bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of permeability–porosity functions on simulated morphological evolution of a chemical dissolution front
Authors: Lai Keng‐Hsin , Chen Jui‐Sheng , Liu Chen‐Wuing , Yang Suh‐Yuh
Published: July 2012

The dissolution‐induced finger pattern in geological medium plays an important role in both geological processes and engineering practices. Numerical models have been developed to investigate the evolution of the chemical dissolution front within a fluid‐saturated porous medium. In these models, several permeability–porosity relationships have been proposed and incorporated into the numerical model for describing simultaneous changes in permeability and porosity induced by mineral dissolution, but limited experimental data are available to justify one form superior to the other. This study investigates the effects of the permeability–porosity relationships on the morphological evolution of the chemical dissolution front. Three porosity–permeability relationships, namely, modified Fair–Hatch, Kozeny–Carman and Verma–Pruess (VP) models are incorporated into the numerical model. A series of numerical simulations are performed to evaluate the morphological evolution of reaction front, and the corresponding behaviour diagrams are constructed. Results shows that the morphological development are similar each other for modified Fair–Fatch and Kozeny–Carman model. The VP model yields a relative low primary and secondary critical upstream pressure gradient value owing to the flow‐focusing effect enhanced by the stronger dependence of permeability on porosity. A comparison of behaviour diagrams of front morphology among three relationships show that the double‐fingering front occurs under condition of lower upstream pressure gradient and smaller non‐uniformity spacing for VP model. Our simulations demonstrate that the choice of the permeability–porosity function plays important roles on the evolution patterns of dissolution front. Therefore, an adequate description of the permeability–porosity relationship may lead to a more realistic simulation of field problems. Copyright © 2012 John Wiley & Sons, Ltd.
Estimating groundwater discharge to rivers from river chemistry surveys
Authors: Cook Peter G.
Published: July 2012

Environmental tracer methods have been used to quantify groundwater discharge to rivers for the past few decades. A number of different tracers have been used in these studies, including individual ion concentrations, electrical conductivity, stable isotopes 2H and 18O, and the dissolved gases helium, chlorofluorocarbons and radon. This paper discusses the assumptions of the method, as well as its resolution and accuracy. The method will be most accurate when the tracer concentration in groundwater is very distinct from that in the river. On the basis of typical parameters, groundwater inflow rates as low as 5 mm/day can usually be estimated with electrical conductivity and ion tracers. A lower limit of resolution of approximately 2 mm/day is usually possible with radon, principally because the ratio of the river concentration to the groundwater concentration will be higher. However, hyporheic exchange can also contribute radon to the river. Where this process is significant, it is more difficult to estimate groundwater inflow from radon activities in the river, thus reducing the accuracy of the method. For CFCs, the lower limit of resolution is approximately 30 mm/day. Helium has not been widely used but can potentially be very accurate if the groundwater is old.

The method assumes steady‐state conditions and so can only be applied when river flows are stable. Sampling resolution is also particularly important for dissolved gases, and uncertainty in where groundwater inflow occurs between sampling points can cause large uncertainty in inflow rates if the distance between sample locations is large. Poor mixing of solutes within the river can limit the method if the river is wide and shallow. When correctly applied, however, the environmental tracer method is able to provide robust estimates of groundwater discharge at a scale and accuracy that is not possible with most other methods. Copyright © 2012 John Wiley & Sons, Ltd.
Multifractal behaviour of long‐term karstic discharge fluctuations
Authors: Labat D. , Hoang C. T. , Masbou J. , Mangin A. , Tchiguirinskaia I. , Lovejoy S. , Schertzer D.
Published: July 2012

Karstic watersheds are highly complex hydrogeological systems that are characterized by a multiscale behaviour corresponding to the different pathways of water in these systems. The main issue of karstic spring discharge fluctuations consists in the presence and the identification of characteristic time scales in the discharge time series.

To identify and characterize these dynamics, we acquired, for many years at the outlet of two karstic watersheds in South of France, discharge data at 3‐mn, 30‐mn and daily sampling rate. These hydrological records constitute to our knowledge the longest uninterrupted discharge time series available at these sampling rates. The analysis of the hydrological records at different levels of detail leads to a natural scale analysis of these time series in a multifractal framework.

From a universal class of multifractal models based on cascade multiplicative processes, the time series first highlights two cut‐off scales around 1 and 16 h that correspond to distinct responses of the aquifer drainage system. Then we provide estimates of the multifractal parameters α and C1 and the moment of divergence qD corresponding to the behaviour of karstic systems. These results constitute the first estimates of the multifractal characteristics of karstic spingflows based on 10 years of high‐resolution discharge time series and should lead to several improvements in rainfall‐karstic springflow simulation models. Copyright © 2012 John Wiley & Sons, Ltd.
Molecular mechanism of a novel CD59‐binding peptide sp22 induced tumor cells apoptosis
Authors: Li Bing , Gao Mei‐Hua , Chu Xian‐Ming
Published: July 2012

Some short peptides discovered by phage display are found to be able to inhibit cancer growth and induce cancer cell apoptosis. In this study, a novel cancer‐targeting short peptide which was composed of 22 amino acids (ACHWPWCHGWHSACDLPMHPMC, abbreviated as sp22) and specifically bound to human CD59 was screened from a M13 phage display library so as to counteract tumor immune escape activity. The mechanism of exogenous sp22 peptide in inducing apoptosis of MCF‐7 cells was investigated. The results suggested that sp22 could lower CD59 expression level, downregulate Bcl‐2 expression, activate Fas and caspase‐3, and finally increase apoptotic cell numbers of MCF‐7 cells. However, sp22 had no obvious influence on normal human embryonic lung cells. In addition, the effects of endogenous sp22 gene on CD59 expression and NKM cell apoptosis were explored using the recombinant plasmid sp22‐PIRES. It showed that sp22 gene was efficiently expressed in transfected NKM cells. Compared with normal NKM cells, NKM cells transfected with sp22 displayed reduced mRNA and protein expression levels of CD59, increased sensitivity to complement‐mediated cytolysis, decreased cell survival ratio, changes of the expression of apoptosis associated proteins, increased number of apoptotic cells and the appearance of apoptotic morphology. The results suggested that sp22 protein could bind to CD59 and inhibit the expression of CD59. The cytolytic activity of complement on tumor cells strengthened and apoptosis signal was stepwise transferred which might be a potential way to kill tumor cells. J. Cell. Biochem. 113: 3810–3822, 2012. © 2012 Wiley Periodicals, Inc.
SAP30L (Sin3A‐associated protein 30‐like) is involved in regulation of cardiac development and hematopoiesis in zebrafish embryos
Authors: Teittinen Kaisa J. , Grönroos Toni , Parikka Mataleena , Junttila Sini , Uusimäki Annemari , Laiho Asta , Korkeamäki Hanna , Kurppa Kalle , Turpeinen Hannu , Pesu Marko , Gyenesei Attila , Rämet Mika , Lohi Olli
Published: July 2012

The Sin3A‐associated proteins SAP30 and SAP30L share 70% sequence identity and are part of the multiprotein Sin3A corepressor complex. They participate in gene repression events by linking members of the complex and stabilizing interactions among the protein members as well as between proteins and DNA. While most organisms have both SAP30 and SAP30L, the zebrafish is exceptional because it only has SAP30L. Here we demonstrate that SAP30L is expressed ubiquitously in embryonic and adult zebrafish tissues. Knockdown of SAP30L using morpholino‐mediated technology resulted in a morphant phenotype manifesting as cardiac insufficiency and defective hemoglobinization of red blood cells. A microarray analysis of gene expression in SAP30L morphant embryos revealed changes in the expression of genes involved in regulation of transcription, TGF‐beta signaling, Wnt‐family transcription factors, and nuclear genes encoding mitochondrial proteins. The expression of the heart‐specific nkx2.5 gene was markedly down‐regulated in SAP30L morphants, and the cardiac phenotype could be partially rescued by nkx2.5 mRNA. In addition, changes were detected in the expression of genes known to be important in hemoglobin synthesis and erythropoiesis. Our results demonstrate that SAP30L regulates several transcriptional pathways in zebrafish embryos and is involved in the development of cardiac and hematopoietic systems. J. Cell. Biochem. 113: 3843–3852, 2012. © 2012 Wiley Periodicals, Inc.
Mathematical modeling of biofilm‐covered granular activated carbon: a review
Authors: Shen Liang , Lu Yinghua , Liu Yu
Published: July 2012

This paper reviewed the mass‐transfer of the target substance in the biofilm‐covered granular activated carbon (BGAC) system. Representative hypotheses and equations related to developing the mathematical models for a BGAC reactor were discussed in terms of granular activated carbon (GAC) phase, biofilm phase and bulk solution, respectively. It should be noted that discrete phenomena such as biofilm detachment due to erosion or sloughing were not considered for the modeling system. Recent advances on this topic were thoroughly updated, as well as those models proposed in past decades. It appears that a general BGAC model has not been available so far, and further efforts are required to obtain models more approaching of the physical mechanism of this complicate system. Copyright © 2012 Society of Chemical Industry
Assessment of aged biodegradable polymer‐coated nano‐zero‐valent iron for degradation of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX)
Authors: Xiao Ru , Wazne Mahmoud
Published: July 2012

BACKGROUND: This study reports on the effects of aging on suspension behavior of biodegradable polymer‐coated nano‐zero‐valent iron (nZVI) and its degradation rates of hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine (RDX) under reductive conditions. The polymers investigated included guar gum, potato starch, alginic acid (AA), and carboxymethyl cellulose (CMC). Polymer coating was used to mitigate nZVI delivery hindrance for in situ treatment of RDX‐contaminated groundwater.

RESULTS: The RDX degradation rates by bare nZVI and starch‐coated nZVI suspensions were least affected by aging although these suspensions exhibited the least favorable dispersion behavior. CMC, AA, and guar gum coating improved nZVI rates of degradation of RDX but these rates decreased upon aging. The best suspension stability upon aging was achieved by CMC and AA. Guar gum with loadings rates one order of magnitude lower than that of CMC and AA achieved good iron stabilization but significantly higher RDX degradation rates.

CONCLUSION: It is demonstrated that both migration and reactivity of polymer‐stabilized nZVI should be explicitly evaluated over a long period before application in the field. Guar gum coated nZVI appeared best suited for in situ application because it maintained good suspension stability, with RDX degradation rates least affected by aging compared with the other polymers tested. © 2012 Society of Chemical Industry
Determining the limiting reaction in anaerobic digestion processes. How has this been tackled?
Authors: Donoso‐Bravo Andres , Mairet Francis
Published: July 2012

The rate‐limiting step concept has been widely used in anaerobic digestion processes as well as in many different biological processes. Sometimes it is described as part of the study introduction, but many times is used to support the specific objectives of the work. However, there is no clear consensus of how to define this step or how to determine it. This review presents a critical revision of several methods and procedures proposed to determine the rate‐limiting step in the anaerobic digestion field. The review is structured as follows: first, the justification of this revision is presented, followed by the very basic original definition and the latest applications in determining the rate‐limiting step. It ends with a discussion about the existing methodologies and the possible directions for addressing this issue. Different experimental approaches have been used for determining the rate‐limiting step which, in general terms, can be grouped into two procedures: steady states and batch test evaluation. Modeling applications have rarely been employed despite them allowing a more detailed picture of the anaerobic digestion system Copyright © 2012 Society of Chemical Industry
Sexually Dimorphic Levels of Color Trait Integration and the Resolution of Sexual Conflict inLakeMalawi Cichlids
Authors: BRZOZOWSKI FRANCES , ROSCOE JENNIFER , PARSONS KEVIN , ALBERTSON CRAIG
Published: July 2012

EastAfrican cichlids are renowned for their propensity to radiate, and variation in color patterns accounts for much of endemic cichlid diversity. Sexual dimorphism in color among cichlid species likely represents the outcome of different selective regimes acting on each sex, and is a classic example of sexual conflict. It is generally assumed that this conflict has been mitigated through the evolution of sex‐linked color polymorphisms. Here, we propose that the evolution of sex‐specific differences in levels of color trait integration may represent an additional mechanism through which sexual conflict has been resolved in this group. Specifically, we predict: (1) that general patterns of integration are influenced by early developmental events and thus conserved across sexes and (2) that male color is less integrated than females, and thus more evolvable in terms of producing an elaborate palette (i.e., in response to sexual selection), whereas female color is more integrated, facilitating wholesale shifts in color for background matching (i.e., in response to natural selection for crypsis). We tested these hypotheses using anF2design to compare the segregation of male and female color patterns. Both exploratory methods and hypothesis‐driven analyses of integration demonstrate that the covariance structure of color traits in males and females is distinct, and that males are significantly less integrated than females. We suggest that the ability of species to promote different levels, and to a lesser extent patterns, of phenotypic integration between males and females may have contributed to the evolutionary success of this group.J. Exp. Zool. (Mol. Dev. Evol.) 318:268–278, 2012. © 2012 Wiley Periodicals, Inc.
Disparate Igf1 Expression and Growth in the Fore‐ and Hind Limbs of a Marsupial Mammal (Monodelphis domestica)
Authors: SEARS KAREN E. , PATEL ANKIT , HÜBLER MERLA , CAO XIAOYI , VANDEBERG JOHN L. , ZHONG SHENG
Published: July 2012

Proper regulation of growth is essential to all stages of life, from development of the egg into an embryo to the maintenance of normal cell cycle progression in adults. However, despite growth's importance to basic biology and health, little is known about how mammalian growth is regulated. In this study, we investigated the molecular basis of the highly disparate growth of opossum fore‐ and hind limbs in utero. We first used a novel, opossum‐specific microarray to identify several growth‐related genes that are differentially expressed in opossum fore‐ and hind limbs of comparable developmental stages. These genes included Igf1. Given Igf1's role in the growth of other systems, we further investigated the role of Igf1 in opossum limb growth. Supporting the microarray results, RT‐PCR indicated that Igf1 levels are approximately two times higher in opossum fore‐ than hind limbs. Consistent with this, while Igf1 transcripts were readily detectable in opossum forelimbs using whole‐mount in situ hybridization, they were not detectable in opossum hind limbs. Furthermore, opossum limbs treated with exogenous Igf1 protein experienced significantly greater cellular proliferation and growth than control limbs in vitro. Taken together, results suggest that the differential expression of Igf1 in developing opossum limbs contributes to their divergent rate of growth, and the unique limb phenotype of opossum newborns. This study establishes the opossum limb as a new mammalian model system for study of organ growth. J. Exp. Zool. (Mol. Dev. Evol.) 318:279–293, 2012. © 2012 Wiley Periodicals, Inc.
Differential Expression and Regulation of Angiopoietin‐3 in Mouse Uterus during Preimplantation Period
Authors: GUO BIN , ZHANG XUE‐MING , LI SHI‐JIE , TIAN XUE‐CHAO , WANG SHOU‐TANG , LI DANG‐DANG , LIU JU‐XIONG , YUE ZHAN‐PENG
Published: July 2012

Angiogenesis is necessary for successful implantation and decidualization. This study was to investigate the differential expression of angiopoietin‐3 (Ang‐3) in mouse uterus during early pregnancy and its regulation by steroid hormones using in situ hybridization and reverse transcription polymerase chain reaction (RT‐PCR). There was no detectable Ang‐3 mRNA signal on days 1–5 of pregnancy by in situ hybridization. On day 6 of pregnancy, a low level of Ang‐3 mRNA signal was seen in the primary decidua. Ang‐3 mRNA expression gradually increased on days 7 and 8 of pregnancy along with the development of decidua, and its expression scope was also expanded. The RT‐PCR result indicated that Ang‐3 mRNA expression was low on days 1–4 of pregnancy. On day 5, as embryo implanted, Ang‐3 mRNA was highly expressed in mouse uterus, and the expression gradually increased on days 6–8 of pregnancy, with peak level on day 8 of pregnancy. Similarly, Ang‐3 mRNA was also strongly expressed in decidualized cells under artificial decidualization. Compared with the delayed uterus, a high level of Ang‐3 mRNA expression was detected in activated implantation uterus by RT‐PCR. In the ovariectomized mouse uterus, Ang‐3 mRNA expression increased and reached the highest level at 12 hr after injection of estrogen, progesterone, and estrogen plus progesterone, respectively. These results suggest that Ang‐3 may play an important role during the process of mouse decidualization. Both estrogen and progesterone can induce the expression of Ang‐3 in ovariectomized mouse uterus. J. Exp. Zool. (Mol. Dev. Evol.) 318:316–324, 2012. © 2012 Wiley Periodicals, Inc.
Temporal Bone Arrangements in Turtles: An Overview
Authors: WERNEBURG INGMAR
Published: July 2012

The temporal region of turtles is characterized by significant anatomical diversity. Turtles show a pure anapsid morphotype that exhibits various different marginal reductions known as emarginations. As a result of this diversity, turtles can be taken as a model by which to understand the processes that may have resulted in the highly debated anatomy of the amniote temporal region in general. In this review on almost forgotten literature, I summarize ten potential factors that may act on the skull to shape the temporal region of turtles. These are: (1) phylogenetic constraints, (2) skull weights, (3) type of food, (4) skull dimensions, (5) muscle bulging, (6) ear anatomy and jaw muscle bending mechanisms, (7) extent and nature of muscle attachment sites, (8) internal forces within the jaw adductor chamber, (9) environmental pressure, and (10) neck bending mechanisms. Particular focus is laid on the interrelationship of the jaw musculature and the dermatocranial armour, which were assumed to influence each other to a certain degree. In the literature, cranial dimensions were assumed to influence temporal bone formation within major tetrapod groups. Among these, turtles seem to represent a kind of intermixture, a phenomenon that may be reflected in their specific anatomy. The references presented should be understood as product of the scientific environment in which they developed and the older literature does not always insist current empirical demands. However, the intuitive and creative ideas and the comprehensive anatomical considerations of these authors may inspire future studies in several fields related to this topic. J. Exp. Zool. (Mol. Dev. Evol.) 318:235–249, 2012. © 2012 Wiley Periodicals, Inc.
Spermiogenesis in the Australian cockatiel Nymphicus hollandicus
Authors: Lovas Erica M. , Filippich Lucio J. , Johnston Stephen D.
Published: July 2012

Information on the ultrastructure of parrot spermatids and spermatozoa is limited to only four species with no comprehensive study of spermiogenesis conducted within the order Psittaciformes. The present study was undertaken to describe the development of the cockatiel spermatid using electron microscopy. Four phases of spermatid maturation were documented on the basis of nuclear morphology, development of the acrosome, perforatorium, and axial filament. These phases included 1) round nuclei, 2) irregular nuclei, 3) elongated nuclei with granular chromatin, and 4) elongated nuclei with homogenous chromatin. While development of the cockatiel spermatid was comparable to that of other domestic avian species, we have noted the hollow nature of some chromatin granules, an abnormal formation of the axoneme, the absence of the fibrous sheath around the axoneme of the principal piece, and the absence of an annulus. J. Morphol. , 2012. © 2012 Wiley Periodicals, Inc.
Kefir inhibits 3T3‐L1 adipocyte differentiation through down‐regulation of adipogenic transcription factor expression
Authors: Ho Jin‐Nyoung , Choi Jae‐Woo , Lim Won‐Chul , Kim Mi‐Kyoung , Lee In‐Young , Cho Hong‐Yon
Published: July 2012

BACKGROUND: Kefir, a traditional fermented milk composed of microbial symbionts, is reported to have various health benefits such as anti‐tumour, anti‐inflammatory, anti‐neoplastic and pro‐digestive effects. In this study, to elucidate the effects of kefir on adipocyte differentiation and lipid accumulation, three fractions were prepared from kefir culture broth. The inhibitory effects of kefir liquid culture broth fraction (Fr‐1), soluble fraction (Fr‐2) and insoluble fraction (Fr‐3), prepared by sonication of kefir solid culture broth, on adipocyte differentiation in 3T3‐L1 preadipocytes were examined.

RESULTS: Fr‐3 (0.1 mg mL−1) significantly decreased lipid accumulation and glycerol‐3‐phosphate dehydrogenase (GPDH) activity by 60 and 68% respectively without affecting cell viability. In addition, Fr‐3 treatment down‐regulated the mRNA expression of adipogenic transcription factors including C/EBPα (32%), PPARγ (46%) and SREBP‐1c (34%) during adipocyte differentiation compared with untreated control cells. The mRNA expression of adipocyte‐specific genes (aP2, FAS and ACC) was also clearly decreased.

CONCLUSION: The results suggest that the insoluble fraction of kefir (Fr‐3) mediates anti‐adipogenic effects through the inhibition of adipocyte differentiation, partly via suppression of the C/EBPα‐, SREBP‐1c‐ and PPARγ‐dependent pathways. © 2012 Society of Chemical Industry
Association of life threat and betrayal with posttraumatic stress disorder symptom severity
Authors: Kelley Lance P. , Weathers Frank W. , Mason Elizabeth A. , Pruneau Genevieve M.
Published: July 2012

The Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM‐IV‐TR; American Psychiatric Association [APA], 2000) emphasizes life threat as the defining feature of psychological trauma. Recent theoretical and empirical work, however, indicates the need to identify and evaluate other key aspects of trauma. Betrayal has been proposed as a pertinent, distinct, and complementary factor that can explain effects of trauma not accounted for by life threat alone. This study examined the relationship between injury, perceived life threat (PLT), and betrayal with posttraumatic stress disorder (PTSD) symptom severity. Trauma‐exposed college students (N = 185) completed self‐report measures of trauma exposure and PTSD, as well as items regarding life threat, betrayal, and level of medical care received. In hierarchical regressions incorporating injury, PLT, and betrayal, betrayal was associated with all PTSD symptom clusters and PTSD total severity (f2 = .08), whereas PLT was associated with hyperarousal (f2 = .05) and PTSD total (f2 = .03), and injury had no association with PTSD symptoms. In a revised model with trauma type as an additional variable, betrayal was associated with avoidance (f2 = .03), numbing (f2 = .04), and PTSD total (f2 = .03), whereas PLT was associated with reexperiencing (f2 = .04), hyperarousal (f2 = .04), and PTSD total (f2 = .03), and injury was associated with avoidance (f2 = .03). These findings support the idea that betrayal is a core dimension of psychological trauma that may play an important role in the etiology of PTSD.
Long-term quality of life of donors after living donor liver transplantation
Authors: Takada Yasutsugu , Suzukamo Yoshimi , Oike Fumitaka , Egawa Hiroto , Morita Satoshi , Fukuhara Shunichi , Uemoto Shinji , Tanaka Koichi
Published: July 2012

The aims of this study were to investigate the long-term effects of living donor liver transplantation (LDLT) on the health-related quality of life (HRQOL) of donors with the Short Form 36 health survey and to determine the risk factors for poor outcomes. Between June 1990 and June 2004, LDLT was performed 1000 times at Kyoto University Hospital. In July 2005, 997 of the 1000 donors were contacted by mail so that data on their HRQOL could be collected. In all, 578 donors responded (ie, there was a 58.0% response rate). The norm-based HRQOL scores for donors were better than the scores for Japanese norms across all time periods. All scores were similar for left lobe donors (n = 367) and right lobe donors (n = 211). For all donors, a multivariate logistic regression analysis revealed that age, the number of months until recovery to the preoperative health status, hospital visits due to donation-related symptoms, rest from work related to donation in the past month, and the existence of 2 or more comorbidities were significantly associated with decreased HRQOL scores. Postoperative complications and recipient mortality were not predictors of poor HRQOL. In conclusion, HRQOL was better for both right lobe donors and left lobe donors versus the Japanese norm population in the long term (mean postdonation period = 6.8 years). However, the prolongation of symptoms or sequelae related to donation lowered mental health or social functioning. The emergence of comorbidities after donation also significantly affected HRQOL in the long term. Careful follow-up and sustained counseling are required for donors with risk factors for lower HRQOL. Liver Transpl 18:1343–1352, 2012. © 2012 AASLD.
Polymer Micelles for Delayed Release of Therapeutics from Drug‐Releasing Surfaces with Nanotubular Structures
Authors: Aw Moom Sinn , Addai‐Mensah Jonas , Losic Dusan
Published: July 2012

A new approach to engineer a local drug delivery system with delayed release using nanostructured surface with nanotube arrays is presented. TNT arrays electrochemically generated on a titanium surface are used as a model substrate. Polymer micelles as drug carriers encapsulated with drug are loaded at the bottom of the TNT structure and their delayed release is obtained by loading blank micelles (without drug) on the top. The delayed and time‐controlled drug release is successfully demonstrated by controlling the ratio of blank and drug loaded‐micelles. The concept is verified using four different polymer micelles (regular and inverted) loaded with water‐insoluble (indomethacin) and water‐soluble drugs (gentamicin).

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Methylated actinomycin D, a novel actinomycin D analog induces apoptosis in HepG2 cells through Fas‐ and mitochondria‐mediated pathways
Authors: Chen Yongqiang , Liu Jinjuan , Yuan Bo , Cao Chengliang , Qin Sheng , Cao Xiaoying , Bian Guangkai , Wang Zhe , Jiang Jihong
Published: July 2012

Actinomycin D (Act D), a well known of clinical antitumor drug, has been used for the treatment of some highly malignant tumors, however, the clinical application was limited by its extreme cytotoxicity. In the present study, we reported that methylated actinomycin D (mAct D), a novel actinomycin D analog isolated from Streptomyces sp. KLBMP 2541 in our previous study, could not only exert stronger inhibitory effects on several human cancer cells than Act D in dose‐ and time‐dependent manner at ng concentrations, especially on HepG2 cells, but also lower cytotoxicity in normal cells (HL‐7702). Base on these results, HepG2 cells were treated for further study to illustrate the potential mechanism of mAct D. The results of nuclei morphology examination, DNA fragmentation detection, sub‐G1 analysis, annexin V‐FITC/PI staining and activation of caspase‐3 indicated mAct D significantly induced HepG2 cells apoptosis. Semiquantitative RT‐PCR and Western blot analysis revealed that mAct D induced apoptosis in HepG2 cells through mitochondria‐dependent pathway by increasing levels of caspase‐9, Bax, Bak while decreasing levels of Bcl‐2, Bid, and Fas‐dependent pathway by increasing levels of Fas, FasL, FADD, and caspase‐8. Subsequently, pretreatment with specific inhibitor of caspase‐8 Z‐LEHD‐FMK and caspase‐9 Z‐LEHD‐FMK significantly attenuated caspase‐3 activity, the cleavage of caspase‐3 and PARP, meanwhile increased the cell viability. In addition, p53 and mitochondrial transcription factor A (mtTFA) were also upregulated. Taken together, ng concentrations mAct D induces the apoptosis of HepG2 through Fas‐ and mitochondria‐mediated pathway and presents a potential novel alternative agent for the treatment of human hepatic carcinoma. © 2012 Wiley Periodicals, Inc.
High‐resolution functional MRI at 3 T: 3D/2D echo‐planar imaging with optimized physiological noise correction
Authors: Lutti Antoine , Thomas David L. , Hutton Chloe , Weiskopf Nikolaus
Published: July 2012

High‐resolution functional MRI (fMRI) offers unique possibilities for studying human functional neuroanatomy. Although high‐resolution fMRI has proven its potential at 7 T, most fMRI studies are still performed at rather low spatial resolution at 3 T. We optimized and compared single‐shot two‐dimensional echo‐planar imaging (EPI) and multishot three‐dimensional EPI high‐resolution fMRI protocols. We extended image‐based physiological noise correction from two‐dimensional EPI to multishot three‐dimensional EPI. The functional sensitivity of both acquisition schemes was assessed in a visual fMRI experiment. The physiological noise correction increased the sensitivity significantly, can be easily applied, and requires simple recordings of pulse and respiration only. The combination of three‐dimensional EPI with physiological noise correction provides exceptional sensitivity for 1.5 mm high‐resolution fMRI at 3 T, increasing the temporal signal‐to‐noise ratio by more than 25% compared to two‐dimensional EPI. Magn Reson Med, 2013. © 2012 The Authors. Magnetic Resonance in Medicine Published by Wiley Periodicals, Inc. on behalf of International Society of Medicine in Resonance.
Automated algorithm for reconstruction of the complete spine from multistation 7T MR data
Authors: Dzyubachyk Oleh , Lelieveldt Boudewijn P. F. , Blaas Jorik , Reijnierse Monique , Webb Andrew , van der Geest Rob J.
Published: July 2012

Recent technical developments in high‐field MRI have enabled high‐resolution imaging of the whole spine within clinically acceptable times. However, analysis of such data requires intensity inhomogeneity correction and volume stitching, both of which are typically performed manually. In this work, an automated method for reconstruction of the complete spine from multistation 7T MR data is presented. The method consists of a number of image processing steps, in particular intensity inhomogeneity correction and image registration for recovery of unknown interscan bed translations, which result in high‐quality spine volume reconstructions. The registration performance of the developed algorithm was validated on 18 datasets acquired in two or three stations. In all the test cases, our algorithm was able to produce correct reconstruction of the spine volume. The resulting mean registration error (0.53 mm) is found to be lower than the pixel size, demonstrating robustness and accuracy of the proposed method. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.
Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development
Authors: Zhang Qin , He Xueyan , Chen Lai , Zhang Chenxi , Gao Xiang , Yang Zhongzhou , Liu Geng
Published: July 2012

Congenital heart defects (CHDs) are the most prevalent human birth defects. More than 85% of CHDs are thought to result from a combination of genetic susceptibilities and environmental stress. However, the stress‐related signalling pathways involved remain largely unknown. The p53 transcription factor is a key tumour suppressor and a central regulator of the cellular stress responses. p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post‐translational level. Here we used the Cre–loxP system to delete Mdm2 (Tie2Cre;Mdm2FM/FM) or one copy of both Mdm2 and Mdm4 (Tie2Cre;Mdm2FM/+; Mdm4+/−) in endothelial/endocardial cells and their derivatives in mice to examine the regulation of the p53/Mdm2–Mdm4 pathway during vascular and cardiovascular development. The Tie2Cre;Mdm2FM/FM mice died before embryonic day 10.5 (E10.5) and displayed severe vascular defects. On the other hand, the Tie2Cre;Mdm2FM/+; Mdm4+/− mice displayed atrial and ventricular septal defects (ASD, VSD) of the heart, leading to severe heart dysfunction and postnatal death. During cardiac endocardial cushion morphogenesis, p53 activation was associated with defects in both the epithelial‐mesenchymal transition (EMT) of the endocardial cells and the post‐EMT proliferation of the mesenchymal cells, and the valvuloseptal phenotypes of the Tie2Cre;Mdm2FM/+; Mdm4+/− mice were fully rescued by deletion of one copy of p53. Strikingly, maternal exposure to low‐dose X‐rays in C57BL/6 mice mimicked the congenital heart malformations seen in the Tie2Cre;Mdm2FM/+; Mdm4+/− model, which was also dependent on p53 status, establishing a link between maternal exposures and CHD susceptibility through the p53 pathway. These data revealed a new regulatory mechanism in cardiac endocardial cushion morphogenesis and suggested a possible cause of CHDs due to environmental stress. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Familial secondary erythrocytosis due to increased oxygen affinity is caused by destabilization of the T state of hemoglobin Brigham (α2β2Pro100Leu)
Authors: Mollan Todd L. , Abraham Bindu , Strader Michael Brad , Jia Yiping , Lozier Jay N. , Olson John S. , Alayash Abdu I.
Published: July 2012

Hemoglobin Brigham (β Pro100 to Leu) was first reported in a patient with familial erythrocytosis. Erythrocytes of an affected individual from the same family contain both HbA and Hb Brigham and exhibit elevated O2 affinity compared with normal cells (P50 = 23 mm Hg vs. 31 mmHg at pH 7.4 at 37°C). O2 affinities measured for hemolysates were sensitive to changes in pH or chloride concentrations, indicating little change in the Bohr and Chloride effects. Hb Brigham was separated from normal HbA by nondenaturing cation exchange liquid chromatography, and the amino acid substitution was verified by mass spectrometry. The properties of Hb Brigham isolated from the patient's blood were then compared with those of recombinant Hb Brigham expressed in Escherichia coli. Kinetic experiments suggest that the rate constants for ligand binding and release in the high (R) and low (T) affinity quaternary states of Hb Brigham are similar to those of native hemoglobin. However, the Brigham mutation decreases the T to R equilibrium constant (L) which accelerates the switch to the R state during ligand binding to deoxy‐Hb, increasing the rate of association by approximately twofold, and decelerates the switch during ligand dissociation from HbO2, decreasing the rate approximately twofold. These kinetic data help explain the high O2 affinity characteristics of Hb Brigham and provide further evidence for the importance of the contribution of Pro100 to intersubunit contacts and stabilization of the T quaternary structure.
Prostate health index (phi) and prostate cancer antigen 3 (PCA3) significantly improve diagnostic accuracy in patients undergoing prostate biopsy
Authors: Perdonà Sisto , Bruzzese Dario , Ferro Matteo , Autorino Riccardo , Marino Ada , Mazzarella Claudia , Perruolo Giuseppe , Longo Michele , Spinelli Rosa , Di Lorenzo Giuseppe , Oliva Andrea , De Sio Marco , Damiano Rocco , Altieri Vincenzo , Terracciano Daniela
Published: July 2012

BACKGROUND

Prostate health index (phi) and prostate cancer antigen 3 (PCA3) have been recently proposed as novel biomarkers for prostate cancer (PCa). We assessed the diagnostic performance of these biomarkers, alone or in combination, in men undergoing first prostate biopsy for suspicion of PCa.

METHODS

One hundred sixty male subjects were enrolled in this prospective observational study. PSA molecular forms, phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay), and other established biomarkers (tPSA, fPSA, and %fPSA) were assessed before patients underwent a 18‐core first prostate biopsy. The discriminating ability between PCa‐negative and PCa‐positive biopsies of Beckman coulter phi and PCA3 score and other used biomarkers were determined.

RESULTS

One hundred sixty patients met inclusion criteria. %p2PSA (p2PSA/fPSA × 100), phi and PCA3 were significantly higher in patients with PCa compared to PCa‐negative group (median values: 1.92 vs. 1.55, 49.97 vs. 36.84, and 50 vs. 32, respectively, P ≤ 0.001). ROC curve analysis showed that %p2PSA, phi, and PCA3 are good indicator of malignancy (AUCs = 0.68, 0.71, and 0.66, respectively). A multivariable logistic regression model consisting of both the phi index and PCA3 score allowed to reach an overall diagnostic accuracy of 0.77. Decision curve analysis revealed that this “combined” marker achieved the highest net benefit over the examined range of the threshold probability.

CONCLUSIONS

phi and PCA3 showed no significant difference in the ability to predict PCa diagnosis in men undergoing first prostate biopsy. However, diagnostic performance is significantly improved by combining phi and PCA3. Prostate 73: 227–235, 2013. © 2012 Wiley Periodicals, Inc.
Urine TMPRSS2:ERG fusion transcript integrated with PCA3 score, genotyping, and biological features are correlated to the results of prostatic biopsies in men at risk of prostate cancer
Authors: Cornu Jean‐Nicolas , Cancel‐Tassin Géraldine , Egrot Christophe , Gaffory Cécile , Haab François , Cussenot Olivier
Published: July 2012

BACKGROUND

Detection of fusion gene TMPRSS2:ERG transcripts in urine have been recently described in order to refine urine‐based detection of prostate cancer (PCa), but data its clinical impact remain scarce. We aimed at investigating the correlation of TMPRSS2:ERG, prostate cancer antigen 3 (PCA3), prostate specific antigen (PSA) density, genetic variants, and androgenic status with outcome and pathological findings at prostatic biopsy.

METHODS

Between 2007 and 2011, 291 patients at risk of PCa because of PSA > 3.0 ng/ml (55%) or candidate to active surveillance protocol justifying restaging biopsy management (45%) were recruited. TMPRSS2:ERG was detected by urine assay (Progensa™). PCA3‐score, PSA level, bioavailable testosterone level, prostate volume, rs1447295 and rs6983267 genotypes were prospectively assessed. Univariate and multivariate analysis by logistic regression model (logit) were conducted to study the correlation of TMPRSS2:ERG status, PCA3, and PSA density with biopsy results, and Gleason score.

RESULTS

Of 291 patients, 173 had PCa and 118 had negative biopsy. PCA3 score, PSA density and TMPRSS2:ERG‐score were correlated with presence of PCa (P < 0.0001, P = 0.046, and P < 0.0001, respectively). This correlation remained strong on multivariable analysis model (area under curve 0.743). PCA3 score and PSA density were significantly associated with presence of Grade 4 through multivariable analysis. PCA3 score was also correlated to the percentage of positive cores at biopsy (P = 0.008).

CONCLUSIONS

Integration of levels TMPRSS2:ERG transcripts in urine, with PCA3‐score, androgenic status, genetic status and traditional clinical variables could significantly increase detection of high risk localized PCa. Prostate 73: 242–249, 2013. © 2012 Wiley Periodicals, Inc.
Use of β‐blockers is associated with prostate cancer‐specific survival in prostate cancer patients on androgen deprivation therapy
Authors: Grytli Helene Hartvedt , Fagerland Morten Wang , Fosså Sophie D. , Taskén Kristin Austlid , Håheim Lise Lund
Published: July 2012

BACKGROUND

Experimental evidence suggests a role for the β2‐adrenergic receptor pathway in prostate cancer (PCa). We have investigated the association of β‐blocker use with PCa incidence and survival in a Norwegian cohort.

METHODS

Data from the Oslo II study in 2000 (n = 6515) were linked with information from the Cancer Registry of Norway and Statistics Norway. PCa risk and overall‐ and PCa‐specific mortality were analyzed using uni‐ and multi‐variable Cox‐ and competing risk regression models.

RESULTS

At baseline, 776 men (11.9%) reported using a β‐blocker. 212 men (3.3%) were diagnosed with PCa before the survey, leaving 6,303 eligible for incidence analysis. During a median follow‐up of 122 months, 448 (7.1%) men were diagnosed with PCa. β‐blocker use was not associated with PCa risk [hazard ratio (HR): 1.05, 95% CI: 0.79–1.40]. For all patients (n = 655; including med diagnosed before the survey), β‐blocker use was not associated with PCa‐specific mortality (HR: 0.55, 95% CI 0.24–1.26, P = 0.16). However, in the subgroup of men planned to receive androgen deprivation therapy (ADT), as reported to the Cancer Registry (n = 263), β‐blocker use was associated with reduced PCa‐specific mortality (HR: 0.14, 95% CI 0.02–0.85, P = 0.032). No effect on overall mortality was seen (HR, all patients: 0.88, 95% CI 0.56–1.38, P = 0.57). β‐blocker use did not appear to affect PSA level, Gleason score, or T‐stage at diagnosis; however, these variables were missing for many cases.

CONCLUSIONS

Our findings demonstrate a possible benefit of β‐blocker use for men treated with ADT, suggesting the need for investigation in larger cohorts. Prostate 73: 250–260, 2013. © 2012 Wiley Periodicals, Inc.
The activity of the androgen receptor variant AR‐V7 is regulated by FOXO1 in a PTEN‐PI3K‐AKT‐dependent way
Authors: Mediwala Sanjay N. , Sun Huiying , Szafran Adam T. , Hartig Sean M. , Sonpavde Guru , Hayes Teresa G. , Thiagarajan Perumal , Mancini Michael A. , Marcelli Marco
Published: July 2012

BACKGROUND

The androgen receptor (AR) AR‐V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration‐resistant phenotype correlates with AR‐V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR‐V7 constitutive activation is not known.

METHODS

We analyzed potential signaling pathways associated with AR‐V7 constitutive activation in PTEN (−) PC‐3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR‐V7 activation is linked to a kinase‐dependent signaling pathway.

RESULTS

In these cell lines, AR‐V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3‐kinase (PI3K)‐AKT‐FOXO1 signaling pathway, and a significant reduction of AR‐V7 constitutive activity under conditions of PTEN reactivation.

CONCLUSIONS

Our study identifies a pathway regulating AR‐V7 constitutive activity and potential therapeutic targets for the treatment of castration‐resistant PC. Prostate 73: 267–277, 2013. © 2012 Wiley Periodicals, Inc.
Corneal Goblet Cells and Their Niche: Implications for Corneal Stem Cell Deficiency
Authors: Pajoohesh-Ganji Ahdeah , Pal-Ghosh Sonali , Tadvalkar Gauri , Stepp Mary Ann
Published: July 2012

Goblet cells are terminally differentiated cells secreting mucins and antibacterial peptides that play an important role in maintaining the health of the cornea. In corneal stem cell deficiency, the progenitor cells giving rise to goblet cells on the cornea are presumed to arise from differentiation of cells that migrate onto the cornea from the neighboring conjunctiva. This occurs in response to the inability of corneal epithelial progenitor cells at the limbus to maintain an intact corneal epithelium. This study characterizes clusters of cells we refer to as compound niches at the limbal:corneal border in the unwounded mouse. Compound niches are identified by high expression of simple epithelial keratin 8 (K8) and 19 (K19). They contain variable numbers of cells in one of several differentiation states: slow-cycling corneal progenitor cells, proliferating cells, nonproliferating cells, and postmitotic differentiated K12+Muc5ac+ goblet cells. Expression of K12 differentiates these goblet cells from those in the conjunctival epithelium and suggests that corneal epithelial progenitor cells give rise to both corneal epithelial and goblet cells. After wounds that remove corneal epithelial cells near the limbus, compound niches migrate from the limbal:corneal border onto the cornea where K8+ cells proliferate and goblet cells increase in number. By contrast, no migration of goblet cells from the bulbar conjunctiva onto the cornea is observed. This study is the first description of compound niches and corneal goblet cells and demonstration of a role for these cells in the pathology typically associated with corneal stem cell deficiency.
Deficient DNA Damage Response and Cell Cycle Checkpoints Lead to Accumulation of Point Mutations in Human Embryonic Stem Cells
Authors: Hyka-Nouspikel Nevila , Desmarais Joëlle , Gokhale Paul J. , Jones Mark , Meuth Mark , Andrews Peter W. , Nouspikel Thierry
Published: July 2012

Human embryonic stem cells (hESCs) tend to lose genomic integrity during long periods of culture in vitro and to acquire a cancer-like phenotype. In this study, we aim at understanding the contribution of point mutations to the adaptation process and at providing a mechanistic explanation for their accumulation. We observed that, due to the absence of p21/Waf1/Cip1, cultured hESCs lack proper cell cycle checkpoints and are vulnerable to the kind of DNA damage usually repaired by the highly versatile nucleotide excision repair (NER) pathway. In response to UV-induced DNA damage, the majority of hESCs succumb to apoptosis; however, a subpopulation continues to proliferate, carrying damaged DNA and accumulating point mutations with a typical UV-induced signature. The UV-resistant cells retain their proliferative capacity and potential for pluripotent differentiation and are markedly less apoptotic to subsequent UV exposure. These findings demonstrate that, due to deficient DNA damage response, the modest NER activity in hESCs is insufficient to prevent increased mutagenesis. This provides for the appearance of genetically aberrant hESCs, paving the way for further major genetic changes.