146 research outputs found
Can human cardiovascular regulation during exercise be learnt from feedback from arterial baroreceptors?
During dynamic exercise, a large fall in systemic vascular resistance occurs. Arterial pressure (AP) is, however, maintained through a combination of central command and neural activity from muscle afferents that adjust the autonomic outflow to the circulation. How these signals are calibrated to provide accurate regulation of AP remains unclear. This study tests the hypothesis that the calibration can be âlearntâ through feedback from the arterial baroreceptors arising over multiple trials of exercise. Eight healthy subjects undertook three different protocols in random order. The test protocol consisted of 7 days' training, when subjects were exposed on 70 occasions to 4 min of exercise (50% of maximal oxygen uptake capacity) paired with neck suction (â40 mmHg) to mimic an excessive rise in AP at the carotid baroreceptors with exercise. Two control protocols involved training with either exercise or neck suction alone. No significant changes in mean AP, diastolic AP or heart rate during normal exercise were detected following training with any protocol. However, the rise in systolic AP with exercise was attenuated by an average of 7.3 Âą 2.0 mmHg (mean Âą s.e.m., P < 0.01) on the first and second days following training with the test protocol, but not with either control protocol (P < 0.05 for difference between protocols, ANOVA). In conclusion, this study failed to show that mean AP during normal exercise could be reduced through prior conditioning by overstimulation of the baroreceptors during exercise. However, a reduction in systolic AP was observed that suggests the presence of some plasticity within the autonomic response, consistent with our hypothesis
Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach
Background: In this study, we quantified age-related changes in the time-course of face processing
by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our
approach does not rely on peak measurements and can provide a more sensitive measure of
processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded
discrimination task between two faces. The phase spectrum of these faces was manipulated
parametrically to create pictures that ranged between pure noise (0% phase information) and the
undistorted signal (100% phase information), with five intermediate steps.
Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was
higher, in younger than older observers. ERPs from each subject were entered into a single-trial
general linear regression model to identify variations in neural activity statistically associated with
changes in image structure. The earliest age-related ERP differences occurred in the time window
of the N170. Older observers had a significantly stronger N170 in response to noise, but this age
difference decreased with increasing phase information. Overall, manipulating image phase
information had a greater effect on ERPs from younger observers, which was quantified using a
hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus
parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at
multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower
processing in older observers starting around 120 ms after stimulus onset. This age-related delay
increased over time to reach a maximum around 190 ms, at which latency younger observers had
around 50 ms time lead over older observers.
Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual
system sensitivity to image structure, the current study demonstrates that older observers
accumulate face information more slowly than younger subjects. Additionally, the N170 appears to
be less face-sensitive in older observers
VIP Enhances Phagocytosis of Fibrillar Beta-Amyloid by Microglia and Attenuates Amyloid Deposition in the Brain of APP/PS1 Mice
Vasoactive intestinal peptide (VIP) is a multifunctional neuropeptide with demonstrated immunosuppressive and neuroprotective activities. It has been shown to inhibit Amyloid beta (Aβ)-induced neurodegeneration by indirectly suppressing the production and release of a variety of inflammatory and neurotoxic factors by activated microglia. We demonstrated that VIP markedly increased microglial phagocytosis of fibrillar Aβ42 and that this enhanced phagocytotic activity depended on activation of the Protein kinase C (PKC) signaling pathway. In addition, VIP suppressed the release of tumor necrosis factor alpha (TNF-ι) and nitric oxide(NO) from microglia activated by combined treatment with fibrillar Aβ42 and low dose interferon-γ (IFN-γ). We utilized an adenovirus-mediated gene delivery method to overexpress VIP constitutively in the hippocampus of APPswPS1 transgenic mice. The Aβ load was significantly reduced in the hippocampus of this animal model of Alzheimer's disease, possibly due to the accumulation and activation of cd11b-immunoactive microglial cells. The modulation of microglial activation, phagocytosis, and secretion by VIP is a promising therapeutic option for the treatment of Alzheimer's disease(AD)
Synthetic biology to access and expand nature's chemical diversity
Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesize complex chemicals. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms. In this Review, we discuss how advances in synthetic biology â including novel DNA construction technologies, the use of genetic parts for the precise control of expression and for synthetic regulatory circuits â and multiplexed genome engineering can be used to optimize the design and synthesis of pathways that produce natural products
Highly-efficient Cas9-mediated transcriptional programming
The RNA-guided nuclease Cas9 can be reengineered as a programmable transcription factor. However, modest levels of gene activation have limited potential applications. We describe an improved transcriptional regulator obtained through the rational design of a tripartite activator, VP64-p65-Rta (VPR), fused to nuclease-null Cas9. We demonstrate its utility in activating endogenous coding and noncoding genes, targeting several genes simultaneously and stimulating neuronal differentiation of human induced pluripotent stem cells (iPSCs).National Human Genome Research Institute (U.S.) (Grant P50 HG005550)United States. Dept. of Energy (Grant DE-FG02-02ER63445)Wyss Institute for Biologically Inspired EngineeringNational Science Foundation (U.S.). Graduate Research FellowshipMassachusetts Institute of Technology. Department of Biological EngineeringHarvard Medical School. Department of Genetic
Simulation of Front Instabilities in Density-Driven Flow, Using a Reactive Transport Model for Biogrout Combined with a Randomly Distributed Permeability Field
The efficacy of a photolyase-based device on the cancerization field: a clinical and thermographic study
Chronic stroke sensorimotor impairment is related to smaller hippocampal volumes: an ENIGMA analysis
Background Persistent sensorimotor impairments after stroke can negatively impact quality of life. The hippocampus is vulnerable to poststroke secondary degeneration and is involved in sensorimotor behavior but has not been widely studied within the context of poststroke upperâlimb sensorimotor impairment. We investigated associations between nonâlesioned hippocampal volume and upper limb sensorimotor impairment in people with chronic stroke, hypothesizing that smaller ipsilesional hippocampal volumes would be associated with greater sensorimotor impairment. Methods and Results Crossâsectional T1âweighted magnetic resonance images of the brain were pooled from 357 participants with chronic stroke from 18 research cohorts of the ENIGMA (Enhancing NeuoImaging Genetics through MetaâAnalysis) Stroke Recovery Working Group. Sensorimotor impairment was estimated from the FMAâUE (FuglâMeyer Assessment of Upper Extremity). Robust mixedâeffects linear models were used to test associations between poststroke sensorimotor impairment and hippocampal volumes (ipsilesional and contralesional separately; Bonferroniâcorrected, P<0.025), controlling for age, sex, lesion volume, and lesioned hemisphere. In exploratory analyses, we tested for a sensorimotor impairment and sex interaction and relationships between lesion volume, sensorimotor damage, and hippocampal volume. Greater sensorimotor impairment was significantly associated with ipsilesional (P=0.005; β=0.16) but not contralesional (P=0.96; β=0.003) hippocampal volume, independent of lesion volume and other covariates (P=0.001; β=0.26). Women showed progressively worsening sensorimotor impairment with smaller ipsilesional (P=0.008; β=â0.26) and contralesional (P=0.006; β=â0.27) hippocampal volumes compared with men. Hippocampal volume was associated with lesion size (P<0.001; β=â0.21) and extent of sensorimotor damage (P=0.003; β=â0.15). Conclusions The present study identifies novel associations between chronic poststroke sensorimotor impairment and ipsilesional hippocampal volume that are not caused by lesion size and may be stronger in women
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