Publications

2018
Juan Jose Carmona, Richard T Barfield, Tommaso Panni, Jamaji C Nwanaji-Enwerem, Allan C Just, John N Hutchinson, Elena Colicino, Stefan Karrasch, Simone Wahl, Sonja Kunze, Nadereh Jafari, Yinan Zheng, Lifang Hou, Dawn L DeMeo, Augusto A Litonjua, Pantel S Vokonas, Annette Peters, Xihong Lin, Joel Schwartz, Holger Schulz, and Andrea A Baccarelli. 2018. “Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts.” Epigenetics, 13, 10-11, Pp. 1039-1055.Abstract
DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV, FEF) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.
Yan Qin, Brian S Garrison, Wenjiang Ma, Rui Wang, Aiping Jiang, Jing Li, Meeta Mistry, Roderick T Bronson, Daria Santoro, Charlotte Franco, Daisy A Robinton, Beth Stevens, Derrick J Rossi, Chafen Lu, and Timothy A Springer. 2018. “A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System.” Cell, 174, 1, Pp. 156-171.e16.Abstract
Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33 mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33 brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33 microglia in the same brain suggest that there is little spreading of TGF-β activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-β provide localized and selective activation of TGF-β.
Jessalyn M Ubellacker, Ninib Baryawno, Nicolas Severe, Molly J DeCristo, Jaclyn Sceneay, John N Hutchinson, Marie-Therese Haider, Catherine S Rhee, Yuanbo Qin, Walter M Gregory, Ana C Garrido-Castro, Ingunn Holen, Janet E Brown, Robert E Coleman, David T Scadden, and Sandra S McAllister. 2018. “Modulating Bone Marrow Hematopoietic Lineage Potential to Prevent Bone Metastasis in Breast Cancer.” Cancer Res, 78, 18, Pp. 5300-5314.Abstract
The presence of disseminated tumor cells in breast cancer patient bone marrow aspirates predicts decreased recurrence-free survival. Although it is appreciated that physiologic, pathologic, and therapeutic conditions impact hematopoiesis, it remains unclear whether targeting hematopoiesis presents opportunities for limiting bone metastasis. Using preclinical breast cancer models, we discovered that marrow from mice treated with the bisphosphonate zoledronic acid (ZA) are metastasis-suppressive. Specifically, ZA modulated hematopoietic myeloid/osteoclast progenitor cell (M/OCP) lineage potential to activate metastasis-suppressive activity. Granulocyte-colony stimulating factor (G-CSF) promoted ZA resistance by redirecting M/OCP differentiation. We identified M/OCP and bone marrow transcriptional programs associated with metastasis suppression and ZA resistance. Analysis of patient blood samples taken at randomization revealed that women with high-plasma G-CSF experienced significantly worse outcome with adjuvant ZA than those with lower G-CSF levels. Our findings support discovery of therapeutic strategies to direct M/OCP lineage potential and biomarkers that stratify responses in patients at risk of recurrence. Bone marrow myeloid/osteoclast progenitor cell lineage potential has a profound impact on breast cancer bone metastasis and can be modulated by G-CSF and bone-targeting agents. .
Adrianna Z Herskovits, Tegan A Hunter, Nicholas Maxwell, Katherine Pereira, Charles A Whittaker, Gregorio Valdez, and Leonard P Guarente. 2018. “SIRT1 deacetylase in aging-induced neuromuscular degeneration and amyotrophic lateral sclerosis.” Aging Cell, 17, 6, Pp. e12839.Abstract
SIRT1 is an NAD -dependent deacetylase that functions in a variety of cells and tissues to mitigate age-associated diseases. However, it remains unknown if SIRT1 also acts to prevent pathological changes that accrue in motor neurons during aging and amyotrophic lateral sclerosis (ALS). In this study, we show that SIRT1 expression decreases in the spinal cord of wild-type mice during normal aging. Using mouse models either overexpressing or lacking SIRT1 in motor neurons, we found that SIRT1 slows age-related degeneration of motor neurons' presynaptic sites at neuromuscular junctions (NMJs). Transcriptional analysis of spinal cord shows an overlap of greater than 90% when comparing alterations during normal aging with changes during ALS, revealing a substantial upregulation in immune and inflammatory response genes and a downregulation of synaptic transcripts. In addition, overexpressing SIRT1 in motor neurons delays progression to end-stage disease in high copy SOD1 mice. Thus, our findings suggest that there are parallels between ALS and aging, and interventions to impede aging may also slow the progression of this devastating disease.
Ben B Li, Changli Qian, Paulo A Gameiro, Chin-Chih Liu, Tao Jiang, Thomas M Roberts, Kevin Struhl, and Jean J Zhao. 2018. “Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins.” Proc Natl Acad Sci U S A, 115, 40, Pp. E9325-E9332.Abstract
The PI3K-Akt-mTOR signaling pathway is a master regulator of RNA translation. Pharmacological inhibition of this pathway preferentially and coordinately suppresses, in a 4EBP1/2-dependent manner, translation of mRNAs encoding ribosomal proteins. However, it is unclear whether mechanistic target of rapamycin (mTOR)-4EBP1/2 is the exclusive translation regulator of this group of genes, and furthermore, systematic searches for novel translation modulators have been immensely challenging because of difficulties in scaling existing RNA translation profiling assays. Here, we developed a rapid and highly scalable approach for gene-specific quantitation of RNA translation, termed Targeted Profiling of RNA Translation (TPRT). We applied this technique in a chemical screen for translation modulators, and identified numerous preclinical and clinical therapeutic compounds, with diverse nominal targets, that preferentially suppress translation of ribosomal proteins. Surprisingly, some of these compounds act in a manner that bypasses canonical regulation by mTOR-4EBP1/2. Instead, these compounds exert their translation effects in a manner that is dependent on GCN2-eIF2α, a central signaling axis within the integrated stress response. Furthermore, we were also able to identify metabolic perturbations that also suppress ribosomal protein translation in an mTOR-independent manner. Together, we describe a translation assay that is directly applicable to large-scale RNA translation studies, and that enabled us to identify a noncanonical, mTOR-independent mode for translation regulation of ribosomal proteins.
Hong-Wen Tang, Yanhui Hu, Chiao-Lin Chen, Baolong Xia, Jonathan Zirin, Min Yuan, John M Asara, Leonard Rabinow, and Norbert Perrimon. 2018. “The TORC1-Regulated CPA Complex Rewires an RNA Processing Network to Drive Autophagy and Metabolic Reprogramming.” Cell Metab, 27, 5, Pp. 1040-1054.e8.Abstract
Nutrient deprivation induces autophagy through inhibiting TORC1 activity. We describe a novel mechanism in Drosophila by which TORC1 regulates RNA processing of Atg transcripts and alters ATG protein levels and activities via the cleavage and polyadenylation (CPA) complex. We show that TORC1 signaling inhibits CDK8 and DOA kinases, which directly phosphorylate CPSF6, a component of the CPA complex. These phosphorylation events regulate CPSF6 localization, RNA binding, and starvation-induced alternative RNA processing of transcripts involved in autophagy, nutrient, and energy metabolism, thereby controlling autophagosome formation and metabolism. Similarly, we find that mammalian CDK8 and CLK2, a DOA ortholog, phosphorylate CPSF6 to regulate autophagy and metabolic changes upon starvation, revealing an evolutionarily conserved mechanism linking TORC1 signaling with RNA processing, autophagy, and metabolism.
Anshula Samarajeewa, Danielle R Lenz, Lihong Xie, Hao Chiang, Rory Kirchner, Joanna F Mulvaney, Albert SB Edge, and Alain Dabdoub. 2018. “Transcriptional response to Wnt activation regulates the regenerative capacity of the mammalian cochlea.” Development, 145, 23.Abstract
Lack of sensory hair cell (HC) regeneration in mammalian adults is a major contributor to hearing loss. In contrast, the neonatal mouse cochlea retains a transient capacity for regeneration, and forced Wnt activation in neonatal stages promotes supporting cell (SC) proliferation and induction of ectopic HCs. We currently know little about the temporal pattern and underlying mechanism of this age-dependent regenerative response. Using an model, we show that Wnt activation promotes SC proliferation following birth, but prior to postnatal day (P) 5. This age-dependent decline in proliferation occurs despite evidence that the Wnt pathway is postnatally active and can be further enhanced by Wnt stimulators. Using an mouse model and RNA sequencing, we show that proliferation in the early neonatal cochlea is correlated with a unique transcriptional response that diminishes with age. Furthermore, we find that augmenting Wnt signaling through the neonatal stages extends the window for HC induction in response to Notch signaling inhibition. Our results suggest that the downstream transcriptional response to Wnt activation, in part, underlies the regenerative capacity of the mammalian cochlea.
1994
J Breed and MS Sansom. 1994. “Alamethicin channels modelled by simulated annealing and molecular dynamics.” Biochem Soc Trans, 22, 2, Pp. 157S.
1979
TA Ban. 1979. “Pharmacological treatment of psychosomatic manifestations in geropsychiatric patients.” Act Nerv Super (Praha), 21, 2, Pp. 116-21.
1977
L Gráf, A Kenessey, I Berzétei, and AZ Rónai. 1977. “Demonstration of beta-lipotropin activating enzyme in porcine pituitary.” Biochem Biophys Res Commun, 78, 3, Pp. 1114-23.
1976
VA Subramanian and RL Berger. 1976. “Comparative evaluation of a new disposable rotating membrane oxygenator with bubble oxygenator.” Ann Thorac Surg, 21, 1, Pp. 48-54.Abstract
The comparative in vivo performance of adult-size bubble and rotating membrane oxygenators was evaluated during closed-chest cardiopulmonary bypass for six hours in two groups of dogs. The results show that the rotating membrane oxygenator is efficient in oxygen and carbon dioxide transfer with minimal trauma to blood, while platelet destruction and hemolysis were marked with the bubble oxygenator. Cerebral, cardiac, and respiratory complications were frequent with the bubble oxygenator and absent with the membrane oxygenator.
G Gardos and JO Cole. 1976. “Maintenance antipsychotic therapy: is the cure worse than the disease?” Am J Psychiatry, 133, 1, Pp. 32-6.Abstract
The serious long-term complications of maintenance antipsychotic therapy led the authors to undertake a critical review of outpatient withdrawal studies. Key findings included the following: 1) for a least 40% of outpatient schizophrenics, drugs seem to be essential for survival in the community; 2) the majority of patients who relapse after drug withdrawal recompensate fairly rapidly upon reinstitution of antipsychotic drug therapy; 3) placebo survivors seem to function as well as drug survivors--thus the benefit of maintenance drug therapy appears to be prevention of relapse; and 4) some cases of early relapse after drug withdrawal may be due to dyskinesia rather than psychotic decompensation. The authors urge clinicians to evaluate each patient on maintenance antipsychotic therapy in terms of feasibility of drug withdrawal and offer practical guidelines for withdrawal and subsequent management.
1975
J Järvisalo and NE Saris. 1975. “Action of propranolol on mitochondrial functions--effects on energized ion fluxes in the presence of valinomycin.” Biochem Pharmacol, 24, 18, Pp. 1701-5.
GO Carrier, JL Matheny, and RP Ahlquist. 1975. “Adrenergic drug-receptor interaction in the presence of strontium (Sr++) in mammalian myocardium.” Arch Int Pharmacodyn Ther, 218, 1, Pp. 11-8.Abstract
The specificity of Ca++ for the interaction of beta adrenergic agonists with their receptors in rabbit right atrial muscle was evaluated. This was accomplished by substituting Ca++ by an equimolar concentration of Sr++. Dose-response curves which demonstrate the effect of norepinephrine and isoproterenol on the rate of electrical activity in the presence of Ca++ or Sr++ were made. In addition, the antagonistic action of propranolol (1 X 10(-7) M) in a Ca++-containing or Sr++-containing medium was determined. The results clearly demonstrate that Sr++ can effectively substitute for Ca++ in maintaining electrical and mechanical activity in cardiac muscle. Also, norepinephrine and isoproterenol can increase the rate of electrical activity in a Ca++ or Sr++-containing medium. This effect of these beta agonists is mediated through the beta-receptors since propranolol effectively blocked their action. It appears that Ca++ per se is not required for beta agonist or antagonist-receptor interaction in cardiac muscle. The results are discussed in relation to the dependency on extracellular Ca++ for beta agonists to cause a change in the rate of electrical activity after receptor occupancy.
WA Hendrickson and KB Ward. 1975. “Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin.” Biochem Biophys Res Commun, 66, 4, Pp. 1349-56.
JM Jallon, Y Risler, and M Iwatsubo. 1975. “Beef liver L-Glutamate dehydrogenase mechanism: presteady state study of the catalytic reduction of 2.oxoglutarate by NADPH.” Biochem Biophys Res Commun, 67, 4, Pp. 1527-36.
O Isaac and K Thiemer. 1975. “[Biochemical studies on camomile components/III. In vitro studies about the antipeptic activity of (--)-alpha-bisabolol (author's transl)].” Arzneimittelforschung, 25, 9, Pp. 1352-4.Abstract
(--)-alpha-Bisabolol has a primary antipeptic action depending on dosage, which is not caused by an alteration of the pH-value. The proteolytic activity of pepsin is reduced by 50 percent through addition of bisabolol in the ratio of 1/0.5. The antipeptic action of bisabolol only occurs in case of direct contact. In case of a previous contact with the substrate, the inhibiting effect is lost.
K Moroi and T Sato. 1975. “Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase.” Biochem Pharmacol, 24, 16, Pp. 1517-21.
KS Bose and RH Sarma. 1975. “Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution.” Biochem Biophys Res Commun, 66, 4, Pp. 1173-9.
M Fischer, E, C Falkensammer, G Barouch, S Wuketich, O Kromberger, and H Schnack. 1975. “[The diagnosis of cholestasis: lipoprotein X (LP-X) (author's transl)].” Wien Klin Wochenschr, 87, 16, Pp. 524-31.Abstract
The diagnostic specificity of a new method to detect obstructive jaundice by determination of lipoprotein X (LP-X) was tested in 144 patients with different kinds of hepatic diseases and compared with the usual chemical "obstructive jaundice specific" tests, such as bilirubin, SGOT, SGPT, alkaline phosphatase, LAP and gamma-GT. The LP-X test was performed by using all-in test kit LP-X Rapidophor" low-voltage electrophoresis of Immuno AG/Wien. The results were correlated with the histological classification of the liver biopsy specimen. In 82% of the histologically verified cases of obstructive jaundice the result of the LP-X test was positive, whilst in 98.5% of the histologically negative cases the result of the LP-X test was negative. Hence, this LP-X method proved superior to chemical methods in providing a clear-cut positive or negative answer to the presence of cholestasis. Furthermore, the LP-X test was suitable for long-term follow-up investigation of patients with obstructive jaundice.

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