bluuebunny/crossref_metadata_2025 huggingface dataset:
γ-Tubulin plays a key role in inactivating APC/CCdh1 at the G1–S boundary
Authors: Edgerton-Morgan Heather , Oakley Berl R.
Published: August 2012

A γ-tubulin mutation in Aspergillus nidulans, mipA-D159, causes failure of inactivation of the anaphase-promoting complex/cyclosome (APC/C) in interphase, resulting in failure of cyclin B (CB) accumulation and removal of nuclei from the cell cycle. We have investigated the role of CdhA, the A. nidulans homologue of the APC/C activator protein Cdh1, in γ-tubulin–dependent inactivation of the APC/C. CdhA was not essential, but it targeted CB for destruction in G1, and APC/CCdhA had to be inactivated for the G1–S transition. mipA-D159 altered the localization pattern of CdhA, and deletion of the gene encoding CdhA allowed CB to accumulate in all nuclei in strains carrying mipA-D159. These data indicate that mipA-D159 causes a failure of inactivation of APC/CCdhA at G1–S, perhaps by altering its localization to the spindle pole body, and, thus, that γ-tubulin plays an important role in inactivating APC/CCdhA at this point in the cell cycle.
Rad53 is essential for a mitochondrial DNA inheritance checkpoint regulating G1 to S progression
Authors: Crider David G. , García-Rodríguez Luis J. , Srivastava Pallavi , Peraza-Reyes Leonardo , Upadhyaya Krishna , Boldogh Istvan R. , Pon Liza A.
Published: August 2012

The Chk2-mediated deoxyribonucleic acid (DNA) damage checkpoint pathway is important for mitochondrial DNA (mtDNA) maintenance. We show in this paper that mtDNA itself affects cell cycle progression. Saccharomyces cerevisiae rho0 cells, which lack mtDNA, were defective in G1- to S-phase progression. Deletion of subunit Va of cytochrome c oxidase, inhibition of F1F0 adenosine triphosphatase, or replacement of all mtDNA-encoded genes with noncoding DNA did not affect G1- to S-phase progression. Thus, the cell cycle progression defect in rho0 cells is caused by loss of DNA within mitochondria and not loss of respiratory activity or mtDNA-encoded genes. Rad53p, the yeast Chk2 homologue, was required for inhibition of G1- to S-phase progression in rho0 cells. Pif1p, a DNA helicase and Rad53p target, underwent Rad53p-dependent phosphorylation in rho0 cells. Thus, loss of mtDNA activated an established checkpoint kinase that inhibited G1- to S-phase progression. These findings support the existence of a Rad53p-regulated checkpoint that regulates G1- to S-phase progression in response to loss of mtDNA.
Bipolar and unipolar resistive switching effects in an Al/DLC/W structure
Authors: Peng Pinggang , Xie Dan , Yang Yi , Zhou Changjian , Ma Shuo , Feng Tingting , Tian He , Ren Tianling
Published: August 2012

In this paper, nonvolatile bipolar resistive switching (BRS) as well as unipolar resistive switching (URS) effects are observed in diamond-like carbon (DLC) thin films prepared by the filtered cathodic vacuum arc technique. By controlling the current compliance, either bipolar or unipolar switching is obtained. The fabricated Al/DLC/W structure showing BRS exhibits good performance with a low operation voltage (<1.0 V) and a data retention time of >105 s. The mechanism of BRS is fitted by ohmic and SCLC laws in the low resistance state and high resistance state scenarios. Fuse and antifuse effects are proposed to be the principle for the URS behaviour.
Photocatalytic Si nanowires/TiO2 microparticles with extended absorption edge up to 700 nm
Authors: Chen Chia-Yun , Chen Arh-Hwang
Published: August 2012

Single-crystalline Si nanowires are fabricated by Ag-assisted chemical etching at room temperature. On the basis of efficient light harvesting of Si nanowires, the novel photocatalysts are prepared by mixing the as-prepared Si nanowires with TiO2 microparticles of various weight ratios. The dye degradation of these combined photocatalysts is above two times more efficient than conventionally used TiO2 under 580 nm light irradiation. We have also validated that the involving photodegradation agrees well with the first-order kinetic model. These photocatalysts possess broad-band absorption with extended edge up to 700 nm, facilitating high photocatalytic activity for the urgent treatment of water pollutants.
On the overdamping phenomenon: A general result and applications
Authors: Goldstein Gisèle , Goldstein Jerome , Menzala Gustavo
Published: August 2012

We study the best possible energy decay rates for a class of linear second-order dissipative evolution equations in a Hilbert space. The models we consider are generated by a positive selfadjoint operator

A
A

having a bounded inverse. Our discussion applies to important examples such as the classical wave equation, the dynamical wave equation with Wentzell boundary conditions and many others.
Names Proper and Improper in Richard Millet's Siom Novels
Authors: Jackson Alan
Published: August 2012

Since 1983 Richard Millet has published a considerable volume of fictional and critical writings, including short stories,
récits
, and twelve novels. This study concentrates on four key novels published between 1995 and 2003 that take place in the imaginary village of Siom in the Corrèze:
La Gloire des Pythres
,
L'Amour des trois sœurs Piale
,
Lauve le pur
, and
Ma vie parmi les ombres
. Names feature increasingly prominently in these novels, and the aim of this study is to describe the different ways in which they are present and to analyse the functions they perform. They are found to have extraordinarily powerful effects. Some names, predominantly those from France's literary heritage, act as tokens of a dreamed-of communion with the past. Others, names of fictional characters and places, are found to be so intensely meaningful that they determine destinies. Yet others, the names of the main families in the novels, provide fragile foundations. Their names, on the one hand, serve to root them in a village and a genealogy, but, on the other, embody forces that destroy all hope of enduring. In each case the proper noun expresses a dream of presence that remains unfulfilled.
Sevoflurane Anesthesia Does Not Impair Acquisition Learning or Memory in the Morris Water Maze in Young Adult and Aged Rats
Authors: Callaway Jennifer K. , Jones Nigel C. , Royse Alistair G. , Royse Colin F.
Published: August 2012

Background

Sevoflurane has been found to increase apoptosis and pathologic markers associated with Alzheimer disease, provoking concern over their potential contribution to postoperative cognitive dysfunction.

Methods

The effects of anesthesia with 1 minimum alveolar concentration of sevoflurane for 4 h or sham exposure on cognition were investigated in young adult and aged (20-24 months) rats at 1, 4, and 12 weeks postexposure. Spatial reference memory acquisition and retention were tested in the Morris water maze task. Latency to locate the hidden platform and swim speed were determined and compared between treatments.

Results

Sevoflurane anesthesia significantly reduced latency to find the hidden platform in both young adult (n = 10 per treatment, P < 0.0001) and aged rats (n = 7 per treatment, P < 0.0001) when tested 1 week after exposure. In young rats only, this improved acquisition learning was maintained at 4 (P = 0.003) but not at 12 weeks postexposure (P = 0.061). There were no differences in swim speed or in open field exploration between groups (no confounding effects of stress or locomotion). Retention memory measured using probe trials was not affected by exposure to sevoflurane in young adult or aged rats.

Conclusion

Sevoflurane anesthesia did not impair acquisition learning and retention memory in young adult or aged rats.
Activation of Canonical Notch Signaling Pathway Is Involved in the Ischemic Tolerance Induced by Sevoflurane Preconditioning in Mice
Authors: Yang Qianzi , Yan Wenjun , Li Xin , Hou Lihong , Dong Hui , Wang Qiang , Dong Hailong , Wang Shiquan , Zhang Xia , Xiong Lize
Published: August 2012

Background

A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model.

Methods

C57BL/6 mice were pretreated with 1-h sevoflurane exposure at a dose of 2.5% for 5 consecutive days. Twenty-four hours after the last exposure, all mice were subjected to focal cerebral ischemia by right middle cerebral artery occlusion for 60 min. Neurobehavioral scores, brain infarct volumes, and cellular apoptosis were determined at 72 h after reperfusion (n = 10 per group). The activation of Notch signaling was evaluated (n = 5 per group), and its role in ischemic tolerance was assessed by intraperitoneal administration of γ-secretase inhibitor DAPT (100 mg/kg, n = 10 per group) and conditional Notch-RBP-J knockout technique (n = 8 per group).

Results

Sevoflurane preconditioning reduced brain infarct volumes (42.5%), improved neurologic outcomes (P < 0.01 vs. control), and attenuated neuronal cell apoptosis (cells positive for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling reduced to 21.2%). The expression of Notch1 intracellular domain (1.35 folds) and the transcriptions of Hes1 (1.95 times) and Hes5 (1.48 times) were up-regulated. DAPT augmented the brain infarcts (1.64-fold) and decreased neurologic scores (P = 0.43 vs. sevoflurane) in sevoflurane-preconditioned mice. Brain infarct volumes, neurobehavioral scores, and apoptotic cell numbers showed no significance between Notch knockout mice with sevoflurane preconditioning and wild-type mice without preconditioning.

Conclusions

Sevoflurane preconditioning-induced protective effects against transient cerebral ischemic injuries are mediated by the activation of canonical Notch signaling pathway in mice.
Electroencephalographic and Hypnotic Recoveries after Brief and Prolonged Infusions of Etomidate and Optimized Soft Etomidate Analogs
Authors: Ge Rile , Pejo Ervin , Husain S. Shaukat , Cotten Joseph F. , Raines Douglas E.
Published: August 2012

Background

Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate.

Methods

Etomidate, DMMM, and CPMM where infused into rats (n = 6 per group) for either 5 min or 120 min. After infusion termination, electroencephalographic and hypnotic recovery times were measured. The immobilizing ED50 infusion rates were determined using a tail clamp assay.

Results

Upon terminating 5-min infusions, electroencephalographic and hypnotic recovery times were not different among hypnotics. However, upon terminating 120-min infusions, recovery times varied significantly with respective values (mean ± SD) 48 ± 13 min and 31 ± 6.5 min (etomidate), 17 ± 7.0 min and 14 ± 3.4 min (DMMM), and 4.5 ± 1.1 min and 4.2 ± 1.6 min (CPMM). The immobilizing ED50 infusion rates were (mean ± SD) 0.19 ± 0.03 mg · kg · min (etomidate), 0.60 ± 0.12 mg · kg · min (DMMM), and 0.89 ± 0.18 mg · kg · min (CPMM).

Conclusions

Electroencephalographic and hypnotic recoveries following prolonged infusions of DMMM and CPMM are faster than those following methoxycarbonyl etomidate or etomidate. In the case of CPMM infusion, recovery times are 4 min and context-insensitive.
Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway
Authors: Nagaraj Raghavendra , Gururaja-Rao Shubha , Jones Kevin T. , Slattery Matthew , Negre Nicolas , Braas Daniel , Christofk Heather , White Kevin P. , Mann Richard , Banerjee Utpal
Published: August 2012

Mitochondrial structure and function are highly dynamic, but the potential roles for cell signaling pathways in influencing these properties are not fully understood. Reduced mitochondrial function has been shown to cause cell cycle arrest, and a direct role of signaling pathways in controlling mitochondrial function during development and disease is an active area of investigation. Here, we show that the conserved Yorkie/YAP signaling pathway implicated in the control of organ size also functions in the regulation of mitochondria in Drosophila as well as human cells. In Drosophila, activation of Yorkie causes direct transcriptional up-regulation of genes that regulate mitochondrial fusion, such as opa1-like (opa1) and mitochondria assembly regulatory factor (Marf), and results in fused mitochondria with dramatic reduction in reactive oxygen species (ROS) levels. When mitochondrial fusion is genetically attenuated, the Yorkie-induced cell proliferation and tissue overgrowth are significantly suppressed. The function of Yorkie is conserved across evolution, as activation of YAP2 in human cell lines causes increased mitochondrial fusion. Thus, mitochondrial fusion is an essential and direct target of the Yorkie/YAP pathway in the regulation of organ size control during development and could play a similar role in the genesis of cancer.
Immune tolerance in haemophilia: the long journey to the fork in the road
Authors: DiMichele Donna M.
Published: August 2012

Antibody eradication is the ultimate goal of inhibitor management. The only clinically proven strategy for achieving antigen‐specific tolerance to factorVIIIis immune tolerance induction (ITI). Our knowledge aboutITIin haemophiliaAandBwas, historically, derived from small cohort studies and retrospective national and internationalITIregistries. Practice is now further influenced by prospective cohort data, and the results of a single prospective randomized internationalITItrial. However, due to the low incidence of inhibitors in haemophiliaB, there are few comparable data from which to develop a useful evidence‐based approach to the prevention and eradication of factorIXinhibitors. The lack of an effective strategy is particularly problematic given the morbidity associated with the unique occurrence of allergic and anaphylactic reactions that often herald factorIXantibody development and preclude effective eradication. This paper will discuss our current understanding of immune tolerance outcome and outcome predictors for haemophiliaAandB; review the current consensus practice recommendations forITI; and summarize the emerging body of immunological science relating to antibody formation and tolerance. It will conclude by suggesting how our knowledge might inform the future investigative priorities impacting the therapeutic and preventative tolerance strategies of tomorrow.
Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003–06 from the Japan Association of Childhood Leukaemia Study
Authors: Imamura Toshihiko , Iwamoto Shotaro , Kanai Rie , Shimada Akira , Terui Kiminori , Osugi Yuko , Kobayashi Ryoji , Tawa Akio , Kosaka Yoshiyuki , Kato Koji , Hori Hiroki , Horibe Keizo , Oda Megumi , Adachi Souichi
Published: August 2012

The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5‐year overall survival (OS) and event‐free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5‐year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core‐binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5‐year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.
Impact of metformin monotherapy versus metformin with oestrogen‐progesterone on lipids in adolescent girls with polycystic ovarian syndrome
Authors: Bredella Miriam A. , McManus Shilpa , Misra Madhusmita
Published: August 2012

Objective

Hyperinsulinaemia is an important determinant of the polycystic ovarian syndrome (PCOS). In addition to lifestyle measures, therapeutic strategies include the use of oestrogen–progesterone combination pills (EP), and insulin sensitizers such as metformin, either alone or in combination. Data are limited regarding the impact of metformin alone vs metformin with EP on cardiometabolic risk in overweight adolescents with PCOS. We hypothesized that metformin alone would lead to an improvement in HbA1C and lipid levels in overweight adolescent girls with PCOS compared with meformin with EP.

Study design

Retrospective clinic‐based therapy.

Patients and measurements

We examined the effects of therapy with metformin alone (n = 14) vs metformin with EP (n = 13) on HbA1C and lipid parameters over 10–14 months in 27 overweight girls, drawn from a clinic population of adolescents with PCOS.

Results

The groups did not differ for age, body mass index (BMI), HbA1C or baseline lipids. After at least 10 months, the metformin only group compared with the metformin and EP group had a decrease in total cholesterol (−0·605 ± 0·100 vs 0·170 ± 0·348 mm, P = 0·02, nonparametric test) and triglycerides (−0·342 ± 0·184 vs 0·262 ± 0·133 mm, P = 0·02), despite similar changes in BMI (−1·6 ± 0·7 vs 0·6 ± 2·1 kg/m2, P = 0·25) and HbA1C (0·03 ± 0·06 vs 0·03 ± 0·13%, P = 0·99). Differences between groups remained significant after controlling for baseline parameters and for changes in BMI.

Conclusion

Metformin alone more effectively improves lipid parameters than metformin with EP in adolescent PCOS, as indicated by a decrease in total cholesterol and triglycerides. This effect is not related to BMI changes.
A novel surgical–prosthetic approach for soft tissue dehiscence coverage around single implant
Authors: Zucchelli Giovanni , Mazzotti Claudio , Mounssif Ilham , Mele Monica , Stefanini Martina , Montebugnoli Lucio
Published: August 2012

Objectives

The aim of the study was to evaluate soft‐tissue coverage and patient aesthetic satisfaction of a novel surgical–prosthetic approach to soft tissue dehiscence (STD) around single endosseous implant.

Material and methods

Twenty patients with buccal soft tissues dehiscence around single implants in the aesthetic area were consecutively enrolled. Treatment consisted in: removal of the implant supported crown, reduction in the implant abutment, coronally advanced flap in combination with connective tissue graft (CTG) and final restoration. The unrestored contralateral tooth normally positioned without recession defect was used as a reference. The soft tissue coverage and patient satisfaction were evaluated 1 year after the final restoration.

Results

One‐year mean STD coverage was 96.3%, and complete coverage was achieved in 75% of the treated sites. The increase (1.54 ± 0.21 mm) in buccal soft tissue thickness (STT) at 1 year was significantly correlated with CTG thickness at time of the surgery. The mean difference between graft thickness and STT increase was 0.09 ± 0.14 mm, corresponding to the 5.8% of the original graft thickness. The aesthetic analysis showed a significant improvement between the baseline (median, 3.8; 95% CI, 2–4) and the 1‐year (median, 8.0; 95% CI, 8–10) visual analogue scale (VAS) scores.

Conclusion

The results from the present study demonstrated that the proposed bilaminar technique was effective in the coverage of buccal STD around single dental implant and the suggested prosthetic–surgical approach was aesthetically successful.
Healing of buccal dehiscence defects at implants installed immediately into extraction sockets – an experimental study in dogs
Authors: Bressan Eriberto , Sivolella Stefano , Stellini Edoardo , Almagro Urrutia Zoraya , Lang Niklaus Peter , Botticelli Daniele
Published: August 2012

Aim

To evaluate the influence of implant positioning into extraction sockets on bone formation at buccal alveolar dehiscence defects.

Material and Methods

In six Labrador dogs the pulp tissue of the mesial roots of 4P4 was removed and the root canals were filled. Flaps were elevated bilaterally, the premolars hemi‐sectioned and the distal roots removed. The implants were placed in contact with either the buccal (test site) or with the lingual (control site) bony wall of the extraction sockets. Healing abutments were affixed and triangular buccal bony dehiscence defects, about 2.7 mm deep and 3.5 mm wide, were then prepared. No regenerative procedures were done and a non‐submerged healing was allowed. After 4 months of healing, block sections of the implant sites were obtained for histological processing and peri‐implant tissue assessment.

Results

After 4 months of healing, the bony crest and the coronal border of osseointegration at the test sites were located 1.71 ± 1.20 and 2.50 ± 1.21 mm apically to the implant shoulder, respectively. At the control sites, the corresponding values were 0.68 ± 0.63 and 1.69 ± 0.99 mm, respectively. The differences between test and control reached statistical significance (P < 0.05). Residual marginal bone defects were found both at the test and control sites. A statistically significant difference between test and control sites was only found at the lingual aspects (depth 2.09 ± 1.01 and 1.01 ± 0.48 mm, respectively). Similar heights of the buccal biological width were observed at both sites (about 5.1 mm).

Conclusions

The placement of implants in a lingual position of the extraction sockets allowed a higher degree of bone formation at buccal alveolar dehiscence defects compared with a buccal positioning.
Superior semicircular canal syndrome should be searching for an alternative pathology
Authors: Browning G.G.
Published: August 2012

Clin. Otolaryngol. 2012, 37, 298–299
COMPONENT‐COMPATIBILITY IN HISTORICAL BIOGEOGRAPHY
Authors: ZANDEE M. , ROOS M. C.
Published: August 2012

Abstract—

The problems of reconstructing historical relationships for areas of endemism from distributional data for groups of taxa and the cladistic relationships among the members of those groups can be solved by applying the two principles of parsimony and mutual inclusion or exclusion (compatibility) of components. Components can be extracted from a data matrix by means of transcription into partial monothetic sets. The data matrix thus derived represents the distribution over areas for the monophyletic groups in one or more cladograms. It is derived from two different matrices by boolean multiplication. The first matrix gives the binary representation of distributions of taxa over areas of endemism; the second describes the cladogram for the same taxa, in terms of character states converted into binary form by additive binary coding. The derived data matrix can be used in historical biogeography to represent the given phyletic data (Assumption 0here newly defined), and can be amended to reflectAssumptions 1or2to accomodate the problems of wide‐spread taxa and missing areas. Areacladograms are determined from the derived matrix by searching for the largest sets of mutually compatible components. Area‐cladograms are evaluated in terms of support (vicariance) and contradiction (ad hoc interpretations such as dispersal and extinction). Area‐cladograms that best fit the data matrix regarding the balance between support and contradiction are selected as the best possible recontructions of relationships among the areas of endemism. The procedure is illustrated by the example of the poeciliid fish generaHeterandriaandXiphophorus, and several other standard examples.
T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto’s thyroiditis
Authors: Wang S , Baidoo S E , Liu Y , Zhu C , Tian J , Ma J , Tong J , Chen J , Tang X , Xu H , Lu L
Published: August 2012

Leptin modulates T cell function and plays an important role in autoimmune diseases. Our study aimed to explore the role of leptin and T helper type 17 (Th17) cells in Hashimoto’s thyroiditis patients. Twenty-seven patients with Hashimoto’s thyroiditis (HT) and 20 healthy controls were enrolled into the current study. A modest increase of plasma leptin in HT patients and the CD4+ T cell-derived leptin from HT patients was stronger than that from healthy controls. In HT patients, there are no statistically significant correlations between plasma leptin concentrations and the percentage of Th17 cells or the level of retinoic acid-related orphan receptor γt (RORγt), but strong positive correlations were observed between CD4+ T cell-derived leptin and the percentage of Th17 cells or the level of RORγt mRNA, and additionally significantly up-regulated leptin, interleukin (IL)17 and RORγt mRNA levels in the thyroid tissue. Furthermore, neutralization of leptin decreases the frequency of Th17 cells in vitro. Current study has revealed an increased leptin involvment in Hashimoto’s thyroiditis associated with an increased number of Th17 cells.
Two serine phosphorylation sites in the C‐terminus of Rad9 are critical for 9‐1‐1 binding to TopBP1 and activation of the DNA damage checkpoint response in HeLa cells
Authors: Ueda Satoshi , Takeishi Yukimasa , Ohashi Eiji , Tsurimoto Toshiki
Published: August 2012

A heteromeric proliferating cell nuclear antigen‐like ring complex 9‐1‐1 is comprised of Rad9, Hus1 and Rad1. When assembled, 9‐1‐1 binds to TopBP1 and activates the ATR‐Chk1 checkpoint pathway. This binding in vitro depends on the phosphorylation of Ser‐341 and Ser‐387 in Rad9 and is reduced to 70% and 20% by an alanine substitution for Ser‐341 (S341A) and Ser‐387 (S387A), respectively, and to background level by their simultaneous substitution (2A). Here, we show the importance of phosphorylation of these two serine residues in vivo. siRNA‐mediated knockdown of Rad9 in HeLa cells impaired UV‐induced phosphorylation of checkpoint kinase, Chk1, and conferred hypersensitivity to UV irradiation and to methyl methane sulfonate or hydroxyurea treatments. Either siRNA‐resistant wild‐type Rad9 (Rad9Rr) or Rad9Rr harboring the S341A substitution restored the phosphorylation of Chk1 and damage sensitivity, whereas Rad9Rr harboring S387A or 2A did not. However, high expression of S387A restored Chk1 phosphorylation and partially suppressed the hypersensitivity. Thus, the affinity of Rad9 to TopBP1 correlates with the activation of the cellular DNA damage response and survival after DNA damage in HeLa cells, and phosphorylation of Ser‐341 and Ser‐387 of Rad9 is critical for full activation of the checkpoint response to DNA damage.
Review paper: What Kelvin might have written about Elasticity
Authors: Helbig Klaus
Published: August 2012

One hundred and fifty five years ago, Kelvin published the first part of a fundamental analysis of the elastic tensor, in which he proposed a coordinate‐free representation through its eigensystem. His thoughts were apparently far ahead of his time, since it took 125 years before the paper elicited a positive reaction (it is now accessible through several modern reviews). Science not only lost track for 125 years of the original paper but also lost the ideas Kelvin might have proposed in the second part, a publication that was never put to paper, presumably in view of the lack of appreciation of the first part.

In an attempt to establish what might have been on Kelvin's mind for a second part, one has to ‘forget’ the progress of mathematical physics in the intervening time and base all arguments strictly on the content of the first part and on the state of science in the second half of the 19thcentury.

The theory of elasticity would certainly have developed faster, had Kelvin's paper peen appreciated by his ‘peers’. But a theory based on Kelvin's ideas would be fruitful even today.
Anomalies of the anaerobic tricarboxylic acid cycle in Shewanella oneidensis revealed by Tn‐seq
Authors: Brutinel Evan D. , Gralnick Jeffrey A.
Published: August 2012

The availability of increasingly inexpensive sequencing combined with an ever‐expanding molecular biology toolbox has transported classical bacterial genetics into the 21st century. Whole genome genetic fitness analysis using transposon mutagenesis combined with next‐generation high‐throughput sequencing (Tn‐seq) promises to revolutionize systems level analysis of microbial metabolism. Tn‐seq measures the frequency of actual members of a heterogeneous mutant pool undergoing purifying selection to determine the contribution of every non‐essential gene in the genome to the fitness of an organism under a given condition. Here we use Tn‐seq to assess gene function in the Gram negative γ‐proteobacterium Shewanella oneidensis strain MR‐1. In addition to being a model environmental organism, there is considerable interest in using S. oneidensis as a platform organism for bioremediation and biotechnology, necessitating a complete understanding of the metabolic pathways that may be utilized. Our analysis reveals unique aspects of S. oneidensis metabolism overlooked by over 30 years of classical genetic and systems level analysis. We report the utilization of an alternative citrate synthase and describe a dynamic branching of the S. oneidensis anaerobic tricarboxylic acid cycle, unreported in any other organism, which may be a widespread strategy for microbes adept at dissipating reducing equivalents via anaerobic respiration.
NK Cells Inhibit T‐bet‐deficient, Autoreactive Th17 Cells
Authors: Wu W. , Shi S. , Ljunggren H.‐G. , Cava A. L. , Van Kaer L. , Shi F.‐D. , Liu R.
Published: August 2012

The differentiation and maintenance of Th17 cells require a unique cytokine milieu and activation of lineage‐specific transcription factors. This process appears to be antagonized by the transcription factor T‐bet, which controls the differentiation of Th1 cells. Considering that T‐bet‐deficient (T‐bet−/−) mice are largely devoid of natural killer (NK) cells due to a defect in the terminal maturation of these cells, and because NK cells can influence the differentiation of T helper cells, we investigated whether the absence of NK cells in T‐bet‐deficient mice contributes to the augmentation of autoreactive Th17 cell responses. We show that the loss of T‐bet renders the transcription factors Rorc and STAT3 highly responsive to activation by stimuli provided by NK cells. Furthermore, reconstitution of T‐bet−/− mice with wild‐type NK cells inhibited the development of autoreactive Th17 cells through NK cell‐derived production of IFN‐γ. These results identify NK cells as critical regulators in the development of autoreactive Th17 cells and Th17‐mediated pathology.
Evaluation of immunohistochemical staining using whole‐slide imaging for HER2 scoring of breast cancer in comparison with real glass slides
Authors: Kondo Yuzuru , Iijima Tatsuo , Noguchi Masayuki
Published: August 2012

Whole‐slide imaging (WSI) has been used for education and histological image preservation, and several studies have also reported its validity for practical pathological diagnosis. However, such studies employed materials stained with hematoxylin‐eosin (HE), and very few attempts have been made to use immunohistochemically stained materials for diagnostic purposes. In the present study, we investigated the availability of WSI diagnosis for immunohistochemically stained materials in place of routine glass slides. Thirty pathologists participated in a trial of HER2 expression diagnosis using WSI and compared the results with those obtained by light microscopy. The validity of WSI diagnosis (interobserver agreement) was rated as ‘substantial’ in comparison with glass slide diagnosis (κ‐value = 0.719). There was a tendency for observers to assign higher scores with WSI than with glass slides, probably because WSI requires slides to be scanned into a computer and observed via a monitor. Although we were able to demonstrate the potential utility of WSI for diagnosing immunostained materials, it must be borne in mind that there are some differences in visualization between WSI and glass slides.
Effects of intrapulmonary viral tropism and cytokine expression on the histological patterns of cytomegalovirus pneumonia
Authors: Arai Yoshifumi , Tsuchida Takashi , Kosugi Isao , Kawasaki Hideya , Meguro Shiori , Kinoshita Mana , Baba Satoshi , Maeda Matsuyoshi , Shinmura Yuichiro , Tsutsui Yoshihiro , Iwashita Toshihide
Published: August 2012

Pulmonary cytomegalovirus (CMV) infection causes fatal CMV pneumonia (CMVp) in immunocompromised patients; however, the mechanisms underlying CMV‐infection‐induced pulmonary lesion development remain largely unknown. We examined the relationship between CMVp patterns and intrapulmonary viral tropism, including expression of inflammatory cytokines and related molecules. Double immunohistochemistry of CMV antigen and cellular markers showed that epithelial tropism was associated with a diffuse alveolar damage (DAD) pattern (CMVp‐DAD) while stromal tropism was associated with a predominantly interstitial inflammation/fibrosis (IIF) (CMVp‐IIF) or a combination of DAD and IIF (CMVp‐complex). Transforming growth factor (TGF)‐β1 expression was relevant to CMV‐induced tissue injury, and its expression was higher in CMVp‐complex and CMVp‐IIF than in CMVp‐DAD. Expression of integrin β6 (ITGB6), an adhesion molecule and important activator of TGF‐β1 in interstitial pneumonia, was lost in CMV‐infected pneumocytes, especially CMVp‐DAD, whereas CMV‐negative pneumocytes in CMVp‐complex and CMVp‐IIF showed overexpression. Diffuse interleukin (IL)‐8 up‐regulation and strong expression were present in both CMV‐infected pneumocytes and stromal cells only in CMVp‐IIF cases with marked interstitial neutrophilic infiltration. On the basis of viral tropism and the expression of TGF‐β1, ITGB6, and IL‐8, we conclude that CMV‐infected pulmonary cells play an important role in the development of diverse CMVp patterns.
Early colorectal carcinomas: CD10 expression, mucin phenotype and submucosal invasion
Authors: Hirano Kimikazu , Nimura Satoshi , Mizoguchi Mikio , Hamada Yoshihiro , Yamashita Yuichi , Iwasaki Hiroshi
Published: August 2012

We analyzed 170 tumors (polypoid, 98; non‐polypoid, 72) of early colorectal carcinoma with or without submucosal invasions (Tis and T1 of TNM classification) from 161 patients to evaluate correlations between clinicopathological factors and immunohistochemical expressions of CD10, MUC2, and MUC5AC. The coexistence of adenomatous components was significantly less common in non‐polypoid carcinomas (4.2%) than in polypoid carcinomas (66.3%) (P < 0.0001). Non‐polypoid carcinomas were smaller in size and tended to infiltrate into the submucosa with higher incidence of lymphatic and venous permeations. CD10 was more frequently expressed in non‐polypoid carcinomas (70.8%) than in polypoid carcinomas (51.0%) (P= 0.01). Total carcinomas with high grade atypia showed higher incidence of CD10 expression (60.6%) than those with low grade atypia (28.9%) (P < 0.0001). Carcinomas with low grade atypia exhibited a higher incidence of MUC2 and MUC5AC expression (91.1% and 57.8%, respectively), when compared with carcinomas with high grade atypia (41.6% and 20.0%, respectively) (both, P < 0.0001). In submucosal invasive carcinomas with residual intramucosal carcinoma component (IMCC), CD10 expression in IMCC and submucosal invasive carcinoma component (SMCC) simultaneously exhibited identical positive or negative results, regardless of the polypoid or non‐polypoid growth pattern. The CD10 expression may occur in the early stage of carcinogenesis within the mucosa, and these neoplasms may retain CD10 in SMCC, possibly resulting in more advanced stages of stromal invasion and distant metastases. In conclusion, our data suggest that the CD10 expression and mucin phenotypes may be potentially useful markers for estimating biological properties of early colorectal carcinomas.
Aqueous calcium sulphate as bone graft for voids following open curettage of bone tumours
Authors: Johnson Luke James , Clayer Mark
Published: August 2012

Introduction

Reported strategies for void filling in bone include autograft, allograft, synthetic bone substitutes or various combinations of these materials, but poor response rates and donor morbidity have created a desire to find a better option. Calcium sulphate as a stand‐alone graft material reconstruct bone following curettage has not been previously reported. The purpose of this study was to assess the efficacy and radiological quality of healing, the time to healing, the functional outcomes and the complications following curettage and grafting using an injectable aqueous calcium sulphate (BonePlast; Biomet, Warsaw, IN, USA) as the sole grafting strategy.

Methods

The procedure of curettage and grafting with an aqueous solution of calcium sulphate was undertaken. The patients were regularly reviewed clinically and radiologically for a minimum of 12 months (range: 12–85 months). Forty‐six procedures in 46 patients were reviewed. Radiological outcomes of healing were established and functional outcomes were obtained from each patient at annual follow‐up review.

Results

A complete response was seen in 38 patients (83%) at a median of 6 months following the procedure (range: 1–24 months). Seven patients (15%) displayed only a partial response after a median of 13 months post‐surgery (range: 12–53 months). There was one non‐response to treatment (2%) after 40 months of follow‐up. The mean functional score was 99%.

Discussion

Aqueous calcium sulphate as a sole grafting agent for void management after curettage simplifies current treatment practices and displays good bone reconstruction in a comparatively short time frame, with excellent functional results and acceptable complication rates in the setting of tumour surgery.
The blue light receptor complex WC‐1/2 of Schizophyllum commune is involved in mushroom formation and protection against phototoxicity
Authors: Ohm Robin A. , Aerts David , Wösten Han A. B. , Lugones Luis G.
Published: August 2012

Blue light is necessary for initiation of mushroom formation in Schizophyllum commune. The genome of this basidiomycete contains homologues of the blue light receptor genes wc‐1 and wc‐2 of Neurospora crassa. Here, it is shown that inactivation of either or both of these genes in S. commune results in a blind phenotype. Mushroom formation was abolished in dikaryons and they formed symmetrical instead of asymmetrical colonies. Development was restored in a temperature dependent way in a Δwc‐2Δwc‐2 strain by introducing a construct encompassing the wc‐2 gene under control of the promoter of the heat shock gene hsp3. A genome‐wide expression analysis showed that the transcription factor genes c2h2 and hom1 as well as many hydrophobin genes are downregulated in light‐grown colonies of the Δwc‐2Δwc‐2 mutant when compared with the wild‐type dikaryon. Inactivation of wc‐1 and/or wc‐2 also resulted in sensitivity of the mycelium to intense light. Monokaryotic mutant strains only survived exposure to 6500 lux of light by growing into the agar. Expression analysis indicates that the photosensitivity of the Δwc‐1 and Δwc‐2 strains is due to lower levels of photolyase and ferrochelatase.
Nutrition‐/diet‐induced changes in gene expression in pancreatic β‐cells
Authors: Chadt A. , Yeo G. S. H. , Al‐Hasani H.
Published: August 2012

β‐Cell dysfunction is a critical component in the development of type 2 diabetes. Whilst both genetic and environmental factors contribute to the development of the disease, relatively little is known about the molecular network that is responsible for diet‐induced functional changes in pancreatic β‐cells. Recent genome‐wide association studies for diabetes‐related traits have generated a large number of candidate genes that constitute possible links between dietary factors and the genetic susceptibility for β‐cell failure. Here, we summarize recent approaches for identifying nutritionally regulated transcripts in islets on a genome‐wide scale. Polygenic mouse models for type 2 diabetes have been instrumental for investigating the mechanism of diet‐induced β‐cell dysfunction. Enhanced oxidative metabolism, triggered by a combination of dietary carbohydrates and fat, appears to play a critical role in the pathophysiology of diet‐induced impairment of islets. More systematic studies of gene–diet interactions in β‐cells of rodent models in combination with genetic profiling might reveal the regulatory circuits fundamental for the understanding of diet‐induced impairments of β‐cell function in humans.
Bimodal impact of skeletal muscle on pancreatic β‐cell function in health and disease
Authors: Plomgaard P. , Halban P. A. , Bouzakri K.
Published: August 2012

Diabetes is a complex disease that affects many organs directly or indirectly. Type 2 diabetes mellitus is characterized by insulin resistance with a relative deficiency in insulin secretion. It has become apparent that inter‐organ communication is of great importance in the pathophysiology of diabetes. Far from being an inert tissue in terms of inter‐organ communication, it is now recognized that skeletal muscle can secrete so‐called myokines that can impact on the function of distant organs/tissues both favourably and unfavourably. We have proposed that communication between insulin‐resistant skeletal muscle and β‐cells occurs in diabetes. This is a novel route of communication that we further suggest is modified by the prevailing degree of insulin resistance of skeletal muscle. This review focuses on the various myokines [interleukin‐6 (IL‐6), tumor necrosis factor‐α, CXCL10, follistatin and IL‐8] which have been identified either after different types of exercise or in the secretome from control and insulin‐resistant human skeletal myotubes. We will also summarize studies on the impact of several myokines on pancreatic β‐cell proliferation, survival and function.
Islet function in obese adolescents
Authors: Giannini C. , Caprio S.
Published: August 2012

Concurrent with the epidemic of childhood obesity, an unprecedented increase in the prevalence of several adiposity‐related complications in this age group has emerged. In particular, type 2 diabetes (T2D), once considered an illness restricted to adulthood, is progressively affecting more and more adolescents, and represents now roughly 20–45% of new‐onset cases in this age group. To unravel the pathogenesis of diabetes development during adolescence, many studies have focused on defining early defects in both insulin sensitivity and secretion that might be implicated in the natural history of the disease. Although a lot still need to be clarified, studies have shown that the progression from normal glucose tolerance to T2D involves intermediate stages of impaired fasting glucose and/or impaired glucose tolerance, also known as prediabetes. Insulin resistance and β‐cell dysfunction represent the two major key pathogenetic defects underlying the progression to diabetes in obese youth. In this review, we have sought to mainly describe the role of β‐cell function in relation to the ambient insulin resistance in the development of T2D in obese adolescents.
Glucose metabolism: key endogenous regulator of β‐cell replication and survival
Authors: Dadon D. , Tornovsky‐Babaey S. , Furth‐Lavi J. , Ben‐Zvi D. , Ziv O. , Schyr‐Ben‐Haroush R. , Stolovich‐Rain M. , Hija A. , Porat S. , Granot Z. , Weinberg‐Corem N. , Dor Y. , Glaser B.
Published: August 2012

Recent studies in mice have shown that pancreatic β‐cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β‐cell regeneration is based on the replication of fully differentiated, insulin‐positive β‐cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β‐cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β‐cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β‐cells, and through a signalling cascade that resembles the pathway for glucose‐stimulated insulin secretion. We introduce the concept that the individual β‐cell workload, defined as the amount of insulin that an individual β‐cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell‐autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β‐cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β‐cells may allow for the development of effective regenerative therapies for diabetes.
β‐Cell preservation and regeneration in diabetes by modulation of β‐cell Ca2+ homeostasis
Authors: Herchuelz A. , Nguidjoe E. , Jiang L. , Pachera N.
Published: August 2012

Ca2+ extrusion from the β‐cell is mediated by two processes the Na/Ca exchanger (NCX) and the plasma membrane Ca2+‐ATPase (PMCA). Gain of function studies show that overexpression of NCX or PMCA leads to endoplasmic reticulum (ER) Ca2+ depletion with subsequent ER stress, decrease in β‐cell proliferation and β‐cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acid concentrations also induce ER Ca2+ depletion and β‐cell death in diabetes. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1+/−) leads to an increase in β‐cell function (insulin production and release), and a fivefold increase in both β‐cell mass and proliferation. The mutation also increases β‐cell resistance to hypoxia, and Ncx1+/− islets show a two to four times higher rate of diabetes cure than Ncx1+/+ islets when transplanted in diabetic animals. Thus, down‐regulation of the Na/Ca exchanger leads to various changes in β‐cell function that are opposite to the major abnormalities seen in diabetes. This provides a unique model for the prevention and treatment of β‐cell dysfunction in diabetes and following islet transplantation.
Metabolic programming of insulin action and secretion
Authors: Martin‐Gronert M. S. , Ozanne S. E.
Published: August 2012

Type 2 diabetes (T2D), also known as non‐insulin dependent diabetes mellitus, arises as a consequence of peripheral insulin resistance in combination with an inability of pancreatic islet β‐cells to secrete adequate amounts of insulin. It is widely recognized that the current environment (e.g. an unhealthy diet and sedentary lifestyle) contributes to this process. In recent years, however, the role of the early environment, particularly nutrition, has emerged as an important factor capable of influencing health and disease risk of an individual, including risk of T2D. The impact of early environment on glucose metabolism has been extensively studied. Compelling evidence from epidemiological studies and animal models suggests that early nutrition can affect insulin action as a mediator of glucose homeostasis in peripheral tissues and as an important regulator of appetite and body weight. The early environment can also affect β‐cell mass and function, and hence insulin secretion. The molecular mechanisms underlying the relationship between a suboptimal early environment and impaired insulin action and secretion is thought to include epigenetic modifications of the foetal genome, oxidative stress and mitochondrial dysfunction.