.3) at the end of the TT, as compared to placebo (main effect, placebo vs. AOC, respectively). Our data demonstrate that prior to exercise, ingesting an AOC, but not exposure to hyperoxia, likely disrupts the delicate balance between pro- and antioxidant forces, which negatively impacts ventilation, blood lactate, economy, perception of fatigue, and performance (power output and 5 km time) in young healthy males. Thus, caution is warranted in athletes taking excess exogenous antioxidants.

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.

2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors. This "BRCAness" phenotype of IDH mutant cells can be completely reversed by treatment with small-molecule inhibitors of the mutant IDH1 enzyme, and conversely, it can be entirely recapitulated by treatment with either of the 2HG enantiomers in cells with intact IDH1/2 proteins. We demonstrate mutant IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.