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Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical imaging technique for measuring relative changes in skeletal muscle microvascular perfusion (i.e., fold change above baseline) during reactive hyperemia testing and exercise and is reported as a blood flow index (BFI). Although it is generally accepted that changes in BFI are primarily driven by changes in muscle perfusion, it is well known that large, hyperthermia-induced changes in cutaneous blood flow can uncouple this relationship. What remains unknown, is how much of an impact that changes in cutaneous perfusion have on NIR-DCS BFI and estimates of skeletal muscle perfusion under thermoneutral conditions, where changes in cutaneous blood flow are assumed to be relatively low. We therefore used epinephrine iontophoresis to pharmacologically block changes in cutaneous perfusion throughout a battery of experimental procedures. The data show that 1) epinephrine iontophoresis attenuates changes in cutaneous perfusion for up to 4-h posttreatment, even in the face of significant neural and local stimuli, 2) under thermoneutral conditions, cutaneous perfusion does not significantly impact NIR-DCS BFI during reactive hyperemia testing or moderate-intensity exercise, and 3) during passive whole body heat stress, when cutaneous vasodilation is pronounced, epinephrine iontophoresis preserves NIR-DCS measures of skeletal muscle BFI during moderate-intensity exercise. Collectively, these data suggest that cutaneous perfusion is unlikely to have a major impact on NIR-DCS estimates of skeletal muscle BFI under thermoneutral conditions, but that epinephrine iontophoresis can be used to abolish cutaneous contamination of the NIR-DCS BFI signal during studies where skin blood flow may be elevated but skeletal muscle perfusion is of specific interest.

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood–brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.

KEY POINTS We used 31-phosphorus magnetic resonance spectroscopy to quantify in vivo skeletal muscle metabolic economy (ME; mass-normalized torque or power produced per ATP consumed) during three 24 s maximal-effort contraction protocols: (1) sustained isometric (MVIC), (2) intermittent isokinetic (MVDCIsoK ), and (3) intermittent isotonic (MVDCIsoT ) in the knee extensor muscles of young and older adults. ME was not different between groups during the MVIC but was lower in older than young adults during both dynamic contraction protocols. These results are consistent with an increased energy cost of locomotion, but not postural support, with age. The effects of old age on ME were not due to age-related changes in muscle oxidative capacity or ATP flux. Specific power was lower in older than young adults, despite similar total ATP synthesis between groups. Together, this suggests a dissociation between cross-bridge activity and ATP utilization with age. ABSTRACT Muscle metabolic economy (ME; mass-normalized torque or power produced per ATP consumed) is similar in young and older adults during some isometric contractions, but less is known about potential age-related differences in ME during dynamic contractions. We hypothesized that age-related differences in ME would exist only during dynamic contractions, due to the increased energetic demand of dynamic versus isometric contractions. Ten young (Y; 27.5 ± 3.9 years, 6 men) and 10 older (O; 71 ± 5 years, 5 men) healthy adults performed three 24 s bouts of maximal contractions: (1) sustained isometric (MVIC), (2) isokinetic (120°·s-1 , MVDCIsoK ; 0.5 Hz), and (3) isotonic (load = 20% MVIC, MVDCIsoT ; 0.5 Hz). Phosphorus magnetic resonance spectroscopy of the vastus lateralis muscle was used to calculate ATP flux (mM ATP·s-1 ) through the creatine kinase reaction, glycolysis and oxidative phosphorylation. Quadriceps contractile volume (cm3 ) was measured by MRI. ME was calculated using the torque-time integral (MVIC) or power-time integral (MVDCIsoK and MVDCIsoT ), total ATP synthesis and contractile volume. As hypothesized, ME was not different between Y and O during the MVIC (0.12 ± 0.03 vs. 0.12 ± 0.02 Nm. s. cm-3. mM ATP-1 , mean ± SD, respectively; P = 0.847). However, during both MVDCIsoK and MVDCIsoT , ME was lower in O than Y adults (MVDCIsoK : 0.011 ± 0.003 vs. 0.007 ± 0.002 J. cm-3. mM ATP-1 ; P < 0.001; MVDCIsoT : 0.011 ± 0.002 vs. 0.008 ± 0.002; P = 0.037, respectively), despite similar muscle oxidative capacity, oxidative and total ATP flux in both groups. The lower specific power in older than young adults, despite similar total ATP synthesis between groups, suggests there is a dissociation between cross-bridge activity and ATP utilization with age.

Microglia, the resident immune cells of the CNS, have emerged as key regulators of neural precursor cell activity in the adult brain. However, the microglia-derived factors that mediate these effects remain largely unknown. In the present study, we investigated a role for microglial brain-derived neurotrophic factor (BDNF), a neurotrophic factor with well known effects on neuronal survival and plasticity. Surprisingly, we found that selective genetic ablation of BDNF from microglia increased the production of newborn neurons under both physiological and inflammatory conditions (e.g., LPS-induced infection and traumatic brain injury). Genetic ablation of BDNF from microglia otherwise also interfered with self-renewal/proliferation, reducing their overall density. In conclusion, we identify microglial BDNF as an important factor regulating microglia population dynamics and states, which in turn influences neurogenesis under both homeostatic and pathologic conditions.SIGNIFICANCE STATEMENT(1) Microglial BDNF contributes to self-renewal and density of microglia in the brain. (2) Selective ablation of BDNF in microglia stimulates neural precursor proliferation. (3) Loss of microglial BDNF augments working memory following traumatic brain injury. (4) Benefits of repopulating microglia on brain injury are not mediated via microglial BDNF.

Identifying dynamic changes in biomarkers and clinical profiles is essential for understanding the progression of Alzheimer’s disease (AD). The relevant studies have primarily relied on patients with autosomal dominant AD; however, relevant studies in sporadic AD are poorly understood. Here, we analyzed longitudinal data from 665 participants (mean follow-up 4.90 ± 2.83 years). By aligning normal cognition (CN) baseline with a clinical diagnosis of mild cognitive impairment (MCI) or AD, we studied the progression of AD using a linear mixed model to estimate the clinical and biomarker changes from stable CN to MCI to AD. The results showed that the trajectory of hippocampal volume and fluorodeoxyglucose (FDG) was consistent with the clinical measures in that they did not follow a hypothetical sigmoid curve but rather showed a slow change in the initial stage and accelerated changes in the later stage from MCI conversion to AD. Dramatic hippocampal atrophy and the ADAS13 increase were, respectively, 2.5 and 1 years earlier than the MCI onset. Besides, cognitively normal people with elevated and normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG. These results reveal that pre-MCI to pre-AD may be a better time window for future clinical trial design.

Hippocampal atrophy and cognitive decline are common sequelae of many neurodegenerative disorders, including stroke. To determine whether cognitive decline can be ameliorated by exercise-induced neurogenesis, C57BL/6 mice in which a unilateral hippocampal injury had been induced by injecting the vasoconstrictor endothelin-1 into their right hippocampus, were run voluntarily for 21 days on a running-wheel. We found the severe deficits in spatial learning, as detected by active place-avoidance task, following injury were almost completely restored in animals that ran whereas those that did not run showed no improvement. We show the increase in neurogenesis found in both the injured and contralateral hippocampi following running was responsible for the restoration of learning since bilateral ablation of newborn doublecortin (DCX)-positive neurons abrogated the cognitive improvement, whereas unilateral ablations of DCX-positive neurons did not prevent recovery, demonstrating that elevated neurogenesis in either the damaged or intact hippocampus is sufficient to reverse hippocampal injury-induced deficits.

Key points During maximal exercise, skeletal muscle metabolism and oxygen consumption remain elevated despite precipitous declines in power. Presently, it is unclear whether these responses are caused by an increased ATP cost of force generation (ATPCOST ) or mitochondrial uncoupling; a process that reduces the efficiency of oxidative ATP synthesis (ATPOX ). To address this gap, we used 31-phosphorus magnetic resonance spectroscopy to measure changes in ATPCOST and ATPOX in human quadriceps during repeated trials of maximal intensity knee extensions lasting up to 4 min. ATPCOST remained unchanged. In contrast, ATPOX plateaued by ∼2 min and then declined (∼15%) over the final 2 min. The maximal capacity for ATPOX (Vmax ), as well as ADP-specific rates of ATPOX , were also significantly diminished. Collectively, these results suggest that mitochondrial uncoupling, and not increased ATPCOST , is responsible for altering the regulation of skeletal muscle metabolism and oxygen consumption during maximal exercise. Abstract The relationship between skeletal muscle oxygen consumption and power output is augmented during exercise at workloads above the lactate threshold. Potential mechanisms for this response have been hypothesized, including increased ATP cost of force generation (ATPCOST ) and mitochondrial uncoupling, a process that reduces the efficiency of oxidative ATP synthesis (ATPOX ). To test these hypotheses, we used phosphorus magnetic resonance spectroscopy to non-invasively measure changes in phosphate concentrations and pH in the vastus lateralis muscle of nine young adults during repeated trials of maximal, all-out dynamic knee extensions (120°s-1 , 1 every 2 s) lasting 24, 60, 120, and 240 s. ATPOX was measured at each time point from the initial velocity of PCr resynthesis, and ATPCOST was calculated as the sum of ATP synthesized by the creatine and adenylate kinase reactions, non-oxidative glycolysis, ATPOX and net changes in [ATP]. Power output declined in a reproducible manner for all four trials. ATPCOST did not change over time (main effect P = 0.45). ATPOX plateaued from 60 to 120 s and then decreased over the final 120 s (main effect P = 0.001). The maximal capacity for oxidative ATP synthesis (Vmax ), as well as ADP-specific rates of ATPOX , also decreased over time (main effect P = 0.001, both). Collectively, these results demonstrate that prolonged maximal contraction protocols impair oxidative energetics and implicate mitochondrial uncoupling as the mechanism for this response. The causes of mitochondrial uncoupling are presently unknown but may offer a potential explanation for the dissociation between skeletal muscle power output and oxygen consumption during maximal, all-out exercise protocols.

Geotechnical borehole information is often used for liquefaction hazard mapping, but can be highly variable in terms of quantity and quality. In addition, geotechnical borehole logs are often provided as images in reports rather than delivered in a structured, queryable database, which makes the logs and supplementary information difficult to organize particularly across a large geographic area. In contrast, surficial geologic mapping is generally available and often accessible in geographic information systems (GIS) format. This article’s objective is to describe the compilation of a geotechnical database for regional mapping purposes and to demonstrate the value of documenting geotechnical data into a consistent data format. Specifically, this article describes the development of three geotechnical borehole databases compiled in Utah, which has been coined the Geotechnical Database for Utah (GeoDU). The database is used to quantify geotechnical properties for subsequent liquefaction evaluations of surficial geologic units comprising similar depositional environment and age. The resulting GeoDU is an important resource for future efforts with many applications including community data sharing and planning for preliminary geotechnical site investigations.

Summary We have shown that the improvement in hippocampal-based learning in aged mice following physical exercise observed is dependent on neurogenesis in the dentate gyrus (DG) and is regulated by changes in growth hormone levels. The changes in neurocircuitry, however, which may underlie this improvement, remain unclear. Using in vivo multimodal magnetic resonance imaging to track changes in aged mice exposed to exercise, we show the improved spatial learning is due to enhanced DG connectivity, particularly the strengthening of the DG-Cornu Ammonis 3 and the DG-medial entorhinal cortex connections in the dorsal hippocampus. Moreover, we provide evidence that these changes in circuitry are dependent on neurogenesis since they were abrogated by ablation of newborn neurons following exercise. These findings identify the specific changes in hippocampal circuitry that underlie the cognitive improvements resulting from physical activity and show that they are dependent on the activation of neurogenesis in aged animals., Graphical abstract, Highlights • Exercise can enhance connectivity in the dorsal hippocampus to improve spatial learning • Circuitry changes depend on increased neurogenesis in the hippocampus of aged animals • Identification of the specific changes in circuitry underlying cognitive improvements • Enhanced connectivity occurs only after exercise of a specific duration: the sweet spot, Cognitive neuroscience, Behavioral neuroscience, Biological sciences

Motor neuron disease (MND) comprises a group of fatal neurodegenerative diseases with no effective cure. As progressive motor neuron cell death is one of pathological characteristics of MND, molecules which protect these cells are attractive therapeutic targets. Accumulating evidence indicates that EphA4 activation is involved in MND pathogenesis, and inhibition of EphA4 improves functional outcomes. However, the underlying mechanism of EphA4’s function in MND is unclear. In this review, we first present results to demonstrate that EphA4 signalling acts directly on motor neurons to cause cell death. We then review the three most likely mechanisms underlying this effect.

Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical technique for estimating relative changes in skeletal muscle perfusion during exercise but may be affected by changes in cutaneous blood flow, as photons emitted by the laser must first pass through the skin. Accordingly, the purpose of this investigation was to examine how increased cutaneous blood flow affects NIR-DCS blood flow index (BFI) at rest and during exercise using a passive whole body heating protocol that increases cutaneous, but not skeletal muscle, perfusion in the uncovered limb. BFI and cutaneous perfusion (laser-Doppler flowmetry) were assessed in 15 healthy young subjects before (e.g., rest) and during 5 min of moderate-intensity handgrip exercise in normothermic conditions and after cutaneous blood flow was elevated via whole body heating. Hyperthermia significantly increased both cutaneous perfusion (∼7.3-fold; P ≤ 0.001) and NIR-DCS BFI (∼4.5-fold; P ≤ 0.001). Although relative BFI (i.e., fold-change above baseline) exhibited a typical exponential increase in muscle perfusion during normothermic exercise (2.81 ± 0.95), there was almost no change in BFI during hyperthermic exercise (1.43 ± 0.44). A subset of eight subjects were subsequently treated with intradermal injection of botulinum toxin-A (Botox) to block heating-induced elevations in cutaneous blood flow, which 1) nearly abolished the hyperthermia-induced increase in BFI and 2) restored BFI kinetics during hyperthermic exercise to values that were not different from normothermic exercise (P = 0.091). Collectively, our results demonstrate that cutaneous blood flow can have a substantial, detrimental impact on NIR-DCS estimates of skeletal muscle perfusion and highlight the need for technical and/or pharmacological advancements to overcome this issue moving forward. NEW & NOTEWORTHY We used passive whole body heat stress, in combination with local intradermal botulinum toxin type A treatment, to experimentally manipulate cutaneous blood flow and investigate its impact on NIR-DCS measures of skeletal muscle BFI at rest and during exercise. Collectively, the results show that cutaneous blood flow, which was augmented in response to passive whole body heat stress, markedly affects NIR-DCS-derived BFI, such that the BFI signal becomes dominated by changes in cutaneous red blood cell flux.

Brain-derived neurotrophic factor (BDNF) signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75NTR ) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75NTR receptors are expressed by hippocampal NPCs in the adult mouse brain. Using a clonal neurosphere assay, we demonstrate that pharmacological blockade of TrkB receptors directly activates a distinct subpopulation of NPCs. Moreover, we show that administration of ANA-12, a TrkB-selective antagonist, in vivo either by systemic intraperitoneal injection or by direct infusion within the hippocampus leads to an increase in the production of new neurons. In contrast, we found that NPC-specific knockout of p75NTR had no effect on the proliferation of NPCs and did not alter neurogenesis in the adult hippocampus. Collectively, these results demonstrate a novel role of TrkB receptors in directly regulating the activity of a subset of hippocampal NPCs and suggest that the transient blockade of these receptors could be used to enhance adult hippocampal neurogenesis.

Near-infrared diffuse correlation spectroscopy (DCS) is increasingly used to study relative changes in skeletal muscle blood flow. However, most diffuse correlation spectrometers assume that tissue optical properties—such as absorption (μ(a)) and reduced scattering (μ′(s)) coefficients—remain constant during physiological provocations, which is untrue for skeletal muscle. Here, we interrogate how changes in tissue μ(a) and μ′(s) affect DCS calculations of blood flow index (BFI). We recalculated BFI using raw autocorrelation curves and μ(a)/μ′(s) values recorded during a reactive hyperemia protocol in 16 healthy young individuals. First, we show that incorrectly assuming baseline μ(a) and μ′(s) substantially affects peak BFI and BFI slope when expressed in absolute terms (cm(2)/s, P < 0.01), but these differences are abolished when expressed in relative terms (% baseline). Next, to evaluate the impact of physiologic changes in μ(a) and μ′(s), we compared peak BFI and BFI slope when μ(a) and μ′(s) were held constant throughout the reactive hyperemia protocol versus integrated from a 3-s rolling average. Regardless of approach, group means for peak BFI and BFI slope did not differ. Group means for peak BFI and BFI slope were also similar following ad absurdum analyses, where we simulated supraphysiologic changes in μ(a)/μ′(s). In both cases, however, we identified individual cases where peak BFI and BFI slope were indeed affected, with this result being driven by relative changes in μ(a) over μ′(s). Overall, these results provide support for past reports in which μ(a)/μ′(s) were held constant but also advocate for real-time incorporation of μ(a) and μ′(s) moving forward. NEW & NOTEWORTHY We investigated how changes in tissue optical properties affect near-infrared diffuse correlation spectroscopy (NIR-DCS)-derived indices of skeletal muscle blood flow (BFI) during physiological provocation. Although accounting for changes in tissue optical properties has little impact on BFI on a group level, individual BFI calculations are indeed impacted by changes in tissue optical properties. NIR-DCS calculations of BFI should therefore account for real-time, physiologically induced changes in tissue optical properties whenever possible.

We present a study of the normalized transverse momentum distribution of W bosons produced in p (p) over bar collisions, using data corresponding to an integrated luminosity of 4.35 fb(-1) collecte ...

We describe an analysis comparing the pp[over ¯] elastic cross section as measured by the D0 Collaboration at a center-of-mass energy of 1.96 TeV to that in pp collisions as measured by the TOTEM Collaboration at 2.76, 7, 8, and 13 TeV using a model-independent approach. The TOTEM cross sections, extrapolated to a center-of-mass energy of sqrt[s]=1.96 TeV, are compared with the D0 measurement in the region of the diffractive minimum and the second maximum of the pp cross section. The two data sets disagree at the 3.4σ level and thus provide evidence for the t-channel exchange of a colorless, C-odd gluonic compound, also known as the odderon. We combine these results with a TOTEM analysis of the same C-odd exchange based on the total cross section and the ratio of the real to imaginary parts of the forward elastic strong interaction scattering amplitude in pp scattering for which the significance is between 3.4σ and 4.6σ. The combined significance is larger than 5σ and is interpreted as the first observation of the exchange of a colorless, C-odd gluonic compound.

KEY POINTS The oxygen cost of high-intensity exercise at power outputs above an individual's lactate threshold (LT) is greater than would be predicted by the linear oxygen consumption-power relationship observed below the LT. However, whether these augmentations are caused by an increased ATP cost of force generation (ATPCOST ) or an increased oxygen cost of ATP synthesis is unclear. We used 31 P-MRS to measure changes in cytosolic [ADP] (intramyocellular marker of oxidative metabolism), oxidative ATP synthesis (ATPOX ) and ATPCOST during a 6-stage, stepwise knee extension protocol. ATPCOST was unchanged across stages. The relationship between [ADP] and muscle power output was augmented at workloads above the pH threshold (pHT ; proxy for LT), whereas increases in ATPOX were attenuated. These results suggest the greater oxygen cost of contractions at workloads beyond the pHT is not caused by mechanisms that increase ATPCOST , but rather mechanisms that alter intrinsic mitochondrial function or capacity. ABSTRACT Increases in skeletal muscle metabolism and oxygen consumption are linearly related to muscle power output for workloads below the lactate threshold (LT), but are augmented (i.e. greater rate of increase relative to workload) thereafter. Presently, it is unclear whether these metabolic augmentations are caused by increases in the ATP cost of force generation (ATPCOST ) or changes in the efficiency of mitochondrial oxygen consumption and oxidative ATP synthesis (ATPOX ). To partition these two hypotheses in vivo, we used 31 P-MRS to calculate slopes relating step-changes in muscle work to concurrent changes in cytosolic phosphates and ATPOX before and after the pH threshold (pHT ; used here as a proxy for LT) within the vastus lateralis muscle of eight young adults during a stepwise knee extension test. Changes in muscle phosphates and ATPOX were linearly related to workload below the pHT . However, slopes above the pHT were greater for muscle phosphates (P

Postischemia reperfusion kinetics are markedly dissociated when comparing the macro- versus microvasculature. We used Doppler ultrasound and near-infrared diffuse correlation spectroscopy (NIR-DCS), an emerging technique for continuously and noninvasively quantifying relative changes in skeletal muscle microvascular perfusion (i.e., blood flow index or BFI), to measure macro- and microvascular reactive hyperemia (RH) in the nondominant arm of 16 healthy young adults. First, we manipulated the duration of limb ischemia (3 vs. 6 min) with the limb at heart level (neutral, -N). Then, we reduced/increased forearm perfusion pressure (PP) by positioning the arm above (3 min-A, 60°) or below (3 min-B, 30°) the heart. The major novel findings were twofold: first, changes in the ischemic stimulus similarly affected peak macrovascular (i.e., conduit, mL/min) and microvascular (i.e., peak NIR-DCS-derived BFI) reperfusion during reactive hyperemia (6 min-N > 3 min-N, P < 0.05, both) but did not affect the rate at which microvascular reperfusion occurs (i.e., BFI slope). Second, changing forearm PP predictably affected both peak macro- and microvascular reperfusion during RH (3 min-B > N > A, P < 0.05, all), as well as the rate at which microvascular reperfusion occurred (BFI slope; 3 min-B >N > A, P < 0.05). Together, the data suggest that kinetic differences between macro- and microvascular reperfusion are largely determined by differences in fluid mechanical energy (i.e., pressure, gravitational, and kinetic energies) between the two compartments that work in tandem to restore pressure across the arterial tree following a period of tissue ischemia. NEW & NOTEWORTHY We extend our understanding of macro- versus microvascular hemodynamics in humans, by using near-infrared diffuse correlation spectroscopy (micro-) and Doppler ultrasound (macro-) to characterize reperfusion hemodynamics following experimental manipulation of the ischemic stimulus and tissue perfusion pressure. Our results suggest kinetic differences between macro- and microvascular reperfusion are largely determined by differences in fluid mechanical energy (i.e., pressure, gravitational, and kinetic energies) between the two compartments, rather than inherent differences between the macro- and microvasculature.

Background: Benign Childhood Epilepsy with Centro-temporal Spikes (BECTS) is the most common form of idiopathic epilepsy in children, accounting for up to 23% of pediatric epilepsy. The pathogenesis of BECTS is unknown, but it is thought that genetic factors play a role in susceptibility to the disease. Methods: To investigate the role of common genetic variants in BECTS pathogenesis, a 2-stage genome-wide association study (GWAS) was performed in 1,800 Chinese Han BECTS patients, and 7,090 healthy controls. Genetic findings were used in a Mendelian Randomization study in the UK Biobank dataset to investigate the potential role of smoking in BECTS. Findings: Definitive evidence of a role for common-variant heritability was demonstrated, with heritability of BECTS of >10% observed even with conservative disease prevalence assumptions. Although no individual locus achieved genome-wide significance, twelve loci achieved suggestive evidence of association (5 × 10-8

PurposeAlthough high-velocity contractions elicit greater muscle fatigue in older than young adults, the cause of this difference is unclear. We examined the potential roles of resting muscle architecture and baseline contractile properties, as well as changes in voluntary activation and low-frequency fatigue in response to high-velocity knee extensor work.MethodsVastus lateralis muscle architecture was determined in quiescent muscle by ultrasonography in 8 young (23.4±1.8 yrs) and 8 older women (69.6±1.1). Maximal voluntary dynamic (MVDC) and isometric (MVIC), and stimulated (80Hz and 10Hz, 500ms) isometric contractions were performed before and immediately after 120 MVDCs (240°·s−1, one every 2s).ResultsArchitecture variables did not differ between groups (p≥0.209), but the half-time of torque relaxation (T1/2) was longer in older than young women at baseline (151.9±6.0 vs. 118.8±4.4 ms, respectively, p=0.001). Older women fatigued more than young (to 33.6±4.7% vs. 55.2±4.2% initial torque, respectively; p=0.004), with no evidence of voluntary activation failure (ΔMVIC:80Hz torque) in either group (p≥0.317). Low-frequency fatigue (Δ10:80Hz torque) occurred in both groups (p1/2 (p=0.001), with no differences between groups. Baseline T1/2 was inversely associated with fatigue in older (r2=0.584, p=0.045), but not young women (r2=0.147, p=0.348).ConclusionsThese results indicate that differences in muscle architecture, voluntary activation, and low-frequency fatigue do not explain the greater fatigue of older compared with young women during high-velocity contractions. The inverse association between baseline T1/2 and fatigue in older women suggests that factors related to slower muscle contractile properties may be protective against fatigue during fast, repetitive contractions in aging.

A magnetic resonance (MR) compatible ergometer has been developed to study contracting lower limb muscles during acquisition of MR spectroscopy data, a technique to noninvasively measure metabolic energy in muscle tissue. Current active and passive MR-compatible ergometer designs lack torque or velocity control to allow precise mechanical measurements during isotonic and isokinetic contractions; incorporating load and velocity controllers while maintaining MR-compatibility is the main challenge. Presented in this paper is the design and evaluation of an MR-compatible ergometer designed to control knee torque or velocity up to 420 N·m and 270 deg/s and is able to operate in a 3 Tesla magnetic field. The ergometer comprising of a passive component with no electronics or ferrous materials is located inside the bore of the scanner. The active component with the electronics and actuator located outside of the magnetic field in an adjacent room. The active components connect to the passive components via a cable that passes through the waveguide, a hole in the wall of the scanner room. System evaluations were performed and human subject evaluations were performed that measured the mechanical performance and show the mean percent errors below 9% in isotonic and 2% in isokinetic conditions.

IMPORTANCEThe dynamic changes of biomarkers and clinical profiles in sporadic Alzheimer’s disease (SAD) are poorly understood.OBJECTIVETo evaluate the impact of amyloid-β (Aβ) biomarkers on SAD by measuring the dynamic changes in biomarkers and clinical profiles in the progression of SAD.DESIGN AND SETTINGThis retrospective and longitudinal study analyzed clinical and biomarker data from 665 participants (mean follow-up 4.90 ± 2.83 years) from a subset of the AD Neuroimaging Initiative (ADNI) participants collected from August 2005 to December 2018. By aligning the timing of the changes in the various biomarkers with the stable normal cognition (CN) baseline and mild cognitive impairment (MCI) or AD onset timepoints, we combined data from the stable CN, CN conversion to MCI (CN2MCI), and MCI conversion to AD (MCI2AD) groups to identify the trajectories associated with the progression of AD.PARTICIPANTSThe participants were 294 CN, 69 CN2MCI, 300 MCI2AD, and 24 who converted from CN to MCI to AD (CN2MCI2AD) (of whom 22 were also included in the CN2MCI).EXPOSURESAmyloid-β measured by florbetapir positron emission tomography (PET) or cerebrospinal fluid assay of amyloid-β (CSF Aβ42).MAIN OUTCOMES AND MEASURESThe measures included the 13-item cognitive subscale of the AD Assessment Scale (ADAS13, as a clinical measure), hippocampal volume, and the fluorodeoxyglucose (FDG) PET standardized uptake value ratio (SUVR).RESULTSThe CN, CN2MCI, and MCI2AD subgroups’ median (interquartile range [IQR]) annual changes in ADAS13 were (0.388 [−0.278, 0.818], 1.000 [0.239, 2.330], and 3.388 [1.750, 6.169]). The annual changes in hippocampal volume for each group were (−0.005 %ICV [−0.011, −0.001], −0.006 %ICV [−0.012, −0.002], and −0.014 %ICV [−0.021, −0.009]). The annual changes in FDG PET SUVR for each group were (−0.011 [−0.030, 0.010], −0.027 [−0.056, −0.012], and −0.039 [−0.063, 0.014]). Changes in the amyloid biomarkers were inconsistent with clinical profile changes. The annual changes in CSF Aβ42 for each group were (−1.500 pg/ml [−6.000, 4.000], −2.200 [−5.667, 4.000], and −2.000 [−7.000, 2.650]) and in Aβ PET SUVR for each group were (0.004 [−0.002, 0.012], 0.004 [−0.001,0.011], and 0.005 [−0.006, 0.014]). During the stable CN and CN2MCI stages, subjects with elevated and those with normal amyloid showed no significant differences (likelihood ratio test, p < .01) in clinical measures, hippocampal volume, or FDG.CONCLUSIONS AND RELEVANCEHippocampal volume and FDG associated with clinical profiles impairment in the SAD progression. Aβ alone is not associated with clinical profiles, hippocampal volume, and FDG impairment in the preclinical stage of SAD.Key PointsQuestion: What is the role of amyloid-β in dynamic changes in biomarkers and clinical profiles in the progression of sporadic Alzheimer’s disease?Findings: The changes of the hippocampal volume and FDG that were consistent with the changes of the clinical profiles showed a non-linear change in the initial stage and an accelerated non-linear change during MCI2AD, changes in amyloid biomarkers were inconsistent with the clinical profile. Cognitively normal people with elevated or normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG.Meaning: Amyloid-β alone may not be used as the central index for defining the preclinical stage of SAD.

Several methods have been developed for using 31 P-MRS to calculate rates of oxidative ATP synthesis (ATPOX ) during muscular contractions based on assumptions that (1) the ATP cost of force generation (ATPCOST ) remains constant or (2) Michaelis-Menten coupling between cytosolic ADP and ATPOX does not change. However, growing evidence suggests that one, or both, of these assumptions are invalid during high-intensity fatigue protocols. Consequently, there is a need to examine the validity and accuracy of traditional ATPOX calculation methods under these conditions. To address this gap, we measured phosphate concentrations and pH in the vastus lateralis muscle of nine young adults during four rest-contraction-recovery trials lasting 24, 60, 120, and 240 s. The initial velocity of phosphocreatine resynthesis (ViPCr ) following each trial served as the criterion measure of ATPOX because this method makes no assumptions of constant ATPCOST or Michaelis-Menten coupling between changes in cytosolic ADP and ATPOX . Subsequently, we calculated ATPOX throughout the 240 s trial using several traditional calculation methods and compared estimations of ATPOX from each method with time-matched measurements of ViPCr . Method 1, which assumes that ATPCOST does not change, was able to model changes in ViPCr over time, but showed poor accuracy for predicting ViPCr across a wide range of ATPOX values. In contrast, Michaelis-Menten methods, which assume that the relationship between changes in cytosolic ADP and ATPOX remains constant, were invalid because they could not model the decline in ViPCr . However, adjusting these Michaelis-Menten methods for observed changes in maximal ATPOX capacity (i.e., Vmax ) permitted modeling of the decline in ViPCr and markedly improved accuracy. The results of these comprehensive analyses demonstrate that valid, accurate measurements of ATPOX can be obtained during high-intensity contractions by adjusting Michaelis-Menten ATPOX calculations for changes in Vmax observed from baseline to post-fatigue.

Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory.

The hippocampal dentate gyrus (DG) is a major region of the adult rodent brain in which neurogenesis occurs throughout life. The EphA4 receptor, which regulates neurogenesis and boundary formation in the developing brain, is also expressed in the adult DG, but whether it regulates adult hippocampal neurogenesis is not known. Here, we show that, in the adult mouse brain, EphA4 inhibits hippocampal precursor cell proliferation but does not affect precursor differentiation or survival. Genetic deletion or pharmacological inhibition of EphA4 significantly increased hippocampal precursor proliferation in vivo and in vitro, by blocking EphA4 forward signaling. EphA4 was expressed by mature hippocampal DG neurons but not neural precursor cells, and an EphA4 antagonist, EphA4-Fc, did not activate clonal cultures of precursors until they were co-cultured with non-precursor cells, indicating an indirect effect of EphA4 on the regulation of precursor activity. Supplementation with d-serine blocked the increased precursor proliferation induced by EphA4 inhibition, whereas blocking the interaction between d-serine and N-methyl-d-aspartate receptors (NMDARs) promoted precursor activity, even at the clonal level. Collectively, these findings demonstrate that EphA4 indirectly regulates adult hippocampal precursor proliferation and thus plays a role in neurogenesis via d-serine-regulated NMDAR signaling.

Lightweight material for civil engineering application is primarily used for accelerated roadway and bridge approach construction, settlement mitigation, utility and tunnel abandonment, reduction of static and seismic earth pressures against retained or buried structures (e.g., pipelines, culverts, and tunnels), protection of underground utilities, slope stabilization, and landscaping. Such construction for transportation projects is routine with standardized design and construction methods available in Japan, Norway, the E.U., and the U.S.