Observation of b2_2 symmetry vibrational levels of the SO2_2 \tilde{\mbox{C}} 1^1B2_2 state: Vibrational level staggering, Coriolis interactions, and rotation-vibration constants

The $\mathrm{\tilde{C}}$ $^1$B$_2$ state of SO$_2$ has a double-minimum potential in the antisymmetric stretch coordinate, such that the minimum energy geometry has nonequivalent SO bond lengths. However, low-lying levels with odd quanta of antisymmetric stretch (b$_2$ vibrational symmetry) have not previously been observed because transitions into these levels from the zero-point level of the $\mathrm{\tilde{X}}$ state are vibronically forbidden. We use IR-UV double resonance to observe the b$_2$ vibrational levels of the $\mathrm{\tilde{C}}$ state below 1600 cm$^{-1}$ of vibrational excitation. This enables a direct characterization of the vibrational level staggering that results from the double-minimum potential. In addition, it allows us to deperturb the strong $c$-axis Coriolis interactions between levels of a$_1$ and b$_2$ vibrational symmetry, and to determine accurately the vibrational dependence of the rotational constants in the distorted $\mathrm{\tilde{C}}$ electronic state

Perceptions of health risk among parents of overweight children: a cross-sectional study within a cohort.

OBJECTIVE: To identify the socio-demographic and behavioural characteristics associated with perceptions of weight-related health risk among the parents of overweight children. METHODS: Baseline data from a cohort of parents of children aged 4-11 years in five areas in England in 2010-2011 were analysed; the sample was restricted to parents of overweight children (body mass index ≥ 91(st) centile of UK 1990 reference; n=579). Associations between respondent characteristics and parental perception of health risk associated with their child's weight were examined using logistic regression analyses. RESULTS: Most parents (79%) did not perceive their child's weight to be a health risk. Perception of a health risk was associated with recognition of the child's overweight status (OR 10.59, 95% CI 5.51 to 20.34), having an obese child (OR 4.21, 95% CI 2.28 to 7.77), and having an older child (OR 2.67, 95% CI 1.32 to 5.41). However, 41% of parents who considered their child to be overweight did not perceive a health risk. CONCLUSIONS: Parents that recognise their child's overweight status, and the parents of obese and older children, are more likely to perceive a risk. However, many parents that acknowledge their child is overweight do not perceive a related health risk

The importance of broadband for socio-economic development: a perspective from rural Australia

Advanced connectivity offers rural communities prospects for socio-economic development. Despite Australia’s national broadband infrastructure plans, inferior availability and quality of rural Internet connections remain persistent issues. This article examines the impact of limited connectivity on rural socio-economic opportunities, drawing from the views of twelve citizens from the Boorowa local government area in New South Wales. The available fixed wireless and satellite connections in Boorowa are slow and unreliable, and remote regions in the municipality are still without any Internet access. Participants identified four key areas in their everyday lives that are impacted by insufficient connectivity: business development, education, emergency communication, and health. Rural citizens often already face challenges in these areas, and infrastructure advancements in urban spaces can exacerbate rural-urban disparities. Participants’ comments demonstrated apprehension that failure to improve connectivity would result in adverse long-term consequences for the municipality. This article suggests that current broadband policy frameworks require strategic adaptations to account for the socio-economic and geographic contexts of rural communities. In order to narrow Australia’s rural-urban digital divide, infrastructure developments should be prioritised in the most underserved regions

Digital biomarkers of physical frailty and frailty phenotypes using sensor-based physical activity and machine learning

Remote monitoring of physical frailty is important to personalize care for slowing down the frailty process and/or for the healthy recovery of older adults following acute or chronic stressors. Taking the Fried frailty criteria as a reference to determine physical frailty and frailty phenotypes (slowness, weakness, exhaustion, inactivity), this study aimed to explore the benefit of machine learning to determine the least number of digital biomarkers of physical frailty measurable from a pendant sensor during activities of daily living. Two hundred and fifty-nine older adults were classified into robust or pre-frail/frail groups based on the physical frailty assessments by the Fried frailty criteria. All participants wore a pendant sensor at the sternum level for 48 h. Of seventeen sensor-derived features extracted from a pendant sensor, fourteen significant features were used for machine learning based on logistic regression modeling and a recursive feature elimination technique incorporating bootstrapping. The combination of percentage time standing, percentage time walking, walking cadence, and longest walking bout were identified as optimal digital biomarkers of physical frailty and frailty phenotypes. These findings suggest that a combination of sensor-measured exhaustion, inactivity, and speed have potential to screen and monitor people for physical frailty and frailty phenotypes

XIAP upregulates expression of HIF target genes by targeting HIF1 alpha for Lys(63)-linked polyubiquitination

The cellular response to hypoxia is characterised by a switch in the transcriptional program, mediated predominantly by the hypoxia inducible factor family of transcription factors (HIF). Regulation of HIF1 is primarily controlled by post-translational modification of the HIF1α subunit, which can alter its stability and/or activity. This study identifies an unanticipated role for the X-linked inhibitor of apoptosis (XIAP) protein as a regulator of Lys63-linked polyubiquitination of HIF1α. Lys63-linked ubiquitination of HIF1α by XIAP is dependent on the activity of E2 ubiquitin conjugating enzyme Ubc13. We find that XIAP and Ubc13 dependent Lys63-linked polyubiquitination promotes HIF1α nuclear retention leading to an increase in the expression of HIF1 responsive genes. Inhibition of the Lys63-linked polyubiquitination pathway leads to reduced levels of nuclear HIF1α, promoter occupancy, HIF-dependent gene expression and cell viability. Our data reveals an additional and significant level of control of the HIF1 by XIAP, with important implications in understanding the role of HIF1 and XIAP in human disease

The role of NF-kB in the response to reoxygenation-induced oxidative stress

PhD ThesisHypoxia followed by rapid reoxygenation within the body can lead to cell and tissue damage through the production of reactive oxygen species (ROS) and the resulting oxidative stress. This ischemia and reperfusion is associated with a number of common human diseases such as cancer, stroke and cardiovascular conditions. The cellular response to oxidative stress is characterised by post-translational modification and changes in gene expression. This project focusses on how oxidative stress induced by hypoxia and rapid reoxygenation affects the activation of NF-κB; a rapidly-acting transcription factor that plays a key role in the eukaryotic cell response to infection, radiation and oxidative stress. NF-κB is perpetually activated in a variety of common human diseases such as heart disease, chronic inflammation and cancer; conditions that are also associated with oxidative stress. Investigations presented in this thesis demonstrate the profound effects that hypoxia and reoxygenation have on cell biology, as well as highlighting how these opposite stimuli are so closely connected. The effects of hypoxia and reoxygenation on the cell cycle, DNA damage, cell proliferation and cell survival are all explored in this project, giving great insight into the possible mechanisms at work in response to these stresses. It has been demonstrated previously that certain members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family such as Ataxia Telangiectasia-Mutated (ATM) are able to coordinate the activation of NF-κB pathways in response to specific stimuli such as following DNA damage or oxidative stress. This project has identified a novel role of another member of this family, Ataxia Telangiectasia and Rad-3-related protein (ATR) in the NF-κB response to reoxygenation-induced oxidative stress

Outcomes following oesophagectomy in patients with oesophageal cancer: a secondary analysis of the ICNARC Case Mix Programme Database

Introduction: This report describes the case mix and outcomes of patients with oesophageal cancer admitted to adult critical care units following elective oesophageal surgery in England, Wales and Northern Ireland. Methods: Admissions to critical care following elective oesophageal surgery for malignancy were identified using data from the Intensive Care National Audit and Research Centre (ICNARC) Case Mix Programme Database. Information on admissions between December 1995 and September 2007 were extracted and the association between in-hospital mortality and patient characteristics on admission to critical care was assessed using multiple logistic regression analysis. The performance of three prognostic models (Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II and the ICNARC physiology score) was also evaluated. Results: Between 1995 and 2007, there were 7227 admissions to 181 critical care units following oesophageal surgery for malignancy. Overall mortality in critical care was 4.4% and in-hospital mortality was 11%, although both declined steadily over time. Eight hundred and seventy-three (12.2%) patients were readmitted to critical care, most commonly for respiratory complications (49%) and surgical complications (25%). Readmitted patients had a critical care unit mortality of 24.7% and in-hospital mortality of 33.9%. Overall in-hospital mortality was associated with patient age, and various physiological measurements on admission to critical care (partial pressure of arterial oxygen (PaO2):fraction of inspired oxygen (FiO2) ratio, lowest arterial pH, mechanical ventilation, serum albumin, urea and creatinine). The three prognostic models evaluated performed poorly in measures of discrimination, calibration and goodness of fit. Conclusions: Surgery for oesophageal malignancy continues to be associated with significant morbidity and mortality. Age and organ dysfunction in the early postoperative period are associated with an increased risk of death. Postoperative serum albumin is confirmed as an additional prognostic factor. More work is required to determine how this knowledge may improve clinical management

PERK/eIF2 alpha signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1 alpha translation

HIF1α (hypoxia inducible factor 1α) is the central regulator of the cellular response to low oxygen and its activity is deregulated in multiple human pathologies. Consequently, given the importance of HIF signaling in disease, there is considerable interest in developing strategies to modulate HIF1α activity and down-stream signaling events. In the present study we find that under hypoxic conditions, activation of the PERK branch of the unfolded protein response (UPR) can suppress the levels and activity of HIF1α by preventing efficient HIF1α translation. Activation of PERK inhibits de novo HIF1α protein synthesis by preventing the RNA-binding protein, YB-1, from interacting with the HIF1α mRNA 5′UTR. Our data indicate that activation of the UPR can sensitise tumor cells to hypoxic stress, indicating that chemical activation of the UPR could be a strategy to target hypoxic malignant cancer cells