242 research outputs found
Oscillatory mechanisms for controlling information flow in neural circuits
Mammalian brains generate complex, dynamic structures of oscillatory activity, in which
distributed regions transiently engage in coherent oscillation, often at specific stages in behavioural
or cognitive tasks. Much is now known about the dynamics underlying local circuit
synchronisation and the phenomenology of where and when such activity occurs. While
oscillations have been implicated in many high level processes, for most such phenomena we
cannot say with confidence precisely what they are doing at an algorithmic or implementational
level. This thesis presents work towards understanding the dynamics and possible function of large
scale oscillatory network activity. We first address the question of how coherent oscillatory activity
emerges between local networks by measuring phase response curves of an oscillating network in
vitro. The network phase response curves provide mechanistic insight into inter-region
synchronisation of local network oscillators. Highly simplified firing models are shown to
reproduce the experimental data with remarkable accuracy. We then focus on one hypothesised
computational function of network oscillations; flexibly controlling the gain of signal flow between
anatomically connected networks. We investigate coding strategies and algorithmic operations that
support flexible control of signal flow by oscillations, and their implementation by network
dynamics. We identify two readout algorithms which selectively recover population rate coded
signal with specific oscillatory modulations while ignoring other distracting inputs. By designing a
spiking network model that implements one of these mechanisms, we demonstrate oscillatory
control of signal flow in convergent pathways. We then investigate constraints on the structures of
oscillatory activity that can be used to accurately and selectively control signal flow. Our results
suggest that for inputs to be accurately distinguished from one another their oscillatory modulations
must be close to orthogonal. This has implications for interpreting in vivo oscillatory activity, and
may be an organising principle for the spatio-temporal structure of brain oscillations
Inference of Temporally Varying Bayesian Networks
When analysing gene expression time series data an often overlooked but
crucial aspect of the model is that the regulatory network structure may change
over time. Whilst some approaches have addressed this problem previously in the
literature, many are not well suited to the sequential nature of the data. Here
we present a method that allows us to infer regulatory network structures that
may vary between time points, utilising a set of hidden states that describe
the network structure at a given time point. To model the distribution of the
hidden states we have applied the Hierarchical Dirichlet Process Hideen Markov
Model, a nonparametric extension of the traditional Hidden Markov Model, that
does not require us to fix the number of hidden states in advance. We apply our
method to exisiting microarray expression data as well as demonstrating is
efficacy on simulated test data
Recommended from our members
Does visual flicker phase at gamma frequency modulate neural signal propagation and stimulus selection?
Oscillatory synchronization of neuronal populations has been proposed to play a role in perceptual integration and attentional processing. However, some conflicting evidence has been found with respect to its causal relevance for sensory processing, particularly when using flickering visual stimuli with the aim of driving oscillations. We tested psychophysically whether the relative phase of gamma frequency flicker (60 Hz) between stimuli modulates well-known facilitatory lateral interactions between collinear Gabor patches (Experiment 1) or crowding of a peripheral target by irrelevant distractors (Experiment 2). Experiment 1 assessed the impact of suprathreshold Gabor flankers on detection of a near-threshold central Gabor target (“Lateral interactions paradigm”). The flanking stimuli could flicker either in phase or in anti-phase with each other. The typical facilitation of target detection was found with collinear flankers, but this was unaffected by flicker phase. Experiment 2 employed a “crowding” paradigm, where orientation discrimination of a peripheral target Gabor patch is disrupted when surrounded by irrelevant distractors. We found the usual crowding effect, which declined with spatial separation, but this was unaffected by relative flicker phase between target and distractors at all separations. These results imply that externally driven manipulations of gamma frequency phase cannot modulate perceptual integration in vision
Retention in an antiretroviral therapy programme during an era of decreasing drug cost in Limbe, Cameroon
<p>Abstract</p> <p>Background</p> <p>In 2002, Cameroon initiated scale up of antiretroviral therapy (ART); on 1 October 2004, a substantial reduction in ART cost occurred. We assessed the impact of this event and other factors on enrolment and retention in care among HIV-infected patients initiating ART from February 2002 to December 2005 at the single ART clinic serving the Southwest Region in Limbe, Cameroon.</p> <p>Methods</p> <p>We retrospectively analyzed clinical and pharmacy payment records of HIV-infected patients initiating ART according to national guidelines. We compared two cohorts of patients, enrolled before and after 1 October 2004, to determine if price reduction was associated with enhanced enrolment. We assessed factors associated with retention and survival by Cox proportional hazards models. Retention in care implied patients who had contact with the healthcare system as of 31 December 2005 (including those who were transferred to continue care in other ART centres), although these patients may have interrupted therapy at some time. A patient who was not retained in care may have dropped out (lost to follow up) or died.</p> <p>Results</p> <p>Mean enrolment rates for 2920 patients who initiated ART before and after the price reduction were 46.5 and 95.5 persons/month, respectively (p < 0.001). The probabilities of remaining alive and in care were 0.66 (95% CI 0.64-0.68) at six months, 0.58 (95% CI 0.56-0.60) at one year, 0.47 (95% CI 0.45-0.49) at two years and 0.35 (95% CI 0.32-0.38) at three years; they were not significantly different between the two cohorts of patients enrolled before and after the price reduction over the first 15 months of comparable follow up (hazard ratio 1.1; 95% CI 0.9-1.2, p = 0.27). In multivariable analysis using multiple imputations to compensate for missing values, factors associated with dropping out of care or dying were male gender (HR 1.33 [1.18-1.50], p = 0.003), treatment paid by self, family or partly by other (HR 3.05 [1.99-4.67], p < 0.001), and, compared with residents of Limbe, living more than 150 km from Limbe (HR 1.41 [1.18-1.69], p < 0.001), or being residents of Douala (HR 1.51 [1.16-1.98], p < 0.001).</p> <p>Conclusions</p> <p>Reducing the cost of ART increased enrolment of clients in the programme, but did not change retention in care. In a system where most clients pay for ART, an accessible clinic location may be more important than the cost of medication for retention in care. Decentralizing ART clinics might improve retention and survival among patients on ART.</p
Does globalization and energy usage influence carbon emissions in South Asia? An empirical revisit of the debate
The 2030 United Nations Sustainable Development Goal (SDG) 13 agenda hinges on attaining a sustainable environment with the need to “take urgent action to combat climate change and its impacts”. Hence, this study empirically revisits the debate on the effect of nonrenewable energy and globalization on carbon emissions within the framework of the Kuznets hypothesis using an unbalanced panel data from seven South Asian countries (Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka) covering 1980–2019. The variables of interest are carbon emissions measured in metric tons per capita, energy use measured as kg of oil equivalent per capita, and globalization index. To address five main objectives, we deploy four techniques: panel-corrected standard errors (PCSE), feasible generalized least squares (FGLS), quantile regression (QR), and fully modified ordinary least squares (FMOLS). For the most part, the findings reveal that the (1) inverted U-shaped energy-Kuznets curve holds; (2) U-shaped globalization-Kuznets curve is evident; (3) inverted U-shaped turning points for nonrenewable energy are 496.03 and 640.84, while for globalization are 38.83 and 39.04, respectively; (4) globalization-emission relationship indicates a U-shaped relationship at the median and 75th quantile; and (5) inverted U-shaped energy-Kuznets holds in Pakistan but a U-shaped nexus prevails in Nepal and Sri Lanka; inverted U-shaped globalization-Kuznets holds in Bangladesh and Sri Lanka, but U-shaped nexus is evident in Bhutan, Maldives, and Nepal. Deductively, our results show that South Asia countries (at early stage of development) are faced with the hazardous substance that deteriorates human health. Moreover, the non-linear square term of the nonrenewable energy-emissions relationship is negative, which validates the inverted U-shaped EKC theory. Overall, the effect of energy and globalization on carbon emissions is opposite while the consistency at the 75th quantile result indicates that countries with intense globalization are prone to environmental degradation
Protein Crosslinking by Transglutaminase Controls Cuticle Morphogenesis in Drosophila
Transglutaminase (TG) plays important and diverse roles in mammals, such as blood coagulation and formation of the skin barrier, by catalyzing protein crosslinking. In invertebrates, TG is known to be involved in immobilization of invading pathogens at sites of injury. Here we demonstrate that Drosophila TG is an important enzyme for cuticle morphogenesis. Although TG activity was undetectable before the second instar larval stage, it dramatically increased in the third instar larval stage. RNA interference (RNAi) of the TG gene caused a pupal semi-lethal phenotype and abnormal morphology. Furthermore, TG-RNAi flies showed a significantly shorter life span than their counterparts, and approximately 90% of flies died within 30 days after eclosion. Stage-specific TG-RNAi before the third instar larval stage resulted in cuticle abnormality, but the TG-RNAi after the late pupal stage did not, indicating that TG plays a key role at or before the early pupal stage. Immediately following eclosion, acid-extractable protein from wild-type wings was nearly all converted to non-extractable protein due to wing maturation, whereas several proteins remained acid-extractable in the mature wings of TG-RNAi flies. We identified four proteins—two cuticular chitin-binding proteins, larval serum protein 2, and a putative C-type lectin—as TG substrates. RNAi of their corresponding genes caused a lethal phenotype or cuticle abnormality. Our results indicate that TG-dependent protein crosslinking in Drosophila plays a key role in cuticle morphogenesis and sclerotization
The Anterior Cingulate Cortex Predicts Future States to Mediate Model-Based Action Selection
Behavioral control is not unitary. It comprises parallel systems, model based and model free, that respectively generate flexible and habitual behaviors. Model-based decisions use predictions of the specific consequences of actions, but how these are implemented in the brain is poorly understood. We used calcium imaging and optogenetics in a sequential decision task for mice to show that the anterior cingulate cortex (ACC) predicts the state that actions will lead to, not simply whether they are good or bad, and monitors whether outcomes match these predictions. ACC represents the complete state space of the task, with reward signals that depend strongly on the state where reward is obtained but minimally on the preceding choice. Accordingly, ACC is necessary only for updating model-based strategies, not for basic reward-driven action reinforcement. These results reveal that ACC is a critical node in model-based control, with a specific role in predicting future states given chosen actions.Akam et al. investigate mouse anterior cingulate cortex (ACC) in a sequential decision-making task, finding that ACC predicts future states given chosen actions and indicates when these predictions are violated. Transiently inhibiting ACC prevents mice from using observed state transitions to guide subsequent choices, impairing model-based reinforcement learning
Robustness under Functional Constraint: The Genetic Network for Temporal Expression in Drosophila Neurogenesis
Precise temporal coordination of gene expression is crucial for many developmental processes. One central question in developmental biology is how such coordinated expression patterns are robustly controlled. During embryonic development of the Drosophila central nervous system, neural stem cells called neuroblasts express a group of genes in a definite order, which leads to the diversity of cell types. We produced all possible regulatory networks of these genes and examined their expression dynamics numerically. From the analysis, we identified requisite regulations and predicted an unknown factor to reproduce known expression profiles caused by loss-of-function or overexpression of the genes in vivo, as well as in the wild type. Following this, we evaluated the stability of the actual Drosophila network for sequential expression. This network shows the highest robustness against parameter variations and gene expression fluctuations among the possible networks that reproduce the expression profiles. We propose a regulatory module composed of three types of regulations that is responsible for precise sequential expression. This study suggests that the Drosophila network for sequential expression has evolved to generate the robust temporal expression for neuronal specification
A Rapid and Highly Sensitive Method of Non Radioactive Colorimetric In Situ Hybridization for the Detection of mRNA on Tissue Sections
Background: Non Radioactive colorimetric In Situ Hybridization (NoRISH) with hapten labeled probes has been widely used for the study of gene expression in development, homeostasis and disease. However, improvement in the sensitivity of the method is still needed to allow for the analysis of genes expressed at low levels. Methodology/Principal Findings: A stable, non-toxic, zinc-based fixative was tested in NoRISH experiments on sections of mouse embryos using four probes (Lhx6, Lhx7, ncapg and ret) that have different spatial patterns and expression levels. We showed that Z7 can successfully replace paraformaldehyde used so far for tissue fixation in NoRISH; the morphology of the cryosections of Z7-fixed tissues was excellent, and the fixation time required for tissues sized 1 cm was 1 hr instead of 24 hr for paraformaldehyde. The hybridization signal on the sections of the Z7-treated embryos always appeared earlier than that of the PFA-fixed embryos. In addition, a 50–60 % shorter detection time was observed in specimen of Z7-treated embryos, reducing significantly the time required to complete the method. Finally and most importantly, the strength of the hybridization signal on the sections of the Z7-treated embryos always compared favorably to that of the sections of PFAfixed embryos; these data demonstrate a significant improvement of the sensitivity the method that allows for the analysis of mRNAs that are barely or not detected by the standard colorimetric NoRISH method. Conclusions/Significance: Our NoRISH method provides excellent preservation of tissue morphology, is rapid, highl
- …