bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Demographic and Treatment Variables in Long-Term Colon Cancer Survival
Authors: Lincourt Amy E. , Sing Ronald F. , Kercher Kent W. , Stewart Andrew , Demeter Bradley L. , Hope William W. , Lang Nicholas P. , Greene  , Heniford B. Todd
Published: April 2008

The purpose of this study is to examine demographic and treatment variables because they relate to 5-year survival in colon cancer. The study design is analysis of 174 471 patients with colon and rectosigmoid cancer as reported to the American College of Surgeons National Cancer Data Base. Factors associated with a reduced risk of mortality included female gender (hazard ratio = 0.89; 95% confidence interval, 0.87-0.90), education status (hazard ratio = 0.87; 95% confidence interval, 0.85-0.89), increased number of lymph nodes resected (compared with <8, 8-12: hazard ratio = 0.90; 95% confidence interval, 0.89-0.92; >12: hazard ratio = 0.79; 95% confidence interval, 0.77-0.80), and addition of chemotherapy (hazard ratio = 0.69; 95% CI, 0.68-0.71). African American race (hazard ratio = 1.14; 95% confidence interval, 1.11-1.18) and increasing age correlated with an increased hazard risk (61-75 years: hazard ratio = 1.26; 95% confidence interval, 1.23-1.29; ≥76 years: hazard ratio = 2.15; 95% confidence interval, 2.09-2.21, compared with age <60 years). Survival in colon cancer is significantly impacted by patient's age, race, gender, and education status but not by income or area of residence.
Body Esteem Improves After Bariatric Surgery
Authors: Madan Atul K. , Beech Bettina M. , Tichansky David S.
Published: April 2008

Body esteem is an issue for the morbidly obese. Although the primary goal of bariatric surgery is to improve, cure, and prevent medical comorbidities, the psychological aspect of bariatric surgery is just as important. Few studies have investigated the body esteem of patients after laparoscopic gastric bypass. This investigation tested the hypothesis that body esteem improves after bariatric surgery. Preoperative and postoperative patients were asked to fill out an institutional review board—exempted survey that included the Body-Esteem Scale for Adolescents and Adults (BESAA). The subscales include Appearance, Weight, and Attribution. Postoperative patients were told to fill the BESAA as they felt currently and as they felt before surgery. They felt that they had better scores currently than before surgery. Preoperative patients had worse scores than postoperative patients. As in many medical issues, body esteem improves after bariatric surgery. When discussing its benefits, psychological aspects of body esteem should be touted as well.
Proficiency-Based Laparoscopic Simulator Training Leads to Improved Operating Room Skill That Is Resistant to Decay
Authors: Stefanidis Dimitrios , Acker Christina , Heniford B. Todd
Published: April 2008

The aim of this study was to assess skill retention in the operating room following completion of a proficiency-based laparoscopic skills curriculum. Novices (n = 15) were randomized to a control and a training group that practiced to proficiency on the Fundamentals of Laparoscopic Surgery suturing model. The performance of both groups was assessed on the simulator and on a live porcine laparoscopic Nissen fundoplication model at training completion (posttest) and 5 months later (retention test). Training to proficiency required 4.7 ±1.2 hours and 41 ± 10 repetitions. Trained participants outperformed controls, and their performance deteriorated slightly between posttests and retention tests on the simulator (505 ± 22 vs 462 ± 50, respectively; P < .05) but not in operating room (263 ± 138 vs 279 ± 88, respectively; P = .38). Proficiency-based simulator training results in durable improvement in operative skill of trainees even in the absence of practice for up to 5 months. Minute simulator performance changes do not translate to the operating room.
Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia
Authors: Jankovic Dragana , Gorello Paolo , Liu Ting , Ehret Sabire , La Starza Roberta , Desjobert Cecile , Baty Florent , Brutsche Martin , Jayaraman Padma-Sheila , Santoro Alessandra , Mecucci Christina , Schwaller Juerg
Published: April 2008

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1+) as well as markers of the B-cell lineage (B220+). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.
CD4+CD25+ Treg cells inhibit human memory γδ T cells to produce IFN-γ in response to M tuberculosis antigen ESAT-6
Authors: Li Li , Wu Chang-You
Published: April 2008

γδ T cells play an important role in innate immunity against infections; however, the regulation of these cells remains largely unknown. In the present study, we show that ESAT-6, an antigen of Mycobacterium tuberculosis, induces IFN-γ secretion by human γδ T cells. In addition, ESAT-6 also induces the activation and proliferation of γδ T cells. Phenotypic analysis indicates that IFN-γ–producing γδ T cells are mainly effector memory cells with the surface phenotype of CD45RA−CD62L−CCR7−. These results were further confirmed by the fact that naive γδ T cells from cord blood did not produce IFN-γ in response to ESAT-6. Further studies indicated that stimulation with ESAT-6 directly induced purified γδ T cells to produce IFN-γ, independent of both antigen-presenting cells and CD4+ T cells. Unexpectedly, depletion of CD4+ T cells markedly enhanced IFN-γ production by γδ T cells, indicating that CD4+ T cells regulate the response of γδ T cells. Importantly, CD4+CD25+ T regulatory (Treg) cells but not CD4+CD25− T cells significantly inhibited IFN-γ production by γδ T cells. Taken together, these data demonstrate for the first time that Treg cells can play an important role in the regulation of immune responses of antigen-specific human memory γδ T cells.
Longitudinal association of body mass index with lung function: The CARDIA Study
Authors: Thyagarajan Bharat , Jacobs David R , Apostol George G , Smith Lewis J , Jensen Robert L , Crapo Robert O , Barr R Graham , Lewis Cora E , Williams O Dale
Published: April 2008

Background

Lung function at the end of life depends on its peak and subsequent decline. Because obesity is epidemic in young adulthood, we quantified age-related changes in lung function relative to body mass index (BMI).

Methods

The Coronary Artery Risk Development in Young Adults (CARDIA) study in 1985–86 (year 0) recruited 5,115 black and white men and women, aged 18–30. Spirometry testing was conducted at years 0, 2, 5 and 10. We estimated 10 year change in FVC, FEV1and FEV1/FVC according to baseline BMI and change in BMI within birth cohorts with initial average ages 20, 24, and 28 years, controlling for race, sex, smoking, asthma, physical activity, and alcohol consumption.

Measurements and Main Results

Participants with baseline BMI < 21.3 kg/m2experienced 10 year increases of 71 ml in FVC and 60 ml in FEV1and neither measure declined through age 38. In contrast, participants with baseline BMI ≥ 26.4 kg/m2experienced 10 year decreases of 185 ml in FVC and 64 ml in FEV1. FEV1/FVC increased with increasing BMI. Weight gain was also associated with lung function. Those who gained the most weight over 10 years had the largest decrease in FVC, but FVC increased with weight gain in those initially thinnest. In contrast, FEV1decreased with increasing weight gain in all participants, with maximum decline in obese individuals who gained the most weight during the study.

Conclusion

Among healthy young adults, increasing BMI in the initially thin participants was associated with increasing then stable lung function through age 38, but there were substantial lung function losses with higher and increasing fatness. These results suggest that the obesity epidemic threatens the lung health of the general population.
A new classification system for bacterial Rieske non-heme iron aromatic ring-hydroxylating oxygenases
Authors: Kweon Ohgew , Kim Seong-Jae , Baek Songjoon , Chae Jong-Chan , Adjei Michael D , Baek Dong-Heon , Kim Young-Chang , Cerniglia Carl E
Published: April 2008

Background

Rieske non-heme iron aromatic ring-hydroxylating oxygenases (RHOs) are multi-component enzyme systems that are remarkably diverse in bacteria isolated from diverse habitats. Since the first classification in 1990, there has been a need to devise a new classification scheme for these enzymes because many RHOs have been discovered, which do not belong to any group in the previous classification. Here, we present a scheme for classification of RHOs reflecting new sequence information and interactions between RHO enzyme components.

Result

We have analyzed a total of 130 RHO enzymes in which 25 well-characterized RHO enzymes were used as standards to test our hypothesis for the proposed classification system. From the sequence analysis of electron transport chain (ETC) components of the standard RHOs, we extracted classification keys that reflect not only the phylogenetic affiliation within each component but also relationship among components. Oxygenase components of standard RHOs were phylogenetically classified into 10 groups with the classification keys derived from ETC components. This phylogenetic classification scheme was converted to a new systematic classification consisting of 5 distinct types. The new classification system was statistically examined to justify its stability. Type I represents two-component RHO systems that consist of an oxygenase and an FNRC-type reductase. Type II contains other two-component RHO systems that consist of an oxygenase and an FNRN-type reductase. Type III represents a group of three-component RHO systems that consist of an oxygenase, a [2Fe-2S]-type ferredoxin and an FNRN-type reductase. Type IV represents another three-component systems that consist of oxygenase, [2Fe-2S]-type ferredoxin and GR-type reductase. Type V represents another different three-component systems that consist of an oxygenase, a [3Fe-4S]-type ferredoxin and a GR-type reductase.

Conclusion

The new classification system provides the following features. First, the new classification system analyzes RHO enzymes as a whole. RwithSecond, the new classification system is not static but responds dynamically to the growing pool of RHO enzymes. Third, our classification can be applied reliably to the classification of incomplete RHOs. Fourth, the classification has direct applicability to experimental work. Fifth, the system provides new insights into the evolution of RHO systems based on enzyme interaction.
Protein folding and conformational stress in microbial cells producing recombinant proteins: a host comparative overview
Authors: Gasser Brigitte , Saloheimo Markku , Rinas Ursula , Dragosits Martin , Rodríguez-Carmona Escarlata , Baumann Kristin , Giuliani Maria , Parrilli Ermenegilda , Branduardi Paola , Lang Christine , Porro Danilo , Ferrer Pau , Tutino Maria Luisa , Mattanovich Diethard , Villaverde Antonio
Published: April 2008

Different species of microorganisms including yeasts, filamentous fungi and bacteria have been used in the past 25 years for the controlled production of foreign proteins of scientific, pharmacological or industrial interest. A major obstacle for protein production processes and a limit to overall success has been the abundance of misfolded polypeptides, which fail to reach their native conformation. The presence of misfolded or folding-reluctant protein species causes considerable stress in host cells. The characterization of such adverse conditions and the elicited cell responses have permitted to better understand the physiology and molecular biology of conformational stress. Therefore, microbial cell factories for recombinant protein production are depicted here as a source of knowledge that has considerably helped to picture the extremely rich landscape of in vivo protein folding, and the main cellular players of this complex process are described for the most important cell factories used for biotechnological purposes.
Hydrogenated fat diet intake during pregnancy and lactation modifies the PAI-1 gene expression in white adipose tissue of offspring in adult life
Authors: Pisani Luciana P , Oller do Nascimento Claudia M , Bueno Allain A , Biz Carolina , Albuquerque Kelse T , Ribeiro Eliane B , Oyama Lila M
Published: April 2008

We examine whether feeding pregnant and lactating rats hydrogenated fats rich in trans fatty acids modifies the plasma lipid profiles and the expression of adipokines involved with insulin resistance and cardiovascular disease in their 90-day-old offspring. Pregnant and lactating Wistar rats were fed with either a control diet (C group) or one enriched with hydrogenated vegetable fat (T group). Upon weaning, the male pups were sorted into four groups: CC, mothers were receiving C and pups were kept on C; CT, mothers were receiving C and pups were fed with T; TT, mothers were receiving T and pups were kept on T; TC, mothers were receiving T and pups were fed with C. Pups' food intake and body weight were quantified weekly and the pups were killed at day 90 of life by decapitation. Blood and carcass as well as retroperitoneal, epididymal, and subcutaneous white adipose tissues were collected. Food intake and body weight were lower in TC and TT, and metabolic efficiency was reduced in TT. Offspring of TT and TC rats had increased white adipose tissue PAI-1 gene expression. Insulin receptor was higher in TT than other groups. Ingestion of hydrogenated vegetable fat by the mother during gestation and lactation could promote deleterious consequences, even after the withdrawal of the causal factor.
The Merendino procedure following preoperative imatinib mesylate for locally advanced gastrointestinal stromal tumor of the esophagogastric junction
Authors: Staiger Wilko I , Ronellenfitsch Ulrich , Kaehler Georg , Schildhaus Hans Ulrich , Dimitrakopoulou-Strauss Antonia , Schwarzbach Matthias HM , Hohenberger Peter
Published: April 2008

Background

Gastrointestinal stromal tumors (GIST) of the esophagogastric junction might pose a major problem to surgical resection. If locally advanced, extended or multivisceral resection with relevant procedural-specific morbidity and mortality is often necessary.

Case presentation

We report a case of a patient with a locally advanced GIST of the esophagogastric junction who was treated by transhiatal resection of the lower esophagus and gastric cardia with reconstruction by interposition of segment of the jejunum (Merendino procedure). Prior to resection, downsizing of the tumor had successfully been achieved by treatment with imatinib mesylate for six months. Histological proof of GIST by immunohistochemical expression of c-KIT and/or PDGF alpha Receptor is crucial to allow embarking on this treatment strategy.

Conclusion

A multimodal approach for an advanced GIST of the esophagogastric junction with preoperative administration of imatinib mesylate could avoid extended resection. The Merendino procedure might be considered as the reconstruction method of choice after resection of GIST at this location.
An integrated genetic, genomic and systems approach defines gene networks regulated by the interaction of light and carbon signaling pathways in Arabidopsis
Authors: Thum Karen E , Shin Michael J , Gutiérrez Rodrigo A , Mukherjee Indrani , Katari Manpreet S , Nero Damion , Shasha Dennis , Coruzzi Gloria M
Published: April 2008

Background

Light and carbon are two important interacting signals affecting plant growth and development. The mechanism(s) and/or genes involved in sensing and/or mediating the signaling pathways involving these interactions are unknown. This study integrates genetic, genomic and systems approaches to identify a genetically perturbed gene network that is regulated by the interaction of carbon and light signaling in Arabidopsis.

Results

Carbon andlightinsensitive (cli) mutants were isolated. Microarray data fromcli186is analyzed to identify the genes, biological processes and gene networks affected by the integration of light and carbon pathways. Analysis of this data reveals 966 genes regulated by light and/or carbon signaling in wild-type. Incli186, 216 of these light/carbon regulated genes are misregulated in response to light and/or carbon treatments where 78% are misregulated in response to light and carbon interactions. Analysis of the gene lists show that genes in the biological processes "energy" and "metabolism" are over-represented among the 966 genes regulated by carbon and/or light in wild-type, and the 216 misregulated genes incli186. To understand connections among carbon and/or light regulated genes in wild-type and the misregulated genes incli186, the microarray data is interpreted in the context of metabolic and regulatory networks. The network created from the 966 light/carbon regulated genes in wild-type, reveals thatcli186is affected in the light and/or carbon regulation of a network of 60 connected genes, including six transcription factors. One transcription factor, HAT22 appears to be a regulatory "hub" in thecli186network as it shows regulatory connections linking a metabolic network of genes involved in "amino acid metabolism", "C-compound/carbohydrate metabolism" and "glycolysis/gluconeogenesis".

Conclusion

The global misregulation of gene networks controlled by light and carbon signaling incli186indicates that it represents one of the first Arabidopsis mutants isolated that is specifically disrupted in the integration of both carbon and light signals to control the regulation of metabolic, developmental and regulatory genes. The network analysis of misregulated genes suggests thatCLI186acts to integrate light and carbon signaling interactions and is a master regulator connecting the regulation of a host of downstream metabolic and regulatory processes.
Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis
Authors: Karantzali Efthimia , Schulz Herbert , Hummel Oliver , Hubner Norbert , Hatzopoulos AK , Kretsovali Androniki
Published: April 2008

Background

Epigenetic mechanisms regulate gene expression patterns affecting cell function and differentiation. In this report, we examine the role of histone acetylation in gene expression regulation in mouse embryonic stem cells employing transcriptomic and epigenetic analysis.

Results

Embryonic stem cells treated with the histone deacetylase inhibitor Trichostatin A (TSA), undergo morphological and gene expression changes indicative of differentiation. Gene profiling utilizing Affymetrix microarrays revealed the suppression of important pluripotency factors, including Nanog, a master regulator of stem cell identity, and the activation of differentiation-related genes. Transcriptional and epigenetic changes induced after 6-12 hours of TSA treatment mimic those that appear during embryoid body differentiation. We show here that the early steps of stem cell differentiation are marked by the enhancement of bulk activatory histone modifications. At the individual gene level, we found that transcriptional reprogramming triggered by histone deacetylase inhibition correlates with rapid changes in activating K4 trimethylation and repressive K27 trimethylation of histone H3. The establishment of H3K27 trimethylation is required for stable gene suppression whereas in its absence, genes can be reactivated upon TSA removal.

Conclusion

Our data suggest that inhibition of histone deacetylases accelerates the early events of differentiation by regulating the expression of pluripotency- and differentiation-associated genes in an opposite manner. This analysis provides information about genes that are important for embryonic stem cell function and the epigenetic mechanisms that regulate their expression.
Diminishment of α-MSH anti-inflammatory activity in MC1r siRNA-transfected RAW264.7 macrophages
Authors: Li Dayu , Taylor Andrew W
Published: April 2008

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a powerful suppressor of inflammation mediated by macrophages, which express at least two receptors, melanocortin 1 and 3 receptors (MC1r and MC3r) that bind α-MSH. Albeit, the anti-inflammatory activity of α-MSH has been well documented in macrophages, the mechanisms of α-MSH activity in macrophages are not clearly understood. This study is to investigate which of the MCr expressed on macrophages is associated with the immunosuppressive activities of α-MSH on LPS-stimulated macrophages. To address this question, we transfected RAW264.7 macrophage cells with MC1r small interfering (si)RNA, which specifically targets mouse MC1r mRNA. The diminution of MC1r mRNA expression was 82% at 24 h and 67% at 48 h after transfection. There was a significant loss in α-MSH suppression of NO generation and TNF-α production by MC1r siRNA-transfected macrophages stimulated with LPS. There was an equally diminished α-MSH suppression of LPS-stimulated intracellular activation of NF-κB and p38 phosphorylation. In addition, the diminishment of MC1r expression by siRNA transfection had no influence on MC3r expression and function in the macrophages. These findings demonstrate that α-MSH suppression of LPS-induced inflammatory activity in macrophages requires expression of MC1r. The results imply that although all of the MCr are G-coupled proteins, they may not necessarily function through the same intracellular pathways in macrophages.
Reduced Plasma High-Density Lipoprotein Cholesterol in Hyperthyroid Mice Coincides with Decreased Hepatic Adenosine 5′-Triphosphate-Binding Cassette Transporter 1 Expression
Authors: Tancevski Ivan , Wehinger Andreas , Demetz Egon , Eller Philipp , Duwensee Kristina , Huber Julia , Hochegger Kathrin , Schgoer Wilfried , Fievet Catherine , Stellaard Frans , Rudling Mats , Patsch Josef R. , Ritsch Andreas
Published: April 2008

The aim of the study was to investigate the influence of severe hyperthyroidism on plasma high-density lipoprotein cholesterol (HDL-C). Recently, it was shown in mice that increasing doses of T3 up-regulate hepatic expression of scavenger receptor class B, type I, resulting in increased clearance of plasma HDL-C. Here, we show that severe hyperthyroidism in mice did not affect hepatic expression of scavenger receptor class B, type I, but reduced hepatic expression of ATP-binding cassette transporter 1, accompanied by a 40% reduction of HDL-C. The sterol content of bile, liver, and feces was markedly increased, accompanied by up-regulation of hepatic cholesterol 7α-hydroxylase, and ATP-binding cassette transporter 5, which is known to promote biliary sterol secretion upon dimerization with ATP-binding cassette transporter 8. Both control and hyperthyroid mice exerted identical plasma clearance of iv injected [3H]HDL-C, supporting the view that severe hyperthyroidism does not affect HDL-C clearance but, rather, its formation via hepatic ATP-binding cassette transporter 1.
Autoimmune Hypophysitis of SJL Mice: Clinical Insights from a New Animal Model
Authors: Tzou Shey-Cherng , Lupi Isabella , Landek Melissa , Gutenberg Angelika , Tzou Ywh-Min , Kimura Hiroaki , Pinna Giovanni , Rose Noel R. , Caturegli Patrizio
Published: April 2008

Autoimmune hypophysitis (AH) is a rare but increasingly recognized disease of the pituitary gland. Its autoantigens are unknown, and the management is difficult because it is often misdiagnosed as a nonsecreting adenoma. By immunizing female SJL/J mice with mouse pituitary extracts, we established a new mouse model of experimental AH. Immunized mice developed severe lymphocytic infiltration in the anterior pituitary that closely mimicked the human pathology. In the early phase of experimental AH, the pituitary enlarged, consistent with the compression symptoms reported by hypophysitis patients at presentation. In the florid phase, adrenal insufficiency and pituitary antibodies developed, in strong correlation with the pituitary pathology. In the late phase, hypothyroidism ensued, and the pituitary gland became atrophic. Using immune sera as probes in a two-dimensional immunoblotting screen followed by mass spectrometry, we identified several proteins that could function as pituitary autoantigens. These findings provide new insights into the pathogenesis of AH, and establish a platform for developing novel diagnostic biomarkers and therapeutics.
Low-Frequency Electro-Acupuncture and Physical Exercise Improve Metabolic Disturbances and Modulate Gene Expression in Adipose Tissue in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome
Authors: Mannerås Louise , Jonsdottir Ingibjörg H. , Holmäng Agneta , Lönn Malin , Stener-Victorin Elisabet
Published: April 2008

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, abdominal obesity, and insulin resistance. Pharmacotherapy is often unsatisfactory. This study evaluates the effects of low-frequency electro-acupuncture (EA) and physical exercise on metabolic disturbances and adipose tissue mRNA expression of selected genes in a rat PCOS model characterized by insulin resistance and adiposity. Dihydrotestosterone (inducing PCOS) or vehicle (control) was administrated continuously, beginning before puberty. At age 10 wk, PCOS rats were randomly divided into three groups; PCOS, PCOS EA, and PCOS exercise. PCOS EA rats received 2-Hz EA (evoking muscle twitches) three times/wk during 4–5 wk. PCOS exercise rats had free access to a running wheel for 4–5 wk. EA and exercise improved insulin sensitivity, measured by clamp, in PCOS rats. Exercise also reduced adiposity, visceral adipocyte size, and plasma leptin. EA increased plasma IGF-I. Real-time RT-PCR revealed increased expression of leptin and IL-6 and decreased expression of uncoupling protein 2 in visceral adipose tissue of PCOS rats compared with controls. EA restored the expression of leptin and uncoupling protein 2, whereas exercise normalized adipose tissue leptin and IL-6 expression in PCOS rats. Thus, EA and exercise ameliorate insulin resistance in rats with PCOS. This effect may involve regulation of adipose tissue metabolism and production because EA and exercise each partly restore divergent adipose tissue gene expression associated with insulin resistance, obesity, and inflammation. In contrast to exercise, EA improves insulin sensitivity and modulates adipose tissue gene expression without influencing adipose tissue mass and cellularity.
Identification of Key Amino Acid Residues in a Thyrotropin Receptor Monoclonal Antibody Epitope Provides Insight into Its Inverse Agonist and Antagonist Properties
Authors: Chen Chun-Rong , McLachlan Sandra M. , Rapoport Basil
Published: April 2008

CS-17 is a murine monoclonal antibody to the human TSH receptor (TSHR) with both inverse agonist and antagonist properties. Thus, in the absence of ligand, CS-17 reduces constitutive TSHR cAMP generation and also competes for TSH binding to the receptor. The present data indicate that for both of these functions, the monovalent CS-17 Fab (50 kDa) behaves identically to the intact, divalent IgG molecule (150 kDa). The surprising observation that CS-17 competes for TSH binding to the human but not porcine TSHR enabled identification of a number of amino acids in its epitope. Replacement of only three human TSHR residues (Y195, Q235, and S243) with the homologous porcine TSHR residues totally abolishes CS-17 binding as detected by flow cytometry. TSH binding is unaffected. Of these residues, Y195 is most important, with Q235 and S243 contributing to CS-17 binding to a much lesser degree. The functional effects of CS-17 IgG and Fab on constitutive cAMP generation by porcinized human TSHR confirm the CS-17 binding data. The location of TSHR amino acid residues Y195, Q235, and S243 deduced from the crystal structure of the FSH receptor leucine-rich domain provides valuable insight into the CS-17 and TSH binding sites. Whereas hormone ligands bind primarily to the concave surface of the leucine-rich domains, a major portion of the CS-17 epitope lies on the opposite convex surface with a minor component in close proximity to known TSH binding residues.
Relaxin Ameliorates Fibrosis in Experimental Diabetic Cardiomyopathy
Authors: Samuel Chrishan S. , Hewitson Tim D. , Zhang Yuan , Kelly Darren J.
Published: April 2008

Fibrosis (extracellular matrix accumulation) is the final end point in diabetic cardiomyopathy. The current study evaluated the therapeutic effects of the antifibrotic hormone relaxin (RLX) in streptozotocin-treated transgenic mRen-2 rats, which undergo pathological and functional features similar to human diabetes. Twelve-week-old hyperglycemic mRen-2 rats, normoglycemic control rats, and animals treated with recombinant human gene-2 (H2) RLX from wk 10–12 were assessed for various measures of left ventricular (LV) fibrosis, hemodynamics, and function, while the mechanism of RLX’s actions was also determined. Hyperglycemic mRen-2 rats had increased LV collagen concentration (fibrosis) and gelatinase activity (all P < 0.05 vs. controls) but equivalent levels of interstitial collagenase and tissue inhibitor of metalloproteinase-1 to that measured in control rats. The increased LV fibrosis associated with diabetic animals led to significant alterations in the E/A wave ratio and E-wave deceleration time (both P < 0.05 vs. controls) in the absence of blood pressure changes, reflective of myocardial stiffness and LV diastolic dysfunction. H2-RLX treatment of diabetic rats led to significant decreases in interstitial and total LV collagen deposition (both P < 0.05 vs. diabetic group), resulting in decreased myocardial stiffness and improved LV diastolic function, without affecting nondiabetic animals. The protective effects of H2-RLX in diabetic rats were associated with a reduction in mesenchymal cell differentiation and tissue inhibitor of metalloproteinase-1 expression in addition to a promotion of extracellular matrix-degrading matrix metalloproteinase-13 (all P < 0.05 vs. diabetic group) but were independent of blood pressure regulation. These findings demonstrate that RLX is an antifibrotic with rapid-occurring efficacy and may represent a novel therapy for the treatment of diabetes.
Update on the Molecular Diagnosis of Endocrine Tumors: Toward –omics-Based Personalized Healthcare?
Authors: Weber Frank , Eng Charis
Published: April 2008

Genetic advances in endocrine neoplasia provided the paradigm for the practice of clinical cancer genetics: germline RET mutations in multiple endocrine neoplasia type 2. In the last 14 yr, both genetics and –omics advances have occurred, almost exponentially in the last 5 yr. The time has come to reevaluate recent advances in genomic medicine’s promise to revolutionize personalized healthcare in the context of endocrine neoplasias. This update focuses on two examples of endocrine neoplasias, those of the thyroid and of the adrenal, and discusses recent advances in germline and somatic genetics and genomics, as they relate to clinical application.
Dorsal–Ventral Gradient for Neuronal Plasticity in the Embryonic Spinal Cord
Authors: Pineda Ricardo H. , Ribera Angeles B.
Published: April 2008

Within the developingXenopusspinal cord, voltage-gated potassium (Kv) channel genes display different expression patterns, many of which occur in opposing dorsal–ventral gradients. Regional differences in Kv gene expression would predict different patterns of potassium current (IKv) regulation. However, during the first 24 h of postmitotic differentiation, all primary spinal neurons undergo a temporally coordinated upregulation ofIKvdensity that shortens the duration of the action potential. Here, we tested whether spinal neurons demonstrate regional differences inIKvregulation subsequent to action potential maturation. We show that two types of neurons, I and II, can be identified in culture on the basis of biophysical and pharmacological properties ofIKvand different firing patterns. Chronic increases in extracellular potassium, a signature of high neuronal activity, do not alter excitability properties of either neuron type. However, elevating extracellular potassium acutely after the period of action potential maturation leads to different changes in membrane properties of the two types of neurons.IKvof type I neurons gains sensitivity to the blocker XE991, whereas type II neurons increaseIKvdensity and fire fewer action potentials. Moreover, by recording from neuronsin vivo, we found that primary spinal neurons can be identified as either type I or type II. Type I neurons predominate in dorsal regions, whereas type II neurons localize to ventral regions. The findings reveal a dorsal–ventral gradient forIKvregulation and a novel form of neuronal plasticity in spinal cord neurons.
Effects on Differentiation of Embryonic Ventral Midbrain Progenitors by Lmx1a, Msx1, Ngn2, and Pitx3
Authors: Roybon Laurent , Hjalt Tord , Christophersen Nicolaj S. , Li Jia-Yi , Brundin Patrik
Published: April 2008

Neurons derived from neural stem cells could potentially be used for cell therapy in neurodegenerative disorders, such as Parkinson's disease. To achieve controlled differentiation of neural stem cells, we expressed transcription factors involved in the development of midbrain dopaminergic neurons in rat and human neural progenitors. Using retroviral-mediated transgene delivery, we overexpressed Lmx1a (LIM homeobox transcription factor 1, alpha), Msx1 (msh homeobox homolog 1), Ngn2 (neurogenin 2), or Pitx3 (paired-like homeodomain transcription factor 3) in neurospheres derived from embryonic day 14.5 rat ventral mesencephalic progenitors. We also expressed either Lmx1a or Msx1 in the human embryonic midbrain-derived progenitor cell line NGC-407. Rat cells transduced with Ngn2 exited the cell cycle and expressed the neuronal marker microtubule-associated protein 2 and catecholamine-neuron protein vesicular monoamine transporter 2. Interestingly, Pitx3 downregulated the expression of SOX2 (SRY-box containing gene 2) and Nestin, altered cell morphology, but never induced neuronal or glial differentiation. Ngn2 exhibited a strong neuron-inducing effect. In contrast, few Lmx1a-transduced cells matured into neurons, and Msx1 overexpression promoted oligodendrogenesis rather than neuronal differentiation. Importantly, none of these four genes, alone or in combination, enhanced differentiation of rat neural stem cells into dopaminergic neurons. Notably, the overexpression of Lmx1a, but not Msx1, in human neural progenitors increased the yield of tyrosine hydroxylase-immunoreactive cells by threefold. Together, we demonstrate that induced overexpression of transcription factor genes has profound and specific effects on the differentiation of rat and human midbrain progenitors, although few dopamine neurons are generated.
Neurodevelopmental Trajectories of the Human Cerebral Cortex
Authors: Shaw Philip , Kabani Noor J. , Lerch Jason P. , Eckstrand Kristen , Lenroot Rhoshel , Gogtay Nitin , Greenstein Deanna , Clasen Liv , Evans Alan , Rapoport Judith L. , Giedd Jay N. , Wise Steve P.
Published: April 2008

Understanding the organization of the cerebral cortex remains a central focus of neuroscience. Cortical maps have relied almost exclusively on the examination of postmortem tissue to construct structural, architectonic maps. These maps have invariably distinguished between areas with fewer discernable layers, which have a less complex overall pattern of lamination and lack an internal granular layer, and those with more complex laminar architecture. The former includes several agranular limbic areas, and the latter includes the homotypical and granular areas of association and sensory cortex. Here, we relate these traditional maps to developmental data from noninvasive neuroimaging. Changes in cortical thickness were determinedin vivofrom 764 neuroanatomic magnetic resonance images acquired longitudinally from 375 typically developing children and young adults. We find differing levels of complexity of cortical growth across the cerebrum, which align closely with established architectonic maps. Cortical regions with simple laminar architecture, including most limbic areas, predominantly show simpler growth trajectories. These areas have clearly identified homologues in all mammalian brains and thus likely evolved in early mammals. In contrast, polysensory and high-order association areas of cortex, the most complex areas in terms of their laminar architecture, also have the most complex developmental trajectories. Some of these areas are unique to, or dramatically expanded in primates, lending an evolutionary significance to the findings. Furthermore, by mapping a key characteristic of these development trajectories (the age of attaining peak cortical thickness) we document the dynamic, heterochronous maturation of the cerebral cortex through time lapse sequences (“movies”).
Solid-phase crystallization under continuous heating: Kinetic and microstructure scaling laws
Authors: Farjas J. , Roura P.
Published: April 2008

The kinetics and microstructure of solid-phase crystallization under continuous heating conditions and random distribution of nuclei are analyzed. An Arrhenius temperature dependence is assumed for both nucleation and growth rates. Under these circumstances, the system has a scaling law such that the behavior of the scaled system is independent of the heating rate. Hence, the kinetics and microstructure obtained at different heating rates differ only in time and length scaling factors. Concerning the kinetics, it is shown that the extended volume evolves with time according to αex = [exp(κCt′)]m+1, where t′ is the dimensionless time. This scaled solution not only represents a significant simplification of the system description, it also provides new tools for its analysis. For instance, it has been possible to find an analytical dependence of the final average grain size on kinetic parameters. Concerning the microstructure, the existence of a length scaling factor has allowed the grain-size distribution to be numerically calculated as a function of the kinetic parameters.
Effect of aging in hydrogen atmosphere on electrical conductivity of Cu–3at.%Ti alloy
Authors: Semboshi Satoshi , Konno Toyohiko J.
Published: April 2008

The electrical conductivities of Cu–3at.%Ti alloys aged at 773 K in a hydrogen atmosphere were investigated as a function of aging time. The electrical conductivity of the quenched alloy, 5.2% International Annealed Copper Standard (IACS), improved with aging time to 66% IACS after 48 h. This was mainly caused by the dilution of the Cu–Ti solid solution in the alloy, which is supported by the fact that the lattice parameter of the face-centered cubic (fcc) phase approaches that of pure Cu by aging in a hydrogen atmosphere.
Ultrastructural analyses of nanoscale apatite biomimetically grown on organic template
Authors: Hong S.I. , Lee K.H. , Outslay M.E. , Kohn D.H.
Published: April 2008

The ultrastructure of nanoscale apatite biomimetically formed on an organic template from a supersaturated mineralizing solution was studied to examine the morphological and crystalline arrangement of mineral apatites. Needle-shaped apatite crystal plates with a size distribution of ∼100 to ∼1000 nm and the long axis parallel to thecaxis ([002]) were randomly distributed in the mineral films. Between these randomly distributed needle-shaped apatite crystals, amorphous phases and apatite crystals (∼20–40 nm) with the normal of the grains quasi-perpendicular to thecaxis were observed. These observations suggest that the apatite film is an interwoven structure of amorphous phases and apatite crystals with various orientations. The mechanisms underlying the shape of the crystalline apatite plate and aggregated apatite nodules are discussed from an energy-barrier point of view. The plate or needle-shaped apatite is favored in single-crystalline form, whereas the granular nodules are favored in the polycrystalline apatite aggregate. The similarity in shape in both single-crystalline needle-shaped apatite and polycrystalline granular apatite over a wide range of sizes is explained by the principle of similitude, in which the growth and shape are determined by the forces acting upon the surface area and the volume.
Synthesis and self-assembly of zinc oxide nanoparticles with septahedral morphology
Authors: Bell Nelson S. , Tallant David R. , Raymond Rebecca , Boyle Timothy J.
Published: April 2008

The formation of 10-nm ZnO nanopyramids using a simple synthetic route has been isolated from the reaction of Zn(OAc)2·2H2O in 1,4-butanediol followed by ripening at 90 °C. This was accomplished by establishing control over the Ostwald ripening process through the use of a carboxylic acid specific adsorbate. Using a variety of analytical methods, it is proposed that the carboxylate groups in the acetate precursor stabilize the {101} habit planes, creating septahedral shapes or nanopyramids. Particle assembly into crystallographically oriented dimers was observed with high specificity, and the association mechanism is suggested to relate to the crystal polarity and the variation in specific adsorption of the carboxylic acid to the surface facets. These materials are a candidate for biological labeling applications in living cells.
Polar-molecules-driven enhanced colloidal electrostatic interactions and their applications in achieving high active electrorheological materials
Authors: Xu L. , Tian W.J. , Wu X.F. , Cao J.G. , Zhou L.W. , Huang J.P. , Gu G.Q.
Published: April 2008

We have fabricated a class of colloidal electrorheological (ER) fluids, in which suspended TiO2 particles were synthesized by a sol-gel method and modified by 1,4-butyrolactone molecules with a permanent molecular dipole moment of 4.524 D. Compared with pure TiO2 ER fluids, the quasi-static yield stress of the polar- molecules-modified ER fluid is enhanced as high as 48.1 kPa when subjected to an external electric field of 5 kV/mm. Also, it possesses other attractive characters such as low current density (<14 μA/cm2) and low sedimentation. Based on a Green’s function method, we present a first-principles approach to investigate colloidal electrostatic interactions. Excellent agreement between experiment and theory has been shown for the enhancement ratio of quasi-static yield stress, which quantitatively reveals that enough polar molecules oriented within the field-directed gap between the colloidal particles can unexpectedly enhance the interactions, thus yielding the unusual enhancement. This shows a promising and flexible direction for achieving more highly active ER materials.
Deformation of amorphous silicon nanostructures subjected to monotonic and cyclic loading
Authors: Gaire C. , Ye D-X. , Lu T-M. , Wang G-C. , Picu R.C.
Published: April 2008

An atomic force microscope (AFM) was used to characterize the deformation behavior of amorphous Si (a-Si) nanostructures subjected to monotonic and cyclic loading. The sample geometry was specially designed (in the form of elbow) using finite element modeling for the purpose of these tests, and the samples were grown by glancing angle deposition. When deformed monotonically at room temperature, the a-Si specimens exhibited a nonlinear force–displacement response at forces larger than a critical force, a phenomenon not observed in bulk silicon. A fatigue testing methodology based on the use of the AFM was established. The fatigue life of the a-Si specimens was observed to increase by five orders of magnitude with a 50% reduction in the applied force amplitude. It was verified that this delayed failure is caused by progressive damage accumulation during cyclic loading. These results are compared with literature data obtained from micron-size specimens.
Improvement of oxidation-resistance of NiCrAlY coatings by application of CrN or CrON interlayer
Authors: Li W.Z. , Yao Y. , Wang Q.M. , Bao Z.B. , Gong J. , Sun C. , Jiang X.
Published: April 2008

NiCrAlY coatings with and without CrN or CrON interlayer as diffusion barrier were deposited on superalloy DSM11 by arc ion plating (AIP). The oxidation performance of the coating systems was evaluated by isothermal oxidation tests at 1100 °C for 100 h. The element interdiffusion and oxidation behavior of the coating systems were described. It was found that the NiCrAlY coatings provided protective effect for the DSM11 substrate. However, serious interdiffusion between the coatings and substrate resulted in rapid degradation of the coatings. The addition of CrN or CrON interlayer between the coatings and substrate markedly decreased the interdiffusion. CrON interlayer performed better than CrN interlayer, which was attributed to the excellent diffusion barrier ability of Al2O3 layer formed in the interlayer at high temperature. Also, the NiCrAlY/CrON coating system exhibited more effective protection for DSM11 than the NiCrAlY/CrN coating system.
Oxygen diffusivities in mullite/zirconia composites measured by 18O/16O isotope exchange and secondary ion mass spectrometry
Authors: Ko Hong-Da , Lin Chien-Cheng
Published: April 2008

Oxygen diffusivities in mullite/zirconia composites were measured by 18O/16O isotope exchange and secondary ion mass spectrometry. They exhibited a wide range of values from 10−21 to 10−10 m2/s at temperatures between 1000 and 1350 °C in the composites with 0 to 80 vol% zirconia. At a fixed temperature, oxygen diffusivities in high-zirconia composites were larger by at least eight orders of magnitude than those in low-zirconia composites. The percolation threshold occurred between 30 and 40 vol% zirconia, where oxygen diffusivities dramatically changed. There was a clear tendency of the activation energies of oxygen diffusion in composites to decrease with increasing zirconia contents. The large oxygen diffusivities in the high-zirconia composites were attributed to the interconnected channels of zirconia from the microstructural aspect.
Multiple dielectric anomalies in xBiLaO3–(1 − x)PbTiO3 piezoelectrics
Authors: Duan Runrun , Haluska Michael S. , Speyer Robert F.
Published: April 2008

Compositions of xBiLaO3–(1 − x) PbTiO3 over the range 0 ≤ x ≤ 0.225 were calcined and sintered. The dielectric constant with temperature and differential scanning calorimetry measurements were in excellent agreement with respect to Curie-like tetragonal to cubic transformations starting at 495 °C for pure PbTiO3, shifting to lower temperatures with increasing x. For compositions of x ≥ 0.05, a second higher-temperature (∼600 °C) endotherm, and matching dielectric anomaly, were consistently observed, for which there were no structural changes indicated by hot-stage x-ray diffraction. This transformation was speculated to be based on a thermally induced desegregation of B-site cations.