Uncovering the hidden mechanisms governing the transcriptional regulation of inflammation

Inflammation provides broad immunological protection that is essential for our survival. This cellular response is characterised by a biphasic cycle consisting of an initial acute pro-inflammatory phase and a subsequent resolving anti-inflammatory phase. Underlying each of these phases are changes in the expression of hundreds of immune genes, which encode for inflammatory mediators called cytokines. Importantly, the biphasic nature of inflammation requires cytokine expression to be highly regulated and coordinated to different timescales during each phase of inflammation. For the initial proinflammatory response, cytokine expression needs to be rapid and robust to efficiently initiate host defence mechanisms and provide effective immunological protection. In contrast, the expression of anti-inflammatory cytokines is temporally delayed to ensure that anti-inflammation always follows pro-inflammation. In order to choreograph the expression of these cytokines during inflammation, numerous mechanisms within the cell serve to regulate and coordinate cytokine transcription. Within the eukaryotic nucleus, multiple modes of transcriptional regulation function cooperatively to provide the regulatory capacity that is required for complex transcription patterns to emerge. These include the organisation of the genome, which confine cognate chromosomal contacts that are causal to transcription, and long-non coding RNAs (lncRNAs) that function to discretely fine tune transcriptional activity. Although many of the mechanisms that regulate transcription have been well described, their role in cytokine expression during inflammation remains largely unknown. In particular, the mechanisms that facilitate rapid and robust cytokine expression during proinflammation and the regulatory networks that coordinate the biphasic regulation of inflammation are unresolved. In this work, two novel lncRNAs were discovered to transcriptionally regulate these key features of cytokine expression during inflammation. The first, UMLILO (Upstream Master LncRNA of the Inflammatory chemokine LOcus), was found to emanate from the ELR+ CXCL chemokine TAD and regulate the transcriptional activation of the pro-inflammatory ELR+ CXCL chemokines (IL-8, CXCL1, CXCL2 and CXCL3). By exploiting the pre-formed local 3D topology, UMLILO is able to epigenetically prime the chemokines for transcriptional activation. This involves the discrete deposition of H3K4me3 onto the promoters of the chemokines, which allows for the pre-loading of transcriptional machinery prior to their signal-dependent activation. This reveals a fundamental mechanism for the epigenetic priming and rapid activation of pro-inflammatory cytokine genes. The second lncRNA, called AMANZI (A MAster Non-coding RNA antagoniZing Inflammation), was found to coordinate the transcription of two functionally opposed cytokines: the master pro-inflammatory IL-1β and the broad antiinflammatory IL-37. AMANZI is encoded in the promoter of IL-1β, which results in its concomitant expression when IL-1β is transcriptionally active. Functionally, AMANZI mediates the formation of a dynamic chromosomal contact between IL-1β and IL-37. This leads to the delayed transcriptional activation of IL-37 ensuring that the pro-inflammatory function of IL-1β precedes IL-37 mediated anti-inflammation. This revealed a novel biphasic circuit that coordinated the expression of IL-1β and IL-37, through the activity of AMANZI, to regulate the two functionally opposed states of inflammation. Clinical observations in healthy individuals revealed that a polymorphism occurring in AMANZI (rs16944) was able to augment the state of this genetic circuit and shift the relative levels of IL-1β and IL-37 to influence an individual's inflammatory capacity. This affected the establishment of innate immunological memory, which is involved in the progression of many inflammatory conditions and the efficacy of certain vaccines. The work described here uncovers novel mechanisms that transcriptionally regulate key features of the inflammatory response. Importantly, this work implicates the role of two novel lncRNAs in inflammation, essentially contributing to the functional annotation to the genome and providing novel targets for the modulation of pathogenic inflammation

The prevalence of problem-drinking and other health-related behaviours in a sample of Hong Kong general hospital patients

Author name used in this publication: David ArthurAuthor name used in this publication: Leung Sau FongVersion of RecordPublishe

Detection of Children Abuse by Voice and Audio Classification by Short-Time Fourier Transform Machine Learning implemented on Nvidia Edge GPU device

The safety of children in children home has become an increasing social concern, and the purpose of this experiment is to use machine learning applied to detect the scenarios of child abuse to increase the safety of children. This experiment uses machine learning to classify and recognize a child's voice and predict whether the current sound made by the child is crying, screaming or laughing. If a child is found to be crying or screaming, an alert is immediately sent to the relevant personnel so that they can perceive what the child may be experiencing in a surveillance blind spot and respond in a timely manner. Together with a hybrid use of video image classification, the accuracy of child abuse detection can be significantly increased. This greatly reduces the likelihood that a child will receive violent abuse in the nursery and allows personnel to stop an imminent or incipient child abuse incident in time. The datasets collected from this experiment is entirely from sounds recorded on site at the children home, including crying, laughing, screaming sound and background noises. These sound files are transformed into spectrograms using Short-Time Fourier Transform, and then these image data are imported into a CNN neural network for classification, and the final trained model can achieve an accuracy of about 92% for sound detection.Comment: 5 pages, 7 figures, PRAI 202

Buildup of the ring current during periodic loading‐unloading cycles in the magnetotail driven by steady southward interplanetary magnetic field

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95239/1/jgra18825.pd

The prevalence of problem drinking and other health-related behaviours in a sample of Hong Kong general hospital patients

Objective: Little research evidence is available on the prevalence of problem drinking and other health related behaviours in Hong Kong. The purpose of this study was to test the utility, the validity and reliability of the AUDIT, a well-tested and validated screening instrument for alcohol consumption, in the Chinese language and with a sample of Hong Kong hospital patients. The study examined the prevalence of problem-drinkers amongst a sample of general hospital patients and compared this to the prevalence of other health-related behaviours. Method: The AUDIT was translated into Chinese and embedded in a broader lifestyle questionnaire and administered to a convenience sample of 121 general hospital patients in a busy Hong Kong general hospital. Results: 44% of the sample had received no formal education or were educated at the primary level and the respondents felt the people who should be interested in their health were relatives and friends ahead of doctors and nurses. The sample expressed they had a definite weight problem (28%); an eating problem (16%); a smoking problem (22%); a drinking problem (4%) and a fitness problem (23%). The AUDIT proved internally consistent and was able to detect that 44% of the respondents were non-drinkers and that 11 % were drinking at a hazardous or harmful level. Conclusions: The findings encouraged the future use of this Chinese version of the AUDIT in future research and provided useful baseline data for health related behaviours as well as suggesting that Hong Kong health care workers consider seriously their role in working with people and their families in relation to health promotion and education

Dynamic Boundaries in Asymmetric Exclusion Processes

We investigate the dynamics of a one-dimensional asymmetric exclusion process with Langmuir kinetics and a fluctuating wall. At the left boundary, particles are injected onto the lattice; from there, the particles hop to the right. Along the lattice, particles can adsorb or desorb, and the right boundary is defined by a wall particle. The confining wall particle has intrinsic forward and backward hopping, a net leftward drift, and cannot desorb. Performing Monte Carlo simulations and using a moving-frame finite segment approach coupled to mean field theory, we find the parameter regimes in which the wall acquires a steady state position. In other regimes, the wall will either drift to the left and fall off the lattice at the injection site, or drift indefinitely to the right. Our results are discussed in the context of non-equilibrium phases of the system, fluctuating boundary layers, and particle densities in the lab frame versus the frame of the fluctuating wall.Comment: 13 page

Plasmasphere Modeling with Ring Current Heating

Coulomb collisions between ring current ions and the thermal plasma in the plasmasphere will heat the plasmaspheric electrons and ions. During a storm such heating would lead to significant changes in the temperature and density of the thermal plasma. This was modeled using a time- dependent, one-stream hydrodynamic model for plasmaspheric flows, in which the model flux tube is connected to the ionosphere. The model simultaneously solves the coupled continuity, momentum, and energy equations of a two-ion (H(+) and O(+) quasineutral, currentless plasma. Heating rates due to collisions with ring current ions were calculated along the field line using a kinetic ring current model. First, diurnally reproducible results were found assuming only photoelectron heating of the thermal electrons. Then results were found with heating of the H(+) ions by the ring current during the recovery phase of a magnetic storm

Mathematical models for vulnerable plaques

A plaque is an accumulation and swelling in the artery walls and typically consists of cells, cell debris, lipids, calcium deposits and fibrous connective tissue. A person is likely to have many plaques inside his/her body even if they are healthy. However plaques may become "vulnerable", "high-risk" or "thrombosis-prone" if the person engages in a high-fat diet and does not exercise regularly. In this study group, we proposed two mathematical models to describe plaque growth and rupture. The first model is a mechanical one that approximately treats the plaque as an inflating elastic balloon. In this model, the pressure inside the core increases and then decreases suggesting that plaque stabilization and prevention of rupture is possible. The second model is a biochemical one that focuses on the role of MMPs in degrading the fibrous plaque cap. The cap stress, MMP concentration, plaque volume and cap thickness are coupled together in a system of phenomenological equations. The equations always predict an eventual rupture since the volume, stresses and MMP concentrations generally grow without bound. The main weakness of the model is that many of the important parameters that control the behavior of the plaque are unknown. The two simple models suggested by this group could serve as a springboard for more realistic theoretical studies. But most importantly, we hope they will motivate more experimental work to quantify some of the important mechanical and biochemical properties of vulnerable plaques

Anisotropic diffusion in continuum relaxation of stepped crystal surfaces

We study the continuum limit in 2+1 dimensions of nanoscale anisotropic diffusion processes on crystal surfaces relaxing to become flat below roughening. Our main result is a continuum law for the surface flux in terms of a new continuum-scale tensor mobility. The starting point is the Burton, Cabrera and Frank (BCF) theory, which offers a discrete scheme for atomic steps whose motion drives surface evolution. Our derivation is based on the separation of local space variables into fast and slow. The model includes: (i) anisotropic diffusion of adsorbed atoms (adatoms) on terraces separating steps; (ii) diffusion of atoms along step edges; and (iii) attachment-detachment of atoms at step edges. We derive a parabolic fourth-order, fully nonlinear partial differential equation (PDE) for the continuum surface height profile. An ingredient of this PDE is the surface mobility for the adatom flux, which is a nontrivial extension of the tensor mobility for isotropic terrace diffusion derived previously by Margetis and Kohn. Approximate, separable solutions of the PDE are discussed.Comment: 14 pages, 1 figur