bluuebunny/crossref_metadata_2025 huggingface dataset:
Krüppel-like Factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension
Authors: Courboulin Audrey , Tremblay Véronique L , Barrier Marjorie , Meloche Jolyane , Jacob Maria Helena , Chapolard Mathilde , Bisserier Malik , Paulin Roxane , Lambert Caroline , Provencher Steeve , Bonnet Sébastien
Published: September 2011

Background

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation of pulmonary artery smooth muscle cell (PASMC) and suppressed apoptosis. This phenotype has been associated with the upregulation of the oncoprotein survivin promoting mitochondrial membrane potential hyperpolarization (decreasing apoptosis) and the upregulation of growth factor and cytokines like PDGF, IL-6 and vasoactive agent like endothelin-1 (ET-1) promoting PASMC proliferation. Krüppel-like factor 5 (KLF5), is a zinc-finger-type transcription factor implicated in the regulation of cell differentiation, proliferation, migration and apoptosis. Recent studies have demonstrated the implication of KLF5 in tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Nonetheless, the implication of KLF5 in pulmonary arterial hypertension (PAH) remains unknown. We hypothesized that KLF5 up-regulation in PAH triggers PASMC proliferation and resistance to apoptosis.

Methods and results

We showed that KFL5 is upregulated in both human lung biopsies and cultured human PASMC isolated from distal pulmonary arteries from PAH patients compared to controls. Using stimulation experiments, we demonstrated that PDGF, ET-1 and IL-6 trigger KLF-5 activation in control PASMC to a level similar to the one seen in PAH-PASMC. Inhibition of the STAT3 pathway abrogates KLF5 activation in PAH-PASMC. Once activated, KLF5 promotes cyclin B1 upregulation and promotes PASMC proliferation and triggers survivin expression hyperpolarizing mitochondria membrane potential decreasing PASMC ability to undergo apoptosis.

Conclusion

We demonstrated for the first time that KLF5 is activated in human PAH and implicated in the pro-proliferative and anti-apoptotic phenotype that characterize PAH-PASMC. We believe that our findings will open new avenues of investigation on the role of KLF5 in PAH and might lead to the identification of new therapeutic targets.
Schmidtea mediterraneaphylogeography: an old species surviving on a few Mediterranean islands?
Authors: Lázaro Eva M , Harrath Abdul Halim , Stocchino Giacinta A , Pala Maria , Baguñà Jaume , Riutort Marta
Published: September 2011

Background

Schmidtea mediterranea (Platyhelminthes, Tricladida, Continenticola) is found in scattered localities on a few islands and in coastal areas of the western Mediterranean. Although S. mediterranea is the object of many regeneration studies, little is known about its evolutionary history. Its present distribution has been proposed to stem from the fragmentation and migration of the Corsica-Sardinia microplate during the formation of the western Mediterranean basin, which implies an ancient origin for the species. To test this hypothesis, we obtained a large number of samples from across its distribution area. Using known and new molecular markers and, for the first time in planarians, a molecular clock, we analysed the genetic variability and demographic parameters within the species and between its sexual and asexual populations to estimate when they diverged.

Results

A total of 2 kb from three markers (COI, CYB and a nuclear intron N13) was amplified from ~200 specimens. Molecular data clustered the studied populations into three groups that correspond to the west, central and southeastern geographical locations of the current distribution of S. mediterranea. Mitochondrial genes show low haplotype and nucleotide diversity within populations but demonstrate higher values when all individuals are considered. The nuclear marker shows higher values of genetic diversity than the mitochondrial genes at the population level, but asexual populations present lower variability than the sexual ones. Neutrality tests are significant for some populations. Phylogenetic and dating analyses show the three groups to be monophyletic, with the west group being the basal group. The time when the diversification of the species occurred is between ~20 and ~4 mya, although the asexual nature of the western populations could have affected the dating analyses.

Conclusions

S. mediterranea is an old species that is sparsely distributed in a harsh habitat, which is probably the consequence of the migration of the Corsica-Sardinia block. This species probably adapted to temperate climates in the middle of a changing Mediterranean climate that eventually became dry and hot. These data also suggest that in the mainland localities of Europe and Africa, sexual individuals of S. mediterranea are being replaced by asexual individuals that are either conspecific or are from other species that are better adapted to the Mediterranean climate.
New Dystrophin/Dystroglycan interactors control neuron behavior in Drosophila eye
Authors: Marrone April K , Kucherenko Mariya M , Rishko Valentyna M , Shcherbata Halyna R
Published: September 2011

Background

The Dystrophin Glycoprotein Complex (DGC) is a large multi-component complex that is well known for its function in muscle tissue. When the main components of the DGC, Dystrophin (Dys) and Dystroglycan (Dg) are affected cognitive impairment and mental retardation in addition to muscle degeneration can occur. Previously we performed an array of genetic screens using a Drosophila model for muscular dystrophy in order to find novel DGC interactors aiming to elucidate the signaling role(s) in which the complex is involved. Since the function of the DGC in the brain and nervous system has not been fully defined, we have here continued to analyze the DGC modifiers' function in the developing Drosophila brain and eye.

Results

Given that disruption of Dys and Dg leads to improper photoreceptor axon projections into the lamina and eye neuron elongation defects during development, we have determined the function of previously screened components and their genetic interaction with the DGC in this tissue. Our study first found that mutations in chif, CG34400, Nrk, Lis1, capt and Cam cause improper axon path-finding and loss of SP2353, Grh, Nrk, capt, CG34400, vimar, Lis1 and Cam cause shortened rhabdomere lengths. We determined that Nrk, mbl, capt and Cam genetically interact with Dys and/or Dg in these processes. It is notable that most of the neuronal DGC interacting components encountered are involved in regulation of actin dynamics.

Conclusions

Our data indicate possible DGC involvement in the process of cytoskeletal remodeling in neurons. The identification of new components that interact with the DGC not only helps to dissect the mechanism of axon guidance and eye neuron differentiation but also provides a great opportunity for understanding the signaling mechanisms by which the cell surface receptor Dg communicates via Dys with the actin cytoskeleton.
Nuclease-resistant immunostimulatory phosphodiester CpG oligodeoxynucleotides as human Toll-like receptor 9 agonists
Authors: Meng Wenjun , Yamazaki Tomohiko , Nishida Yuuki , Hanagata Nobutaka
Published: September 2011

Background

Unmethylated cytosine-guanine (CpG) motif-containing oligodeoxynucleotides (ODNs) have been well characterized as agonists of Toll-like receptor 9 (TLR9). ODNs with a phosphorothioate (PTO) backbone have been studied as TLR9 agonists since natural ODNs with a phosphodiester (PD) backbone are easily degraded by a serum nuclease, which makes them problematic for therapeutic applications. However, ODNs with a PTO backbone have been shown to have undesirable side effects. Thus, our goal was to develop nuclease-resistant, PD ODNs that are effective as human TLR9 (hTLR9) agonists.

Results

The sequence of ODN2006, a CpG ODN that acts as an hTLR9 agonist, was used as the basic CpG ODN material. The 3'-end modification of ODN2006 with a PD backbone (PD-ODN2006) improved its potential as an hTLR9 agonist because of increased resistance to nucleolytic degradation. Moreover, 3'-end modification with oligonucleotides showed higher induction than modification with biotin, FITC, and amino groups. Further, enhancement of hTLR9 activity was found to be dependent on the number of CpG core motifs (GTCGTT) in the PD ODN containing the 3'-end oligonucleotides. In particular, ODN sequences consisting of two to three linked ODN2006 sequences with a PD backbone (e.g., PD-ODN2006-2006 and PD-ODN2006-2006-2006) acted as effective agonists of hTLR9 even at lower concentrations.

Conclusions

This study showed that PD-ODN2006-2006 and PD-ODN-2006-2006-2006 can be used as potentially safe agonists for hTLR9 activation instead of CpG ODNs with a PTO backbone. We propose these CpG ODNs consisting of only a PD backbone as a novel class of CpG ODN.
Antiproliferative effect of methanolic extraction of tualang honey on human keloid fibroblasts
Authors: Nurul Syazana Mohamad Shah , Halim Ahmad Sukari , Gan Siew Hua , Shamsuddin Shaharum
Published: September 2011

Background

Keloid is a type of scar which extends beyond the boundaries of the original wound. It can spread to the surrounding skin by invasion. The use of Tualang honey is a possible approach for keloid treatment. The objective of this study was to determine the antiproliferative effect of methanolic extraction of Tualang honey to primary human keloid fibroblasts and to identify the volatile compounds in methanol extraction of Tualang honey.

Methods

Crude Tualang honey was extracted with methanol and then dried using rota vapor to remove remaining methanol from honey. Normal and keloid fibroblasts were verified and treated with the extracted honey. Cell proliferation was tested with [3-(4,5-dimethylthiazol-2-yi)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay. Extraction of Tualang honey using methanol was carried out and the extracted samples were analysed using gas chromatography-mass spectrometry (GC-MS). The result was analysed using SPSS and tested with Kruskal-Wallis and Mann-Whitney tests.

Results

Methanolic extraction of honey has positive anti proliferative effect on keloid fibroblasts in a dose-dependent manner. The presence of fatty acids such as palmitic acid, stearic acid, oleic acid, linoleic acid and octadecanoic acid may contribute to the anti-proliferative effect in keloid fibroblasts.

Conclusions

The methanolic honey extraction has an antiproliferative effect on keloid fibroblasts and a range of volatile compounds has been identified from Tualang honey. The antiproliferative effect of keloid fibroblasts towards Tualang honey may involve cell signaling pathway. Identifying other volatile compounds from different organic solvents should be carried out in future.
Analysing the operative experience of basic surgical trainees in Ireland using a web-based logbook
Authors: Lonergan Peter E , Mulsow Jurgen , Tanner W Arthur , Traynor Oscar , Tierney Sean
Published: September 2011

Background

There is concern about the adequacy of operative exposure in surgical training programmes, in the context of changing work practices. We aimed to quantify the operative exposure of all trainees on the National Basic Surgical Training (BST) programme in Ireland and compare the results with arbitrary training targets.

Methods

Retrospective analysis of data obtained from a web-based logbook (http://www.elogbook.org) for all general surgery and orthopaedic training posts between July 2007 and June 2009.

Results

104 trainees recorded 23,918 operations between two 6-month general surgery posts. The most common general surgery operation performed was simple skin excision with trainees performing an average of 19.7 (± 9.9) over the 2-year training programme. Trainees most frequently assisted with cholecystectomy with an average of 16.0 (± 11.0) per trainee. Comparison of trainee operative experience to arbitrary training targets found that 2-38% of trainees achieved the targets for 9 emergency index operations and 24-90% of trainees achieved the targets for 8 index elective operations. 72 trainees also completed a 6-month post in orthopaedics and recorded 7,551 operations. The most common orthopaedic operation that trainees performed was removal of metal, with an average of 2.90 (± 3.27) per trainee. The most common orthopaedic operation that trainees assisted with was total hip replacement, with an average of 10.46 (± 6.21) per trainee.

Conclusions

A centralised web-based logbook provides valuable data to analyse training programme performance. Analysis of logbooks raises concerns about operative experience at junior trainee level. The provision of adequate operative exposure for trainees should be a key performance indicator for training programmes.
Complications after radical gastrectomy following FOLFOX7 neoadjuvant chemotherapy for gastric cancer
Authors: Li Zi-Yu , Shan Fei , Zhang Lian-Hai , Bu Zhao-De , Wu Ai-Wen , Wu Xiao-Jiang , Zong Xiang-Long , Wu Qi , Ren Hui , Ji Jia-Fu
Published: September 2011

Background

This study assessed the postoperative morbidity and mortality occurring in the first 30 days after radical gastrectomy by comparing gastric cancer patients who did or did not receive the FOLFOX7 regimen of neoadjuvant chemotherapy.

Methods

We completed a retrospective analysis of 377 patients after their radical gastrectomies were performed in our department between 2005 and 2009. Two groups of patients were studied: the SURG group received surgical treatment immediately after diagnosis; the NACT underwent surgery after 2-6 cycles of neoadjuvant chemotherapy.

Results

There were 267 patients in the SURG group and 110 patients in the NACT group. The NACT group had more proximal tumours (P = 0.000), more total/proximal gastrectomies (P = 0.000) and longer operative time (P = 0.005) than the SURG group. Morbidity was 10.0% in the NACT patients and 17.2% in the SURG patients (P = 0.075). There were two cases of postoperative death, both in the SURG group (P = 1.000). No changes in complications or mortality rate were observed between the SURG and NACT groups.

Conclusion

The FOLFOX7 neoadjuvant chemotherapy is not associated with increased postoperative morbidity, indicating that the FOLFOX7 neoadjuvant chemotherapy is a safe choice for the treatment of local advanced gastric cancer.
Increased APOBEC3G and APOBEC3F expression is associated with low viral load and prolonged survival in simian immunodeficiency virus infected rhesus monkeys
Authors: Mußil Bianka , Sauermann Ulrike , Motzkus Dirk , Stahl-Hennig Christiane , Sopper Sieghart
Published: September 2011

Background

The cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) are innate cellular factors that inhibit replication of a number of viruses, including HIV-1. Since antiviral activity of APOBEC3 has been mainly confirmed by in vitro data, we examined their role for disease progression in the SIV/macaque model for AIDS.

Results

We quantified A3G and A3F mRNA in PBMC and leukocyte subsets of uninfected and SIVmac-infected rhesus macaques. Compared with uninfected animals, we found increased A3G and A3F mRNA levels in PBMC, purified CD4+ T-cells and CD14+ monocytes as well as lymph node cells from asymptomatic SIV-infected macaques. APOBEC3 mRNA levels correlated negatively with plasma viral load, and highest amounts of APOBEC3 mRNA were detected in long term non-progressors (LTNPs). During acute viremia, A3G mRNA increased in parallel with MxA, a prototype interferon-stimulated gene indicating a common regulation by the initial interferon response. This association disappeared during the asymptomatic stage.

Conclusion

Our findings suggest a protective effect of APOBEC3 for HIV and SIV in vivo and indicate regulation of APOBEC3 by interferon during early infection and by contribution of other, hitherto undefined factors at later disease stages. Elucidating the regulatory mechanisms leading to increased APOBEC3 mRNA levels in LTNPs could help to develop new therapies against HIV.
Expression and characterization of UL16 gene from duck enteritis virus
Authors: He Qin , Yang Qiao , Cheng Anchun , Wang Mingshu , Xiang Jun , Zhu Dekang , Jia Renyong , Luo Qihui , Chen Zhengli , Zhou Yi , Chen Xiaoyue
Published: September 2011

Background

Previous studies have indicated that the UL16 protein and its homologs from herpesvirus were conserved and played similar roles in viral DNA packaging, virion assembly, budding, and egress. However, there was no report on the UL16 gene product of duck enteritis virus (DEV). In this study, we analyzed the amino acid sequence of UL16 using bioinformatics tools and expressed in Escherichia coli Rosetta (DE3) induced by isopropy1-β-D-thiogalactopyranoside (IPTG). The recombinant protein was produced, purified using a Ni-NTA column and used to generate the polyclonal antibody against UL16. The intracellular distribution of the DEV UL16 product was carried out using indirect immunofluorescence assay.

Results

In our study, UL16 gene of DEV was composed of 1089 nucleotides, which encoded 362 amino acids. Multiple sequence alignment suggested that the UL16 gene was highly conserved in herpesvirus family. The UL16 gene was cloned into a pET prokaryotic expression vector and transformed into Escherichia coli Rossetta (DE3) induced by IPTG. A 60kDa fusion protein band corresponding to the predicted size was produced on the SDS-PAGE, purified using a Ni-NTA column. Anti-UL16 polyclonal sera was prepared by immunizing rabbits, and reacted with a band in the IPTG induced cell lysates with an apparent molecular mass of 60 kDa. In vivo expression of the UL16 protein in DEV infected duck embryo fibroblast cells (DEFs) was localized mostly around perinuclear cytoplasmic area and in cytosol using indirect immunofluorescence assay.

Conclusions

The UL16 gene of DEV was successfully cloned, expressed and detected in DEV infected DEFs for the first time. The UL16 protein localized mostly around perinuclear cytoplasmic area and in cytosol in DEV infected DEFs. DEV UL16 shared high similarity with UL16 family members, indicating that DEV UL16 many has similar function with its homologs. All these results may provide some insight for further research about full characterizations and functions of the DEV UL16.
Toll-Like Receptor 2 Contributes to Chemokine Gene Expression and Macrophage Infiltration in the Dorsal Root Ganglia after Peripheral Nerve Injury
Authors: Kim Donghoon , You Byunghyun , Lim Hyoungsub , Lee Sung Joong
Published: September 2011

Background:

We have previously reported that nerve injury-induced neuropathic pain is attenuated in toll-like receptor 2 (TLR2) knock-out mice. In these mice, inflammatory gene expression and spinal cord microglia actvation is compromised, whereas the effects in e dorsal root ganglia (DRG) have not been tested. In this study, we investigated the role of TLR2 in inflammatory responses in the DRG after peripheral nerve injury.

Results:

L5 spinal nerve transection injury induced the expression of macrophage-attracting chemokines such as CCL2/MCP-1 and CCL3/MIP-1 and subsequent macrophage infiltration in the DRG of wild-type mice. In TLR2 knockout mice, however, the induction of chemokine expression and macrophage infiltration following nerve injury were markedly reduced. Similarly, the induction of IL-1β and TNF-α expression in the DRG by spinal nerve injury was ameliorated in TLR2 knock-out mice. The reduced inflammatory response in the DRG was accompanied by attenuation of nerve injury-induced spontaneous pain hypersensitivity in TLR2 knock-out mice.

Conclusions:

Our data show that TLR2 contributes to nerve injury-induced proinflammatory chemokine/cytokine gene expression and macrophage infiltration in the DRG, which may have relevance in the reduced pain hypersensitivity in TLR2 knock-out mice after spinal nerve injury.
Epistemic fault lines in biomedical and social approaches to HIV prevention
Authors: Adam Barry D
Published: September 2011

This paper raises the question of how knowledge creation is organized in the area of HIV prevention and how this concatenation of expertise, resources, at‐risk people and viruses shapes the knowledge used to impede the epidemic. It also seeks to trouble the discourses of biomedical pre‐eminence in the field of HIV prevention by examining the claim for treatment as prevention, looking at evidence constructed through the biomedical frame and through the lens of the sociology of science. These questions lie within a larger socio‐historical context of lagging worldwide attention and funding to prevention in the HIV area and, in particular, neglect of populations at greatest risk. Much contemporary HIV prevention research relies on a population science divided over an epistemic fault line from the communities and individuals who must make sense of the intrusion of a life‐threatening disease into their pursuit of pleasure and intimacy. There are, nevertheless, lessons to be learned from prevention success stories among sex workers, injection drug users, and gay and bisexual men. The success stories point to a need for a robust social science agenda that examines: the ways that people are socially organized and networked; the popular strategies and folk wisdoms developed in the face of HIV risk; socio‐historical movement of sexual and drug cultures; the dynamics of popular mobilization to advance health; the institutional sources of HIV discourses; and popular understandings of HIV technologies and messages.
Conceptual and methodological challenges to measuring political commitment to respond to HIV
Authors: Fox Ashley M , Goldberg Allison B , Gore Radhika J , Bärnighausen Till
Published: September 2011

Background

Researchers have long recognized the importance of a central government’s political “commitment” in order to mount an effective response to HIV. The concept of political commitment remains ill‐defined, however, and little guidance has been given on how to measure this construct and its relationship with HIV‐related outcomes. Several countries have experienced declines in HIV infection rates, but conceptual difficulties arise in linking these declines to political commitment as opposed to underlying social and behavioural factors.

Methods

This paper first presents a critical review of the literature on existing efforts to conceptualize and measure political commitment to respond to HIV and the linkages between political commitment and HIV‐related outcomes. Based on the elements identified in this review, the paper then develops and presents a framework to assist researchers in making choices about how to assess a government's level of political commitment to respond to HIV and how to link political commitment to HIV‐related outcomes.

Results

The review of existing studies identifies three components of commitment (expressed, institutional and budgetary commitment) as different dimensions along which commitment can be measured. The review also identifies normative and ideological aspects of commitment and a set of variables that mediate and moderate political commitment that need to be accounted for in order to draw valid inferences about the relationship between political commitment and HIV‐related outcomes. The framework summarizes a set of steps that researchers can follow in order to assess a government's level of commitment to respond to HIV and suggests ways to apply the framework to country cases.

Conclusions

Whereas existing studies have adopted a limited and often ambiguous conception of political commitment, we argue that conceiving of political commitment along a greater number of dimensions will allow researchers to draw a more complete picture of political commitment to respond to HIV that avoids making invalid inferences about the relationship between political commitment and HIV outcomes.
α-Tocopherol induces hematopoietic stem/progenitor cell expansion and ERK1/2-mediated differentiation
Authors: Nogueira-Pedro Amanda , Barbosa Christiano M V , Segreto Helena Regina Comodo , Lungato Lisandro , D'Almeida Vania , Moraes Andrea Aparecida F S , Miranda Antonio , Paredes-Gamero Edgar Julian , Ferreira Alice Teixeira
Published: September 2011

Tocopherols promote or inhibit growth in different cell types. In the hematopoietic system, the radioprotective property of tocopherols is thought to act through the expansion of primitive hematopoietic cells. However, the mechanisms activated by tocopherols and which HPs are affected remain poorly understood. To better address these questions, mice were treated with α-tocopherol, and its effects were investigated in the BM microenvironment. α-Tocopherol induced increased proliferation in HSC/HP cells, leading to BM hyperplasia. In addition, differentiation to the granulocytic/monocytic lineage was enhanced by α-tocopherol treatment. α-Tocopherol treatment resulted in decreased basal phosphorylation of ERK1/2, PKC, and STAT-5 in HSC/HP cells. In contrast, α-tocopherol enhanced ERK1/2 activation in response to IL-3 stimulation in HSC/HP cells without altering the expression of IL-3Rs. Moreover, α-tocopherol-induced differentiation and ERK1/2 activation were abolished in mice pretreated with a MEK inhibitor (PD98059); however, pretreatment with PD98059 did not reduce the α-tocopherol-mediated increase in HSC/HP cells but instead, further enhanced their proliferation. Therefore, α-tocopherol induces expansion of HSC/HP cells by a nonidentified intracellular pathway and granulocytic/monocytic differentiation through ERK1/2 activation.
Inhibition of the Protein Tyrosine Phosphatase SHP-1 Increases Glucose Uptake in Skeletal Muscle Cells by Augmenting Insulin Receptor Signaling and GLUT4 Expression
Authors: Bergeron Sébastien , Dubois Marie-Julie , Bellmann Kerstin , Schwab Michael , Larochelle Nancy , Nalbantoglu Joséphine , Marette André
Published: September 2011

The protein tyrosine phosphatase (PTPase) Src-homology 2-domain-containing phosphatase (SHP)-1 was recently reported to be a novel regulator of insulin's metabolic action. In order to examine the role of this PTPase in skeletal muscle, we used adenovirus (AdV)-mediated gene transfer to express an interfering mutant of SHP-1 [dominant negative (DN)SHP-1; mutation C453S] in L6 myocytes. Expression of DNSHP-1 increased insulin-induced Akt serine-threonine kinase phosphorylation and augmented glucose uptake and glycogen synthesis. Pharmacological inhibition of glucose transporter type 4 (GLUT4) activity using indinavir and GLUT4 translocation assays revealed an important role for this transporter in the increased insulin-induced glucose uptake in DNSHP-1-expressing myocytes. Both GLUT4 mRNA and protein expression were also found to be increased by DNSHP-1 expression. Furthermore, AdV-mediated delivery of DNSHP-1 in skeletal muscle of transgenic mice overexpressing Coxsackie and AdV receptor also enhanced GLUT4 protein expression. Together, these findings confirm that SHP-1 regulates muscle insulin action in a cell-autonomous manner and further suggest that the PTPase negatively modulates insulin action through down-regulation of both insulin signaling to Akt and GLUT4 translocation, as well as GLUT4 expression.
In pursuit of Irving and Scholander: a review of oxygen store management in seals and penguins
Authors: Ponganis Paul J. , Meir Jessica U. , Williams Cassondra L.
Published: September 2011

Since the introduction of the aerobic dive limit (ADL) 30 years ago, the concept that most dives of marine mammals and sea birds are aerobic in nature has dominated the interpretation of their diving behavior and foraging ecology. Although there have been many measurements of body oxygen stores, there have been few investigations of the actual depletion of those stores during dives. Yet, it is the pattern, rate and magnitude of depletion of O2 stores that underlie the ADL. Therefore, in order to assess strategies of O2 store management, we review (a) the magnitude of O2 stores, (b) past studies of O2 store depletion and (c) our recent investigations of O2 store utilization during sleep apnea and dives of elephant seals (Mirounga angustirostris) and during dives of emperor penguins (Aptenodytes forsteri). We conclude with the implications of these findings for (a) the physiological responses underlying O2 store utilization, (b) the physiological basis of the ADL and (c) the value of extreme hypoxemic tolerance and the significance of the avoidance of re-perfusion injury in these animals.
Principles underlying chromatophore addition during maturation in the European cuttlefish, Sepia officinalis
Authors: Yacob Jarred , Lewis Alexandra Cosima , Gosling Allyson , Hilaire Debra H. J. St , Tesar Lindsay , McRae Michelle , Tublitz Nathan J.
Published: September 2011

The goal of this work was to identify some of the principles underlying chromatophore growth and development in the European cuttlefish, Sepia officinalis. One set of experiments used a regeneration model to follow the re-growth of black chromatophores for 30 days following excision of a small piece of fin tissue. A separate set of experiments tracked and analyzed the addition of new fin chromatophores during a month of normal, undisturbed growth. We also followed the development of individual chromatophores from their initial appearance to full maturation to determine whether their color type was fixed. Based on the results of these studies, we propose five guiding principles for chromatophore growth and maturation. (1) The three chromatophore cell types – black, reddish-brown and yellow – are present at different spatial frequencies in the cuttlefish fin. (2) During normal growth, new chromatophores are inserted at a higher spatial frequency than existing (control) chromatophores of the same color type. (3) In regenerating tissue, new black chromatophores are initially added at low spatial frequencies. As regeneration continues, new black chromatophores appear at increasing spatial frequencies until they are inserted at a spatial frequency higher than that observed in control tissue, similar to the way in which chromatophores were observed to be added in normally growing tissue. (4) All chromatophores first appear as pale orange cells and slowly darken into their respective color types without passing through intermediate color stages. (5) New black chromatophores undergo a doubling in size as they mature, while reddish-brown and yellow chromatophores do not grow at all after they are inserted in the dermis.
Pleated turtle escapes the box – shape changes in Dermochelys coriacea
Authors: Davenport John , Plot Virginie , Georges Jean-Yves , Doyle Thomas K. , James Michael C.
Published: September 2011

Typical chelonians have a rigid carapace and plastron that form a box-like structure that constrains several aspects of their physiology and ecology. The leatherback sea turtle, Dermochelys coriacea, has a flexible bony carapace strengthened by seven longitudinal ridges, whereas the plastron is reduced to an elliptical outer bony structure, so that the ventrum has no bony support. Measurements of the shell were made on adult female leatherbacks studied on the feeding grounds of waters off Nova Scotia (NS) and on breeding beaches of French Guiana (FG) to examine whether foraging and/or breeding turtles alter carapace size and/or shape. NS turtles exhibited greater mass and girth for a given curved carapace length (CCL) than FG turtles. Girth:CCL ratios rose during the feeding season, indicating increased girth. Measurements were made of the direct (straight) and surface (curved) distances between the medial longitudinal ridge and first right-hand longitudinal ridge (at 50% CCL). In NS turtles, the ratio of straight to curved inter-ridge distances was significantly higher than in FG turtles, indicating distension of the upper surfaces of the NS turtles between the ridges. FG females laid 11 clutches in the breeding season; although CCL and curved carapace width remained stable, girth declined between each nesting episode, indicating loss of mass. Straight to curved inter-ridge distance ratios did not change significantly during the breeding season, indicating loss of dorsal blubber before the onset of breeding. The results demonstrate substantial alterations in size and shape of female D. coriacea over periods of weeks to months in response to alterations in nutritional and reproductive status.
Silicon-mediated Direct Conversion of Acyl Chlorides to Carbamoyl Azides or/and Tetrazolinones under Mild Conditions
Authors: Salama Tarek A , Elmorsy Saad S , Khalil Abdel-Galil M , Ismail Mohamed A
Published: September 2011

A simple and mild one-pot procedure for the synthesis of carbamoyl azides from acyl chlorides utilizing a combination of tetrachlorosilane and sodium azide in acetonitrile at ambient temperature is reported. Under gentle heating, 1-aryltetrazolin-5-ones were also obtained in one-pot process presumably via a [3 + 2] cycloaddition step.
The Xist RNA A-repeat comprises a novel AUCG tetraloop fold and a platform for multimerization
Authors: Duszczyk Malgorzata M. , Wutz Anton , Rybin Vladimir , Sattler Michael
Published: September 2011

X-chromosome inactivation (XCI) in female mammals depends on the noncoding RNA X inactivation specific transcript (Xist). The mechanism of chromosome-wide silencing by Xist is poorly understood. While it is established that the 5′ region of Xist RNA, comprising the A-repeats and holding 7.5–8.5 copies of a conserved 26-mer sequence, is essential for Xist-mediated silencing, high-resolution structural information for the A-repeats is not available. Here, we report the three-dimensional solution structure of a 14-mer hairpin in the 5′ region of a human A-repeat. This hairpin is remarkably stable and adopts a novel AUCG tetraloop fold, the integrity of which is required for silencing. We show that, contrary to previous predictions, the 3′ region of single or tandem A-repeats mediates duplex formation in vitro. Significantly, mutations in this region disrupt the inter-repeat duplex formation in vitro and abrogate the silencing function of Xist A-repeats in vivo. Our data suggest that the complete A-repeat region may be stabilized by inter-repeat duplex formation and, as such, may provide a platform for multimerization and specific recognition of the AUCG tetraloops by trans-acting factors.
Sunitinib-Induced Hyperammonemic Encephalopathy in Gastrointestinal Stromal Tumors
Authors: Lee Na-Ri , Yhim Ho-Young , Yim Chang-Yeol , Kwak Jae-Yong , Song Eun-Kee
Published: September 2011

Objective:

To report 2 cases of hyperammonemic encephalopathy induced by sunitinib in patients with metastatic gastrointestinal stromal tumor (GIST).

Case Summary:

A 58-year-old man with imatinib-resistant metastatic GIST presented to the emergency department with confusion that developed 17 days after the initiation of sunitinib 50 mg/day. His serum ammonia level was markedly elevated (210 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. His neurologic status normalized within 24 hours and his serum ammonia level decreased to 64 μg/dL A 68-year-old woman with imatinib-resistant metastatic GIST was admitted into the emergency department with confusion and irritability that developed 10 days after the start of sunitinib therapy. Her serum ammonia level was markedly elevated (389 μg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. Within 24 hours, her mental status was improved and her serum ammonia level was decreased to 116 μg/dL. Sunitinib was reintroduced, and the same symptoms occurred after day 7 of administration. Sunitinib was not prescribed afterward and the woman did not experience any further encephalopathy symptoms.

Discussion:

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases such as stem cell factor receptor, vascular endothelial growth factor, and platelet-derived growth factor. It is used as second-line therapy for patients with imatinib-resistant GIST. Hyperammonemic encephalopathy is an uncommon fatal complication of chemotherapy. According to the Naranjo probability scale, sunitinib was a probable cause of hyperammonemic encephalopathy in the patients described here. Although the mechanism of hyperammonemia is unclear, hyperammonemic encephalopathy might be caused by a vascular disorder related to the antiangiogenic properties of sunitinib, and it has ethnic differences associated with genetic polymorphisms.

Conclusions:

Sunitinib may Induce hyperammonemic encephalopathy in some patients. Although further studies are warranted, clinicians should be aware of this severe adverse event when using sunitinib for treatment of GIST.
Chlorine-free copper-catalyzed oxidative synthesis of 1,3,4-oxadiazoles with molecular oxygen as the sole oxidant
Authors: Jiang Huanfeng , Li Xianwei , Pan Xiaoyan , Zhou Peng
Published: September 2011

Chlorine-free is not only one of the new concepts of green chemistry, but also a problematical task for chemical processes in industrial utility. During the past several decades, we devoted ourselves to the study of chlorine-free organic synthesis. Herein, we describe an efficient chlorine-free copper-catalyzed oxidative approach providing 1,3,4-oxadiazoles in good yields from readily available starting materials. This transformation requires only a green and inexpensive reagent to afford the structurally useful motifs, and has a broad functional groups tolerance.
Molecular Alterations during Progression of Prostate Cancer to Androgen Independence
Authors: Saraon Punit , Jarvi Keith , Diamandis Eleftherios P
Published: September 2011

BACKGROUND

Prostate cancer is the most commonly diagnosed cancer among men in North America and is a leading cause of death. Standard treatments include androgen deprivation therapy, which leads to improved clinical outcomes. However, over time, most tumors become androgen independent and no longer respond to hormonal therapies. Several mechanisms have been implicated in the progression of prostate cancer to androgen independence.

CONTENT

Most tumors that have become androgen independent still rely on androgen receptor (AR) signaling. Mechanisms that enhance AR signaling in androgen-depleted conditions include: AR gene amplification, AR mutations, changes in the balance of AR cofactors, increases in steroidogenic precursors, and activation via “outlaw” pathways. Along with AR signaling, various other AR-independent “bypass” pathways have been shown to operate aberrantly during androgen independence. Changes in the epigenetic signatures and microRNA concentrations have also been implicated in the development of androgen-independent prostate cancer.

Understanding of the molecular mechanisms that lead to the development of androgen-independent prostate cancer will allow for improved therapeutic strategies that target key pathways and molecules that are essential for these cells to survive.
Seeding Strategies for Viral Marketing: An Empirical Comparison
Authors: Hinz Oliver , Skiera Bernd , Barrot Christian , Becker Jan U.
Published: September 2011

Seeding strategies have strong influences on the success of viral marketing campaigns, but previous studies using computer simulations and analytical models have produced conflicting recommendations about the optimal seeding strategy. This study compares four seeding strategies in two complementary small-scale field experiments, as well as in one real-life viral marketing campaign involving more than 200,000 customers of a mobile phone service provider. The empirical results show that the best seeding strategies can be up to eight times more successful than other seeding strategies. Seeding to well-connected people is the most successful approach because these attractive seeding points are more likely to participate in viral marketing campaigns. This finding contradicts a common assumption in other studies. Well-connected people also actively use their greater reach but do not have more influence on their peers than do less well-connected people.
Social Effects on Customer Retention
Authors: Nitzan Irit , Libai Barak
Published: September 2011

This study explores the role of customers’ social network in their defection from a service provider. The authors use data on communication among one million customers of a cellular company to create a large-scale social system composed of customers’ individual social networks. The study's results indicate that exposure to a defecting neighbor is associated with an increase of 80% in the defection hazard, after controlling for a host of social, personal, and purchase-related variables. This effect is comparable in both magnitude and nature to social effects observed in the highly researched case of product adoption: The extent of social influence on retention decays exponentially over time, and the likelihood of defection is affected by tie strength and homophily with defecting neighbors and by these neighbors’ average number of connections. Highly connected customers are more affected, and loyal customers are less affected by defections that occur in their social networks. These results carry important implications for the theoretical understanding of the drivers of customer retention and should be considered by firms that aim to predict and affect customer retention.
Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX
Authors: Niu Wenze , Zou Yuhua , Shen ChengCheng , Zhang Chun-Li
Published: September 2011

Neural stem cells (NSCs) continually produce new neurons in postnatal brains. However, the majority of these cells stay in a nondividing, inactive state. The molecular mechanism that is required for these cells to enter proliferation still remains largely unknown. Here, we show that nuclear receptor TLX (NR2E1) controls the activation status of postnatal NSCs in mice. Lineage tracing indicates that TLX-expressing cells give rise to both activated and inactive postnatal NSCs. Surprisingly, loss of TLX function does not result in spontaneous glial differentiation, but rather leads to a precipitous age-dependent increase of inactive cells with marker expression and radial morphology for NSCs. These inactive cells are mispositioned throughout the granular cell layer of the dentate gyrus during development and can proliferate again after reintroduction of ectopic TLX. RNA-seq analysis of sorted NSCs revealed a TLX-dependent global expression signature, which includes the p53 signaling pathway. TLX regulatesp21expression in a p53-dependent manner, and acute removal ofp53can rescue the proliferation defect of TLX-null NSCs in culture. Together, these findings suggest that TLX acts as an essential regulator that ensures the proliferative ability of postnatal NSCs by controlling their activation through genetic interaction with p53 and other signaling pathways.
Dynamic Activation of Frontal, Parietal, and Sensory Regions Underlying Anticipatory Visual Spatial Attention
Authors: Simpson Gregory V. , Weber Darren L. , Dale Corby L. , Pantazis Dimitrios , Bressler Steven L. , Leahy Richard M. , Luks Tracy L.
Published: September 2011

Although it is well established that multiple frontal, parietal, and occipital regions in humans are involved in anticipatory deployment of visual spatial attention, less is known about the electrophysiological signals in each region across multiple subsecond periods of attentional deployment. We used MEG measures of cortical stimulus-locked, signal-averaged (event-related field) activity during a task in which a symbolic cue directed covert attention to the relevant location on each trial. Direction-specific attention effects occurred in different cortical regions for each of multiple time periods during the delay between the cue and imperative stimulus. A sequence of activation from V1/V2 to extrastriate, parietal, and frontal regions occurred within 110 ms after cue, possibly related to extraction of cue meaning. Direction-specific activations ∼300 ms after cue in frontal eye field (FEF), lateral intraparietal area (LIP), and cuneus support early covert targeting of the cued location. This was followed by coactivation of a frontal–parietal system [superior frontal gyrus (SFG), middle frontal gyrus (MFG), LIP, anterior intraparietal sulcus (IPSa)] that may coordinate the transition from targeting the cued location to sustained deployment of attention to both space and feature in the last period. The last period involved direction-specific activity in parietal regions and both dorsal and ventral sensory regions [LIP, IPSa, ventral IPS, lateral occipital region, and fusiform gyrus], which was accompanied by activation that was not direction specific in right hemisphere frontal regions (FEF, SFG, MFG). Behavioral performance corresponded with the magnitude of attention-related activity in different brain regions at each time period during deployment. The results add to the emerging electrophysiological characterization of different cortical networks that operate during anticipatory deployment of visual spatial attention.
Functional Dissociation of Hippocampal Mechanism during Implicit Learning Based on the Domain of Associations
Authors: Rose Michael , Haider Hilde , Salari Neda , Büchel Christian
Published: September 2011

Traditionally, the medial temporal lobe (MTL) was linked to explicit or declarative memory in associative learning. However, recent studies have reported MTL involvement even when volunteers are not consciously aware of the learned contingencies. Therefore, the mechanism of the MTL-related learning process cannot be described sufficiently by the explicit/implicit distinction, and the underlying process in the MTL for associative learning needs a more functional characterization. A possible feature that would allow a functional specification also for implicit learning is the nature of the material that is learned. Given that implicit memory tasks often comprise a combination of perceptual and motor learning, we hypothesized that implicit learning of the perceptual but not the motor component entails MTL activation in these studies. To directly test this hypothesis, we designed a purely perceptual and a purely motor variant of the serial reaction time task. In two groups of human volunteers, behavioral results clearly showed that both variants were learned without awareness. Neuronal recordings using fMRI revealed that bilateral hippocampal activation was observed only for implicit learning of the perceptual sequence, not for the motor sequence. This dissociation clearly shows that the functional role of the hippocampus for learning is determined by the domain of the learned association and that the function of the medial temporal lobe system is the processing of contingencies between perceptual features regardless of the explicit or implicit nature of the ensuing memory.
Spongiform Encephalopathy in Transgenic Mice Expressing a Point Mutation in the β2–α2 Loop of the Prion Protein
Authors: Sigurdson Christina J. , Joshi-Barr Shivanjali , Bett Cyrus , Winson Olivia , Manco Giuseppe , Schwarz Petra , Rülicke Thomas , Nilsson K. Peter R. , Margalith Ilan , Raeber Alex , Peretz David , Hornemann Simone , Wüthrich Kurt , Aguzzi Adriano
Published: September 2011

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases attributed to misfolding of the cellular prion protein, PrPC, into a β-sheet-rich, aggregated isoform, PrPSc. We previously found that expression of mouse PrP with the two amino acid substitutions S170N and N174T, which result in high structural order of the β2–α2 loop in the NMR structure at pH 4.5 and 20°C, caused transmissiblede novoprion disease in transgenic mice. Here we report that expression of mouse PrP with the single-residue substitution D167S, which also results in a structurally well ordered β2–α2 loop at 20°C, elicits spontaneous PrP aggregationin vivo. Transgenic mice expressing PrPD167Sdeveloped a progressive encephalopathy characterized by abundant PrP plaque formation, spongiform change, and gliosis. These results add to the evidence that the β2–α2 loop has an important role in intermolecular interactions, including that it may be a key determinant of prion protein aggregation.