Although obesity and cardiometabolic traits commonly overlap, underlying pathways remain incompletely defined. The association of metabolite profiles across multiple cardiometabolic traits may lend ...insights into the interaction of obesity and metabolic health. We sought to investigate metabolic signatures of obesity and related cardiometabolic traits in the community using broad-based metabolomic profiling.
We evaluated the association of 217 assayed metabolites and cross-sectional as well as longitudinal changes in cardiometabolic traits among 2,383 Framingham Offspring cohort participants. Body mass index (BMI) was associated with 69 of 217 metabolites (P<0.00023 for all), including aromatic (tyrosine, phenylalanine) and branched chain amino acids (valine, isoleucine, leucine). Additional metabolic pathways associated with BMI included the citric acid cycle (isocitrate, alpha-ketoglutarate, aconitate), the tryptophan pathway (kynurenine, kynurenic acid), and the urea cycle. There was considerable overlap in metabolite profiles between BMI, abdominal adiposity, insulin resistance IR and dyslipidemia, modest overlap of metabolite profiles between BMI and hyperglycemia, and little overlap with fasting glucose or elevated blood pressure. Metabolite profiles were associated with longitudinal changes in fasting glucose, but the involved metabolites (ornithine, 5-HIAA, aminoadipic acid, isoleucine, cotinine) were distinct from those associated with baseline glucose or other traits. Obesity status appeared to "modify" the association of 9 metabolites with IR. For example, bile acid metabolites were strongly associated with IR among obese but not lean individuals, whereas isoleucine had a stronger association with IR in lean individuals.
In this large-scale metabolite profiling study, body mass index was associated with a broad range of metabolic alterations. Metabolite profiling highlighted considerable overlap with abdominal adiposity, insulin resistance, and dyslipidemia, but not with fasting glucose or blood pressure traits.
We introduce xCOLD GASS, a legacy survey providing a census of molecular gas in the local universe. Building on the original COLD GASS survey, we present here the full sample of 532 galaxies with CO ...(1-0) measurements from the IRAM 30 m telescope. The sample is mass-selected in the redshift interval from the Sloan Digital Sky Survey (SDSS) and therefore representative of the local galaxy population with . The CO (1-0) flux measurements are complemented by observations of the CO (2-1) line with both the IRAM 30 m and APEX telescopes, H i observations from Arecibo, and photometry from SDSS, WISE, and GALEX. Combining the IRAM and APEX data, we find that the ratio of CO (2-1) to CO (1-0) luminosity for integrated measurements is , with no systematic variations across the sample. The CO (1-0) luminosity function is constructed and best fit with a Schechter function with parameters , , and . With the sample now complete down to stellar masses of 109 , we are able to extend our study of gas scaling relations and confirm that both molecular gas fractions ( ) and depletion timescale ( ) vary with specific star formation rate (or offset from the star formation main sequence) much more strongly than they depend on stellar mass. Comparing the xCOLD GASS results with outputs from hydrodynamic and semianalytic models, we highlight the constraining power of cold gas scaling relations on models of galaxy formation.
As molecular dynamics (MD) simulations continue to evolve into powerful computational tools for studying complex biomolecular systems, the necessity of flexible and easy-to-use software tools for the ...analysis of these simulations is growing. We have developed MDTraj, a modern, lightweight, and fast software package for analyzing MD simulations. MDTraj reads and writes trajectory data in a wide variety of commonly used formats. It provides a large number of trajectory analysis capabilities including minimal root-mean-square-deviation calculations, secondary structure assignment, and the extraction of common order parameters. The package has a strong focus on interoperability with the wider scientific Python ecosystem, bridging the gap between MD data and the rapidly growing collection of industry-standard statistical analysis and visualization tools in Python. MDTraj is a powerful and user-friendly software package that simplifies the analysis of MD data and connects these datasets with the modern interactive data science software ecosystem in Python.
Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin ...sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology. (Circ J 2015; 79: 1647–1655)
Cancer is one of the major causes of death and is difficult to cure using existing clinical therapies. Clinical cancer treatments such as surgery, chemotherapy (CHT), radiotherapy (RT) and ...immunotherapy (IT) are widely used but they have limited therapeutic effects and unavoidable side effects. Recently, the development of novel nanomaterials offers a platform for combinational therapy (meaning a combination of two or more therapeutic agents) which is a promising approach for cancer therapy. Recent studies have demonstrated several types of nanomaterials suitable for photothermal therapy (PTT) based on a near-infrared (NIR) light-responsive system. PTT possesses favorable properties such as being low in cost, and having high temporospatial control with minimal invasiveness. However, short NIR light penetration depth limits its functions.
In this review, due to their promise, we focus on inorganic nanomaterials such as hollow mesoporous silica nanoparticles (HMSNs), tungsten sulfide quantum dots (WS
QDs), and gold nanorods (AuNRs) combining PTT with CHT, RT or IT in one treatment, aiming to provide a comprehensive understanding of PTT-based combinational cancer therapy.
This review found much evidence for the use of inorganic nanoparticles for PTT-based combinational cancer therapy.
Under synergistic effects, inorganic nanomaterial-based combinational treatments exhibit enhanced therapeutic effects compared to PTT, CHT, RT, IT or PDT alone and should be further investigated in the cancer field.
Opioid overdose survivors have an increased risk for death. Whether use of medications for opioid use disorder (MOUD) after overdose is associated with mortality is not known.
To identify MOUD use ...after opioid overdose and its association with all-cause and opioid-related mortality.
Retrospective cohort study.
7 individually linked data sets from Massachusetts government agencies.
17 568 Massachusetts adults without cancer who survived an opioid overdose between 2012 and 2014.
Three types of MOUD were examined: methadone maintenance treatment (MMT), buprenorphine, and naltrexone. Exposure to MOUD was identified at monthly intervals, and persons were considered exposed through the month after last receipt. A multivariable Cox proportional hazards model was used to examine MOUD as a monthly time-varying exposure variable to predict time to all-cause and opioid-related mortality.
In the 12 months after a nonfatal overdose, 2040 persons (11%) enrolled in MMT for a median of 5 months (interquartile range, 2 to 9 months), 3022 persons (17%) received buprenorphine for a median of 4 months (interquartile range, 2 to 8 months), and 1099 persons (6%) received naltrexone for a median of 1 month (interquartile range, 1 to 2 months). Among the entire cohort, all-cause mortality was 4.7 deaths (95% CI, 4.4 to 5.0 deaths) per 100 person-years and opioid-related mortality was 2.1 deaths (CI, 1.9 to 2.4 deaths) per 100 person-years. Compared with no MOUD, MMT was associated with decreased all-cause mortality (adjusted hazard ratio AHR, 0.47 CI, 0.32 to 0.71) and opioid-related mortality (AHR, 0.41 CI, 0.24 to 0.70). Buprenorphine was associated with decreased all-cause mortality (AHR, 0.63 CI, 0.46 to 0.87) and opioid-related mortality (AHR, 0.62 CI, 0.41 to 0.92). No associations between naltrexone and all-cause mortality (AHR, 1.44 CI, 0.84 to 2.46) or opioid-related mortality (AHR, 1.42 CI, 0.73 to 2.79) were identified.
Few events among naltrexone recipients preclude confident conclusions.
A minority of opioid overdose survivors received MOUD. Buprenorphine and MMT were associated with reduced all-cause and opioid-related mortality.
National Center for Advancing Translational Sciences of the National Institutes of Health.
Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the ...amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1 . U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.
Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific ...events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot ...penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.
Cross‐linked polydimethylsiloxane (PDMS) is simultaneously water‐repellent and highly permeable to water vapor. Unfilled and silica‐free cross‐linked PDMS films of variable thickness (8–160 µm) are ...prepared and their water vapor transmission rates and permeability values are determined. Vapor transmission rate increases as membrane thickness decreased from 160 to 15 µm, but does not increase further when the film thickness is decreased to 8 µm. Rate‐limiting sorption is implicated as the cause of this effect and substantiated by a surface modification to enhance adsorption rate. Water vapor does not macroscopically condense on films thin enough to operate in this kinetic regime, and vapor transmission rates as high as 60% of the transmission rates through air are measured. A mechanism for water permeation is offered based on those proposed for nanoscopically confined water in carbon nanotubes and aquaporins.
Polydimethylsiloxane films are water‐repellent yet highly permeable to water vapor. Water vapor transmission rates increase as membrane thickness decreases to ≈15 µm, but does not increase further below this value. A mechanism for the anomalous water permeation rates is offered based on those proposed for nanoscopically confined water in carbon nanotubes and aquaporins.
PDF
