bluuebunny/crossref_metadata_2025 huggingface dataset:
Who's Driving Take-up? An Examination of Patterns of Small Business Engagement with Business Link
Authors: Atherton Andrew , Kim Jun Yeup , Kim Hyeyoen
Published: April 2010

We explore patterns of take-up of Business Link services in Northamptonshire, a county in the East Midlands region of the UK. Our findings indicate a relationship between small firm growth and use of Business Link. The results suggest that newer firms that are larger and experiencing growth are more likely to approach Business Link in order to ‘cope with’ rapid growth, whereas those seeking to internationalise are more likely to do so when stimulated by Business Link. On the basis of these findings we develop a framework for understanding different forms of engagement between small and medium-sized enterprises and Business Link service providers, and how these relationships develop and change over time. This framework highlights variations in the modes of engagement between these two parties and highlights the dynamic and evolving nature of interaction between small business and Business Link as an intrinsic driver of take-up of services.
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy
Authors: Matsuda Noriyuki , Sato Shigeto , Shiba Kahori , Okatsu Kei , Saisho Keiko , Gautier Clement A. , Sou Yu-shin , Saiki Shinji , Kawajiri Sumihiro , Sato Fumiaki , Kimura Mayumi , Komatsu Masaaki , Hattori Nobutaka , Tanaka Keiji
Published: April 2010

Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C
Authors: Hsu Chieh , Morohashi Yuichi , Yoshimura Shin-ichiro , Manrique-Hoyos Natalia , Jung SangYong , Lauterbach Marcel A. , Bakhti Mostafa , Grønborg Mads , Möbius Wiebke , Rhee JeongSeop , Barr Francis A. , Simons Mikael
Published: April 2010

Oligodendrocytes secrete vesicles into the extracellular space, where they might play a role in neuron–glia communication. These exosomes are small vesicles with a diameter of 50–100 nm that are formed within multivesicular bodies and are released after fusion with the plasma membrane. The intracellular pathways that generate exosomes are poorly defined. Because Rab family guanosine triphosphatases (GTPases) together with their regulators are important membrane trafficking organizers, we investigated which Rab GTPase-activating proteins interfere with exosome release. We find that TBC1D10A–C regulate exosome secretion in a catalytic activity–dependent manner. We show that Rab35 is the target of TBC1D10A–C and that the inhibition of Rab35 function leads to intracellular accumulation of endosomal vesicles and impairs exosome secretion. Rab35 localizes to the surface of oligodendroglia in a GTP-dependent manner, where it increases the density of vesicles, suggesting a function in docking or tethering. These findings provide a basis for understanding the biogenesis and function of exosomes in the central nervous system.
Cohesinopathies, gene expression, and chromatin organization
Authors: Bose Tania , Gerton Jennifer L.
Published: April 2010

The cohesin protein complex is best known for its role in sister chromatid cohesion, which is crucial for accurate chromosome segregation. Mutations in cohesin proteins or their regulators have been associated with human diseases (termed cohesinopathies). The developmental defects observed in these diseases indicate a role for cohesin in gene regulation distinct from its role in chromosome segregation. In mammalian cells, cohesin stably interacts with specific chromosomal sites and colocalizes with CTCF, a protein that promotes long-range DNA interactions, implying a role for cohesin in genome organization. Moreover, cohesin defects compromise the subnuclear position of chromatin. Therefore, defects in the cohesin network that alter gene expression and genome organization may underlie cohesinopathies.
Underestimating the Impact of Ventilator-Associated Pneumonia by Use of Surveillance Data
Authors: Drees Marci , Hausman Sherry , Rogers Andrea , Freeman Leslie , Frosh Karen , Wroten Kathy
Published: April 2010

We calculated rates of ventilator-associated pneumonia (VAP) by using surveillance data, clinical data, and coding data. Compared with the VAP rates calculated on the basis of surveillance data, the VAP rates calculated on the basis of coding data were significantly overestimated in 4 of 5 intensive, care units. Efforts to improve coding and clinical documentation will address much but not all of this discrepancy between surveillance and administrative data.
Quantitative Analysis and Molecular Fingerprinting of Methicillin-ResistantStaphylococcus aureusNasal Colonization in Different Patient Populations: A Prospective, Multicenter Study
Authors: Mermel L. A. , Eells S. J. , Acharya M. K. , Cartony J. M. , Dacus D. , Fadem S. , Gay E. A. , Gordon S. , Lonks J. R. , Perl T. M. , McDougal L. K. , McGowan J. E. , Maxey G. , Morse D. , Tenover F. C.
Published: April 2010

Objectives.

To better understand the prevalence of methicillin-resistantStaphylococcus aureus(MRSA) colonization or infection in different patient populations, to perform quantitative analysis of MRSA in nasal cultures, and to characterize strains using molecular fingerprinting.

Design.

Prospective, multicenter study.

Setting.

Eleven different inpatient and outpatient healthcare facilities.

Participants.

MRSA-positive inpatients identified in an active surveillance program; inpatients and outpatients receiving hemodialysis; inpatients and outpatients with human immunodeficiency virus (HIV) infection; patients requiring cardiac surgery; and elderly patients requiring long-term care.

Methods.

Nasal swab samples were obtained from January 23, 2006, through July 27, 2007; MRSA strains were quantified and characterized by molecular fingerprinting.

Results.

A total of 444 nares swab specimens yielded MRSA (geometric mean quantity, 794 CFU per swab; range, 3-15,000,000 CFU per swab). MRSA prevalence was 20% for elderly residents of long-term care facilities (25 of 125 residents), 16% for HIV-infected outpatients (78 of 494 outpatients), 15% for outpatients receiving hemodialysis (31 of 208 outpatients), 14% for inpatients receiving hemodialysis (86 of 623 inpatients), 3% for HIV-infected inpatients (5 of 161 inpatients), and 3% for inpatients requiring cardiac surgery (6 of 199 inpatients). The highest geometric mean quantity of MRSA was for inpatients requiring cardiac surgery (11,500 CFU per swab). An association was found between HIV infection and colonization with the USA300 or USA500 strain of MRSA (P≤ .001). The Brazilian clone was found for the first time in the United States. Pulsed-field gel electrophoresis patterns for 11 isolates were not compatible with known USA types or clones.

Conclusion.

Nasal swab specimens positive for MRSA had a geometric mean quantity of 794 CFU per swab, with great diversity in the quantity of MRSA at this anatomic site. Outpatient populations at high risk for MRSA carriage were elderly residents of long-term care facilities, HIV-infected outpatients, and outpatients receiving hemodialysis.
Prevention of Travel-Related Illness
Authors: Mehrali Tauseef H
Published: April 2010

Travel abroad is becoming increasingly commonplace. In the 1960s, international travellers numbered almost 100 million. The 1990s saw over 4% growth annually in the tourism industry. By 2002, this number was closer to 715 million. This increasing mobility is in part due to the availability of economical air transport. Despite the 6% fall in visits abroad by UK travellers in light of the recent financial downturn, large numbers of people continue to travel abroad.
Research in General Practice and Primary Care
Authors: Wallace Paul
Published: April 2010

Research was defined for the purposes of the UK Universities Research Assessment Exercise in 2001 as ‘original investigation undertaken in order to gain knowledge and understanding’. This article will examine how this translates in practical terms in general practice, what impact research has had on our clinical work as GPs and what opportunities exist for Associates-in-Training interested in engaging in research at different stages of their career.
Climate change and geomorphological hazards in the eastern European Alps
Authors: Keiler Margreth , Knight Jasper , Harrison Stephan
Published: April 2010

Climate and environmental changes associated with anthropogenic global warming are being increasingly identified in the European Alps, as seen by changes in long-term high-alpine temperature, precipitation, glacier cover and permafrost. In turn, these changes impact on land-surface stability, and lead to increased frequency and magnitude of natural mountain hazards, including rock falls, debris flows, landslides, avalanches and floods. These hazards also impact on infrastructure, and socio-economic and cultural activities in mountain regions. This paper presents two case studies (2003 heatwave, 2005 floods) that demonstrate some of the interlinkages between physical processes and human activity in climatically sensitive alpine regions that are responding to ongoing climate change. Based on this evidence, we outline future implications of climate change on mountain environments and its impact on hazards and hazard management in paraglacial mountain systems.
A Palaeogene perspective on climate sensitivity and methane hydrate instability
Authors: Dunkley Jones T. , Ridgwell A. , Lunt D. J. , Maslin M. A. , Schmidt D. N. , Valdes P. J.
Published: April 2010

The Palaeocene–Eocene thermal maximum (PETM), a rapid global warming event and carbon-cycle perturbation of the early Palaeogene, provides a unique test of climate and carbon-cycle models as well as our understanding of sedimentary methane hydrate stability, albeit under conditions very different from the modern. The principal expression of the PETM in the geological record is a large and rapid negative excursion in the carbon isotopic composition of carbonates and organic matter from both marine and terrestrial environments. Palaeotemperature proxy data from across the PETM indicate a coincident increase in global surface temperatures of approximately 5–6°C. Reliable estimates of atmospheric CO
2
changes and global warming through past transient climate events can provide an important test of the climate sensitivities reproduced by state-of-the-art atmosphere–ocean general circulation models. Here, we synthesize the available carbon-cycle model estimates of the magnitude of the carbon input to the ocean–atmosphere–biosphere system, and the consequent atmospheric
p
CO
2
perturbation, through the PETM. We also review the theoretical mass balance arguments and available sedimentary evidence for the role of massive methane hydrate dissociation in this event. The plausible range of carbon mass input, approximately 4000–7000 PgC, strongly suggests a major alternative source of carbon in addition to any contribution from methane hydrates. We find that the potential range of PETM atmospheric
p
CO
2
increase, combined with proxy estimates of the PETM temperature anomaly, does not necessarily imply climate sensitivities beyond the range of state-of-the-art climate models.
How will melting of ice affect volcanic hazards in the twenty-first century?
Authors: Tuffen Hugh
Published: April 2010

Glaciers and ice sheets on many active volcanoes are rapidly receding. There is compelling evidence that melting of ice during the last deglaciation triggered a dramatic acceleration in volcanic activity. Will melting of ice this century, which is associated with climate change, similarly affect volcanic activity and associated hazards? This paper provides a critical overview of the evidence that current melting of ice will increase the frequency or size of hazardous volcanic eruptions. Many aspects of the link between ice recession and accelerated volcanic activity remain poorly understood. Key questions include how rapidly volcanic systems react to melting of ice, whether volcanoes are sensitive to small changes in ice thickness and how recession of ice affects the generation, storage and eruption of magma at stratovolcanoes. A greater frequency of collapse events at glaciated stratovolcanoes can be expected in the near future, and there is strong potential for positive feedbacks between melting of ice and enhanced volcanism. Nonetheless, much further research is required to remove current uncertainties about the implications of climate change for volcanic hazards in the twenty-first century.
Projected future climate changes in the context of geological and geomorphological hazards
Authors: Liggins Felicity , Betts Richard A. , McGuire Bill
Published: April 2010

On palaeoclimate time scales, enhanced levels of geological and geomorphological activity have been linked to climatic factors, including examples of processes that are expected to be important in current and future anthropogenic climate change. Planetary warming leading to increased rainfall, ice-mass loss and rising sea levels is potentially relevant to geospheric responses in many geologically diverse regions. Anthropogenic climate change, therefore, has the potential to alter the risk of geological and geomorphological hazards through the twenty-first century and beyond. Here, we review climate change projections from both global and regional climate models in the context of geohazards. In assessing the potential for geospheric responses to climate change, it appears prudent to consider regional levels of warming of 2°C above average pre-industrial temperature as being potentially unavoidable as an influence on processes requiring a human adaptation response within this century. At the other end of the scale when considering changes that could be avoided by reduction of emissions, scenarios of unmitigated warming exceeding 4°C in the global average include much greater local warming in some regions. However, considerable further work is required to better understand the uncertainties associated with these projections, uncertainties inherent not only in the climate modelling but also in the linkages between climate change and geospheric responses.
Recent and future warm extreme events and high-mountain slope stability
Authors: Huggel C. , Salzmann N. , Allen S. , Caplan-Auerbach J. , Fischer L. , Haeberli W. , Larsen C. , Schneider D. , Wessels R.
Published: April 2010

The number of large slope failures in some high-mountain regions such as the European Alps has increased during the past two to three decades. There is concern that recent climate change is driving this increase in slope failures, thus possibly further exacerbating the hazard in the future. Although the effects of a gradual temperature rise on glaciers and permafrost have been extensively studied, the impacts of short-term, unusually warm temperature increases on slope stability in high mountains remain largely unexplored.

We describe several large slope failures in rock and ice in recent years in Alaska, New Zealand and the European Alps, and analyse weather patterns in the days and weeks before the failures. Although we did not find one general temperature pattern, all the failures were preceded by unusually warm periods; some happened immediately after temperatures suddenly dropped to freezing.

We assessed the frequency of warm extremes in the future by analysing eight regional climate models from the recently completed European Union programme ENSEMBLES for the central Swiss Alps. The models show an increase in the higher frequency of high-temperature events for the period 2001–2050 compared with a 1951–2000 reference period. Warm events lasting 5, 10 and 30 days are projected to increase by about 1.5–4 times by 2050 and in some models by up to 10 times.

Warm extremes can trigger large landslides in temperature-sensitive high mountains by enhancing the production of water by melt of snow and ice, and by rapid thaw. Although these processes reduce slope strength, they must be considered within the local geological, glaciological and topographic context of a slope.
Potential for a hazardous geospheric response to projected future climate changes
Authors: McGuire B.
Published: April 2010

Periods of exceptional climate change in Earth history are associated with a dynamic response from the geosphere, involving enhanced levels of potentially hazardous geological and geomorphological activity. The response is expressed through the adjustment, modulation or triggering of a broad range of surface and crustal phenomena, including volcanic and seismic activity, submarine and subaerial landslides, tsunamis and landslide ‘splash’ waves, glacial outburst and rock-dam failure floods, debris flows and gas-hydrate destabilization. In relation to anthropogenic climate change, modelling studies and projection of current trends point towards increased risk in relation to a spectrum of geological and geomorphological hazards in a warmer world, while observations suggest that the ongoing rise in global average temperatures may already be eliciting a hazardous response from the geosphere. Here, the potential influences of anthropogenic warming are reviewed in relation to an array of geological and geomorphological hazards across a range of environmental settings. A programme of focused research is advocated in order to: (i) understand better those mechanisms by which contemporary climate change may drive hazardous geological and geomorphological activity; (ii) delineate those parts of the world that are most susceptible; and (iii) provide a more robust appreciation of potential impacts for society and infrastructure.
Aromatase, oestrogens and human male reproduction
Authors: Carreau Serge , Wolczynski Slaweck , Galeraud-Denis Isabelle
Published: April 2010

In most mammalian species aromatase is encoded by a single gene (Cyp19), which contains 18 exons, nine of them being translated. In man, the presence of a biologically active aromatase and oestrogen receptors (ERα and ERβ) has been reported in Leydig cells, and also in immature germ cells and ejaculated spermatozoa. Concerning aromatase, the amount of transcript and enzymatic activity are decreased in immotile compared with motile sperm. We have amplified aromatase mRNA by real-time polymerase chain reaction in spermatozoa from asthenospermic, teratospermic and asthenoteratospermic men and recorded, respectively, 44, 52 and 67 per cent decreases of the amount of transcripts compared with fertile donors. A high degree of correlation (r= −0.64) between the abnormal spermatozoa (especially microcephaly and acrosome malformations) and aromatase/GAPDH transcript ratio has been observed. Idiopathic infertility is a wide health problem and no treatment is currently available. In humans, even if the role of oestrogens in spermatogenesis is still a matter of debate, the observations of decreased sperm number and motility in men genetically deficient in aromatase, together with our data and those reported in the literature, may suggest a role for aromatase/oestrogens not only during the development and maintenance of spermatogenesis but also in the final maturation of spermatozoa.
Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis
Authors: Pointis Georges , Gilleron Jérome , Carette Diane , Segretain Dominique
Published: April 2010

Spermatogenesis is a highly regulated process of germ cell proliferation and differentiation, starting from spermatogonia to spermatocytes and giving rise to spermatids, the future spermatozoa. In addition to endocrine regulation, testicular cell–cell interactions are essential for spermatogenesis. This precise control is mediated through paracrine/autocrine pathways, direct intercellular contacts and through intercellular communication channels, consisting of gap junctions and their constitutive proteins, the connexins. Gap junctions are localized between adjacent Leydig cells, between Sertoli cells and between Sertoli cells and specific germ cells. This review focuses on the distribution of connexins within the seminiferous epithelium, their participation in gap junction channel formation, the control of their expression and the physiological relevance of these junctions in both the Sertoli–Sertoli cell functional synchronization and the Sertoli–germ cell dialogue. In this review, we also discuss the potential implication of disrupted connexin in testis cancer, since impaired expression of connexin has been described as a typical feature of tumoral proliferation.
Male germ cell apoptosis: regulation and biology
Authors: Shaha Chandrima , Tripathi Rakshamani , Mishra Durga Prasad
Published: April 2010

Cellular apoptosis appears to be a constant feature in the adult testis and during early development. This is essential because mammalian spermatogenesis is a complex process that requires precise homeostasis of different cell types. This review discusses the latest information available on male germ cell apoptosis induced by hormones, toxins and temperature in the context of the type of apoptotic pathway either the intrinsic or the extrinsic that may be used under a variety of stimuli. The review also discusses the importance of mechanisms pertaining to cellular apoptosis during testicular development, which is independent of exogenous stimuli. Since instances of germ cell carcinoma have increased over the past few decades, the current status of research on apoptotic pathways in teratocarcinoma cells is included. One other important aspect that is covered in this review is microRNA-mediated control of germ cell apoptosis, a field of research that is going to see intense activity in near future. Since knockout models of various kinds have been used to study many aspects of germ cell development, a comprehensive summary of literature on knockout mice used in reproduction studies is also provided.
Environmental/lifestyle effects on spermatogenesis
Authors: Sharpe Richard M.
Published: April 2010

The high incidence of low sperm counts in young (European) men and evidence for declining sperm counts in recent decades mean that the environmental/lifestyle impact on spermatogenesis is an important health issue. This review assesses potential causes involving adverse effects on testis development in perinatal life (primarily effects on Sertoli cell number), which are probably irreversible, or effects on the process of spermatogenesis in adulthood, which are probably mainly reversible. Several lifestyle-related (obesity, smoking) and environmental (exposure to traffic exhaust fumes, dioxins, combustion products) factors appear to negatively affect both the perinatal and adult testes, emphasizing the importance of environmental/lifestyle impacts throughout the life course. Apart from this, public concern about adverse effects of environmental chemicals (ECs) (pesticides, food additives, persistent pollutants such as DDT, polychlorinated biphenyls) on spermatogenesis in adult men are, in general, not supported by the available data for humans. Where adverse effects of ECs have been shown, they are usually in an occupational setting rather than applying to the general population. In contrast, a modern Western lifestyle (sedentary work/lifestyle, obesity) is potentially damaging to sperm production. Spermatogenesis in normal men is poorly organized and inefficient so that men are poorly placed to cope with environmental/lifestyle insults.
Non-classical actions of testosterone and spermatogenesis
Authors: Walker William H.
Published: April 2010

Testosterone is essential to maintain spermatogenesis and male fertility. In the absence of testosterone stimulation, spermatogenesis does not proceed beyond the meiosis stage. After withdrawal of testosterone, germ cells that have progressed beyond meiosis detach from supporting Sertoli cells and die, whereas mature sperm cannot be released from Sertoli cells resulting in infertility. The classical mechanism of testosterone action in which testosterone activates gene transcription by causing the androgen receptor to translocate to and bind specific DNA regulatory elements does not appear to fully explain testosterone regulation of spermatogenesis. This review discusses two non-classical testosterone signalling pathways in Sertoli cells and their potential effects on spermatogenesis. Specifically, testosterone-mediated activation of phospholipase C and calcium influx into Sertoli cells is described. Also, testosterone activation of Src, EGF receptor and ERK kinases as well as the activation of the CREB transcription factor and CREB-mediated transcription is reviewed. Regulation of germ cell adhesion to Sertoli cells and release of mature sperm from Sertoli cells by kinases regulated by the non-classical testosterone pathway is discussed. The evidence accumulated suggests that classical and non-classical testosterone signalling contribute to the maintenance of spermatogenesis and male fertility.
Evolution and spermatogenesis
Authors: White-Cooper Helen , Bausek Nina
Published: April 2010

Sexual reproduction depends on the production of haploid gametes, and their fusion to form diploid zygotes. Here, we discuss sperm production and function in a molecular and functional evolutionary context, drawing predominantly from studies in model organisms (mice,Drosophila,Caenorhabditis elegans). We consider the mechanisms involved in establishing and maintaining a germline stem cell population in testes, as well as the factors that regulate their contribution to the pool of differentiating cells. These processes involve considerable interaction between the germline and the soma, and we focus on regulatory signalling events in a variety of organisms. The male germline has a unique transcriptional profile, including expression of many testis-specific genes. The evolutionary pressures associated with gene duplication and acquisition of testis function are discussed in the context of genome organization and transcriptional regulation. Post-meiotic differentiation of spermatids involves very dramatic changes in cell shape and acquisition of highly specialized features. We discuss the variety of sperm motility mechanisms and how various reproductive strategies are associated with the diversity of sperm forms found in animals.
Spermatogonial stem cell regulation and spermatogenesis
Authors: Phillips Bart T. , Gassei Kathrin , Orwig Kyle E.
Published: April 2010

This article will provide an updated review of spermatogonial stem cells and their role in maintaining the spermatogenic lineage. Experimental tools used to study spermatogonial stem cells (SSCs) will be described, along with research using these tools to enhance our understanding of stem cell biology and spermatogenesis. Increased knowledge about the biology of SSCs improves our capacity to manipulate these cells for practical application. The chapter concludes with a discussion of future directions for fundamental investigation and practical applications of SSCs.
Hypoxia promotes metastasis in human gastric cancer by up‐regulating the 67‐kDa laminin receptor
Authors: Liu Lili , Sun Li , Zhao Pengtao , Yao Liping , Jin Haifeng , Liang Shuhui , Wang Yanxia , Zhang Dexin , Pang Yanglin , Shi Yongquan , Chai Na , Zhang Hongbo , Zhang Helong
Published: April 2010

It has been reported that the 67‐kDa laminin receptor (67LR) is implicated in cancer metastasis. We recently showed that 37LRP, the 67LR precursor, is a hypoxia‐inducible factor 1 (HIF‐1) target gene exposed to hypoxia in gastric cancer. Here, we investigated the role of 67LR in hypoxic metastasis and invasion in gastric cancer. Immunohistochemical analysis, western blotting, and RT‐PCR assays revealed that 67LR was highly expressed in metastatic gastric cancers in vivo. Knockdown of the 67LR protein by RNA interference significantly decreased the adhesive, invasive, and in vivo metastatic abilities of the gastric cancer cell lines SGC7901 and MKN‐45. Western blot analysis showed that 67LR increased the expression of urokinase‐type plasminogen activator (uPA) and matrix metalloproteinase (MMP)‐9, and decreased tissue inhibitor of matrix metalloproteinase (TIMP)‐1 protein. We further showed that hypoxia induced 67LR expression in a time‐dependent manner and this induction was inhibited by HIF‐1 small‐interfering (si) RNA. Both ERK and JNK inhibitors significantly inhibited hypoxia‐induced expression of 67LR and the subsequent expression of uPA and MMP 9. SiRNA against 67LR or antibody against MMP9 and uPA significantly inhibited hypoxia‐induced in vitro invasive ability. Taken together, these results reveal that 67LR promotes the invasive and metastatic ability of the gastric cancer cells through increasing uPA and MMP 9 expression, with involvement of the ERK and JNK signal pathway in hypoxia‐induced 67 LR expressions and subsequent uPA and MMP9 expression. (Cancer Sci 2010)
Combined inhibitory effect of formestane and herceptin on a subpopulation of CD44+/CD24low breast cancer cells
Authors: Cavaliere Carla , Corvigno Sara , Galgani Mario , Limite Gennaro , Nardone Agostina , Veneziani Bianca Maria
Published: April 2010

In breast cancer, stromal cells surrounding cancer epithelial cells can influence phenotype by producing paracrine factors. Among many mediators of epithelial–stromal interactions, aromatase activity is perhaps one of the best studied. Clinical data suggest that estrogen‐independent signaling leads to increased proliferation even during therapy with aromatase inhibitors (AIs). Molecular mechanism of crosstalk between the estrogen receptor (ER) and the epidermal growth factor receptor (HER) family have been implicated in resistance to endocrine therapy, but this interaction is unclear. The ability of aromatase to induce estradiol biosynthesis provides a molecular rationale to combine agents that target aromatase activity and the HER pathway. We targeted stromal–epithelial interactions using formestane, which exerts antiaromatase activity, combined with the monoclonal anti‐HER2 antibody herceptin, in a subpopulation of CD44+/CD24low cells sorted from epithelial‐mesenchymal co‐cultures of breast cancer tissues. The growth inhibition was respectively 16% (P < 0.01) in the response to herceptin, 25% to formestane (P < 0.01), and 50% (P < 0.001) with the combination of the two drugs, suggesting that herceptin cooperates with formestane‐induced inhibition of aromatase and this effect could be mediated through HER family receptors. In cells which expressed ERα, formestane/herceptin combination suppressed the mRNA expression of aromatase and HER2 and decreased cyclin D1 expression. These results show that combination therapies involving AIs and anti‐HER2 can be efficacious for the treatment of cancer in experimental models and suggest that subtyping breast tumors gives useful information about response to treatment. (Cancer Sci 2010)
Differences between bispectral index and spectral entropy during xenon anaesthesia: a comparison with propofol anaesthesia
Authors: Höcker J. , Raitschew B. , Meybohm P. , Broch O. , Stapelfeldt C. , Gruenewald M. , Cavus E. , Steinfath M. , Bein B.
Published: April 2010

We enrolled 114 patients, aged 65–83 years, undergoing elective surgery (duration > 2h) into a randomised, controlled study to evaluate the performance of bispectral index and spectral entropy for monitoring depth of xenon versus propofol anaesthesia. In the propofol group, bispectral index and state entropy values were comparable. In the xenon group, bispectral index values resembled those in the propofol group, but spectral entropy levels were significantly lower. Mean arterial blood pressure was higher and heart rate was lower in the xenon group than in the propofol group. Bispectral index and spectral entropy considerably diverged during xenon but not during propofol anaesthesia. We therefore conclude that these measures are not interchangeable for the assessment of depth of hypnosis and that bispectral index is likely to reflect actual depth of anaesthesia more precisely compared with spectral entropy.
Carbon 13 discrimination during lipid biosynthesis varies with dietary concentration of stable isotopes: implications for stable isotope analyses
Authors: Wessels Frank J. , Hahn Daniel A.
Published: April 2010

1. Carbon stable isotopes are commonly used as a research tool in physiological ecology. When elements are consumed, they are naturally enriched or depleted as the consumer processes them. The difference in isotopic composition between the consumer and the diet is known as the discrimination factor (Δ13C).

2. Mixing models are used to estimate the contribution of multiple dietary components to a consumer’s tissues and discrimination must be estimated in the model. Often, discrimination factors vary depending on multiple factors, yet in many models the discrimination factor is assumed to be constant for each dietary component.

3. Few studies have evaluated the mechanistic basis of stable isotope metabolism and discrimination during macromolecule biosynthesis, despite the potential to improve estimations of discrimination factors. We tested whether 13C discrimination depends on the dietary concentration of 13C by culturing the bacterium Bacillus subtilis in a gradient of broths ranging from a δ13C of −11·8‰ to −25·3‰. We found an increase in discrimination in whole bacterial tissue, bulk lipid, and lipid‐extracted fractions as dietary the concentration of 13C increased, with lipids showing the greatest discrimination ranging from 2·72‰ in the low 13C broths to 15·5‰ in the high13C broths.

4. These findings contrast with the majority of isotopic ecology data that typically show a moderate enrichment of 13C as trophic level increases. This discrepancy is attributed to the de novo biosynthesis of the majority of cellular components in this study as opposed to the effects of isotopic routing seen in more metabolically complex taxa.
BDDrFVIII (Moroctocog alfa [AF‐CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study
Authors: WINDYGA J. , RUSEN L. , GRUPPO R. , O’BRIEN A. C. , KELLY P. , ROTH D. A , ARKIN S.
Published: April 2010

Summary.  Moroctocog alfa (AF‐CC) (Xyntha™, BDDrFVIII) is manufactured by a process designed to enhance the theoretical viral safety profile relative to ReFacto®, its predecessor, and to provide alignment with clinical monitoring by the one‐stage clotting assay. To evaluate the efficacy and safety of B‐domain‐deleted recombinant factor VIII (BDDrFVIII) was given as bolus injection (BI) or continuous infusion (CI) in haemophilia patients undergoing major surgery. BDDrFVIII was administered by BI or CI per investigator discretion peri‐operatively for at least 6 days. Thirty patients enrolled and were treated with at least one dose of BDDrFVIII. Twenty‐five patients were evaluable for efficacy. Outcomes were favourable against a background of multiple major surgical procedures. All haemostatic efficacy ratings were ‘excellent’ or ‘good’. End‐of‐surgery haemostasis ratings, the primary efficacy endpoint, were excellent for 72% (18/25) and good for 28% (7/25) of patients. Haemostasis ratings following the initial postoperative period were excellent for 92% (23/25) and good for 8% (2/25) of patients. Intra‐operative blood loss was rated as normal in all patients. Thirteen patients had postoperative blood loss; in 10, this was rated as normal. A low frequency of transfusion was reported in both the intra‐operative and postoperative settings. Adverse events (AEs) were consistent with surgery; three were considered related to BDDrFVIII. One patient had a related AE of postoperative haemorrhage. A clinically silent low‐titre inhibitor was detected in one patient, and one patient had a false‐positive inhibitor titre. This study demonstrates that BDDrFVIII is safe and efficacious for surgical prophylaxis in haemophilia A patients undergoing major surgery.
Phenotypic quality influences fertility in Gombe chimpanzees
Authors: Jones James Holland , Wilson Michael L. , Murray Carson , Pusey Anne
Published: April 2010

1. Fertility is an important fitness component, but is difficult to measure in slowly reproducing, long‐lived animals such as chimpanzees (Pan troglodytes).

2. We measured fertility and the effect of measured covariates on fertility in a 43‐year sample of birth intervals of chimpanzees from the Gombe National Park, Tanzania using Cox proportional hazards regression with individual‐level random effects.

3. The birth hazard declined with mothers’ age at a rate of 0·84 per year following age at first reproduction. This value is somewhat stronger than previous estimates.

4. Loss of the infant that opened the birth interval increased the birth hazard 134‐fold.

5. Birth intervals following the first complete birth interval were shorter than this first interval, while sex of the previous infant had no significant effect.

6. Maternal dominance rank was significant at the P < 0·1 level when coded as high/middle/low but was highly significant when we simply considered high rank vs. others.

7. Individual heterogeneity had a substantial impact on birth interval duration. We interpret this individual effect as a measure of phenotypic quality, controlling for the measured covariates such as dominance rank. This interpretation is supported by the correlation of individual heterogeneity scores with similar independent measures of body mass.
WRKY72‐type transcription factors contribute to basal immunity in tomato and Arabidopsis as well as gene‐for‐gene resistance mediated by the tomato R gene Mi‐1
Authors: Bhattarai Kishor K. , Atamian Hagop S. , Kaloshian Isgouhi , Eulgem Thomas
Published: April 2010

WRKY transcription factors play a central role in transcriptional reprogramming associated with plant immune responses. However, due to functional redundancy, typically the contribution of individual members of this family to immunity is only subtle. Using microarray analysis, we found that the paralogous tomato WRKY genes SlWRKY72a and b are transcriptionally up‐regulated during disease resistance mediated by the R gene Mi‐1. Virus‐induced gene silencing of these two genes in tomato resulted in a clear reduction of Mi‐1‐mediated resistance as well as basal defense against root‐knot nematodes (RKN) and potato aphids. Using Arabidopsis T‐DNA insertion mutants, we found that their Arabidopsis ortholog, AtWRKY72, is also required for full basal defense against RKN as well as to the oomycete Hyaloperonospora arabidopsidis. Despite their similar roles in basal defense against RKN in both tested plant species, WRKY72‐type transcription factors in tomato, but not in Arabidopsis, clearly contributed to basal defense against the bacterial pathogen Pseudomonas syringae. Of the five R genes that we tested in tomato and Arabidopsis, only Mi‐1 appeared to be dependent on WRKY72‐type transcription factors. Interestingly, AtWRKY72 target genes, identified by microarray analysis of H. arabidopsidis‐triggered transcriptional changes, appear to be largely non‐responsive to analogs of the defense hormone salicylic acid (SA). Thus, similarly to Mi‐1, which in part acts independently of SA, AtWRKY72 appears to utilize SA‐independent defense mechanisms. We propose that WRKY72‐type transcription factors play a partially conserved role in basal defense in tomato and Arabidopsis, a function that has been recruited to serve Mi‐1‐dependent immunity.
A HECT E3 ubiquitin ligase negatively regulates Arabidopsis leaf senescence through degradation of the transcription factor WRKY53
Authors: Miao Ying , Zentgraf Ulrike
Published: April 2010

WRKY transcription factors play a central role in controlling leaf senescence in Arabidopsis. One important member, WRKY53, is tightly regulated by various mechanisms, and is a convergence node between senescence and pathogen responses. Using WRKY53 in a yeast two‐hybrid screen, we isolated the HECT domain E3 ubiquitin ligase UPL5. In contrast to mammals, Arabidopsis contains only seven HECT E3 ubiquitin ligases, whose targets and functions are largely unknown. In yeast cells, UPL5 interacts with WRKY53 via its leucine zipper domain, and this interaction was confirmed in the cytoplasm of plant cells by a bimolecular fluorescence complementation assay. UPL5 was able to use the WRKY53 protein as a substrate for polyubiquitination in an in vitro system, and induction of UPL5 expression by an ethanol‐inducible system in upl5 plants led to degradation of the WRKY53 protein. Expression of both genes is regulated antagonistically in response to hydrogen peroxide, jasmonic acid and plant development. Two T‐DNA insertion lines (upl5‐1 and upl5‐2) showed the same senescence phenotype as WRKY53 over‐expressers. Over‐expression of WRKY53 in the upl5 background enhanced the accelerated senescence phenotype of WRKY53 over‐expressers. Therefore, we conclude that UPL5 regulates leaf senescence in Arabidopsis through degradation of WRKY53 and ensures that senescence is executed in the correct time frame.
BROTHER OF FT AND TFL1(BFT) hasTFL1‐like activity and functions redundantly withTFL1in inflorescence meristem development in Arabidopsis
Authors: Yoo Seong Jeon , Chung Kyung Sook , Jung Seung Hye , Yoo So Yeon , Lee Jong Seob , Ahn Ji Hoon
Published: April 2010

TheFLOWERING LOCUS T(FT)/TERMINAL FLOWER 1(TFL1) family is a small gene family that encodes important regulators that control flower development in Arabidopsis. Here, we investigated the biological role of the product ofBROTHER OF FT AND TFL1(BFT), a member of this family, whose function remains unknown. Comparison of the critical residues that play a role in distinguishingFT‐ orTFL1‐like activity revealed thatBFTis more similar toFT. Similar toFTexpression,BFTexpression showed a diurnal oscillation pattern, peaking in the evening.In situhybridization revealedBFTexpression in the shoot apical meristem, young leaf and axillary inflorescence meristem. Transgenic plants over‐expressingBFTexhibited delayed flowering and severe floral defects (floral indeterminacy and compact inflorescences surrounded by serrate leaves), similar to35S::TFL1plants.LEAFY(LFY) andAPETALA1(AP1) expression was significantly reduced in35S::BFTplants.BFTover‐expression failed to rescue the terminal flower phenotype oftfl1mutants; however, it delayed both terminal flower formation in the primary inflorescence and axillary inflorescence development in thetfl1mutant background. Consistent with this, the loss‐of‐functionBFTalleles,bft‐2and anBFTRNAi line, accelerated termination of the primary inflorescence and formation of axillary inflorescences in thetfl1mutant background. Taken together, our results suggest that, despite similarities in the critical residues of BFT and FT,BFTpossesses aTFL1‐like activity and functions redundantly withTFL1in inflorescence meristem development, and possibly contributes to the regulation of plant architecture.
Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome?
Authors: Zhang Y , Dai Y , Liu Y , Ren J
Published: April 2010

Zhang Y, Dai Y, Liu Y, Ren J. Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome?

The acrofacial dysostoses (AFDs) are a heterogeneous group of disorders involving craniofacial dysostosis and limb anomalies. Depending on the type of limb defects, two major groups have been defined: Nager syndrome with predominant preaxial anomalies and Miller syndrome with postaxial malformations. Genomic copy number variation, a common type of genomic variability, can influence gene expression by disrupting coding sequences, perturbing long‐range gene regulation, or altering gene dosage, and these effects could contribute to phenotypic variations or disease risk. We present a distinct AFD case with mandibulofacial dysostosis, microtia and limb malformations but without limb defects, which may represent a new form of AFD. To investigate the etiology of the phenotype, whole genomic high‐resolution array comparative genomic hybridization analysis was carried out, revealing two cryptic duplications, 1p36.33 and 1q21.3‐q22 duplications. Two genes, VWA1 and PYGO2, contained in the two duplications, respectively, are likely to be the candidate genes for the phenotype of our patient.
The Complete Genome Sequence of Two Isolates of Southern rice black‐streaked dwarf virus, a New Member of the Genus Fijivirus
Authors: Wang Qiang , Yang Jian , Zhou Guo‐Hui , Zhang Heng‐Mu , Chen Jian‐Ping , Adams Michael J.
Published: April 2010

The nucleotide sequences of genomic segments S1–S8 and S1–S6, respectively, of the Hainan (HN) and Guangdong (GD) isolates of a rice‐infecting fijivirus were determined, completing the genome sequences of these isolates. The isolates were most closely related to Rice black‐streaked dwarf virus (RBSDV): S1, S2 and S10 were most conserved with identities of 78.5–79.2% nt (83.4–89.0% aa) while S5 and S6 were the least conserved with 70.6–71.6% nt (63.1–69.9% aa) identity. Whole genome comparisons and phylogenetic analyses supported suggestions that the isolates represent a new species within the genus Fijivirus, family Reoviridae. Of the two names previously suggested for this virus, Southern rice black‐streaked dwarf virus is preferred.
Medical mushrooms used for biochemical failure after radical treatment for prostate cancer: An open‐label study
Authors: Yoshimura Koji , Kamoto Toshiyuki , Ogawa Osamu , Matsui Shigeyuki , Tsuchiya Norihiko , Tada Harue , Murata Keiko , Yoshimura Kenichi , Habuchi Tomonori , Fukushima Masanori
Published: April 2010

Objective:  The aim of this study was to assess the efficacy and safety of two different types of medical mushrooms in patients with prostate cancer in Japan.

Methods:  Patients with biochemical failure after radical treatment for non‐metastasized prostate cancer were enrolled in this open‐label study. For 6 months they ingested one of the two following supplements: Senseiro, containing extracts from the Agaricus blazei Murill mushroom; and Rokkaku Reishi, containing the Ganoderma lucidum mushroom. Levels of serum prostate‐specific antigen (PSA) level and PSA doubling time were examined before and after study entry to assess the impact of these supplements on disease progression. The primary end‐point of this study was partial response rate (50% or more decrease of serum PSA). Hormonal status, represented by serum testosterone levels, and toxicity were also assessed.

Results:  A total of 51 patients were enrolled following radical prostatectomy. Forty‐seven completed the protocol and could be assessed. Thirty‐two patients received Senseiro and the remaining 15 received Rokkaku Reishi. No partial response in terms of PSA was observed. Alteration of PSA doubling time did not correlate with that of serum testosterone levels. Serious adverse effects were not observed.

Conclusions:  No significant anticancer effects were observed with the intake of these two medical mushrooms.