Canonical Melnikov theory for diffeomorphisms

We study perturbations of diffeomorphisms that have a saddle connection between a pair of normally hyperbolic invariant manifolds. We develop a first-order deformation calculus for invariant manifolds and show that a generalized Melnikov function or Melnikov displacement can be written in a canonical way. This function is defined to be a section of the normal bundle of the saddle connection. We show how our definition reproduces the classical methods of Poincar\'{e} and Melnikov and specializes to methods previously used for exact symplectic and volume-preserving maps. We use the method to detect the transverse intersection of stable and unstable manifolds and relate this intersection to the set of zeros of the Melnikov displacement.Comment: laTeX, 31 pages, 3 figure

Dominant B-cell epitopes from cancer/stem cell antigen SOC2 recognized by serum samples from cancer patients

Cataloged from PDF version of article.Human sex determining region Y-box 2 (SOX2) is an important transcriptional factor involved in the pluripotency and stemness of human embryonic stem cells. SOX2 plays important roles in maintaining cancer stem cell activities of melanoma and cancers of the brain, prostate, breast, and lung. SOX2 is also a lineage survival oncogene for squamous cell carcinoma of the lung and esophagus. Spontaneous cellular and humoral immune responses against SOX2 present in cancer patients classify it as a tumor-associated antigen (TAA) shared by lung cancer, glioblastoma, and prostate cancer among others. In this study, B-cell epitopes were predicted using computer-assisted algorithms. Synthetic peptides based on the prediction were screened for recognition by serum samples from cancer patients using ELISA. Two dominant B-cell epitopes, SOX2:52-87 and SOX2:98-124 were identified. Prostate cancer, glioblastoma and lung cancer serum samples that recognized the above SOX2 epitopes also recognized the full-length protein based on Western blot. These B-cell epitopes may be used in assessing humoral immune responses against SOX2 in cancer immunotherapy and stem cell-related transplantation

Antithetic and Monte Carlo kernel estimators for partial rankings

In the modern age, rankings data is ubiquitous and it is useful for a variety of applications such as recommender systems, multi-object tracking and preference learning. However, most rankings data encountered in the real world is incomplete, which prevents the direct application of existing modelling tools for complete rankings. Our contribution is a novel way to extend kernel methods for complete rankings to partial rankings, via consistent Monte Carlo estimators for Gram matrices: matrices of kernel values between pairs of observations. We also present a novel variance reduction scheme based on an antithetic variate construction between permutations to obtain an improved estimator for the Mallows kernel. The corresponding antithetic kernel estimator has lower variance and we demonstrate empirically that it has a better performance in a variety of Machine Learning tasks. Both kernel estimators are based on extending kernel mean embeddings to the embedding of a set of full rankings consistent with an observed partial ranking. They form a computationally tractable alternative to previous approaches for partial rankings data. An overview of the existing kernels and metrics for permutations is also provided

Exploring how people with chronic pain understand their pain: A qualitative study

A fundamental principle of pain management is educating patients on their pain using current neuroscience. However, current pain neurophysiology education (PNE) interventions show variable success in improving pain outcomes, and may be difficult to integrate with existing understanding of pain. This study aimed to investigate how people with chronic pain understand their pain, using qualitative exploration of their conceptualisations of pain, and how this understanding accommodated, or resisted, the messages of PNE. Twelve UK adults with chronic pain were recruited through advertisements on online pain networks. Semi-structured interviews were conducted remotely, with responses elicited using the Grid Elaboration Method (GEM) and then a PNE article. Participants' grid elaborations and responses to PNE were analysed using thematic analysis (TA). Three main themes were extracted from participants' grid elaborations: communicating pain, explaining pain and living with pain. These themes incorporated varied, inconsistent sub-themes: of pain as simultaneously experiential and conceptual; in the body and in the mind; diagnosable and inexplicable; manageable and insuperable. Generalised, meta-level agreement was identified in participants' PNE responses, but with doubts about its practical value. This study shows that people understand pain through inconsistent experiential models that may resist attempts at conceptual integration. Participants' elaborations showed diverse and dissonant conceptualisations, with experiential themes of restricted living; assault on the self; pursuit of understanding pain and abandonment of that pursuit. Responses, although unexpectedly compatible with PNE, suggested that PNE was perceived as intellectually engaging but practically inadequate. Experiential disconfirmation may be required for behavioural change inhibited by embedded fears and aversive experiences. UCL REC# 17833/003

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.Fil: Hutchison, M. A.. National Institutes of Health; Estados UnidosFil: Gu, X.. National Institutes of Health; Estados UnidosFil: Adrover, Martín Federico. National Institutes of Health; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Lee, M. R.. National Institutes of Health; Estados UnidosFil: Hnasko, T. S.. University of California at San Diego; Estados UnidosFil: Alvarez, V. A.. National Institutes of Health; Estados UnidosFil: Lu, W.. National Institutes of Health; Estados Unido

From Challenge to Opportunity: Virtual Qualitative Research During COVID-19 and Beyond

COVID-19 has required researchers to adapt methodologies for remote data collection. While virtual interviewing has traditionally received limited attention in the qualitative literature, recent adaptations to the pandemic have prompted increased discussion and adoption. Yet, current discussion has focussed on practical and ethical concerns and retained a tone of compromise, of coping in a crisis. This paper extends the nascent conversations begun prior to the pandemic to consider the wider methodological implications of video-call interviews. Beyond the short-term, practical challenges of the pandemic, these adaptations demonstrate scope for longer-term, beneficial digitalisation of both traditional and emergent interview methods. Updating traditional interview methods digitally has demonstrated how conversion to video interviewing proves beneficial in its own right. Virtual focus-group-based research during COVID-19, for example, accessed marginalised populations and elicited notable rapport and rich data, uniting people in synchronous conversation across many environments. Moreover, emergent interview methods such as the Grid Elaboration Method (a specialised free-associative method) demonstrated further digitalised enhancements, including effective online recruitment with flexible scheduling, virtual interactions with significant rapport, and valuable recording and transcription functions. This paper looks beyond the pandemic to future research contexts where such forms of virtual interviewing may confer unique advantages: supporting researcher and participant populations with mobility challenges; enhancing international research where researcher presence or travel may be problematic. When opportunities for traditional face-to-face methods return, the opportunity for virtual innovation should not be overlooked

Measurement Challenges for Cyber Cyber Digital Twins: Experiences from the Deployment of Facebook's WW Simulation System

A cyber cyber digital twin is a deployed software model that executes in tandem with the system it simulates, contributing to, and drawing from, the systems behaviour. This paper outlines Facebooks cyber cyber digital twin, dubbed WW, a twin of Facebooks WWW platform, built using web-enabled simulation. The paper focuses on the current research challenges and opportunities in the area of measurement. Measurement challenges lie at the heart of modern simulation. They directly impact how we use simulation outcomes for automated online and semi-Automated offline decision making. Measurements also encompas how we verify and validate those outcomes. Modern simulation systems are increasingly becoming more like cyber cyber digital twins, effectively moving from manual to automated decision making, hence, these measurement challenges acquire ever greater significance

Exploring how people with chronic pain understand their pain: a qualitative study

Objectives A fundamental principle of pain management is educating patients on their pain using current neuroscience. However, current pain neurophysiology education (PNE) interventions show variable success in improving pain outcomes, and may be difficult to integrate with existing understanding of pain. This study aimed to investigate how people with chronic pain understand their pain, using qualitative exploration of their conceptualisations of pain, and how this understanding accommodated, or resisted, the messages of PNE. Methods Twelve UK adults with chronic pain were recruited through advertisements on online pain networks. Semi-structured interviews were conducted remotely, with responses elicited using the Grid Elaboration Method (GEM) and then a PNE article. Participants’ grid elaborations and responses to PNE were analysed using thematic analysis (TA). Results Three main themes were extracted from participants' grid elaborations: communicating pain, explaining pain and living with pain. These themes incorporated varied, inconsistent sub-themes: of pain as simultaneously experiential and conceptual; in the body and in the mind; diagnosable and inexplicable; manageable and insuperable. Generalised, meta-level agreement was identified in participants' PNE responses, but with doubts about its practical value. Conclusions This study shows that people understand pain through inconsistent experiential models that may resist attempts at conceptual integration. Participants' elaborations showed diverse and dissonant conceptualisations, with experiential themes of restricted living; assault on the self; pursuit of understanding pain and abandonment of that pursuit. Responses, although unexpectedly compatible with PNE, suggested that PNE was perceived as intellectually engaging but practically inadequate. Experiential disconfirmation may be required for behavioural change inhibited by embedded fears and aversive experiences