bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatty Acid Receptor Gpr40 Mediates Neuromicrovascular Degeneration Induced by Transarachidonic Acids in Rodents
Authors: Honoré Jean-Claude , Kooli Amna , Hamel David , Alquier Thierry , Rivera José-Carlos , Quiniou Christiane , Hou Xin , Kermorvant-Duchemin Elsa , Hardy Pierre , Poitout Vincent , Chemtob Sylvain 
Published: March 2013

Objective—
Nitro-oxidative stress exerts a significant role in the genesis of hypoxic-ischemic (HI) brain injury. We previously reported that the ω-6 long chain fatty acids, transarachidonic acids (TAAs), which are nitrative stress-induced nonenzymatically generated arachidonic acid derivatives, trigger selective microvascular endothelial cell death in neonatal neural tissue. The primary molecular target of TAAs remains unidentified. GPR40 is a G protein–coupled receptor activated by long chain fatty acids, including ω-6; it is highly expressed in brain, but its functions in this tissue are largely unknown. We hypothesized that TAAs play a significant role in neonatal HI-induced cerebral microvascular degeneration through GPR40 activation.

Approach and Results—

Within 24 hours of a HI insult to postnatal day 7 rat pups, a cerebral infarct and a 40% decrease in cerebrovascular density was observed. These effects were associated with an increase in nitrative stress markers (3-nitrotyrosine immunoreactivity and TAA levels) and were reduced by treatment with nitric oxide synthase inhibitor. GPR40 was expressed in rat pup brain microvasculature. In vitro, in GPR40-expressing human embryonic kidney (HEK)-293 cells, [
14
C]-14
E
-AA (radiolabeled TAA) bound specifically, and TAA induced calcium transients, extracellular signal–regulated kinase 1/2 phosphorylation, and proapoptotic thrombospondin-1 expression. In vivo, intracerebroventricular injection of TAAs triggered thrombospondin-1 expression and cerebral microvascular degeneration in wild-type mice, but not in GPR40-null congeners. Additionally, HI-induced neurovascular degeneration and cerebral infarct were decreased in GPR40-null mice.

Conclusions—
GPR40 emerges as the first identified G protein–coupled receptor conveying actions of nonenzymatically generated nitro-oxidative products, specifically TAAs, and is involved in (neonatal) HI encephalopathy.
Leptin-Dependent and Leptin-Independent Paracrine Effects of Perivascular Adipose Tissue on Neointima Formation
Authors: Schroeter Marco R. , Eschholz Norman , Herzberg Sebastian , Jerchel Isabel , Leifheit-Nestler Maren , Czepluch Frauke S. , Chalikias Georgios , Konstantinides Stavros , Schäfer Katrin 
Published: March 2013

Objective—
Clinical and experimental evidence suggests that periadventitial adipose tissue may modulate vascular lesion formation. The aim of this study was to determine the role of perivascular leptin expression on neointima formation and to differentiate it from local inflammation and systemically elevated leptin levels.

Approach and Results—

Increased neointima formation after carotid artery injury was observed in hyperleptinemic, diet–induced obese wild-type mice, but not in leptin-deficient
ob/ob
mice. High-fat diet was associated with increased leptin expression in visceral adipose tissue (VAT) as well as in perivascular adipose tissue. Perivascular leptin overexpression achieved by adenoviral vectors enhanced intimal cell proliferation and neointima formation in wild-type mice, but not in leptin receptor–deficient mice. Perivascular transplantation of VAT from high-fat diet–induced obese wild-type mice around the carotid artery of immunodeficient mice also promoted neointima formation, without affecting body weight or systemic leptin levels, and this effect was absent, if VAT from
ob/ob
mice was used. On the contrary, perivascular transplantation of VAT from
ob/ob
mice fed high-fat diet, characterized by marked immune cell accumulation, promoted neointimal hyperplasia also in the absence of leptin. In vitro, recombinant leptin and VAT-conditioned medium increased human arterial smooth muscle cell proliferation in a (partly) leptin-dependent manner.

Conclusions—
Our findings suggest that locally elevated leptin levels may promote neointima formation, independent of obesity and systemic hyperleptinemia, but also underline the importance of perivascular inflammation in mediating the increased cardiovascular risk in obesity.
Drug Screening Using a Library of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity
Authors: Liang Ping , Lan Feng , Lee Andrew S. , Gong Tingyu , Sanchez-Freire Veronica , Wang Yongming , Diecke Sebastian , Sallam Karim , Knowles Joshua W. , Wang Paul J. , Nguyen Patricia K. , Bers Donald M. , Robbins Robert C. , Wu Joseph C. 
Published: March 2013

Background—
Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.

Methods and Results—

Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell–derived cardiomyocytes (hESC-CMs) and the human
ether-a-go-go
–related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.

Conclusions—

We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human
ether-a-go-go
–related gene test or healthy control hiPSC-CM/hESC-CM screening assays.
Using Mentally Incompetent Adults as Living Organ Donors: Widely Diverging Regulations in Europe
Authors: Van Assche Kristof , Genicot Gilles , Sterckx Sigrid 
Published: March 2013

Abstract
With the current situation in Belgium as its initial focus, this article will examine the regulatory framework that governs the use of mentally incompetent adults as living organ donors in Europe. Our survey of the national regulation of 22 countries will reveal widely diverging viewpoints, ranging from an absolute prohibition on organ procurement to a barely restricted authorisation to retrieve even non-regenerable organs. We also have a look at the way in which American and English court decisions have applied the best interests standard in an attempt to define the contours of acceptable organ removal from mentally incompetent donors. Taking the best interests of the mentally incompetent person as a yardstick, we suggest that legally prohibiting organ removal from mentally incompetents may be problematic, even if it concerns only non-regenerable organs, and that regulations should be refined accordingly.
California Winter Precipitation Change under Global Warming in the Coupled Model Intercomparison Project Phase 5 Ensemble
Authors: Neelin J. David , Langenbrunner Baird , Meyerson Joyce E. , Hall Alex , Berg Neil 
Published: March 2013

Abstract
Projections of possible precipitation change in California under global warming have been subject to considerable uncertainty because California lies between the region anticipated to undergo increases in precipitation at mid-to-high latitudes and regions of anticipated decrease in the subtropics. Evaluation of the large-scale model experiments for phase 5 of the Coupled Model Intercomparison Project (CMIP5) suggests a greater degree of agreement on the sign of the winter (December–February) precipitation change than in the previous such intercomparison, indicating a greater portion of California falling within the increased precipitation zone. While the resolution of global models should not be relied on for accurate depiction of topographic rainfall distribution within California, the precipitation changes depend substantially on large-scale shifts in the storm tracks arriving at the coast. Significant precipitation increases in the region arriving at the California coast are associated with an eastward extension of the region of strong Pacific jet stream, which appears to be a robust feature of the large-scale simulated changes. This suggests that effects of this jet extension in steering storm tracks toward the California coast constitute an important factor that should be assessed for impacts on incoming storm properties for high-resolution regional model assessments.
Greenland Ice Sheet Mass Balance Reconstruction. Part II: Surface Mass Balance (1840–2010)*
Authors: Box Jason E. 
Published: March 2013

Abstract
Meteorological station records, ice cores, and regional climate model output are combined to develop a continuous 171-yr (1840–2010) reconstruction of Greenland ice sheet climatic surface mass balance (Bclim) and its subcomponents including near-surface air temperature (SAT) since the end of the Little Ice Age. Independent observations are used to assess and compensate errors. Melt water production is computed using separate degree-day factors for snow and bare ice surfaces. A simple meltwater retention scheme yields the time variation of internal accumulation, runoff, and bare ice area.
At decadal time scales over the 1840–2010 time span, summer (June–August) SAT increased by 1.6°C, driving a 59% surface meltwater production increase. Winter warming was +2.0°C. Substantial interdecadal variability linked with episodic volcanism and atmospheric circulation anomalies is also evident. Increasing accumulation and melt rates, bare ice area, and meltwater retention are driven by increasing SAT. As a consequence of increasing accumulation and melt rates, calculated meltwater retention by firn increased 51% over the period, nearly compensating a 63% runoff increase. Calculated ice sheet end of melt season bare ice area increased more than 5%.
Multiple regression of interannual SAT and precipitation anomalies suggests a dominance of melting on Bclim and a positive SAT precipitation sensitivity (+32 Gt yr−1 K−1 or 6.8% K−1).
The Bclim component magnitudes from this study are compared with results from Hanna et al. Periods of shared interannual variability are evident. However, the long-term trend in accumulation differs in sign.
Performance Evaluation of the Next‐Generation Sequencing Approach for Molecular Diagnosis of Hereditary Hearing Loss
Authors: Sivakumaran Theru A. , Husami Ammar , Kissell Diane , Zhang Wenying , Keddache Mehdi , Black Angela P. , Tinkle Brad T. , Greinwald John H. , Zhang Kejian 
Published: March 2013

ObjectiveTo evaluate the performance of a next‐generation sequencing (NGS)–based targeted resequencing genetic test, OtoSeq, to identify the sequence variants in the genes causing sensorineural hearing loss (SNHL).Study DesignRetrospective study.SettingTertiary children's hospital.Subjects and MethodsA total of 8 individuals presenting with prelingual hearing loss were used in this study. The coding and flanking intronic regions of 24 well‐studied SNHL genes were enriched using microdroplet polymerase chain reaction and sequenced on an Illumina HiSeq 2000 sequencer. The filtered high‐quality sequence reads were mapped to reference sequence, and variants were detected using NextGENe software.ResultsA total of 1148 sequence variants were detected in 8 samples in 24 genes. Using in‐house developed NGS data analysis criteria, we classified 810 (~71%) of these variants as potential true variants that include previously detected pathogenic mutations in 5 patients. To validate our strategy, we Sanger sequenced the target regions of 5 of the 24 genes, accounting for about 29.2% of all target sequence. Our results showed >99.99% concordance between NGS and Sanger sequencing in these 5 genes, resulting in an analytical sensitivity and specificity of 100% and 99.997%, respectively. We were able to successfully detect single base substitutions, small deletions, and insertions of up to 22 nucleotides.ConclusionThis study demonstrated that our NGS‐based mutation screening strategy is highly sensitive and specific in detecting sequence variants in the SNHL genes. Therefore, we propose that this NGS‐based targeted sequencing method would be an alternative to current technologies for identifying the multiple genetic causes of SNHL.
Pharyngeal Dysphagia in Children with Down Syndrome
Authors: O'Neill Ashley C. , Richter Gresham T. 
Published: March 2013

ObjectivePharyngeal dysphagia (PD) in children with Down syndrome (DS) has not been examined. This study aims to describe the incidence, duration, and precipitating factors of PD in a large cohort of children with DS.Study DesignCase series with chart review.SettingTertiary care children's hospital.MethodsThe International Classification of Diseases, Ninth Revision (ICD‐9) code for DS was used to identify all children treated at a single institution from 1992 to 2012. Patient charts were reviewed for signs, symptoms, and documentation of PD. Videofluoroscopic swallow studies (VFSS) established the final diagnosis of PD in affected patients. Otolaryngologic interventions and their impact on PD were also explored.ResultsA total of 228 patients with the ICD‐9 code for DS were found. Twenty‐seven patients (11.8%) were excluded due to record deficiencies. Thus, of the 201 children with DS who were available for complete review, 116 (57.7%) had and established diagnosis of PD by VFSS. The mean age at first diagnosis of PD was 1.69 years. At the time of the study, the cohort mean age was 7.45 years, with only 20 patients demonstrating resolution of PD. Patients with a tracheotomy or significant neurologic delays were more likely to have worsening or prolonged PD. Laryngeal clefts were identified in 3 patients, whereas 78 (67%) underwent surgery for upper airway obstruction that did not consistently improve PD.ConclusionThis study suggests that PD is common, persistent, and should be routinely explored in children with DS. Intervention for upper airway obstruction had a limited role for PD in this study cohort.
Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients
Authors: Dufour Annika , Palermo Giuseppe , Zellmeier Evelyn , Mellert Gudrun , Duchateau-Nguyen Guillemette , Schneider Stephanie , Benthaus Tobias , Kakadia Purvi M. , Spiekermann Karsten , Hiddemann Wolfgang , Braess Jan , Truong Sim , Patten Nancy , Wu Lin , Lohmann Sabine , Dornan David , GuhaThakurta Debraj , Yeh Ru-Fang , Salogub Galina , Solal-Celigny Philippe , Dmoszynska Anna , Robak Tadeusz , Montillo Marco , Catalano John , Geisler Christian H. , Weisser Martin , Bohlander Stefan K. 
Published: March 2013

Key Points
Only a complete disruption of TP53 function increases the risk for disease progression in previously treated CLL patients. MiR-34a expression significantly correlates with the predicted TP53 activity in previously treated CLL patients with TP53 abnormalities.
SDM-Assist software to design site-directed mutagenesis primers introducing “silent” restriction sites
Authors: Karnik Abhijit , Karnik Rucha , Grefen Christopher 
Published: March 2013

Abstract

Background
Over the past decades site-directed mutagenesis (SDM) has become an indispensable tool for biological structure-function studies. In principle, SDM uses modified primer pairs in a PCR reaction to introduce a mutation in a cDNA insert. DpnI digestion of the reaction mixture is used to eliminate template copies before amplification in E. coli; however, this process is inefficient resulting in un-mutated clones which can only be distinguished from mutant clones by sequencing.

Results
We have developed a program - ‘SDM-Assist’ which creates SDM primers adding a specific identifier: through additional silent mutations a restriction site is included or a previous one removed which allows for highly efficient identification of ‘mutated clones’ by a simple restriction digest.

Conclusions
The direct identification of SDM clones will save time and money for researchers. SDM-Assist also scores the primers based on factors such as Tm, GC content and secondary structure allowing for simplified selection of optimal primer pairs.
Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient
Authors: Zhang Jian , Shi Yuhao , Lalonde Emilie , Li Lili , Cavallone Luca , Ferenczy Alex , Gotlieb Walter H , Foulkes William D , Majewski Jacek 
Published: March 2013

Abstract

Background
Ovarian carcinoma is a common, and often deadly, gynecological cancer. Mutations in BRCA1 and BRCA2 genes are present in at least a fifth of patients. Uncovering other genes that become mutated subsequent to BRCA1/BRCA2 inactivation during cancer development will be helpful for more effective treatments.

Methods
We performed exome sequencing on the blood, primary tumor, omental metastasis and recurrence following therapy with carboplatin and paclitaxel, from a patient carrying a BRCA1 S1841R mutation.

Results
We observed loss of heterozygosity in the BRCA1 mutation in the primary and subsequent tumors, and somatic mutations in the TP53 and NF1 genes were identified, suggesting their role along with BRCA1 driving the tumor development. Notably, we show that exome sequencing is effective in detecting large chromosomal rearrangements such as deletions and amplifications in cancer. We found that a large deletion was present in the three tumors in the regions containing BRCA1, TP53, and NF1 mutations, and an amplification in the regions containing MYC. We did not observe the emergence of any new mutations among tumors from diagnosis to relapse after chemotherapy, suggesting that mutations already present in the primary tumor contributed to metastases and chemotherapy resistance.

Conclusions
Our findings suggest that exome sequencing of matched samples from one patient is a powerful method of detecting somatic mutations and prioritizing their potential role in the development of the disease.
Resveratrol abrogates the Temozolomide-induced G2 arrest leading to mitotic catastrophe and reinforces the Temozolomide-induced senescence in glioma cells
Authors: Filippi-Chiela Eduardo C , Thomé Marcos Paulo , Bueno e Silva Mardja Manssur , Pelegrini Alessandra Luíza , Ledur Pitia Flores , Garicochea Bernardo , Zamin Lauren L , Lenz Guido 
Published: March 2013

Abstract

Background
Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects.

Methods
Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We further evaluated the long term senescence induction and clonogenic capacity.

Results
As expected, temozolomide caused a G2 cell cycle arrest and extensive DNA damage response. Rsv did not reduced this response, even increasing pATM, pChk2 and gammaH2Ax levels, but abrogated the temozolomide-induced G2 arrest, increasing levels of cyclin B and pRb(S807/811) and reducing levels of pWee1(S642) and pCdk1(Y15). This suggests a cellular state of forced passage through G2 checkpoint despite large DNA damage, a scenario that may produce mitotic catastrophe. Indeed, the proportion of cells with high nuclear irregularity increased from 6 to 26% in 48 h after cotreatment. At a long term, a reduction in clonogenic capacity was observed, accompanied by a large induction of senescence.

Conclusion
The presence of Rsv forces cells treated with TMZ through mitosis leading to mitotic catastrophe and senescence, reducing the clonogenic capacity of glioma cells and increasing the chronic effects of temozolomide.
The effect of Lycium barbarum on spinal cord injury, particularly its relationship with M1 and M2 macrophage in rats
Authors: Zhang Yu-Kai , Wang Jian , Liu Ling , Chang Raymond Chuen-Chung , So Kwok-Fai , Ju Gong 
Published: March 2013

AbstractBackgroundOur past researches suggested thatL. barbarumexhibits direct neuroprotective and immune regulatory effects on the central nervous system, which are highly related to the events involved in the spinal cord injury, but not yet been investigated. Immune responses play an important role in the development of the pathology after secondary injury, particularly the M1 and M2 types of macrophage, on which special emphasis was laid in this study.MethodsIn our previous studiesL. barbarumwas administrated orally from 7 days before the injury to ensure a stabilized concentration in the blood. For clinical application,L. barbarumcan only be administered after the injury. Therefore, both pre-injury and post-injury administration protocols were compared.In vivoandin vitrostudies were conducted and analyzed immunohistochemically, including Western blotting.ResultsThe lesion size in the pre-treated group was much larger than that in the post-treated group. To explain this difference, we first studied the effect ofL. barbarumon astrocytes, which forms the glial scar encircling the lesion.L. barbarumdid not significantly affect the astrocytes. Then we studied the effect ofL. barbarumon microglia/macrophages, particularly the M1 and M2 polarization. After spinal cord injury, the deleterious M1 cells dominant the early period, whereas the beneficial M2 cells dominate later. We found that in the pre-treated groupL. barbarumsignificantly enhanced the expression of M1 cells and suppressed that of M2 cells, while in the post-treated group LBP markedly promoted the activity of M2 cells. This explained the difference between the pre- and post-treated groups.ConclusionsLycium barbarumhas been wildly accepted to have beneficial effects in various central nervous system diseases. Our finding of deleterious effect of LBP administered at early period of spinal cord injury, indicates that its application should be avoided. The substantial beneficial effect of LBP when administered at later stage has an important impact for clinical application.