bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effectiveness of Family History Questionnaires in Cancer Genetic Counseling
Authors: Randall Armel Susan , McCuaig Jeanna , Finch Amy , Demsky Rochelle , Panzarella Tony , Murphy Joan , Rosen Barry
Published: May 2009

The number of individuals receiving genetic counseling for hereditary breast and ovarian cancer syndrome has steadily risen. To triage patients for genetic counseling and to help reduce the amount of time needed by a genetic counselor in direct patient contact, many clinics have implemented the use of family history questionnaires. Although such questionnaires are widely used, scant literature exists evaluating their effectiveness. This article explores the extent to which family history questionnaires are being used in Ontario and addresses the utility of such questionnaires in one familial cancer clinic. By comparing the pedigrees created from questionnaires to those updated during genetic counseling, the accuracy and effectiveness of the questionnaires was explored. Of 121 families recruited into the study, 12% acquired changes to their pedigree that led to a revised probability estimate for having a BRCA1 or BRCA2 mutation and 5% acquired changes that altered their eligibility for genetic testing. No statistically significant difference existed between the eligibility for genetic testing prior to and post counseling. This suggests that family history questionnaires can be effective at obtaining a family history and accurately assessing eligibility for genetic testing. Based on the variables that were significantly associated with a change in probability estimate, we further present recommendations for improving the clarity of such questionnaires and therefore the ease of use by patients.
“Ru”: Xunzi’s thoughts on Ru and its significance
Authors: Lai CHEN
Published: May 2009

No matter what the original meaning of “Ru” was, looking at it from the perspective of the history of philosophy, the image of “Ru” as portrayed by other schools in the Warring States period was infused with the characteristics of Confucianism of that time. The self-understanding of Warring States Confucians expressed by their employment of the character “Ru” clearly displayedRu’s character as well as the main points of theRuschool, namely Confucianism. In particular, the words and thoughts of Xunzi, the great Confucian master, on “Ru”, epitomize Pre-Qin Confucian’s understanding and expectations of themselves, and also reflect the Confucian new pursuit in facing the age of the unification of Qin.
On the creativity and innateness of the “strong, moving vital force”: A discussion of Feng Youlan’s “explanation of Mencius’ chapter on the ‘strong, moving vital force’ ”
Authors: Jinglin LI
Published: May 2009

Feng Youlan emphasizes the concept of “creativity” in his article “Explanation of Mencius’ Chapter on Strong, Moving Vital Force”, in particular highlighting the problem whether the “strong, moving vital force” is “innate” or “acquired”. Cheng Hao and Zhu Xi believed the “strong, moving vital force” was endowed by Heaven, so was therefore innate; “nourishment” cleared fog and allowed one to “recover one’s original nature”. Mencius’ theory on “the good of human nature” is illustrated in the concept of integrated “original endowment”. So Cheng Hao and Zhu Xi’s theory of “recovering the original nature” proposed that the “strong, moving vital force” was innate, which is in complete agreement with Mencius and of which there is ample evidence in Mencius. However, “nature” is “created by the accumulation of righteousness”. Namely, it is the completion and presentation of the process of creation and transformation of human beings. Only when we consider both Cheng Hao and Zhu Xi’s theory and Feng Youlan’s theory can we fully understand Mencius’ theory of “the nourishment of the strong, moving vital force”, which is of great theoretical and academic value in accurately understanding Mencius and the Confucian theory of mind-nature.
Ethics and ethicists in the modern context
Authors: Junren WAN
Published: May 2009

Ethics in the modern context is under the dual pressure of scientific-technological rationality and market commercialization, which has led to breakthroughs in the original boundaries of knowledge and academic methodology. The gradual separation of the domain of public life and that of private life in modern society and the former’s increasing pressure on the latter, in addition to the above dual pressure on ethics, is causing a dramatic transformation of the structure of ethical knowledge itself. All of these raise new theoretical problems for ethics and ethicists in the modern context. Answering and solving these problems makes sense for the future development of ethics as one of the classic humanities, and tests modern ethicists’ ability to realize their moral and theoretical duties.
Preparation and Characterization of Cationic PLA-PEG Nanoparticles for Delivery of Plasmid DNA
Authors: Zou Weiwei , Liu Chunxi , Chen Zhijin , Zhang Na
Published: May 2009

The purpose of the present work was to formulate and evaluate cationic poly(lactic acid)-poly(ethylene glycol) (PLA-PEG) nanoparticles as novel non-viral gene delivery nano-device. Cationic PLA-PEG nanoparticles were prepared by nanoprecipitation method. The gene loaded nanoparticles were obtained by incubating the report gene pEGFP with cationic PLA-PEG nanoparticles. The physicochemical properties (e.g., morphology, particle size, surface charge, DNA binding efficiency) and biological properties (e.g., integrity of the released DNA, protection from nuclease degradation, plasma stability, in vitro cytotoxicity, and in vitro transfection ability in Hela cells) of the gene loaded PLA-PEG nanoparticles were evaluated, respectively. The obtained cationic PLA-PEG nanoparticles and gene loaded nanoparticles were both spherical in shape with average particle size of 89.7 and 128.9 nm, polydispersity index of 0.185 and 0.161, zeta potentials of +28.9 and +16.8 mV, respectively. The obtained cationic PLA-PEG nanoparticles with high binding efficiency (>95%) could protect the loaded DNA from the degradation by nuclease and plasma. The nanoparticles displayed sustained-release properties in vitro and the released DNA maintained its structural and functional integrity. It also showed lower cytotoxicity than Lipofectamine 2000 and could successfully transfect gene into Hela cells even in presence of serum. It could be concluded that the established gene loaded cationic PLA-PEG nanoparticles with excellent properties were promising non-viral nano-device, which had potential to make cancer gene therapy achievable.
China's Embrace of the Market Economy: Understanding Its Innovation Strategy
Authors: Crookes Paul C. Irwin
Published: May 2009

The financial crisis now afflicting the world's economies has Chinese leaders and citizens worried as the ripple effect from US markets aggravates already slumping Chinese markets. As the country attempts to improve its productive capabilities, enhancing China's capacity to innovate remains a top priority. The author explores the initiatives which are being taken both within the country and abroad, illustrating how the country's competences within the innovation, technology and research field are being reformed in order to shape China for the future.
Last glacial climate instability documented by coarse-grained sediments within the loess sequence, at Fanjiaping, Lanzhou, China
Authors: Jiang Hanchao , Wang Ping , Thompson Jessica , Ding Zhongli , Lu Yanchou
Published: May 2009

Optically Stimulated Luminescence dating, grain-size analysis and magnetic susceptibility measurements were conducted on the Fanjiaping loess section, from the western Chinese Loess Plateau. The results confirm that last glacial high-frequency climatic shifts were documented in mid-latitude continental archives. The grain-size record indicated that coarse-grained sediments with horizontal bedding and channel-fill structures were only deposited in several short intervals, equivalent to the beginning of marine oxygen isotope stage (MIS) 4 and the early to middle MIS 3. This probably implies brief rainfall intensification of the Asian summer monsoon, and its disappearance since the late MIS 3 to MIS 2 may have been a response to significant glacial cooling in the Northern Hemisphere. Previous investigations revealed high sea-surface temperatures at high latitudes at the start of MIS 4, and the early to middle MIS 3 intensification of summer insolation in the Northern Hemisphere, implying evident climate amelioration. Climate improvement favors boreal forest recovery, enhancing both winter and summer air temperatures. The resultant smaller equator-polar temperature gradient probably helped the moisture-laden summer monsoon to penetrate northward. This study thus provides new significant information about the response of terrestrial loessic palaeoenvironments to millennial-timescale climatic fluctuations during the last glacial period.
Influence of coexisting myringosclerosis on myringoplasty outcomes in children
Authors: Migirov L , Volkov A
Published: May 2009

Objective:

To obtain information on the success rate of tympanoplasty with concomitant myringosclerosis.

Methods:

The medical records of 40 children with myringosclerosis (23 girls, 17 boys; age range six to 16 years, mean age 9.85 years) who had undergone primary tympanoplasty were retrospectively studied. Surgical success was defined as the perforation remaining closed 12 months post-operatively.

Results:

Sclerotic plaques occupied whole remnant eardrums in 17 patients, and were located in various parts of the eardrum in 23. Tympanosclerosis associated with myringosclerosis was present in six patients. The success rate of primary tympanoplasty was 92.5 per cent. All three surgical failures were observed in girls with marginal perforations. These children underwent successful revision procedures for their residual perforations, variously at four, eight and 10 months after the initial surgery.

Conclusion:

Appropriate freshening of the perforation edges, with removal of sclerotic plaques, can result in a high rate of successful closure of perforated tympanic membrane with coexisting myringosclerosis.
Wildlife disease and conservation in Hawaii: Pathogenicity of avian malaria (Plasmodium relictum) in experimentally infected Iiwi (Vestiaria coccinea)
Authors: Atkinson C. T. , Woods K. L. , Dusek R. J. , Sileo L. S. , Iko W. M.
Published: May 2009

Native Hawaiian forest birds are facing a major extinction crisis with more than 75% of species recorded in historical times either extinct or endangered. Reasons for this catastrophe include habitat destruction, competition with non-native species, and introduction of predators and avian diseases. We tested susceptibility of Iiwi (Vestiaria coccinea), a declining native species, and Nutmeg Mannikins (Lonchura punctulata), a common non-native species, to an isolate ofPlasmodium relictumfrom the island of Hawaii. Food consumption, weight, and parasitaemia were monitored in juvenile Iiwi that were infected by either single (low-dose) or multiple (high-dose) mosquito bites. Mortality in both groups was significantly higher than in uninfected controls, reaching 100% of high-dose birds and 90% of low-dose birds. Significant declines in food consumption and a corresponding loss of body weight occurred in malaria-infected birds. Both sex and body weight had significant effects on survival time, with males more susceptible than females and birds with low initial weights more susceptible than those with higher initial weights. Gross and microscopic lesions in malaria fatalities included massive enlargement of the spleen and liver, hyperplasia of the reticuloendothelial system with extensive deposition of malarial pigment, and overwhelming anaemia in which over 30% of the circulating erythrocytes were parasitized. Nutmeg Mannikins, by contrast, were completely refractory to infection. Our findings support previous studies documenting high susceptibility of native Hawaiian forest birds to avian malaria. This disease continues to threaten remaining high elevation populations of endangered native birds.
Jarry's Caesar Antichrist and the Theatre of the Book
Authors: Jannarone Kimberly
Published: May 2009

The familiarity bred by the notoriety in its own times of Alfred Jarry's Ubu Roi has been accompanied by neglect for his other work, especially that which seems of peripheral interest to the theatre practitioner. In this article, Kimberly Jannarone argues that his earlier Caesar Antichrist falls into the unusual category of ‘a piece of theatre not intended for the stage’ – apparently unstageable, yet not a closet drama since, in Jarry's scrupulous care for its published form, he created his own ‘theatre of the book’, anticipating the later modernist use of collage while also demonstrating in words and pictures his ‘pataphysical’ interest in the dialectics of opposites. Kimberly Jannarone received her MFA and DFA from the Yale School of Drama, and is currently teaching in the Department of Theater Arts at the University of California, Santa Cruz. She wrote on ‘Puppetry and Pataphysics: Populism and the Ubu Cycle’, in NTQ67 (2001).
Two decades of Ripple Down Rules research
Authors: Richards Debbie
Published: May 2009

Ripple Down Rules (RDR) were developed in answer to the problem of maintaining medium to large rule-based knowledge systems. Traditional approaches to knowledge-based systems gave little thought to maintenance as it was expected that extensive upfront domain analysis involving a highly trained specialist, the knowledge engineer, and the time-poor domain expert would produce a complete model capturing what was in the expert’s head. The ever-changing, contextual and embrained nature of knowledge were not a part of the philosophy upon which they were based. RDR was a paradigm shift, which made knowledge acquisition and maintenance one and the same thing by incrementally acquiring knowledge as domain experts directly interacted with naturally occurring cases in their domain. Cases played an integral part of the acquisition process by motivating the capture of new knowledge, framing the context in which new knowledge would apply and ensuring that previously correctly classified cases remained so by requiring that the classification of the new case distinguish it from the system’s classification and be justified by features of the new case. RDR has moved beyond its first representation which handled single classification tasks within the domain of pathology to support multiple conclusions across a wide range of domains such as help-desk support, email classification and RoboCup and problem types including configuration, simulation, planning and natural language processing. This paper reviews the history of RDR research over the past two decades with a view to its future.
A NOTE ON GROWTH EXPECTATION
Authors: Fujiwara Ippei
Published: May 2009

Recently, several researchers have succeeded in producing expectation–driven cycles by balancing the tension between the wealth effect and the substitution effect stemming from the higher expected future productivity. Especially, seminal research by Christiano et al. (“Monetary Policy and Stock Market Boom–Bust Cycles,” mimeo, Northwestern University, 2007), explains “stock market boom–bust cycles,” characterized by increases in consumption, labor inputs, investment, and stock prices relating to high expected future technology levels. We, however, show that such expectation–driven cycles are difficult to generate based on “growth expectation,” which reflects expectations of higher productivity growth rates.
Diurnal dependence of ELF/VLF hiss and its relation to chorus at L = 2.4
Authors: Golden D. I. , Spasojevic M. , Inan U. S.
Published: May 2009

We present the observation and analysis of all very low frequency (0.3–10 kHz) chorus and hiss emissions observed at Palmer Station, Antarctica (L = 2.4), from January through October 2003, near the peak of the most recent solar cycle. We classify three separate categories of emissions: chorus occurring without the presence of hiss (“chorus only”), hiss occurring without the presence of chorus (“hiss only”), and chorus and hiss occurring simultaneously (“chorus with hiss”). We find that observed chorus only and chorus with hiss emissions are confined to the dawn sector, below 6 kHz in frequency. Observed hiss only emissions are confined to the dusk sector, below 4 kHz in frequency. We conclude that there are at least two distinct types of hiss observed at Palmer Station: hiss that is observed with chorus in the dawn sector and hiss that is observed without chorus in the dusk sector. The correspondence of dawn chorus with dawn hiss suggests that these two emissions are strongly related to each other, while the frequency spectrum and local time distribution of dusk hiss, coupled with the absence of simultaneous chorus, suggest that dusk hiss may be generated by terrestrial lightning.
Ecohydrology of groundwater‐dependent ecosystems: 1. Stochastic water table dynamics
Authors: Laio Francesco , Tamea Stefania , Ridolfi Luca , D'Odorico Paolo , Rodriguez‐Iturbe Ignacio
Published: May 2009

Areas with a relatively shallow water table are environments where the groundwater plays a key role on the ecosystem function, and important interactions exist between hydrology and ecosystem processes. We propose here an analytical model to study the interactions between rainfall, water table, and vegetation in groundwater‐dependent ecosystems. The water table dynamics are studied as a random process stochastically driven by a marked Poisson noise representing rainfall events. Infiltration, root water uptake, water flow to/from an external water body, and capillary rise are accounted for in a probabilistic description of water table fluctuations. We obtain analytical expressions for the steady state probability distribution of water table depth, which allows us to investigate the long‐term behavior of water table dynamics, and their sensitivity to changes in climate, vegetation cover, and water management.
Sea ice conditions and melt season duration variability within the Canadian Arctic Archipelago: 1979–2008
Authors: Howell Stephen E. L. , Duguay Claude R. , Markus Thorsten
Published: May 2009

Sea ice conditions and melt season duration within the Canadian Arctic Archipelago (CAA) were investigated from 1979–2008. The CAA is exhibiting statistically significant decreases in average September total sea ice area at −8.7% decade−1. The melt season duration within the CAA is increasing significantly at 7 days decade−1. 2008 represented the longest melt season duration within the CAA over the satellite record at 129 days. Average September multi‐year ice (MYI) area is decreasing at −6.4% decade−1 but has yet to reach statistical significance as a result of increasing MYI dynamic import from the Arctic Ocean. Results also find that the Western Parry Channel (WPC) region of the Northwest Passage (NWP) will continue to be susceptible to MYI as the transition to a summer‐time sea ice free Arctic continues. The processes responsible for the temporary clearing of the WPC region of the NWP in 2007 were also identified.
A comparison of thermal infrared and ultraviolet retrievals of SO2 in the cloud produced by the 2003 Al‐Mishraq State sulfur plant fire
Authors: Kearney C. , Watson I. M. , Bluth G. J. S. , Carn S. , Realmuto V. J.
Published: May 2009

The detection of SO2 plumes by space‐based sensors has been demonstrated in the UV and TIR. However, the relationship between these retrieval techniques is poorly constrained. In this paper we compare near‐coincidental EP TOMS and MODIS data of a near‐pure SO2 plume from the Al‐Mishraq State sulfur plant fire on 29 June 2003. We resampled the MODIS data to the spatial resolution of EP TOMS in order to compare the two SO2 retrievals at the pixel scale. EP TOMS and MODIS return SO2 total tonnages of 103 and 118 kt, respectively. Overall, the agreement between the techniques on a pixel scale ranges between 10% to greater than 90% with no discernible spatial pattern. The variable agreement between the two retrievals is likely the result of differences in spatial resolution, presence of sulfates, and variations in plume height with distance from the fire.
Beijing Olympics as an aerosol field experiment
Authors: Cermak J. , Knutti R.
Published: May 2009

During the 2008 Olympic Summer Games, emission reductions were enforced in Beijing to improve air quality. Here we explore their effect on the regional aerosol load. We compare satellite‐retrieved aerosol optical thickness (AOT) of that period with previous years, both in absolute terms and in a neural network approach taking into account the meteorological conditions. A statistically significant reduction of aerosol load is found in Beijing that decreases in magnitude and significance with increasing region size. Locally, the aerosol load (log(AOT)) was about 0.4 to 0.75 standard deviations below the levels expected for the prevailing meteorological situation. The small size of this effect relative to meteorological variability highlights the importance of regional aerosol transport.
Entropy and plasma sheet transport
Authors: Wolf R. A. , Wan Yifei , Xing X. , Zhang J.‐C. , Sazykin S.
Published: May 2009

This paper presents a focused review of the role of entropy in plasma sheet transport and also describes new calculations of the implications of plasma sheet entropy conservation for the case where the plasma pressure is not isotropic. For the isotropic case, the entropy varies in proportion to log[PV5/3], where P is plasma pressure and V is the volume of a tube containing one unit of magnetic flux. Theory indicates that entropy should be conserved in the ideal MHD approximation, and a generalized form of entropy conservation also holds when transport by gradient/curvature drift is included. These considerations lead to the conclusion that under the assumption of strong, elastic pitch angle scattering, PV5/3 should be approximately conserved over large regions of the plasma sheet, though gradient/curvature drift causes major violations in the innermost region. Statistical magnetic field and plasma models lead to the conclusion that PV5/3 increases significantly with distance downtail (pressure balance inconsistency). We investigate the possibility that the inconsistency could be removed or reduced by eliminating the assumption of strong, elastic pitch angle scattering but find that the inconsistency becomes worse if the first two adiabatic invariants are conserved as the particles drift. We consider two previously suggested mechanisms, bubbles and gradient/curvature drift, and conclude that the combination of the two is likely adequate for resolving the pressure balance inconsistency. Quantitatively accurate estimation of the efficiency of these mechanisms depends on finding a method of estimating PV5/3 (or equivalent) from spacecraft measurements. Two present approaches to that problem are discussed.
Clonidine Transport at the Mouse Blood—Brain Barrier by a New H+Antiporter that Interacts with Addictive Drugs
Authors: André Pascal , Debray Marcel , Scherrmann Jean-Michel , Cisternino Salvatore
Published: May 2009

Identifying drug transporters and their in vivo significance will help to explain why some central nervous system (CNS) drugs cross the blood-brain barrier (BBB) and reach the brain parenchyma. We characterized the transport of the drug Clonidine at the luminal BBB by in situ mouse brain perfusion. Clonidine influx was saturable, followed by Michaelis–Menten kinetics ( Km= 0.62 mmol/L, Vmax= 1.76 nmol/sec per g at pH 7.40), and was insensitive to both sodium and trans-membrane potential. In vivo manipulation of intracellular and/or extracellular pH and Trans-stimulation showed that Clonidine was transported by an H+-coupled antiporter regulated by both proton and Clonidine gradients, and that diphenhydramine was also a substrate. Organic cation transporters (Oct1–3), P-gp, and Bcrp did not alter Clonidine transport at the BBB in knockout mice. Secondary or tertiary amine CNS compounds such as oxycodone, morphine, diacetylmorphine, methylenedioxyamphetamine (MDMA), cocaine, and nicotine inhibited Clonidine transport. However, cationic compounds that interact with choline, Mate, Octn, and Pmat transporters did not. This suggests that Clonidine is transported at the luminal mouse BBB by a new H+-coupled reversible antiporter.
Biologic Effects of Simvastatin in Patients with Aneurysmal Subarachnoid Hemorrhage: A Double-Blind, Placebo-Controlled Randomized Trial
Authors: Vergouwen Mervyn DI , Meijers Joost CM , Geskus Ronald B , Coert Bert A , Horn Janneke , Stroes Erik SG , van der Poll Tom , Vermeulen Marinus , Roos Yvo BWEM
Published: May 2009

Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol ( P < 0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH (ISRCTN45662651).
Overexpression of Drosophila mitoferrin in l(2)mbn cells results in dysregulation of Fer1HCH expression
Authors: Metzendorf Christoph , Wu Wenlin , Lind Maria I.
Published: May 2009

Mrs3p and Mrs4p (Mrs3/4p) are yeast mitochondrial iron carrier proteins that play important roles in ISC (iron-sulphur cluster) and haem biosynthesis. At low iron conditions, mitochondrial and cytoplasmic ISC protein maturation is correlated with MRS3/4 expression. Zebrafish mitoferrin1 (mfrn1), one of two MRS3/4 orthologues, is essential for erythropoiesis, but little is known about the ubiquitously expressed paralogue mfrn2. In the present study we identified a single mitoferrin gene (dmfrn) in the genome of Drosophila melanogaster, which is probably an orthologue of mfrn2. Overexpression of dmfrn in the Drosophila l(2)mbn cell line (mbn-dmfrn) resulted in decreased binding between IRP-1A (iron regulatory protein 1A) and stem-loop RNA structures referred to as IREs (iron responsive elements). mbn-dmfrn cell lines also had increased cytoplasmic aconitase activity and slightly decreased iron content. In contrast, iron loading results in decreased IRP-1A–IRE binding, but increased cellular iron content, in experimental mbn-dmfrn and control cell lines. Iron loading also increases cytoplasmic aconitase activity in all cell lines, but with slightly higher activity observed in mbn-dmfrn cells. From this we concluded that dmfrn overexpression stimulates cytoplasmic ISC protein maturation, as has been reported for MRS3/4 overexpression. Compared with control cell lines, mbn-dmfrn cells had higher Fer1HCH (ferritin 1 heavy chain homologue) transcript and protein levels. RNA interference of the putative Drosophila orthologue of human ABCB7, a mitochondrial transporter involved in cytoplasmic ISC protein maturation, restored Fer1HCH transcript levels of iron-treated mbn-dmfrn cells to those of control cells grown in normal medium. These results suggest that dmfrn overexpression in l(2)mbn cells causes an ‘overestimation’ of the cellular iron content, and that regulation of Fer1HCH transcript abundance probably depends on cytoplasmic ISC protein maturation.
The DNA-damage response: new molecular insights and new approaches to cancer therapy
Authors: Jackson Stephen P.
Published: May 2009

The DNA of all cells is continually under assault from a wide range of DNA-damaging agents. To counter this threat to their genetic integrity, cells possess systems, collectively known as the DDR (DNA-damage response), to detect DNA damage, signal its presence and mediate its repair. In the present article, I provide an overview of the DDR and then describe how work in my laboratory and elsewhere has identified some of the key protein players that mediate cellular responses to the most cytotoxic form of DNA damage: the DNA DSB (double-strand break). I also discuss some of my laboratory's recent work, which has revealed that the way cells respond to DSBs is modulated in a cell-cycle-dependent manner to ensure that the cell uses the DSB repair system that is most suited to its cell-cycle stage. Finally, I explain how our increasing knowledge of the DDR is suggesting new avenues for treating cancer and provide an example of a DDR-inhibitory drug that is showing promise in clinical trials.
The search for a human Holliday junction resolvase
Authors: West Stephen C.
Published: May 2009

Four-way DNA intermediates, known as Holliday junctions, are formed during mitotic and meiotic recombination, and their efficient resolution is essential for proper chromosome segregation. Bacteria, bacteriophages and archaea promote Holliday junction resolution by the introduction of symmetrically related nicks across the junction, in reactions mediated by Holliday junction resolvases. In 2008, after a search that lasted almost 20 years, a Holliday junction resolvase was identified in humans. The protein, GEN1, was identified using MS following the brute-force fractionation of extracts prepared from human cells grown in tissue culture. GEN1 fits the paradigm developed from studies of prokaryotic Holliday junction resolvases, in that it specifically recognizes junctions and resolves them using a mechanism similar to that exhibited by the Escherichia coli RuvC protein.
Repairing DNA double-strand breaks by the prokaryotic non-homologous end-joining pathway
Authors: Brissett Nigel C. , Doherty Aidan J.
Published: May 2009

The NHEJ (non-homologous end-joining) pathway is one of the major mechanisms for repairing DSBs (double-strand breaks) that occur in genomic DNA. In common with eukaryotic organisms, many prokaryotes possess a conserved NHEJ apparatus that is essential for the repair of DSBs arising in the stationary phase of the cell cycle. Although the bacterial NHEJ complex is much more minimal than its eukaryotic counterpart, both pathways share a number of common mechanistic features. The relative simplicity of the prokaryotic NHEJ complex makes it a tractable model system for investigating the cellular and molecular mechanisms of DSB repair. The present review describes recent advances in our understanding of prokaryotic end-joining, focusing primarily on biochemical, structural and cellular aspects of the mycobacterial NHEJ repair pathway.
Structure, function and evolution of the XPD family of iron–sulfur-containing 5′→3′ DNA helicases
Authors: White Malcolm F.
Published: May 2009

The XPD (xeroderma pigmentosum complementation group D) helicase family comprises a number of superfamily 2 DNA helicases with members found in all three domains of life. The founding member, the XPD helicase, is conserved in archaea and eukaryotes, whereas the closest homologue in bacteria is the DinG (damage-inducible G) helicase. Three XPD paralogues, FancJ (Fanconi's anaemia complementation group J), RTEL (regular of telomere length) and Chl1, have evolved in eukaryotes and function in a variety of DNA recombination and repair pathways. All family members are believed to be 5′→3′ DNA helicases with a structure that includes an essential iron–sulfur-cluster-binding domain. Recent structural, mutational and biophysical studies have provided a molecular framework for the mechanism of the XPD helicase and help to explain the phenotypes of a considerable number of mutations in the XPD gene that can cause three different genetic conditions: xeroderma pigmentosum, trichothiodystrophy and Cockayne's syndrome. Crystal structures of XPD from three archaeal organisms reveal a four-domain structure with two canonical motor domains and two unique domains, termed the Arch and iron–sulfur-cluster-binding domains. The latter two domains probably collaborate to separate duplex DNA during helicase action. The role of the iron–sulfur cluster and the evolution of the XPD helicase family are discussed.
Genomic instability and cancer: lessons from analysis of Bloom's syndrome
Authors: Payne Miranda , Hickson Ian D.
Published: May 2009

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability and cancer predisposition. The underlying genetic defect is mutation of the BLM gene, producing deficiency in the RecQ helicase BLM (Bloom's syndrome protein). The present article begins by introducing BLM and its binding partners before reviewing its known biochemical activities and its potential roles both as a pro-recombinase and as a suppressor of homologous recombination. Finally, the evidence for an emerging role in mitotic chromosome segregation is examined.
Regulation of activation-induced cytidine deaminase DNA deamination activity in B-cells by Ser38 phosphorylation
Authors: Basu Uttiya , Franklin Andrew , Schwer Bjoern , Cheng Hwei-Ling , Chaudhuri Jayanta , Alt Frederick W.
Published: May 2009

Human and mouse Ig genes are diversified in mature B-cells by distinct processes known as Ig heavy-chain CSR (class switch recombination) and Ig variable-region exon SHM (somatic hypermutation). These DNA-modification processes are initiated by AID (activation-induced cytidine deaminase), a DNA cytidine deaminase predominantly expressed in activated B-cells. AID is post-transcriptionally regulated via multiple mechanisms, including microRNA regulation, nucleocytoplasmic shuttling, ubiquitination and phosphorylation. Among these regulatory processes, AID phosphorylation at Ser38 has been a focus of particularly intense study and debate. In the present paper, we discuss recent biochemical and mouse genetic studies that begin to elucidate the functional significance of AID Ser38 phosphorylation in the context of the evolution of this mode of AID regulation and the potential roles that it may play in activated B-cells during a normal immune response.
The impact of heterochromatin on DSB repair
Authors: Goodarzi Aaron A. , Noon Angela T. , Jeggo Penny A.
Published: May 2009

DNA NHEJ (non-homologous end-joining) is the major DNA DSB (double-strand break) repair pathway in mammalian cells. Although NHEJ-defective cell lines show marked DSB-repair defects, cells defective in ATM (ataxia telangiectasia mutated) repair most DSBs normally. Thus NHEJ functions independently of ATM signalling. However, ∼15% of radiation-induced DSBs are repaired with slow kinetics and require ATM and the nuclease Artemis. DSBs persisting in the presence of an ATM inhibitor, ATMi, localize to heterochromatin, suggesting that ATM is required for repairing DSBs arising within or close to heterochromatin. Consistent with this, we show that siRNA (small interfering RNA) of key heterochromatic proteins, including KAP-1 [KRAB (Krüppel-associated box) domain-associated protein 1], HP1 (heterochromatin protein 1) and HDAC (histone deacetylase) 1/2, relieves the requirement for ATM for DSB repair. Furthermore, ATMi addition to cell lines with genetic alterations that have an impact on heterochromatin, including Suv39H1/2 (suppressor of variegation 3–9 homologue 1/2)-knockout, ICFa (immunodeficiency, centromeric region instability, facial anomalies syndrome type a) and Hutchinson–Guilford progeria cell lines, fails to have an impact on DSB repair. KAP-1 is a highly dose-dependent, transient and ATM-specific substrate, and mutation of the ATM phosphorylation site on KAP-1 influences DSB repair. Collectively, the findings show that ATM functions to overcome the barrier to DSB repair posed by heterochromatin. However, even in the presence of ATM, γ-H2AX (phosphorylated histone H2AX) foci form on the periphery rather than within heterochromatic centres. Finally, we show that KAP-1's association with heterochromatin is diminished as cells progress through mitosis. We propose that KAP-1 is a critical heterochromatic factor that undergoes specific modifications to promote DSB repair and mitotic progression in a manner that allows localized and transient chromatin relaxation, but precludes significant dismantling of the heterochromatic superstructure.
X-ray dark-field and phase-contrast imaging using a grating interferometer
Authors: Pfeiffer F. , Bech M. , Bunk O. , Donath T. , Henrich B. , Kraft P. , David C.
Published: May 2009

In this letter, we report results obtained with a recently developed approach for grating-based x-ray dark-field imaging [F. Pfeiffer et al., Nat. Mater. 7, 134 (2008)]. Since the image contrast is formed through the mechanism of small-angle scattering, it provides complementary and otherwise inaccessible structural information about the specimen at the micron and submicron length scales. Our approach is fully compatible with conventional transmission radiography and the grating-based hard x-ray phase-contrast imaging scheme [F. Pfeiffer et al., Nat. Phys. 2, 258 (2006)]. Since it can be used with standard x-ray tube sources, we envisage widespread applications to x-ray medical imaging, industrial nondestructive testing, or security screening.
Towards microsystems for automatic acquisition of in vivo gastrointestinal information
Authors: Morimoto Katsuya , Yamaguchi Shigeki , Fukuda Junji , Suzuki Hiroaki
Published: May 2009

The possibility to develop a microanalysis system for the acquisition of gastrointestinal information is presented here. The system consists of four assay sites for trypsin, pepsin, and other biochemical compounds. The major components in each assay site were a pH-responsive valve, a pH-stat used to maintain the pH of the solution to be analyzed and used for electrochemical pH-titration, and a freeze-dried enzyme substrate stored in the pH-stat. The operation of the valve is based on electrowetting, and the valve is made pH-responsive by means of a nonstandard three-electrode system. The sample solution was automatically injected into the compartment and rapidly dissolved into the substrate layer. The automatic pH-stat, based on another nonstandard use of the electrochemical three-electrode system, maintained the solution pH and, at the same time, conducted pH-titration. The determination of the activity of the proteases was conducted at their optimum pHs. The output current showed a clear dependence on the activity of the enzymes. Integrating the functions provides significant advantages for the use of this system as an isolated telemetric microsystem that may operate with wireless signal transmission using a small power supply.
Photodissociation dynamics of Ar2+ and Ar3+ excited by 527 nm photons
Authors: Lepère V. , Picard Y. J. , Barat M. , Fayeton J. A. , Lucas B. , Béroff K.
Published: May 2009

The photofragmentation dynamics of Ar2+ and Ar3+ clusters has been investigated at a 527 nm wavelength (2.35 eV) using a setup that allows simultaneous detection of the ionic and neutral fragments in a coincidence experiment. Measurement of positions and times of flight enables in principle a complete description of the fragmentation dynamics. The photofragmentation dynamics of Ar3+ clusters is similar to that of Ar2+ with, in addition, the ejection of a third fragment that can be neutral or ionized via a resonant electron capture. This is attributed to the triangular geometry of the Ar3+ ion.
On computational complexity of Clifford algebra
Authors: Budinich Marco
Published: May 2009

After a brief discussion of the computational complexity of Clifford algebras, we present a new basis for even Clifford algebra Cl(2m) that simplifies greatly the actual calculations and, without resorting to the conventional matrix isomorphism formulation, obtains the same complexity. In the last part we apply these results to the Clifford algebra formulation of the NP-complete problem of the maximum clique of a graph introduced by Budinich and Budinich [“A spinorial formulation of the maximum clique problem of a graph,” J. Math. Phys. 47, 043502 (2006)].
Hydrogenated double wall carbon nanotubes
Authors: Denis Pablo A. , Iribarne Federico , Faccio Ricardo
Published: May 2009

Herein, we investigate the chemisorption of hydrogen on double wall carbon nanotubes (DWCNT) employing density functional theory and periodic boundary conditions. In agreement with recent investigations based on Lennard-Jones potentials, we found that the (n,m)@(n+9,m) combination is favored for tubes with small diameters. The C–H binding energies determined for the (16,0) single wall carbon nanotubes (SWCNT) are nearly identical to those computed for the (7,0)@(16,0) and (8,0)@(16,0) DWCNTs. For both of the latter we found that interlayer interaction modifies the band structure of the inner tube. In the case of hydrogenated DWCNTs, the electronic structure of the inner tube experiences very small changes at high coverages (50%). However, at lower hydrogen coverages (3%–25%) changes are observed in the electronic structure of the inner tube. In agreement with recent experimental results we conclude that, for heavily functionalized DWCNTs, the electronic properties of the inner tube remain unchanged. For zigzag SWCNTs, the band gap becomes larger upon increase in hydrogen coverage; at 50% of coverage the hydrogenated (16,0) SWCNT has a band gap of 3.38 eV. Finally, based on the fact that high coverages significantly elongate C–H bond distances, we propose that the hydrogenation coverage may be determined measuring the C–H vibrational modes.
Nonlinear regimes of anticonvection, thermocapillarity, and Rayleigh–Benard convection in two-layer systems
Authors: Simanovskii Ilya B. , Viviani Antonio , Dubois Frank , Legros Jean–Claude
Published: May 2009

The nonlinear regimes of anticonvection and Rayleigh–Benard convection in a two-layer system with periodic boundary conditions on lateral walls in the presence of the interfacial heat release are studied. The region where anticonvective and the Rayleigh–Benard instability mechanisms act simultaneously is considered. The influence of the thermocapillary effect on anticonvective and Rayleigh–Benard flows, is investigated. New types of nonlinear traveling waves and modulated traveling waves are found.
Drag and flow reversal in mixed convection past a heated sphere
Authors: Kotouč Miroslav , Bouchet Gilles , Dušek Jan
Published: May 2009

Axisymmetric simulation of mixed convection past a heated sphere presented in a recent paper of Mograbi and Bar-Ziv [J. Aerosol Sci. 36, 387 (2005)] reveals a “huge” recirculation in the opposing flow configuration at very small Reynolds numbers and at Richardson numbers exceeding unity, the size of which seems to adjust to a computational domain of any size. In this paper we show that, for Reynolds numbers as low as one, the flow is nonaxisymmetric and that its three dimensionality brings the recirculation within finite bounds. At higher Reynolds numbers (Re), the cases of Re=10 and 100 are considered at a fixed Prandtl number of 0.72. The flow becomes very soon not only three dimensional but also chaotic. Especially at higher Reynolds numbers (100), the arising convective structures do not resist the opposing flow and do not travel upstream more than several sphere diameters.
Delayed diagnosis of HIV infection in Victoria 1994 to 2006
Authors: Lemoh Chris , Guy Rebecca , Yohannes Keflemariam , Lewis Jenny , Street Alan , Biggs Bev , Hellard Margaret
Published: May 2009

Background: The identification of factors associated with delayed diagnosis of HIV infection in Victoria, Australia was the aim of the present study. Methods: Demographic and epidemiological characteristics of cases notified to the Victorian HIV surveillance database between 1 January 1994 and 31 December 2006 were analysed. Delayed diagnosis was defined as: CD4 count below 200 cells mm−3 at HIV diagnosis or diagnosis of AIDS earlier than 3 months after HIV diagnosis. Results: Diagnosis of HIV was delayed in 627 (22.6%) of 2779 cases. Of these, 528 (84.2%) had either a high-risk exposure or were born in a high-prevalence country. The most common exposure was male homosexual contact in 64.3% of cases. Independent risk factors for delayed diagnosis were: older age at diagnosis (30–39 years odds ratio [OR] 2.15, ≥ 50 years OR 7.50, P < 0.001), exposure via routes other than male homosexual sex or injecting drug use (heterosexual sex OR 2.51, P < 0.001, unknown/other route OR 4.24, P < 0.001); birth in Southern/Eastern Europe (OR 2.54), South-east Asia (OR 2.70) or the Horn of Africa/North Africa (OR 3.71, P < 0.001), and male gender (OR 0.47 for females, P < 0.001). Conclusion: Delay in the diagnosis of HIV infection is common in Victoria, but potentially avoidable in the majority of cases. Most people with delayed diagnosis had a history of male homosexual contact, injecting drug use, birth in a high-prevalence country or sexual contact with such individuals. An accurate sexual history, together with knowledge of their country of birth, should identify most individuals who should be offered an HIV test.
Confidentiality and access to sexual health services
Authors: Ryder Nathan , McNulty Anna M.
Published: May 2009

Background: Confidentiality concerns are often described as barriers to seeking sexual health care. There has been little research describing the relative importance of confidentiality to clients of sexual health clinics, and whether members of high-risk groups have greater concerns. This study aimed to determine the importance of confidentiality and anonymity to clients of a public sexual health clinic, and determine associations with gender and sexuality. Methods: A self-administered questionnaire was offered to consecutive new English-speaking clients in October and November 2007. Participants were asked to describe the reasons for presenting, likelihood of disclosing identifying information, and concern should specific people and agencies become aware of their attendance. Results: Of 350 eligible clients, 270 (77%) participated in the survey. Expert care was included in the top three reasons for choosing a sexual health clinic rather than a general practitioner by over half of participants, while confidentiality and cost were each included in the top three reasons by one-third of respondents respectively. Over 90% of clients reported they were likely to give accurate identifying information to the clinic. Participants were comfortable with disclosure of information to other health-care workers but became increasingly unwilling for information to be shared with services not directly involved in their care. Overall there were few associations with gender or sexuality. Conclusion: Clients choose to attend our clinic for a variety of reasons, with confidentiality and anonymity being of lesser importance than competence and cost. Confidentiality is important to the majority of clients, whereas few desire anonymity. Most clients would accept information being shared with other health services, suggesting that confidentiality may not be a barrier to the use of electronic health records in sexual health clinics.