The use of strong personal media in the context of chronic disease treatment : music as a mediator of depression and pain experience

Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2013.Cataloged from PDF version of thesis.Includes bibliographical references.Introduction: It is postulated that music has been part of society for at least 50,000 years, since the time that humans lived in one location of the world before dispersing across the globe (44). Over the eras it evolved in its manifestation, from classical performances enjoyed only by the elite, to soulful songs sung in the fields, to myriad forms of expression to be used by anyone. Today, its prominence has even evolved into being used as a tool for cognitive therapy, such as for aphasia patients (41), or to heal those who no longer have the ability to move their bodies (40). Given its incredible, seemingly endless potential, it is fruitful to explore new innovations in its usage - with treatment for chronic diseases such as depression, anxiety, and other mental disorders being ideal candidates. These diseases are high in their cost on resources, both human and monetary, and have weighty long-term impacts on patients' lives as well as their families', with depression being the leading cause of disability worldwide according to the World Health Organization (43). Music is positioned as a potent remedy, as its attributes are almost the mirror negative of the effects from chronic disease: it is low cost, pleasurably pervasive, and socially connecting Thus, the intention behind the design of study 1 in this thesis was to create a pilot, self -driven, wellness-enhancing music treatment that could be used as the basis for a future treatment for depression. It was meant to be a relatively brief longitudinal study examining adherence and feasibility for a personal music augmented mindfulness practice in a small group of healthy subjects. From the insights gleaned during this study, it was determined that the choice of strongly emotional, personal music could be potentially powerful in another disease context. In study 2, the design contracted from a longitudinal one to an acute, nuanced observation of enhanced music analgesia during experimental heat pain with healthy subjects. The clinical tool of interest was a proven analgesia boosting conditioning paradigm, which was combined in this study with personal music. Together, the two studies provide a revealing glimpse of humankind's ability to harness the best attributes it can for self-care from a medium it itself created.by Christine L. Hsieh.Ph.D

Age-related changes to macrophages are detrimental to fracture healing in mice.

The elderly population suffers from higher rates of complications during fracture healing that result in increased morbidity and mortality. Inflammatory dysregulation is associated with increased age and is a contributing factor to the myriad of age-related diseases. Therefore, we investigated age-related changes to an important cellular regulator of inflammation, the macrophage, and the impact on fracture healing outcomes. We demonstrated that old mice (24 months) have delayed fracture healing with significantly less bone and more cartilage compared to young mice (3 months). The quantity of infiltrating macrophages into the fracture callus was similar in old and young mice. However, RNA-seq analysis demonstrated distinct differences in the transcriptomes of macrophages derived from the fracture callus of old and young mice, with an up-regulation of M1/pro-inflammatory genes in macrophages from old mice as well as dysregulation of other immune-related genes. Preventing infiltration of the fracture site by macrophages in old mice improved healing outcomes, with significantly more bone in the calluses of treated mice compared to age-matched controls. After preventing infiltration by macrophages, the macrophages remaining within the fracture callus were collected and examined via RNA-seq analysis, and their transcriptome resembled macrophages from young calluses. Taken together, infiltrating macrophages from old mice demonstrate detrimental age-related changes, and depleting infiltrating macrophages can improve fracture healing in old mice

Well-Loved Music Robustly Relieves Pain: A Randomized, Controlled Trial

Music has pain-relieving effects, but its mechanisms remain unclear. We sought to verify previously studied analgesic components and further elucidate the underpinnings of music analgesia. Using a well-characterized conditioning-enhanced placebo model, we examined whether boosting expectations would enhance or interfere with analgesia from strongly preferred music. A two-session experiment was performed with 48 healthy, pain experiment-naïve participants. In a first cohort, 36 were randomized into 3 treatment groups, including music enhanced with positive expectancy, non-musical sound enhanced with positive expectancy, and no expectancy enhancement. A separate replication cohort of 12 participants received only expectancy-enhanced music following the main experiment to verify the results of expectancy-manipulation on music. Primary outcome measures included the change in subjective pain ratings to calibrated experimental noxious heat stimuli, as well as changes in treatment expectations. Without conditioning, expectations were strongly in favor of music compared to non-musical sound. While measured expectations were enhanced by conditioning, this failed to affect either music or sound analgesia significantly. Strongly preferred music on its own was as pain relieving as conditioning-enhanced strongly preferred music, and more analgesic than enhanced sound. Our results demonstrate the pain-relieving power of personal music even over enhanced expectations. Trial Information Clinicaltrials.gov NCT01835275

The Effect of Galaxy Interactions on Molecular Gas Properties

© 2018. The American Astronomical Society. All rights reserved.Galaxy interactions are often accompanied by an enhanced star formation rate (SFR). Since molecular gas is essential for star formation, it is vital to establish whether and by how much galaxy interactions affect the molecular gas properties. We investigate the effect of interactions on global molecular gas properties by studying a sample of 58 galaxies in pairs and 154 control galaxies. Molecular gas properties are determined from observations with the JCMT, PMO, and CSO telescopes and supplemented with data from the xCOLD GASS and JINGLE surveys at 12CO(1-0) and 12CO(2-1). The SFR, gas mass (), and gas fraction (f gas) are all enhanced in galaxies in pairs by ∼2.5 times compared to the controls matched in redshift, mass, and effective radius, while the enhancement of star formation efficiency (SFE ≡SFR/) is less than a factor of 2. We also find that the enhancements in SFR, and f gas, increase with decreasing pair separation and are larger in systems with smaller stellar mass ratio. Conversely, the SFE is only enhanced in close pairs (separation <20 kpc) and equal-mass systems; therefore, most galaxies in pairs lie in the same parameter space on the SFR- plane as controls. This is the first time that the dependence of molecular gas properties on merger configurations is probed statistically with a relatively large sample and a carefully selected control sample for individual galaxies. We conclude that galaxy interactions do modify the molecular gas properties, although the strength of the effect is dependent on merger configuration.Peer reviewedFinal Accepted Versio

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Microfluidic Chip for Molecular Amplification of Influenza A RNA in Human Respiratory Specimens

A rapid, low cost, accurate point-of-care (POC) device to detect influenza virus is needed for effective treatment and control of both seasonal and pandemic strains. We developed a single-use microfluidic chip that integrates solid phase extraction (SPE) and molecular amplification via a reverse transcription polymerase chain reaction (RT-PCR) to amplify influenza virus type A RNA. We demonstrated the ability of the chip to amplify influenza A RNA in human nasopharyngeal aspirate (NPA) and nasopharyngeal swab (NPS) specimens collected at two clinical sites from 2008–2010. The microfluidic test was dramatically more sensitive than two currently used rapid immunoassays and had high specificity that was essentially equivalent to the rapid assays and direct fluorescent antigen (DFA) testing. We report 96% (CI 89%,99%) sensitivity and 100% (CI 95%,100%) specificity compared to conventional (bench top) RT-PCR based on the testing of n = 146 specimens (positive predictive value = 100%(CI 94%,100%) and negative predictive value = 96%(CI 88%,98%)). These results compare well with DFA performed on samples taken during the same time period (98% (CI 91%,100%) sensitivity and 96%(CI 86%,99%) specificity compared to our gold standard testing). Rapid immunoassay tests on samples taken during the enrollment period were less reliable (49%(CI 38%,61%) sensitivity and 98%(CI 98%,100%) specificity). The microfluidic test extracted and amplified influenza A RNA directly from clinical specimens with viral loads down to 103 copies/ml in 3 h or less. The new test represents a major improvement over viral culture in terms of turn around time, over rapid immunoassay tests in terms of sensitivity, and over bench top RT-PCR and DFA in terms of ease of use and portability

Combining modularity, conservation, and interactions of proteins significantly increases precision and coverage of protein function prediction

<p>Abstract</p> <p>Background</p> <p>While the number of newly sequenced genomes and genes is constantly increasing, elucidation of their function still is a laborious and time-consuming task. This has led to the development of a wide range of methods for predicting protein functions in silico. We report on a new method that predicts function based on a combination of information about protein interactions, orthology, and the conservation of protein networks in different species.</p> <p>Results</p> <p>We show that aggregation of these independent sources of evidence leads to a drastic increase in number and quality of predictions when compared to baselines and other methods reported in the literature. For instance, our method generates more than 12,000 novel protein functions for human with an estimated precision of ~76%, among which are 7,500 new functional annotations for 1,973 human proteins that previously had zero or only one function annotated. We also verified our predictions on a set of genes that play an important role in colorectal cancer (<it>MLH1</it>, <it>PMS2</it>, <it>EPHB4 </it>) and could confirm more than 73% of them based on evidence in the literature.</p> <p>Conclusions</p> <p>The combination of different methods into a single, comprehensive prediction method infers thousands of protein functions for every species included in the analysis at varying, yet always high levels of precision and very good coverage.</p

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

Global Functional Analyses of Cellular Responses to Pore-Forming Toxins

Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson’s and Alzheimer’s Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer’s Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED “Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)”. HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978).Peer reviewe