bluuebunny/crossref_metadata_2025 huggingface dataset:
Signal Transducer and Activator of Transcription 5a Mediates Mammary Ductal Branching and Proliferation in the Nulliparous Mouse
Authors: Santos Sarah J. , Haslam Sandra Z. , Conrad Susan E.
Published: April 2010

Signal transducer and activator of transcription (Stat)5a is a critical regulator of mammary gland development. Previous studies have focused on Stat5a’s role in the late pregnant and lactating gland, and although active Stat5a is detectable in mammary epithelial cells in virgin mice, little is known about its role during early mammary gland development. In this report, we compare mammary gland morphology in pubertal and adult nulliparous wild-type and Stat5a−/− mice. The Stat5a-null mammary glands exhibited defects in secondary and side branching, providing evidence that Stat5a regulates these processes. In addition, Stat5a−/− mammary glands displayed an attenuated proliferative response to pregnancy levels of estrogen plus progesterone (E+P), suggesting that it plays an important role in early pregnancy. Finally, we examined one potential mediator of Stat5a’s effects, receptor activator of nuclear factor-κB ligand (RANKL). Stat5a−/− mammary glands were defective in inducing RANKL in response to E+P treatment. In addition, regulation of several reported RANKL targets, including inhibitor of DNA binding 2 (Id2), cyclin D1, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1, was altered in Stat5a−/− mammary cells, suggesting that one or more of these proteins mediate the effects of Stat5a in E+P-treated mammary epithelial cells.
A Selective Androgen Receptor Modulator Enhances Male-Directed Sexual Preference, Proceptive Behavior, and Lordosis Behavior in Sexually Experienced, But Not Sexually Naive, Female Rats
Authors: Kudwa A. E. , López F. J. , McGivern R. F. , Handa R. J.
Published: April 2010

Androgens influence many aspects of reproductive behavior, including sexual preference of females for males. In oophorectomized women with sexual desire disorder, testosterone patches improve libido, but their use is limited because of adverse side effects. Selective androgen receptor modulators offer an improved safety profile for both sexes: enhancing libido and muscle and bone growth in a manner similar to steroidal androgens but with fewer adverse effects, such as hirsutism, acne, and prostate growth. The current study investigated the action of a novel selective androgen receptor modulator (LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one]) on male-directed sexual preference, proceptivity, and lordosis behavior of female rats. LGD-3303 is a nonsteroidal, nonaromatizable, highly selective ligand for the androgen receptor and effectively crosses the blood-brain barrier. Gonadectomized female rats were treated with LGD-3303 (3–30 mg/kg) or vehicle by daily oral gavage. Results showed that LGD-3303 treatment enhanced sexual preference of females for males but only if females had previous sexual experience. This occurred after 1 or 7 d of treatment. In contrast, preference for males was inhibited by LGD-3303 treatments of sexually naive females. The LGD-3303 increase in male preference was blocked by pretreatment with the androgen receptor antagonist flutamide. LGD-3303 treatment increased lordosis and proceptivity behaviors in ovariectomized females primed with suboptimal doses of estradiol benzoate plus progesterone. These data support the concept that LGD-3303 can stimulate aspects of female sexual behavior and may serve as a potential therapeutic for women with sexual desire disorders.
Therapeutic Concentrations of Mitotane (o,p′-DDD) Inhibit Thyrotroph Cell Viability and TSH Expression and Secretion in a Mouse Cell Line Model
Authors: Zatelli Maria Chiara , Gentilin Erica , Daffara Fulvia , Tagliati Federico , Reimondo Giuseppe , Carandina Gianni , Ambrosio Maria Rosaria , Terzolo Massimo , degli Uberti Ettore C.
Published: April 2010

Mitotane therapy is associated with many side effects, including thyroid function perturbations mimicking central hypothyroidism, possibly due to laboratory test interference or pituitary direct effects of mitotane. We investigated whether increasing concentrations of mitotane in the therapeutic range might interfere with thyroid hormone assays and evaluated the effects of mitotane on a mouse TSH-producing pituitary cell line. TSH, free T4, and free T3 levels do not significantly change in sera from hypo-, hyper-, or euthyroid patients after addition of mitotane at concentrations in the therapeutic window. In the mouse TαT1 cell line, mitotane inhibits both TSH expression and secretion, blocks TSH response to TRH, and reduces cell viability, inducing apoptosis at concentrations in the therapeutic window. TRH is not capable of rescuing TαT1 cells from the inhibitory effects of mitotane on TSH expression and secretion, which appear after short time treatment and persist over time. Our results demonstrate that mitotane does not interfere with thyroid hormone laboratory tests but directly reduces both secretory activity and cell viability on pituitary TSH-secreting mouse cells. These data represent a possible explanation of the biochemical picture consistent with central hypothyroidism in patients undergoing mitotane therapy and open new perspectives on the direct pituitary effects of this drug.
Minireview: Rapid Actions of Sex Steroids in the Endothelium
Authors: Chow Renee W. Y. , Handelsman David J. , Ng Martin K. C.
Published: April 2010

The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.
Prenatal Plus Postnatal Exposure to Di(n-Butyl) Phthalate and/or Flutamide Markedly Reduces Final Sertoli Cell Number in the Rat
Authors: Auharek Sarah A. , de Franca Luiz R. , McKinnell Chris , Jobling Matthew S. , Scott Hayley M. , Sharpe Richard M.
Published: April 2010

Androgens may be important regulators of Sertoli cell (SC) proliferation perinatally, with implications for the testicular dysgenesis syndrome (TDS) hypothesis. Fetal exposure of rats to 500 mg/kg · d di(n-butyl) phthalate (DBP) reduces fetal testosterone production and SC number at birth, but SC number recovers to normal by postnatal d (Pnd)25. It is unclear when and how SC proliferation is affected prenatally by DBP exposure or when and how postnatal compensation occurs. This study addressed these questions and investigated whether continued maternal exposure to DBP or to flutamide from Pnd1–Pnd15 could prevent SC number compensation, because this would have implications for how sperm counts might be lowered in TDS. DBP exposure attenuated SC proliferation by 7–18% throughout embryonic d (e)15.5–e21.5 (P < 0.05 at e21.5). After birth, SC proliferation increased significantly (>1.5-fold) between Pnd6 and Pnd10 in prenatally DBP-exposed animals, explaining the compensation. Continued maternal administration of DBP after birth attenuated (19% reduction) SC number compensation at Pnd25 and maternal administration of flutamide (100 mg/kg · d) to prenatally DBP-exposed animals was even more effective (42% reduction), suggesting the postnatal compensatory increase in SC proliferation after prenatal DBP exposure is androgen dependent. SC maturation (Pnd25) was unaffected, based on analysis of expression of key proteins, but lumen formation/expansion was attenuated in parallel with treatment-induced reduction in SC number. Our results provide further evidence that perinatal SC proliferation is androgen dependent and, importantly, show that similar exposure of mothers to antiandrogenic chemicals before birth and during lactation reduces final SC number, with implications for the origin of low sperm counts in TDS.
Matrix Metalloproteinase-9 Is Increased in Obese Subjects and Decreases in Response to Pioglitazone
Authors: Unal Resat , Yao-Borengasser Aiwei , Varma Vijayalakshmi , Rasouli Neda , Labbate Craig , Kern Philip A. , Ranganathan Gouri
Published: April 2010

Context: The study investigated the regulation of matrix metalloproteinases (MMP)-9 in obesity-associated insulin resistance in humans.

Objectives: The objectives of the investigation were to study MMP-9 regulation by insulin resistance and pioglitazone treatment in impaired glucose tolerant subjects using adipose tissue biopsies and study the mechanism of MMP-9 regulation by pioglitazone in adipocyte cultures.

Research Design: 86 nondiabetic, weight-stable subjects between 21 and 66 yr of age were recruited in a university hospital research center setting. All subjects underwent a sc adipose tissue incisional biopsy from the lower abdominal wall and insulin sensitivity testing using a frequently sampled iv glucose tolerance test. Impaired glucose-tolerant subjects were randomized to receive metformin or pioglitazone for 10 wk. To study the mechanism of MMP-9 regulation in adipocytes, cells were treated with pioglitazone or protein kinase Cα antisense oligomers, and MMP-9 levels were examined.

Results: There was a positive correlation between MMP-9 and body mass index (r = 0.40, P < 0.01) and negative correlation between MMP-9 and insulin sensitivity (r = −0.46, P < 0.001). The improvement in insulin sensitivity from pioglitazone resulted in a 52 ± 0.2% reduction in MMP-9 mRNA. Fractionation of adipose tissue indicated that MMP-9 was mostly in the stromal vascular fraction. Pioglitazone also decreased MMP-9 in 3T3-F442A adipocytes and THP1 macrophages. Coculture of adipocytes with macrophages augmented MMP-9 expression in adipocytes and pioglitazone decreased MMP-9 in both adipocytes and macrophages.

Conclusion: These data indicate that MMP-9 is elevated in insulin resistance and is reduced by pioglitazone.
Estrogen Coordinates Translation and Transcription, Revealing a Role for NRSF in Human Breast Cancer Cells
Authors: Bronson Michael W. , Hillenmeyer Sara , Park Richard W. , Brodsky Alexander S.
Published: April 2010

Posttranscriptional regulation may enhance or inhibit estrogen transcriptional control to promote proliferation of breast cancer cells. To understand how transcriptome and translational responses coordinate to drive proliferation, we determined estrogen’s global and specific effects on translation regulation by comparing the genome-wide profiles of total mRNA, polysome-associated mRNA, and monosome-associated mRNAs in MCF-7 cells after stimulation by 1 h of 10 nm 17β-estradiol (E2). We observe three significant, novel findings. 1) E2 regulates several transcripts and pathways at the translation level. 2) We find that polysome analysis has higher sensitivity than total RNA in detecting E2-regulated transcripts as exemplified by observing stronger E2-induced enrichment of E2 expression signatures in polysomes more than in total RNA. This increased sensitivity allowed the identification of the repression of neural restrictive silencing factor targets in polysome-associated RNA but not total RNA. NRSF activity was required for E2 stimulation of the cell cycle. 3) We observe that the initial translation state is already high for E2 up-regulated transcripts before E2 treatment and vice versa for E2 down-regulated transcripts. This suggests that the translation state anticipates potential E2-induced transcriptome levels. Together, these data suggest that E2 stimulates breast cancer cells by regulating translation using multiple mechanisms. In sum, we show that polysome profiling of E2 regulation of breast cancer cells provides novel insights into hormone action and can identify novel factors critical for breast cancer cell growth.
The PAR complex regulates pulsed actomyosin contractions during amnioserosa apical constriction in Drosophila
Authors: David Daryl J. V. , Tishkina Alisa , Harris Tony J. C.
Published: April 2010

Apical constriction is a major mechanism underlying tissue internalization during development. This cell constriction typically requires actomyosin contractility. Thus, understanding apical constriction requires characterization of the mechanics and regulation of actomyosin assemblies. We have analyzed the relationship between myosin and the polarity regulators Par-6, aPKC and Bazooka (Par-3) (the PAR complex) during amnioserosa apical constriction at Drosophila dorsal closure. The PAR complex and myosin accumulate at the apical surface domain of amnioserosa cells at dorsal closure, the PAR complex forming a patch of puncta and myosin forming an associated network. Genetic interactions indicate that the PAR complex supports myosin activity during dorsal closure, as well as during other steps of embryogenesis. We find that actomyosin contractility in amnioserosa cells is based on the repeated assembly and disassembly of apical actomyosin networks, with each assembly event driving constriction of the apical domain. As the networks assemble they translocate across the apical patch of PAR proteins, which persist at the apical domain. Through loss- and gain-of-function studies, we find that different PAR complex components regulate distinct phases of the actomyosin assembly/disassembly cycle: Bazooka promotes the duration of actomyosin pulses and Par-6/aPKC promotes the lull time between pulses. These results identify the mechanics of actomyosin contractility that drive amnioserosa apical constriction and how specific steps of the contractile mechanism are regulated by the PAR complex.
Emergence of traveling waves in the zebrafish segmentation clock
Authors: Ishimatsu Kana , Takamatsu Atsuko , Takeda Hiroyuki
Published: April 2010

The spatial and temporal periodicity of somite formation is controlled by the segmentation clock, in which numerous cells cyclically express hairy-related transcriptional repressors with a posterior-to-anterior phase delay, creating ‘traveling waves’ of her1 expression. In zebrafish, the first traveling wave buds off from the synchronous oscillation zone in the blastoderm margin. Here we show that the emergence of a traveling wave coincides with the anterior expansion of Fgf signaling and that transplanted Fgf8b-soaked beads induce ectopic traveling waves. We thus propose that as development proceeds, the activity of Fgf signaling gradually expands anteriorly, starting from the margin, so that cells initiate her1 oscillation with a posterior-to-anterior phase delay. Furthermore, we suggest that Fgf has an essential role in establishing the period gradient that is required for the her1 spatial oscillation pattern at the emergence of the traveling wave.
A novel F-box protein is required for caspase activation during cellular remodeling inDrosophila
Authors: Bader Maya , Arama Eli , Steller Hermann
Published: April 2010

Terminal differentiation of male germ cells in Drosophila and mammals requires extensive cytoarchitectural remodeling, the elimination of many organelles, and a large reduction in cell volume. The associated process, termed spermatid individualization, is facilitated by the apoptotic machinery, including caspases, but does not result in cell death. From a screen for genes defective in caspase activation in this system, we isolated a novel F-box protein, which we termed Nutcracker, that is strictly required for caspase activation and sperm differentiation. Nutcracker interacts through its F-box domain with members of a Cullin-1-based ubiquitin ligase complex (SCF): Cullin-1 and SkpA. This ubiquitin ligase does not regulate the stability of the caspase inhibitors DIAP1 and DIAP2, but physically binds Bruce, a BIR-containing giant protein involved in apoptosis regulation. Furthermore, nutcracker mutants disrupt proteasome activity without affecting their distribution. These findings define a new SCF complex required for caspase activation during sperm differentiation and highlight the role of regulated proteolysis during this process.
APC16 is a conserved subunit of the anaphase-promoting complex/cyclosome
Authors: Kops Geert J. P. L. , van der Voet Monique , Manak Michael S. , van Osch Maria H. J. , Naini Said M. , Brear Andrea , McLeod Ian X. , Hentschel Dirk M. , Yates John R. , van den Heuvel Sander , Shah Jagesh V.
Published: April 2010

Error-free chromosome segregation depends on timely activation of the multi-subunit E3 ubiquitin ligase APC/C. Activation of the APC/C initiates chromosome segregation and mitotic exit by targeting critical cell-cycle regulators for destruction. The APC/C is the principle target of the mitotic checkpoint, which prevents segregation while chromosomes are unattached to spindle microtubules. We now report the identification and characterization of APC16, a conserved subunit of the APC/C. APC16 was found in association with tandem-affinity-purified mitotic checkpoint complex protein complexes. APC16 is a bona fide subunit of human APC/C: it is present in APC/C complexes throughout the cell cycle, the phenotype of APC16-depleted cells copies depletion of other APC/C subunits, and APC16 is important for APC/C activity towards mitotic substrates. APC16 sequence homologues can be identified in metazoans, but not fungi, by four conserved primary sequence stretches. We provide evidence that the C. elegans gene K10D2.4 and the D. rerio gene zgc:110659 are functional equivalents of human APC16. Our findings show that APC/C is composed of previously undescribed subunits, and raise the question of why metazoan APC/C is molecularly different from unicellular APC/C.
Stepwise evolution of the centriole-assembly pathway
Authors: Carvalho-Santos Zita , Machado Pedro , Branco Pedro , Tavares-Cadete Filipe , Rodrigues-Martins Ana , Pereira-Leal José B. , Bettencourt-Dias Mónica
Published: April 2010

The centriole and basal body (CBB) structure nucleates cilia and flagella, and is an essential component of the centrosome, underlying eukaryotic microtubule-based motility, cell division and polarity. In recent years, components of the CBB-assembly machinery have been identified, but little is known about their regulation and evolution. Given the diversity of cellular contexts encountered in eukaryotes, but the remarkable conservation of CBB morphology, we asked whether general mechanistic principles could explain CBB assembly. We analysed the distribution of each component of the human CBB-assembly machinery across eukaryotes as a strategy to generate testable hypotheses. We found an evolutionarily cohesive and ancestral module, which we term UNIMOD and is defined by three components (SAS6, SAS4/CPAP and BLD10/CEP135), that correlates with the occurrence of CBBs. Unexpectedly, other players (SAK/PLK4, SPD2/CEP192 and CP110) emerged in a taxon-specific manner. We report that gene duplication plays an important role in the evolution of CBB components and show that, in the case of BLD10/CEP135, this is a source of tissue specificity in CBB and flagella biogenesis. Moreover, we observe extreme protein divergence amongst CBB components and show experimentally that there is loss of cross-species complementation among SAK/PLK4 family members, suggesting species-specific adaptations in CBB assembly. We propose that the UNIMOD theory explains the conservation of CBB architecture and that taxon- and tissue-specific molecular innovations, gained through emergence, duplication and divergence, play important roles in coordinating CBB biogenesis and function in different cellular contexts.
Formation of Reactive Microporous Networks from Alkoxyvinylsilylated Siloxane Cages
Authors: Hagiwara Yoshiaki , Shimojima Atsushi , Kuroda Kazuyuki
Published: April 2010

A bifunctional siloxane cage, where double four-membered ring (D4R) silicate was capped with alkoxyvinylsilyl groups, was synthesized as a novel building block for the formation of inorganic–organic microporous solids in order to show its usefulness for synthesizing silica-based nanomaterials with unique structures and properties. The nanobuilding blocks were connected to each other either by hydrolysis and condensation of alkoxysilyl groups to form Si–O–Si linkages or by hydrosilylation of vinyl groups with hydrogen-terminated D4R (H8Si8O12), which was used as a linking agent, to form Si–CH2CH2–Si linkages. Xerogel obtained by hydrosilylation showed a significant increase in the surface area upon removal of alkoxy groups by post treatment. The molecular design of bifunctionally-silylated D4R units provides a new approach to the formation of microporous networks with uniform distribution of reactive groups that allow post-modification.
Application of five frozen human-pooled serum samples assigned by the International Federation of Clinical Chemistry and Laboratory Medicine reference procedure in a traceability investigation of γ-glutamyltransferase catalytic concentration measurements in China
Authors: Xia Changyu , Tong Qing , Wang Qingtao , Tang Zhuling , Qi Lili , Chi Shan , Zhang Man , Wang Xuejing , Li Haixia , Xu Guobin
Published: April 2010

Background

The in vitro directive of the European Union requires traceability to the international recommended reference procedures. The application of the reference procedures is necessary in order to evaluate the accuracy of γ-glutamyltransferase (GGT) assays of routine measurement systems in China.

Methods

Five frozen patient-pooled serum samples were assigned values by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference procedure in order to evaluate the traceability of the results of GGT catalytic activity from six homogeneous systems. One of the serum samples was used to calibrate seven non-homogeneous systems.

Results

All of the homogeneous systems, except the Dade system (Dade Bering Inc, IL, USA), achieved traceability within the measurement range. The Roche and Hitachi systems were better than the other systems. After calibration, the variance of the non-homogeneous systems decreased dramatically from between 14.50% and 25.23% to between 1.25% and 3.09% and the bias decreased from between −11.4% and −4.1% to between 0.5% and 3.5%.

Conclusion

Manufacturers in China should ensure that their calibration systems correspond to the IFCC reference procedures. Fresh frozen pooled patient serum assigned by reference laboratories can be used to calibrate non-homogeneous systems in order to achieve traceability.
A simple liquid chromatography linked to tandem mass spectrometry method for measurement of serum cholinesterase activity using succinylcholine as substrate
Authors: Spencer Jennifer D , Rushton David , Allen Keith R
Published: April 2010

Background

Individuals who are unable to metabolize the short-acting muscle relaxant succinylcholine due to abnormal cholinesterase activity are currently investigated via spectrophotometry using artificial substrates and enzyme inhibitors. Methods have been described using succinylcholine as substrate but with measurement of the product choline. However, choline may be released from other endogenous substrates within the serum. Direct measurement of the in vitro metabolism of succinylcholine as substrate may provide a better indication of the in vivo situation with regard to cholinesterase status.

Methods

The rate of in vitro metabolism of succinylcholine by cholinesterase was measured using liquid chromatography linked to tandem mass spectrometry (LC-MS/MS). A comparison was made using serum samples in which cholinesterase activity had been measured using propionylthiocholine as substrate and phenotyped by enzyme inhibitor studies.

Results

A good correlation ( r = 0.9, P < 0.0001) was found between cholinesterase activity measured by LC-MS/MS using succinylcholine as substrate compared with propionylthiocholine as substrate measured spectrophotometrically. All serum samples with a cholinesterase activity of <1 IU/L, as measured using succinylcholine as substrate, were considered to be at increased risk of succinylcholine sensitivity. These latter results correlated well to the atypical phenotypes.

Conclusions

A simple and fast LC-MS/MS technique for the measurement of cholinesterase activity using succinylcholine as substrate has been described. This method clearly identifies patients at risk of prolonged apnoea following succinylcholine administration and compares favourably with existing spectrophotometric methods using artificial substrates.
Reflex and reflective testing: efficiency and effectiveness of adding on laboratory tests
Authors: Srivastava Rajeev , Bartlett William A , Kennedy Ian M , Hiney Allan , Fletcher Colin , Murphy Michael J
Published: April 2010

Background

Laboratory investigations may be added to existing requests either automatically on the basis of algorithms (reflex testing) or by laboratory professionals (reflective testing). The clinical utility of reflex and reflective testing is not fully established. We studied efficiency (number of tests that needs to be added to make a diagnosis) and effectiveness (number of diagnoses) of reflex and reflective testing in selected biochemical scenarios.

Methods

Using fixed rules, we prospectively measured efficiency and effectiveness of reflex and reflective testing in the following scenarios (reflex initiators in parentheses): (1) hypovitaminosis D (hypocalcaemia plus elevated alkaline phosphatase activity); (2) hypomagnesaemia (hypokalaemia or hypocalcaemia); (3) hypothyroidism (high thyroid-stimulating hormone [TSH]); (4) hyperthyroidism (low TSH); (5) haemochromatosis (reflex or reflective addition of iron studies, followed by reflective addition of genetic studies). Separately, using a different data-set, we examined the impact of varying TSH thresholds on outcomes in the biochemical diagnosis of hyper- and hypothyroidism.

Results

In patients aged over 55 y, 25-hydroxy-vitamin D <50 nmol/L could be predicted with ≥90% certainty when albumin-adjusted calcium was ≤2.1 mmol/L plus alkaline phosphatase >150 U/L. Higher numbers of tests were needed to make a diagnosis in other scenarios. In general, more diagnoses were made by reflex testing. Outside the euthyroid TSH range, efficiency of diagnosis of hyper- and hypothyroidism became asymptotic, while effectiveness declined.

Conclusions

Near-maximal efficiency of reflex testing can be achieved, depending on the reflex and diagnostic thresholds applied. Reflective and reflex testing are complementary activities, the clinical utility of which depends on the initiators used.
Why Do Software Firms Fail? Capabilities, Competitive Actions, and Firm Survival in the Software Industry from 1995 to 2007
Authors: Li Shanling , Shang Jennifer , Slaughter Sandra A.
Published: April 2010

This study examines why firms fail or survive in the volatile software industry. We provide a novel perspective by considering how software firms' capabilities and their competitive actions affect their ultimate survival. Drawing on the resource-based view (RBV), we conceptualize capabilities as a firm's ability to efficiently transform input resources into outputs, relative to its peers. We define three critical capabilities of software-producing firms—research and development (RD), marketing (MK), and operations (OP)—and hypothesize that in the dynamic, high-technology software industry, RD and MK capabilities are most important for firm survival. We then draw on the competitive dynamics literature to theorize that competitive actions distinguished by a greater emphasis on innovation-related moves will increase firm survival more than actions emphasizing resource-related moves. Finally, we postulate that firms' capabilities will complement their competitive actions in affecting firm survival. Our empirical evaluation examines a cross-sectional, time series panel of 5,827 observations on 870 software companies from 1995 to 2007. We use a stochastic frontier production function to measure the capability for each software firm in each time period. We then use the Cox proportional hazard regression technique to relate capabilities and competitive actions to software firms' failure rates. Unexpectedly, our results reveal that higher OP capability increases software firm survival more than higher MK and RD capabilities. Further, firms with a greater emphasis on innovation-related than resource-related competitive actions have a greater likelihood of survival, and this likelihood increases even further when these firms have higher MK and OP capabilities. Additional analyses of subsectors within the software industry reveal that firms producing visual applications (e.g., graphical and video game software) have the highest MK capability but the lowest OP and RD capabilities and make twice as many innovation-related as resource-related moves. These firms have the highest market values but the worst Altman Z scores, suggesting that they are valued highly but also are at high risk for failure, and indeed the firms in this sector fail at a greater rate than expected. In contrast, firms producing traditional decision-support applications and infrastructure software have different capabilities and make different competitive moves. Our findings suggest that the firms that persist and survive over the long term in the dynamic software industry are able to capitalize on their competitive actions because of their greater capabilities, and particularly OP capabilities.
Lipid-Rich Variant of Appendiceal Well-Differentiated Endocrine Tumor (Carcinoid)
Authors: La Rosa Stefano , Finzi Giovanna , Puppa Giacomo , Capella Carlo
Published: April 2010

Well-differentiated endocrine tumors (WDETs) of the appendix show characteristic morphologic features, including proliferation of cells with finely granulated eosinophilic cytoplasm. However, clear cell WDETs, which can present a diagnostic challenge, have been occasionally described, but it is unknown whether they represent a morphologic variant with distinct clinicopathologic features. Moreover, the clear cell appearance of the cytoplasm has never been explained. We studied 13 appendiceal WDETs composed of clear cells, which showed an immunophenotype identical to that of conventional appendiceal WDETs. Ultrastructural examination demonstrated abundant lipid accumulation. Patient survival was excellent and equal to that of conventional appendiceal WDETs. These neoplasms, which represent a lipid-rich variant of appendiceal WDETs, do not have different relevant clinical implications compared with conventional WDETs, but it is important to know of their existence for the differential diagnosis with more aggressive neoplasms, including goblet cell carcinoids and appendiceal metastases from clear cell carcinomas.
A Novel Flow Cytometric Antibody Panel for Distinguishing Burkitt Lymphoma From CD10+ Diffuse Large B-Cell Lymphoma
Authors: Schniederjan Stephanie D. , Li Shiyong , Saxe Debra F. , Lechowicz Mary J. , Lee Kathryn L. , Terry Paul D. , Mann Karen P.
Published: April 2010

Rapid and accurate differential diagnosis between Burkitt lymphoma (BL) and CD10+ diffuse large B-cell lymphoma (DLBCL) is imperative because their treatment differs. Recent studies have characterized several antigens differentially expressed in these 2 types of lymphoma. Our goal was to determine whether use of these markers would aid in the differential diagnosis of BL vs CD10+ DLBCL by flow cytometric immunophenotyping (FCI). Twenty-three cases of CD10+ B-cell lymphomas with available cryopreserved samples were identified (13 BL and 10 CD10+ DLBCL). Multiparameter FCI was performed using the following antibodies: CD18, CD20, CD43, CD44, and CD54 and isotype controls. Expression of CD44 and CD54 was detected at a significantly lower level in BL compared with CD10+ DLBCL (P = .001 and P = .01, respectively). There was not a significant difference in expression of CD18 and CD43. Our data show that expression of CD44 and CD54 differs significantly between BL and CD10+ DLBCL.
Genetic health messages in the mass media: Do the general public perceive non‐personalized genetic health message as personally relevant?
Authors: Smerecnik Chris M. R. , Mesters Ilse , Candel Math J. J. M. , de Vries Hein , de Vries Nanne K.
Published: April 2010

Objectives. Although health messages communicating the role of genetics in health and disease development are increasingly prevalent in our society, no research has examined whether the general public perceives such messages as believable or personally relevant. We examined whether the general public accepted genetic health messages and viewed them personally relevant in promoting their preventive behaviour.

Design. Experimental pre‐test–post‐test measurement design was employed to contrast the information acceptance and perceived personal relevance of the genetic health message with a general health message.

Methods. We presented a randomly selected group of Dutch participants (N=1,319) with either a health message about the genetic risk factors for salt sensitivity or with a general health message about salt sensitivity without reference to genetic risk factors. Risk perception and intention to restrict salt intake was assessed before and after participants read the messages while information acceptance and perceived personal relevance was only assessed post‐test.

Results. Although we observed no effects of health message type on information processing, previously aware participants perceived the genetic health message as less personally relevant compared to the general health message. This difference in personal relevance resulted in lower estimates of susceptibility and a lower intention to engage in preventive behaviour among previously unaware participants.

Conclusions. Genetic health messages in the mass media may not be effective in promoting (intentions to engage in) preventive behaviour due to their low perceived personal relevance by the public. Hence, identifying strategies to increase personal relevance for genetic education is needed.
Chronic hyponatremia impairs memory in rats: effects of vasopressin antagonist tolvaptan
Authors: Miyazaki Toshiki , Ohmoto Koji , Hirose Tsuyoshi , Fujiki Hiroyuki
Published: April 2010

The effects of stable chronic hyponatremia on the central nervous system are largely unknown, clinically, or in experimental animals. The aim of this study was to identify and characterize these effects in rats. Tolvaptan, a vasopressin V2 receptor antagonist, was used to correct hyponatremia and determine any potential benefits of such treatment in this condition. Stable chronic hyponatremia was induced by combination of the continuous vasopressin V2 receptor stimulation and liquid food intake. The hyponatremic rats did not exhibit significant changes in general symptoms or neurological functions assessed by modified Irwin's method, or in motor function assessed by the rotarod test. In passive avoidance test, however, rats with moderate and severe hyponatremia had significantly reduced step-through latency, indicating impairment in memory. This reduced step-through latency was improved by the treatment of tolvaptan (0.25–8 mg/kg daily doses), a vasopressin V2 receptor antagonist. This improvement is associated with normalization of plasma sodium concentrations in hyponatremic rats. In conclusion, these data suggest that chronic hyponatremia may impair memory, and treatments that normalize sodium level, such as vasopressin V2 receptor antagonists, may be beneficial to patients with hyponatremia.
Cocoa Butter Saturated with Supercritical Carbon Dioxide: Measurements and Modelling of Solubility, Volumetric Expansion, Density and Viscosity
Authors: Calvignac Brice , Rodier Elisabeth , Letourneau Jean-Jacques , Almeida dos Santos Pedro Miguel , Fages Jacques
Published: April 2010

The use of supercritical carbon dioxide technology for lipid processing has recently developed at the expense of traditional processes. For designing new processes the knowledge of thermophysical properties is a prerequisite. This work is focused on the characterization of physical and thermodynamic properties of CO2-cocoa butter (CB) saturated mixture. Measurements of density, volumetric expansion, viscosity and CO2 solubility were carried out on CB-rich phase at 313 and 353 K and pressures up to 40 MPa. The experimental techniques have previously been compared and validated. Density measurements of CB and CB saturated with CO2, were performed using the vibrating tube technology at pressures ranging from 0.1 to 25 MPa. Experimental values correlated well with the modified Tait equation. CO2 solubility measurements were coupled to those of density in the same pressures ranges. At 25 MPa, the solubility of CO2 is 31.4 % and 28.7 % at 313 and 353 K. Phase behaviour was investigated using a view cell in order to follow the expansion of the CB-rich phase with the rise in pressure. Volumetric expansion up to 47 % was measured and correlated to the CO2 solubility. Phase inversion was observed at 313 K and 40 MPa. Lastly, we developed an innovative falling ball viscometer for high pressure measurements. Viscosity measurements were carried out up to 25 MPa showing a viscosity reduction up to 90 % upon CO2 dissolution. These results were correlated with two empirical models. A new model here presented, was favourably compared with the Grunberg and Nissan model. All the experimental results are consistent with the available literature data for the CB-CO2 mixture and other fat systems. This work is a new contribution to the characterization of physical and thermodynamic behaviour of fats in contact with CO2 which is necessary to design supercritical fluid processes for fats processing.
Modulatory Effect of Psidium Guajava Linn and Ocimum Gratissimum Linn on Lipid Profile and Selected Biochemical Indices in Rabbits Fed High Cholesterol Diet
Authors: Akinloye Oluyemi , Akinmoladun Afolabi Clement , Farombi Ebenezer Olatunde
Published: April 2010

The effect of aqueous leaf extracts of Psidium guajava(PG) and Ocimum gratissimum(OG) on fasting plasma glucose (FPG), total protein (TP), albumin (ALB), globulin (GLB), total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL), LDL-cholesterol (LDL) and lactate dehydrogenase (LDH) concentrations in rabbits fed high-cholesterol diet was investigated. Four groups of animals were used (n = 6). Animals in group A were fed normal laboratory pellet and water ad libitum; those in group B were fed the high-cholesterol diet (normal diet + 1% w/w cholesterol + 1% w/w vegetable oil) while those in groups C and D received a daily oral administration of 250 mg/kg body weight of the extract of Psidium guajava and Ocimum gratissimum, respectively, in addition to the high-cholesterol diet for a period of six weeks. Hypercholesterolemia, associated with hyperglycemia was induced significantly in animals in group B compared to normal control group (A) (P<0.01). There were also significant increases in the levels of LDL (P<0.05) and HDL (P<0.01). Treatments with PG and OG reduced the plasma cholesterol level by 15% and 28%, respectively, compared to animals in Group B. PG caused a remarkable increase in HDL (69%) but a decrease in LDL (74%) levels. OG on the other hand reduced the levels of both HDL and LDL by 50% and 26%, respectively, compared to animals in Group B. While the level of HDL in the OG group was similar to that of normal controls, the LDL level was significantly higher (71%). Furthermore, both extracts reduced the associated hyperglycemia significantly (P<0.05). This decrease was more pronounced in PG treated rabbits (PG; 43%, OG; 19%). In addition, OG stimulated a significant increase in the concentrations of LDH and serum protein, particularly albumin. These results show that aqueous extracts of both plants especially PG ameliorated the hypercholesterolemic and associated hyperglycemic effects of high cholesterol diet. However, OG shows possible contraindications and the safety of its ethnomedical usage warrants further investigation.
Thermal treatment of kaolin clay to obtain metakaolin
Authors: Ilic Biljana , Mitrovic Aleksandra , Milicic Ljiljana
Published: April 2010

The metakaolin was produced by thermal treatment (calcination) of the starting high-quality kaolin clay from Serbia. The optimal calcination parameters, for which nearly complete dehydroxylation of the material was achieved, are: temperature 650?C and heating time of 90 min. The conversion of the kaolinite to metakaolin was confirmed by XRD and IR analyses of the starting and thermally treated kaolin samples. The pozzolanic activity was determined by Chapelle test. The obtained value 0.65 g Ca(OH)2/g of metakaolin indicates that produced metakaolin may be used as supplementary cementitious material.
Early Hepatic Insulin Resistance Precedes the Onset of Diabetes in Obese C57BLKS-db/db Mice
Authors: Davis Richard C. , Castellani Lawrence W. , Hosseini Maryam , Ben-Zeev Osnat , Mao Hui Z. , Weinstein Michael M. , Jung Dae Young , Jun John Y. , Kim Jason K. , Lusis Aldons J. , Péterfy Miklós
Published: April 2010

OBJECTIVE

To identify metabolic derangements contributing to diabetes susceptibility in the leptin receptor–deficient obese C57BLKS/J-db/db (BKS-db) mouse strain.

RESEARCH DESIGN AND METHODS

Young BKS-db mice were used to identify metabolic pathways contributing to the development of diabetes. Using the diabetes-resistant B6-db strain as a comparison, in vivo and in vitro approaches were applied to identify metabolic and molecular differences between the two strains.

RESULTS

Despite higher plasma insulin levels, BKS-db mice exhibit lower lipogenic gene expression, rate of lipogenesis, hepatic triglyceride and glycogen content, and impaired insulin suppression of gluconeogenic genes. Hepatic insulin receptor substrate (IRS)-1 and IRS-2 expression and insulin-stimulated Akt-phosphorylation are decreased in BKS-db primary hepatocytes. Hyperinsulinemic-euglycemic clamp studies indicate that in contrast to hepatic insulin resistance, skeletal muscle is more insulin sensitive in BKS-db than in B6-db mice. We also demonstrate that elevated plasma triglyceride levels in BKS-db mice are associated with reduced triglyceride clearance due to lower lipase activities.

CONCLUSIONS

Our study demonstrates the presence of metabolic derangements in BKS-db before the onset of β-cell failure and identifies early hepatic insulin resistance as a component of the BKS-db phenotype. We propose that defects in hepatic insulin signaling contribute to the development of diabetes in the BKS-db mouse strain.
Lipoprotein Subfraction Cholesterol Distribution Is Proatherogenic in Women With Type 1 Diabetes and Insulin Resistance
Authors: Maahs David M. , Hokanson John E. , Wang Hong , Kinney Gregory L. , Snell-Bergeon Janet K. , East Ashley , Bergman Bryan C. , Schauer Irene E. , Rewers Marian , Eckel Robert H.
Published: April 2010

OBJECTIVE

Individuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk.

RESEARCH DESIGN AND METHODS

Fast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp.

RESULTS

Among men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes.

CONCLUSIONS

The expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes.
Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin Action
Authors: Takashima Mototsugu , Ogawa Wataru , Hayashi Kumiko , Inoue Hiroshi , Kinoshita Shinichi , Okamoto Yasuo , Sakaue Hiroshi , Wataoka Yu , Emi Aki , Senga Yoko , Matsuki Yasushi , Watanabe Eijiro , Hiramatsu Ryuji , Kasuga Masato
Published: April 2010

OBJECTIVE

An increase in the rate of gluconeogenesis is largely responsible for the hyperglycemia in individuals with type 2 diabetes, with the antidiabetes action of metformin being thought to be achieved at least in part through suppression of gluconeogenesis.

RESEARCH DESIGN AND METHODS

We investigated whether the transcription factor KLF15 has a role in the regulation of gluconeogenesis and whether KLF15 participates in the antidiabetes effect of metformin.

RESULTS

Here we show that KLF15 regulates the expression of genes for gluconeogenic or amino acid–degrading enzymes in coordination with the transcriptional coactivator peroxisome proliferator–activated receptor γ coactivator 1α. Liver-specific ablation of KLF15 in diabetic mice resulted in downregulation of the expression of genes for gluconeogenic or amino acid catabolic enzymes and in amelioration of hyperglycemia. Exposure of cultured hepatocytes to metformin reduced the abundance of KLF15 through acceleration of its degradation and downregulation of its mRNA. Metformin suppressed the expression of genes for gluconeogenic or amino acid–degrading enzymes in cultured hepatocytes, and these effects of metformin were attenuated by restoration of KLF15 expression. Administration of metformin to mice inhibited both the expression of KLF15 and glucose production in the liver, the latter effect also being attenuated by restoration of hepatic KLF15 expression.

CONCLUSIONS

KLF15 plays an important role in regulation of the expression of genes for gluconeogenic and amino acid–degrading enzymes and that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part by downregulation of KLF15 and consequent attenuation of the expression of such genes.