bluuebunny/crossref_metadata_2025 huggingface dataset:
Upregulation of Nestin Protects Podocytes from Apoptosis Induced by Puromycin Aminonucleoside
Authors: Wen Donghai , You Li , Zhang Qian , Zhang Liying , Gu Yong , Hao Chuan-Ming , Chen Jing
Published: September 2011

Background: Nestin is an intermediate filament protein widely used as a marker of stem cells or progenitor cells. Nestin is also highly expressed in the glomerular podocyte, a type of terminally differentiated epithelial cell. Little is known about the significance of nestin in podocytes. Methods: Puromycin aminonucleoside (PAN) was injected into the rats to produce a PAN nephrosis model. Transmission electronic microscopy and terminal dUTP nick end-labeling assay were used to examine the podocyte foot process (FP) effacement and apoptosis, respectively. A mouse podocyte cell line was cultured and incubated with PAN. Immunoblot was used to examine the level of nestin expression both in vivo and in vitro. Enhanced green fluorescence protein-tagged plasmids containing nestin shRNA were transfected into the cultured podocytes to silence nestin expression. F-actin arrangement within cultured podocytes was investigated by immunofluorescence, while the apoptosis rate was examined by both Hoechst stain and flow cytometry. Results: In the PAN-induced rat nephrosis model, podocyte nestin expression was increased in the absence of apparent podocyte apoptosis, even though the FP was significantly effaced. In the cultured mouse podocytes, PAN upregulated nestin expression in a time-dependent manner within 24 h of treatment. Notably, no significant apoptosis occurred, however knocking down nestin expression resulted in a remarkable derangement of actin cytoskeleton and an increase in apoptosis in the cultured podocytes 24 h after being incubated with PAN. Conclusions: Upregulation of nestin expression during PAN nephrosis could protect podocytes from apoptosis and that this process is mediated by maintaining the regular arrangement of actin cytoskeleton.
Cardiac Defects Are Infrequent Findings in Individuals With 8p23.1 Genomic Duplications Containing
GATA4
Authors: Yu Shihui , Zhou Xin-Gang , Fiedler Stephanie D. , Brawner Sarah J. , Joyce Julie M. , Liu Hong-Yu
Published: September 2011

Background—

The
GATA4
gene is critical to regulating myocardial differentiation and function. Haploinsufficiency of
GATA4
is strongly associated with congenital heart defects (CHD). However, it is inconclusive whether duplicated
GATA4
causes CHD.

Methods and Results—

We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 8 probands and 2 relatives with pathogenic genomic imbalances containing
GATA4
. Four probands contain an ≈4.0-Mb interstitial duplication of 8p23.1 flanked by the 2 olfactory receptor gene clusters REPD and REPP, representing 0.24% (4/1645) of the patients analyzed. None of the 4 patients has CHD or any other heart diseases and 1 mother who transmitted the duplication to her child has a history of aortic stenosis. Two patients who carry multiple genomic abnormalities, including a duplication containing
GATA4
, have complex CHD. Only 1 of the 3 individuals carrying genomic deletion containing
GATA4
has atrial septal and ventricular septal defects.

Conclusions—

Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing
GATA4.
A 0.24% detection rate of this duplication in this study is significantly higher than previously estimated. Observation in 2 patients with multiple genomic abnormalities and complex CHD is consistent with a 2-hit model that emphasizes accumulative effects of >1 insult to the genome, leading to a visible or more severe clinical manifestation. Haploinsufficient
GATA4
may show variable expressivity with a wide spectrum of clinical findings, including CHD.
Neighborhood Effects in Temporal Perspective
Authors: Wodtke Geoffrey T. , Harding David J. , Elwert Felix
Published: September 2011

Theory suggests that neighborhood effects depend not only on where individuals live today, but also on where they lived in the past. Previous research, however, usually measures neighborhood context only once and does not account for length of residence, thereby understating the detrimental effects of long-term neighborhood disadvantage. This study investigates effects of duration of exposure to disadvantaged neighborhoods on high school graduation. It follows 4,154 children in the Panel Study of Income Dynamics, measuring neighborhood context once per year from age 1 to 17. The analysis overcomes the problem of dynamic neighborhood selection by adapting novel methods of causal inference for time-varying treatments. In contrast to previous analyses, these methods do not “control away” the effect of neighborhood context operating indirectly through time-varying characteristics of the family; thus, they capture the full impact of a lifetime of neighborhood disadvantage. We find that sustained exposure to disadvantaged neighborhoods has a severe impact on high school graduation that is considerably larger than effects reported in prior research. We estimate that growing up in the most (compared to the least) disadvantaged quintile of neighborhoods reduces the probability of graduation from 96 to 76 percent for black children, and from 95 to 87 percent for nonblack children.
Teacher Preparation For Quality Teaching
Authors: Hollins Etta R.
Published: September 2011

In this article, the author presents a holistic practice-based approach, consisting of two parts, to preparing candidates for quality teaching. The first part describes the essential knowledge, skills, and habits of mind for quality teaching. The emphasis is on understanding the learning process as influenced by the cultural and experiential background of particular learners and the philosophical stance through which the purpose of school learning is appropriated. The philosophical stance influences the design of learning experiences, the framing of the curriculum, and the social context in classrooms. The second part describes the design of opportunities for leaning to teach with an emphasis on epistemic practices and program qualities. In this discussion, at the core, the practices in teacher preparation are a mirror image of practices for quality teaching in PK-12 schools. The standards of evidence for integrity and trustworthiness are the same in teacher preparation and in PK-12 schools.
Roles for Rat Hepatocyte Malignant Transforming Factor (HMTF) in Late Stage of Hepatocarcinogenesis
Authors: Suzuki Shugo , Pitchakarn Pornsiri , Takeshita Kentaro , Asamoto Makoto , Takahashi Satoru , Sato Shinya , Shirai Tomoyuki
Published: September 2011

In a previous study, to identify genes of importance for hepatocellular carcinogenesis, and especially for processes involved in malignant transformation, the authors investigated differences in gene expression between adenomas and carcinomas by DNA microarray. In the present study, the authors investigated AW434047, one of the sequences that was upregulated in carcinomas. The investigation led to the identification of a novel gene, which the authors named hepatocyte malignant transforming factor (HMTF), of unknown function whose expression was increased in hepatocellular carcinomas. Northern blot and in situ hybridization also demonstrated high levels of HMTF in rat hepatocellular carcinoma (HCC) cell lines, lymphocytes in the spleen, colon mucosal epithelia, spermatocytes, and granule cells of the hippocampus. Reduction of HMTF by RNA interference (RNAi) in N1 cells, an HCC cell line, caused suppression of cell proliferation, invasion, and migration. Suppression of proliferation appeared to be due to cell cycle arrest without increased apoptosis. Decreased HMTF expression resulted in down-regulation of STAT3, PCNA, and cyclin D1 and upregulation of p27. These results suggest that HMTF is a new marker for rat HCC and is involved in HCC cell proliferation and may also be linked to cell proliferation in the spleen, colon, brain, and testis.
Sclerosing Cholangitis in Baboons (Papio spp) Resembling Primary Sclerosing Cholangitis of Humans
Authors: Arenas-Gamboa A. M. , Bearss J. J. , Hubbard G. B. , Porter B. F. , Owston M. A. , Jr E. J. Dick
Published: September 2011

Primary sclerosing cholangitis is a chronic and progressive cholestatic liver disease that has been extensively documented in the human literature. Although it shares many features in common with chronic lymphocytic cholangitis in cats, primary sclerosing cholangitis has never been reported in a nonhuman primate. Primary sclerosing cholangitis is characterized by the presence of intrahepatic and/or extrahepatic inflammation and concentric fibrosis of bile ducts, eventually leading to cirrhosis and hepatic failure. The pathogenesis and cause remain unknown, but the disease likely involves a multifactorial mechanism with genetic- and immune-mediated components. The authors report 2 cases that histologically resemble the condition in humans; they consist of 2 adult male baboons with a clinical history of chronic elevated liver enzymes. In both cases, the liver was histologically characterized by thick bands of fibrosis and mild lymphoplasmacytic periportal cholangiohepatitis with concentric periductal fibrosis, resulting in atrophy and loss of bile ducts. Immunohistochemical analysis revealed positivity of hepatocytes to cytokeratin 7. Masson stain demonstrated marked biliary fibrosis. This is the first report that resembles sclerosing cholangitis in a nonhuman primate, and it suggests that the baboon may provide a useful animal model for this condition in humans.
Medication Therapy Management in the Primary Care Setting
Authors: Koenigsfeld Carrie Foust , Horning Kristin K. , Logemann Craig D. , Schmidt Ginelle A.
Published: September 2011

Objectives: To evaluate the effect of medication therapy management on chronic disease management and generic drug prescribing in the clinic setting. Methods: Private insurer initiates Pay-for-Performance (PFP) project for clinic-based pharmacists in Iowa and South Dakota (n = 9 clinics) in 2009. Each pharmacist was assigned ∽300 patients with at least 1 of 4 disease states (diabetes mellitus, hyperlipidemia, hypertension, and asthma). Pharmacists were expected to complete 2 medication reviews for each patient. The primary outcome was frequency of patients achieving goal levels: diabetes: hemoglobin A1c (A1c) <8%, low-density lipoprotein (LDL) <130 mg/dL, and blood pressure (BP) <140/80 mm Hg; hypertension: BP <140/90 mm Hg; hyperlipidemia: LDL <130 mg/dL; and asthma: percentage of persistent asthmatics on controller medication. Generic prescribing rates were evaluated for antihypertensives, cholesterol-lowering agents, proton pump inhibitors, and antidepressants. Results: A total of 827 patients at 3 clinics were included in the analysis. For diabetes, 77.1% had A1c <8%, 83.2% had LDL <130 mg/dL, and 76.3% had BP <140/80 mm Hg. For hypertension, 86.2% had BP <140/90 mm Hg. For hyperlipidemia, 80.6% had LDL <130 mg/dL. For asthma, 100% were on controller medication. One medication review was completed on 88.8% of patients. Generic prescribing rates ranged from 65.8% to 79.4%. Implications/Adaptability: A high percentage of patients achieved goal levels at clinics with clinical pharmacist services. A multidisciplinary approach to patient care may improve disease state management and medication cost savings.
Six-minute walking test but not ejection fraction predicts mortality in elderly patients undergoing cardiac rehabilitation following coronary artery bypass grafting
Authors: Cacciatore Francesco , Abete Pasquale , Mazzella Francesca , Furgi Giuseppe , Nicolino Antonio , Longobardi Giancarlo , Testa Gianluca , Langellotto Assunta , Infante Teresa , Napoli Claudio , Ferrara Nicola , Rengo Franco
Published: September 2011

Background

Age-related effects on the ability of 6-min walking test (6MWT) and ejection fraction (EF) to predict mortality in coronary artery bypass grafting (CABG) patients undergoing cardiac rehabilitation (CR) is still debated.

Design and methods

In order to verify the role of 6MWT and EF on all-cause mortality in patients undergoing CR following CABG, 882 CABG patients undergoing CR stratified in adults (<65 years) and elderly (≥65 years) were studied.

Results

At the admission, EF was 52.6 ± 9.1% in adults and 51.3 ± 8.9% in elderly (p = 0.234, NS) while 6MWT was 343.8 ± 93.5 m in adults and 258.9 ± 95.7 m in elderly (p < 0.001). After 42.9 ± 14.1 months follow up, mortality was 8.2% in adults and 10.9% in elderly (p = 0.176, NS). Cox regression analysis shows that EF ≥ 50% and 6MWT ≥300 m are protective on mortality in all CABG patients before CR. However, EF ≥50% in adults (HR 0.18, 95% CI 0.06–0.49, p < 0.005) but not in elderly (HR 1.16, 95% CI 0.45–3.42, p = 0.354, NS) and 6MWT ≥300 m in elderly (HR 0.34, 95% CI 0.10–0.79, p = 0.033) but not in adults (HR 0.76, 95% CI 0.31–2.12, p = 0.654, NS) exert a protective role on mortality.

Conclusions

Our results indicate that both EF ≥ 50% and 6MWT ≥ 300 m independently protect against mortality in CABG patients before CR. However, their protective role is age dependent. In fact, EF ≥ 50% is protective in adults but not in elderly while 6MWT ≥ 300 m is protective in elderly but not in adult patients.
Physico-chemical characterization of nano-emulsions in cosmetic matrix enriched on omega-3
Authors: Kabri Tin-hinan , Arab-Tehrany Elmira , Belhaj Nabila , Linder Michel
Published: September 2011

Background

Nano-emulsions, as non-equilibrium systems, present characteristics and properties which depend not only on composition but also on their method of preparation. To obtain better penetration, nanocosmeceuticals use nano-sized systems for the delivery of active ingredients to targeted cells. In this work, nano-emulsions composed of miglyol, rapeseed oil and salmon oil were developed as a cosmetic matrix. Measurements of different physico-chemical properties of nano-emulsions were taken according to size, electrophoretic mobility, conductivity, viscosity, turbidity, cristallization and melting point. The RHLB was calculated for each formulation in order to achieve maximum stability.

Results

Both tween 80 and soya lecithin were found to stabilize formulations. The results showed that rapeseed oil and miglyol are the predominant parameters for determining the expression of results concerning the characterization of emulsion. Based on the mixture design, we achieved the optimal point using the following formulation: 56.5% rapessed oil, 35.5% miglyol, and 8% salmon oil. We considered this formulation to be the best as a nanocosmeceutical product due to the small size, good turbidity, and average HLB.

Conclusions

This study demonstrates the influence of formulation on the physico-chemical properties of each nano-emulsion obtained by the mixture design.
On the Possible Role of ERK, p38 and CaMKII in the Regulation of CGRP Expression in Morphine-Tolerant Rats
Authors: Wang Zhiyong , Chabot Jean-Guy , Quirion Remi
Published: September 2011

Background:

The neuropeptide, calcitonin gene-related peptide (CGRP) has been proposed to be a regulator of the development of morphine analgesic tolerance and thereby could be a target to reduce the induction of this phenomenon under clinical conditions. However, the mechanisms of CGRP regulation are unclear. We investigated here the possible role of the extracellular signal-regulated protein kinase (ERK), p38 and calcium/calmodulin-dependent protein kinase II (CaMKII) in CGRP regulation following chronic morphine treatment.

Results:

A 7-day treatment with morphine (15 μg/day) led to an increase in CGRP contents in the spinal cord dorsal horn (SCDH) and dorsal root ganglion (DRG) and this effect was prevented by the inhibition of the ERK, p38 or CaMKII pathway. The phosphorylation/activation of ERK, p38 and CaMKII was enhanced in the SCDH following chronic morphine while in DRG only the phosphorylation of CaMKII was increased. Moreover, our chronic morphine treatment up-regulated neuronal nitric oxide synthase (nNOS) levels in the SCDH, an effect blocked by the inhibition of the ERK, p38 or CaMKII pathway. The blockade of nNOS activity also suppressed chronic morphine-induced CGRP increases in the DRG and SCDH. Double immunofluorescence studies revealed that nNOS and CaMKII are co-localized in the SCDH and that CaMKII is activated in CGRP-expressing DRG neurons. Conclusions: The activation of spinal ERK, p38 and CaMKII, alongside nNOS, is involved in chronic morphine-induced CGRP up-regulation in both the DRG and SCDH. Moreover, the stimulation of CaMKII in the DRG likely directly regulates the expression of CGRP associated with morphine analgesic tolerance.
An unusual T-cell childhood acute lymphoblastic leukemia harboring a yet unreported near-tetraploid karyotype
Authors: Garcia Daniela RN , Bhatt Samarth , Manvelyan Marina , de Souza Mariana T , Binato Renata , Aguiar Thais F , Abdelhay Eliana , Silva Maria Luiza M
Published: September 2011

Background

Near-tetraploid (model #81-103) and near-triploid (model #67-81) karyotypes are found in around 1% of childhood acute lymphoblastic leukemia. Due to its rarity, these two cytogenetic subgroups are generally included in the hyperdiploid group (model # > 51). Therefore separate informations about these two subgroups are limited to a few reports. Some studies found that near-tetraploidy is relatively more frequent in higher median ages and it is associated to Frech-American-British Classification subtype L2. Although the mechanisms by which leukemic blast cells divide is still unclear, studies have suggested that hyperdiploidy, near-triploidy and near-tetraploidy do not seem to share the same mechanism.

Findings

Herewith, we present a new childhood T-acute lymphoblastic leukemia case of near-tetraploid karyotype with loss of two p53-gene copies, characterized in detail by cytogenetic and molecular studies.

Conclusion

We suggest that p53 is a good target gene to be screened, once p53 is one of the main effectors of cell cycle checkpoints.
SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing
Authors: Tariq Muhammad , Belmont John W , Lalani Seema , Smolarek Teresa , Ware Stephanie M
Published: September 2011

Background

Heterotaxy-spectrum cardiovascular disorders are challenging for traditional genetic analyses because of clinical and genetic heterogeneity, variable expressivity, and non-penetrance. In this study, high-resolution SNP genotyping and exon-targeted array comparative genomic hybridization platforms were coupled to whole-exome sequencing to identify a novel disease candidate gene.

Results

SNP genotyping identified absence-of-heterozygosity regions in the heterotaxy proband on chromosomes 1, 4, 7, 13, 15, 18, consistent with parental consanguinity. Subsequently, whole-exome sequencing of the proband identified 26,065 coding variants, including 18 non-synonymous homozygous changes not present in dbSNP132 or 1000 Genomes. Of these 18, only 4 - one each in CXCL2, SHROOM3, CTSO, RXFP1 - were mapped to the absence-of-heterozygosity regions, each of which was flanked by more than 50 homozygous SNPs, confirming recessive segregation of mutant alleles. Sanger sequencing confirmed the SHROOM3 homozygous missense mutation and it was predicted as pathogenic by four bioinformatic tools. SHROOM3 has been identified as a central regulator of morphogenetic cell shape changes necessary for organogenesis and can physically bind ROCK2, a rho kinase protein required for left-right patterning. Screening 96 sporadic heterotaxy patients identified four additional patients with rare variants in SHROOM3.

Conclusions

Using whole exome sequencing, we identify a recessive missense mutation in SHROOM3 associated with heterotaxy syndrome and identify rare variants in subsequent screening of a heterotaxy cohort, suggesting SHROOM3 as a novel target for the control of left-right patterning. This study reveals the value of SNP genotyping coupled with high-throughput sequencing for identification of high yield candidates for rare disorders with genetic and phenotypic heterogeneity.
The Oxysterol, 27-Hydroxycholesterol, Links Cholesterol Metabolism to Bone Homeostasis Through Its Actions on the Estrogen and Liver X Receptors
Authors: Nelson Erik R. , DuSell Carolyn D. , Wang Xiaojuan , Howe Matthew K. , Evans Glenda , Michalek Ryan D. , Umetani Michihisa , Rathmell Jeffrey C. , Khosla Sundeep , Gesty-Palmer Diane , McDonnell Donald P.
Published: September 2011

Osteoporosis and age-related bone loss are important public health concerns. Therefore, there is a high level of interest in the development of medical interventions and lifestyle changes that reduce the incidence of osteoporosis and age-related bone loss. Decreased bone mineral density is associated with high cholesterol, and patients on statins have increased bone mineral densities, strongly implicating cholesterol as a negative regulator of bone homeostasis. In this study, using both molecular and pharmacological approaches, we have been able to demonstrate that the primary cholesterol metabolite, 27-hydroxycholesterol, through its actions on both estrogen receptors and liver X receptors, decreases osteoblast differentiation and enhances osteoclastogenesis, resulting in increased bone resorbtion in mice. Induction of the short heterodimer partner protein by estrogens in osteoblasts can attenuate the liver X receptor-mediated actions of 27-hydroxycholesterol in bone. These data establish a mechanistic link between cholesterol and bone quality, highlight an unexpected target of estrogens in osteoblasts, and define a signaling axis, the therapeutic exploitation of which is likely to yield novel antiosteoporotic drugs.
Molecular Properties of Kiss1 Neurons in the Arcuate Nucleus of the Mouse
Authors: Gottsch Michelle L. , Popa Simina M. , Lawhorn Janessa K. , Qiu Jian , Tonsfeldt Karen J. , Bosch Martha A. , Kelly Martin J. , Rønnekleiv Oline K. , Sanz Elisenda , McKnight G. Stanley , Clifton Donald K. , Palmiter Richard D. , Steiner Robert A.
Published: September 2011

Neurons that produce kisspeptin play a critical role in reproduction. However, understanding the molecular physiology of kisspeptin neurons has been limited by the lack of an in vivo marker for those cells. Here, we report the development of a Kiss1-CreGFP knockin mouse, wherein the endogenous Kiss1 promoter directs the expression of a Cre recombinase-enhanced green fluorescent protein (GFP) fusion protein. The pattern of GFP expression in the brain of the knockin recapitulates what has been described earlier for Kiss1 in the male and female mouse, with prominent expression in the arcuate nucleus (ARC) (in both sexes) and the anteroventral periventricular nucleus (in females). Single-cell RT-PCR showed that the Kiss1 transcript is expressed in 100% of GFP-labeled cells, and the CreGFP transcript was regulated by estradiol in the same manner as the Kiss1 gene (i.e. inhibited in the ARC and induced in the anteroventral periventricular nucleus). We used this mouse to evaluate the biophysical properties of kisspeptin (Kiss1) neurons in the ARC of the female mouse. GFP-expressing Kiss1 neurons were identified in hypothalamic slice preparations of the ARC and patch clamped. Whole-cell (and loose attached) recordings revealed that Kiss1 neurons exhibit spontaneous activity and expressed both h- (pacemaker) and T-type calcium currents, and hyperpolarization-activated cyclic nucleotide-regulated 1–4 and CaV3.1 channel subtypes (measured by single cell RT-PCR), respectively. N-methyl-D-aspartate induced bursting activity, characterized by depolarizing/hyperpolarizing oscillations. Therefore, Kiss1 neurons in the ARC share molecular and electrophysiological properties of other CNS pacemaker neurons.
Islet1-mediated activation of the β-catenin pathway is necessary for hindlimb initiation in mice
Authors: Kawakami Yasuhiko , Marti Merce , Kawakami Hiroko , Itou Junji , Quach Thu , Johnson Austin , Sahara Setsuko , O’Leary Dennis D. M. , Nakagawa Yasushi , Lewandoski Mark , Pfaff Samuel , Evans Sylvia M. , Belmonte Juan Carlos Izpisua
Published: September 2011

The transcriptional basis of vertebrate limb initiation, which is a well-studied system for the initiation of organogenesis, remains elusive. Specifically, involvement of the β-catenin pathway in limb initiation, as well as its role in hindlimb-specific transcriptional regulation, are under debate. Here, we show that the β-catenin pathway is active in the limb-forming area in mouse embryos. Furthermore, conditional inactivation of β-catenin as well as Islet1, a hindlimb-specific factor, in the lateral plate mesoderm results in a failure to induce hindlimb outgrowth. We further show that Islet1 is required for the nuclear accumulation of β-catenin and hence for activation of the β-catenin pathway, and that the β-catenin pathway maintains Islet1 expression. These two factors influence each other and function upstream of active proliferation of hindlimb progenitors in the lateral plate mesoderm and the expression of a common factor, Fgf10. Our data demonstrate that Islet1 and β-catenin regulate outgrowth and Fgf10-Fgf8 feedback loop formation during vertebrate hindlimb initiation. Our study identifies Islet1 as a hindlimb-specific transcriptional regulator of initiation, and clarifies the controversy regarding the requirement of β-catenin for limb initiation.
Two additional midline barriers function with midlinelefty1expression to maintain asymmetric Nodal signaling during left-right axis specification in zebrafish
Authors: Lenhart Kari F. , Lin Shin-Yi , Titus Tom A. , Postlethwait John H. , Burdine Rebecca D.
Published: September 2011

Left-right (L/R) patterning is crucial for the proper development of all vertebrates and requires asymmetric expression of nodal in the lateral plate mesoderm (LPM). The mechanisms governing asymmetric initiation of nodal have been studied extensively, but because Nodal is a potent activator of its own transcription, it is also crucial to understand the regulation required to maintain this asymmetry once it is established. The ‘midline barrier’, consisting of lefty1 expression, is a conserved mechanism for restricting Nodal activity to the left. However, the anterior and posterior extremes of the LPM are competent to respond to Nodal signals yet are not adjacent to this barrier, suggesting that lefty1 is not the only mechanism preventing ectopic Nodal activation. Here, we demonstrate the existence of two additional midline barriers. The first is a ‘posterior barrier’ mediated by Bmp signaling that prevents nodal propagation through the posterior LPM. In contrast to previous reports, we find that Bmp represses Nodal signaling independently of lefty1 expression and through the activity of a ligand other than Bmp4. The ‘anterior barrier’ is mediated by lefty2 expression in the left cardiac field and prevents Nodal activation from traveling across the anterior limit of the notochord and propagating down the right LPM. Both barriers appear to be conserved across model systems and are thus likely to be present in all vertebrates.
Aggregation and Manipulation in Prediction Markets: Effects of Trading Mechanism and Information Distribution
Authors: Jian Lian , Sami Rahul
Published: September 2011

We conduct laboratory experiments on variants of market scoring rule prediction markets, under different information distribution patterns, to evaluate the efficiency and speed of information aggregation, as well as test recent theoretical results on manipulative behavior by traders. We find that markets structured to have a fixed sequence of trades exhibit greater accuracy of information aggregation than the typical form that has unstructured trade. In comparing two commonly used mechanisms, we find no significant difference between the performance of the direct probability-report form and the indirect security-trading form of the market scoring rule. In the case of the markets with a structured order, we find evidence supporting the theoretical prediction that information aggregation is slower when information is complementary. In structured markets, the theoretical prediction that there will be more delayed trading in complementary markets is supported, but we find no support for the prediction that there will be more bluffing in complementary markets. However, the theoretical predictions are not borne out in the unstructured markets.

This paper was accepted by Brad Barber, Teck Ho, and Terrance Odean, special issue editors.
Covenants in Venture Capital Contracts
Authors: Bengtsson Ola
Published: September 2011

This paper studies how covenants are included in contracts between venture capitalists (VCs) and entrepreneurs. I show that VCs hold covenanted veto rights even though they are shareholders who have access to other powerful governance solutions. Unlike bank loans and bonds, venture capital (VC) contracts exhibit considerable variation in their contractual designs. I exploit this variation to confirm the argument that covenants are in place to overcome a conflict of interest that arises from debt-like contractual features of a venture capitalist's preferred stock. In particular, I find that contracts with higher fixed payoffs include 1.6 more covenants than do contracts with lower fixed payoffs. Similarly, VC contracts with no VC board majority requirement include 0.6 more covenants than do contracts that require a VC board majority. Covenants are also more common with older companies and when fewer VCs invest in a round. My findings contribute to both the debt covenant literature and the entrepreneurial finance literature.

This paper was accepted by Brad Barber, finance.
Drug-Induced Yawning—A Review
Authors: Patatanian Edna , Williams Nancy Toedter
Published: September 2011

Objective:

To review the current literature on drug-induced yawning.

Data Sources:

Literature was accessed through MEDLINE/PubMed (1996-July 2011), International Pharmaceutical Abstracts (1997-July 2011), and EMBASE, using the search terms yawning, drug-induced yawning, and adverse drug reactions.

Study Selection and Data Extraction:

Relevant clinical trials and case reports were selected and included to present background information. Bibliographies of all relevant articles were reviewed for additional citations.

Data Synthesis:

Yawning is a common stereotype behavior with unknown physiologic function that occurs in most vertebrates and humans as early as 15 weeks of intrauterine life. Yawning Is under the control of several neurotransmitters and neuropeptides, Including dopamine, serotonin, oxytocin, and acetylcholine. Among drugs, antidepressants, opioids, dopaminergic agents, benzodiazepines, and induction agents are the main pharmacologic classes associated with yawning.

Conclusions:

Yawning is rarely a serious adverse reaction and is not frequently listed in the drug summary. Most available data are based on case reports, small studies, and older literature. Clinicians should be aware of the agents commonly triggering this behavior.
mRNA degradation and maturation in prokaryotes: the global players
Authors: Laalami Soumaya , Putzer Harald
Published: September 2011

The degradation of messenger RNA is of universal importance for controlling gene expression. It directly affects protein synthesis by modulating the amount of mRNA available for translation. Regulation of mRNA decay provides an efficient means to produce just the proteins needed and to rapidly alter patterns of protein synthesis. In bacteria, the half-lives of individual mRNAs can differ by as much as two orders of magnitude, ranging from seconds to an hour. Most of what we know today about the diverse mechanisms of mRNA decay and maturation in prokaryotes comes from studies of the two model organismsEscherichia coliandBacillus subtilis. Their evolutionary distance provided a large picture of potential pathways and enzymes involved in mRNA turnover. Among them are three ribonucleases, two of which have been discovered only recently, which have a truly general role in the initiating events of mRNA degradation: RNase E, RNase J and RNase Y. Their enzymatic characteristics probably determine the strategies of mRNA metabolism in the organism in which they are present. These ribonucleases are coded, alone or in various combinations, in all prokaryotic genomes, thus reflecting how mRNA turnover has been adapted to different ecological niches throughout evolution.
Some Remarks on a Paper of V. A. Liskovets
Authors: Tóth László
Published: September 2011

We deduce new properties of the orbicyclic function
Semantic Analysis Does Not Occur in the Absence of Awareness Induced by Interocular Suppression
Authors: Kang Min-Suk , Blake Randolph , Woodman Geoffrey F.
Published: September 2011

It has been intensely debated whether visual stimuli are processed to the point of semantic analysis in the absence of awareness. In the present study, we measured the extent to which the meaning of a stimulus was registered using the N400 component of human event-related potentials (ERPs), a highly sensitive index of the semantic mismatch between a stimulus and the context in which it is presented. Observers judged the semantic relatedness of a context and target word while ERPs were recorded under continuous flash suppression (Experiments 1 and 2) and binocular rivalry (Experiment 3). Finally, we parametrically manipulated the visibility of the target word by increasing the contrast between the target word and the suppressive stimulus presented to the other eye (Experiment 4). We found that the amplitude of the N400 was attenuated with increasing suppression depth and was absent whenever the observers could not discriminate the meaning of suppressed words. We discuss these findings in the context of single-process models of consciousness, which can account for a large body of empirical evidence obtained from visual masking, attentional manipulations, and, now, interocular suppression paradigms.
Forebrain CRF1Modulates Early-Life Stress-Programmed Cognitive Deficits
Authors: Wang Xiao-Dong , Rammes Gerhard , Kraev Igor , Wolf Miriam , Liebl Claudia , Scharf Sebastian H. , Rice Courtney J. , Wurst Wolfgang , Holsboer Florian , Deussing Jan M. , Baram Tallie Z. , Stewart Michael G. , Müller Marianne B. , Schmidt Mathias V.
Published: September 2011

Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF1), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF1knock-out (CRF1-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF1in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF1deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF1-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF1signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
Complementary Function and Integrated Wiring of the Evolutionarily DistinctDrosophilaOlfactory Subsystems
Authors: Silbering Ana F. , Rytz Raphael , Grosjean Yael , Abuin Liliane , Ramdya Pavan , Jefferis Gregory S. X. E. , Benton Richard
Published: September 2011

To sense myriad environmental odors, animals have evolved multiple, large families of divergent olfactory receptors. How and why distinct receptor repertoires and their associated circuits are functionally and anatomically integrated is essentially unknown. We have addressed these questions through comprehensive comparative analysis of theDrosophilaolfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs). We identify ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols. IR and OR sensory neurons exhibit glomerular convergence in segregated, although interconnected, zones of the primary olfactory center, but these circuits are extensively interdigitated in higher brain regions. Consistently, behavioral responses to odors arise from an interplay between IR- and OR-dependent pathways. We integrate knowledge on the different phylogenetic and developmental properties of these receptors and circuits to propose models for the functional contributions and evolution of these distinct olfactory subsystems.
Reorganization of Somatosensory Cortical Areas 3b and 1 after Unilateral Section of Dorsal Columns of the Spinal Cord in Squirrel Monkeys
Authors: Qi Hui-Xin , Chen Li M. , Kaas Jon H.
Published: September 2011

An incomplete lesion of the ascending afferents from the hand in the dorsal columns of the spinal cord in monkeys is followed after weeks of recovery by a reactivation of much of the territory of the hand representations in primary somatosensory cortex (area 3b). However, the relationship between the extent of the dorsal column lesion and the amount of cortical reactivation has not been clear. Largely, this is due to the uncertainties about axon sparing after spinal cord lesions. Here, we unilaterally sectioned dorsal column afferents in the cervical spinal cord (C4–C6) in adult squirrel monkeys. After weeks of recovery, cholera toxin subunit B (CTB) was injected into the distal phalanges to label normal and surviving afferents to the cuneate nuclei representing the hands. Days later, the responsiveness of neurons in cortical areas 3b and 1 to tactile stimulation on the hand was evaluated in a microelectrode mapping session. The sizes and densities of CTB-labeled patches in the cuneate nuclei of both sides were quantified and compared. The results indicate that extensive reactivations of the hand representations in cortical areas 3b and 1 occur contralateral to the spinal cord lesion, even when <1% of labeled dorsal column terminations in the cuneate nucleus remained. These results raise the possibilities that secondary afferents from innervated neurons in the spinal cord contribute to the reactivation, and that the reactivation of area 1 is not completely dependent on inputs from area 3b.
Relief of Mg2+-Dependent Inhibition of TRPM1 by PKCα at the Rod Bipolar Cell Synapse
Authors: Rampino Melissa Ann F. , Nawy Scott A.
Published: September 2011

In the retina, light onset hyperpolarizes photoreceptors and depolarizes ON bipolar cells at the sign inverting photoreceptor–ON bipolar cell synapse. Transmission at this synapse is mediated by a signaling cascade comprised of mGluR6, a G-protein containing Gαo, and the cation channel TRP melastatin 1 (TRPM1). This system is thought to be common to both the rod- and ON-cone-driven pathways, which control vision under scotopic and photopic conditions, respectively. In this study, we present evidence that the rod pathway is uniquely susceptible to modulation by PKCα at the rod–rod bipolar cell synapse. Decreased production of DAG (an activator of PKC) by inhibition of PIP2(phosphatidylinositol-4,5-bisphosphate) hydrolysis caused depression of the TRPM1 current. Conversely, addition of a DAG analog, 2-acetyl-1-oleoyl-sn-glycerol (OAG), potentiated the current in rod bipolar cells but not in ON-cone bipolar cells. The potentiating effects of OAG were absent both in mutant mice that lack PKCα expression and in wild-type mice in which enzymatic activity of PKCα was pharmacologically inhibited. In addition, we found that, like other members of the TRPM subfamily, TRPM1 current is susceptible to voltage-independent inhibition by intracellular magnesium, and that modulation by PKCα relieves this inhibition, as the potentiating effects of OAG are absent in low intracellular magnesium. We conclude that activation of PKCα initiates a modulatory mechanism at the rod–rod bipolar cell synapse whose function is to reduce inhibition of the TRPM1 current by magnesium, thereby increasing the gain of transmission at this synapse.
Nerve Terminal Nicotinic Acetylcholine Receptors Initiate Quantal GABA Release from Perisomatic Interneurons by Activating Axonal T-Type (Cav3) Ca2+Channels and Ca2+Release from Stores
Authors: Tang Ai-Hui , Karson Miranda A. , Nagode Daniel A. , McIntosh J. Michael , Uebele Victor N. , Renger John J. , Klugmann Matthias , Milner Teresa A. , Alger Bradley E.
Published: September 2011

Release of conventional neurotransmitters is mainly controlled by calcium (Ca2+) influx via high-voltage-activated (HVA), Cav2, channels (“N-, P/Q-, or R-types”) that are opened by action potentials. Regulation of transmission by subthreshold depolarizations does occur, but there is little evidence that low-voltage-activated, Cav3 (“T-type”), channels take part. GABA release from cortical perisomatic-targeting interneurons affects numerous physiological processes, and yet its underlying control mechanisms are not fully understood. We investigated whether T-type Ca2+channels are involved in regulating GABA transmission from these cells in rat hippocampal CA1 using a combination of whole-cell voltage-clamp, multiple-fluorescence confocal microscopy, dual-immunolabeling electron-microscopy, and optogenetic methods. We show that Cav3.1, T-type Ca2+channels can be activated by α3β4 nicotinic acetylcholine receptors (nAChRs) that are located on the synaptic regions of the GABAergic perisomatic-targeting interneuronal axons, including the parvalbumin-expressing cells. Asynchronous, quantal GABA release can be triggered by Ca2+influx through presynaptic T-type Ca2+channels, augmented by Ca2+from internal stores, following focal microiontophoretic activation of the α3β4 nAChRs. The resulting GABA release can inhibit pyramidal cells. The T-type Ca2+channel-dependent mechanism is not dependent on, or accompanied by, HVA channel Ca2+influx, and is insensitive to agonists of cannabinoid, μ-opioid, or GABABreceptors. It may therefore operate in parallel with the normal HVA-dependent processes. The results reveal new aspects of the regulation of GABA transmission and contribute to a deeper understanding of ACh and nicotine actions in CNS.
Knocking Out P2X Receptors Reduces Transmitter Secretion in Taste Buds
Authors: Huang Yijen A. , Stone Leslie M. , Pereira Elizabeth , Yang Ruibiao , Kinnamon John C. , Dvoryanchikov Gennady , Chaudhari Nirupa , Finger Thomas E. , Kinnamon Sue C. , Roper Stephen D.
Published: September 2011

In response to gustatory stimulation, taste bud cells release a transmitter, ATP, that activates P2X2 and P2X3 receptors on gustatory afferent fibers. Taste behavior and gustatory neural responses are largely abolished in mice lacking P2X2 and P2X3 receptors [P2X2 and P2X3 double knock-out (DKO) mice]. The assumption has been that eliminating P2X2 and P2X3 receptors only removes postsynaptic targets but that transmitter secretion in mice is normal. Using functional imaging, ATP biosensor cells, and a cell-free assay for ATP, we tested this assumption. Surprisingly, although gustatory stimulation mobilizes Ca2+in taste Receptor (Type II) cells from DKO mice, as from wild-type (WT) mice, taste cells from DKO mice fail to release ATP when stimulated with tastants. ATP release could be elicited by depolarizing DKO Receptor cells with KCl, suggesting that ATP-release machinery remains functional in DKO taste buds. To explore the difference in ATP release across genotypes, we used reverse transcriptase (RT)-PCR, immunostaining, and histochemistry for key proteins underlying ATP secretion and degradation: Pannexin1, TRPM5, and NTPDase2 (ecto-ATPase) are indistinguishable between WT and DKO mice. The ultrastructure of contacts between taste cells and nerve fibers is also normal in the DKO mice. Finally, quantitative RT-PCR show that P2X4 and P2X7, potential modulators of ATP secretion, are similarly expressed in taste buds in WT and DKO taste buds. Importantly, we find that P2X2 is expressed in WT taste buds and appears to function as an autocrine, positive feedback signal to amplify taste-evoked ATP secretion.
An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons
Authors: Pieraut Simon , Lucas Olivier , Sangari Sina , Sar Chamroeun , Boudes Mathieu , Bouffi Carine , Noel Danièle , Scamps Frédérique
Published: September 2011

The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6−/−mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6−/−dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.
Epidermal growth factor induces adult human islet cell dedifferentiation
Authors: Hanley Stephen C , Assouline-Thomas Béatrice , Makhlin Julia , Rosenberg Lawrence
Published: September 2011

Given the inherent therapeutic potential of the morphogenetic plasticity of adult human islets, the identification of factors controlling their cellular differentiation is of interest. The epidermal growth factor (EGF) family has been identified previously in the context of pancreatic organogenesis. We examined the role of EGF in anin vitromodel whereby adult human islets are embedded in a collagen gel and dedifferentiated into duct-like epithelial structures (DLS). We demonstrated that DLS formation was EGF dependent, while residual DLS formation in the absence of added EGF was abrogated by EGF receptor inhibitor treatment. With respect to signaling, EGF administration led to an increase in c-Jun NH2-terminal kinase (JNK) phosphorylation early in DLS formation and in AKT and extracellular signal-regulated kinase (ERK) phosphorylation late in the process of DLS formation, concomitant with the increased proliferation of dedifferentiated cells. In the absence of EGF, these phosphorylation changes are not seen and the typical increase in DLS epithelial cell proliferation seen after 10 days in culture is attenuated. Thus, in our model, EGF is necessary for islet cell dedifferentiation, playing an important role in both the onset of DLS formation (through JNK) and in the proliferation of these dedifferentiated cells (through AKT and ERK).