bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genome resource to address mechanisms of developmental programming: determination of the fetal sheep heart transcriptome
Authors: Cox Laura A. , Glenn Jeremy P. , Spradling Kimberly D. , Nijland Mark J. , Garcia Roy , Nathanielsz Peter W. , Ford Stephen P. 
Published: April 2012

Key points
The sheep is a valuable model for biomedical research, including the study of developmental programming mechanisms that are critical to better understand gene–environment interactions responsible for each individual's phenotype and predisposition to chronic diseases.
The lack of genetic and genomic resources for the sheep has limited the power of this model, impeding progress in emerging areas of pregnancy biology and other fields of biomedical research.
In this study, we examined the expressed fetal sheep heart transcriptome using high‐throughput sequencing technologies.
We identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms.
The data presented in this study provide a foundation of genetic information on the repertoire of genes expressed in the fetal heart transcriptome, which will augment annotation and assembly of the sheep genome.
Abstract  The pregnant sheep has provided seminal insights into reproduction related to animal and human development (ovarian function, fertility, implantation, fetal growth, parturition and lactation). Fetal sheep physiology has been extensively studied since 1950, contributing significantly to the basis for our understanding of many aspects of fetal development and behaviour that remain in use in clinical practice today. Understanding mechanisms requires the combination of systems approaches uniquely available in fetal sheep with the power of genomic studies. Absence of the full range of sheep genomic resources has limited the full realization of the power of this model, impeding progress in emerging areas of pregnancy biology such as developmental programming. We have examined the expressed fetal sheep heart transcriptome using high‐throughput sequencing technologies. In so doing we identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms. Genes with the highest expression levels and with novel exons in the fetal heart transcriptome are known to play central roles in muscle development. We show that high‐throughput sequencing methods can generate extensive transcriptome information in the absence of an assembled and annotated genome for that species. The gene sequence data obtained provide a unique genomic resource for sheep specific genetic technology development and, combined with the polymorphism data, augment annotation and assembly of the sheep genome. In addition, identification and pathway analysis of novel fetal sheep heart transcriptome splice variants is a first step towards revealing mechanisms of genetic variation and gene environment interactions during fetal heart development.
Hydrogen sulfide activates Ca2+ sparks to induce cerebral arteriole dilatation
Authors: Liang Guo Hua , Xi Qi , Leffler Charles W. , Jaggar Jonathan H. 
Published: April 2012

Key points
Hydrogen sulfide (H2S), a gas produced by endothelial cells, relaxes smooth muscle cells within the vascular wall to increase organ blood flow and lower systemic blood pressure.
Mechanisms by which H2S produces vasodilatation in the cerebral circulation are unclear.
We demonstrate that H2S increases the quantity of calcium ions (Ca2+) contained with the sarcoplasmic reticulum (SR), the intracellular Ca2+ store, of cerebral arteriole smooth muscle cells.
This elevation in SR Ca2+ stimulates the generation of local intracellular Ca2+ signals called Ca2+ sparks, which in turn activate Ca2+‐sensitive potassium (KCa) channels on the cell membrane, leading to membrane hyperpolarization and vasodilatation.
Elucidating this novel mechanism of H2S‐induced vasodilatation is important to better understand physiological control of blood flow within the brain.
Antimalarial Activity of the Anticancer Histone Deacetylase Inhibitor SB939
Authors: Sumanadasa Subathdrage D. M. , Goodman Christopher D. , Lucke Andrew J. , Skinner-Adams Tina , Sahama Ishani , Haque Ashraful , Do Tram Anh , McFadden Geoffrey I. , Fairlie David P. , Andrews Katherine T. 
Published: April 2012

ABSTRACT

Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the
in vitro
and
in vivo
antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of
Plasmodium falciparum
asexual-stage parasites
in vitro
(50% inhibitory concentration [IC
50
], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the
in vitro
growth of exoerythrocytic-stage
Plasmodium
parasites in liver cells (IC
50
, ∼150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental
in vivo
murine model of cerebral malaria, orally administered SB939 significantly inhibited
P. berghei
ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.
In Vitro
Anti-Trypanosoma cruzi Activity of Dronedarone, a Novel Amiodarone Derivative with an Improved Safety Profile
Authors: Benaim Gustavo , Hernandez-Rodriguez Vanessa , Mujica-Gonzalez Sheira , Plaza-Rojas Lourdes , Silva May Li , Parra-Gimenez Nereida , Garcia-Marchan Yael , Paniz-Mondolfi Alberto , Uzcanga Graciela 
Published: April 2012

ABSTRACT

Amiodarone, a commonly used antiarrhythmic, is also a potent and selective anti-
Trypanosoma cruzi
agent. Dronedarone is an amiodarone derivative in which the 2,5-diiodophenyl moiety of the parental drug has been replaced with an unsubstituted phenyl group aiming to eliminate the thyroid toxicity frequently observed with amiodarone treatment. Dronedarone has been approved by the Food and Drug Administration (FDA), and its use as a safe antiarrhythmic has been extensively documented. We show here that dronedarone also has potent anti-
T. cruzi
activity, against both extracellular epimastigotes and intracellular amastigotes, the clinically relevant form of the parasite. The 50% inhibitory concentrations against both proliferative stages are lower than those previously reported for amiodarone. The mechanism of action of dronedarone resembles that of amiodarone, as it induces a large increase in the intracellular Ca
2+
concentration of the parasite, which results from the release of this ion from intracellular storage sites, including a direct effect of the drug on the mitochondrial electrochemical potential, and through alkalinization of the acidocalcisomes. Our results suggest a possible future repurposed use of dronedarone for the treatment of Chagas' disease.
Antiviral Effects of Small Interfering RNA Simultaneously Inducing RNA Interference and Type 1 Interferon in Coxsackievirus Myocarditis
Authors: Ahn Jeonghyun , Ko Ara , Jun Eun Jung , Won Minah , Kim Yoo Kyum , Ju Eun-Seon , Jeon Eun Seok , Lee Heuiran 
Published: April 2012

ABSTRACT
Antiviral therapeutics are currently unavailable for treatment of coxsackievirus B3, which can cause life-threatening myocarditis. A modified small interfering RNA (siRNA) containing 5′-triphosphate, 3p-siRNA, was shown to induce RNA interference and interferon activation. We aimed to develop a potent antiviral treatment using CVB3-specific 3p-siRNA and to understand its underlying mechanisms. Virus-specific 3p-siRNA was superior to both conventional virus-specific siRNA with an empty hydroxyl group at the 5′ end (OH-siRNA) and nonspecific 3p-siRNA in decreasing viral replication and subsequent cytotoxicity. A single administration of 3p-siRNA dramatically attenuated virus-associated pathological symptoms in mice with no signs of toxicity, and their body weights eventually reached the normal range. Myocardial inflammation and fibrosis were rare, and virus production was greatly reduced. A nonspecific 3p-siRNA showed relatively less protective effect under identical conditions, and a virus-specific OH-siRNA showed no protective effects. We confirmed that virus-specific 3p-siRNA simultaneously activated target-specific gene silencing and type I interferon signaling. We provide a clear proof of concept that coxsackievirus B3-specific 3p-siRNA has 2 distinct modes of action, which significantly enhance antiviral activities with minimal organ damage. This is the first direct demonstration of improved antiviral effects with an immunostimulatory virus-specific siRNA in coxsackievirus myocarditis, and this method could be applied to many virus-related diseases.
pfmdr1
Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine
Authors: Veiga M. I. , Ferreira P. E. , Malmberg M. , Jörnhagen L. , Björkman A. , Nosten F. , Gil J. P. 
Published: April 2012

ABSTRACT

The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the
Plasmodium falciparum
multidrug resistance locus on chromosome 5, containing the
pfmdr1
gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC
50
s) and IC
90
s for piperaquine and chloroquine in a set of 46 adapted
P. falciparum
cultures originating from the Thai-Burmese border, we have characterized the regions around the
pfmdr1
gene and identified a significant association between the presence of
pfmdr1
duplications and enhanced sensitivity to piperaquine (
P
= 0.005 for IC
50
and
P
= 0.002 for IC
90
) and chloroquine, reaching statistical significance at IC
90
s (
P
= 0.026). These results substantiate the potential importance of
pfmdr1
copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.
Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease:
In Vivo
Efficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies
Authors: Zhu Xiaohua , Liu Qiang , Yang Sihyung , Parman Toufan , Green Carol E. , Mirsalis Jon C. , de Nazaré Correia Soeiro Maria , Mello de Souza Elen , da Silva Cristiane França , da Gama Jaen Batista Denise , Stephens Chad E. , Banerjee Moloy , Farahat Abdelbasset A. , Munde Manoj , Wilson W. David , Boykin David W. , Wang Michael Zhuo , Werbovetz Karl A. 
Published: April 2012

ABSTRACT

Arylimidamides (AIAs) have shown outstanding
in vitro
potency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed good
in vivo
efficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility and
in vivo
antikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day × 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murine
Trypanosoma cruzi
infection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day × 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.
Borrelia burgdorferi Needs Chemotaxis To Establish Infection in Mammals and To Accomplish Its Enzootic Cycle
Authors: Sze Ching Wooen , Zhang Kai , Kariu Toru , Pal Utpal , Li Chunhao 
Published: April 2012

ABSTRACT

Borrelia burgdorferi
, the causative agent of Lyme disease, can be recovered from different organs of infected animals and patients, indicating that the spirochete is very invasive. Motility and chemotaxis contribute to the invasiveness of
B. burgdorferi
and play important roles in the process of the disease. Recent reports have shown that motility is required for establishing infection in mammals. However, the role of chemotaxis in virulence remains elusive. Our previous studies showed that
cheA
2
, a gene encoding a histidine kinase, is essential for the chemotaxis of
B. burgdorferi
. In this report, the
cheA
2
gene was inactivated in a low-passage-number virulent strain of
B. burgdorferi. In vitro
analyses (microscopic observations, computer-based bacterial tracking analysis, swarm plate assays, and capillary tube assays) showed that the
cheA
2
mutant failed to reverse and constantly ran in one direction; the mutant was nonchemotactic to attractants. Mouse needle infection studies showed that the
cheA
2
mutant failed to infect either immunocompetent or immunodeficient mice and was quickly eliminated from the initial inoculation sites. Tick-mouse infection studies revealed that although the mutant was able to survive in ticks, it failed to establish a new infection in mice via tick bites. The altered phenotypes were completely restored when the mutant was complemented. Collectively, these data demonstrate that
B. burgdorferi
needs chemotaxis to establish mammalian infection and to accomplish its natural enzootic cycle.
Invasive Potential of Nonencapsulated Disease Isolates of Neisseria meningitidis
Authors: Johswich Kay O. , Zhou Jianwei , Law Dennis K. S. , St. Michael Frank , McCaw Shannon E. , Jamieson Frances B. , Cox Andrew D. , Tsang Raymond S. W. , Gray-Owen Scott D. 
Published: April 2012

ABSTRACT

The capsule of
Neisseria meningitidis
is the major virulence factor that enables this bacterium to overcome host immunity elicited by complement and phagocytes, rendering it capable of surviving in blood. As such, nonencapsulated
N. meningitidis
isolates are generally considered nonpathogenic. Here, we consider the inherent virulence of two nonencapsulated
N. meningitidis
isolates obtained from our national surveillance of infected blood cultures in Canada. Capsule deficiency of both strains was confirmed by serology and PCR for the
ctrA
to
ctrD
genes and
siaA
to
siaC
genes, as well as
siaD
genes specific to serogroups B, C, Y, and W135. In both strains, the capsule synthesis genes were replaced by the capsule null locus,
cnl-2
. In accordance with a lack of capsule, both strains were fully susceptible to killing by both human and baby rabbit complement. However, in the presence of cytidine-5′ monophospho-
N
-acetylneuraminic acid (CMP-NANA), allowing for lipooligosaccharide (LOS) sialylation, a significant increase of resistance to complement killing was observed. Mass spectrometry of purified LOS did not reveal any uncommon modifications that would explain their invasive phenotype. Finally, in a mouse intraperitoneal challenge model, these nonencapsulated isolates displayed enhanced virulence relative to an isogenic mutant of serogroup B strain MC58 lacking capsule (MC58Δ
siaD
). Virulence of all nonencapsulated isolates tested was below that of encapsulated serogroup B strains MC58 and B16B6. However, whereas no mortality was observed with MC58Δ
siaD
, 5/10 mice succumbed to infection with strain 2275 and 2/11 mice succumbed to strain 2274. Our results suggest the acquisition of a new virulence phenotype by these nonencapsulated strains.
Toll-Like Receptor- and Filarial Antigen-Mediated, Mitogen-Activated Protein Kinase- and NF-κB-Dependent Regulation of Angiogenic Growth Factors in Filarial Lymphatic Pathology
Authors: Babu Subash , Anuradha R. , Kumar N. Pavan , George P. Jovvian , Kumaraswami V. , Nutman Thomas B. 
Published: April 2012

ABSTRACT
Filarial lymphatic pathology is of multifactorial origin, with inflammation, lymphangiogenesis, and innate immune responses all playing important roles. The role of Toll-like receptors (TLRs) in the development of filarial pathology is well characterized. Similarly, the association of pathology with elevated levels of plasma angiogenic factors has also been documented. To examine the association between TLR function and the development of lymphangiogenesis in filarial infections, we examined TLR- and filarial antigen-induced expression and production of various angiogenic growth factors. We demonstrate that TLR ligands (specifically TLR2, -3, and -5 ligands) induce significantly increased expression/production of vascular endothelial growth factor A (VEGF-A) and angiopoietin-1 (Ang-1) in the peripheral blood mononuclear cells of individuals with lymphatic pathology (CP individuals) compared to that in cells of asymptomatic infected (INF) individuals. Similarly, filarial antigens induce significantly enhanced production of VEGF-C in CP compared with INF individuals. TLR2-mediated enhancement of angiogenic growth factor production in CP individuals was shown to be dependent on mitogen-activated protein kinase (MAPK) and NF-κB signaling, as pharmacologic inhibition of either extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, or NF-κB signaling resulted in significantly diminished production of VEGF-A and Ang-1. Our data therefore strongly suggest an important association between TLR signaling and lymphangiogenesis in the development of pathology in human lymphatic filariasis.
Antibody Targeting of Cell-Bound MUC1 SEA Domain Kills Tumor Cells
Authors: Pichinuk Edward , Benhar Itai , Jacobi Oded , Chalik Michael , Weiss Lotem , Ziv Ravit , Sympson Carolyn , Karwa Amolkumar , Smorodinsky Nechama I. , Rubinstein Daniel B. , Wreschner Daniel H. 
Published: April 2012

Abstract
The cell-surface glycoprotein MUC1 is a particularly appealing target for antibody targeting, being selectively overexpressed in many types of cancers and a high proportion of cancer stem–like cells. However the occurrence of MUC1 cleavage, which leads to the release of the extracellular α subunit into the circulation where it can sequester many anti-MUC1 antibodies, renders the target problematic to some degree. To address this issue, we generated a set of unique MUC1 monoclonal antibodies that target a region termed the SEA domain that remains tethered to the cell surface after MUC1 cleavage. In breast cancer cell populations, these antibodies bound the cancer cells with high picomolar affinity. Starting with a partially humanized antibody, DMB5F3, we created a recombinant chimeric antibody that bound a panel of MUC1+ cancer cells with higher affinities relative to cetuximab (anti-EGFR1) or tratuzumab (anti-erbB2) control antibodies. DMB5F3 internalization from the cell surface occurred in an efficient temperature-dependent manner. Linkage to toxin rendered these DMB5F3 antibodies to be cytotoxic against MUC1+ cancer cells at low picomolar concentrations. Our findings show that high-affinity antibodies to cell-bound MUC1 SEA domain exert specific cytotoxicity against cancer cells, and they point to the SEA domain as a potential immunogen to generate MUC1 vaccines. Cancer Res; 72(13); 3324–36. ©2012 AACR.
Serum Cholesterol and mTOR Inhibitors: Surrogate Biomarker or Epiphenomenon?
Authors: Cho Daniel C. , Atkins Michael B. 
Published: April 2012

Abstract
Lee and colleagues report that increase in serum cholesterol is associated with improved clinical outcomes in patients with renal cell carcinoma treated with temsirolimus. Although these findings must be validated prospectively, it should also be determined if this marker is a true mechanism-based toxicity or an epiphenomenon associated with therapy. Clin Cancer Res; 18(11); 2999–3001. ©2012 AACR.
XIAP Inhibition and Generation of Reactive Oxygen Species Enhances TRAIL Sensitivity in Inflammatory Breast Cancer Cells
Authors: Allensworth Jennifer L. , Aird Katherine M. , Aldrich Amy J. , Batinic-Haberle Ines , Devi Gayathri R. 
Published: April 2012

AbstractWe recently identified superoxide dismutase (SOD) overexpression and decreased induction of reactive oxygen species (ROS)-mediated apoptosis in models of inflammatory breast cancer (IBC) cells with acquired therapeutic resistance. This population of cells has high expression of X-linked inhibitor of apoptosis protein (XIAP), which inhibits both extrinsic and intrinsic apoptosis pathways. We therefore wanted to evaluate the effect of classical apoptosis-inducing agent TRAIL, a proapoptotic receptor agonist that selectively triggers death receptor (DR)-mediated apoptosis in cancer cells, in the IBC acquired resistance model. XIAP levels and subsequent inhibition of caspase activity inversely correlated with TRAIL sensitivity in our models of IBC. These include SUM149, a basal-type cell line isolated from primary IBC tumors and isogenic SUM149-derived lines rSUM149 and SUM149 wtXIAP, models of acquired therapeutic resistance with endogenous and exogenous XIAP overexpression, respectively. Inhibition of XIAP function using embelin, a plant-derived cell permeable small molecule, in combination with TRAIL caused a synergistic decrease in cell viability. Embelin treatment resulted in activation of extracellular signal–regulated kinase (ERK)1/2 and ROS accumulation, which correlated with downregulation of antioxidant protein SOD1 and consumption of redox modulator reduced glutathione in the XIAP-overexpressing cells. Simultaneous treatment with an SOD mimic, which protects against ROS accumulation, reversed the decrease in cell viability caused by embelin + TRAIL treatment. Embelin primes IBC cells for TRAIL-mediated apoptosis by its direct action on the anti-caspase activity of XIAP and by shifting the cellular redox balance toward oxidative stress–mediated apoptosis. Thus, ROS modulators represent a novel approach to enhance efficacy of TRAIL-based treatment protocols in IBC. Mol Cancer Ther; 11(7); 1518–27. ©2012 AACR.