Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging

Multiphoton microscopy (MPM) is a nonlinear fluorescence microscopic technique widely used for cellular imaging of thick tissues and live animals in biological studies. However, MPM application to human tissues is limited by weak endogenous fluorescence in tissue and cytotoxicity of exogenous probes. Herein, we describe the applications of moxifloxacin, an FDA-approved antibiotic, as a cell-labeling agent for MPM. Moxifloxacin has bright intrinsic multiphoton fluorescence, good tissue penetration and high intracellular concentration. MPM with moxifloxacin was demonstrated in various cell lines, and animal tissues of cornea, skin, small intestine and bladder. Clinical application is promising since imaging based on moxifloxacin labeling could be 10 times faster than imaging based on endogenous fluorescence.David H. Koch Institute for Integrative Cancer Research at MIT (Bridge Initiative

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes

Background: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. Methods: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n similar to 1400) and WHRadjBMI GWAS data (n similar to 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. Results: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. Conclusions: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.Peer reviewe

Study design and rationale of "Synergistic Effect of Combination Therapy with Cilostazol and ProbUcol on Plaque Stabilization and Lesion REgression (SECURE)" study: a double-blind randomised controlled multicenter clinical trial

<p>Abstract</p> <p>Background</p> <p>Probucol, a cholesterol-lowering agent that paradoxically also lowers high-density lipoprotein cholesterol has been shown to prevent progression of atherosclerosis. The antiplatelet agent cilostazol, which has diverse antiatherogenic properties, has also been shown to reduce restenosis in previous clinical trials. Recent experimental studies have suggested potential synergy between probucol and cilostazol in preventing atherosclerosis, possibly by suppressing inflammatory reactions and promoting cholesterol efflux.</p> <p>Methods/design</p> <p>The Synergistic Effect of combination therapy with Cilostazol and probUcol on plaque stabilization and lesion REgression (SECURE) study is designed as a double-blind, randomised, controlled, multicenter clinical trial to investigate the effect of cilostazol and probucol combination therapy on plaque volume and composition in comparison with cilostazol monotherapy using intravascular ultrasound and Virtual Histology. The primary end point is the change in the plaque volume of index intermediate lesions between baseline and 9-month follow-up. Secondary endpoints include change in plaque composition, neointimal growth after implantation of stents at percutaneous coronary intervention target lesions, and serum levels of lipid components and biomarkers related to atherosclerosis and inflammation. A total of 118 patients will be included in the study.</p> <p>Discussion</p> <p>The SECURE study will deliver important information on the effects of combination therapy on lipid composition and biomarkers related to atherosclerosis, thereby providing insight into the mechanisms underlying the prevention of atherosclerosis progression by cilostazol and probucol.</p> <p>Trial registration number</p> <p>ClinicalTrials (NCT): <a href="http://www.clinicaltrials.gov/ct2/show/NCT01031667">NCT01031667</a></p

In Situ Observation of Carbon Dioxide Capture on Pseudo-Liquid Eutectic Mixture-Promoted Magnesium Oxide

Eutectic mixtures of alkali nitrates are known to increase the sorption capacity and kinetics of MgO-based sorbents. Underlying principles and mechanisms for CO₂ capture on such sorbents have already been established; however, real-time observation of the system was not yet accomplished. In this work, we present the direct-observation of the CO₂ capture phenomenon on a KNO₃–LiNO₃ eutectic mixture (EM)-promoted MgO sample, denoted as KLM, via in situ transmission electron microscopy (in situ TEM). Results revealed that the pseudoliquid EM undergoes structural rearrangement as MgCO₃ evolves from the surface of MgO, resulting in surface roughening and evolution of cloudy structures that stay finely distributed after regeneration. From this, we propose a nucleation and structural rearrangement scheme for MgCO₃ and EM, which involves the rearrangement of bulk EM to evenly distributed EM clusters due to MgCO₃ saturation as adsorption proceeds. We also conducted studies on the interface between EM over solid MgO and MgCO₃ formed during sorption, which further clarifies the interaction between MgO and EM. This study provides better insight into the sorption and regeneration mechanism, as well as the structural rearrangements involved in EM-promoted sorbents by basing not only on intrinsic evolutions but also on real-time observation of the system as a whole

In Situ Observation of Carbon Dioxide Capture on Pseudo-Liquid Eutectic Mixture-Promoted Magnesium Oxide

Eutectic mixtures of alkali nitrates are known to increase the sorption capacity and kinetics of MgO-based sorbents. Underlying principles and mechanisms for CO₂ capture on such sorbents have already been established; however, real-time observation of the system was not yet accomplished. In this work, we present the direct-observation of the CO₂ capture phenomenon on a KNO₃–LiNO₃ eutectic mixture (EM)-promoted MgO sample, denoted as KLM, via in situ transmission electron microscopy (in situ TEM). Results revealed that the pseudoliquid EM undergoes structural rearrangement as MgCO₃ evolves from the surface of MgO, resulting in surface roughening and evolution of cloudy structures that stay finely distributed after regeneration. From this, we propose a nucleation and structural rearrangement scheme for MgCO₃ and EM, which involves the rearrangement of bulk EM to evenly distributed EM clusters due to MgCO₃ saturation as adsorption proceeds. We also conducted studies on the interface between EM over solid MgO and MgCO₃ formed during sorption, which further clarifies the interaction between MgO and EM. This study provides better insight into the sorption and regeneration mechanism, as well as the structural rearrangements involved in EM-promoted sorbents by basing not only on intrinsic evolutions but also on real-time observation of the system as a whole

Age-dependent genes in adipose stem and precursor cells affect regulation of fat cell differentiation and link aging to obesity via cellular and genetic interactions

Background: Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner. Methods: We integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI). Results: We found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level. Conclusions: Overall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions.Peer reviewe