tbuckley/cabot-search huggingface dataset:
Natural Selection Canalizes Expression Variation of Environmentally Induced Plasticity-Enabling Genes
Authors: Joseph R. Shaw, Thomas H. Hampton, Benjamin L. King, Andrew Whitehead, Fernando Galvez, Robert H. Gross, Nathan Keith, Emily Notch, Dawoon Jung, Stephen P. Glaholt, Celia Y. Chen, John K. Colbourne, Bruce A. Stanton
Journal: Molecular Biology and Evolution (2014)

Many organisms survive fluctuating and extreme environmental conditions by manifesting multiple distinct phenotypes during adulthood by means of developmental processes that enable phenotypic plasticity. We report on the discovery of putative plasticity-enabling genes that are involved in transforming the gill of the euryhaline teleost fish, Fundulus heteroclitus, from its freshwater to its seawater gill-type, a process that alters both morphology and function. Gene expression that normally enables osmotic plasticity is inhibited by arsenic. Gene sets defined by antagonistic interactions between arsenic and salinity show reduced transcriptional variation among individual fish, suggesting unusually accurate and precise regulatory control of these genes, consistent with the hypothesis that they participate in a canalized developmental response. We observe that natural selection acts to preserve canalized gene expression in populations of killifish that are most tolerant to abrupt salinity change and that these populations show the least variability in their transcription of genes enabling plasticity of the gill. We found that genes participating in this highly canalized and conserved plasticity-enabling response had significantly fewer and less complex associations with transcriptional regulators than genes that respond only to arsenic or salinity. Collectively these findings, which are drawn from the relationships between environmental challenge, plasticity, and canalization among populations, suggest that the selective processes that facilitate phenotypic plasticity do so by targeting the regulatory networks that gives rise to the response. These findings also provide a generalized, conceptual framework of how genes might interact with the environment and evolve toward the development of plastic traits.
Pattern of cutaneous immunoglobulin G deposition in subacute cutaneous lupus erythematosus is reproduced by infusing purified anti-Ro (SSA) autoantibodies into human skin-grafted mice.
Authors: L A Lee, K K Gaither, S N Coulter, D A Norris, J B Harley
Journal: Journal of Clinical Investigation (1989)

Subacute cutaneous lupus and neonatal lupus are closely associated with the presence of anti-Ro (SSA) autoantibodies, but there is no direct evidence establishing a role for anti-Ro (SSA) in these diseases. After parental injection into mice, IgG from sera containing anti-Ro (SSA) will bind human skin grafted onto the mice. To determine whether the antibody binding is due to anti-Ro (SSA), affinity-purified anti-Ro (SSA) and serum depleted of anti-Ro (SSA) were prepared. After injection into human skin-grafted mice, purified anti-Ro (SSA) antibodies bound an antigen in the human skin graft, while preabsorbing anti-Ro (SSA) serum with Ro (SSA) virtually abolished binding to the human skin graft. Moreover, the pattern of IgG deposition was primarily epidermal and was identical in the human skin-grafted mice injected with purified anti-Ro (SSA) when compared with that found in five patients with subacute lupus (four adults, one neonate). These data directly show that anti-Ro (SSA) antibodies bind to the skin, and support the hypothesis that anti-Ro (SSA) autoantibodies are involved in the disease process that produces subacute cutaneous lupus and neonatal lupus.
Systemic thrombolytic therapy of acute myocardial infarction?
Authors: D Collen, M Verstraete
Journal: Circulation (1983)

Rationale for thrombolytic therapy of myocardial infarctionThe rationale for thrombolytic treatment of acute myocardial infarction is based on two established facts and a reasonable assumption.The first fact is that a thrombus obstructing an atherosclerotic coronary ar- tery is the most frequent precipitating cause of acute transmural infarction.The second fact is that intracor- onary administration of thrombolytic agents (strepto- kinase or urokinase) can reopen the occluded coronary artery within 1 hr and that reperfusion of ischemic myocardial tissue is generally well tolerated.The rea- sonable assumption is that timely reopening of an oc- cluded coronary artery will save myocardial tissue and therefore may improve myocardial function, reduce reinfarction rate, and possibly decrease early and late mortality.Thrombosis ofan atherosclerotic coronary arterv is the most frequent cause precipitating a transmural myocardial infarction.The long-standing debate among cardiologists and assertive pathologists as to whether coronary thrombo- sis is the immediate cause rather than a consequence of myocardial infarction has been based mainly on analysis of pathologic findings.Recently, it has been con- vincingly demonstrated by results of coronary angiog- raphy and surgery that in the early stages of transmural myocardial infarction, thrombotic occlusion of a coro- nary artery is present in well over 80% of patients.Cardiologists were prompted to reexamine their con- cepts concerning the significance of coronary throm- bosis in and optimal treatment of acute myocardial infarction.In particular, the question of recanalization with thrombolytic agents or with angioplasty of an occluded atherosclerotic coronary artery has been reexamined.
Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages
Authors: L.-s. Jiang, J. Pu, Z.-h. Han, L.-h. Hu, B. He
Journal: Cardiovascular Research (2008)

Evidence from recent studies suggests that the endocannabinoid system participates in the regulation of lipid metabolism and body composition. We hypothesize that the system is activated by oxidized low-density lipoprotein (oxLDL) and regulates cellular cholesterol metabolism in macrophages.Primary peritoneal macrophages isolated from Sprague-Dawley rats and RAW264.7 mice macrophages were cultured. A liquid chromatography/mass spectrometry (LC/MS) system was used to measure the endocannabinoid anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cellular cholesterol levels in macrophages. The regulatory mechanisms of cellular cholesterol metabolism were also investigated by molecular biology methods. The results showed that the endocannabinoid system in macrophages was activated by oxLDL through elevation of the AEA and 2-AG levels and the up-regulation of the cannabinoid CB1 and CB2 receptor expression. Win55,212-2, a synthetic cannabinoid, promotes cellular cholesterol accumulation in macrophages, which was associated with an increase in the expression of CD36 and a decrease in the expression of ATP-binding cassette protein A1 (ABCA1) as mediated by an up-regulated peroxisome proliferator-activated receptor gamma (PPARgamma). AM251, a selective cannabinoid CB1 receptor antagonist, impaired the abilities of Win55,212-2-treated macrophages to accumulate cholesterol by down-regulating CD36 receptor expression and up-regulating ABCA1 expression.We have demonstrated, for the first time, that the endocannabinoid system in macrophages is activated by oxLDL and that the activated endocannabinoid system promotes cellular cholesterol accumulation in macrophages. The results also indicate that selectively blocking the CB1 receptor can reduce oxLDL accumulation in macrophages, which might represent a promising therapeutic strategy for atherosclerosis.
Cyst Growth Rate Predicts Malignancy in Patients With Branch Duct Intraductal Papillary Mucinous Neoplasms
Authors: Mee Joo Kang, Jin–Young Jang, Soo Jin Kim, Kyoung Bun Lee, Ji Kon Ryu, Yong–Tae Kim, Yong Bum Yoon, Sun–Whe Kim
Journal: Clinical Gastroenterology and Hepatology (2010)
Expression, topography, and function of integrin receptors are severely altered in keratinocytes from involved and uninvolved psoriatic skin.
Authors: G Pellegrini, M De Luca, G Orecchia, F Balzac, O Cremona, P Savoia, R Cancedda, P C Marchisio
Journal: Journal of Clinical Investigation (1992)

Psoriasis is a hyperproliferative cutaneous disease of unknown etiology and etiopathogenesis. Alteration of keratinocyte adhesiveness to basal lamina has been proposed as the initial disturbance leading to poorly controlled proliferation. Keratinocyte adhesion to basal lamina and lateral interactions among basal epidermal cells are mediated, besides other molecules, by integrin receptors that are segregated to discrete membrane domains. In this paper, the expression and function of integrins in psoriatic keratinocytes were examined, both in vivo and in vitro. We found that: (a) in psoriatic keratinocytes the integrin heterodimers alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 4 have lost their polarized distribution on the plasma membrane; (b) the role of these integrins in mediating keratinocyte adhesion in vitro is altered; (c) psoriatic keratinocytes form focal contacts containing both beta 1 and beta 4 integrins. In normal adult keratinocytes the alpha 5 beta 1 fibronectin receptor is poorly expressed and diffusely distributed on the basal keratinocyte plasma membrane and is not organized in defined adhesive structures. In contrast, psoriatic keratinocytes show a clear fibronectin receptor staining in vivo, and organize alpha 5 beta 1 in typical focal contacts in vitro without any obvious increase of its expression and synthesis. These multiple alterations of integrins are also present in uninvolved keratinocytes from psoriatic patients, suggesting a key role for altered integrin-mediated adhesion in the pathogenesis of this disease.
Nuclear magnetic resonance. Potential applications in clinical cardiology
Authors: G. M. Pohost
Journal: JAMA (1984)

UNTIL recently, the major clinical imaging modalities, with the exception of ultrasound, have employed ionizing radiation. Nuclear magnetic resonance (NMR), a physical phenomenon discovered in the 1940s and only recently applied to medicine, now allows high-resolution tomographic and three-dimensional imaging without ionizing radiation. In addition, this technology shows promise of allowing the evaluation of tissue pathological characteristics and the assessment of metabolic function noninvasively.  Nuclear magnetic resonance was first applied as a spectroscopic technique by chemists to determine molecular structure. Subsequently, NMR spectroscopy was applied to biologic substances and systems. Recently developed methods allow NMR spectroscopic techniques to be applied to the intact animal or human noninvasively.  Ten years ago, Lauterbur1described a method for obtaining images using the principles of NMR. With subsequent technical improvements, NMR images can now be generated with spatial resolution approaching that of x-ray computed tomography without the need for radio-opaque contrast medium and
Monitoring circulating tumor cell (CTC) levels to predict rapid progression in metastatic breast cancer (MBC): A prospective, multi-institutional tria
Authors: D. F. Hayes, M. Cristofanilli, G. T. Budd, M. Ellis, A. Stopeck, J. Matera, M. C. Miller, G. V. Doyle, W. J. Allard, L. W. Terstappen
Journal: Journal of Clinical Oncology (2004)

509 Background: For patients with MBC, early indication that a chosen therapy is not effective would permit initiation of an alternative regimen. We conducted a prospective, multi-institutional clinical trial to determine if monitoring CTC levels might identify such patients. Methods: 177 patients with measurable MBC about to start a new systemic therapy were enrolled and monitored at 3–4 week intervals for up to six months. CTC were immunomagnetically separated from 7.5 ml whole blood based on EpCAM binding. After multi-color fluorescent labeling, cells were classified by microscopy as CTC if they stained positive for both DAPI and cytokeratin 8,18 and/or 19 and if they stained negative for CD45. Clinical outcomes were determined by the participating clinical sites without knowledge of CTC levels. Results: Data from the first 102 patients were used in a training set to establish that ≥5 CTC/7.5 ml blood at both baseline and 1st follow-up was the optimal cutoff to best distinguish short Progression Free Survival (PFS) and/or Overall Survival (OS). The remaining 75 patients were then used as a validation set. Overall, 87/177 (49%) had ≥5 CTC at baseline, and 49/163 (30%) had persistent or newly elevated levels at 1st follow-up. At baseline, =5CTC/7.5ml was associated with significantly shorter PFS (2.7 vs 7.0 months; p=0.0001) and OS (10.1 vs >18 months, p=0.0001). At 1st follow-up, =5 CTC/7.5ml was associated with very short PFS (2.1 vs. 7.0 months from baseline blood draw; p=0.0001) and OS (8.2 vs. >18 months; p= 0.0001). PFS and OS for patients with a reduction in CTC to <5/7.5ml at 1st follow-up were equivalent to those of patients with <5/7.5ml CTC at baseline. In multi-variate analyses, CTC was the strongest and most significant predictor of poor outcome. Conclusions: Baseline CTC levels are a strong independent predictor of PFS and OS. Importantly, patients with =5 CTC/7.5ml at 1st follow-up appear to be on futile therapy and may benefit from an alternative regimen. A prospective, randomized trial is being designed to test this hypothesis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunicon Corp. Immunicon Corp. Immunicon Corp. Immunicon Corp. Immunicon Corp. Immunicon Corp.
A Double-Blind, Placebo-Controlled Study of Memantine in the Treatment of Major Depression
Authors: Carlos A. Zarate, Jaskaran B. Singh, Jorge A. Quiroz, Georgette De Jesus, Kirk K. Denicoff, David A. Luckenbaugh, Husseini K. Manji, Dennis S. Charney
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: This study was designed to assess possible antidepressant effects of memantine, a selective N-methyl-D-aspartate (NMDA) receptor antagonist in humans. METHOD: In a double-blind, placebo-controlled study, 32 subjects with major depression were randomly assigned to receive memantine (5–20 mg/day) (N=16) or placebo (N=16) for 8 weeks. Primary efficacy was assessed by performance on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The linear mixed models for total MADRS scores showed no treatment effect. CONCLUSIONS: In an 8-week trial, the low-to-moderate-affinity NMDA antagonist memantine in doses of 5–20 mg/day was not effective in the treatment of major depressive disorder.
Targeted analysis of nucleotide and copy number variation by exon capture in allotetraploid wheat genome
Authors: Cyrille Saintenac, Dayou Jiang, Eduard D Akhunov
Journal: Genome biology (2011)

Abstract Background The ability of grass species to adapt to various habitats is attributed to the dynamic nature of their genomes, which have been shaped by multiple rounds of ancient and recent polyploidization. To gain a better understanding of the nature and extent of variation in functionally relevant regions of a polyploid genome, we developed a sequence capture assay to compare exonic sequences of allotetraploid wheat accessions. Results A sequence capture assay was designed for the targeted re-sequencing of 3.5 Mb exon regions that surveyed a total of 3,497 genes from allotetraploid wheat. These data were used to describe SNPs, copy number variation and homoeologous sequence divergence in coding regions. A procedure for variant discovery in the polyploid genome was developed and experimentally validated. About 1% and 24% of discovered SNPs were loss-of-function and non-synonymous mutations, respectively. Under-representation of replacement mutations was identified in several groups of genes involved in translation and metabolism. Gene duplications were predominant in a cultivated wheat accession, while more gene deletions than duplications were identified in wild wheat. Conclusions We demonstrate that, even though the level of sequence similarity between targeted polyploid genomes and capture baits can bias enrichment efficiency, exon capture is a powerful approach for variant discovery in polyploids. Our results suggest that allopolyploid wheat can accumulate new variation in coding regions at a high rate. This process has the potential to broaden functional diversity and generate new phenotypic variation that eventually can play a critical role in the origin of new adaptations and important agronomic traits.
Calcium-Activated Potassium (BK) Channels Are Encoded by Duplicate slo1 Genes in Teleost Fishes
Authors: Kevin N. Rohmann, David L. Deitcher, Andrew H. Bass
Journal: Molecular Biology and Evolution (2009)

Calcium-activated, large conductance potassium (BK) channels in tetrapods are encoded by a single slo1 gene, which undergoes extensive alternative splicing. Alternative splicing generates a high level of functional diversity in BK channels that contributes to the wide range of frequencies electrically tuned by the inner ear hair cells of many tetrapods. To date, the role of BK channels in hearing among teleost fishes has not been investigated at the molecular level, although teleosts account for approximately half of all extant vertebrate species. We identified slo1 genes in teleost and nonteleost fishes using polymerase chain reaction and genetic sequence databases. In contrast to tetrapods, all teleosts examined were found to express duplicate slo1 genes in the central nervous system, whereas nonteleosts that diverged prior to the teleost whole-genome duplication event express a single slo1 gene. Phylogenetic analyses further revealed that whereas other slo1 duplicates were the result of a single duplication event, an independent duplication occurred in a basal teleost (Anguilla rostrata) following the slo1 duplication in teleosts. A third, independent slo1 duplication (autotetraploidization) occurred in salmonids. Comparison of teleost slo1 genomic sequences to their tetrapod orthologue revealed a reduced number of alternative splice sites in both slo1 co-orthologues. For the teleost Porichthys notatus, a focal study species that vocalizes with maximal spectral energy in the range electrically tuned by BK channels in the inner ear, peripheral tissues show the expression of either one (e.g., vocal muscle) or both (e.g., inner ear) slo1 paralogues with important implications for both auditory and vocal physiology. Additional loss of expression of one slo1 paralogue in nonneural tissues in P. notatus suggests that slo1 duplicates were retained via subfunctionalization. Together, the results predict that teleost fish achieve a diversity of BK channel subfunction via gene duplication, rather than increased alternative splicing as witnessed for the tetrapod and invertebrate orthologue.
Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase
Authors: Hayato Nakagawa, Yoshihiro Hirata, Kohsuke Takeda, Yoku Hayakawa, Takehiro Sato, Hiroto Kinoshita, Kei Sakamoto, Wachiko Nakata, Yohko Hikiba, Masao Omata, Haruhiko Yoshida, Kazuhiko Koike, Hidenori Ichijo, Shin Maeda
Journal: Hepatology (2011)

The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1(-/-) ) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1(-/-) mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1(-/-) HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1(-/-) HCCs. ASK1(-/-) mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1(-/-) mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway.ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis.
Intracardiac Blood Flow Patterns Related to the Yolk Sac Circulation of the Chick Embryo
Authors: B. Hogers, M.C. DeRuiter, A.M.J. Baasten, A.C. Gittenberger-de Groot, R.E. Poelmann
Journal: Circulation Research (1995)

Abstract Intracardiac flow patterns during heart development were studied by injection of india ink into the yolk sac circulation of chick embryos at Hamburger-Hamilton stages 10 to 17. We injected india ink into a small venule or capillary, carefully preventing application of overpressure to the vascular system, and recorded the intracardiac route by video. From stage 12 onward, blood flow was laminar, and separate intracardiac currents were visualized. The yolk sac was divided into a left and a right half. Blood coursed through each half in concentric loops, ranging from the marginal sinus to the sinus venosus. This parallel array persisted within the heart. Bilateral to the embryo, two lateral regions arose that extended wedgelike within each half, resulting in six equally sized yolk sac regions at stage 16. The process of heart looping was not accompanied by a change in flow pattern. However, developmental changes of the yolk sac circulation were reflected in alteration of the intracardiac flow pattern. From stage 16 onward, the intracardiac flow pattern was no longer determined by the left- or right-hand side of the yolk sac but by bilateral anterior, lateral, and posterior regions of the yolk sac. Blood from the lateral regions of the yolk sac was preferentially distributed to the head. The results show that in preseptation stages a relatively stable flow pattern is present. We suggest that alterations in blood flow could influence the process of normal heart development.
Estrogen Receptor α–Negative Breast Cancer Tissues Express Significant Levels of Estrogen-Independent Transcription Factors, ERβ1 and ERβ5: Potential Molecular Targets for Chemoprevention
Authors: Indira Poola, Suzanne A.W. Fuqua, Robert L. De Witty, Jessy Abraham, Josephine J. Marshallack, Aiyi Liu
Journal: Clinical Cancer Research (2005)

Abstract We have investigated the expression of two estrogen receptor β (ERβ) isoforms, ERβ1 and ERβ5, which activate gene transcription independent of estrogen or growth factors, in ERα-negative breast cancer tissues. We report here, for the first time, that ERα-negative tissues express significant levels of ERβ1 and ERβ5, and their expression levels are not different from levels in ERα positive tumors. However, significant differences exist between the two racial groups, African American and Caucasian, in that the patients from the former group express higher levels of ERβ1 and ERβ5 but not ERα. These two transcription factors could be potential molecular targets for designing chemopreventive drugs to treat ERα-negative breast cancers.