Continuity of Local Time: An applied perspective

Continuity of local time for Brownian motion ranks among the most notable mathematical results in the theory of stochastic processes. This article addresses its implications from the point of view of applications. In particular an extension of previous results on an explicit role of continuity of (natural) local time is obtained for applications to recent classes of problems in physics, biology and finance involving discontinuities in a dispersion coefficient. The main theorem and its corollary provide physical principles that relate macro scale continuity of deterministic quantities to micro scale continuity of the (stochastic) local time.Comment: To appear in: "The fascination of Probability, Statistics and Their Applications. In honour of Ole E. Barndorff-Nielsen on his 80th birthday

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization

Towards a General Theory of Neural Computation Based on Prediction by Single Neurons

Although there has been tremendous progress in understanding the mechanics of the nervous system, there has not been a general theory of its computational function. Here I present a theory that relates the established biophysical properties of single generic neurons to principles of Bayesian probability theory, reinforcement learning and efficient coding. I suggest that this theory addresses the general computational problem facing the nervous system. Each neuron is proposed to mirror the function of the whole system in learning to predict aspects of the world related to future reward. According to the model, a typical neuron receives current information about the state of the world from a subset of its excitatory synaptic inputs, and prior information from its other inputs. Prior information would be contributed by synaptic inputs representing distinct regions of space, and by different types of non-synaptic, voltage-regulated channels representing distinct periods of the past. The neuron's membrane voltage is proposed to signal the difference between current and prior information (“prediction error” or “surprise”). A neuron would apply a Hebbian plasticity rule to select those excitatory inputs that are the most closely correlated with reward but are the least predictable, since unpredictable inputs provide the neuron with the most “new” information about future reward. To minimize the error in its predictions and to respond only when excitation is “new and surprising,” the neuron selects amongst its prior information sources through an anti-Hebbian rule. The unique inputs of a mature neuron would therefore result from learning about spatial and temporal patterns in its local environment, and by extension, the external world. Thus the theory describes how the structure of the mature nervous system could reflect the structure of the external world, and how the complexity and intelligence of the system might develop from a population of undifferentiated neurons, each implementing similar learning algorithms

Information content and reward processing in the human striatum during performance of a declarative memory task

Negative feedback can signal poor performance, but it also provides information that can help learners reach the goal of task mastery. The primary aim of this study was to test the hypothesis that the amount of information provided by negative feedback during a paired-associate learning task influences feedback-related processing in the caudate nucleus. To do this, we manipulated the number of response options: With two options, positive and negative feedback provide equal amounts of information, whereas with four options, positive feedback provides more information than does negative feedback. We found that positive and negative feedback activated the caudate similarly when there were two response options. With four options, the caudate’s response to negative feedback was reduced. A secondary goal was to investigate the link between brain-based measures of feedback-related processing and behavioral indices of learning. Analysis of the posttest measures showed that trials with positive feedback were associated with higher posttest confidence ratings. Additionally, when positive feedback was delivered, caudate activity was greater for trials with high than with low posttest confidence. This experiment demonstrated the context sensitivity of feedback processing and provided evidence that feedback processing in the striatum can contribute to the strengthening of the representations available within declarative memory

Participatory monitoring and evaluation approaches that influence decision-making: lessons from a maternal and newborn study in Eastern Uganda

BACKGROUND: The use of participatory monitoring and evaluation (M&E) approaches is important for guiding local decision-making, promoting the implementation of effective interventions and addressing emerging issues in the course of implementation. In this article, we explore how participatory M&E approaches helped to identify key design and implementation issues and how they influenced stakeholders’ decision-making in eastern Uganda. METHOD: The data for this paper is drawn from a retrospective reflection of various M&E approaches used in a maternal and newborn health project that was implemented in three districts in eastern Uganda. The methods included qualitative and quantitative M&E techniques such as key informant interviews, formal surveys and supportive supervision, as well as participatory approaches, notably participatory impact pathway analysis. RESULTS: At the design stage, the M&E approaches were useful for identifying key local problems and feasible local solutions and informing the activities that were subsequently implemented. During the implementation phase, the M&E approaches provided evidence that informed decision-making and helped identify emerging issues, such as weak implementation by some village health teams, health facility constraints such as poor use of standard guidelines, lack of placenta disposal pits, inadequate fuel for the ambulance at some facilities, and poor care for low birth weight infants. Sharing this information with key stakeholders prompted them to take appropriate actions. For example, the sub-county leadership constructed placenta disposal pits, the district health officer provided fuel for ambulances, and health workers received refresher training and mentorship on how to care for newborns. CONCLUSION: Diverse sources of information and perspectives can help researchers and decision-makers understand and adapt evidence to contexts for more effective interventions. Supporting districts to have crosscutting, routine information generating and sharing platforms that bring together stakeholders from different sectors is therefore crucial for the successful implementation of complex development interventions

Human Processing of Behaviorally Relevant and Irrelevant Absence of Expected Rewards: A High-Resolution ERP Study

Acute lesions of the posterior medial orbitofrontal cortex (OFC) in humans may induce a state of reality confusion marked by confabulation, disorientation, and currently inappropriate actions. This clinical state is strongly associated with an inability to abandon previously valid anticipations, that is, extinction capacity. In healthy subjects, the filtering of memories according to their relation with ongoing reality is associated with activity in posterior medial OFC (area 13) and electrophysiologically expressed at 220–300 ms. These observations indicate that the human OFC also functions as a generic reality monitoring system. For this function, it is presumably more important for the OFC to evaluate the current behavioral appropriateness of anticipations rather than their hedonic value. In the present study, we put this hypothesis to the test. Participants performed a reversal learning task with intermittent absence of reward delivery. High-density evoked potential analysis showed that the omission of expected reward induced a specific electrocortical response in trials signaling the necessity to abandon the hitherto reward predicting choice, but not when omission of reward had no such connotation. This processing difference occurred at 200–300 ms. Source estimation using inverse solution analysis indicated that it emanated from the posterior medial OFC. We suggest that the human brain uses this signal from the OFC to keep thought and behavior in phase with reality

IL-6 Stabilizes Twist and Enhances Tumor Cell Motility in Head and Neck Cancer Cells through Activation of Casein Kinase 2

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide. Unfortunately, the survival of patients with SCCHN has not improved in the last 40 years, and thus new targets for therapy are needed. Recently, elevations in serum level of interleukin 6 (IL-6) and expression of Twist in tumor samples were found to be associated with poor clinical outcomes in multiple types of cancer, including SCCHN. Although Twist has been proposed as a master regulator of epithelial-mesenchymal transition and metastasis in cancers, the mechanisms by which Twist levels are regulated post-translationally are not completely understood. Tumor progression is characterized by the involvement of cytokines and growth factors and Twist induction has been connected with a number of these signaling pathways including IL-6. Since many of the effects of IL-6 are mediated through activation of protein phosphorylation cascades, this implies that Twist expression must be under a tight control at the post-translational level in order to respond in a timely manner to external stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Our data show that IL-6 increases Twist expression via a transcription-independent mechanism in many SCCHN cell lines. Further investigation revealed that IL-6 stabilizes Twist in SCCHN cell lines through casein kinase 2 (CK2) phosphorylation of Twist residues S18 and S20, and that this phosphorylation inhibits degradation of Twist. Twist phosphorylation not only increases its stability but also enhances cell motility. Thus, post-translational modulation of Twist contributes to its tumor-promoting properties. CONCLUSIONS/SIGNIFICANCE: Our study shows Twist expression can be regulated at the post-translational level through phosphorylation by CK2, which increases Twist stability in response to IL-6 stimulation. Our findings not only provide novel mechanistic insights into post-translational regulation of Twist but also suggest that CK2 may be a viable therapeutic target in SCCHN

MicroRNA profiling of diverse endothelial cell types

<p>Abstract</p> <p>Background</p> <p>MicroRNAs are ~22-nt long regulatory RNAs that serve as critical modulators of post-transcriptional gene regulation. The diversity of miRNAs in endothelial cells (ECs) and the relationship of this diversity to epithelial and hematologic cells is unknown. We investigated the baseline miRNA signature of human ECs cultured from the aorta (HAEC), coronary artery (HCEC), umbilical vein (HUVEC), pulmonary artery (HPAEC), pulmonary microvasculature (HPMVEC), dermal microvasculature (HDMVEC), and brain microvasculature (HBMVEC) to understand the diversity of miRNA expression in ECs.</p> <p>Results</p> <p>We identified 166 expressed miRNAs, of which 3 miRNAs (miR-99b, miR-20b and let-7b) differed significantly between EC types and predicted EC clustering. We confirmed the significance of these miRNAs by RT-PCR analysis and in a second data set by Sylamer analysis. We found wide diversity of miRNAs between endothelial, epithelial and hematologic cells with 99 miRNAs shared across cell types and 31 miRNAs unique to ECs. We show polycistronic miRNA chromosomal clusters have common expression levels within a given cell type.</p> <p>Conclusions</p> <p>EC miRNA expression levels are generally consistent across EC types. Three microRNAs were variable within the dataset indicating potential regulatory changes that could impact on EC phenotypic differences. MiRNA expression in endothelial, epithelial and hematologic cells differentiate these cell types. This data establishes a valuable resource characterizing the diverse miRNA signature of ECs.</p