APOBEC shapes tumor evolution and age at onset of lung cancer in smokers.

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues1,2. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6. However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence7, apoptosis8, and cell regeneration9, as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals.

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma.

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa.

In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10-11 and 3.74×10-2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.

Genomic and evolutionary classification of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.

Exertional hypoxia in a healthy adult: a pulmonary arteriovenous malformation.

Pulmonary arteriovenous malformations (PAVMs) are a rare cause of pulmonary symptoms, including dyspnoea on exertion, hypoxemia and haemoptysis. PAVMs are an aetiology that is often overlooked by physicians when developing a differential diagnosis for pulmonary symptoms and unidentified lung masses. However, it is an important differential diagnosis to have as PAVMs can have serious sequelae including strokes, brain abscess and life-threatening bleeding. We present a case of an impressive PAVM presenting with chest pain, chronic cough, feelings of anxiety, mild resting hypoxemia and exertional hypoxemia. Of note, on previous chest X-ray, 8 years prior to presentation, an incidental mass was found during a shoulder repair presurgical workup but not further evaluated.

Telemedicine-Based Health Coaching Is Effective for Inducing Weight Loss and Improving Metabolic Markers.

BACKGROUND: To assess the efficacy of health coaching (HC) delivered through videoconferencing (VC) to favorably change physical activity (PA), weight, and metabolic markers in adults with high body mass index (BMI). MATERIALS AND METHODS: Thirty adults (BMI ≥30 kg/m2) were randomly assigned to one of three groups: VC, in-person (IP), or control group (CG). Participants received wireless watches and weight scales to sync with their personal smartphones; recorded data were wirelessly uploaded to a secure database. Participants assigned to VC and IP received individualized HC by a multidisciplinary team (registered dietitian, exercise physiologist, and medical doctor) based on data uploaded over the 12-week intervention. Steps/day and weight loss were analyzed through analyses of covariance. RESULTS: Within- and between-group changes in weight (kg), glucose, insulin, hemoglobin A1c (HbA1c), and Homeostasis Model Assessment estimate of insulin resistance (HOMA-IR) were analyzed through analyses of variance. Weight loss was greater (p < 0.05) for VC (8.23 ± 4.5 kg; 7.7%) than IP (3.2 ± 2.6 kg; 3.4%) and CG (2.9 ± 3.9 kg; 3.3%), respectively. Steps/day were significantly higher in VC than IP at week 4 and VC was significantly higher than the CG at weeks 6, 8, 9, and 11 (p ≤ 0.05). No within- or between-group differences were found for glucose, insulin, or HbA1C. HOMA-IR decreased for VC only (p ≤ 0.05). CONCLUSIONS: Our innovative, multidisciplinary, telemedicine HC delivered through VC led to more favorable changes in weight loss, PA (steps/day), and HOMA-IR than IP or no HC. VC may be an economical approach to improve health and promote behavior change in obese adults. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03278951.

Autophagy and aging: Maintaining the proteome through exercise and caloric restriction.

Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity.

Effect of Branched-Chain Amino Acid Supplementation on Recovery Following Acute Eccentric Exercise.

This study investigated the effect of branched-chain amino acid (BCAA) supplementation on recovery from eccentric exercise. Twenty males ingested either a BCAA supplement or placebo (PLCB) prior to and following eccentric exercise. Creatine kinase (CK), vertical jump (VJ), maximal voluntary isometric contraction (MVIC), jump squat (JS) and perceived soreness were assessed. No significant (p > 0.05) group by time interaction effects were observed for CK, soreness, MVIC, VJ, or JS. CK concentrations were elevated above baseline (p < 0.001) in both groups at 4, 24, 48 and 72 hr, while CK was lower (p = 0.02) in the BCAA group at 48 hr compared to PLCB. Soreness increased significantly from baseline (p < 0.01) in both groups at all time-points; however, BCAA supplemented individuals reported less soreness (p < 0.01) at the 48 and 72 hr time-points. MVIC force output returned to baseline levels (p > 0.05) at 24, 48 and 72 hr for BCAA individuals. No significant difference between groups (p > 0.05) was detected for VJ or JS. BCAA supplementation may mitigate muscle soreness following muscle-damaging exercise. However, when consumed with a diet consisting of ~1.2 g/kg/day protein, the attenuation of muscular performance decrements or corresponding plasma CK levels are likely negligible.

Hemodynamic and metabolic responses to self-paced and ramp-graded exercise testing protocols.

Recent examinations have shown lower maximal oxygen consumption during traditional ramp (RAMP) compared with self-paced (SPV) graded exercise testing (GXT) attributed to differences in cardiac output. The current study examined the differences in hemodynamic and metabolic responses between RAMP and SPV during treadmill exercise. Sixteen recreationally trained men (aged23.7 ± 3.0 years) completed 2 separate treadmill GXT protocols. SPV consisted of five 2-min stages (10 min total) of increasing speed clamped by the Borg RPE6-20 scale. RAMP increased speed by 0.16 km/h every 15 s until volitional exhaustion. All testing was performed at 3% incline. Oxygen consumption was measured via indirect calorimetry; hemodynamic function was measured via thoracic impedance and blood lactate (BLa-) was measured via portable lactate analyzer. Differences between SPV and RAMP protocols were analyzed as group means by using paired-samples t tests (R Core Team 2017). Maximal values for SPV and RAMP were similar (p > 0.05) for oxygen uptake (47.1 ± 3.4 vs. 47.4 ± 3.4 mL·kg-1·min-1), heart rate (198 ± 5 vs. 200 ± 6 beats·min-1), ventilation (158.8 ± 20.7 vs. 159.3 ± 19.0 L·min-1), cardiac output (26.9 ± 5.5 vs. 27.9 ± 4.2 L·min-1), stroke volume (SV) (145.9 ± 29.2 vs. 149.8 ± 25.3 mL·beat-1), arteriovenous oxygen difference (18.5 ± 3.1 vs. 19.7 ± 3.1 mL·dL-1), ventilatory threshold (VT) (78.2 ± 7.2 vs. 79.0% ± 7.6%), and peak BLa- (11.7 ± 2.3 vs. 11.5 ± 2.4 mmol·L-1), respectively. In conclusion, SPV elicits similar maximal hemodynamic responses in comparison to RAMP; however, SV kinetics exhibited unique characteristics based on protocol. These results support SPV as a feasible GXT protocol to identify useful fitness parameters (maximal oxygen uptake, oxygen uptake kinetics, and VT).

Chemometric Methods for Estimating the Strain Hardening Modulus in Polyethylene Resins.

The feasibility of using multiway or N-way partial least square (NPLS) methods to estimate physical properties of 1-butene and 1-hexene polyethylene (PE) copolymers directly from multidimensional data obtained from size exclusion chromatography coupled to a Fourier transform infrared detector (SEC FT-IR) was explored. Digital sample sets of horizontal slices (slabs) of two-dimensional data simulating the molecular weight distribution and the corresponding orthogonal FT-IR spectra were correlated to a particular Y-block response using NPLS. The NPLS results were compared to those obtained through separate estimations using various algorithms and exploratory response surface methods. The estimated strain hardening modulus () for bimodal PE-like digital structures could adequately be modeled using both the linear response surface method (RSM) and NPLS. Although different input values were used, the predicted values for by NPLS was found to mirror both the analytical results and the expected structural effects obtained using linear RSM models.

The Effects of Eccentric Contraction Duration on Muscle Strength, Power Production, Vertical Jump, and Soreness.

Mike, JN, Cole, N, Herrera, C, VanDusseldorp, T, Kravitz, L, and Kerksick, CM. The effects of eccentric contraction duration on muscle strength, power production, vertical jump, and soreness. J Strength Cond Res 31(3): 773-786, 2017-Previous research has investigated the effects of either eccentric-only training or comparing eccentric and concentric exercise on changes related to strength and power expression, but no research to date has investigated the impact of altering the duration of either the concentric or the eccentric component on these parameters. Therefore, the purpose of this study was to assess the duration of eccentric (i.e., 2-second, 4-second vs. 6-second) muscle contractions and their effect on muscle strength, power production, vertical jump, and soreness using a plate-loaded barbell Smith squat exercise. Thirty college-aged men (23 ± 3.5 years, 178 ± 6.8 cm, 82 ± 12 kg, and 11.6 ± 5.1% fat) with 3.0 ± 1.0 years of resistance training experience and training frequency of 4.3 ± 0.9 days per week were randomized and assigned to 1 of 3 eccentric training groups that incorporated different patterns of contraction. For every repetition, all 3 groups used 2-second concentric contractions and paused for 1 second between the concentric and eccentric phases. The control group (2S) used 2-second eccentric contractions, whereas the 4S group performed 4-second eccentric contractions and the 6S group performed 6-second eccentric contractions. All repetitions were completed using the barbell Smith squat exercise. All participants completed a 4-week training protocol that required them to complete 2 workouts per week using their prescribed contraction routine for 4 sets of 6 repetitions at an intensity of 80-85% one repetition maximum (1RM). For all performance data, significant group × time (G × T) interaction effects were found for average power production across all 3 sets of a squat jump protocol (p = 0.04) while vertical jump did not reach significance but there was a trend toward a difference (G × T, p = 0.07). No other significant (p > 0.05) G × T interaction effects were found for the performance variables. All groups showed significant main effects for time in 1RM (p < 0.001), vertical jump (p = 0.004), peak power (p < 0.001), and average power (p < 0.001). Peak velocity data indicated that the 6S group experienced a significant reduction in peak velocity during the squat jump protocol as a result of the 4-week training program (p = 0.03). Soreness data revealed significant increases across time in all groups at both week 0 and week 4. Paired sample t-tests revealed greater differences in soreness values across time in the 2S group. The results provide further evidence that resistance training with eccentrically dominated movement patterns can be an effective method to acutely increase maximal strength and power expression in trained college age men. Furthermore, longer eccentric contractions may negatively impact explosive movements such as the vertical jump, whereas shorter eccentric contractions may instigate greater amounts of soreness. These are important considerations for the strength and conditioning professional to more fully understand that expressions of strength and power through eccentric training and varying durations of eccentric activity can have a significant impact for populations ranging from athletes desiring peak performance.

Effect of Acute Dietary Nitrate Consumption on Oxygen Consumption During Submaximal Exercise in Hypobaric Hypoxia.

Reduced partial pressure of oxygen impairs exercise performance at altitude. Acute nitrate supplementation, at sea level, may reduce oxygen cost during submaximal exercise in hypobaric hypoxia. Therefore, we investigated the metabolic response during exercise at altitude following acute nitrate consumption. Ten well-trained (61.0 ± 7.4 ml/kg/min) males (age 28 ± 7 yr) completed 3 experimental trials (T1, T2, T3). T1 included baseline demographics, a maximal aerobic capacity test (VO2max) and five submaximal intensity cycling determination bouts at an elevation of 1600 m. A 4-day dietary washout, minimizing consumption of nitrate-rich foods, preceded T2 and T3. In a randomized, double-blind, placebo-controlled, crossover fashion, subjects consumed either a nitrate-depleted beetroot juice (PL) or ~12.8 mmol nitrate rich (NR) beverage 2.5 hr before T2 and T3. Exercise at 3500 m (T2 and T3) via hypobaric hypoxia consisted of a 5-min warm-up (25% of normobaric VO2max) and four 5-min cycling bouts (40, 50, 60, 70% of normobaric VO2max) each separated by a 4-min rest period. Cycling RPM and watts for each submaximal bout during T2 and T3 were determined during T1. Preexercise plasma nitrite was elevated following NR consumption compared with PL (1.4 ± 1.2 and 0.7 ± 0.3 uM respectively; p < .05). There was no difference in oxygen consumption (-0.5 ± 1.8, 0.1 ± 1.7, 0.7 ± 2.1, and 1.0 ± 3.0 ml/kg/min) at any intensity (40, 50, 60, 70% of VO2max, respectively) between NR and PL. Further, respiratory exchange ratio, oxygen saturation, heart rate and rating of perceived exertion were not different at any submaximal intensity between NR and PL either. Blood lactate, however, was reduced following NR consumption compared with PL at 40 and 60% of VO2max (p < .0.05). Our findings suggest that acute nitrate supplementation before exercise at 3500 m does not reduce oxygen cost but may reduce blood lactate accumulation at lower intensity workloads.

Nitrate-Containing Beetroot Juice Reduces Oxygen Consumption During Submaximal Exercise in Low but Not High Aerobically Fit Male Runners.

Purpose: to examine the effect of a 4-day NO3- loading protocol on the submaximal oxygen cost of both low fit and high fit participants at five different exercise intensities. Methods: participants were initially assigned to a placebo (PL; negligible NO3-) or inorganic nitrate-rich (NR; 6.2 mmol nitrate/day) group; double-blind, placebo-controlled, crossover. Participants completed three trials (T1, T2 and T3). T1 included a maximal aerobic capacity (VO2max) treadmill test. A 6-day washout, minimizing nitrate consumption, preceded T2. Each of the four days prior to T2 and T3, participants consumed either PL or NR; final dose 2.5 hours prior to exercise. A 14-day washout followed T2. T2 and T3 consisted of 5-minute submaximal treadmill bouts (45, 60, 70, 80 and 85% VO2max) determined during T1. Results: Low fit nitrate-supplemented participants consumed less oxygen (p<0.05) at lower workloads (45% and 60% VO2max) compared to placebo trials; changes not observed in high fit participants. The two lowest intensity workloads of 45 and 60% VO2max revealed the greatest correlation (r=0.54, p=0.09 and r=0.79, p<0.05; respectively). No differences were found between conditions for heart rate, respiratory exchange ratio or rating of perceived exertion for either fitness group. Conclusion: Nitrate consumption promotes reduced oxygen consumption at lower exercise intensities in low fit, but not high fit males. Lesser fit individuals may receive greater benefit than higher fit participants exercising at intensities <60% VO2max.

Impact of creatine on muscle performance and phosphagen stores after immobilization.

PURPOSE: This study investigated the effect of creatine (CR) supplementation during cast-immobilization to preserve skeletal muscle total work, power and intramuscular phosphocreatine (PCr) kinetics during dynamic exercise. METHODS: Twenty-five active individuals (24 ± 4 years,) performed wrist flexion exercise within a 1.9 Tesla superconducting magnet before and after 1 week of cast-immobilization. An incremental protocol to fatigue and two constant load (CL1 and CL2) exercise bouts were performed. While casted, participants consumed either 20 g day(-1) of CR or a placebo (PLA). (31)P magnetic resonance spectroscopy was used to quantify in vivo intramuscular PCr levels. RESULTS: No significant group × time interaction effects were found for work or power throughout all exercise bouts. Total work was significantly reduced over time in both groups (p = 0.049) during the incremental exercise bout. Work production in CL1 tended (p = 0.073) to attenuate in the CR group, compared to PLA. No changes were observed in CL2. Baseline PCr significantly decreased with casting in PLA (PRE: 26.6 ± 6.3 vs. POST: 22.5 ± 5.6 mM kg(-1) wet muscle, p = 0.003). No change (p = 0.31) was observed in the CR group. Changes in work production were significantly correlated with changes in resting PCr in CR (r = -0.63, p = 0.021) but not PLA (r = -0.36, p = 0.26) group. CONCLUSIONS: Results suggest decreases in short-term endurance may be due to alternations of PCr status and/or metabolism. More research is needed to fully determine the efficacy of CR supplementation during short-term immobilization.

Dietary selenium protects against selected signs of aging and methylmercury exposure.

Acute or short-term exposure to high doses of methylmercury (MeHg) causes a well-characterized syndrome that includes sensory and motor deficits. The environmental threat from MeHg, however, comes from chronic, low-level exposure, the consequences of which are poorly understood. Selenium (Se), an essential nutrient, both increases deposition of mercury (Hg) in neurons and mitigates some of MeHg's neurotoxicity in the short term, but it is unclear whether this deposition produces long-term adverse consequences. To investigate these issues, adult Long-Evans rats were fed a diet containing 0.06 or 0.6 ppm of Se as sodium selenite. After 100 days on these diets, the subjects began consuming 0.0, 0.5, 5.0, or 15 ppm of Hg as methylmercuric chloride in their drinking water for 16 months. Somatosensory sensitivity, grip strength, hindlimb cross (clasping reflex), flexion, and voluntary wheel-running in overnight sessions were among the measures examined. MeHg caused a dose- and time-dependent impairment in all measures. No effects appeared in rats consuming 0 or 0.5 ppm of Hg. Somatosensory function, grip strength, and flexion were among the earliest signs of exposure. Selenium significantly delayed or blunted MeHg's effects. Selenium also increased running in unexposed animals as they aged, a novel finding that may have important clinical implications. Nerve pathology studies revealed axonal atrophy or mild degeneration in peripheral nerve fibers, which is consistent with abnormal sensorimotor function in chronic MeHg neurotoxicity. Lidocaine challenge reproduced the somatosensory deficits but not hindlimb cross or flexion. Together, these results quantify the neurotoxicity of long-term MeHg exposure, support the safety and efficacy of Se in ameliorating MeHg's neurotoxicity, and demonstrate the potential benefits of Se during aging.