bluuebunny/crossref_metadata_2025 huggingface dataset:
Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney
Authors: Kelsen Silvia , He Xiaochen , Chade Alejandro R.
Published: May 2012

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution regarding antioxidant strategies in RAS.
A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice
Authors: Evans Louise C. , Livingstone Dawn E. , Kenyon Christopher J. , Jansen Maurits A. , Dear James W. , Mullins John J. , Bailey Matthew A.
Published: May 2012

In aldosterone target tissues, 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2−/−mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2−/−mice and controls. Hsd11b2−/−mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (∼2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport ( aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2−/−mice (>6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2−/−mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2−/−mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin.
Prostaglandin E2EP3 receptor regulates cyclooxygenase-2 expression in the kidney
Authors: Vio Carlos P. , Quiroz-Munoz Mariana , Cuevas Catherina A. , Cespedes Carlos , Ferreri Nicholas R.
Published: May 2012

Cyclooxygenase-2 (COX-2) is constitutively expressed and highly regulated in the thick ascending limb (TAL). As COX-2 inhibitors (Coxibs) increase COX-2 expression, we tested the hypothesis that a negative feedback mechanism involving PGE2EP3 receptors regulates COX-2 expression in the TAL. Sprague-Dawley rats were treated with a Coxib [celecoxib (20 mg·kg−1·day−1) or rofecoxib (10 mg·kg−1·day−1)], with or without sulprostone (20 μg·kg−1·day−1). Sulprostone was given using two protocols, namely, previous to Coxib treatment (prevention effect; Sulp7-Coxib5 group) and 5 days after initiation of Coxib treatment (regression effect; Coxib10-Sulp5 group). Immunohistochemical and morphometric analysis revealed that the stained area for COX-2-positive TAL cells (μm2/field) increased in Coxib-treated rats (Sham: 412 ± 56.3, Coxib: 794 ± 153.3). The Coxib effect was inhibited when sulprostone was used in either the prevention (285 ± 56.9) or regression (345 ± 51.1) protocols. Western blot analysis revealed a 2.1 ± 0.3-fold increase in COX-2 protein expression in the Coxib-treated group, an effect abolished by sulprostone using either the prevention (1.2 ± 0.3-fold) or regression (0.6 ± 0.4-fold vs. control, P < 0.05) protocols. Similarly, the 6.4 ± 0.6-fold increase in COX-2 mRNA abundance induced by Coxibs ( P < 0.05) was inhibited by sulprostone; prevention: 0.9 ± 0.3-fold ( P < 0.05) and regression: 0.6 ± 0.1 ( P < 0.05). Administration of a selective EP3 receptor antagonist, L-798106, also increased the area for COX-2-stained cells, COX-2 mRNA accumulation, and protein expression in the TAL. Collectively, the data suggest that COX-2 levels are regulated by a novel negative feedback loop mediated by PGE2acting on its EP3 receptor in the TAL.
Gamma oscillations are involved in the sensorimotor transformation of pain
Authors: Schulz Enrico , Tiemann Laura , Witkovsky Viktor , Schmidt Paul , Ploner Markus
Published: May 2012

Pain signals threat and initiates motor responses to avoid harm. The transformation of pain into a motor response is thus an essential part of pain. Here, we investigated the neural mechanisms subserving the sensorimotor transformation of pain at the cortical level by using electroencephalography. In a simple reaction time experiment, brief painful stimuli were delivered to the left hand of healthy human subjects who responded with button presses of the right hand. The results show that the simple reaction time task was associated with neuronal responses at delta/theta, alpha/beta, and gamma frequencies. The analysis of the relationship between neuronal activity and response speed revealed that gamma oscillations, which were temporally coupled to the painful stimuli, but not temporally coupled to the motor response, predicted reaction times. Lateralization of gamma oscillations indicates that they originate from motor areas rather than from sensory areas. We conclude that gamma oscillations are involved in the sensorimotor transformation of pain whose efficiency they reflect. We hypothesize that the relationship between stimulus-locked gamma oscillations and reaction times reflects a direct thalamo-motor route of nociceptive information that is central to the biological function of pain.
The state of somatosensory cortex during neuromodulation
Authors: Favero Morgana , Varghese Gladis , Castro-Alamancos Manuel A.
Published: May 2012

During behavioral quiescence, such as slow-wave sleep and anesthesia, the neocortex is in a deactivated state characterized by the presence of slow oscillations. During arousal, slow oscillations are absent and the neocortex is in an activated state that greatly impacts information processing. Neuromodulators acting in neocortex are believed to mediate these state changes, but the mechanisms are poorly understood. We investigated the actions of noradrenergic and cholinergic activation on slow oscillations, cellular excitability, and synaptic inputs in thalamocortical slices of somatosensory cortex. The results show that neuromodulation abolishes slow oscillations, dampens the excitability of principal cells, and rebalances excitatory and inhibitory synaptic inputs in thalamocortical-recipient layers IV–III. Sensory cortex is much more selective about the inputs that can drive it. The source of neuromodulation is critically important in determining this selectivity. Cholinergic activation suppresses the excitatory and inhibitory conductances driven by thalamocortical and intracortical inputs. Noradrenergic activation suppresses the excitatory conductance driven by intracortical inputs but not by thalamocortical inputs and enhances the inhibitory conductance driven by thalamocortical inputs but not by intracortical inputs. Thus noradrenergic activation emphasizes thalamocortical (sensory) inputs relative to intracortical inputs, while cholinergic activation suppresses both.
Modulation of soleus H reflex by spinal DC stimulation in humans
Authors: Lamy Jean-Charles , Ho Chris , Badel Anne , Arrigo Robert T. , Boakye Maxwell
Published: May 2012

Transcranial direct current stimulation (tDCS) of the human motor cortex induces changes in excitability within cortical and spinal circuits that occur during and after the stimulation. Recently, transcutaneous spinal direct current stimulation (tsDCS) has been shown to modulate spinal conduction properties, as assessed by somatosensory-evoked potentials, and transynaptic properties of the spinal neurons, as tested by postactivation depression of the H reflex or by the RIII nociceptive component of the flexion reflex in the lower limb. To further explore tsDCS-induced plastic changes in spinal excitability, we examined, in a double-blind crossover randomized study, the stimulus-response curves of the soleus H reflex before, during, at current offset and 15 min after anodal, cathodal, and sham tsDCS delivered at the Th11 level (2.5 mA, 15 min, 0.071 mA/cm2, 0.064 C/cm2) in 17 healthy subjects. Anodal tsDCS induced a progressive leftward shift of the recruitment curve of the soleus H reflex during the stimulation; the effects persisted for at least 15 min after current offset. In contrast, both cathodal and sham tsDCS had no significant effects. This exploratory study provides further evidence for the use of tsDCS as an expedient, noninvasive tool to induce long-lasting plastic changes in spinal circuitry. Increased spinal excitability after anodal tsDCS may have potential for spinal neuromodulation in patients with central nervous system lesions.
MET Signaling Regulates Glioblastoma Stem Cells
Authors: Joo Kyeung Min , Jin Juyoun , Kim Eunhee , Ho Kim Kang , Kim Yonghyun , Gu Kang Bong , Kang Youn-Jung , Lathia Justin D. , Ho Cheong Kwang , Song Paul H. , Kim Hyunggee , Seol Ho Jun , Kong Doo-Sik , Lee Jung-Il , Rich Jeremy N. , Lee Jeongwu , Nam Do-Hyun
Published: May 2012

Glioblastomas multiforme (GBM) contain highly tumorigenic, self-renewing populations of stem/initiating cells [glioblastoma stem cells (GSC)] that contribute to tumor propagation and treatment resistance. However, our knowledge of the specific signaling pathways that regulate GSCs is limited. The MET tyrosine kinase is known to stimulate the survival, proliferation, and invasion of various cancers including GBM. Here, we identified a distinct fraction of cells expressing a high level of MET in human primary GBM specimens that were preferentially localized in perivascular regions of human GBM biopsy tissues and were found to be highly clonogenic, tumorigenic, and resistant to radiation. Inhibition of MET signaling in GSCs disrupted tumor growth and invasiveness both in vitro and in vivo, suggesting that MET activation is required for GSCs. Together, our findings indicate that MET activation in GBM is a functional requisite for the cancer stem cell phenotype and a promising therapeutic target. Cancer Res; 72(15); 3828–38. ©2012 AACR.
TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells
Authors: Fitzgerald Daniel P. , Emerson David L. , Qian Yongzhen , Anwar Talha , Liewehr David J. , Steinberg Seth M. , Silberman Sandra , Palmieri Diane , Steeg Patricia S.
Published: May 2012

Brain metastases of breast and other cancers remain resistant to chemotherapeutic regimens that are effective systemically, in part due to the blood–brain barrier. We report that TPI-287, a new microtubule-stabilizing agent, displays in vitro cytotoxic activity similar to taxanes and epothilones. Unlike the taxanes, TPI-287 is permeable through the blood–brain barrier. Brain-to-plasma ratios of TPI-287 after a single injection typically exceeded one and were as high as 63.8 in the rat and 14.1 in the mouse. A brain-tropic derivative of the MDA-MB-231 triple-negative breast cancer cell line, 231-BR, was used to test whether TPI-287 may be efficacious at preventing or treating brain metastases. TPI-287 had growth inhibitory effects comparable with paclitaxel when 231-BR tumor cells were injected into the mammary fat pad. Brain metastatic colonization was determined by intracardiac injection of 231-BR cells, with treatment beginning on day 3 to 4 postinjection, culminating in a histologic count of brain metastases in brains necropsied days 25 to 28 postinjection. In this assay, paclitaxel, ixabepilone, and nab paclitaxel did not have significant inhibitory activity. TPI-287 was ineffective in the same assay using a 6 mg/kg every week schedule; however an 18 mg/kg dose delivered on days 3, 7, and 11 significantly reduced the outgrowth of brain metastases (55% reduction, P = 0.028) and reduced proliferation in brain metastases (16% reduction, P = 0.008). When TPI-287 treatment was delayed until days 18, 22, and 26 postinjection, efficacy was reduced (17% reduction, not significant). These data suggest that TPI-287 may have efficacy when administered early in the course of the disease. Mol Cancer Ther; 11(9); 1959–67. ©2012 AACR.
Assessment of Fetal Cardiac Function Using Tissue Doppler Techniques
Authors: Comas Montse , Crispi Fatima
Published: May 2012

Objective: Tissue Doppler echocardiography is being increasingly used in fetal medicine as a clinical and research tool. The objective of this study was to review the current status of tissue Doppler imaging (TDI) techniques applied to the fetus. Methods: Fetal cardiac function was evaluated using spectral and color TDI modes in normal fetuses and in several clinical conditions. Results: Annular peak velocities and their ratios as well as the myocardial performance index were evaluated using spectral TDI, and changes throughout gestation were described. Color TDI has several limitations in fetal life, particularly the use of low frame rates with current methods of acquisition and the lack of normal references for deformation parameters. Conclusions: Despite its limitations, TDI is a sensitive and promising method to evaluate fetal cardiac function.
Corticosteroid Treatment of Pure Red Cell Aplasia in a Patient with Hepatitis A
Authors: Yoon Young Kyung , Park Dae Won , Sohn Jang Wook , Kim Min Ja , Kim Insun , Nam Myung Hyun
Published: May 2012

Secondary pure red cell aplasia (PRCA), as an extrahepatic manifestation of hepatitis A virus infection, has been reported on rare occasions. We report herein an unusual case of hepatitis A complicated by PRCA. In addition, we reviewed nine cases reported in the English literature. Our case of nonfulminant hepatitis A complicated by PRCA and hemolytic anemia was successfully treated with initial transfusion and corticosteroid therapy for 18 weeks. The patient’s hematologic abnormalities and liver function tests re-normalized completely. We review clinical features and effective therapeutic strategies for this disease entity.
Transthyretin Aggregates Induce Production of Reactive Nitrogen Species
Authors: Fong Vai-Hong , Vieira Amandio
Published: May 2012

Background and Objective: Misfolded and aggregated transthyretins (agTTR) contribute to neurodegenerative amyloid diseases such as familial amyloid polyneuropathy and senile systemic amyloidosis. The neurotoxicity mechanisms of agTTR, however, are not well understood. In the current study, the possible contribution of reactive nitrogen species (RNS) to such mechanisms was investigated by examining agTTR-mediated changes in cellular RNS levels. Methods and Results: The production of RNS was assessed through nitrate and nitrite assays in two human cell lines after exposure to agTTR (2.4 µm pre-aggregation concentration). In both epidermoid (A431) and schwannoma (sNF94.3) cell lines, agTTR induced significant increases in RNS (p < 0.05 relative to the same concentration of normal TTR, or no-TTR controls). Redox modulators such as apocynin (1-(4-hydroxy-3-methoxy-phenyl)ethanone) and l-NMMA (NG-monomethyl-l-arginine) were tested for their effects on RNS production. These modulators decreased RNS production in both cell lines; although the effects of l-NMMA were statistically significant only in the schwannoma cells. Moreover, cells treated with agTTR exhibited decreases in metabolic activity relative to TTR- or non-TTR-treated cells (p < 0.05) as assessed by reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Conclusion: The results provide novel evidence for involvement of RNS in pro-oxidative effects of agTTR in two different human cell lines, and show that agTTR can induce more generalized changes in cellular metabolic activity.
Number of Tracts or Stone Size: Which Influences Outcome of Percutaneous Nephrolithotomy for Staghorn Renal Stones?
Authors: Maghsoudi Robab , Etemadian Masoud , Shadpour Pejman , Radfar Mohammad Hadi , Ghasemi Hadi , Shati Mohsen
Published: May 2012

Introduction: Percutaneous nephrolithotomy (PCNL) is the recommended first-line treatment for staghorn stones. To achieve complete stone clearance, PCNL may require using multiple tracts. Objective: To evaluate outcome of PCNL in patients with staghorn calculi and its correlation with the number of tracts and stone features. Materials and Methods: One hundred consecutive patients with staghorn renal stone who underwent PCNL were included in the study. Perioperative and postoperative features were recorded. Correlation of the variables with number of tracts and stone size was assessed. Results: Mean age (±SD) was 49.6 ± 14.7 years. Our patients were ASA class I. The mean cumulative stone burden was 365.9 ± 156.5 mm2. The mean number of tracts was 2.4 (range: 1–7), and stone-free rate was 83%. The stone-free rate (p = 0.026) and hospital stay (p = 0.005) correlated with stone size, but not with number of tracts. Postoperative fever correlated with stone size (p = 0.017) and number of tracts (p = 0.037). Conclusion: PCNL using multiple tracts seem to be effective and safe in treatment of staghorn calculi. Most outcome measures correlated with stone size rather than number of tracts.
High-Frequency Variant p.T60M in NaCl Cotransporter and Blood Pressure Variability in Han Chinese
Authors: Shao Leping , Lang Yanhua , Wang Yan , Gao Yanxia , Zhang Wei , Niu Haitao , Liu Shiguo , Chen Nan
Published: May 2012

Objective: Frequent studies have confirmed that homozygous or compound heterozygous loss-of-function mutation p.Thr60Met in NaCl cotransporter (NCC) lead to the salt-wasting Gitelman’s syndrome (GS) of hypotension. The finding that Thr60 is a key SPAK/OSR1 phosphorylation site on NCC also raises the possible importance of Thr60 in regulating the activity of NCC and blood pressure (BP). However, the association of heterozygous NCC mutation p.Thr60Met and BP has not yet been studied. Methods: We collected 38 heterozygous mutation p.Thr60Met carriers, respectively, from 14 GS families confirmed by our previous studies and 1,000 unrelated Han Chinese, and matched them pairwise (sex, age ±2 years and BMI ±1) with 38 unrelated healthy controls. BP and biochemistry data were obtained. Student’s t test and χ2 test were used to compare the differences between these study subjects with the heterozygous variant p.T60M and the controls. p < 0.05 was considered statistically significant. Results p.Thr60Met carriers had markedly lower BP (systolic 110.3 ± 13.5 vs. 119.1 ± 15.0 mm Hg; diastolic 70.2 ± 7.0 vs. 75.4 ± 8.2 mm Hg, p < 0.01) than controls. p.Thr60Met heterozygotes had higher fasting plasma glucose concentration (5.35 ± 0.73 vs. 4.95 ± 0.69 mmol/l, p < 0.01). 14 carriers versus 6 control subjects had impaired fasting glucose (36.8 vs. 15.8%, p < 0.01), and p.Thr60Met carriers had higher 24-hour urinary sodium excretion than controls but not significantly (170.2 ± 35.6 vs. 159.5 ± 39.0 mmol, p = 0.10). Conclusions: The NCC mutation p.Thr60Met carriers in Han populations have markedly lower BP and slightly higher fasting plasma glucose compared with normal controls.
Duration of Dual Antiplatelet Therapy and Long-Term Clinical Outcome After Coronary Drug-Eluting Stent Implantation
Authors: Tada Tomohisa , Natsuaki Masahiro , Morimoto Takeshi , Furukawa Yutaka , Nakagawa Yoshihisa , Byrne Robert A. , Kastrati Adnan , Kadota Kazushige , Iwabuchi Masashi , Shizuta Satoshi , Tazaki Junichi , Shiomi Hiroki , Abe Mitsuru , Ehara Natsuhiko , Mizoguchi Tetsu , Mitsuoka Hirokazu , Inada Tsukasa , Araki Makoto , Kaburagi Satoshi , Taniguchi Ryoji , Eizawa Hiroshi , Nakano Akira , Suwa Satoru , Takizawa Akinori , Nohara Ryuji , Fujiwara Hisayoshi , Mitsudo Kazuaki , Nobuyoshi Masakiyo , Kita Toru , Kimura Takeshi
Published: May 2012

Background—

Optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation has not been yet fully elucidated.

Methods and Results—

We assessed the influence of prolonged thienopyridine therapy on clinical outcomes with landmark analysis at 4 and 13 months after DES implantation. Among 6802 patients with at least 1 DES implantation in the CREDO-Kyoto Registry Cohort-2, 6309 patients (on thienopyridine, 5438 patients; off thienopyridine, 871 patients) and 5901 patients (on thienopyridine, 4098 patients; off thienopyridine, 1803 patients) were eligible for the 4- and 13-month landmark analyses, respectively. The majority of patients had stable coronary artery disease (73%) and received sirolimus-eluting stents (93%), and approximately 90% of thienopyridine was ticlopidine. Patients taking thienopyridine had more complex comorbidities and more complex lesion and procedural characteristics as compared with patients not taking thienopyridine. After adjusting for confounders, thienopyridine use was not associated with decreased risk for death/myocardial infarction/stroke (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.89–1.43,
P
=0.32 in the 4-month landmark analysis; HR, 1.14; 95% CI, 0.90–1.45,
P
=0.29 in the 13-month landmark analysis, respectively), whereas the risk for GUSTO moderate/severe bleeding tended to be higher in patients taking thienopyridine (HR, 1.51; 95% CI, 1.00–2.23,
P
=0.049 in the 4-month landmark analysis; HR, 1.44; 95% CI, 0.99–2.09,
P
=0.057 in the 13-month landmark analysis, respectively).

Conclusions—

Prolonged thienopyridine therapy beyond 4 and 13 months appeared not to be associated with reduction in ischemic events but to be associated with a trend toward increased bleeding. Optimal duration of DAPT after DES implantation might be shorter than the currently recommended 1-year interval.
Role of Coronin 1B in PDGF-Induced Migration of Vascular Smooth Muscle Cells
Authors: Williams Holly C. , San Martín Alejandra , Adamo Candace M. , Seidel-Rogol Bonnie , Pounkova Lily , Datla Srinivasan Raju , Lassègue Bernard , Bear James E. , Griendling Kathy
Published: May 2012

Rationale:

The type I subclass of coronins, a family of actin-binding proteins, regulates various actin-dependent cellular processes, including migration. However, the existence and role of coronins in vascular smooth muscle cell (VSMC) migration has yet to be determined.

Objective:

The goal of the present study was to define the mechanism by which coronins regulate platelet-derived growth factor (PDGF)–induced VSMC migration.

Methods and Results:

Coronin 1B (Coro1B) and 1C (Coro1C) were both found to be expressed in VSMCs at the mRNA and protein levels. Downregulation of Coro1B by siRNA increases PDGF-induced migration, while downregulation of Coro1C has no effect. We confirmed through kymograph analysis that the Coro1B-downregulation-mediated increase in migration is directly linked to increased lamellipodial protraction rate and protrusion distance in VSMC. In other cell types, coronins exert their effects on lamellipodia dynamics by an inhibitory interaction with the ARP2/3 complex, which is disrupted by the phosphorylation of Coro1B. We found that PDGF induces phosphorylation of Coro1B on serine-2 via PKCɛ, leading to a decrease in the interaction of Coro1B with the ARP2/3 complex. VSMCs transfected with a phosphodeficient S2A Coro1B mutant showed decreased migration in response to PDGF, suggesting that the phosphorylation of Coro1B is required for the promotion of migration by PDGF. In both the rat and mouse, Coro1B phosphorylation was increased in response to vessel injury in vivo.

Conclusions:

Our data suggest that phosphorylation of Coro1B and the subsequent reduced interaction with ARP2/3·complex participate in PDGF-induced VSMC migration, an important step in vascular lesion formation.
Iroquois
Homeodomain Transcription Factors in Heart Development and Function
Authors: Kim Kyoung-Han , Rosen Anna , Bruneau Benoit G. , Hui Chi-chung , Backx Peter H.
Published: May 2012

Numerous cardiac transcription factors play overlapping roles in both the specification and proliferation of the cardiac tissues and chambers during heart development. It has become increasingly apparent that cardiac transcription factors also play critical roles in the regulation of expression of many functional genes in the prenatal and postnatal hearts. Accordingly, mutations of cardiac transcription factors cannot only result in congenital heart defects but also alter heart function thereby predisposing to heart disease and cardiac arrhythmias. In this review, we summarize the roles of
Iroquois homeobox
(
Irx
) family of transcription factors in heart development and function. In all, 6
Irx
genes are expressed with distinct and overlapping patterns in the mammalian heart. Studies in several animal models demonstrate that
Irx
genes are important for the establishment of ventricular chamber properties, the ventricular conduction system, as well as heterogeneity of the ventricular repolarization. The molecular mechanisms by which Irx proteins regulate gene expression and the clinical relevance of
Irx
functions in the heart are discussed.
Cardiac-Specific Inducible and Conditional Gene Targeting in Mice
Authors: Doetschman Thomas , Azhar Mohamad
Published: May 2012

Mouse genetic engineering has revolutionized our understanding of the molecular and genetic basis of heart development and disease. This technology involves conditional tissue-specific and temporal transgenic and gene targeting approaches, as well as introduction of polymorphisms into the mouse genome. These approaches are increasingly used to elucidate the genetic pathways underlying tissue homeostasis, physiology, and pathophysiology of adult heart. They have also led to the development of clinically relevant models of human cardiac diseases. Here, we review the technologies and their limitations in general and the cardiovascular research community in particular.
Posttraumatic Stress Disorder and Adherence to Medications in Survivors of Strokes and Transient Ischemic Attacks
Authors: Kronish Ian M. , Edmondson Donald , Goldfinger Judith Z. , Fei Kezhen , Horowitz Carol R.
Published: May 2012

Background and Purpose—

Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical events such as strokes and transient ischemic attacks (TIAs). Little is known regarding how PTSD triggered by medical events affects patients' adherence to medications.

Methods—

We surveyed 535 participants, age ≥40 years old, who had at least 1 stroke or TIA in the previous 5 years. PTSD was assessed using the PTSD Checklist-Specific for stroke; a score ≥50 on this scale is highly specific for PTSD diagnosis. Medication adherence was measured using the 8-item Morisky scale. Logistic regression was used to test whether PTSD after stroke/TIA was associated with increased risk of medication nonadherence. Covariates for adjusted analyses included sociodemographics, Charlson comorbidity index, modified Rankin Scale score, years since last stroke/TIA, and depression.

Results—

Eighteen percent of participants had likely PTSD (PTSD Checklist-Specific for stroke ≥50), and 41% were nonadherent to medications according to the Morisky scale. A greater proportion of participants with likely PTSD were nonadherent to medications than other participants (67% versus 35%,
P
<0.001). In the adjusted model, participants with likely PTSD were nearly 3 times more likely (relative risk, 2.7; 95% CI, 1.7–4.2) to be nonadherent compared with participants without PTSD (PTSD Checklist-Specific for stroke <25) even after controlling for depression, and there was a graded association between PTSD severity and medication nonadherence.

Conclusion—

PTSD is common after stroke/TIA. Patients who have PTSD after stroke or TIA are at increased risk for medication nonadherence.
“Young Goodman Brown” and the Mathers
Authors: Ronan John
Published: May 2012

“‘Young Goodman Brown’ and the Mathers” contends that Hawthorne's famous tale is an allegorical representation of Increase and Cotton Mather's agency in bringing about the Salem witch trials through their demonological publications.
“Once Masculines … Now Feminines Awhile”: Gendered Imagery and the Significance of Anne Bradstreet's The Tenth Muse
Authors: Henton Alice
Published: May 2012

Anne Bradstreet's early poems showcase a poet working within established tropes and traditions to destabilize gender frameworks and posit a poetic landscape dominated by feminine symbols. Rather than creating an alternative to a Puritan identity, Bradstreet creates an alternative Puritan identity, one that lays the groundwork for numerous American women writers.
The Trouble with Grace: Reading Jonathan Edwards's Faithful Narrative
Authors: Sederholm Carl
Published: May 2012

Critics have long noted but never adequately explained why Jonathan Edwards deliberately reordered the Northampton revival's chronology in his Faithful Narrative. This essay argues that by declaring that Joseph Hawley's suicide signified the withdrawal of God's Spirit, Edwards sought to protect his community from the social, cultural, and theological ramifications of that self-murder.
Implementation, Characterization, and Evaluation of an Inexpensive Low-Power Low-Noise Infrasound Sensor Based on a Micromachined Differential Pressure Transducer and a Mechanical Filter
Authors: Marcillo Omar , Johnson Jeffrey B. , Hart Darren
Published: May 2012

The implementation, characterization, and evaluation of a low-cost infrasound sensor developed at the Infrasound Laboratory at the New Mexico Institute of Mining and Technology (Infra-NMT) are described. This sensor is based on a commercial micromachined piezoresistive differential pressure transducer that uses a mechanical high-pass filter to reject low-frequency outband energy. The sensor features a low-noise, 2.02-mPa rms (0.5–2 Hz), 5.47-mPa rms (0.1–20 Hz), or 5.62-mPa rms (0.05–20 Hz), flat response between 0.01 and at least 40 Hz; inband sensitivity of 45.13 ± 0.23 μV Pa−1; and a nominal linear range from −124.5 to +124.5 Pa. Intended for outdoor applications, the influence of thermal changes in the sensor’s response has been minimized by using a thermal compensated pressure transducer powered by an ultralow drift (<5 ppm °C−1) and noise (<4μV from peak to peak) voltage reference. The sensor consumes a minimum of 24 mW and operates with voltages above 8 V while drawing 3 mA of current. The Infra-NMT specifications described above were independently verified using the infrasound test chamber at the Sandia National Laboratories’ (SNL’s) Facility for Acceptance, Calibration, and Testing (FACT), and the following procedures are for comparison calibration against traceable reference stands in voltage and pressure. Because of the intended broad frequency response of this sensor, the testing chamber was configured in a double-reference sensor scheme. A well-characterized microbarometer (with a flat-amplitude response between 0.01 and 8 Hz) and a microphone (with a flat-amplitude response above 8 Hz) were used simultaneously in this double-reference test configuration.
Impairments to the GH-IGF-I Axis in hSOD1G93A Mice Give Insight into Possible Mechanisms of GH Dysregulation in Patients with Amyotrophic Lateral Sclerosis
Authors: Steyn F. J. , Ngo S. T. , Lee J. D. , Leong J. W. , Buckley A. J. , Veldhuis J. D. , McCombe P. A. , Chen C. , Bellingham M. C.
Published: May 2012

GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1G93A transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1G93A transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1G93A mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1G93A mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1G93A mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.
Cardioprotective Effects of Metformin and Vildagliptin in Adult Rats with Insulin Resistance Induced by a High-Fat Diet
Authors: Apaijai Nattayaporn , Pintana Hiranya , Chattipakorn Siriporn C. , Chattipakorn Nipon
Published: May 2012

Insulin resistance has been shown to be associated with cardiac sympathovagal imbalance, myocardial dysfunction, and cardiac mitochondrial dysfunction. Whereas metformin is a widely used antidiabetic drug to improve insulin resistance, vildagliptin is a novel oral antidiabetic drug in a group of dipeptidyl peptidase-4 inhibitors in which its cardiac effect is unclear. This study aimed to determine the cardiovascular effects of metformin and vildagliptin in rats with insulin resistance induced by high-fat diet. Male Wistar rats were fed with either a normal diet or high-fat diet (n =24 each) for 12 wk. Rats in each group were divided into three subgroups to receive the vehicle, metformin (30 mg/kg, twice daily), or vildagliptin (3 mg/kg, once daily) for another 21 d. Heart rate variability (HRV), cardiac function, and cardiac mitochondrial function were determined and compared among these treatment groups. Rats exposed to a high-fat diet developed increased body weight, visceral fat, plasma insulin, cholesterol, oxidative stress, depressed HRV, and cardiac mitochondrial dysfunction. Metformin and vildagliptin did not alter body weight and plasma glucose levels but decreased the plasma insulin, total cholesterol, and oxidative stress levels. Although both metformin and vildagliptin attenuated the depressed HRV, cardiac dysfunction, and cardiac mitochondrial dysfunction, vildagliptin was more effective in this prevention. Furthermore, only vildagliptin prevented cardiac mitochondrial membrane depolarization caused by consumption of a high-fat diet. We concluded that vildagliptin is more effective in preventing cardiac sympathovagal imbalance and cardiac dysfunction, as well as cardiac mitochondrial dysfunction, than metformin in rats with insulin resistance induced by high-fat diet.
lyve1 expression reveals novel lymphatic vessels and new mechanisms for lymphatic vessel development in zebrafish
Authors: Okuda Kazuhide S. , Astin Jonathan W. , Misa June P. , Flores Maria V. , Crosier Kathryn E. , Crosier Philip S.
Published: May 2012

We have generated novel transgenic lines that brightly mark the lymphatic system of zebrafish using the lyve1 promoter. Facilitated by these new transgenic lines, we generated a map of zebrafish lymphatic development up to 15 days post-fertilisation and discovered three previously uncharacterised lymphatic vessel networks: the facial lymphatics, the lateral lymphatics and the intestinal lymphatics. We show that a facial lymphatic vessel, termed the lateral facial lymphatic, develops through a novel developmental mechanism, which initially involves vessel growth through a single vascular sprout followed by the recruitment of lymphangioblasts to the vascular tip. Unlike the lymphangioblasts that form the thoracic duct, the lymphangioblasts that contribute to the lateral facial lymphatic vessel originate from a number of different blood vessels. Our work highlights the additional complexity of lymphatic vessel development in the zebrafish that may increase its versatility as a model of lymphangiogenesis.
FGF signaling establishes the anterior border of the Ciona neural tube
Authors: Wagner Eileen , Levine Michael
Published: May 2012

The Ciona tadpole is constructed from simple, well-defined cell lineages governed by provisional gene networks that have been defined via extensive gene disruption assays. Here, we examine the patterning of the anterior neural plate, which produces placodal derivatives such as the adhesive palps and stomodeum, as well as the sensory vesicle (simple brain) of the Ciona tadpole. Evidence is presented that the doublesex-related gene DMRT is expressed throughout the anterior neural plate of neurulating embryos. It leads to the activation of FoxC and ZicL in the palp placode and anterior neural tube, respectively. This differential expression depends on FGF signaling, which inhibits FoxC expression in the anterior neural tube. Inhibition of FGF signaling leads to expanded expression of FoxC, the loss of ZicL, and truncation of the anterior neural tube.
Olig2-dependent developmental fate switch of NG2 cells
Authors: Zhu Xiaoqin , Zuo Hao , Maher Brady J. , Serwanski David R. , LoTurco Joseph J. , Lu Q. Richard , Nishiyama Akiko
Published: May 2012

NG2-expressing cells (NG2 cells or polydendrocytes) generate oligodendrocytes throughout the CNS and a subpopulation of protoplasmic astrocytes in the gray matter of the ventral forebrain. The mechanisms that regulate their oligodendrocyte or astrocyte fate and the degree to which they exhibit lineage plasticity in vivo have remained unclear. The basic helix-loop-helix transcription factor Olig2 is required for oligodendrocyte specification and differentiation. We have found that Olig2 expression is spontaneously downregulated in NG2 cells in the normal embryonic ventral forebrain as they differentiate into astrocytes. To further examine the role of Olig2 in NG2 cell fate determination, we used genetic fate mapping of NG2 cells in constitutive and tamoxifen-inducible Olig2 conditional knockout mice in which Olig2 was deleted specifically in NG2 cells. Constitutive deletion of Olig2 in NG2 cells in the neocortex and corpus callosum but not in ventral forebrain caused them to convert their fate into astrocytes, with a concomitant severe reduction in the number of oligodendrocytes and myelin. Deletion of Olig2 in NG2 cells in perinatal mice also resulted in astrocyte generation from neocortical NG2 cells. These observations indicate that the developmental fate of NG2 cells can be switched by altering a single transcription factor Olig2.
The C. elegans F-box proteins LIN-23 and SEL-10 antagonize centrosome duplication by regulating ZYG-1 levels
Authors: Peel Nina , Dougherty Michael , Goeres Jacqueline , Liu Yan , O'Connell Kevin F.
Published: May 2012

The correct segregation of DNA during cell division requires formation of a bipolar spindle, organized at each pole by a centrosome. The regulation of centrosome duplication such that each mitotic cell has exactly two centrosomes is therefore of central importance to cell division. Deregulation of centrosome duplication causes the appearance of supernumerary centrosomes, which are a hallmark of many cancer cells and can contribute to tumorigenesis. Overexpression of the kinase Plk4, which is required for centrosome duplication, causes the formation of extra centrosomes, and aberrant Plk4 expression levels are associated with cancer. Data from Drosophila and human cells show that Plk4 levels are regulated by the SCF ubiquitin ligase and proteasomal degradation. Recognition of Plk4 by the SCF complex is mediated by the F-box protein Slimb/βTrCP. We show that levels of the C. elegans Plk4 homolog ZYG-1 are elevated by impairing proteasome or SCF function, indicating that ZYG-1 is regulated by a conserved mechanism. In C. elegans, similar to Drosophila and humans, we find that the Slimb/βTrCP homolog LIN-23 regulates ZYG-1 levels. In addition, we show that a second F-box protein, SEL-10, also contributes to ZYG-1 regulation. Co-depletion of LIN-23 and SEL-10 suggests these proteins function cooperatively. Because SEL-10 is the homolog of human FBW7, which is frequently mutated in cancer, our findings have implications for understanding tumorigenesis.
MLL1, a Histone H3K4 Methyltransferase, Regulates the Expression of TNFα-mediated NF-κB Downstream Genes
Authors: Wang Xiang , Zhu Kun , Li Shangze , Liao Yifang , Du Runlei , Zhang Xiaodong , Shu Hong-Bing , Guo An-Yuan , Li Lianyun , Wu Min
Published: May 2012

Genes of mixed lineage leukemia family regulate transcription via methylating histone H3K4. Six members of MLL1 family exist in human, including SETD1A, SETD1B and MLL1-4. Each of them plays non-redundant roles in development and disease genesis. MLL1 regulates cell cycle and the oscillation of circadian gene expression. Its fusion proteins are involved in leukemogenesis. Here we studied the role of MLL1 in innate immunity and found it selectively regulates the activation of NF-κB downstream genes mediated by TNFα and LPS. Real time PCR and genome wide gene expression profile analysis proved the deficiency of MLL1 reduced the expression of a group of NF-κB downstream genes. However, the activation of NF-κB molecule itself was not affected. The MLL1 complex is localized both in nuclear and cytoplasm and associated with NF-κB. CHIP assays proved the translocation of MLL1 to chromatin was dependent on NF-κB. Our results suggested MLL1 is recruited to its targeting genes by activated NF-κB and regulates their transcription.
Opposing microtubule motors drive robust nuclear dynamics in developing muscle cells
Authors: Wilson Meredith H. , Holzbaur Erika L. F.
Published: May 2012

Dynamic interactions with the cytoskeleton drive the movement and positioning of nuclei in many cell types. During muscle cell development, myoblasts fuse to form syncytial myofibers with nuclei positioned regularly along the length of the cell. Nuclear translocation in developing myotubes requires microtubules, but the mechanisms involved have not been elucidated. We find that as nuclei actively translocate through the cell, they rotate in three-dimensions. The nuclear envelope, nucleoli, and chromocenters within the nucleus rotate together as a unit. Both translocation and rotation require an intact microtubule cytoskeleton, which forms a dynamic bipolar network around nuclei. The plus- and minus-end directed microtubule motor proteins, kinesin-1 and dynein, localize to the nuclear envelope in myotubes. Kinesin-1 localization is mediated at least in part by interaction with klarsicht/ANC-1/Syne homology (KASH) proteins. Depletion of kinesin-1 abolishes nuclear rotation and significantly inhibits nuclear translocation, resulting in the abnormal aggregation of nuclei at the midline of the myotube. Dynein depletion also inhibits nuclear dynamics, but to a lesser extent, leading to altered spacing between adjacent nuclei. Thus, oppositely directed motors acting from the surface of the nucleus drive nuclear motility in myotubes. The variable dynamics observed for individual nuclei within a single myotube likely result from the stochastic activity of competing motors interacting with a complex bipolar microtubule cytoskeleton that is also continuously remodeled as the nuclei move. The three-dimensional rotation of myotube nuclei may facilitate their motility through the complex and crowded cellular environment of the developing muscle cell, allowing for proper myonuclear positioning.
A Fluorescence Turn-on Sensor for Cyanide Anion Based on Exciplex Signaling Mechanism
Authors: Zhou Xianshu , Yang Hengquan , Hao Junsheng , Yin Caixia , Liu Diansheng , Guo Wei
Published: May 2012

A new fluorescent chemosensor comprising anthracene and indanedione-based Michael receptor, which recognizes cyanide anion with high selectivity was designed and synthesized. The Michael addition of cyanide to the chemosensor elicits a fluorescence enhancement at a longer wavelength, which constituted the signature for cyanide detection. The mechanism of exciplex formation was proposed for the interesting observation.
Crystal Structures and Dielectric Properties of 2-Imidazoline Derivatives Having Intermolecular Hydrogen-bonded Networks
Authors: Morimoto Masakazu , Takashio Naoya , Irie Masahiro
Published: May 2012

A 2-imidazoline derivative and its monoprotonated iodide salt construct different types of intermolecular N–H···N hydrogen bonds in the crystalline state. The two crystals give completely different dielectric responses, and the difference is correlated to their different hydrogen-bonded networks.
Preparation of α-Zirconium Phosphate from Fluorozirconate and Phosphoric Acid by Liquid-phase Deposition
Authors: Tahara Seiichi , Takakura Yoshie , Sugahara Yoshiyuki
Published: May 2012

α-Zirconium phosphate (α-ZrP) was prepared by liquid-phase deposition. Boric acid was added to a solution containing [ZrF6]2− anions, and phosphoric acid dropwise to cause slow decomposition of [ZrF6]2− and the subsequent reaction with H3PO4 to form α-ZrP. X-ray diffraction, scanning electron microscopy, solid-state 31P nuclear magnetic resonance spectroscopy, infrared spectroscopy, thermogravimetry, and elemental analyses indicate the formation of single-phase α-ZrP.
Handling Endogenous Regressors by Joint Estimation Using Copulas
Authors: Park Sungho , Gupta Sachin
Published: May 2012

We propose a new statistical instrument-free method to tackle the endogeneity problem. The proposed method models the joint distribution of the endogenous regressor and the error term in the structural equation of interest (the structural error) using a copula method, and it makes inferences on the model parameters by maximizing the likelihood derived from the joint distribution. Similar to the “exclusion restriction” in instrumental variable methods, extant instrument-free methods require the assumption that the unobserved instruments are exogenous, a requirement that is difficult to meet. The proposed method does not require such an assumption. Other benefits of the proposed method are that it allows the modeling of discrete endogenous regressors and offers a new solution to the slope endogeneity problem. In addition to linear models, the method is applicable to the popular random coefficient logit model with either aggregate-level or individual-level data. We demonstrate the performance of the proposed method via a series of simulation studies and an empirical example.