Photoplethysmography for Quantitative Assessment of Sympathetic Nerve Activity (SNA) During Cold Stress

The differences in the degree of sympathetic nerve activity (SNA) over cutaneous blood vessels, although known to be more prominent in the periphery than the core vasculature, has not been thoroughly investigated quantitatively. Hence, two studies were carried out to investigate the differences in SNA between the periphery and the core during the cold pressor test (CPT) (right-hand immersion in ice water) and cold exposure (whole body exposed to cold air) using photoplethysmography (PPG). Two methods utilizing PPG, namely differential multi-site PTT measurements and low-frequency spectral analysis were explored for quantitative determination of SNA. Each study involved 12 healthy volunteers, and PPG signals were acquired from the right index finger (RIF), left index finger (LIF) (periphery) and the ear canal (core). During CPT, Pulse Transit Time (PTT) was measured to the respective locations and the mean percentage change in PTT during ice immersion at each location was used as an indicator for the extent of SNA. During cold exposure, the low-frequency spectral analysis was performed on the acquired raw PPGs to extract the power of the sympathetic [low-frequency (LF): 0.04–0.15 Hz] and parasympathetic components [high-frequency (HF): 0.15–0.4 Hz]. The ratio of LF/HF components was then used to quantify the differences in the influence of SNA on the peripheral and core circulation. PTT measured from the EC, and the LIF has dropped by 5 and 7%, respectively during ice immersion. The RIF PTT, on the other hand, has dropped significantly (P < 0.05) by 12%. During the cold exposure, the LF/HF power ratio at the finger has increased to 86.4 during the cold exposure from 19.2 at the baseline (statistically significant P = 0.002). While the ear canal LF/HF ratio has decreased to 1.38 during the cold exposure from 1.62 at baseline (P = 0.781). From these observations, it is evident that differential PTT measurements or low-frequency analysis can be used to quantify SNA. The results also demonstrate the effectiveness of the central auto-regulation during both short and long-term stress stimulus as compared to the periphery

Daily, Weekly and Monthly Variation in Lunch Time Calories

Introduction & Background Despite the level of attention that healthy and unhealthy eating receive from academic research, policymakers and the wider public, objective data on food consumption is limited. This is because studies of individual eating patterns using food diaries are subject to underreporting, particularly by people who are overweight. For example, the UK population is estimated to consume between 30% to 50% more calories than they report in surveys. New data sources such as office canteen ordering systems and individual records of supermarket transactions recorded through supermarket loyalty or bonus cards offer larger and potentially more robust data on real world individual eating behaviours. Objectives & Approach We used 2,831,403 machine-recorded ‘meal deal’ transactions from 205,781 individuals over the course of one year from one of the UK’s largest suppliers of lunch time foods to investigate whether there is a relationship between patterns of choice and higher calorie consumption. A meal deal comprises three items; a main (e.g., a sandwich or a salad), a snack (e.g., crisps, fruit or a chocolate bar) and a drink (e.g., a smoothie or a bottle of water). In contrast to diary studies or aggregate transactional data from supermarkets, our dataset included “meal deal’ purchase which is highly likely to be made by an individual for their own consumption or soon afterwards. Relevance to Digital Footprints Lunch time food consumption can reflect the overall diet the individual is exposed to, helping to understand population level patterns of people’s food choices through a type of digital footprints data - shopping history records. Results Controlling for gender, general index of variety in the choice of lunch food items, income and education, we found that individuals who vary in their calorie consumption most across the time of day, day of the week, and month of the year are the individuals who consume the greatest number of calories overall. These time sensitivity effects are large, together explaining a substantial amount of variance in calorie consumption. Time sensitivity effects are strongly correlated across all three time scales suggesting they measure a stable underlying trait. Conclusions & Implications Individuals vary calorific composition of their lunch over time of the day, day of the week and month of the year by 100 calories per meal between highest and lowest in sensitivity which is about 9% of the recommended amount of lunchtime calories. Those whose consumption varies the most with time consume the most calories, independently of income and gender. The variation in calories at all three time scales demonstrates the properties of an individual disposition. These findings can be used to understand why and when people make unhealthy food choices

Characterization of Postjunctional Alpha-i and Alpha -2 Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Vein

Experiments were designed to characterize alpha-i and alpha-2 adrenoceptor-mediated effects in the canine saphenou

Thrombosis Is Reduced by Inhibition of COX-1, but Unaffected by Inhibition of COX-2, in an Acute Model of Platelet Activation in the Mouse

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Cancer stem cells, not bulk tumor cells, determine mechanisms of resistance to SMO inhibitors.

The emergence of treatment resistance significantly reduces the clinical utility of many effective targeted therapies. Although both genetic and epigenetic mechanisms of drug resistance have been reported, whether these mechanisms are stochastically selected in individual tumors or governed by a predictable underlying principle is unknown. Here, we report that the dependence of cancer stem cells (CSCs), not bulk tumor cells, on the targeted pathway determines the molecular mechanism of resistance in individual tumors. Using both spontaneous and transplantable mouse models of sonic hedgehog (SHH) medulloblastoma (MB) treated with an SHH/Smoothened inhibitor, sonidegib/LDE225, we show that genetic-based resistance occurs only in tumors that contain SHH-dependent CSCs (SD-CSCs). In contrast, SHH MBs containing SHH-dependent bulk tumor cells but SHH-independent CSCs (SI-CSCs) acquire resistance through epigenetic reprogramming. Mechanistically, elevated proteasome activity in SMOi-resistant SI-CSC MBs alters the tumor cell maturation trajectory through enhanced degradation of specific epigenetic regulators, including histone acetylation machinery components, resulting in global reductions in H3K9Ac, H3K14Ac, H3K56Ac, H4K5Ac, and H4K8Ac marks and gene expression changes. These results provide new insights into how selective pressure on distinct tumor cell populations contributes to different mechanisms of resistance to targeted therapies. This insight provides a new conceptual framework to understand responses and resistance to SMOis and other targeted therapies

Purine synthesis promotes maintenance of brain tumor initiating cells in glioma

Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy

Chronic Cough and Eosinophilic Esophagitis: An Uncommon Association

An increasing number of children, usually with gastrointestinal symptoms, is diagnosed with eosinophilic esophagitis (EE), and a particular subset of these patients complains of airway manifestations. We present the case of a 2-year-old child with chronic dry cough in whom EE was found after a first diagnosis of gastroesophageal reflux disease (GERD) due to pathological 24-hour esophageal pH monitoring. Traditional allergologic tests were negative, while patch tests were diagnostic for cow's milk allergy. We discuss the intriguing relationship between GERD and EE and the use of patch test for the allergologic screening of patients

Salmonella Typhi Colonization Provokes Extensive Transcriptional Changes Aimed at Evading Host Mucosal Immune Defense During Early Infection of Human Intestinal Tissue

Commensal microorganisms influence a variety of host functions in the gut, including immune response, glucose homeostasis, metabolic pathways and oxidative stress, among others. This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples and “mini-guts,” organoids grown from intestinal tissue taken from biopsy specimens. We analyzed gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection. This work adds novel information regarding S. Typhi infection pathogenesis in humans, by replicating work shown in traditional cell models, and providing new data that can be applied to future vaccine development strategies

The SARS-CoV-2 spike protein binds and modulates estrogen receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor alpha (ER alpha). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 sub-unit. In cultured cells, S DNA transfection increased ER alpha cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ER alpha lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ER alpha and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ER alpha interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology

When TADs go bad: chromatin structure and nuclear organisation in human disease

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease