Publications by authors named "Omary M"

329 Publications

Enhancing career development of postdoctoral trainees: act locally and beyond.

J Physiol 2019 05 31;597(9):2317-2322. Epub 2019 Mar 31.

Office of Graduate & Postdoctoral Studies, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1113/JP277684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487921PMC
May 2019

Ratiometric Phosphorescent Silver Sensor: Detection and Quantification of Free Silver Ions within Silver Nanoparticles.

ACS Appl Mater Interfaces 2019 Apr 15;11(16):15038-15043. Epub 2019 Apr 15.

Department of Chemistry , University of North Texas , Denton , Texas 76203 , United States.

Silver nanoparticles (AgNPs) have well-known antibacterial properties that have stimulated their widespread production and usage, which nonetheless concomitantly raises concerns regarding their release into the environment. Understanding the toxicity of AgNPs to biological systems, the environment, and the role that each silver species (Ag ions vs AgNPs) plays in that toxicity has received significant attention. One of the critical objectives of this research is the development of a reliable method that can sense and differentiate free silver ions from AgNPs and is able to characterize silver ions leaching from nanosilver. A number of analytical methods described in the literature that are available for sensing silver ions are costly, time consuming, tedious, and, more importantly, destroy the AgNP sample. To address these issues, a phosphorescent gold(I)-pyrazolate cyclic trinuclear complex (AuT) known to detect free silver ions was employed to detect and differentiate silver ions from AgNPs within an AgNP sample. The advantage of the proposed silver sensor is its ratiometric emission capability that undermines any background interference. The sensor exhibits a strong red emission (λ = ∼690 nm) that, in the presence of Ag ions, will form a bright-green emissive adduct with a blue-shifted peak maximum near 475 nm yet red-shifted excitation peak. The presence of AgNPs did not inhibit the silver detection and quantification ability of the phosphorescent silver sensor. To understand the chemical transformation of nanosilver, the leaching of silver ions from AgNPs over a period of 35 days was monitored and quantified by measuring the I/ I changes of the sensor. Furthermore, through adduct formation, the AuT molecular system was able to remediate free silver ions from the solution. The stronger affinity of the AuT complex to "sandwich" free silver ions than AgNPs was demonstrated in the presence of KCl salt that is well documented to form AgCl in the presence of silver ions. To our knowledge, this is the only ratiometric luminescence-based silver sensor able to successfully differentiate between Ag ions and AgNPs, sense the silver leakage from AgNPs, and remediate toxic silver ions from an aqueous solution. The synthesis and characterization of this sensor is a simple, single-step process-anticipating its viability for various applications.
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http://dx.doi.org/10.1021/acsami.9b01224DOI Listing
April 2019

Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice.

J Clin Invest 2019 03 19;129(6):2305-2317. Epub 2019 Mar 19.

Department of Molecular & Integrative Physiology.

Chronic alcohol consumption causes liver injury, inflammation and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a novel hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT, and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin that suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
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http://dx.doi.org/10.1172/JCI124376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546460PMC
March 2019

NIH Career Development Awards: conversion to research grants and regional distribution.

J Clin Invest 2018 12 29;128(12):5187-5190. Epub 2018 Oct 29.

Department of Molecular and Integrative Physiology, and.

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http://dx.doi.org/10.1172/JCI123875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264617PMC
December 2018

A transportome-scale amiRNA-based screen identifies redundant roles of Arabidopsis ABCB6 and ABCB20 in auxin transport.

Nat Commun 2018 10 11;9(1):4204. Epub 2018 Oct 11.

School of Plant Sciences and Food Security, Tel Aviv University, Tel Aviv, 69978, Israel.

Transport of signaling molecules is of major importance for regulating plant growth, development, and responses to the environment. A prime example is the spatial-distribution of auxin, which is regulated via transporters to govern developmental patterning. A critical limitation in our ability to identify transporters by forward genetic screens is their potential functional redundancy. Here, we overcome part of this functional redundancy via a transportome, multi-targeted forward-genetic screen using artificial-microRNAs (amiRNAs). We generate a library of 3000 plant lines expressing 1777 amiRNAs, designed to target closely homologous genes within subclades of transporter families and identify, genotype and quantitatively phenotype, 80 lines showing reproducible shoot growth phenotypes. Within this population, we discover and characterize a strong redundant role for the unstudied ABCB6 and ABCB20 genes in auxin transport and response. The unique multi-targeted lines generated in this study could serve as a genetic resource that is expected to reveal additional transporters.
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http://dx.doi.org/10.1038/s41467-018-06410-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182007PMC
October 2018

Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury.

J Hepatol 2019 01 1;70(1):108-117. Epub 2018 Oct 1.

Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States; Pittsburgh Liver Research Center, Pittsburgh, PA, United States. Electronic address:

Background & Aims: Porphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury.

Methods: β-Catenin (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a DDC diet for 2 weeks. β-Catenin was exogenously inhibited in hepatocytes by administering β-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were collected; livers were analyzed by histology, western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography-mass spectrometry.

Results: DDC-fed mice lacking β-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous mice that underwent β-catenin suppression by DsiRNA during DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking β-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of β-catenin, preventing accumulation of toxic protoporphyrins. Additionally, mice lacking β-catenin exhibited fewer protein aggregates, improved proteasomal activity, and reduced induction of autophagy, all contributing to protection from injury.

Conclusions: β-Catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for patients with porphyria.

Lay Summary: Porphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause build-up of toxic by-products called porphyrins. Liver is commonly either a source or a target of excess porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/β-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting β-catenin affected multiple components of the heme biosynthesis pathway, thus preventing build-up of porphyrin intermediates. Our study suggests that drugs inhibiting β-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.
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http://dx.doi.org/10.1016/j.jhep.2018.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459193PMC
January 2019

Hepatic NF-kB-inducing kinase (NIK) suppresses mouse liver regeneration in acute and chronic liver diseases.

Elife 2018 08 2;7. Epub 2018 Aug 2.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States.

Reparative hepatocyte replication is impaired in chronic liver disease, contributing to disease progression; however, the underlying mechanism remains elusive. Here, we identify Map3k14 (also known as NIK) and its substrate Chuk (also called IKKα) as unrecognized suppressors of hepatocyte replication. Chronic liver disease is associated with aberrant activation of hepatic NIK pathways. We found that hepatocyte-specific deletion of or substantially accelerated mouse hepatocyte proliferation and liver regeneration following partial-hepatectomy. Hepatotoxin treatment or high fat diet feeding inhibited the ability of partial-hepatectomy to stimulate hepatocyte replication; remarkably, inactivation of hepatic NIK markedly increased reparative hepatocyte proliferation under these liver disease conditions. Mechanistically, NIK and IKKα suppressed the mitogenic JAK2/STAT3 pathway, thereby inhibiting cell cycle progression. Our data suggest that hepatic NIK and IKKα act as rheostats for liver regeneration by restraining overgrowth. Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression.
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http://dx.doi.org/10.7554/eLife.34152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078493PMC
August 2018

Pancreatic HIF2α Stabilization Leads to Chronic Pancreatitis and Predisposes to Mucinous Cystic Neoplasm.

Cell Mol Gastroenterol Hepatol 2018 10;5(2):169-185.e2. Epub 2017 Nov 10.

Department of Surgery, University of Michigan, Ann Arbor, Michigan.

Background & Aims: Tissue hypoxia controls cell differentiation in the embryonic pancreas, and promotes tumor growth in pancreatic cancer. The cellular response to hypoxia is controlled by the hypoxia-inducible factor (HIF) proteins, including HIF2α. Previous studies of HIF action in the pancreas have relied on loss-of-function mouse models, and the effects of HIF2α expression in the pancreas have remained undefined.

Methods: We developed several transgenic mouse models based on the expression of an oxygen-stable form of HIF2α, or indirect stabilization of HIF proteins though deletion of von Hippel-Lindau, thus preventing HIF degradation. Furthermore, we crossed both sets of animals into mice expressing oncogenic Kras in the pancreas.

Results: We show that HIF2α is not expressed in the normal human pancreas, however, it is up-regulated in human chronic pancreatitis. Deletion of von Hippel-Lindau or stabilization of HIF2α in mouse pancreata led to the development of chronic pancreatitis. Importantly, pancreatic HIF1α stabilization did not disrupt the pancreatic parenchyma, indicating that the chronic pancreatitis phenotype is specific to HIF2α. In the presence of oncogenic Kras, HIF2α stabilization drove the formation of cysts resembling mucinous cystic neoplasm (MCN) in humans. Mechanistically, we show that the pancreatitis phenotype is linked to expression of multiple inflammatory cytokines and activation of the unfolded protein response. Conversely, MCN formation is linked to activation of Wnt signaling, a feature of human MCN.

Conclusions: We show that pancreatic HIF2α stabilization disrupts pancreatic homeostasis, leading to chronic pancreatitis, and, in the context of oncogenic Kras, MCN formation. These findings provide new mouse models of both chronic pancreatitis and MCN, as well as illustrate the importance of hypoxia signaling in the pancreas.
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http://dx.doi.org/10.1016/j.jcmgh.2017.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904051PMC
November 2017

Types I and II Keratin Intermediate Filaments.

Cold Spring Harb Perspect Biol 2018 04 2;10(4). Epub 2018 Apr 2.

Departments of Molecular & Integrative Physiology and Medicine, University of Michigan, Ann Arbor, Michigan 48109.

Keratins-types I and II-are the intermediate-filament-forming proteins expressed in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Here, we review how keratins serve multiple homeostatic and stress-triggered mechanical and nonmechanical functions, including maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications and keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility or altered tissue homeostasis. Furthermore, keratin mutation or misregulation represents risk factors or genetic modifiers for several additional acute and chronic diseases.
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http://dx.doi.org/10.1101/cshperspect.a018275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880164PMC
April 2018

Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.

Gastroenterology 2018 05 13;154(6):1602-1619.e1. Epub 2018 Mar 13.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Åbo Akademi University, Turku, Finland.

The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.
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http://dx.doi.org/10.1053/j.gastro.2018.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038707PMC
May 2018

The hepatic BMAL1/AKT/lipogenesis axis protects against alcoholic liver disease in mice via promoting PPARα pathway.

Hepatology 2018 09 20;68(3):883-896. Epub 2018 May 20.

Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI.

Alcohol liver disease (ALD) is one of the major chronic liver diseases worldwide, ranging from fatty liver, alcoholic hepatitis, cirrhosis, and potentially, hepatocellular carcinoma. Epidemiological studies suggest a potential link between ALD and impaired circadian rhythms, but the role of hepatic circadian proteins in the pathogenesis of ALD remains unknown. Here we show that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect mice from ALD. Ethanol diet-fed mice with liver-specific knockout (Bmal1-LKO) or depletion of Bmal1 develop more severe liver steatosis and injury as well as a simultaneous suppression of both de novo lipogenesis and fatty acid oxidation, which can be rescued by the supplementation of synthetic PPARα ligands. Restoring de novo lipogenesis in the liver of Bmal1-LKO mice by constitutively active AKT not only elevates hepatic fatty acid oxidation but also alleviates ethanol-induced fatty liver and liver injury. Furthermore, hepatic over-expression of lipogenic transcription factor ChREBP, but not SREBP-1c, in the liver of Bmal1-LKO mice also increases fatty acid oxidation and partially reduces ethanol-induced fatty liver and liver injury. Conclusion: we identified a protective role of BMAL1 in hepatocytes against ALD. The protective action of BMAL1 during alcohol consumption depends on its ability to couple ChREBP-induced de novo lipogenesis with PPARα-mediated fatty oxidation. (Hepatology 2018).
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http://dx.doi.org/10.1002/hep.29878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428639PMC
September 2018

The sweet side of vimentin.

Elife 2018 03 7;7. Epub 2018 Mar 7.

Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States.

A protein modification called O-linked glycosylation regulates the interactions between vimentin molecules under normal conditions, and the ability of bacteria to replicate after they infect cells.
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http://dx.doi.org/10.7554/eLife.35336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841928PMC
March 2018

Mechanistic Investigations of Photoinduced Oxygenation of Ru(II) Bis-bipyridyl Flavonolate Complexes.

Inorg Chem 2018 Mar 20;57(5):2416-2424. Epub 2018 Feb 20.

Department of Chemistry and Biochemistry , Baylor University , Waco , Texas 76798 , United States.

We previously reported that a Ru-bound flavonolate model of flavonol dioxygenases, [Ru(bpy)(3-hydroxyfla)][PF], photochemically reacts with dioxygen in two different manners. Broad-band excitation generates mixtures of products characteristic of 1,3-addition of dioxygen across the central pyrone ring, as is observed in enzymatic reactions. However, low temperature excitation at wavelengths longer than 400 nm generates a unique Ru-bound 2-benzoatophenylglyoxylate product resulting from a 1,2-dioxetane intermediate. Herein, we investigate this reactivity in a series of Ru(II)bis-bipyridyl flavonolate complexes [Ru(bpy)(3-hydroxyfla)][PF] (bpy = 2,2'-bipyridine; fla = flavonolate; R = p-OMe (1), p-Me (2), p-H (3), p-Cl (4)), and [Ru(bpy)(5-hydroxyfla)][PF] (5). The complexes' structures, photophysical and electrochemical properties, and photochemical reactivity with oxygen were investigated in detail. Two different reaction product mixtures, from 1,2- and 1,3-additions of dioxygen, are observed by illumination into distinct excitation/emission manifolds. By analogy to previous reports of excited state intramolecular proton transfer, the two manifolds are attributed to tautomeric diradicals that predict the observed reactivity patterns.
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http://dx.doi.org/10.1021/acs.inorgchem.7b01384DOI Listing
March 2018

HIF1-alpha Regulates Acinar Cell Function and Response to Injury in Mouse Pancreas.

Gastroenterology 2018 05 1;154(6):1630-1634.e3. Epub 2018 Feb 1.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Åbo Akademi University, Turku, Finland.

We investigated whether intrapancreatic coagulation, with deposition of the fibrinogen-γ dimer (Fib-γD) and hypoxia, affect the severity of acute pancreatitis (AP) in mice. Pancreata of mice with AP induced by administration of cerulein or by L-arginine, or from patients with pancreatitis, had increased deposition of Fib-γD compared with control pancreata. Heparin administration protected mice from cerulein-induced AP and prevented Fib-γD formation. Cerulein administration resulted in activation and stabilization of hypoxia-inducible factor-1α (HIF1α) in pancreata of oxygen-dependent degradation domain-luciferase HIF1α reporter mice. Cerulein also led to induction of genes regulated by HIF1α, including Vegfa and Ero1a, before evidence of Fib-γD deposition or histologic features of AP. Expression of tissue factor, which is regulated by vascular endothelial growth factor, also increased following cerulein administration. Mice with acinar cell-specific disruption of Hif1a (Hif1a) developed spontaneous endoplasmic reticulum stress and less severe AP, but did not accumulate Fib-γD following administration of cerulein. Feeding mice increased pancreatic expression of HIF1α, indicating a physiologic role in the exocrine pancreas. Therefore, HIF1α has bifunctional roles, in exocrine pancreas homeostasis and progression of AP that is promoted by intrapancreatic coagulation.
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http://dx.doi.org/10.1053/j.gastro.2018.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927829PMC
May 2018

Lamin A/C Maintains Exocrine Pancreas Homeostasis by Regulating Stability of RB and Activity of E2F.

Gastroenterology 2018 05 31;154(6):1625-1629.e8. Epub 2018 Jan 31.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Åbo Akademi University, Turku, Finland. Electronic address:

Lamins have important roles in nuclear structure and cell signaling. Several diseases are associated with mutations in the lamin A/C gene (LMNA in humans). Patients with familial partial lipodystrophy caused by LMNA mutations develop pancreatitis, but lamin function in the pancreas and how these mutations affect pancreatic regulation are unknown. We generated mice with inducible exocrine pancreas-specific disruption of Lmna and showed that LMNA is lost from most exocrine pancreas cells. LMNA-knockout pancreata develop endoplasmic reticulum stress with loss of acinar cell markers, increased autophagy, apoptosis, and cell proliferation, compared to CreERT2 mice (littermate controls). Disruption of Lmna led to a phenotype that resembled chronic pancreatitis, with increased Sirius Red staining and α-smooth muscle actin in male LMNA-knockout mice compared to littermate males, but not in female mice. LMNA-knockout pancreata have reduced levels of RB and activation of E2F, based on increased expression of E2F target genes. Therefore, lamins maintain pancreatic homeostasis by regulating RB stability and E2F activity.
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http://dx.doi.org/10.1053/j.gastro.2018.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927841PMC
May 2018

An OLTAM system for analysis of brown/beige fat thermogenic activity.

Int J Obes (Lond) 2018 04 23;42(4):939-945. Epub 2018 Jan 23.

Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.

Background/objectives: Thermogenic fat is present in humans and emerging evidence indicates that increasing the content and activity of these adipocytes may lead to weight loss and improved metabolic health. Multiple reporter systems have been developed to assay thermogenic fat activity based on the transcriptional and translational activation of Ucp1, the key molecule that mediates nonshivering thermogenesis. Our study aims to develop a much-needed tool to monitor thermogenic fat activity through a mechanism independent of Ucp1 regulation, therefore effectively assaying not only canonical β-adrenergic activation but also various non-UCP1-mediated thermogenic pathways that have been increasingly appreciated.

Methods: We detected increased luciferase activity upon thermogenic activation in interscapular brown and inguinal subcutaneous fat in ODD-Luc mice, a hypoxia reporter mouse model. We then developed an OLTAM (ODD-Luc based Thermogenic Activity Measurement) system to assay thermogenic fat cell activity.

Results: In both primary murine and human adipocytes and an immortalized adipose cell line that were transduced with the OLTAM system, luciferase activity can be readily measured and visualized by bioluminescence imaging in response to a variety of stimuli, including UCP1-independent thermogenic signaling. This system can offer a convenient method to assay thermogenic activity for both basic and translational research.

Conclusions: The OLTAM system offers a convenient way to measure the activation of thermogenic fat and presents opportunities to discover novel signaling pathways and unknown compounds targeting metabolically active adipocytes to counteract human obesity.
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http://dx.doi.org/10.1038/ijo.2017.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962373PMC
April 2018

A Phosphorescent Trinuclear Gold(I) Pyrazolate Chemosensor for Silver Ion Detection and Remediation in Aqueous Media.

Anal Chem 2018 04 26;90(8):4999-5006. Epub 2018 Mar 26.

Department of Chemistry , University of North Texas , Denton , Texas 76203 , United States.

We report a phosphorescent chemosensor based on a trinuclear Au(I) pyrazolate complex or [Au(3-CH,5-COOH)Pz] (aka AuPz) stabilized in aqueous chitosan (CS) polymer media. AuPz is synthesized in situ within aqueous CS media at pH ∼ 6.5 and room temperature (RT). AuPz exhibits strong red emission (λ ∼ 690 nm) in such solutions. On addition of silver salt to AuPz/CS aqueous media, a bright-green emissive adduct (AuPz/Ag) with a peak maximum within 475-515 nm is developed. The silver adduct exhibits a 4-fold increase in quantum yield (0.19 ± 0.02) compared to AuPz alone (0.05 ± 0.01), along with a corresponding increase in phosphorescence lifetime. With almost zero interference from 15 other metal ions tested, AuPz exhibits extreme selectivity for Ag with nM/ppb detection limits (6.4-72 ppb, depending on %CS and on the sensitivity basis being a signal-to-noise ratio (S/N) = 3 or a baseline-corrected signal change = 10%). AuPz exhibits sensitivity to higher concentrations (>1 mM) of other metal ions (Tl/Pb/Gd). The sensing methodology is simple, fast, convenient, and can even be detected by the naked eye. On addition of ethylenediaminetetraacetic acid (EDTA), the red AuPz emission can be restored. AuPz and its silver adduct retain their characteristic photophysical properties in thin film forms. Remarkable photostability with <7% photobleaching after 4 h of UV irradiation is attained for AuPz solutions or thin films.
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http://dx.doi.org/10.1021/acs.analchem.7b04334DOI Listing
April 2018

Insights into Molecular Structures and Optical Properties of Stacked [Au(RN═CR')] Complexes.

Inorg Chem 2018 Jan 26;57(2):718-730. Epub 2017 Dec 26.

Department of Chemistry, University of Helsinki , P.O. Box 55, A. I. Virtanens plats 1, FI-00014 Helsinki, Finland.

The molecular structure of stacked cyclic trinuclear gold(I) complexes [Au(RN═CR')], with n = 1-4, where R = H, methyl (Me), cyclopentyl (Pe), and phenyl (Ph) and R' = OH and methoxy (OMe) were studied computationally at the second-order Møller-Plesset (MP2) and density functional theory (DFT) levels of theory. At the DFT level, the aurophilic and dispersion interactions were accounted for by using the TPSS functional in combination with the semiempirical D3 correction. The structure optimizations yielded the lowest energy for a slided stacked structure of the [Au(HN═COH)] dimer, where monomers are slightly shifted relative to one another. At the MP2 level, the slided structure is 32 kJ/mol more stable than the staggered dimer structure, which in turn is energetically 11 kJ/mol below the eclipsed structure. The calculations show that aromatic ligands lead to a planar and prismatic structure of [Au(PhN═COMe)], whereas for [Au(PeN═COMe)], a chair conformation is obtained due to steric effects. Excitation energies were calculated for [Au(RN═CR')] and [Au(RN═CR')] with R = H, Me, and Pe and R' = OH and OMe at the time-dependent DFT level using the optimized molecular structures of the singlet ground state. To simulate the luminescence spectra, the lowest triplet excitation energy was also calculated for the molecular structure of the lowest triplet state. The calculated excitation energies of [Au(HN═COH)] and [Au(HN═COH)] are compared with values obtained at the approximate singles and doubles coupled cluster (CC2) and the second-order algebraic diagrammatic construction (ADC(2)) levels of theory. The calculated absorption and emission energies reproduce the experimental trends, with extremely large Stokes shifts. A solvoluminescence mechanism is also proposed.
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http://dx.doi.org/10.1021/acs.inorgchem.7b02593DOI Listing
January 2018

Remarkable Aurophilicity and Photoluminescence Thermochromism in a Homoleptic Cyclic Trinuclear Gold(I) Imidazolate Complex.

Inorg Chem 2017 Oct 28;56(20):12086-12089. Epub 2017 Sep 28.

Department of Chemistry, University of North Texas , Denton, Texas 76203, United States.

A new aurophilically-bonded cyclic trinuclear gold(I) complex, tris[μ-(1-ethylimidazolato-N,C)gold(I)] ([Au(EtIm)], 1), has been synthesized and characterized by temperature-dependent crystallographic and photophysical investigations. The crystal packing of 1 reveals two independent molecules in the unit cell, signifying two distinct pairs of dimer-of-trimer units convened by pairwise intermolecular Au···Au interactions of 3.0662(3) and 3.1407(3) Å at 100 K, representing the shortest pairwise intermolecular aurophilic interactions among all cyclic trimetallic gold(I) complexes to date. Remarkably, crystals of 1 exhibit gigantic photoluminescence thermochromism of 10164 cm-from violet to red!-attributed to internal conversion between a higher-energy (T → S; λ ∼409 nm) and lower-energy (T → S; λ ∼700 nm) phosphorescent band below and above 200 K, respectively, likely representing an excited-state phase change.
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http://dx.doi.org/10.1021/acs.inorgchem.7b01679DOI Listing
October 2017

Hepatocyte-Specific Deletion of Mouse Lamin A/C Leads to Male-Selective Steatohepatitis.

Cell Mol Gastroenterol Hepatol 2017 Nov 6;4(3):365-383. Epub 2017 Jul 6.

Department of Molecular and Integrative Physiology.

Background & Aims: Lamins are nuclear intermediate filament proteins that comprise the major components of the nuclear lamina. Mutations in , which encodes lamins A/C, cause laminopathies, including lipodystrophy, cardiomyopathy, and premature aging syndromes. However, the role of lamins in the liver is unknown, and it is unclear whether laminopathy-associated liver disease is caused by primary hepatocyte defects or systemic alterations.

Methods: To address these questions, we generated mice carrying a hepatocyte-specific deletion of (knockout [KO] mice) and characterized the KO liver and primary hepatocyte phenotypes by immunoblotting, immunohistochemistry, microarray analysis, quantitative real-time polymerase chain reaction, and Oil Red O and Picrosirius red staining.

Results: KO hepatocytes manifested abnormal nuclear morphology, and KO mice showed reduced body mass. KO mice developed spontaneous male-selective hepatosteatosis with increased susceptibility to high-fat diet-induced steatohepatitis and fibrosis. The hepatosteatosis was associated with up-regulated transcription of genes encoding lipid transporters, lipid biosynthetic enzymes, lipid droplet-associated proteins, and interferon-regulated genes. Hepatic deficiency led to enhanced signal transducer and activator of transcription 1 (Stat1) expression and blocked growth hormone-mediated Janus kinase 2 (Jak2), signal transducer and activator of transcription 5 (Stat5), and extracellular signal-regulated kinase (Erk) signaling.

Conclusions: Lamin A/C acts cell-autonomously to maintain hepatocyte homeostasis and nuclear shape and buffers against male-selective steatohepatitis by positively regulating growth hormone signaling and negatively regulating Stat1 expression. Lamins are potential genetic modifiers for predisposition to steatohepatitis and liver fibrosis. The microarray data can be found in the Gene Expression Omnibus repository (accession number: GSE93643).
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http://dx.doi.org/10.1016/j.jcmgh.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582719PMC
November 2017

Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease.

Hepatology 2018 05 24;67(5):1710-1725. Epub 2018 Mar 24.

Department of Molecular and Integrative Physiology and Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial, but twin and familial studies indicate significant heritability, which is not fully explained by currently known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina-associated proteins predispose to NAFLD and used a candidate gene-sequencing approach to test for variants in 10 nuclear lamina-related genes in a cohort of 37 twin and sibling pairs: 21 individuals with and 53 without NAFLD. Twelve heterozygous sequence variants were identified in four lamina-related genes (ZMPSTE24, TMPO, SREBF1, SREBF2). The majority of NAFLD patients (>90%) had at least one variant compared to <40% of controls (P < 0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P < 0.0001). Presence of a lamina variant segregated with NAFLD independently of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina-associated polypeptide-2 (LAP2) that has not been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin-LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin-binding protein p62/SQSTM1.

Conclusion: Several variants in nuclear lamina-related genes were identified in a cohort of twins and siblings with NAFLD; one such variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents an association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. (Hepatology 2018;67:1710-1725).
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http://dx.doi.org/10.1002/hep.29522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849478PMC
May 2018

Thermo-mechanically responsive crystalline organic cantilever.

Chem Commun (Camb) 2017 Aug;53(71):9890-9893

Department of Chemistry and Biochemistry, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080-3021, USA.

We report thermo-mechanically responsive and thermochromic behavior in the single crystalline organic semiconductor butoxyphenyl N-substituted naphthalene diimide (BNDI). We show that initially monoclinic single crystals of BNDI undergo a single-crystal to single-crystal transition to a triclinic phase. This transition accompanies large changes in the crystal packing, a visible decrease in crystal size, reversible thermochromic behavior, and motion including bending, jumping, and splitting. We have shown that by fixing single crystals to a surface, we can harness the energy of the phase transition to create a single crystal cantilever capable of lifting weights with masses nigh two orders of magnitude heavier than the single crystal itself.
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http://dx.doi.org/10.1039/c7cc04346eDOI Listing
August 2017

Photochemical formation of chitosan-stabilized near-infrared-absorbing silver Nanoworms: A "Green" synthetic strategy and activity on Gram-negative pathogenic bacteria.

J Colloid Interface Sci 2017 Dec 4;507:437-452. Epub 2017 Aug 4.

University of North Texas, Departments of Chemistry and Biological Sciences, Denton, TX 76203, United States.

A facile, single-step, non-seeded photochemical protocol for producing a new type of anisotropic silver nanostructure, "nanoworms", with curved longer dimensions and smooth, rounded edges. The nanoworms exhibit surface plasmon resonance (SPR) absorption in the near-infrared window (NIRW) region and are stabilized using biocompatible polymer chitosan, rendering biocompatibility and amplified safety for biological utility of the composition. Both NIRW-absorbing nanoworms and visible-absorbing nanospheres herein are attained exclusively by employing green chemistry principles. Contrary to seed-mediated or polyol techniques, the protocol demonstrates the feasibility to selectively synthesize NIRW-absorbing silver nanostructures in a single step and in complete absence of any known reducing agent. The effect of irradiation, pH, and concentration of starting materials on the formation of nanoworms vs nanospheres is investigated in detail and analyzed by optical spectroscopy and electron microscopy. The dominant SPR obtained in the NIRW region of the nanoworms results from anisotropic AgNPs, as opposed to agglomeration. From TEM images, it is also very clear that a strong correlation exists between the SPR peak maximum and the size distribution of the anisotropic nanoworm structures, with SPR peak maximum exhibiting red shift with the increase in the size of the nanoworm population. Although there is significant size variation of different nanoworms of a given population, all samples exhibit remarkable stability. The nanoworms retained their NIRW-absorbing features even at physiological pH and at a constant ionic strength. The nanodispersions also retained their SPR features in King's B medium. Antipathogenic assays reveal that the anisotropic NIRW-absorbing nanoworms exhibit the highest growth inhibition compared to other spherical nanosilver and molecular silver forms on Gram-negative pathogenic bacteria, Pseudomonas syringae pv. maculicola ES4326 and P. syringae pv. tomato DC3000. These results underscore shape effects of AgNPs and suggest that nanoworms favor the adhesion to (curved) rod-shaped Gram-negative bacteria, resulting in the highest inhibition compared to isotropic AgNPs (smaller spheres), sulfa antibiotics (silver sulfadiazine), and silver ions (AgNO).
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http://dx.doi.org/10.1016/j.jcis.2017.08.009DOI Listing
December 2017

Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity.

J Clin Invest 2017 Jun 19;127(7):2855-2867. Epub 2017 Jun 19.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Epidemiologic and animal studies implicate overconsumption of fructose in the development of nonalcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remain largely unknown. Here, we have presented evidence supporting the essential function of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) in mediating adaptive responses to fructose and protecting against fructose-induced hepatotoxicity. In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis. In Chrebp-KO mouse livers, a HFrD reduced levels of molecular chaperones and activated the C/EBP homologous protein-dependent (CHOP-dependent) unfolded protein response, whereas administration of a chemical chaperone or Chop shRNA rescued liver injury. Elevated expression levels of cholesterol biosynthesis genes in HFrD-fed Chrebp-KO livers were paralleled by an increased nuclear abundance of sterol regulatory element-binding protein 2 (SREBP2). Atorvastatin-mediated inhibition of hepatic cholesterol biosynthesis or depletion of hepatic Srebp2 reversed fructose-induced liver injury in Chrebp-KO mice. Mechanistically, we determined that ChREBP binds to nuclear SREBP2 to promote its ubiquitination and destabilization in cultured cells. Therefore, our findings demonstrate that ChREBP provides hepatoprotection against a HFrD by preventing overactivation of cholesterol biosynthesis and the subsequent CHOP-mediated, proapoptotic unfolded protein response. Our findings also identified a role for ChREBP in regulating SREBP2-dependent cholesterol metabolism.
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http://dx.doi.org/10.1172/JCI89934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490767PMC
June 2017

Cupriphication of gold to sensitize d-d metal-metal bonds and near-unity phosphorescence quantum yields.

Proc Natl Acad Sci U S A 2017 06 14;114(26):E5042-E5051. Epub 2017 Jun 14.

Department of Chemistry, University of North Texas, Denton, TX 76203;

Outer-shell s/p orbital mixing with d orbitals and symmetry reduction upon cupriphication of cyclic trinuclear trigonal-planar gold(I) complexes are found to sensitize ground-state Cu(I)-Au(I) covalent bonds and near-unity phosphorescence quantum yields. Heterobimetallic AuCu {[Au(μ-C,N-EtIm)Cu(µ-3,5-(CF)Pz)], (4a)}, AuCu {[Au(μ-C,N-BzIm)Cu(µ-3,5-(CF)Pz)], (1) and [Au(μ-C,N-MeIm)Cu(µ-3,5-(CF)Pz)], (3a)}, AuCu {[Au(μ-C,N-MeIm)Cu(µ-3,5-(CF)Pz)], (3b) and [Au(μ-C,N-EtIm)Cu(µ-3,5-(CF)Pz)], (4b)} and stacked Au/Cu {[Au(μ-C,N-BzIm)][Cu(µ-3,5-(CF)Pz)], (2)} form upon reacting Au {[Au(μ-C,N-(N-R)Im)] ((N-R)Im = imidazolate; R = benzyl/methyl/ethyl = BzIm/MeIm/EtIm)} with Cu {[Cu(μ-3,5-(CF)Pz)] (3,5-(CF)Pz = 3,5-bis(trifluoromethyl)pyrazolate)}. The crystal structures of 1 and 3a reveal stair-step infinite chains whereby adjacent dimer-of-trimer units are noncovalently packed via two Au(I)⋯Cu(I) metallophilic interactions, whereas 4a exhibits a hexanuclear cluster structure wherein two monomer-of-trimer units are linked by a genuine d-d polar-covalent bond with ligand-unassisted Cu(I)-Au(I) distances of 2.8750(8) Å each-the shortest such an intermolecular distance ever reported between any two d centers so as to deem it a "metal-metal bond" vis-à-vis "metallophilic interaction." Density-functional calculations estimate 35-43 kcal/mol binding energy, akin to typical M-M single-bond energies. Congruently, FTIR spectra of 4a show multiple far-IR bands within 65-200 cm, assignable to as validated by both the Harvey-Gray method of crystallographic-distance-to-force-constant correlation and dispersive density functional theory computations. Notably, the heterobimetallic complexes herein exhibit photophysical properties that are favorable to those for their homometallic congeners, due to threefold-to-twofold symmetry reduction, resulting in cuprophilic sensitization in extinction coefficient and solid-state photoluminescence quantum yields approaching unity (Φ = 0.90-0.97 vs. 0-0.83 for Au and Cu precursors), which bodes well for potential future utilization in inorganic and/or organic LED applications.
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http://dx.doi.org/10.1073/pnas.1700890114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495244PMC
June 2017

Globalization and changing trends of biomedical research output.

JCI Insight 2017 Jun 15;2(12). Epub 2017 Jun 15.

Departments of Molecular and Integrative Physiology.

The US continues to lead the world in research and development (R&D) expenditures, but there is concern that stagnation in federal support for biomedical research in the US could undermine the leading role the US has played in biomedical and clinical research discoveries. As a readout of research output in the US compared with other countries, assessment of original research articles published by US-based authors in ten clinical and basic science journals during 2000 to 2015 showed a steady decline of articles in high-ranking journals or no significant change in mid-ranking journals. In contrast, publication output originating from China-based investigators, in both high- and mid-ranking journals, has steadily increased commensurate with significant growth in R&D expenditures. These observations support the current concerns of stagnant and year-to-year uncertainty in US federal funding of biomedical research.
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http://dx.doi.org/10.1172/jci.insight.95206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470885PMC
June 2017

Adsorption and molecular siting of CO, water, and other gases in the superhydrophobic, flexible pores of FMOF-1 from experiment and simulation.

Chem Sci 2017 May 10;8(5):3989-4000. Epub 2017 Mar 10.

Department of Chemistry , University of North Texas , Denton , Texas 76203 , USA . Email: ; Email:

FMOF-1 is a flexible, superhydrophobic metal-organic framework with a network of channels and side pockets decorated with -CF groups. CO adsorption isotherms measured between 278 and 313 K and up to 55 bar reveal a maximum uptake of 6.16 mol kg (11.0 mol L) and unusual isotherm shapes at the higher temperatures, suggesting framework expansion. We used neutron diffraction and molecular simulations to investigate the framework expansion behaviour and the accessibility of the small pockets to N, O, and CO. Neutron diffraction experiments on the crystalline powder show that CO molecules are favourably adsorbed at three distinct adsorption sites in the large channels of FMOF-1 and cannot access the small pockets in FMOF-1 at 290 K and oversaturated pressure at 61 bar. Stepped adsorption isotherms for N and O at 77 K can be explained by combining Monte Carlo simulations in several different crystal structures of FMOF-1 obtained from neutron and X-ray diffraction under different conditions. A similar analysis is successful for CO adsorption at 278 and 283 K up to 30 bar; however, at 298 K and pressures above 30 bar, the results suggest even more substantial expansion of the FMOF-1 framework. The measured contact angle for water on an FMOF-1 pellet is 158°, demonstrating superhydrophobicity. Simulations and adsorption measurements also show that FMOF-1 is hydrophobic and water is not adsorbed in FMOF-1 at room temperature. Simulated mixture isotherms of CO in the presence of 80% relative humidity predict that water does not influence the CO adsorption in FMOF-1, suggesting that hydrophobic MOFs could hold promise for CO capture from humid gas streams.
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http://dx.doi.org/10.1039/c7sc00278eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433493PMC
May 2017

Intermediate filament proteins of digestive organs: physiology and pathophysiology.

Authors:
M Bishr Omary

Am J Physiol Gastrointest Liver Physiol 2017 Jun 30;312(6):G628-G634. Epub 2017 Mar 30.

Department of Molecular and Integrative Physiology and Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three major cytoskeletal protein families. Whether in digestive organs or other tissues, IFs share several unique features including stress-inducible overexpression, abundance, cell-selective and differentiation state expression, and association with >80 human diseases when mutated. Whereas most IF mutations cause disease, mutations in simple epithelial keratins 8, 18, or 19 or in lamin A/C predispose to liver disease with or without other tissue manifestations. Keratins serve major functions including protection from apoptosis, providing cellular and subcellular mechanical integrity, protein targeting to subcellular compartments, and scaffolding and regulation of cell-signaling processes. Keratins are essential for Mallory-Denk body aggregate formation that occurs in association with several liver diseases, whereas an alternate type of keratin and lamin aggregation occurs upon liver involvement in porphyria. IF-associated diseases have no known directed therapy, but high-throughput drug screening to identify potential therapies is an appealing ongoing approach. Despite the extensive current knowledge base, much remains to be discovered regarding IF physiology and pathophysiology in digestive and nondigestive organs.
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http://dx.doi.org/10.1152/ajpgi.00455.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495917PMC
June 2017

Finely Resolved On-Road PM and Estimated Premature Mortality in Central North Carolina.

Risk Anal 2017 12 28;37(12):2420-2434. Epub 2017 Feb 28.

Institute for the Environment, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

To quantify the on-road PM -related premature mortality at a national scale, previous approaches to estimate concentrations at a 12-km × 12-km or larger grid cell resolution may not fully characterize concentration hotspots that occur near roadways and thus the areas of highest risk. Spatially resolved concentration estimates from on-road emissions to capture these hotspots may improve characterization of the associated risk, but are rarely used for estimating premature mortality. In this study, we compared the on-road PM -related premature mortality in central North Carolina with two different concentration estimation approaches-(i) using the Community Multiscale Air Quality (CMAQ) model to model concentration at a coarser resolution of a 36-km × 36-km grid resolution, and (ii) using a hybrid of a Gaussian dispersion model, CMAQ, and a space-time interpolation technique to provide annual average PM concentrations at a Census-block level (∼105,000 Census blocks). The hybrid modeling approach estimated 24% more on-road PM -related premature mortality than CMAQ. The major difference is from the primary on-road PM where the hybrid approach estimated 2.5 times more primary on-road PM -related premature mortality than CMAQ due to predicted exposure hotspots near roadways that coincide with high population areas. The results show that 72% of primary on-road PM premature mortality occurs within 1,000 m from roadways where 50% of the total population resides, highlighting the importance to characterize near-road primary PM and suggesting that previous studies may have underestimated premature mortality due to PM from traffic-related emissions.
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http://dx.doi.org/10.1111/risa.12775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784485PMC
December 2017

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

Clin Endocrinol (Oxf) 2017 May 27;86(5):698-707. Epub 2017 Mar 27.

Brehm Center for Diabetes Research and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA.

Context: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described.

Objective: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics.

Design: Cross-sectional evaluation.

Participants: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD).

Measurements: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies.

Results: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization.

Conclusions: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.
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http://dx.doi.org/10.1111/cen.13311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395301PMC
May 2017