bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin B12 Supplement Exerts a Beneficial Effect on the Seminiferous Epithelium of Cimetidine-Treated Rats
Authors: Beltrame Flávia L. , Caneguim Breno H. , Miraglia Sandra M. , Cerri Paulo S. , Sasso-Cerri Estela
Published: October 2010

Treatment of gastric ulcer with cimetidine reduces acid secretion and interferes in the vitamin B12 absorption. Regarding the harmful effect of cimetidine on the seminiferous tubules, the aim of the present study was to verify if prolonged treatment with cimetidine causes vitamin B12 deficiency and whether the testicular damages are attenuated by vitamin B12 supplementation. Adult male rats received, for 50 days, cimetidine (CMTG), cimetidine and vitamin B12 (CMT/B12G), vitamin B12 (B12G) and saline solution (CG). Vitamin B12 and homocysteine plasma levels were evaluated and the testes were embedded in glycol methacrylate for the morphometric analyses of total, epithelial and luminal areas of the seminiferous tubules, number of Sertoli cells and frequencies of tubules according to stages and containing Sertoli and germ cells in the lumen. Terminal deoxynucleotidyl-transferase mediated dUTP nick end labeling (TUNEL) method and proliferating cell nuclear antigen (PCNA) immunohistochemistry were carried out. CMTG showed TUNEL-positive Sertoli cells and significant reductions in the epithelial and total tubular areas, number of Sertoli cells and frequency of tubules VII-VIII. In the CMT/B12G, the number of Sertoli cells and the epithelial and total tubular areas were similar to CG. The number of Sertoli cells (in B12G) and the frequency of tubules at stages VII-VIII (in B12G and CMT/B12G) increased significantly; PCNA-positive Sertoli cells were found in these groups. Although cimetidine was not able to induce vitamin B12 deficiency, this drug causes tubular atrophy due to Sertoli cell damage and loss of germ cells. However, vitamin B12 supplement is able to stimulate spermatogenesis and restore the number of Sertoli cells, softening the harmful effect of cimetidine on spermatogenesis.
The Morphology of the Rat Vibrissal Follicle-Sinus Complex Revealed by Three-Dimensional Computer-Aided Reconstruction
Authors: Kim Jeong-Nam , Koh Ki-Seok , Lee Eun , Park Soon-Cheol , Song Wu-Chul
Published: October 2010

The vibrissal follicle-sinus complex (FSC) is a sensory receptor of the mammalian integumentary system that is located around the mouth. The purpose of the present study was to identify the actual 3-dimensional structure of the rat vibrissal FSC. Rat skin tissue was serially sectioned at a thickness of 10 µm and then stained with Masson’s trichrome. The serial sections were reconstructed 3-dimensionally using Reconstruct software. The rat vibrissal follicle is a spindle-shaped structure that is embedded within a blood sinus and enveloped within a thick collagenous capsule. The vibrissal FSC is innervated by the deep vibrissal and superficial vibrissal nerves. The deep vibrissal nerve, travelling in the basal-to-apical direction, penetrates the thick collagenous capsule of the vibrissal FSC. The sinus system can be divided into a superior portion, known as the ring sinus, and an inferior portion, known as the cavernous sinus. The ring sinus contains a C-shaped structure, the ringwulst, which is suspended from the mesenchymal sheath of the follicle. Collagenous trabeculae can be seen in the cavernous sinus but not in the ring sinus. The ring sinus encircles the follicle obliquely and asymmetrically. The ringwulst encircles the follicle incompletely, in a C-shaped fashion. This study has demonstrated the previously underappreciated 3-dimensional structure of the vibrissal FSC, which differs from previously reported descriptions, and provides data that will enhance the understanding of vibrissal function.
Venous Thromboembolism and Port-Related Thrombosis in Metastatic Colorectal Cancer Patients: A Monocenter Experience
Authors: Nobili Elisabetta , Di Cicilia Roberto , Di Battista Monica , Morselli-Labate Antonio Maria , Paragona Marco , Corbelli Jody , Macchini Marina , Prandoni Paolo , Biasco Guido , Brandi Giovanni
Published: October 2010

Venous thromboembolism (VTE) may occur during the natural history of neoplastic disease and is a common cause of mortality and morbidity in cancer patients. Major risk factors for VTE in cancer patients include surgery, immobilization, hospitalization, and the administration of granulopoietic and/or erythropoietic (stimulatory) agents. Chemotherapy is a supplementary independent risk factor for VTE and the use of central venous catheters (CVC) in clinical practice has increased the risk of thromboembolic events. We conducted a retrospective study to evaluate CVC-related thrombosis and the VTE rate in 145 consecutive metastatic colorectal cancer patients. We observed only 2 cases of symptomatic CVC- related thrombotic events (1.38%) and 10 cases of thromboembolic events (6.9%) in our series. Only surgery for metastases was found to be significantly related to the development of VTE, with an incidence of 16.1% vs. 4.4 in patients who did not undergo surgery (p = 0.037). In addition, a history of VTE seems to be a supplementary risk factor for CVC-related thrombosis (p = 0.055).
Telephone Administration of the Mental Alternation Test: Sensitivity to Cognitive Decline and Practice Effects across Midlife and Late Life
Authors: McComb Erin , Brewster Paul , Chou Pak Hei Benedito , Crossley Margaret , Simard Martine , Tuokko Holly
Published: October 2010

Background: We evaluated the utility of the telephone-administered Mental Alternation Test (MAT, an oral variant of the Trail-Making Test) for remote assessment of cognitive functioning in older adults. We examined (1) the sensitivity of MAT scores to cognitive change across 4 age groups, (2) practice effects associated with repeat administration, and (3) the uniformity of practice effects across age groups. Methods: Community-dwelling volunteers were recruited randomly and categorized as young-middle-aged (45–54 years; n = 51), middle-aged (55–64 years; n = 58), young-old (65–74 years; n = 43) or old-old (75–85 years; n = 43). The participants completed the MAT twice within 2 weeks. The data were analyzed using mixed ANOVA. Results: We found an effect of age on MAT performance [F(3, 191) = 11.37; p < 0.001], with planned comparisons revealing significantly lower scores in the old-old (p < 0.05). The scores on the second MAT administration were significantly higher than on the first administration [F(1, 191) = 12.82; p < 0.001], but this practice effect did not differ across age groups. Conclusions: The MAT was sensitive to cognitive decline in older adulthood. Practice effects were measurable but uniform across the observed age cohorts. As a brief telephone-administered test, the MAT represents a promising measure of cognitive functioning in older adults that is feasible for use in large-scale epidemiological studies.
Purification of the Major Group 1 Allergen from Bahia Grass Pollen, Pas n 1
Authors: Drew Alexander C. , Davies Janet M. , Dang Thanh D. , Rolland Jennifer M. , O’Hehir Robyn E.
Published: October 2010

Background: Group 1 grass pollen allergens are glycoproteins of the β-expansin family. They are a predominant component of pollen and are potent allergens with a high frequency of serum IgE reactivity in grass pollen-allergic patients. Bahia grass is distinct from temperate grasses and has a prolonged pollination period and wide distribution in warmer climates. Here we describe the purification of the group 1 pollen allergen, Pas n 1, from Bahia grass (Paspalum notatum), an important subtropical aeroallergen source. Methods: Pas n 1 was purified from an aqueous Bahia grass pollen extract by ammonium sulphate precipitation, hydrophobic interaction and size exclusion chromatography, and assessed by one- and two-dimensional gel electrophoresis, immunoblotting and ELISA. Results: Pas n 1 was purified to a single 29-kDa protein band containing two dominant isoforms detected by an allergen-specific monoclonal antibody and serum IgE of a Bahia grass pollen-allergic donor. The frequency of serum IgE reactivity with purified Pas n 1 in 51 Bahia grass pollen-allergic patients was 90.6%. Serum IgE reactivity with purified Pas n 1 was highly correlated with serum IgE reactivity with Bahia grass pollen extract and recombinant Pas n 1 (r = 0.821 and 0.913, respectively). Conclusions: Pas n 1 is a major allergen reactive at high frequency with serum IgE of Bahia grass pollen-allergic patients. Purified natural Pas n 1 has utility for improved specific diagnosis and immunotherapy for Bahia grass pollen allergy.
Levels of Tumour Necrosis Factor-Alpha and Interleukin-6 in Severely Ill Patients with Eating Disorders
Authors: Ahrén-Moonga Jennie , Lekander Mats , von Blixen Nils , Rönnelid Johan , Holmgren Sven , af Klinteberg Britt
Published: October 2010

Background: The underlying pathophysiology of eating disorders (ED) is dependent on complex interactions between psychological, biological and social factors. The purpose of the present study was to examine a possible increase in cytokines indicating inflammation, as measured by tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in ED patients, and to explore possible relationships between cytokines and self-reported personality traits. Methods: Female patients with severe ED (n = 26) were recruited consecutively from an inpatient clinic and were compared to age-matched healthy females (n = 12). Commercial ELISA tests developed for the measurement of serum levels of TNF-α and IL-6 were employed. Personality traits were measured using Karolinska Scales of Personality. Results: The patient group displayed increased levels of the cytokine TNF-α and a tendency towards increased IL-6 levels. Spearman’s rank correlation coefficient was used to examine possible relationships between levels of cytokines and personality traits. The results showed that IL-6 levels were positively related to both somatic and psychic anxiety and to aggression scales, such as irritability and suspicion. Increased levels of TNF-α, in turn, were significantly correlated with high scores on the depression-related anxiety scale Inhibition of Aggression. However, increased levels of cytokines in the ED group did not seem to be mainly associated with symptoms of depression. Conclusion: We cannot rule out the possibility that comorbid conditions in the group contribute to the higher cytokine values. Further studies need to explore the possible influence of cytokines on the severity of ED and whether this might be mediated or moderated by specific personality traits.
Hair MDMA Samples Are Consistent with Reported Ecstasy Use: Findings from a Study Investigating Effects of Ecstasy on Mood and Memory
Authors: Scholey A.B. , Owen L. , Gates J. , Rodgers J. , Buchanan T. , Ling J. , Heffernan T. , Swan P. , Stough C. , Parrott A.C.
Published: October 2010

Aims: Our group has conducted several Internet investigations into the biobehavioural effects of self-reported recreational use of MDMA (3,4-methylenedioxymethamphetamine or Ecstasy) and other psychosocial drugs. Here we report a new study examining the relationship between self-reported Ecstasy use and traces of MDMA found in hair samples. Methods: In a laboratory setting, 49 undergraduate volunteers performed an Internet-based assessment which included mood scales and the University of East London Drug Use Questionnaire, which asks for history and current drug use. They also provided a hair sample for determination of exposure to MDMA over the previous month. Results: Self-report of Ecstasy use and presence in hair samples were consistent (p < 0.00001). Both subjective and objective measures predicted lower self-reported ratings of happiness and higher self-reported stress. Self-reported Ecstasy use, but not presence in hair, was also associated with decreased tension. Conclusion: Different psychoactive drugs can influence long-term mood and cognition in complex and dynamically interactive ways. Here we have shown a good correspondence between self-report and objective assessment of exposure to MDMA. These data suggest that the Internet has potentially high utility as a useful medium to complement traditional laboratory studies into the sequelae of recreational drug use.
Smaller Hippocampus Volume Is Associated with Short Variant of 5-HTTLPR Polymorphism in Medication-Free Major Depressive Disorder Patients
Authors: Eker M. Cagdas , Kitis Omer , Okur Hamza , Eker Ozlem Donat , Ozan Erol , Isikli Serhan , Akarsu Nurten , Gonul Ali Saffet
Published: October 2010

Aim: Serotonin is known for its importance in the pathophysiology of major depressive disorder. Although the hippocampus is one of the key regions in which neurogenesis occurs, and serotonin plays an important role in neurogenesis, results of studies that investigate effect of the 5-HTTLPR polymorphism on hippocampal volumes in major depressive disorder are inconclusive. Method: We looked for a relationship between the 5-HTTLPR polymorphism and hippocampal volumes in 44 depressed patients (mean age ± SD 33.6 ± 9.5 years) and 43 healthy controls (30.4 ± 6.7 years). Region of interest analysis was conducted on the images acquired via MRI. Results: Although hippocampal volumes were similar in healthy and patient groups, there was a significant interaction between genotype and diagnosis on hippocampus volumes. Post-hoc ANCOVA showed that hippocampal volumes of S/S homozygous depressed patients were smaller compared to healthy controls in both hemispheres. Conclusion: The 5-HTTLPR polymorphism has an effect on hippocampal volumes of depressed patients, which is apparent only in S/S genotype. It seems that decreased neurogenesis by effects of reduced serotoninergic transmission may be responsible for smaller hippocampal volumes observed in S/S homozygous depressed patients.
Magnitude of Perceived Change in Natural Images May Be Linearly Proportional to Differences in Neuronal Firing Rates
Authors: Chua Pei-Ying , Troscianko Tom , Lovell P. George , Tolhurst David , Chirimuuta Mazviita , To Michelle
Published: October 2010

We are studying how people perceive naturalistic suprathreshold changes in the colour, size, shape or location of items in images of natural scenes, using magnitude estimation ratings to characterise the sizes of the perceived changes in coloured photographs. We have implemented a computational model that tries to explain observers' ratings of these naturalistic differences between image pairs. We model the action-potential firing rates of millions of neurons, having linear and non-linear summation behaviour closely modelled on real V1 neurons. The numerical parameters of the model's sigmoidal transducer function are set by optimising the same model to experiments on contrast discrimination (contrast 'dippers') on monochrome photographs of natural scenes. The model, optimised on a stimulus-intensity domain in an experiment reminiscent of the Weber–Fechner relation, then produces tolerable predictions of the ratings for most kinds of naturalistic image change. Importantly, rating rises roughly linearly with the model's numerical output, which represents differences in neuronal firing rate in response to the two images under comparison; this implies that rating is proportional to the neuronal response.
Relationship Between Workplace Spatial Settings and Occupant-Perceived Support for Collaboration
Authors: Hua Ying , Loftness Vivian , Heerwagen Judith H. , Powell Kevin M.
Published: October 2010

The increasingly collaborative nature of knowledge-based work requires workplaces to support both dynamic interactions and concentrated work, both of which are critical for collaboration performance. Given the prevalence of open-plan settings, this requirement has created new challenges for workplace design. Therefore, an understanding of the relationship between the spatial characteristics of workplace settings and the support for collaboration that is perceived by office workers is valuable and timely. Based on a study of 308 office workers in 27 office spaces, this article examines the relationship between a series of workplace spatial characteristics and the support that is perceived by the occupants for collaborations. The spatial characteristics that were examined included individual workstation characteristics that were derived from the literature and a new set of floor-plan layout variables that highlighted shared spaces that are critical for a variety of formal and informal collaboration activities at work. The key characteristics of workplace spatial settings that were associated with the support that the occupants perceived for collaboration were the distance from workstation to meeting space, the distance from workstation to shared service area, the distance from workstation to kitchen/coffee area, and the percentage of floor space that was dedicated to shared services and amenities.
Motorcycle Conspicuity: Effects of Age and Daytime Running Lights
Authors: Al-Awar Smither Janan , Torrez Lorenzo I.
Published: October 2010

Objective:This study investigated variables that may contribute to motorcycle conspicuity within a high-fidelity simulated environment. The variables included motorcycle lighting, vehicular daytime running lights (DRLs), and age of the driver of the other vehicle.

Background: Research suggests that decreased levels of conspicuity associated with riding a small two-wheeled vehicle reduce the ability of other drivers to detect and respond to that vehicle effectively. This lack of conspicuity is often responsible for the frequent injuries and fatalities incurred by motorcycle riders.

Method: The 75 participants who took part in this study watched a series of video clips of roadway traffic and were asked to indicate when they saw a hazardous situation, such as the presence of pedestrians, motorcycles, or traffic cones. Both motorcycle and following-vehicle lights were manipulated, and participant reaction times were collected and analyzed.

Results: Analyses indicated main effects for all three variables as well as interaction effects between motorcycle lighting and vehicle-following conditions. Overall, findings showed a link between DRLs and the effective detection of motorcycles and suggested that age-related changes affect the ability to detect and respond to a motorcycle effectively.

Conclusion: Although our laboratory findings corroborated previous correlational studies, further research in real-world settings, such as those with high-density traffic or under adverse environmental conditions, needs to be conducted.

Application: Potential applications of this research include the assessment of appropriate lighting technology to enhance conspicuity of motorcycles and reduce the high rate of fatalities and injuries related to motorcycle crashes.
Use of a Standardized Progress Note and Assessment Form for Performance Evaluation and Quality Improvement
Authors: Dickerson Roland N. , Hamilton Leslie A. , Brown Rex O.
Published: October 2010

In addition to filling patient care‐related duties, the Nutrition Support Service also serves as a platform for experiential education and training of pharmacy residents, surgical interns, doctor of pharmacy students, and graduate dietetic students. Because of the diversity in experience and training among members of the team and their trainees, a standardized progress note form with a subsequent progress note assessment form was developed to maintain consistency and to ensure a certain level of quality in the daily progress notes written by the trainees. The instructor randomly chose one of the trainee's patient progress notes for verbal and written evaluation weekly. Twelve trainees from July 2009 to January 2010 were evaluated. A significant improvement in weekly performance scores (from an average score of 74% ± 12% to 91% ± 7% to 96% ± 6%) was noted by the second and third weeks compared with the first week, respectively (P < .001). Trainees were unanimous that this tool facilitated improvement of their clinical skills and ability to write effective daily progress notes.
Professional Outcomes of Completing a Clinical Nutrition Fellowship
Authors: Rivera Rene , Kirby Donald F. , Steiger Ezra , Seidner Douglas L.
Published: October 2010

Background: Cleveland Clinic has trained 17 physician nutrition specialists since the establishment of its clinical nutrition fellowship (CNF) in 1994. The paths taken by the graduates and whether they continue to practice clinical nutrition are largely unknown. Methods: To investigate the professional outcomes of completing a CNF, a survey of graduates was conducted. Results: Fifty‐seven percent of respondents (n = 8) applied to another fellowship prior to applying to a CNF. The 2 most common reasons for applying to a CNF were to increase knowledge of clinical nutrition and increase the chance of acquiring a gastroenterology fellowship. Eighty‐five percent (n = 10) of graduates found the CNF to be valuable. Eighty‐six percent (n = 12) went on to complete a gastroenterology fellowship, and 67% (n = 8) of graduates believed that completing a CNF increased their chances of gaining acceptance to a gastroenterology fellowship. Only 42% (n = 6) of the graduates currently hold professions that specifically dictate the use of clinical nutrition, but 61% (n = 8) reported using clinical nutrition in their daily or weekly practice. Fifty percent (n = 7) of graduates believed that completing a CNF made them more competitive job candidates, but only 21% (n = 3) said that their extra training is reflected in their current salary. Conclusions: It appears that CNFs are being used as a method of subsequently acquiring a gastroenterology or other medical fellowships. Although not working in defined clinical nutrition professions, >50% of graduates continue to apply their CNF skills after completing their training. A small percentage have found dedicated nutrition‐based clinical professions.
Carbohydrate‐ vs Fat‐Controlled Diet Effect on Weight Loss and Coronary Artery Disease Risk
Authors: Mueller Charles , Masri Basem , Hogg Jeannette , Mastrogiacomo Maddalena , Chiu Ya‐Lin
Published: October 2010

This pilot study compared weight loss and serum indicators of coronary artery disease (CAD) risk between 2 weight loss (energy‐deficit) diets, one controlled for carbohydrate as a percentage of total calories and the other controlled for fat as percentage of total calories. Participants were randomized to 1 of 2 diets and fed on an outpatient basis for 70 days, after which they followed their diets using their own resources for an additional 70 days. Energy deficit for the diets was determined by indirect calorimetry with a 500‐ to 750‐calorie per day adjustment. Weight and CAD risk indicators and serum lipid and C‐reactive protein levels were measured at baseline, day 70, and day 140. The study was completed by 16 of 20 participants who were able to comply with the feeding portion of the study as well as with follow‐up appointments during the second (self‐management) period of the study. Participants lost weight in both diet groups (24.4 lbs, carbohydrate controlled; 18.5 lbs, fat controlled), and serum CAD risk factors decreased in both groups. There were no significant differences in CAD risk factors between diet groups, although there was a trend toward lighter low‐density lipoprotein (LDL) size in the carbohydrate‐controlled group. During the self‐management portion of the study, weight loss stalled or regained from loss during the previous feeding period. The results, although underpowered, are consistent with recent studies in which macronutrient ratio of total calories in diet did not affect degree of weight loss and in which carbohydrate‐controlled diets produced a predominance of lighter LDLs.
Article Commentary: Guiding Stars: The Effect of a Nutrition Navigation Program on Consumer Purchases at the Supermarket
Authors: Mullin Gerard E.
Published: October 2010

Guiding Stars: The Effect of a Nutrition Navigation Program on Consumer Purchases at the Supermarket Sutherland LA Kaely LA Fischer L Am J Clin Nutr. 2020; 91:1090S‐1094S.
BP: how U.S. media fed the fire
Authors: Dunn Martin
Published: October 2010

Did America's politicians and journalists transform BP into "British Petroleum" following the Deepwater oil spill for reasons of political expediency or out of ignorance? Former British newspaper editor Martin Dunn, who has just resigned as editor-in-chief of the New York Daily News, discusses the controversy
Neutrality isn’t the same as being fair
Authors: Burns John F
Published: October 2010

We may aspire to impartiality when reporting, even while admitting the impossibility of achieving it, but is it always good enough? John F. Burns, chief foreign correspondent of the New York Times and its London bureau chief, explains why a neutrality that masquerades as impartiality can sometimes – especially in the theatre of war – be too easily translated into a lack of empathy for the people involved. "A bloodless neutrality," he writes, "can fall a long way short of being fair."
How reliable are journalists in exile?
Authors: Skjerdal Terje S
Published: October 2010

Beware journalists in exile, warns Terje S. Skjerdal, a lecturer in journalism in both Norway and Ethiopia. He argues that journalists in the West are too willing to believe accounts from fellow journalists who have fled from oppressive regimes. Uncritical coverage of their stories risk being counterproductive, he argues. Drawing on his knowledge of Ethiopian media fugitives, he points to the fact that many could not be trusted and some were not, strictly speaking, journalists at all. He writes: "Perhaps the problem arises when journalists leave their professional objectivity behind and become activists." His central message: do the basics by checking your sources.
In Search of the Silver Lining
Authors: Anderson Joanna E. , Kay Aaron C. , Fitzsimons Gráinne M.
Published: October 2010

Past research has demonstrated that people’s need to perceive the world as fair and just leads them to blame and derogate victims of tragedy. The research reported here shows that a positive reaction—bestowing additional meaning on the lives of individuals who have suffered—can also serve people’s need to believe that the world is just. In two studies, participants whose justice motive was temporarily heightened or who strongly endorsed the belief that reward and punishment are fairly distributed in the world perceived more meaning and enjoyment in the life of someone who had experienced a tragedy than in the life of someone who had not experienced tragedy, but this pattern was not found for participants whose justice motive was not heightened or who did not strongly endorse a justice belief. These results suggest that being motivated to see the world as just—a motivation traditionally associated with victim derogation—also leads people to perceive a “silver lining” to tragic events.
Tissue Deposition of the Insect Repellent DEET and the Sunscreen Oxybenzone From Repeated Topical Skin Applications in Rats
Authors: Fediuk Daryl J. , Wang Tao , Raizman Joshua E. , Parkinson Fiona E. , Gu Xiaochen
Published: October 2010

Insect repellent N,N-diethyl- m-toluamide (DEET) and sunscreen oxybenzone are capable of enhancing skin permeation of each other when applied simultaneously. We carried out a cellular study in rat astrocytes and neurons to assess cell toxicity of DEET and oxybenzone and a 30-day study in Sprague-Dawley rats to characterize skin permeation and tissue disposition of the compounds. Cellular toxicity occurred at 1 µg/mL for neurons and 7-day treatment for astrocytes and neurons. DEET and oxybenzone permeated across the skin to accumulate in blood, liver, and brain after repeated topical applications. DEET disappeared from the application site faster than oxybenzone. Combined application enhanced the disposition of DEET in liver. No overt sign of behavioral toxicity was observed from several behavioral testing protocols. It was concluded that despite measurable disposition of the study compounds in vivo, there was no evidence of neurotoxicological deficits from repeated topical applications of DEET, oxybenzone, or both.
Oral Repeat Dose and Reproductive Toxicity of the Chlorinated Flame Retardant Dechlorane Plus
Authors: Brock William J. , Schroeder Raymond E. , McKnight Christy A. , VanSteenhouse Jan L. , Nyberg Janice M.
Published: October 2010

This study consisted of a 28-day oral repeat dose (repeat dose toxicity [RDT]) phase and a developmental and reproductive (developmental and reproductive toxicity [DART]) phase with rats. Rats were treated with Dechlorane Plus at doses of 0, 750, 1500, or 5000 mg/kg by gavage. For the RDT phase, no effects were observed on in-life parameters or clinical or anatomic pathology. In the DART phase, no effects were observed on reproductive or fertility indices, or fetal development through lactation day (LD) 4. No effects were noted on gestation day (GD) 20 implantation data, fetal indices, or external and visceral examinations. Mortalities occurred across all dose groups, although these were gavage-related errors and not compound related. Microscopic evidence of gavage-related errors included adhesions, inflammation, and fibrosis in the thoracic and pleural cavities. These findings were not test article related as they were observed only in animals with evidence of gavage injury. The no-observable-effect level (NOEL) in both phases of study was 5000 mg/kg.
CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability
Authors: Lannutti Brian J. , Meadows Sarah A. , Herman Sarah E. M. , Kashishian Adam , Steiner Bart , Johnson Amy J. , Byrd John C. , Tyner Jeffrey W. , Loriaux Marc M. , Deininger Mike , Druker Brian J. , Puri Kamal D. , Ulrich Roger G. , Giese Neill A.
Published: October 2010

Phosphatidylinositol-3-kinase p110δ serves as a central integration point for signaling from cell surface receptors known to promote malignant B-cell proliferation and survival. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ as a treatment approach for patients with B-cell malignancies. We thus identified 5-fluoro-3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one (CAL-101), a highly selective and potent p110δ small molecule inhibitor (half-maximal effective concentration [EC50] = 8nM). Using tumor cell lines and primary patient samples representing multiple B-cell malignancies, we have demonstrated that constitutive phosphatidylinositol-3-kinase pathway activation is p110δ-dependent. CAL-101 blocked constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis. These effects have been observed across a broad range of immature and mature B-cell malignancies, thereby providing a rationale for the ongoing clinical evaluation of CAL-101.
Deciphering the human platelet sheddome
Authors: Fong Karen P. , Barry Colin , Tran Anh N. , Traxler Elizabeth A. , Wannemacher Kenneth M. , Tang Hsin-Yao , Speicher Kaye D. , Blair Ian A. , Speicher David W. , Grosser Tilo , Brass Lawrence F.
Published: October 2010

Activated platelets shed surface proteins, potentially modifying platelet function as well as providing a source of bioactive fragments. Previous studies have identified several constituents of the platelet sheddome, but the full extent of shedding is unknown. Here we have taken a global approach, analyzing protein fragments in the supernate of activated platelets using mass spectroscopy and looking for proteins originating from platelet membranes. After removing plasma proteins and microparticles, 1048 proteins were identified, including 69 membrane proteins. Nearly all of the membrane proteins had been detected previously, but only 10 had been shown to be shed in platelets. The remaining 59 are candidates subject to confirmation. Based on spectral counts, protein representation in the sheddome varies considerably. As proof of principle, we validated one of the less frequently detected proteins, semaphorin 7A, which had not previously been identified in platelets. Surface expression, cleavage, and shedding of semaphorin 7A were demonstrated, as was its association with α-granules. Finally, cleavage of semaphorin 7A and 12 other proteins was substantially reduced by an inhibitor of ADAM17, a known sheddase. These results define a subset of membrane proteins as sheddome candidates, forming the basis for further studies examining the impact of ectodomain shedding on platelet function.
Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome
Authors: Kfoury Youmna , Setterblad Niclas , El-Sabban Marwan , Zamborlini Alessia , Dassouki Zeina , El Hajj Hiba , Hermine Olivier , Pique Claudine , de Thé Hugues , Saïb Ali , Bazarbachi Ali
Published: October 2010

The human T-lymphotropic virus type I oncoprotein Tax is critical for T-cell transformation, acting mainly through nuclear factor kappa B essential modulator (NEMO) binding and subsequent nuclear factor-κB activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and small ubiquitin-like modifier (SUMO)ylation, which are both necessary for complete transcriptional activation. Using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome, depending on its posttranslational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. Finally, both ubiquitylation and SUMOylation of Tax control NEMO targeting to the centrosome. Altogether, we are proposing a model where both ubiquitylation and SUMOylation of Tax control the shuttling of Tax and NEMO between the cytoplasmic and nuclear compartments.
Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche
Authors: Zheng Junke , Huynh HoangDinh , Umikawa Masato , Silvany Robert , Zhang Cheng Cheng
Published: October 2010

The physiologic roles of angiopoietin-like proteins (Angptls) in the hematopoietic system remain unknown. Here we show that hematopoietic stem cells (HSCs) in Angptl3-null mice are decreased in number and quiescence. HSCs transplanted into Angptl3-null recipient mice exhibited impaired repopulation. Bone marrow sinusoidal endothelial cells express high levels of Angptl3 and are adjacent to HSCs. Importantly, bone marrow stromal cells or endothelium deficient in Angptl3 have a significantly decreased ability to support the expansion of repopulating HSCs. Angptl3 represses the expression of the transcription factor Ikaros, whose unregulated overexpression diminishes the repopulation activity of HSCs. Angptl3, as an extrinsic factor, thus supports the stemness of HSCs in the bone marrow niche.
An inventory of the Aspergillus niger secretome by combining in silico predictions with shotgun proteomics data
Authors: Braaksma Machtelt , Martens-Uzunova Elena S , Punt Peter J , Schaap Peter J
Published: October 2010

Background

The ecological niche occupied by a fungal species, its pathogenicity and its usefulness as a microbial cell factory to a large degree depends on its secretome. Protein secretion usually requires the presence of a N-terminal signal peptide (SP) and by scanning for this feature using available highly accurate SP-prediction tools, the fraction of potentially secreted proteins can be directly predicted. However, prediction of a SP does not guarantee that the protein is actually secreted and current in silico prediction methods suffer from gene-model errors introduced during genome annotation.

Results

A majority rule based classifier that also evaluates signal peptide predictions from the best homologs of three neighbouring Aspergillus species was developed to create an improved list of potential signal peptide containing proteins encoded by the Aspergillus niger genome. As a complement to these in silico predictions, the secretome associated with growth and upon carbon source depletion was determined using a shotgun proteomics approach. Overall, some 200 proteins with a predicted signal peptide were identified to be secreted proteins. Concordant changes in the secretome state were observed as a response to changes in growth/culture conditions. Additionally, two proteins secreted via a non-classical route operating in A. niger were identified.

Conclusions

We were able to improve the in silico inventory of A. niger secretory proteins by combining different gene-model predictions from neighbouring Aspergilli and thereby avoiding prediction conflicts associated with inaccurate gene-models. The expected accuracy of signal peptide prediction for proteins that lack homologous sequences in the proteomes of related species is 85%. An experimental validation of the predicted proteome confirmed in silico predictions.
Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC) mouse
Authors: Iancu Ovidiu D , Darakjian Priscila , Walter Nicole AR , Malmanger Barry , Oberbeck Denesa , Belknap John , McWeeney Shannon , Hitzemann Robert
Published: October 2010

Background

The current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS) formed from the same eight inbred strains that have been used to create the collaborative cross (CC). The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6) × DBA/2J (D2) F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum) gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA).

Results

Genes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes). Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented.

Conclusions

Despite the marked differences in genetic diversity, the transcriptome structure was remarkably similar for the F2, HS4 and HS-CC. These data suggest that it should be possible to integrate network data from simple and complex crosses. A careful examination of the HS-CC transcriptome revealed the expected structure for striatal gene expression. Importantly, we demonstrate the integration of anatomical and network expression data.
Is human blood a good surrogate for brain tissue in transcriptional studies?
Authors: Cai Chaochao , Langfelder Peter , Fuller Tova F , Oldham Michael C , Luo Rui , van den Berg Leonard H , Ophoff Roel A , Horvath Steve
Published: October 2010

Background

Since human brain tissue is often unavailable for transcriptional profiling studies, blood expression data is frequently used as a substitute. The underlying hypothesis in such studies is that genes expressed in brain tissue leave a transcriptional footprint in blood. We tested this hypothesis by relating three human brain expression data sets (from cortex, cerebellum and caudate nucleus) to two large human blood expression data sets (comprised of 1463 individuals).

Results

We found mean expression levels were weakly correlated between the brain and blood data (r range: [0.24,0.32]). Further, we tested whether co-expression relationships were preserved between the three brain regions and blood. Only a handful of brain co-expression modules showed strong evidence of preservation and these modules could be combined into a single large blood module. We also identified highly connected intramodular "hub" genes inside preserved modules. These preserved intramodular hub genes had the following properties: first, their expression levels tended to be significantly more heritable than those from non-preserved intramodular hub genes (p < 10-90); second, they had highly significant positive correlations with the following cluster of differentiation genes: CD58, CD47, CD48, CD53 and CD164; third, a significant number of them were known to be involved in infection mechanisms, post-transcriptional and post-translational modification and other basic processes.

Conclusions

Overall, we find transcriptome organization is poorly preserved between brain and blood. However, the subset of preserved co-expression relationships characterized here may aid future efforts to identify blood biomarkers for neurological and neuropsychiatric diseases when brain tissue samples are unavailable.
Cyclosporin A increases recovery after spinal cord injury but does not improve myelination by oligodendrocyte progenitor cell transplantation
Authors: Lü He-Zuo , Wang Yan-Xia , Zhou Jian-Sheng , Wang Feng-Chao , Hu Jian-Guo
Published: October 2010

Background

Transplantation of oligodendrocyte precursor cells (OPCs) is an attractive therapy for demyelinating diseases. Cyclosporin A (CsA) is one of the foremost immunosuppressive agents and has widespread use in tissue and cell transplantation. However, whether CsA affects survival and differentiation of engrafted OPCsin vivois unknown. In this study, the effect of CsA on morphological, functional and immunological aspects, as well as survival and differentiation of engrafted OPCs in injured spinal cord was explored.

Results

We transplanted green fluorescent protein (GFP) expressed OPCs (GFP-OPCs) into injured spinal cords of rats treated with or without CsA (10 mg/kg). Two weeks after cell transplantation, more GFP-positive cells were found in CsA-treated rats than that in vehicle-treated ones. However, the engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes in both groups. In the CsA-treated group, a significant decrease in spinal cord lesion volume along with increase in spared myelin and neurons were found compared to the control group. Such histological improvement correlated well with an increase in behavioral recovery. Further study suggested that CsA treatment could inhibit infiltration of T cells and activation of resident microglia and/or macrophages derived from infiltrating monocytes in injured spinal cords, which contributes to the survival of engrafted OPCs and repair of spinal cord injury (SCI).

Conclusions

These results collectively indicate that CsA can promote the survival of engrafted OPCs in injured spinal cords, but has no effect on their differentiation. The engrafted cells mostly differentiated into astrocytes, but not oligodendrocytes. The beneficial effect of CsA on SCI and the survival of engrafted cells may be attributed to its neuroprotective effect.
Molecular and phylogenetic characterization of the sieve element occlusion gene family in Fabaceae and non-Fabaceaeplants
Authors: Rüping Boris , Ernst Antonia M , Jekat Stephan B , Nordzieke Steffen , Reineke Anna R , Müller Boje , Bornberg-Bauer Erich , Prüfer Dirk , Noll Gundula A
Published: October 2010

Background

The phloem of dicotyledonous plants contains specialized P-proteins (phloem proteins) that accumulate during sieve element differentiation and remain parietally associated with the cisternae of the endoplasmic reticulum in mature sieve elements. Wounding causes P-protein filaments to accumulate at the sieve plates and block the translocation of photosynthate. Specialized, spindle-shaped P-proteins known as forisomes that undergo reversible calcium-dependent conformational changes have evolved exclusively in the Fabaceae. Recently, the molecular characterization of three genes encoding forisome components in the model legume Medicago truncatula (MtSEO1, MtSEO2 and MtSEO3; SEO = sieve element occlusion) was reported, but little is known about the molecular characteristics of P-proteins in non-Fabaceae.

Results

We performed a comprehensive genome-wide comparative analysis by screening the M. truncatula, Glycine max, Arabidopsis thaliana, Vitis vinifera and Solanum phureja genomes, and a Malus domestica EST library for homologs of MtSEO1, MtSEO2 and MtSEO3 and identified numerous novel SEO genes in Fabaceae and even non-Fabaceae plants, which do not possess forisomes. Even in Fabaceae some SEO genes appear to not encode forisome components. All SEO genes have a similar exon-intron structure and are expressed predominantly in the phloem. Phylogenetic analysis revealed the presence of several subgroups with Fabaceae-specific subgroups containing all of the known as well as newly identified forisome component proteins. We constructed Hidden Markov Models that identified three conserved protein domains, which characterize SEO proteins when present in combination. In addition, one common and three subgroup specific protein motifs were found in the amino acid sequences of SEO proteins. SEO genes are organized in genomic clusters and the conserved synteny allowed us to identify several M. truncatula vs G. max orthologs as well as paralogs within the G. max genome.

Conclusions

The unexpected occurrence of forisome-like genes in non-Fabaceae plants may indicate that these proteins encode species-specific P-proteins, which is backed up by the phloem-specific expression profiles. The conservation of gene structure, the presence of specific motifs and domains and the genomic synteny argue for a common phylogenetic origin of forisomes and other P-proteins.