bluuebunny/crossref_metadata_2025 huggingface dataset:
NMR characterisation of the minimal interacting regions of centrosomal proteins 4.1R and NuMA1: effect of phosphorylation
Authors: Treviño Miguel A , Rodríguez-Rodríguez Mar , Correas Isabel , Marcilla Miguel , Albar Juan P , Rico Manuel , Jiménez M Ángeles , Bruix Marta
Published: January 2010

Background

Some functions of 4.1R in non-erythroid cells are directly related with its distinct sub-cellular localisation during cell cycle phases. During mitosis, 4.1R is implicated in cell cycle progression and spindle pole formation, and co-localizes with NuMA1. However, during interphase 4.1R is located in the nucleus and only partially co-localizes with NuMA1.

Results

We have characterized by NMR the structural features of the C-terminal domain of 4.1R and those of the minimal region (the last 64 residues) involved in the interaction with NuMA1. This subdomain behaves as an intrinsically unfolded protein containing a central region with helical tendency. The specific residues implicated in the interaction with NuMA1 have been mapped by NMR titrations and involve the N-terminal and central helical regions. The segment of NuMA1 that interacts with 4.1R is phosphorylated during mitosis. Interestingly, NMR data indicates that the phosphorylation of NuMA1 interacting peptide provokes a change in the interaction mechanism. In this case, the recognition occurs through the central helical region as well as through the C-terminal region of the subdomain meanwhile the N-terminal region do not interact.

Conclusions

These changes in the interaction derived from the phosphorylation state of NuMA1 suggest that phosphorylation can act as subtle mechanism of temporal and spatial regulation of the complex 4.1R-NuMA1 and therefore of the processes where both proteins play a role.
Testing for mean and correlation changes in microarray experiments: an application for pathway analysis
Authors: Alvo Mayer , Liu Zhongzhu , Williams Andrew , Yauk Carole
Published: January 2010

Background

Microarray experiments examine the change in transcript levels of tens of thousands of genes simultaneously. To derive meaningful data, biologists investigate the response of genes within specific pathways. Pathways are comprised of genes that interact to carry out a particular biological function. Existing methods for analyzing pathways focus on detecting changes in the mean or over-representation of the number of differentially expressed genes relative to the total of genes within the pathway. The issue of how to incorporate the influence of correlation among the genes is not generally addressed.

Results

In this paper, we propose a non-parametric rank test for analyzing pathways that takes into account the correlation among the genes and compared two existing methods, Global and Gene Set Enrichment Analysis (GSEA), using two publicly available data sets. A simulation study was conducted to demonstrate the advantage of the rank test method.

Conclusions

The data indicate the advantages of the rank test. The method can distinguish significant changes in pathways due to either correlations or changes in the mean or both. From the simulation study the rank test out performed Global and GSEA. The greatest gain in performance was for the sample size case which makes the application of the rank test ideal for microarray experiments.
Relationship between perceived body weight and body mass index based on self- reported height and weight among university students: a cross-sectional study in seven European countries
Authors: Mikolajczyk Rafael T , Maxwell Annette E , El Ansari Walid , Stock Christiane , Petkeviciene Janina , Guillen-Grima Francisco
Published: January 2010

Background

Despite low rates of obesity, many university students perceive themselves as overweight, especially women. This is of concern, because inappropriate weight perceptions can lead to unhealthy behaviours including eating disorders.

Methods

We used the database from the Cross National Student Health Survey (CNSHS), consisting of 5,900 records of university students from Bulgaria, Denmark, Germany, Lithuania, Poland, Spain and Turkey to analyse differences in perceived weight status based on the question: "Do you consider yourself much too thin, a little too thin, just right, a little too fat or much too fat?". The association between perceived weight and body mass index (BMI) calculated from self-reported weight and height was assessed with generalized non-parametric regression in R library gam.

Results

Although the majority of students reported a normal BMI (72-84% of males, 65-83% of females), only 32% to 68% of students considered their weight "just right". Around 20% of females with BMI of 20 kg/m2 considered themselves "a little too fat" or "too fat", and the percentages increased to 60% for a BMI of 22.5 kg/m2. Male students rarely felt "a little too fat" or "too fat" below BMI of 22.5 kg/m2, but most felt too thin with a BMI of 20 kg/m2.

Conclusions

Weight ideals are rather uniform across the European countries, with female students being more likely to perceive themselves as "too fat" at a normal BMI, while male students being more likely to perceive themselves as "too thin". Programs to prevent unhealthy behaviours to achieve ill-advised weight ideals may benefit students.
Dietary patterns in Canadian men and women ages 25 and older: relationship to demographics, body mass index, and bone mineral density
Authors: Langsetmo Lisa , Poliquin Suzette , Hanley David A , Prior Jerilynn C , Barr Susan , Anastassiades Tassos , Towheed Tanveer , Goltzman David , Kreiger Nancy ,   the CaMos Research Group
Published: January 2010

Background

Previous research has shown that underlying dietary patterns are related to the risk of many different adverse health outcomes, but the relationship of these underlying patterns to skeletal fragility is not well understood. The objective of the study was to determine whether dietary patterns in men (ages 25-49, 50+) and women (pre-menopause, post-menopause) are related to femoral neck bone mineral density (BMD) independently of other lifestyle variables, and whether this relationship is mediated by body mass index.

Methods

We performed an analysis of 1928 men and 4611 women participants in the Canadian Multicentre Osteoporosis Study, a randomly selected population-based longitudinal cohort. We determined dietary patterns based on the self-administered food frequency questionnaires in year 2 of the study (1997-99). Our primary outcome was BMD as measured by dual x-ray absorptiometry in year 5 of the study (2000-02).

Results

We identified two underlying dietary patterns using factor analysis and then derived factor scores. The first factor (nutrient dense) was most strongly associated with intake of fruits, vegetables, and whole grains. The second factor (energy dense) was most strongly associated with intake of soft drinks, potato chips and French fries, certain meats (hamburger, hot dog, lunch meat, bacon, and sausage), and certain desserts (doughnuts, chocolate, ice cream). The energy dense factor was associated with higher body mass index independent of other demographic and lifestyle factors, and body mass index was a strong independent predictor of BMD. Surprisingly, we did not find a similar positive association between diet and BMD. In fact, when adjusted for body mass index, each standard deviation increase in the energy dense score was associated with a BMD decrease of 0.009 (95% CI: 0.002, 0.016) g/cm2 for men 50+ years old and 0.004 (95% CI: 0.000, 0.008) g/cm2 for postmenopausal women. In contrast, for men 25-49 years old, each standard deviation increase in the nutrient dense score, adjusted for body mass index, was associated with a BMD increase of 0.012 (95% CI: 0.002, 0.022) g/cm2.

Conclusions

In summary, we found no consistent relationship between diet and BMD despite finding a positive association between a diet high in energy dense foods and higher body mass index and a strong correlation between body mass index and BMD. Our data suggest that some factor related to the energy dense dietary pattern may partially offset the advantages of higher body mass index with regard to bone health.
Oral cancer overexpressed 1 (ORAOV1) regulates cell cycle and apoptosis in cervical cancer HeLa cells
Authors: Jiang Lu , Zeng Xin , Wang Zhi , Ji Ning , Zhou Yu , Liu Xianting , Chen Qianming
Published: January 2010

Background

Oral Cancer Overexpressed 1 (ORAOV1) is a candidate protooncogene locating on 11q13. Recent studies show that ORAOV1 acts as a primary driving force behind 11q13 gene amplification and plays a functional role in the tumorigenesis in a variety of human squamous cell carcinomas (SCCs). According to the results of molecular cytogenetic methods, 11q13 was characterized to be a high-level and recurrent amplification chromosomal site in cervical cancers. Up till now, the role of ORAOV1 in cervical cancer is unknown. The purpose of this study is to elucidate the function of ORAOV1 in cervical cancer cell growth by studying its roles in HeLa cells using small interfering RNA.

Results

Functional analyses revealed that ORAOV1 was involved in the regulation of HeLa cell growth through its effect on cell cycle and apoptosis. Silence of ORAOV1 in HeLa cells downregulated the expression of Cyclin A, Cyclin B1 and Cdc2, and led to a distinct S cell cycle arrest. Moreover, knockdown of ORAOV1 expression activated both extrinsic and intrinsic apoptotic pathways and led to apoptosis in HeLa cells through its effect on the expression of several apoptosis related proteins such as P53, Bcl-2, Caspase-3, Caspase-8, Caspase-9 and cytochrome c. Interestingly, the expression of Cyclin D1, a pivotal gene for cervical cancer tumorigenesis, was also found to be reduced in ORAOV1 silenced HeLa cells.

Conclusion

Our findings indicate that ORAOV1 has an important role in regulating cell growth of cervical cancer HeLa cells through regulating the cell cycle and apoptosis. Thus, it may be a crucial protooncogene and a novel candidate therapeutic target for cervical cancer.
Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans
Authors: Bader Sophie R , Kothlow Sonja , Trapp Sascha , Schwarz Susanne CN , Philipp Hans-Christian , Weigend Steffen , Sharifi Ahmad R , Preisinger Rudolf , Schmahl Wolfgang , Kaspers Bernd , Matiasek Kaspar
Published: January 2010

Background

Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies.

Methods

Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS) alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR). These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV).

Results

Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded.

Conclusions

The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift.
Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS)
Authors: Escher Niko , Ernst Günther , Melle Christian , Berndt Alexander , Clement Joachim H , Junker Kerstin , Friedrich Karlheinz , Guntinas-Lichius Orlando , von Eggeling Ferdinand
Published: January 2010

In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma.
Indigenous knowledge of medicinal plants used by Saperas community of Khetawas, Jhajjar District, Haryana, India
Authors: Panghal Manju , Arya Vedpriya , Yadav Sanjay , Kumar Sunil , Yadav Jaya Parkash
Published: January 2010

Background

Plants have traditionally been used as a source of medicine in India by indigenous people of different ethnic groups inhabiting various terrains for the control of various ailments afflicting human and their domestic animals. The indigenous community of snake charmers belongs to the 'Nath' community in India have played important role of healers in treating snake bite victims. Snake charmers also sell herbal remedies for common ailments. In the present paper an attempt has been made to document on ethno botanical survey and traditional medicines used by snake charmers of village Khetawas located in district Jhajjar of Haryana, India as the little work has been made in the past to document the knowledge from this community.

Methods

Ethno botanical data and traditional uses of plants information was obtained by semi structured oral interviews from experienced rural folk, traditional herbal medicine practitioners of the 'Nath' community. A total of 42 selected inhabitants were interviewed, 41 were male and only one woman. The age of the healers was between 25 years and 75 years. The plant specimens were identified according to different references concerning the medicinal plants of Haryana and adjoining areas and further confirmation from Forest Research Institute, Dehradun.

Results

The present study revealed that the people of the snake charmer community used 57 medicinal plants species that belonged to 51 genera and 35 families for the treatment of various diseases. The study has brought to light that the main diseases treated by this community was snakebite in which 19 different types of medicinal plants belongs to 13 families were used. Significantly higher number of medicinal plants was claimed by men as compared to women. The highest numbers of medicinal plants for traditional uses utilized by this community were belonging to family Fabaceae.

Conclusion

This community carries a vast knowledge of medicinal plants but as snake charming is banned in India as part of efforts to protect India's steadily depleting wildlife, this knowledge is also rapidly disappearing in this community. Such type of ethno botanical studies will help in systematic documentation of ethno botanical knowledge and availing to the scientific world plant therapies used as antivenin by the Saperas community.
Prediction of clinical toxicity in locally advanced head and neck cancer patients by radio-induced apoptosis in peripheral blood lymphocytes (PBLs)
Authors: Bordón Elisa , Henríquez-Hernández Luis Alberto , Lara Pedro C , Ruíz Ana , Pinar Beatriz , Rodríguez-Gallego Carlos , Lloret Marta
Published: January 2010

Head and neck cancer is treated mainly by surgery and radiotherapy. Normal tissue toxicity due to x-ray exposure is a limiting factor for treatment success. Many efforts have been employed to develop predictive tests applied to clinical practice. Determination of lymphocyte radio-sensitivity by radio-induced apoptosis arises as a possible method to predict tissue toxicity due to radiotherapy. The aim of the present study was to analyze radio-induced apoptosis of peripheral blood lymphocytes in head and neck cancer patients and to explore their role in predicting radiation induced toxicity. Seventy nine consecutive patients suffering from head and neck cancer, diagnosed and treated in our institution, were included in the study. Toxicity was evaluated using the Radiation Therapy Oncology Group scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Radiation-induced apoptosis increased in order to radiation dose and fitted to a semi logarithmic model defined by two constants: α and β. α, as the origin of the curve in the Y axis determining the percentage of spontaneous cell death, and β, as the slope of the curve determining the percentage of cell death induced at a determined radiation dose, were obtained. β value was statistically associated to normal tissue toxicity in terms of severe xerostomia, as higher levels of apoptosis were observed in patients with low toxicity (p = 0.035; Exp(B) 0.224, I.C.95% (0.060-0.904)). These data agree with our previous results and suggest that it is possible to estimate the radiosensitivity of peripheral blood lymphocytes from patients determining the radiation induced apoptosis with annexin V/propidium iodide staining. β values observed define an individual radiosensitivity profile that could predict late toxicity due to radiotherapy in locally advanced head and neck cancer patients. Anyhow, prospective studies with different cancer types and higher number of patients are needed to validate these results.
Retroperitoneal abscess with concomitant hepatic portal venous gas and rectal perforation: a rare triad of complications of acute appendicitis. A case report
Authors: Diana Michele , Paroz Alexandre , Demartines Nicolas , Schäfer Markus
Published: January 2010

Background

While retroperitoneal abscess is a known complication, hepatic portal venous gas and rectal perforation have not been reported as a concomitant sequelae of acute appendicitis. Here we report a case of a patient with a perforated appendicitis that was associated with these triad of complications.

Materials and Methods

In addition to report our case, we carefully reviewed the literature in order to detect similar cases and the causes of such rare conditions.

Results

Only 26 cases (including our patient) of acute appendicitis complicated by retroperitoneal abscesses have been published in the English literature between 1955 and 2008. There was one case having hepatic portal venous gas, and one further case with a rectal perforation associated with acute appendicitis. All patients with retroperitoneal abscess presented with non specific clinic symptoms that not revealed any suspicion for such a complicated disease. Hence, delayed diagnosis and treatment are not uncommon.

Conclusions

So far, no patient has been described with such a triad of rare complications related to acute appendicitis. We want to emphasize the insidious onset of retroperitoneal abscess formation, and the need of prompt recognition and adequate treatment to avoid deleterious outcome.
Acute Complex Type A Dissection associated with peripheral malperfusion syndrome treated with a staged approach guided by lactate levels
Authors: Suliman Amna , Dialynas Michael , Ashrafian Hutan , Bicknell Colin , Mireskandari Maziar , Hamady Mohamad , Athanasiou Thanos
Published: January 2010

Acute type A aortic dissection can be complicated by visceral malperfusion and is associated with a significant surgical morbidity and mortality. We describe a case of successful management of a complex acute type A dissection with mesenteric and lower limb ischemia treated with endovascular thoracic stenting and femoro-femoral crossover bypass grafting followed by aortic arch repair. To accomplish this, we applied a staged therapeutic approach using serial lactate measurements to assess the adequacy of peripheral perfusion and metabolic status prior to surgical repair of the proximal dissection.
Should all excised surgical specimens be examined microscopically? A case report
Authors: Raymond Thomas M , Ibrahim Sam , Basnyat Pradeep S
Published: January 2010

Background

Microscopic examination of all surgical specimens is controversial.

Case Presentation

We report two cases where examination has revealed unexpected results that have changed patient management and treatment.

Conclusions

Histopathological examination of all tissue should be considered. The benefits and disadvantages of routine examination of tissue are discussed.
Repression of zygotic gene expression in theXenopusgermline
Authors: Venkatarama Thiagarajan , Lai Fangfang , Luo Xueting , Zhou Yi , Newman Karen , King Mary Lou
Published: January 2010

Primordial germ cells (PGCs) in Xenopus are specified through the inheritance of germ plasm. During gastrulation, PGCs remain totipotent while surrounding cells in the vegetal mass become committed to endoderm through the action of the vegetal localized maternal transcription factor VegT. We find that although PGCs contain maternal VegT RNA, they do not express its downstream targets at the mid-blastula transition (MBT). Transcriptional repression in PGCs correlates with the failure to phosphorylate serine 2 in the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAPII). As serine 5 is phosphorylated, these results are consistent with a block after the initiation step but before the elongation step of RNAPII-based transcription. Repression of PGC gene expression occurs despite an apparently permissive chromatin environment. Phosphorylation of CTD-serine 2 and expression of zygotic mRNAs in PGCs are first detected at neurula, some 10 hours after MBT, indicating that transcription is significantly delayed in the germ cell lineage. Significantly, Oct-91, a POU subclass V transcription factor related to mammalian Oct3/4, is among the earliest zygotic transcripts detected in PGCs and is a likely mediator of pluripotency. Our findings suggest that PGCs are unable to respond to maternally inherited endoderm determinants because RNAPII activity is transiently blocked while these determinants are present. Our results in a vertebrate system further support the concept that one strategy used repeatedly during evolution for preserving the germline is RNAPII repression.
Evidence for a dynamic spatiotemporal fate map and early fate restrictions of premigratory avian neural crest
Authors: Krispin Shlomo , Nitzan Erez , Kassem Yachia , Kalcheim Chaya
Published: January 2010

Colonization of trunk neural crest derivatives in avians follows a ventral to dorsal order beginning with sympathetic ganglia, Schwann cells, sensory ganglia and finally melanocytes. Continuous crest emigration underlies this process, which is accounted for by a progressive ventral to dorsal relocation of neural tube progenitors prior to departure. This causes a gradual narrowing of FoxD3, Sox9 and Snail2 expression domains in the dorsal tube that characterize the neural progenitors of the crest and these genes are no longer transcribed by the time melanoblasts begin emigrating. Consistently, the final localization of crest cells can be predicted from their relative ventrodorsal position within the premigratory domain or by their time of delamination. Thus, a dynamic spatiotemporal fate map of crest derivatives exists in the dorsal tube at flank levels of the axis with its midline region acting as a sink for the ordered ingression and departure of progenitors. Furthermore, discrete lineage analysis of the dorsal midline at progressive stages generated progeny in single rather than multiple derivatives, revealing early fate restrictions. Compatible with this notion, when early emigrating `neural' progenitors were diverted into the lateral `melanocytic' pathway, they still adopted neural traits, suggesting that initial fate acquisition is independent of the migratory environment and that the potential of crest cells prior to emigration is limited.
Notch signalling regulates the contribution of progenitor cells from the chick Hensen's node to the floor plate and notochord
Authors: Gray Shona D. , Dale J. Kim
Published: January 2010

Hensen's node of the chick embryo contains multipotent self-renewing progenitor cells that can contribute to either the floor plate or the notochord. Floor plate cells are a population of epithelial cells that lie at the ventral midline of the developing neural tube, whereas the notochord is a rod of axial mesoderm that lies directly beneath the floor plate. These two tissues serve as a source of a potent signalling morphogen, sonic hedgehog (Shh), which patterns the dorsoventral axis of the neural tube. We show, through both gain- and loss-of-function approaches, that Notch signalling promotes the contribution of chick axial progenitor cells to the floor plate and inhibits contribution to the notochord. Thus, we propose that Notch regulates the allocation of appropriate numbers of progenitor cells from Hensen's node of the chick embryo to the notochord and the floor plate.
Differential requirements for STRAD in LKB1-dependent functions in C. elegans
Authors: Narbonne Patrick , Hyenne Vincent , Li Shaolin , Labbé Jean-Claude , Roy Richard
Published: January 2010

The protein kinase LKB1 is a crucial regulator of cell growth/proliferation and cell polarity and is the causative gene in the cancer-predisposing disease Peutz-Jeghers syndrome (PJS). The activity of LKB1 is greatly enhanced following its association with the Ste20-like adapter protein STRAD. Unlike LKB1 however, mutations in STRAD have not been identified in PJS patients and thus, the key tumour suppressive role(s) of LKB1 might be STRAD independent. Here, we report that Caenorhabditis elegans strd-1/STRAD mutants recapitulate many phenotypes typical of par-4/LKB1 loss of function, showing defects during early embryonic and dauer development. Interestingly, although the growth/proliferation defects in severe par-4 and strd-1 mutant dauers are comparable, strd-1 mutant embryos do not share the polarity defects of par-4 embryos. We demonstrate that most of par-4-dependent regulation of germline stem cell (GSC) quiescence occurs through AMPK, whereby PAR-4 requires STRD-1 to phosphorylate and activate AMPK. Consistent with this, even though AMPK plays a major role in the regulation of cell proliferation, like strd-1 it does not affect embryonic polarity. Instead, we found that the PAR-4-mediated phosphorylation of polarity regulators such as PAR-1 and MEX-5 in the early embryo occurs in the absence of STRD-1. Thus, PAR-4 requires STRD-1 to phosphorylate AMPK to regulate cell growth/proliferation under reduced insulin signalling conditions, whereas PAR-4 can promote phosphorylation of key proteins, including PAR-1 and MEX-5, to specify early embryonic polarity independently of STRD-1. Our results therefore identify a key strd-1/STRAD-independent function of par-4/LKB1 in polarity establishment that is likely to be important for tumour suppression in humans.
Insulin signaling promotes germline proliferation inC. elegans
Authors: Michaelson David , Korta Dorota Z. , Capua Yossi , Hubbard E. Jane Albert
Published: January 2010

Cell proliferation must be coordinated with cell fate specification during development, yet interactions among pathways that control these two critical aspects of development are not well understood. The coordination of cell fate specification and proliferation is particularly crucial during early germline development, when it impacts the establishment of stem/progenitor cell populations and ultimately the production of gametes. In C. elegans, insulin/IGF-like receptor (IIR) signaling has been implicated in fertility, but the basis for the fertility defect had not been previously characterized. We found that IIR signaling is required for robust larval germline proliferation, separate from its well-characterized role in preventing dauer entry. IIR signaling stimulates the larval germline cell cycle. This activity is distinct from Notch signaling, occurs in a predominantly germline-autonomous manner, and responds to somatic activity of ins-3 and ins-33, genes that encode putative insulin-like ligands. IIR signaling in this role acts through the canonical PI3K pathway, inhibiting DAF-16/FOXO. However, signaling from these ligands does not inhibit daf-16 in neurons nor in the intestine, two tissues previously implicated in other IIR roles. Our data are consistent with a model in which: (1) under replete reproductive conditions, the larval germline responds to insulin signaling to ensure robust germline proliferation that builds up the germline stem cell population; and (2) distinct insulin-like ligands contribute to different phenotypes by acting on IIR signaling in different tissues.
Blimp1 controls photoreceptor versus bipolar cell fate choice during retinal development
Authors: Brzezinski Joseph A. , Lamba Deepak A. , Reh Thomas A.
Published: January 2010

Photoreceptors, rods and cones are the most abundant cell type in the mammalian retina. However, the molecules that control their development are not fully understood. In studies of photoreceptor fate determination, we found that Blimp1 (Prdm1) is expressed transiently in developing photoreceptors. We analyzed the function of Blimp1 in the mouse retina using a conditional deletion approach. Developmental analysis of mutants showed that Otx2+ photoreceptor precursors ectopically express the bipolar cell markers Chx10 (Vsx2) and Vsx1, adopting bipolar instead of photoreceptor fate. However, this fate shift did not occur until the time when bipolar cells are normally specified during development. Most of the excess bipolar cells died around the time of bipolar cell maturation. Our results suggest that Blimp1 expression stabilizes immature photoreceptors by preventing bipolar cell induction. We conclude that Blimp1 regulates the decision between photoreceptor and bipolar cell fates in the Otx2+ cell population during retinal development.
Hair follicle renewal: authentic morphogenesis that depends on a complex progression of stem cell lineages
Authors: Legué Emilie , Sequeira Inês , Nicolas Jean-François
Published: January 2010

The hair follicle (HF) grows during the anagen phase from precursors in the matrix that give rise to each differentiated HF layer. Little is known about the lineal relationship between these layer-restricted precursors and HF stem cells. To understand how the HF stem cells regenerate the typical anagen organization, we conducted in vivo clonal analysis of key stages of the HF cycle in mice. Unexpectedly, we found that the pool of HF stem cells contains precursors with both multipotent and restricted contributions. This implies that the lineal relationships between HF stem cells (persisting during telogen) and layer-restricted precursors (in the germinative layer), responsible for HF elongation during anagen, are not stereotyped. Formation of the matrix at each cycle is accompanied by the transient expansion of an intermediary pool of precursors at the origin of the germinative layer and by the progressive restriction of cell dispersion. The regionalization of clonal patterns within the outer HF structure (the outer root sheath) suggests that the position of the precursors might be a crucial factor in determining their fate. The presence of HF stem cells with multipotent contribution and the progressive segregation of HF lineages upon anagen activation indicate that each HF renewal cycle constitutes an authentic morphogenetic process. A comprehensive model was constructed based on the different clonal patterns observed. In this model, the positions of the precursors relative to the dermal papilla together with the progressive restriction of cell dispersion are part of the mechanism that restricts their contribution to the different HF lineages.
Morphological evolution and embryonic developmental diversity in metazoa
Authors: Salazar-Ciudad Isaac
Published: January 2010

Most studies of pattern formation and morphogenesis in metazoans focus on a small number of model species, despite the fact that information about a wide range of species and developmental stages has accumulated in recent years. By contrast, this article attempts to use this broad knowledge base to arrive at a classification of developmental types through which metazoan body plans are generated. This classification scheme pays particular attention to the diverse ways by which cell signalling and morphogenetic movements depend on each other, and leads to several testable hypotheses regarding morphological variation within and between species, as well as metazoan evolution.
Involucrin–claudin-6 tail deletion mutant (CΔ206) transgenic mice: a model of delayed epidermal permeability barrier formation and repair
Authors: Enikanolaiye Adebola , Larivière Nathalie , Troy Tammy-Claire , Arabzadeh Azadeh , Atasoy Elif , Turksen Kursad
Published: January 2010

Preterm birth is a major global health problem that results in a large number of infant deaths, many of which are attributable to the complications of an immature epidermal permeability barrier (EPB), for which there is currently no effective therapeutic option. The mammalian EPB is formed during development and is essential for survival as it maintains thermoregulation and hydration, and provides a defense against infection. Using transgenic mouse technology, we have demonstrated the importance of claudin (Cldn)-containing tight junctions (TJs) in epidermal differentiation and, in particular, that epidermal suprabasal overexpression of Cldn6 results in an EPB-deficient phenotype that phenocopies the dysfunctional EPB of premature human infants. In this study, we used the same approach to target a Cldn6 tail deletion mutant to the epidermis of mice [involucrin (Inv)-Cldn6-CΔ206 transgenic mice]. The Inv-Cldn6-CΔ206 transgenic mice displayed a developmental delay in EPB formation, as shown by the expression of keratins and Cldns, and by X-Gal penetration assays. Trans-epidermal water loss measurements and immunolocalization studies indicated that the epidermal differentiation program was also perturbed in postnatal Inv-Cldn6-CΔ206 transgenic mice resulting in a delayed maturation. Notably, however, expression/localization of epidermal differentiation and maturation markers, including Cldns, indicated that the transgenic epidermis matured and normalized by postnatal day 10, which is 3 days after the wild-type epidermis. Our results suggest that activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and Cldn1 phosphorylation are associated with the repair and maturation of the skin barrier processes. These studies provide additional support for the crucial role of Cldns in epidermal differentiation, maturation and the formation of the EPB, and describe a novel animal model for evaluating postnatal epidermal maturation and therapies that may accelerate the process.
Formation of a stalled early intermediate of pseudouridine synthesis monitored by real-time FRET
Authors: Hengesbach Martin , Voigts-Hoffmann Felix , Hofmann Benjamin , Helm Mark
Published: January 2010

Pseudouridine is the most abundant of more than 100 chemically distinct natural ribonucleotide modifications. Its synthesis consists of an isomerization reaction of a uridine residue in the RNA chain and is catalyzed by pseudouridine synthases. The unusual reaction mechanism has become the object of renewed research effort, frequently involving replacement of the substrate uridines with 5-fluorouracil (f5U). f5U is known to be a potent inhibitor of pseudouridine synthase activity, but the effect varies among the target pseudouridine synthases. Derivatives of f5U have previously been detected, which are thought to be either hydrolysis products of covalent enzyme-RNA adducts, or isomerization intermediates. Here we describe the interaction of pseudouridine synthase 1 (Pus1p) with f5U-containing tRNA. The interaction described is specific to Pus1p and position 27 in the tRNA anticodon stem, but the enzyme neither forms a covalent adduct nor stalls at a previously identified reaction intermediate of f5U. The f5U27 residue, as analyzed by a DNAzyme-based assay using TLC and mass spectrometry, displayed physicochemical properties unaltered by the reversible interaction with Pus1p. Thus, Pus1p binds an f5U-containing substrate, but, in contrast to other pseudouridine synthases, leaves the chemical structure of f5U unchanged. The specific, but nonproductive, interaction demonstrated here thus constitutes an intermediate of Pus turnover, stalled by the presence of f5U in an early state of catalysis. Observation of the interaction of Pus1p with fluorescence-labeled tRNA by a real-time readout of fluorescence anisotropy and FRET revealed significant structural distortion of f5U-tRNA structure in the stalled intermediate state of pseudouridine catalysis.
Ciliate telomerase RNA loop IV nucleotides promote hierarchical RNP assembly and holoenzyme stability
Authors: Robart Aaron R. , O'Connor Catherine M. , Collins Kathleen
Published: January 2010

Telomerase adds simple-sequence repeats to chromosome 3′ ends to compensate for the loss of repeats with each round of genome replication. To accomplish this de novo DNA synthesis, telomerase uses a template within its integral RNA component. In addition to providing the template, the telomerase RNA subunit (TER) also harbors nontemplate motifs that contribute to the specialized telomerase catalytic cycle of reiterative repeat synthesis. Most nontemplate TER motifs function through linkage with the template, but in ciliate and vertebrate telomerases, a stem–loop motif binds telomerase reverse transcriptase (TERT) and reconstitutes full activity of the minimal recombinant TERT+TER RNP, even when physically separated from the template. Here, we resolve the functional requirements for this motif of ciliate TER in physiological RNP context using the Tetrahymena thermophila p65-TER-TERT core RNP reconstituted in vitro and the holoenzyme reconstituted in vivo. Contrary to expectation based on assays of the minimal recombinant RNP, we find that none of a panel of individual loop IV nucleotide substitutions impacts the profile of telomerase product synthesis when reconstituted as physiological core RNP or holoenzyme RNP. However, loop IV nucleotide substitutions do variably reduce assembly of TERT with the p65-TER complex in vitro and reduce the accumulation and stability of telomerase RNP in endogenous holoenzyme context. Our results point to a unifying model of a conformational activation role for this TER motif in the telomerase RNP enzyme.
Cross-Business Information Technology Integration and Acquirer Value Creation in Corporate Mergers and Acquisitions
Authors: Tanriverdi Hüseyin , Uysal Vahap Bülent
Published: January 2010

This study develops and tests the idea that the cross-business information technology integration (CBITI) capability of an acquirer creates significant value for shareholders of the acquirer in mergers and acquisitions (M&A). In M&A, integrating the IT systems and IT management processes of acquirer and target could generate benefits such as (a) the consolidation of IT resources and the reduction of overall IT costs of the combined firm, (b) the development of an IT-based coordination mechanism and the realization of cross-firm business synergies, (c) the minimization of potential disruptions to business operations, and (d) greater ability to comply with relevant laws and regulations and the reduction of regulatory compliance costs. We test these ideas in a sample of 141 acquisitions conducted by 86 Fortune 1000 firms. In the short run, acquirers that have high levels of CBITI capabilities receive positive and significant cumulative abnormal returns to their M&A announcements. Announcement period returns indicate that the capital markets value CBITI similarly in same-industry and different-industry acquisitions. In the long run, acquirers with high levels of CBITI capabilities obtain significantly higher abnormal operating performance. They create significantly greater value in complementary acquisitions from different industries than in related acquisitions from the same industry. The findings have important implications for M&A research and practice.
Research Note—The Impact of Community Commitment on Participation in Online Communities
Authors: Bateman Patrick J. , Gray Peter H. , Butler Brian S.
Published: January 2010

Online discussion communities have become a widely used medium for interaction, enabling conversations across a broad range of topics and contexts. Their success, however, depends on participants' willingness to invest their time and attention in the absence of formal role and control structures. Why, then, would individuals choose to return repeatedly to a particular community and engage in the various behaviors that are necessary to keep conversation within the community going? Some studies of online communities argue that individuals are driven by self-interest, while others emphasize more altruistic motivations. To get beyond these inconsistent explanations, we offer a model that brings dissimilar rationales into a single conceptual framework and shows the validity of each rationale in explaining different online behaviors. Drawing on typologies of organizational commitment, we argue that members may have psychological bonds to a particular online community based on (a) need, (b) affect, and/or (c) obligation. We develop hypotheses that explain how each form of commitment to a community affects the likelihood that a member will engage in particular behaviors (reading threads, posting replies, moderating the discussion). Our results indicate that each form of community commitment has a unique impact on each behavior, with need-based commitment predicting thread reading, affect-based commitment predicting reply posting and moderating behaviors, and obligation-based commitment predicting only moderating behavior. Researchers seeking to understand how discussion-based communities function will benefit from this more precise theorizing of how each form of member commitment relates to different kinds of online behaviors. Community managers who seek to encourage particular behaviors may use our results to target the underlying form of commitment most likely to encourage the activities they wish to promote.
Managing the Versions of a Software Product Under Variable and Endogenous Demand
Authors: Doğan Kutsal , Ji Yonghua , Mookerjee Vijay S. , Radhakrishnan Suresh
Published: January 2010

Software product versioning (i.e., upgrading the product after its initial release) is a widely adopted practice followed by leading software providers such as Microsoft, Oracle, and IBM. Unlike conventional durable goods, software products are relatively easy to upgrade, making upgrades a strategic consideration in commercial software production. We consider a two-period model with a monopoly software provider who develops and releases a software product to the market. Unlike previous research, we consider demand variability and endogeneity to determine the functionality of the software in the first and second periods. Demand endogeneity is the impact of the word-of-mouth effect that positively relates the features in the initial release of the product to its demand in the second period. We also determine the design effort that should be spent in the first period to prepare for upgrading the product in the second period—upgrade design effort—to tap into the possible future demand. Results show that the upgrade design effort can be lower or higher when there is more market demand uncertainty. We also show that the features of the product in its initial release and upgrade design effort can be complements as well as substitutes, depending on the strength of the word-of-mouth effect. The results in this paper provide insights into how demand-side factors (market demand variability or demand endogeneity) can influence supply-side decisions (initial features and upgrade design effort). A key insight of the analysis is that a high word-of-mouth effect helps manage the product in the face of demand variability.
Anatomy on tour: Postgraduate surgical training in a mobile teaching unit
Authors: Griggs RKL , Wilde C , Lee J , Greene JRT
Published: January 2010

Candidates for postgraduate surgical exams now have to learn much of their anatomy de novo rather than simply revise what they learned as medical students. A number of short courses have developed that help candidates prepare for the Intercollegiate Membership of the Royal College of Surgeons (MRCS). Unfortunately these courses tend to be centralised and trainees incur high travel and accommodation costs when attending them. Trainees are also absent from their hospitals for long periods, which can disrupt clinical services.
Motivational factors of surgeons interested in postgraduate surgical education: a narrative inquiry
Authors: Scott HJ
Published: January 2010

Clinical teachers are central to the successful education of medical graduates and dedicated surgical trainers are pivotal to the training of surgical trainees. The structure of education has changed within the NHS: the instigation of the Postgraduate Medical Education and Training Board (PMETB) and Modernising Medical Careers (MMC) has taken the ultimate responsibility for quality assurance from the colleges and the profession, into a government-run body.
We enter the second decade
Authors: Black John
Published: January 2010

I wonder how many royal college presidents have ever been in the UNISON building on the Euston Road? I suspect I may have been the first when I went there recently to address their medical secretaries' group and to take part in a panel discussion. The loss of consultant surgeons' personal secretaries that has occurred in many NHS hospitals over the last ten years is deplorable. It is a common event when a hospital moves to a new site or a new building that individual office accommodation for consultants and their secretaries is forgotten or even worse, that many of the tasks are outsourced abroad.
Paediatric surgical training for general surgical trainees: a trainee's experience
Authors: Evans C , Reece-Smith H , Grant HW
Published: January 2010

'The provision of GPS [general paediatric surgery] in the DGH [district general hospital] setting is reaching a crisis. The underlying problem is a failure to train and recruit general surgeons with appropriate paediatric skills and experience.