Background/Objectives: Adenosine monophosphate deaminase deficiency has been implicated in impaired exercise capacity. We examined whether the AMPD1 C34T (rs17602729) genotype was associated with athlete status and performance in distance runners (DRs) and rugby union (RU) athletes. Methods: Participants included 621 elite male RU athletes, 666 elite/sub-elite male and female DRs, and 1029 male and female non-athletes (NA), all of European ancestry. Genotyping was performed using real-time PCR with TaqMan reagents. Genotype and allele frequencies were compared using χ2 tests, while performance data were analysed using Kruskal-Wallis H, Mann-Whitney U, one-way ANOVA, and t-tests, with Benjamini-Hochberg correction applied for multiple comparisons. Results: Genotype and allele frequencies did not differ between athletes and NA or between athlete groups. In all DRs, run times did not differ between genotypes, although participants with the CT genotype in the elite and elite male subgroups were up to 5% faster than CC and TT homozygotes. In RU, participants with the CC genotype played 13% longer per appearance than those with the CT genotype, while forwards and front five participants with the CC genotype played 13% and 26% longer per appearance than T-allele carriers, respectively. Front five T-allele carriers made 75% more clean breaks than the front five with the CC genotype despite playing for a shorter time, although this finding should be interpreted cautiously. Conclusions: In summary, while the AMPD1 C34T genotype was not associated with athlete status, the CC genotype was associated with greater RU playing time per appearance in forwards, and the CT genotype was associated with superior performance in elite DRs.

OBJECTIVES:To investigate associations between genetic variants within COLGALT1, COL1A1, COL3A1, COL5A1, KDR, MIR608, MMP3, NID1, TIMP2 and VEGFA and injury history in elite male rugby athletes. DESIGN:A case-control genetic association study was conducted on 184 elite male rugby athletes. METHODS:Participants were genotyped for 13 genetic polymorphisms previously associated with soft tissue injury using standard PCR assays. Injury data were collected via a self-reported injury-history questionnaire. Single-locus association and Total Genotype Score (TGS) analyses were conducted using χ2 tests. In addition, multifactor dimensionality reduction and inferred haplotype analysis were used to identify genetic interactions. RESULTS:The TT genotype of MMP3 rs679620 was underrepresented in the non-injured ligament group compared to the ligament sprain and ligament rupture groups (10 %, 32 %, 25 %; P < 0.04, respectively). The T allele of MMP3 rs679620 was overrepresented in the non-injured tendon group compared to the tendinopathy group (50 %, 38 %; P < 0.02). The proportion of C allele carriers of COL5A1 rs12722 was higher in the tendon rupture group than the non-injured tendon group (96 %, 75 %; P < 0.02). Furthermore, the T-C inferred haplotype frequency of COL5A1 rs12722 and COL5A1 rs3196378 was higher in the tendon rupture, ligament sprain and total injured athlete groups compared to their respective non-injured groups (P < 0.02). CONCLUSIONS:This study is the first to identify associations between MMP3 rs679620 and COL5A1 rs12722 and soft-tissue injury history in elite male rugby athletes. These findings support the growing evidence that soft-tissue injury could be influenced by an athlete's genetic predisposition.

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer’s disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aβ pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2–/– mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aβ, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aβ pathology in patients with diabetes or prediabetes.

Objective: Concussions are common match injuries in elite rugby, and reports exist of reduced cognitive function and long-term health consequences that can interrupt or end a playing career and produce continued ill health. The aim of this study was to investigate the association between elite rugby status and 8 concussion-associated risk polymorphisms. We hypothesized that concussion-associated risk genotypes and alleles would be underrepresented in elite rugby athletes compared with nonathletes. Design: A case–control genetic association study. Setting: Institutional (university). Participants: Elite White male rugby athletes [n = 668, mean (SD) height 1.85 (0.07) m, mass 102 (12) kg, and age 29 (7) years] and 1015 nonathlete White men and women (48% men). Interventions: Genotype was the independent variable, obtained by PCR of genomic DNA using TaqMan probes. Main Outcome Measure: Elite athlete status with groups compared using χ 2 and odds ratio (OR). Results: The COMT rs4680 Met/Met (AA) genotype, Met allele possession, and Met allele frequency were lower in rugby athletes (24.8%, 74.6%, and 49.7%, respectively) than nonathletes (30.2%, 77.6%, and 54.0%; P < 0.05). The Val/Val (GG) genotype was more common in elite rugby athletes than nonathletes (OR 1.39, 95% confidence interval 1.04-1.86). No other polymorphism was associated with elite athlete status. Conclusions: Elite rugby athlete status is associated with COMT rs4680 genotype that, acting pleiotropically, could affect stress resilience and behavioral traits during competition, concussion risk, and/or recovery from concussion. Consequently, assessing COMT rs4680 genotype might aid future individualized management of concussion risk among athletes.

Dines, HR, Nixon, J, Lockey, SJ, Herbert, AJ, Kipps, C, Pedlar, CR, Day, SH, Heffernan, SM, Antrobus, MR, Brazier, J, Erskine, RM, Stebbings, GK, Hall, ECR, and Williams, AG. Collagen gene polymorphisms previously associated with resistance to soft-tissue injury are more common in competitive runners than nonathletes. J Strength Cond Res 37(4): 799-805, 2023-Single-nucleotide polymorphisms (SNPs) of collagen genes have been associated with soft-tissue injury and running performance. However, their combined contribution to running performance is unknown. We investigated the association of 2 collagen gene SNPs with athlete status and performance in 1,429 Caucasian subjects, including 597 competitive runners (354 men and 243 women) and 832 nonathletes (490 men and 342 women). Genotyping for COL1A1 rs1800012 (C > A) and COL5A1 rs12722 (C > T) SNPs was performed by a real-time polymerase chain reaction. The numbers of "injury-resistant" alleles from each SNP, based on previous literature (rs1800012 A allele and rs12722 C allele), were combined as an injury-resistance score (RScore, 0-4; higher scores indicate injury resistance). Genotype frequencies, individually and combined as an RScore, were compared between cohorts and investigated for associations with performance using official race times. Runners had 1.34 times greater odds of being rs12722 CC homozygotes than nonathletes (19.7% vs. 15.5%, p = 0.020) with no difference in the rs1800012 genotype distribution (p = 0.659). Fewer runners had an RScore 0 of (18.5% vs. 24.7%) and more had an RScore of 4 (0.6% vs. 0.3%) than nonathletes (p < 0.001). Competitive performance was not associated with the COL1A1 genotype (p = 0.933), COL5A1 genotype (p = 0.613), or RScore (p = 0.477). Although not associated directly with running performance among competitive runners, a higher combined frequency of injury-resistant COL1A1 rs1800012 A and COL5A1 rs12722 C alleles in competitive runners than nonathletes suggests these SNPs may be advantageous through a mechanism that supports, but does not directly enhance, running performance.

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.

Due to the high-velocity collision-based nature of elite rugby league and union, the risk of sustaining a concussion is high. Occurrence of and outcomes following a concussion are probably affected by the interaction of multiple genes in a polygenic manner. This study investigated whether suspected concussion-associated polygenic profiles of elite rugby athletes differed from non-athletes and between rugby union forwards and backs. We hypothesised that a total genotype score (TGS) using eight concussion-associated polymorphisms would be higher in elite rugby athletes than non-athletes, indicating selection for protection against incurring or suffering prolonged effects of, concussion in the relatively high-risk environment of competitive rugby. In addition, multifactor dimensionality reduction was used to identify genetic interactions. Contrary to our hypothesis, TGS did not differ between elite rugby athletes and non-athletes (p ≥ 0.065), nor between rugby union forwards and backs (p = 0.668). Accordingly, the TGS could not discriminate between elite rugby athletes and non-athletes (AUC ~0.5), suggesting that, for the eight polymorphisms investigated, elite rugby athletes do not have a more ‘preferable’ concussion-associated polygenic profile than non-athletes. However, the COMT (rs4680) and MAPT (rs10445337) GC allele combination was more common in rugby athletes (31.7%; p < 0.001) and rugby union athletes (31.8%; p < 0.001) than non-athletes (24.5%). Our results thus suggest a genetic interaction between COMT (rs4680) and MAPT (rs10445337) assists rugby athletes in achieving elite status. These findings need exploration vis-à-vis sport-related concussion injury data and could have implications for the management of inter-individual differences in concussion risk.

14 Alcohol use disorder is a risk factor for Alzheimer’s disease (AD), yet the mechanisms underlying 15 this relationship are poorly understood. Here, we employed the APP/PS1 mouse model of Aβ pathology 16 to examine the effects of a 10 week moderate ethanol drinking paradigm on AD-related phenotypes. 17 Ethanol drinking led to a circadian shift in feeding behavior and glucose intolerance in 18 APPswe/PSEN1dE9 (APP/PS1), but not wild-type or ethanol-naïve APP/PS1 mice. Ethanol exposure 19 also selectively disrupted nest building, a metric of self-care, and decreased brain mass in APP/PS1 20 mice. While there was a trend towards increased cortical Aβ deposition in APP/PS1 mice, ethanol 21 exposure shifted the distribution of plaque size and numbers, increasing the number of smaller plaques. 22 Lastly, we used in vivo microdialysis to determine if acute ethanol directly affected hippocampal 23 interstitial fluid (ISF) Aβ levels in unanesthetized APP/PS1 mice. Aβ levels were bidirectionally 24 modulated by acute ethanol decreasing as brain ethanol levels rose and increasing above baseline 25 during withdrawal. Collectively, these studies provide the first evidence that acute ethanol alters ISF 26 Aβ levels and suggest that even modest levels of chronic ethanol consumption interact with Aβ to 27 exacerbate AD-related pathology, behavioral dysfunction, and metabolic deficits. 28

There is growing evidence of genetic contributions to tendon and ligament pathologies. Given the high incidence and severity of tendon and ligament injuries in elite rugby, we studied whether 13 gene polymorphisms previously associated with tendon/ligament injury were associated with elite athlete status. Participants from the RugbyGene project were 663 elite Caucasian male rugby athletes (RA) (mean (standard deviation) height 1.85 (0.07) m, mass 101 (12) kg, age 29 (7) yr), including 558 rugby union athletes (RU) and 105 rugby league athletes. Non-athletes (NA) were 909 Caucasian men and women (56% female; height 1.70 (0.10) m, mass 72 (13) kg, age 41 (23) yr). Genotypes were determined using TaqMan probes and groups compared using Χ2 and odds ratio (OR). COLGALT1 rs8090 AA genotype was more frequent in RA (27%) than NA (23%; P = 0.006). COL3A1 rs1800255 A allele was more frequent in RA (26%) than NA (23%) due to a greater frequency of GA genotype (39% vs 33%). For MIR608 rs4919510, RA had 1.7 times the odds of carrying the CC genotype compared to NA. MMP3 rs591058 TT genotype was less common in RA (25.1%) than NA (31.2%; P < 0.04). For NID1 rs4660148, RA had 1.6 times the odds of carrying the TT genotype compared to NA. It appears that elite rugby athletes have an inherited advantage that contributes to their elite status, possibly via resistance to soft tissue injury. These data may, in future, assist personalised management of injury risk amongst athletes.Highlights The elite rugby athletes we studied had differing genetic characteristics to non-athletes regarding genetic variants previously associated with soft-tissue injury risk.COLGALT1 rs8090, COL3A1 rs1800255, MIR608 rs4919510, MMP3 rs591058 and NID1 rs4660148 were all associated with elite status in rugby.We propose that elite rugby athletes might possess an inherited resistance to soft tissue injury, which has enabled them to achieve elite status despite exposure to the high-risk environment of elite rugby.

Part 1 of this genetic association series highlighted several genetic variants independently associated with elite status in rugby. However, it is highly likely that the genetic influence on elite status is polygenic due to the interaction of multiple genes. Therefore, the aim of the present study was to investigate whether polygenic profiles of elite rugby athletes differed from non-athletes utilising 13 genetic polymorphisms previously associated with tendon/ligament injury. Total genotype score (TGS) was calculated and multifactor dimensionality reduction (MDR) was used to calculate SNP-SNP epistasis interactions. Based on our elite rugby data from Part 1, mean TGS was significantly higher in elite rugby athletes (52.1 ± 10.7) than non-athletes (48.7 ± 10.8). There were more elite rugby athletes (54%) within the upper TGS quartile, and fewer (46%) within the lower quartile, compared to non-athletes (31% and 69%, respectively; P = 5·10-5), and the TGS was able to distinguish between elite rugby athletes and non-athletes (area under the curve = 0.59; 95% confidence interval 0.55-0.63; P = 9·10-7). Furthermore, MDR identified a three-SNP model of COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 that was best able to predict elite athlete status, with a greater frequency of the CC-CC-CC genotype combination in elite rugby athletes (9.8%) than non-athletes (5.3%). We propose that elite rugby athletes possess "preferable" musculoskeletal soft-tissue injury-associated polygenic profiles that have helped them achieve success in the high injury risk environment of rugby. These data may, in future, have implications for the individual management of musculoskeletal soft-tissue injury.HighlightsElite rugby athletes have preferable polygenic profiles to non-athletes in terms of genetic variants previously associated with musculoskeletal soft-tissue injury.The total genotype score was able to distinguish between elite rugby athletes and non-athletes.COL5A1 rs12722, COL5A1 rs3196378 and MIR608 rs4919510 produced the best model for predicting elite athlete status.We propose that elite rugby athletes may have an inherited advantage to achieving elite status due to an increased resistance to soft-tissue injury.

ABSTRACT Hyperexcitability is a defining feature of Alzheimer’s disease (AD), where aberrant neuronal activity is both a cause and consequence of AD. Therefore, identifying novel targets that modulate cellular excitability is an important strategy for treating AD. ATP-sensitive potassium (K ATP ) channels are metabolic sensors that modulate cellular excitability. Sulfonylureas are K ATP channel antagonists traditionally used to combat hyperglycemia in diabetic patients by inhibiting pancreatic K ATP channels, thereby stimulating insulin release. However, K ATP channels are not limited to the pancreas and systemic modulation of K ATP channels has pleotropic physiological effects, including profound effects on vascular function. Here, we demonstrate that human AD patients have higher cortical expression of vascular K ATP channels, important modulators of vasoreactivity. We demonstrate that peripheral treatment with the sulfonylurea and K ATP channel inhibitor, glyburide, reduced the aggregation and activity-dependent production of amyloid-beta (Aβ), a hallmark of AD, in mice. Since glyburide does not readily cross the blood brain barrier, our data suggests that glyburide targets vascular K ATP channel activity to reduce arterial stiffness, improve vasoreactivity, and normalize pericyte-endothelial cell morphology, offering a novel therapeutic target for AD. Graphical abstract Targeting vascular K ATP channel activity for the treatment of Alzheimer’s disease pathology.

While non-suicidal self-injury (NSSI) occurs in the general population at a surprisingly high rate, with higher rates among certain clinical populations, its etiology is not well-understood. Consequently, the DSM-5 lists NSSI as requiring further research. This study utilizes a translational model of naturally-occurring NSSI to assess the role of early parental neglect and variation in the serotonin transporter genotype (5-HTT) in the etiology of NSSI. Subjects (N = 161) were rhesus macaques (Macaca mulatta) reared in one of three conditions (mother-reared (MR), peer-reared (PR), or surrogate peer-reared (SPR)), and classified as NSSI (n = 18) or non-NSSI (n = 143). Subjects were genotyped for 5-HTT and their behaviors were recorded during an ecologically-meaningful, stress-evoking, intruder paradigm. Two weeks prior to testing, blood samples were obtained and assayed for plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations. NSSI subjects were more likely to be SPR, paralleling human studies showing that individuals that exhibit NSSI tend to have experienced abuse or neglect early in life. Results also indicated that variation in the 5-HTT genotype differentiated the NSSI subjects. NSSI subjects that were homozygous for the L allele exhibited high plasma ACTH and high rates of stress-induced stereotypies; whereas NSSI subjects with the s allele exhibited impulsive behaviors, including frequently approaching the potentially dangerous intruder, high rates of aggressive vocal threats, and more activity. These results suggest that there may be different 5-HTT genotype-mediated NSSI typologies and that both early experiences and variation in the 5-HTT genotype may be important factors in understanding the etiology of NSSI.

PURPOSEGenetic polymorphisms have been associated with the adaptation to training in maximal oxygen uptake (V˙O2max). However, the genotype distribution of selected polymorphisms in athletic cohorts is unknown, with their influence on performance characteristics also undetermined. This study investigated whether the genotype distributions of 3 polymorphisms previously associated with V˙O2max training adaptation are associated with elite athlete status and performance characteristics in runners and rugby athletes, competitors for whom aerobic metabolism is important.METHODSGenomic DNA was collected from 732 men including 165 long-distance runners, 212 elite rugby union athletes, and 355 nonathletes. Genotype and allele frequencies of PRDM1 rs10499043 C/T, GRIN3A rs1535628 G/A, and KCNH8 rs4973706 T/C were compared between athletes and nonathletes. Personal-best marathon times in runners, as well as in-game performance variables and playing position, of rugby athletes were analyzed according to genotype.RESULTSRunners with PRDM1 T alleles recorded marathon times ∼3 minutes faster than CC homozygotes (02:27:55 [00:07:32] h vs 02:31:03 [00:08:24] h, P = .023). Rugby athletes had 1.57 times greater odds of possessing the KCNH8 TT genotype than nonathletes (65.5% vs 54.7%, χ2 = 6.494, P = .013). No other associations were identified.CONCLUSIONSThis study is the first to demonstrate that polymorphisms previously associated with V˙O2max training adaptations in nonathletes are also associated with marathon performance (PRDM1) and elite rugby union status (KCNH8). The genotypes and alleles previously associated with superior endurance-training adaptation appear to be advantageous in long-distance running and achieving elite status in rugby union.

BACKGROUND: The aim of the study was to establish the bone and body composition characteristics of high-level athletes with and without a history of stress fracture injury. METHODS: Overall, 279 high-level athletes (212 men, 67 women) (age 28.0 +/- 9.2 years; body mass 75.0 +/- 17.4 kg; height 1.78 +/- 0.10 m) and 112 non-athletic controls (60 women, 52 men) 36.2 +/- 15.0 years; 70.9 +/- 12.9 kg; 1.71 +/- 0.10 m) were assessed by DXA to establish their bone mineral density and content, body fat and lean mass. Athletes completed a questionnaire detailing their stress fracture history. RESULTS: There were no differences in whole-body bone mineral density (men 1.41 +/- 0.12 g/cm(2), women 1.19 +/- 0.09 g/cm(2)), bone mineral content (men 3709 +/- 626 g, women 2263 +/- 290 g), body fat (men 16.3 +/- 5.0%,women 23.0 +/- 4.6%) and lean mass (men 65.4 +/- 9.9 kg, women 38.7 +/- 3.6 kg) between athletes with a history of stress fracture (34 men, 16 women) and those without (176 men, 40 women). CONCLUSIONS: DXA derived bone and body composition characteristics were not independent risk factors for stress fracture injury in high-level athletes. This study in a large cohort of high-level athletes provides normative bone and body composition values that can be used as a benchmark for researchers and applied practitioners.

Elite rugby league and union have some of the highest reported rates of concussion (mild traumatic brain injury) in professional sport due in part to their full-contact high-velocity collision-based nature. Currently, concussions are the most commonly reported match injury during the tackle for both the ball carrier and the tackler (8–28 concussions per 1000 player match hours) and reports exist of reduced cognitive function and long-term health consequences that can end a playing career and produce continued ill health. Concussion is a complex phenotype, influenced by environmental factors and an individual’s genetic predisposition. This article reviews concussion incidence within elite rugby and addresses the biomechanics and pathophysiology of concussion and how genetic predisposition may influence incidence, severity and outcome. Associations have been reported between a variety of genetic variants and traumatic brain injury. However, little effort has been devoted to the study of genetic associations with concussion within elite rugby players. Due to a growing understanding of the molecular characteristics underpinning the pathophysiology of concussion, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose from this review that several genetic variants within or near candidate genes of interest, namely APOE, MAPT, IL6R, COMT, SLC6A4, 5-HTTLPR, DRD2, DRD4, ANKK1, BDNF and GRIN2A, warrant further study within elite rugby and other sports involving high-velocity collisions.

Brazier, J, Antrobus, M, Stebbings, GK, Day, SH, Callus, P, Erskine, RM, Bennett, MA, Kilduff, LP, and Williams, AG. Anthropometric and physiological characteristics of elite male rugby athletes. J Strength Cond Res 34(6): 1790-1801, 2020-This is the first article to review the anthropometric and physiological characteristics required for elite rugby performance within both rugby union (RU) and rugby league (RL). Anthropometric characteristics such as height and body mass, and physiological characteristics such as speed and muscular strength, have previously been advocated as key discriminators of playing level within rugby. This review aimed to identify the key anthropometric and physiological properties required for elite performance in rugby, distinguishing between RU and RL, forwards and backs and competitive levels. There are differences between competitive standards such that, at the elite level, athletes are heaviest (RU forwards similar to 111 kg, backs similar to 93 kg; RL forwards similar to 103 kg, backs similar to 90 kg) with lowest % body fat (RU forwards similar to 15%, backs similar to 12%; RL forwards similar to 14%, backs similar to 11%), they have most fat-free mass and are strongest (back squat: RU forwards similar to 176 kg, backs similar to 157 kg; RL forwards similar to 188 kg, backs similar to 168 kg; bench press: RU forwards similar to 131 kg, backs similar to 118 kg; RL forwards similar to 122 kg, backs similar to 113 kg) and fastest (10 m: RU forwards similar to 1.87 seconds, backs similar to 1.77 seconds; 10 m: RL forwards similar to 1.9 seconds, backs similar to 1.83 seconds). We also have unpublished data that indicate contemporary RU athletes have less body fat and are stronger and faster than the published data suggest. Regardless, well-developed speed, agility, lower-body power, and strength characteristics are vital for elite performance, probably reflect both environmental (training, diet, etc.) and genetic factors, distinguish between competitive levels, and are therefore important determinants of elite status in rugby.

Brain hyperexcitability is a defining feature of AD, where aberrant neuronal activity may be both a cause and consequence of the pathology. Identifying novel targets to modulate cellular excitability is an important treatment strategy. We showed that inward rectifying, ATP-sensitive potassium (K ATP ) channels regulate excitability at the neurovascular unit to impact production and aggregation of amyloid-beta (Aβ), a hallmark of AD. Sulfonylureas such as glyburide (GLY) are antidiabetic medications that inhibit K ATP channels. We demonstrated that systemic treatment with GLY decreased Aβ production and plaque pathology by modulating vascular K ATP channel activity and neuronal excitability. Here, we investigated whether GLY alters cardiac function or pulse wave velocity (PWV) in APPswe, PSEN1dE9 (APP/PS1) mice, a model of Aβ overexpression.Female APP/PS1 mice at 8 months of age with established amyloid plaque pathology were treated for 1 month with GLY (subcutaneous, slow release 2.5mg pellet, ~30μg/GLY/day) or Placebo (n = 5, each group). After 1 month, transthoracic echocardiography was performed (Vevo 2100 LAZR, FUJIFILM/VisualSonics, Inc.; Toronto, Ca) with a 30 MHz linear array transducer. There were no differences in Placebo vs. GLY mice for heart rate, cardiac output, E/e’ ratio, ejection fraction, and fractional shortening. Arterial stiffness, measured as PWV in the aortic arch [Distance (D)/Time (T); D = mm from ascending to descending aorta and T = (R to ascending aorta foot) - (R to descending aorta foot) in ms], was lower in GLY treated mice (5 ± 1 vs. Placebo 9 ± 1 mm/ms; p < 0.04). Wild Type females at 9 months of age (n = 5) reveal similar cardiac function values as Placebo and GLY treated APP/PS1 mice, with a trend for lower PWV (6 ± 1 mm/ms) than the APP/PSI Placebo group. Thus, short-term treatment with GLY does not impact overall cardiac function. Moreover, improved vascular stiffness in GLY-treated APP/PS1 mice may contribute to improved neurovascular coupling independent of changes in Aβ aggregation, since arterial stiffness is associated with increased cerebrovascular pathology in clinical studies. SLM: Bright Focus Fdn, NIA K01AG050719, Donors Cure New Vision; SMD: T32AA007565; Hypertension & Vasc Res Ctr; NCATS UL1TR001420 (Vevo Core)

Persistent psychological stress increases the risk of many chronic diseases of aging. Little progress has been made to effectively reduce stress responses or mitigate stress effects suggesting a need for better understanding of factors that influence stress responses. Limited evidence suggests that diet may be a factor in modifying the effects of stress. However, long-term studies of diet effects on stress reactive systems are not available, and controlled randomized clinical trials are difficult and costly. Here we report the outcomes of a controlled, randomized preclinical trial of the effects of long-term consumption (31 months, ~ equivalent to 9 human years) of Western versus Mediterranean - like diets on behavioral and physiological responses to acute (brief social separation) and chronic (social subordination) psychosocial stress in 38 adult, socially-housed, female cynomolgus macaques. Compared to animals fed a Western diet, those fed the Mediterranean diet exhibited enhanced stress resilience as indicated by lower sympathetic activity, brisker and more overt heart rate responses to acute stress, more rapid recovery, and lower cortisol responses to acute psychological stress and adrenocorticotropin (ACTH) challenge. Furthermore, age-related increases in sympathetic activity and cortisol responses to stress were delayed by the Mediterranean diet. Population level diet modification in humans has been shown to be feasible. Our findings suggest that population-wide adoption of a Mediterranean-like diet pattern may provide a cost-effective intervention on psychological stress and promote healthy aging with the potential for widespread efficacy.

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a 2-4 fold increased risk for developing Alzheimer’s disease (AD), however the exact mechanisms linking the two disease is unknown. In both conditions, the majority of pathophysiological changes (including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau) occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and AD-related pathology, including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, prediabetic (PreD), and T2D vervet monkeys ( Chlorocebus aethiops sabeus ). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to pre-diabetic and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with our previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.