533 research outputs found
Exploring mechanisms of disuse atrophy and optimal rehabilitation strategies for the restoration of muscle mass, structure & function
Disuse atrophy (DA) occurs during situations of unloading and is characterised by a loss of muscle mass and function. These reductions may be observed as early as 5 days into a period of unloading. While the reduction of muscle size is well studied, the reduction in muscle function is less well characterised. Furthermore, different muscles of the lower leg have been shown to express diverging profiles of muscle size loss as a result of DA. In particular, the medial gastrocnemius (MG) is relatively susceptible to DA while the tibialis anterior (TA) is resistant to even long-term bed rest of over a month. The average length of stay in hospital in the UK was last reported at 4.5 days which is enough time for DA to occur in the quadriceps. In older individuals, loss of muscle mass and function may reduce quality of life to the point of frailty and are less well suited to performing resistance exercise. Hence, alternative therapies to attenuate DA may be needed.
This thesis introduces skeletal muscle and its function as an organ in the human body, along with its composition and how this influences its function. It then discusses the study of DA and the situations in which it occurs, before covering the response of different muscles, the time course and strategies used for rehabilitation. General methods used within this thesis are detailed in Chapter 2. In Chapter 3, results of muscle size, strength, and various aspects of function from the vastus lateralis (VL), the MG and the TA to investigate the difference in response to 15-day unilateral lower limb immobilisation in young adults.
In Chapters 4 and 5, this thesis investigates the neuromuscular adaptation to this intervention in the VL compared to the non-immobilised control, and then the immobilised MG and TA, respectively. These results show an impairment of neural input to the VL and the MG following immobilisation which is not seen in the TA.
Finally, in Chapter 6, peripheral nerve stimulation is shown to potentially recruit from a broader pool of motor units than traditional neuromuscular electrical stimulation and as such may be more favourable for rehabilitation
Cell-type specific cholinergic modulation in anterior cingulate and lateral prefrontal cortices of the rhesus macaque
The lateral prefrontal cortex (LPFC) and the anterior cingulate cortex (ACC) are two key regions of the frontal executive control network. Ascending cholinergic pathways differentially innervate these two functionally distinct cortices to modulate arousal and motivational signaling for higher-order functions. The action of acetylcholine (ACh) in sensory cortices is constrained by layer, anatomical cell type, and subcellular localization of distinct receptors, but little is known about the nature and organization of frontal-cholinergic circuitry in primates. In this dissertation, we characterized the anatomical localization of muscarinic acetylcholine receptors (mAChRs), m1 and m2–the predominant subtypes in the cortex–and their expression profiles on distinct cell types and pathways in ACC and LPFC of the rhesus monkey, using immunohistochemistry, anatomical tract-tracing, whole cell patch-clamp recordings, and single nucleus RNA sequencing. In the first series of studies (Chapter 2), we used immunohistochemistry and high-resolution confocal microscopy to reveal regional differences in m1 and m2 receptor localization on excitatory pyramidal and inhibitory neuron subpopulations and subcellular compartments in ACC (A24) versus LPFC (A46) of adult rhesus monkeys (Macaca mulatta; aged 7-11 yrs; 4 males and 2 females). The ACC exhibited a greater proportion of m2+ inhibitory neurons and a greater density of presynaptic m2+ receptors localized on inhibitory (VGAT+) terminations on pyramidal neurons compared to the LPFC. This result suggests a greater cholinergic suppression of GABAergic neurotransmission in ACC. In a second set of experiments (Chapter 3), we examined the heterogeneity of m1 and m2 laminar expression in functionally distinct ACC areas A24, A25, and A32. These differ in their connections with higher order cortical areas and limbic structures, such as the amygdala (AMY). The density of m1+ and/or m2 expressing (m1+/m2+) pyramidal neurons was significantly greater in A24 compared to A25 and to A32, while A25 exhibited a significantly greater density of m2+VGAT+ terminals. In addition, we examined the substrates for cholinergic modulation of long-range cortico-limbic processing using bidirectional neural tracers to label one specific subtype, the AMY-targeting projection neurons in these ACC areas. Compared to A24 and A32, the limbic ventral A25 had a greater density of m1+/m2+ AMY-targeting pyramidal neurons across upper layers 2-3 and deep layers 5-6, suggesting stronger cholinergic modulation of amygdalar outputs. Lastly (Chapter 4), we assessed the functional effects of cholinergic modulation on excitatory and inhibitory synaptic activity as well as the molecular signatures related to m1 and m2 receptor expression. In experiments using in vitro whole-cell patch-clamp recordings of layer 3 pyramidal neurons in ACC and LPFC, we found that application of the cholinergic agonist carbachol (CCh) significantly decreased the frequency of excitatory postsynaptic currents (EPSCs) to a greater extent in ACC A24 than in LPFC A46. Using single nucleus RNA sequencing, we found that enriched m1 and m2 transcriptional profiles in distinct cell-types and frontal areas (ACC A24 and LPFC A46) had differentially expressed genes associated with down-stream signaling cascades related to synaptic signaling and plasticity. Together, these data reveal the anatomical, functional, and transcriptomic neural substrates of diverse cholinergic modulation of local excitatory and inhibitory circuits and long-range cortico-limbic pathways in functionally-distinct ACC and LPFC frontal areas that are important for cognitive-emotional integration
Selected Analytical Techniques of Solid State, Structure Identification, and Dissolution Testing in Drug Life Cycle
The textbook provides an overview of the main techniques applied in pharmaceutical industry, with the focus on solid-state analysis. It discusses spectral methods, thermal analysis, and dissolution testing, explains the theoretical background for each method and shows practical examples from a real-life drug-design and quality control applications. The textbook is thus intended for both pharmacy students and early career professionals
Geographic variation in the calling songs and genetics of Bartram's round-winged katydid Amblycorypha bartrami (Tettigoniidae, Phaneropterinae) reveal new species
Previous work on Bartram's round-winged katydid, Amblycorypha bartrami Walker, found inconsistencies in song variation across the species' range. Individuals of purported populations of A. bartrami from sandhills across the southeastern US were collected, recorded, and their genes were sequenced to better understand their population structure and evolution. Significant differences in songs, morphology, and genetics were found among populations from Alabama (AL), Georgia (GA), North Carolina (NC), and South Carolina (SC), and they differed from those of individuals collected from the type locality in Florida (FL). Males from all populations produced songs composed of a series of similar syllables, but they differed in the rates at which syllables were produced as a function of temperature. At temperatures of 25°C, the calling songs of males from populations in northern AL and GA were found to have the highest syllable rates, those from SC had the lowest rates, and those from NC were found to produce songs with doublet syllables at rates that were intermediate between those of males from FL and those of AL and GA. These song differences formed the basis for cluster analyses and principal component analyses, which showed significant clustering and differences in song spectra and morphology among the song morphs. A Bayesian multi-locus, multi-species coalescent analysis found significant divergences from a panmictic population for the song morphs. Populations from GA and AL are closely related to those of A. bartrami in FL, whereas populations from NC and SC are closely related to each other and differ from the other three. Large river systems may have been important in isolating these populations of flightless katydids. Based on the results of our analyses of songs, morphology, and genetics, three new species of round-winged katydids from the southeastern coastal plain and piedmont are described
LOW POWER AND HIGH SIGNAL TO NOISE RATIO BIO-MEDICAL AFE DESIGN TECHNIQUES
The research work described in this thesis was focused on finding novel techniques to
implement a low-power and noise Bio-Medical Analog Front End (BMEF) circuit
technique to enable high-quality Electrocardiography (ECG) sensing. Usually, an ECG
signal and several bio-medical signals are sensed from the human body through a pair
of electrodes. The electrical characteristics of the very small amplitude (1u-10mV)
signals are corrupted by random noise and have a significant dc offset. 50/60Hz power
supply coupling noise is one of the biggest cross-talk signals compared to the thermally
generated random noise. These signals are even AFE composed of an Instrumentation
Amplifier (IA), which will have a better Common Mode rejection ratio (CMRR). The main
function of the AFE is to convert the weak electrical Signal into large signals whose
amplitude is large enough for an Analog Digital Converter (ADC) to detect without having
any errors. A Variable Gain Amplifier (VGA) is sometimes required to adjust signal
amplitude to maintain the dynamic range of the ADC. Also, the Bio-medical transceiver
needs an accurate and temperature-independent reference voltage and current for the
ADC, commonly known as Bandgap Reference Circuit (BGR). These circuits need to
consume as low power as possible to enable these circuits to be powered from the
battery.
The work started with analysing the existing circuit techniques for the circuits
mentioned above and finding the key important improvements required to reach the
target specifications. Previously proposed IA is generated based on voltage mode signal
processing. To improve the CMRR (119dB), we proposed a current mode-based IA with
an embedded DC cancellation technique. State-of-the-art VGA circuits were built based
on the degeneration principle of the differential pair, which will enable the variable gain
purpose, but none of these techniques discussed linearity improvement, which is very
important in modern CMOS technologies. This work enhances the total Harmonic
distortion (THD) by 21dB in the worst case by exploiting the feedback techniques around
the differential pair. Also, this work proposes a low power curvature compensated
bandgap with 2ppm/0C temperature sensitivity while consuming 12.5uW power from a
1.2V dc power supply. All circuits were built in 45nm TSMC-CMOS technology and
simulated with all the performance metrics with Cadence (spectre) simulator. The circuit
layout was carried out to study post-layout parasitic effect sensitivity
Influence of Platinum Nanoparticles on Ionic Transport and Hydrogen Reactivity of Yttria-Stabilized Zirconia Thin Films
Yttria-stabilized zirconia (YSZ) is a widely used ceramic material in solid oxide fuel cells, oxygen sensors, and sensing applications due to its high ionic conductivity, chemical inertness, and thermal stability. YSZ is promising active coating for use in miniaturized harsh environment wireless surface acoustic sensors to monitor gases such as H2. Adding catalytic Pt nanoparticles can enhance gas reactivity and lead to associated film conductivity changes.
In this work, thin films with an (8% Y2O3 - 92% ZrO2) composition were deposited onto piezoelectric langasite substrates using RF magnetron sputtering in Ar:O2 - 95:5 gas mixture. Films were grown using growth temperatures (30 - 7000C), deposition rates (0.03 - 0.07 nm/s), and substrate bias (-300 - +300 V). Platinum was deposited in-situ via e-beam evaporation at either 30oC or 400oC and then subsequently annealed to cause nanoparticle formation. YSZ and Pt/YSZ films ionic conductivities were measured and characterized with electrochemical impedance spectroscopy (EIS) in pure N2, or in a 4% H2 - 96% N2 mixture.
X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were also used to analyze the surface composition, crystal structure and nanoparticles morphology, respectively.
By manipulating the deposition parameters, either (111) or mixed (111)/(200) YSZ film crystallographic texture can be achieved. Post-deposition annealing up to 1000oC in air causes grain growth, strain relief and yttria segregation. EIS measurements from YSZ films over the range 400oC - 600oC indicate that ionic conductivities are strongly dependent on yttria segregation and film nanostructure.
For YSZ films decorated with Pt nanoparticles, the surface becomes reactive towards hydrogen. Pt nanoparticles form (111) oriented crystallites, and the amount of yttria segregation is less than that for Pt-free films. Ionic conductivities and sensitivities towards hydrogen depend on the nanoparticle size and film nanostructure. Pt nanoparticles lower the H2 adsorption energy and facilitate the interaction. The conductivity changes that occur corresponding to pure N2 versus exposure to 4% H2 - 96% N2 were found to be reversible. These results indicate that Pt/YSZ films hold promise as hydrogen sensing films that can be incorporated onto a variety of sensing platforms for H2 gas detection and management
Storing, single photons in broadband vapor cell quantum memories
Single photons are an essential resource for realizing quantum technologies. Together with compatible quantum memories granting control over when a photon arrives, they form a foundational component both of quantum communication and quantum information processing. Quality solid-state single photon sources deliver on the high bandwidths and rates required for scalable quantum technology, but require memories that match these operational parameters. In this thesis, I report on quantum memories based on electromagnetically induced transparency and built in warm rubidium vapor, with such fast and high bandwidth interfaces in mind. I also present work on a heralded single photon source based on parametric downconversion in an optical cavity, operated in a bandwidth regime of a few 100s of megahertz. The systems are characterized on their own and together in a functional interface. As the photon generation process is spontaneous, the memory is implemented as a fully reactive device, capable of storing and retrieving photons in response to an asynchronous external trigger.
The combined system is used to demonstrate the storage and retrieval of single photons in and from the quantum memory. Using polarization selection rules in the Zeeman substructure of the atoms, the read-out noise of the memory is considerably reduced from what is common in ground-state storage schemes in warm vapor. Critically, the quantum signature in the photon number statistics of the retrieved photons is successfully maintained, proving that the emission from the memory is dominated by single photons. We observe a retrieved single-photon state accuracy of for short storage times, which remains throughout the memory lifetime of ns. The end-to-end efficiency of the memory interfaced with the photon source is , which will be further improved in the future by optimizing the operating regime. With its operation bandwidth of MHz, our system opens up new possibilities for single-photon synchronization and local quantum networking experiments at high repetition rates
The temporal pattern of impulses in primary afferents analogously encodes touch and hearing information
An open question in neuroscience is the contribution of temporal relations between individual impulses in primary afferents in conveying sensory information. We investigated this question in touch and hearing, while looking for any shared coding scheme. In both systems, we artificially induced temporally diverse afferent impulse trains and probed the evoked perceptions in human subjects using psychophysical techniques.
First, we investigated whether the temporal structure of a fixed number of impulses conveys information about the magnitude of tactile intensity. We found that clustering the impulses into periodic bursts elicited graded increases of intensity as a function of burst impulse count, even though fewer afferents were recruited throughout the longer bursts.
The interval between successive bursts of peripheral neural activity (the burst-gap) has been demonstrated in our lab to be the most prominent temporal feature for coding skin vibration frequency, as opposed to either spike rate or periodicity. Given the similarities between tactile and auditory systems, second, we explored the auditory system for an equivalent neural coding strategy. By using brief acoustic pulses, we showed that the burst-gap is a shared temporal code for pitch perception between the modalities.
Following this evidence of parallels in temporal frequency processing, we next assessed the perceptual frequency equivalence between the two modalities using auditory and tactile pulse stimuli of simple and complex temporal features in cross-sensory frequency discrimination experiments. Identical temporal stimulation patterns in tactile and auditory afferents produced equivalent perceived frequencies, suggesting an analogous temporal frequency computation mechanism.
The new insights into encoding tactile intensity through clustering of fixed charge electric pulses into bursts suggest a novel approach to convey varying contact forces to neural interface users, requiring no modulation of either stimulation current or base pulse frequency. Increasing control of the temporal patterning of pulses in cochlear implant users might improve pitch perception and speech comprehension. The perceptual correspondence between touch and hearing not only suggests the possibility of establishing cross-modal comparison standards for robust psychophysical investigations, but also supports the plausibility of cross-sensory substitution devices
Wave-based monitoring and forecasting of structural damage in geological composites
This thesis investigates the use of wave-based techniques for monitoring and forecasting
brittle failure events. It expands upon previous work and observations
of geophysical precursory signals before catastrophic failure events such as earthquakes,
volcanic eruptions, laboratory deformation experiments, and landslides.
These precursory signals have been observed to follow power-law accelerations in
spatial, temporal, and size distributions leading up to catastrophic failure. It is believed
that modeling these precursors is the key to forecasting these failure events
and to effective hazard mitigation. In this thesis, I aim to improve our understanding
of the driving mechanisms of this event rate behavior, to improve upon
current forecasting methods, and to explore the application of current geophysical
monitoring techniques to industrial composite materials, such as concrete.
In previous studies, the behavior of geophysical precursors has been modeled
using Voight’s relation in order to perform ‘hindcasts’ by solving for failure onset
time in a method known as the Failure Forecast Method (FFM) (Bell et al., 2011b;
Kilburn, 2003; Kilburn and Voight, 1998). This method assumes power-law event
rate behavior and is applied in retrospect, creating an observational bias. I aim to
improve upon the FFM and minimize bias by employing a Bayesian Markov Chain
Monte Carlo (MCMC) version to data from laboratory deformation experiments
on Clashach sandstone cores. I also present alternative methods for event rate
distributions that do not follow a power-law.
Triaxial deformation experiments were conducted on Clashach sandstone cores
in two sets, one with identical test conditions and one with varying test conditions.
Acoustic emissions event characteristics and statistics were analyzed to outline
the effects of changing experimental parameters, namely, confining pressure (Pc),
on event rate distribution, and therefore, efficacy of the FFM. I argue that Pc,
or event depth, plays an integral role in the non-linearity of precursory event
rate. I present alternative applications of the FFM to precursory signals other
than event rate, such as event amplitude and root-mean-square (RMS) continuous
amplitude. Event amplitude modeling results suggest the method is less effective
than modeling event rate, but may serve as a suitable alternative when event
rates are not power-law. RMS amplitude modeling results are more accurate
than event-rates, but are considerably more computationally intensive due to the
use of continuous waveform data rather than event data.
I then investigate the use of geophysical wave-based monitoring techniques
on the structural health monitoring of concrete, a man-made heterogeneous composite
material. I visited the German Federal Institute for Materials Testing in
Berlin to conduct an experiment emulating reinforcement corrosion in building
concrete. During this experiment, acoustic emissions were continuously recorded
and Coda Wave Interferometry (CWI) measurements made using hourly ultrasonic
surveys. Results indicate that CWI could be a very effective monitoring
tool for early detection of internal structural damage at a minimal computational
cost
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