Miracle-dz/UniFAR-FTUs huggingface dataset:
Regulation of the ankyrin-B-based targeting pathway following myocardial infarction.

AIMS Ion channel reorganization is a critical step in the pro-arrhythmogenic remodelling process that occurs in heart disease. Ankyrin-B (AnkB) is required for targeting and stabilizing ion channels, exchangers, and pumps. Despite a wealth of knowledge implicating the importance of AnkB in human cardiovascular physiology, nothing is known regarding the role of AnkB in common forms of acquired human disease. METHODS AND RESULTS We present the first report of AnkB regulation following myocardial infarction (MI). AnkB protein levels were reduced in the infarct border zone 5 days following coronary artery occlusion in the canine. We also observed a dramatic increase in AnkB mRNA levels 5 days post-occlusion. Surprisingly, the expression of the upstream AnkB cytoskeletal component beta2-spectrin was unchanged in post-infarct tissues. However, protein levels and/or membrane expression of downstream AnkB-associated ion channels and transporters Na+/K+ ATPase, Na+/Ca2+ exchanger, and IP3 receptor were altered 5 days post-occlusion. Interestingly, protein levels of the protein phosphatase 2A, an AnkB-associated signalling protein, were significantly affected 5 days post-occlusion. AnkB and PP2A protein levels recovered by 14 days post-occlusion, whereas Na+/K+ ATPase levels recovered by 2 months post-occlusion. CONCLUSION These findings reveal the first evidence of ankyrin remodelling following MI and suggest an unexpected divergence point for regulation between ankyrin and the underlying cytoskeletal network. These findings suggest a logical, but unexpected, molecular mechanism underlying ion channel and transporter remodelling following MI.
Lack of Association between the MiR 146 a Polymorphism and Susceptibility to Thai Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. The peak incidence of ALL occurs between age 2 and 5 years (Inaba, 2013). The improvement of ALL therapy is one of the great successes with long-term survival achieved in over 80% of patients (Pui et al., 2006, Vrooman and Silverman, 2009). However, the remaining cases cannot be cured and has poor prognosis. ALL is a heterogenous leukemia based on the type and stage of lymphoblast. The molecular biology of ALL is not completely understood. Genomewide association studies show that genetic polymorphisms of some susceptibility genes are associated with the development of childhood ALL (Treviño LR et al., 2009). Recently, it is discovered that microRNAs (MiRNAs) play a role in the regulation of hematopoiesis (Caterine Labbaye and Ugo, 2012). MiRNAs, small non coding RNAs about 17-22 nucleotide in length, regulate gene expression by translational repression or mRNA degradation (Bartel, 2004). MiR 146a has an important
Estrogens Maintain Bone Mass by Regulating Expression of Genes Controlling Function and Life Span in Mature Osteoclasts

Estrogens play a key role in regulation of bone mass and strength by controlling activity of bone‐forming osteoblasts and bone‐resorbing osteoclasts. Cellular effects of estrogens are mediated predominantly by the action of estrogen receptor alpha (ERα). In earlier studies, ablation of the ERα gene in mice did not result in osteoporotic phenotypes due to systemic endocrine disturbance and compensatory effects of elevated levels of testosterone. Despite the relatively well‐established effects in osteoblasts, little is known about the direct action of estrogen in osteoclasts. Development in the last decade of more sophisticated genetic manipulation approaches opened new possibilities to explore cell‐specific roles of nuclear receptors in bone tissue. Recently, we have generated osteoclast‐specific ERα gene knockout mice and shown that in vivo estrogens directly regulate the life span of mature osteoclasts by inducing the expression of pro‐apoptotic Fas ligand (FasL). Inhibitory effects of estrogens on osteoclast function were further studied in vitro. We observed sufficiently detectable ERα expression in osteoclasts differentiating from primary bone marrow cells or RAW264 cells, although levels of ERα were decreasing during progression of the differentiation into mature osteoclasts. Treatment with estrogens led to reduction in expression of osteoclast‐specific genes controlling bone resorption activity. However, estrogens did not affect the size of multinucleated osteoclasts or number of nuclei in a mature osteoclast. In conclusion, in osteoclasts, estrogens function to inhibit bone resorption activity and vitality rather than differentiation.
Optimal Entry Timing in Markets with Social Influence

Firms routinely face the challenging decision of whether to enter a new market where a firm's strong presence in an existing market has a positive influence (the leverage effect) on product adoption in the new market, but the reciprocal social influence on the existing market is negative (the backlash effect). In this paper, we show that a firm's optimal entry strategy in this situation cannot be characterized by the familiar “now or never” or “now or at maturity” strategies proposed in the literature. We show that a strong leverage effect does not necessarily provide the justification for a firm to enter a new market, and neither should a strong backlash effect necessarily deter a firm from embracing a new market. The optimal strategy is predicated on a judicious trade-off between the three factors of leverage, backlash, and patience. Thus, an astute manager can always find the opportune time to enter the new market if she takes into account the dynamic and recursive nature of cross-market interaction effects, where leverage enhances the backlash but backlash weakens the leverage in a nonlinear, dynamic fashion. We illustrate that firms stand to benefit from explicit considerations of these effects in deciding whether and when to enter a new market. Furthermore, we explore how the optimal time of entry into the new market relates to the time of peak sales for the existing market, demonstrating that depending on the interactive effects of leverage and backlash, entry could be optimal either before or after peak sales in the existing market.
Probing the Architecture of an L-type Calcium Channel with a Charged Phenylalkylamine

Voltage-gated calcium channels are in a closed conformation at rest and open temporarily when the membrane is depolarized. To gain insight into the molecular architecture of Cav1.2, we probed the closed and open conformations with the charged phenylalkylamine (-)devapamil ((-)qD888). To elucidate the access pathway of (-)D888 to its binding pocket from the intracellular side, we used mutations replacing a highly conserved Ile-781 by threonine/proline in the pore-lining segment IIS6 of Cav1.2 (1). The shifted channel gating of these mutants (by 30–40 mV in the hyperpolarizing direction) enabled us to evoke currents with identical kinetics at different potentials and thus investigate the effect of the membrane potentials on the drug access per se. We show here that under these conditions the development of channel block by (-)qD888 is not affected by the transmembrane voltage. Recovery from block at rest was, however, accelerated at more hyperpolarized voltages. These findings support the conclusion that Cav1.2 must be opening widely to enable free access of the charged (-)D888 molecule to its binding site, whereas drug dissociation from the closed channel conformation is restricted by bulky channel gates. The functional data indicating a location of a trapped (-)D888 molecule close to the central pore region are supported by a homology model illustrating that the closed Cav1.2 is able to accommodate a large cation such as (-)D888.
Effect of osmotic stress on the developmental competence of germinal vesicle and metaphase II stage bovine cumulus oocyte complexes and its relevance to cryopreservation

The effects of osmotic stress on germinal vesicle (GV) and metaphase II (MII) stage bovine cumulus oocyte complexes (COCs) were evaluated by first exposing them to various anisotonic NaCl solutions (75, 150, 600, 1200, 2400, and 4800 ± 5 mOsm/kg) for 10 min and then returning them to isotonic TL‐Hepes solution (270 ± 5 mOsm/kg) at 20 ± 2°C. Percentages of oocyte maturation, fertilization, polyspermy, cleavage, and blastocyst formation were measured as endpoints. Exposure to anisotonic conditions had a significant (P < 0.05) effect on the developmental competence of both GV and bovine MII COCs. Oocytes at the GV stage were more sensitive to anisotonic stress than MII oocytes (P < 0.05). None of the GV oocytes developed to the blastocyst stage after exposure to hypertonic conditions (2400 or 4800 mOsm solutions), while exposure to hypotonic conditions (75 or 150 mOsm solutions) resulted in significantly lower (P < 0.05) blastocyst formation (9% and 13%, respectively) compared to the isotonic control (25%). A dramatic decrease to 4% development to blastocyst was observed for MII oocytes following exposure to a 4800 mOsm solution. Blastocyst formation of MII oocytes which were exposed to 75, 150, 600, 1200, or 2400 mOsm solutions were similar (15%, 20%, 18%, 14%, and 13%, respectively; P > 0.05), but lower (P < 0.05) than those in the control group (29%). Exposing GV oocytes to anisotonic conditions increased polyspermic fertilization (P < 0.05), although MII oocytes were not similarly affected (P > 0.05). These data support the hypothesis that osmotic stress is detrimental to bovine oocytes and must be considered when developing optimized cryopreservation procedures for these cells. Mol. Reprod. Dev. 55:212–219, 2000. © 2000 Wiley‐Liss, Inc.
Gay Men’s Explanations of Health and How to Improve It

Little is known about the health views of gay men. In this article we report on how gay men explained health and the ways they discussed how health for gay men can be improved. We conducted a thematic analysis of data collected from 45 gay men in 11 focus groups and identified that health was mainly explained in individual terms, as were the ways to improve health (personal health care services and health promotion). The second way health was explained drew on social and community factors, with the societal acceptance of gay men being reported as essential for health improvements. These individual and social/community approaches were in tension; overall, the individualized approaches dominated. In line with other theorizing in health, we argue that appropriate policy and service provision to meet the health needs of gay men require greater acknowledgment of the social and community explanations of health and ways of improving health.
Can the carbon dioxide laser completely ablate basal cell carcinomas? A histological study.

Carbon dioxide laser ablation has been advocated as an alternative therapeutic modality for basal cell carcinoma. This study examined the limitations of carbon dioxide laser ablation for BCCs by the formal excision and histological examination of the tumour bed, following laser therapy. We evaluated the tumour type and ablation depth required to ablate the tumours completely. Fifty-one selected BCCs, ranging from 4 to 35 mm, were ablated with a carbon dioxide laser combined with a microprocessor controlled optomechanical flash scanner. Clinically there were 21 superficial, 28 nodular and 2 infiltrative types. Complete ablation at the deep margin was associated with ablation depth (P = 0.006) and with tumour type (P = 0.01). Overall, all tumours of superficial subtype (found most commonly on the trunk) could be completely ablated reliably, provided they were lasered to a depth of the middle dermis or deeper. In contrast, nodular tumours could not reliably be ablated by this method. A small subset of nodular tumours less than 10 mm diameter, however, were all completely ablated provided they were lasered to a depth of the lower dermis or deeper, however this may result in delayed healing and scarring. We conclude that this fast modality is useful for the treatment of some BCCs provided strict selection criteria are met. Laser ablation would be most beneficial for patients with multiple superficial BCCs.
A Monte Carlo Evaluation of Tests for Comparing Dependent Correlations

Abstract The authors conducted a Monte Carlo simulation of 8 statistical tests for comparing dependent zero-order correlations. In particular, they evaluated the Type I error rates and power of a number of test statistics for sample sizes (Ns) of 20, 50, 100, and 300 under 3 different population distributions (normal, uniform, and exponential). For the Type I error rate analyses, the authors evaluated 3 different magnitudes of the predictor-criterion correlations (py,x1 = py,x2=.1, .4, and .7). For the power analyses, they examined 3 different effect sizes or magnitudes of discrepancy between py,x2 and py,x2 (values of .1, .3, and .6). They conducted all of the simulations at 3 different levels of predictor intercorrelation (px1,x2 = .1, .3, and .6). The results indicated that both Type I error rate and power depend not only on sample size and population distribution, but also on (a) the predictor intercorrelation and (b) the effect size (for power) or the magnitude of the predictor-criterion correlations (for Type I error rate). When the authors considered Type I error rate and power simultaneously, the findings suggested that O. J. Dunn and V. A. Clark's (1969) z and E. J. Williams's (1959) t have the best overall statistical properties. The findings extend and refine previous simulation research and as such, should have greater utility for applied researchers.
Straw Man Walking: Reply to Varney (2002)

In a recent article, Varney (2002) disagrees with the findings and conclusions of Greiffenstein, Baker and Gola (2002). Varney’s (2002) reply is unusual, in that it offers a blanket dismissal while violating the common conventions of published critiques. First, he does not provide a citation for the Greiffenstein et al. article, a crucial step for orienting the reader. Second and more importantly, he does not even provide a synopsis of our methods or conclusions. Third, the use of all uppercase letters in the title leaves the impression he is shouting rather than speaking. The reader is thus left with a series of seemingly tangential, emotionalized comments in the absence of any context. Varney gets a citation to add to his resume, but the reader only gets an enumerated rant. A brief review is necessary to provide the reader with such context. Greiffenstein et al. (2002) reported that objective posttraumatic anosmic status lacked any unique association with remote psychosocial or executive-cognitive outcome. A major impetus for our study was the methodological problems raised by Varney’s methodology of classifying smell status on the basis of delayed (by years), subjective self-report in persons with minor injuries. We found no differences between objectively diagnosed anosmic and smell-intact groups in employment rates, living status, or executive-cognitive function. There were consistent (but nonsignificant) trends of worse performance on frontal-lobe tasks in the anosmic group, but their initial head injuries were more severe than the nonanosmic group’s, a confounding influence. Our findings were consistent with the mainstream research on anosmia and head trauma. In his reply, Dr. Varney offered a list of reasons to dislike our study. We summarize each of Varney’s points and respond.
Factor IX replacement in surgery and prophylaxis

Considerations for treatment of hemophilia B patients in high-risk settings are the focus of this paper, including differences in recoveries of factor IX products and variable patient responses to replacement therapy. Data support the importance of performing individual pharmacokinetic studies in determining treatment programs for hemophilia patients—for both high-risk periods such as surgery and for prophylaxis. Other considerations in choice of plasma-derived or recombinant factor IX concentrate in high-risk and other situations include product safety, cost, and availability.
CORTISOL PRODUCTION BY ALDOSTERONE‐PRODUCING ADENOMAS IN VITRO

1. In vitro short‐term production of cortisol by dispersed tumour and non‐tumorous adrenal cortical cells was measured with and without added angiotensin II (AII) or adrenocorticotrophin (ACTH) in adrenals removed from five patients with primary aldosteronism.
Glutathione and adenosine triphosphate content of in vivo and in vitro matured porcine oocytes

Glutathione (GSH) content in mature porcine oocytes is correlated with subsequent fertilization and developmental success. Adenosine triphosphate (ATP) is an important energy source for maintaining cellular activities and protein synthesis. The objective of this study was to compare GSH and ATP concentrations of in vivo and in vitro matured porcine oocytes. Ovulated, in vivo matured oocytes were frozen at −80°C in groups of 10–20 (GSH) or 5–10 (ATP). In vitro oocytes were matured in either tissue culture medium‐199 (TCM199) supplemented with polyvinyl alcohol (PVA) or hyaluronic acid (MAP5), or North Carolina State University‐23 (NCSU23) supplemented with porcine follicular fluid (pFF) and frozen as described, or fertilized and cultured. GSH content was determined by the dithionitrobenzoic acid–glutathione disulfide (DTNB–GSSG) reductase recycling assay. ATP content was determined by using the Bioluminescent Somatic Cell Assay Kit. Oocytes matured in vitro in defined TCM199 with PVA or hyaluronic acid, or NCSU23 with pFF had significantly lower concentrations (P < 0.05) of GSH (n = 207, 9.82 ± 0.71 pmol/oocyte; n = 104, 9.73 ± 0.81 pmol/oocyte; n = 108, 7.89 ± 0.66 pmol/oocyte, respectively) compared to in vivo matured oocytes (n = 217, 36.26 ± 11.00 pmol/oocyte). Concentrations of ATP were not different between treatments (in vivo, n = 70, 0.97 ± 0.07 pmol/oocyte; TCM–PVA, n = 117, 0.81 ± 0.13 pmol/oocyte; TCM–MAP, n = 107, 1.02 ± 0.18 pmol/oocyte; NCSU–pFF, n = 134, 0.71 ± 0.08 pmol/oocyte). Intracellular ATP content does not appear to be related to developmental potential in porcine oocytes. Low intracellular GSH may be responsible, in part, for lower developmental competence observed in in vitro matured porcine oocytes. Mol. Reprod. Dev. 64: 492–498, 2003. © 2003 Wiley‐Liss, Inc.
Sex differences in response to steroids in preterm sheep lungs are not explained by glucocorticoid receptor number or binding affinity *

We recently reported that prenatal glucocorticoid therapy is less effective at promoting an improvement in lung function in male than in female sheep. This observation, and the higher incidence of respiratory distress syndrome in human males, suggests that the male fetal lung may be less responsive to glucocorticoids than is the female fetal lung. Since glucocorticoids are known to exert their effects via specific cytoplasmic glucocorticoid receptors (GR), we hypothesized that there may be sexual dimorphism in either the number or binding affinity of lung GR. To test the hypothesis, binding of dexamethasone (a synthetic glucocorticoid, 0.5–40 nM) by cytosolic fractions of male (n = 16) and female (n = 16) fetal sheep lung was measured at 125 days gestation (term = 148 days).
The organization enacts the environment and the environment feeds back: mortality rates in the UK motorcycle industry, 1895-1993

This paper uses the information on 648 manufacturers during the period included between 1895 and 1993 to explore the interaction of different levels of analysis in developing of the United Kingdom motorcycle industry. It provides three general results. First, it demonstrates how long term changes of the organizational environment can be related to the microevolution of firms’ strategies. Second, it sheds light on the fact that organizations and population act in the opposite way in determining the survival of firms. On the one hand, organizations diversify their production in order to obtain economic advantages of scale and superior profits. On the other, the evolution of the population constrains organizational expansion by increasing the level of competition. These two contrasting forces drive the coevolution of niches of generalist and specialist producers within the population. Third, while the increasing age of a population’s members tend to reduce the level of competition, ages’ heterogeneity represents a powerful selective force acting within an organizational population. The implications stemming from this work are related to both the literatures of business strategy and of population ecology.
Radiofrequency thermal ablation: computer analysis of the size of the thermal injury created by overlapping ablations.

OBJECTIVE The purpose of this study was to perform a computer analysis of the size of the thermal injury created by overlapping multiple thermal ablation spheres. MATERIALS AND METHODS A computer-assisted design system was used to create three-dimensional models of a spherical tumor, a spherical tissue volume consisting of the tumor plus a 1-cm tumor-free margin, and individual spherical ablations. These volumes were superimposed in real-time three-dimensional space in different geometric relationships. The effect of the size and geometric configuration of the ablation spheres was analyzed with regard to the ability to ablate the required volume of tissue (tumor plus margin) without leaving untreated areas or interstices. RESULTS The single-ablation model showed that if a 360-degree 1-cm tumor-free margin is included around the tumor targeted for ablation, radiofrequency ablation devices producing 3-, 4-, and 5-cm ablation spheres can be used to treat 1-, 2-, and 3-cm tumors, respectively. The six-sphere model, in which six ablation spheres are placed in orthogonal planes around the tumor, showed that the largest tumor that may be treated with a 3-cm ablation device is 1.75 cm, whereas 4- and 5-cm ablation spheres can be used to treat tumors measuring 3 and 4.25 cm, respectively. The 14- sphere model showed that addition of eight more spheres to the six-sphere model increased the treatable tumor size to 3, 4.6, or 6.3 cm, depending on the diameter of the ablation sphere used. For treating larger tumors, we found a cylindrical model to be less efficient but easier to control. CONCLUSION Our computer analysis showed that the size of the composite thermal injury created by overlapping multiple thermal ablation spheres is surprisingly small relative to the number of ablations performed. These results emphasize the need for a methodic tumor ablation strategy.
Methionine sulphoxide reductases revisited: free methionine as a primary target of H2O2 stress in auxotrophic fission yeast

Amino acid methionine can suffer reversible oxidation to sulphoxide and further irreversible over‐oxidation to methionine sulphone. As part of the cellular antioxidant scavenging activities are the methionine sulphoxide reductases (Msrs), with a reported role in methionine sulphoxide reduction, both free and in proteins. Three families of Msrs have been described, but the fission yeast genome only includes one representative for two of these families: MsrA/Mxr1 and MsrB/Mxr2. We have investigated their role in methionine reduction and H2O2 sensitivity. We show here that MsrA/Mxr1 is able to reduce free oxidized methionine. Cells lacking each one of the genes are not significantly sensitive to different types of oxidative stresses, neither display altered life span. However, only when deletion of msrA/mxr1 is combined with deletion of met6, which confers methionine auxotrophy, the survival upon H2O2 stress decreases by 100‐fold. In fact, cells lacking only Met6, and which therefore require addition of methionine to the growth media, are extremely sensitive to H2O2 stress. These and other evidences suggest that oxidation of free methionine is a primary target of peroxide toxicity in cells devoid of methionine biosynthetic capacity, and that an important role of Msrs is to recycle this oxidized free amino acid.