Statistical properties of first-order bang-bang Pll with nonzero loop delay

A method to solve the stationary state probability is presented for the first-order bang-bang phase-locked loop (BBPLL) with nonzero loop delay. This is based on a delayed Markov chain model and a state How diagram for tracing the state history due to the loop delay. As a result, an eigenequation is obtained, and its closed form solutions are derived for some cases. After obtaining the state probability, statistical characteristics such as mean gain of the binary phase detector and timing error variance are calculated and demonstrated.

Hardware reduction in digital delta-sigma modulators via error masking - part I: MASH DDSM

Two classes of techniques have been developed to whiten the quantization noise in digital delta-sigma modulators (DDSMs): deterministic and stochastic. In this two-part paper, a design methodology for reduced-complexity DDSMs is presented. The design methodology is based on error masking. Rules for selecting the word lengths of the stages in multistage architectures are presented. We show that the hardware requirement can be reduced by up to 20% compared with a conventional design, without sacrificing performance. Simulation and experimental results confirm theoretical predictions. Part I addresses MultistAge noise SHaping (MASH) DDSMs; Part II focuses on single-quantizer DDSMs..

The role of synchronization in digital communications using chaos - Part II: Chaotic modulation and chaotic synchronization.

For pt. I see ibid., vol. 44, p. 927-36 (1997). In a digital communications system, data are transmitted from one location to another by mapping bit sequences to symbols, and symbols to sample functions of analog waveforms. The analog waveform passes through a bandlimited (possibly time-varying) analog channel, where the signal is distorted and noise is added. In a conventional system the analog sample functions sent through the channel are weighted sums of one or more sinusoids; in a chaotic communications system the sample functions are segments of chaotic waveforms. At the receiver, the symbol may be recovered by means of coherent detection, where all possible sample functions are known, or by noncoherent detection, where one or more characteristics of the sample functions are estimated. In a coherent receiver, synchronization is the most commonly used technique for recovering the sample functions from the received waveform. These sample functions are then used as reference signals for a correlator. Synchronization-based coherent receivers have advantages over noncoherent receivers in terms of noise performance, bandwidth efficiency (in narrow-band systems) and/or data rate (in chaotic systems). These advantages are lost if synchronization cannot be maintained, for example, under poor propagation conditions. In these circumstances, communication without synchronization may be preferable. The theory of conventional telecommunications is extended to chaotic communications, chaotic modulation techniques and receiver configurations are surveyed, and chaotic synchronization schemes are described

Paracetamol metabolism in postoperative patients

Introduction: Despite being available for more than 50 years, there is still much to learn about paracetamol. Postoperative analgesic regimens that maintain good pain control while minimising exposure to opiates are beneficial and paracetamol has had a resurgence in this role since an IV formulation came to market. However there is evidence to suggest currently licensed doses are sub-therapeutic, especially when administered orally or rectally. Higher, unlicensed doses are now being advocated but, prior to this study, there was little evidence of their safety in surgical patients. When assessing drug safety in surgical patients a number of surgery and patient related factors influence results, and these must be considered. Methods: Major and intermediate surgical patients were recruited from two hospitals in Ireland. They were administered IV paracetamol at either 9g or 4g daily doses. In addition they received daily sub therapeutic doses of four other medicines to indicate the activity of their CYP450 enzymes that are involved in paracetamol metabolism. Urine and blood samples were collected to determine paracetamol pharmacokinetics, CYP450 activity, inflammatory cytokine concentration and for evidence of hepatotoxicity. Results: There were 33 patients that participated in the study. There was no evidence of clinically significant hepatotoxicity occurring in any patient during the study period, but there could have been changes following this time. Paracetamol disposition was shown to change, however half-life remained relatively constant. There were a number of changes to the way paracetamol was metabolised following surgery that maintained this rate of elimination. Conclusion: Doses of up to 9g per day given to major surgical patients for up to five days postoperatively produced no evidence of hepatotoxicity. Further research is warranted to determine the clinical utility of these higher doses

The development of a model of continuing professional development for teachers of primary science

A new science curriculum was introduced to primary schools in the Republic of Ireland in 2003. This curriculum, broader in scope than its 1971 predecessor (Curaclam na Bunscoile, 1971), requires teachers at all levels of primary school to teach science. A review carried out in 2008 of children’s experiences of this curriculum found that its implementation throughout the country was uneven. This finding, together with the increasing numbers of teachers who were requesting support to implement this curriculum, suggested the need for a review of Irish primary teachers’ needs in the area of science. The research study described in this thesis was undertaken to establish the extent of Irish primary teachers’ needs in the area of science by conducting a national survey. The data from this survey, together with data from international studies, were used to develop a theoretical framework for a model of Continuing Professional Development (CPD). This theoretical framework was used to design the Whole- School, In-School (WSIS) CPD model which was trialled in two case-study schools. The participants in these ‘action-research’ case-studies acted as co-researchers, who contributed to the development and evolution of the CPD model in each school. Analysis of the data gathered as part of the evaluation of the Whole-School, In- School (WSIS) model of CPD found an improved experience of science for children and improved confidence for teachers teaching at all levels of the primary school. In addition, a template for the establishment of a culture of collaborative CPD in schools has been developed from an analysis of the data

Towards a cognitive neurobiology of brain-gut axis disorders

The past two decades have seen substantial gains in our understanding of the complex processes underlying disturbed brain-gut communication in disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Despite a growing understanding of the neurobiology of brain-gut axis dysfunction, there is a relative paucity of investigations into how the various factors involved in dysregulating the brain-gut axis, including stress, immune activation and pain, could impact on fundamental brain processes such as cognitive performance. To this end, we proposed a cognitive neurobiology of brain-gut axis dysfunction and took a novel approach to examine how disturbed brain-gut interactions may manifest as altered cognitive performance in IBS and IBD, both cross-sectionally and prospectively. We have demonstrated that, disorders of the brain-gut axis are characterised by stable deficits in specific cognitive domains. Specifically, patients with IBS exhibit a consistent hippocampal mediated visuospatial memory impairment. In addition we have found evidence to suggest a similar visuospatial impairment in IBD. However, our most consistent finding within this population was that patients with Crohn’s disease exhibit impaired selective attention/ response inhibition on the classic Stroop interference test. These cognitive deficits may serve to perpetuate and sustain brain-gut axis dysfunction. Furthermore, this research has shed light on some of the underlying neurobiological mechanisms that may be mediating cognitive dysfunction in IBS. Our findings may have significant implications for the individual who suffers from a brain-gut axis disorder and may also inform future treatment strategies. Taken together, these findings can be incorporated into existing neurobiological models of brain-gut axis dysfunction, to develop a more comprehensive model accounting for the cognitive-neurobiology of brain-gut axis disorders. This has furthered our understanding of disease pathophysiology and may ultimately aid in both the diagnosis and treatment of these highly prevalent, but poorly understood disorders.

Editorial

Published Version

Finite mixture distributions, sequential likelihood and the EM algorithm

A popular way to account for unobserved heterogeneity is to assume that the data are drawn from a finite mixture distribution. A barrier to using finite mixture models is that parameters that could previously be estimated in stages must now be estimated jointly: using mixture distributions destroys any additive separability of the log-likelihood function. We show, however, that an extension of the EM algorithm reintroduces additive separability, thus allowing one to estimate parameters sequentially during each maximization step. In establishing this result, we develop a broad class of estimators for mixture models. Returning to the likelihood problem, we show that, relative to full information maximum likelihood, our sequential estimator can generate large computational savings with little loss of efficiency.

Electrosprayed core-shell microspheres for protein delivery.

This communication describes a single-step electrospraying technique that generates core-shell microspheres (CSMs) with encapsulated protein as the core and an amphiphilic biodegradable polymer as the shell. The protein release profiles of the electrosprayed CSMs showed steady release kinetics over 3 weeks without a significant initial burst.

Performance metrics of an optical spectral imaging system for intra-operative assessment of breast tumor margins.

As many as 20-70% of patients undergoing breast conserving surgery require repeat surgeries due to a close or positive surgical margin diagnosed post-operatively [1]. Currently there are no widely accepted tools for intra-operative margin assessment which is a significant unmet clinical need. Our group has developed a first-generation optical visible spectral imaging platform to image the molecular composition of breast tumor margins and has tested it clinically in 48 patients in a previously published study [2]. The goal of this paper is to report on the performance metrics of the system and compare it to clinical criteria for intra-operative tumor margin assessment. The system was found to have an average signal to noise ratio (SNR) >100 and <15% error in the extraction of optical properties indicating that there is sufficient SNR to leverage the differences in optical properties between negative and close/positive margins. The probe had a sensing depth of 0.5-2.2 mm over the wavelength range of 450-600 nm which is consistent with the pathologic criterion for clear margins of 0-2 mm. There was <1% cross-talk between adjacent channels of the multi-channel probe which shows that multiple sites can be measured simultaneously with negligible cross-talk between adjacent sites. Lastly, the system and measurement procedure were found to be reproducible when evaluated with repeated measures, with a low coefficient of variation (<0.11). The only aspect of the system not optimized for intra-operative use was the imaging time. The manuscript includes a discussion of how the speed of the system can be improved to work within the time constraints of an intra-operative setting.

Mechanisms of specificity in neuronal activity-regulated gene transcription.

The brain is a highly adaptable organ that is capable of converting sensory information into changes in neuronal function. This plasticity allows behavior to be accommodated to the environment, providing an important evolutionary advantage. Neurons convert environmental stimuli into long-lasting changes in their physiology in part through the synaptic activity-regulated transcription of new gene products. Since the neurotransmitter-dependent regulation of Fos transcription was first discovered nearly 25 years ago, a wealth of studies have enriched our understanding of the molecular pathways that mediate activity-regulated changes in gene transcription. These findings show that a broad range of signaling pathways and transcriptional regulators can be engaged by neuronal activity to sculpt complex programs of stimulus-regulated gene transcription. However, the shear scope of the transcriptional pathways engaged by neuronal activity raises the question of how specificity in the nature of the transcriptional response is achieved in order to encode physiologically relevant responses to divergent stimuli. Here we summarize the general paradigms by which neuronal activity regulates transcription while focusing on the molecular mechanisms that confer differential stimulus-, cell-type-, and developmental-specificity upon activity-regulated programs of neuronal gene transcription. In addition, we preview some of the new technologies that will advance our future understanding of the mechanisms and consequences of activity-regulated gene transcription in the brain.

A von Bertalanffy Based Model for the Estimation of Oyster (Crassostrea virginica) Growth on Restored Oyster Reefs in Chesapeake Bay

A model to estimate the mean monthly growth of Crassostrea virginica oysters in Chesapeake Bay was developed. This model is based on the classic von Bertalanffy growth function, however the growth constant is changed every monthly timestep in response to short term changes in temperature and salinity. Using a dynamically varying growth constant allows the model to capture seasonal oscillations in growth, and growth responses to changing environmental conditions that previous applications of the von Bertalanffy model do not capture. This model is further expanded to include an estimation of Perkinsus marinus impacts on growth rates as well as estimations of ecosystem services provided by a restored oyster bar over time. The model was validated by comparing growth estimates from the model to oyster shell height observations from a variety of restoration sites in the upper Chesapeake Bay. Without using the P. marinus impact on growth, the model consistently overestimates mean oyster growth. However, when P. marinus effects are included in the model, the model estimates match the observed mean shell height closely for at least the first 3 years of growth. The estimates of ecosystem services suggested by this model imply that even with high levels of mortality on an oyster reef, the ecosystem services provided by that reef can still be maintained by growth for several years. Because larger oyster filter more water than smaller ones, larger oysters contribute more to the filtration and nutrient removal ecosystem services of the reef. Therefore a reef with an abundance of larger oysters will provide better filtration and nutrient removal. This implies that if an oyster restoration project is trying to improve water quality through oyster filtration, it is important to maintain the larger older oysters on the reef.

Looking past the model species: diversity in gaze-following skills across primates.

Primates must navigate complex social landscapes in their daily lives: gathering information from and about others, competing with others for food and mates, and cooperating to obtain rewards as well. Gaze-following often provides important clues as to what others see, know, or will do; using information about social attention is thus crucial for primates to be competent social actors. However, the cognitive bases of the gaze-following behaviors that primates exhibit appear to vary widely across species. The ultimate challenge of such analyses will therefore be to understand why such different cognitive mechanisms have evolved across species.

The toxicology of climate change: environmental contaminants in a warming world.

Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.

A genetically engineered thermally responsive sustained release curcumin depot to treat neuroinflammation.

Radiculopathy, a painful neuroinflammation that can accompany intervertebral disc herniation, is associated with locally increased levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Systemic administration of TNF antagonists for radiculopathy in the clinic has shown mixed results, and there is growing interest in the local delivery of anti-inflammatory drugs to treat this pathology as well as similar inflammatory events of peripheral nerve injury. Curcumin, a known antagonist of TNFα in multiple cell types and tissues, was chemically modified and conjugated to a thermally responsive elastin-like polypeptide (ELP) to create an injectable depot for sustained, local delivery of curcumin to treat neuroinflammation. ELPs are biopolymers capable of thermally-triggered in situ depot formation that have been successfully employed as drug carriers and biomaterials in several applications. ELP-curcumin conjugates were shown to display high drug loading, rapidly release curcumin in vitro via degradable carbamate bonds, and retain in vitro bioactivity against TNFα-induced cytotoxicity and monocyte activation with IC50 only two-fold higher than curcumin. When injected proximal to the sciatic nerve in mice via intramuscular (i.m.) injection, ELP-curcumin conjugates underwent a thermally triggered soluble-insoluble phase transition, leading to in situ formation of a depot that released curcumin over 4days post-injection and decreased plasma AUC 7-fold.