We depend upon the olfactory abilities of dogs for critical tasks such as detecting bombs, landmines, other hazardous chemicals and illicit substances. Hence, a mechanistic understanding of the ...olfactory system in dogs is of great scientific interest. Previous studies explored this aspect at the cellular and behavior levels; however, the cognitive-level neural substrates linking them have never been explored. This is critical given the fact that behavior is driven by filtered sensory representations in higher order cognitive areas rather than the raw odor maps of the olfactory bulb. Since sedated dogs cannot sniff, we investigated this using functional magnetic resonance imaging of conscious dogs. We addressed the technical challenges of head motion using a two pronged strategy of behavioral training to keep dogs' head as still as possible and a single camera optical head motion tracking system to account for residual jerky movements. We built a custom computer-controlled odorant delivery system which was synchronized with image acquisition, allowing the investigation of brain regions activated by odors. The olfactory bulb and piriform lobes were commonly activated in both awake and anesthetized dogs, while the frontal cortex was activated mainly in conscious dogs. Comparison of responses to low and high odor intensity showed differences in either the strength or spatial extent of activation in the olfactory bulb, piriform lobes, cerebellum, and frontal cortex. Our results demonstrate the viability of the proposed method for functional imaging of the olfactory system in conscious dogs. This could potentially open up a new field of research in detector dog technology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are characterized by blood-brain barrier (BBB) breakdown leading to abnormal BBB permeability ahead of brain atrophy or dementia. ...Previous findings in AD mouse models have reported the beneficial effect of extra-virgin olive oil (EVOO) against AD, which improved BBB and memory functions and reduced brain amyloid-β (Aβ) and related pathology. This work aimed to translate these preclinical findings to humans in individuals with MCI. We examined the effect of daily consumption of refined olive oil (ROO) and EVOO for 6 months in MCI subjects on BBB permeability (assessed by contrast-enhanced MRI), and brain function (assessed using functional-MRI) as the primary outcomes. Cognitive function and AD blood biomarkers were also assessed as the secondary outcomes. Twenty-six participants with MCI were randomized with 25 participants completed the study. EVOO significantly improved clinical dementia rating (CDR) and behavioral scores. EVOO also reduced BBB permeability and enhanced functional connectivity. While ROO consumption did not alter BBB permeability or brain connectivity, it improved CDR scores and increased functional brain activation to a memory task in cortical regions involved in perception and cognition. Moreover, EVOO and ROO significantly reduced blood Aβ
/Aβ
and p-tau/t-tau ratios, suggesting that both altered the processing and clearance of Aβ. In conclusion, EVOO and ROO improved CDR and behavioral scores; only EVOO enhanced brain connectivity and reduced BBB permeability, suggesting EVOO biophenols contributed to such an effect. This proof-of-concept study justifies further clinical trials to assess olive oil's protective effects against AD and its potential role in preventing MCI conversion to AD and related dementias.
Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for H2O2 relied on linear polydentate ligands to keep the redox-activatable quinols in close ...proximity to the manganese. Although these provide positive T 1-weighted relaxivity responses to H2O2 that result from oxidation of the quinol groups to p-quinones, these reactions weaken the binding affinity of the ligands, promoting dissociation of Mn(II) from the contrast agent in aqueous solution. Here, we report a new ligand, 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane, that consists of two quinols covalently tethered to a cyclam macrocycle. The macrocycle provides stronger thermodynamic and kinetic barriers for metal-ion dissociation in both the reduced and oxidized forms of the ligand. The Mn(II) complex reacts with H2O2 to produce a more highly aquated Mn(II) species that exhibits a 130% greater r 1, quadrupling the percentile response of our next best sensor. With a large excess of H2O2, there is a noticeable induction period before quinol oxidation and r 1 enhancement occurs. Further investigation reveals that, under such conditions, catalase activity initially outcompetes ligand oxidation, with the latter occurring only after most of the H2O2 has been depleted.
We examined how set-volume equated resistance training using either the back squat (SQ) or hip thrust (HT) affected hypertrophy and various strength outcomes. Untrained college-aged participants were ...randomized into HT (n = 18) or SQ (n = 16) groups. Surface electromyograms (sEMG) from the right gluteus maximus and medius muscles were obtained during the first training session. Participants completed 9 weeks of supervised training (15-17 sessions), before and after which gluteus and leg muscle cross-sectional area (mCSA) was assessed via magnetic resonance imaging. Strength was also assessed prior to and after the training intervention via three-repetition maximum (3RM) testing and an isometric wall push test. Gluteus mCSA increases were similar across both groups. Specifically, estimates (-) favors HT (+) favors SQ modestly favored the HT
SQ for lower effect ±SE, -1.6 ± 2.1 cm
; CI
(-6.1, 2.0), mid -0.5 ± 1.7 cm
; CI
(-4.0, 2.6), and upper -0.5 ± 2.6 cm
; CI
(-5.8, 4.1) gluteal mCSAs but with appreciable variance. Gluteus medius + minimus -1.8 ± 1.5 cm
; CI
(-4.6, 1.4) and hamstrings 0.1 ± 0.6 cm
; CI
(-0.9, 1.4) mCSA demonstrated little to no growth with small differences between groups. mCSA changes were greater in SQ for the quadriceps 3.6 ± 1.5 cm
; CI
(0.7, 6.4) and adductors 2.5 ± 0.7 cm
; CI
(1.2, 3.9). Squat 3RM increases favored SQ 14 ± 2 kg; CI
(9, 18), and hip thrust 3RM favored HT -26 ± 5 kg; CI
(-34, -16). 3RM deadlift 0 ± 2 kg; CI
(-4, 3) and wall push strength -7 ± 12N; CI
(-32, 17) similarly improved. All measured gluteal sites showed greater mean sEMG amplitudes during the first bout hip thrust
squat set, but this did not consistently predict gluteal hypertrophy outcomes. Squat and hip thrust training elicited similar gluteal hypertrophy, greater thigh hypertrophy in SQ, strength increases that favored exercise allocation, and similar deadlift and wall push strength increases.
A highly water‐ and air‐stable Fe(II) complex with the quinol‐containing macrocyclic ligand H4qp4 reacts with H2O2 to yield Fe(III) complexes with less highly chelating forms of the ligand that have ...either one or two para‐quinones. The reaction increases the T1‐weighted relaxivity over four‐fold, enabling the complex to detect H2O2 using clinical MRI technology. The iron‐containing sensor differs from its recently characterized manganese analog, which also detects H2O2, in that it is the oxidation of the metal center, rather than the ligand, that primarily enhances the relaxivity.
An Fe(II) complex with the macrocyclic quinol‐containing ligand H4qp4 displays high water‐ and air‐stability. The complex rapidly reacts with H2O2, but not O2, to yield Fe(III) complexes with oxidized ligands that contain para‐quinone groups. Upon oxidation by H2O2, the r1 increases by over four‐fold, enabling the Fe(II) complex to act as an MRI contrast agent sensor for this reactive oxygen species.
Progressive debilitating neurological defects characterize feline G(M1) gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for ...affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of G(M1) gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G(M1) animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G(M1) gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
We evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular adaptations. Trained men (
... = 15, age: 23 ± 3 years; training experience: 7 ± 3 years) performed unilateral lower-body training for 6 weeks (3× weekly), where single legs were randomly assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last training bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within-subject repeated measures ANOVAs were performed on most dependent variables, and tracer data were compared using dependent samples t-tests. A significant interaction existed for VL muscle cross-sectional area (assessed
magnetic resonance imaging; interaction
= 0.046), where HV increased this metric from PRE to POST (+3.2%,
= 0.018) whereas HL training did not (-0.1%,
= 0.475). Additionally, HL increased leg extensor strength more so than HV training (interaction
= 0.032; HV < HL at POST and POSTPR,
< 0.025 for each). Six-week integrated non-myofibrillar protein synthesis (iNon-MyoPS) rates were also higher in the HV versus HL condition, while no difference between conditions existed for iMyoPS rates. No interactions existed for other strength, VL morphology variables, or the relative abundances of major muscle proteins. Compared to HL training, 6 weeks of HV training in previously trained men optimizes VL hypertrophy in lieu of enhanced iNon-MyoPS rates, and this warrants future research.
A hexadentate anionic ligand with two redox-active quinol groups was synthesized and tested as a component for a MRI contrast agent. Although the ligand binds more strongly to Mn(II) than a ...previously reported ligand and can be used to prepare a Mn(II) complex that does not react with O2, its Mn(II) complex does not display a T1-weighted relaxivity response to H2O2.
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•A more anionic version of a diquinol ligand used for redox-responsive MRI contrast agents was prepared.•The ligand binds to Mn(II) approximately 50 times more strongly than a related ligand with a lesser anionic charge.•The Mn(II) complex reacts with hydrogen peroxide, but not air.•Hydrogen peroxide oxidizes the metal ion in the complex, preventing a T1-weighted relaxivity response.
A previously reported quinol- and Mn(II)-containing MRI contrast agent sensor for H2O2 has the drawback of releasing the metal ion upon oxidation of the organic ligand. The release of potentially neurotoxic Mn(II) limits the sensor’s in vivo applicability. We prepared N,N′-bis(2,5-dihydroxybenzyl)ethanediamine-N,N′-diacetic acid (H6qc1) as a substitute ligand that could potentially remain bound to the metal ion after oxidation of the quinol portions to more weakly metal-binding para-quinones. The carboxylic acid groups deprotonate at ambient pH, providing a more anionic coordination environment that stabilizes its Mn(II) complex in water. Although the more anionic coordination sphere doesn’t introduce air sensitivity, it does render the metal center more susceptible to oxidation by hydrogen peroxide, as evidenced by electron paramagnetic resonance. The oxidation of the metal to less paramagnetic Mn(III) is proposed to lower the r1 enough to completely counter any increase in T1-weighted relaxivity that would result from improved aquation.
A manganese(II) complex with a ligand containing an oxidizable quinol group serves as a turn-on sensor for H2O2. Upon oxidation, the relaxivity of the complex in buffered water increases by 0.8 mM–1 ...s–1, providing a signal that can be detected and quantified by magnetic resonance imaging. The complex also serves as a potent antioxidant, suggesting that this and related complexes have the potential to concurrently visualize and alleviate oxidative stress.
Duchenne Muscular Dystrophy (DMD) is associated with progressive cardiac pathology; however, the SIRT1/PGC1-α activator quercetin may cardioprotect dystrophic hearts. We tested the extent to which ...long-term 0.2% dietary quercetin enrichment attenuates dystrophic cardiopathology in Mdx/Utrn
mice. At 2 mo, Mdx/Utrn
mice were fed quercetin-enriched (Mdx/Utrn
-Q) or control diet (Mdx/Utrn
) for 8 mo. Control C57BL/10 (C57) animals were fed a control diet for 10 mo. Cardiac function was quantified by MRI at 2 and 10 mo. Spontaneous physical activity was quantified during the last week of treatment. At 10 mo hearts were excised for histological and biochemical analysis. Quercetin feeding improved various physiological indexes of cardiac function in diseased animals. Mdx/Utrn
-Q also engaged in more high-intensity physical activity than controls. Histological analyses of heart tissues revealed higher expression and colocalization of utrophin and α-sarcoglycan. Lower abundance of fibronectin, cardiac damage (Hematoxylin Eosin-Y), and MMP9 were observed in quercetin-fed vs. control Mdx/Utrn
mice. Quercetin evoked higher protein abundance of PGC-1α, cytochrome c, ETC complexes I-V, citrate synthase, SOD2, and GPX compared with control-fed Mdx/Utrn
Quercetin decreased abundance of inflammatory markers including NFκB, TGF-β1, and F4/80 compared with Mdx/Utrn
; however, P-NFκB, P-IKBα, IKBα, CD64, and COX2 were similar between groups. Dietary quercetin enrichment improves cardiac function in aged Mdx/Utrn
mice and increases mitochondrial protein content and dystrophin glycoprotein complex formation. Histological analyses indicate a marked attenuation in pathological cardiac remodeling and indicate that long-term quercetin consumption benefits the dystrophic heart.
The current investigation provides first-time evidence that quercetin provides physiological cardioprotection against dystrophic pathology and is associated with improved spontaneous physical activity. Secondary findings suggest that quercetin-dependent outcomes are in part due to PGC-1α pathway activation.
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