Miracle-dz/UniFAR-FTUs huggingface dataset:
Disrupting insulin-like growth factor signaling as a potential cancer therapy

The type I insulin-like growth factor receptor (IGF-IR) plays multiple roles in several cancers and increased circulating levels of insulin-like growth factor-I (IGF-I) are associated with increased risk of breast, colon, and prostate cancers. Because IGF-II and insulin signal via the insulin receptor (IR) to stimulate the growth of cancer cells, inhibition of IR might be necessary to totally disrupt the action of IGFs and their receptors. This review describes the well-recognized roles of IGF-IR in driving the malignant phenotype, examines the evidence that perhaps IR should also be targeted to inhibit the effects of the IGF ligands and insulin in cancer, describes the strategies to disrupt IGF signaling in cancer, and highlights some key issues that need to be considered as clinical trials targeting IGF-IR proceed. [Mol Cancer Ther 2007;6(1):1–12]
B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations.

OBJECTIVE To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE). METHODS Sixty-eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression. Twenty normal control subjects underwent similar laboratory evaluations. RESULTS In contrast to the uniformly normal serum BLyS and blood BLyS mRNA phenotypes in control subjects, SLE patients displayed marked heterogeneity, with 50% and 61% of patients manifesting persistently or intermittently elevated serum BLyS and blood BLyS mRNA phenotypes, respectively. Surface BLyS expression by SLE peripheral blood mononuclear cells was also often increased. Treatment of patients who had elevated serum BLyS levels with intensive courses of high-dose corticosteroids resulted in marked reductions in serum BLyS levels, and tapering of the corticosteroid dosage often resulted in increases in serum BLyS levels. Serum BLyS levels generally correlated with anti-double-stranded DNA (anti-dsDNA) titers (in those with detectable anti-dsDNA titers), but changes in serum BLyS levels did not correlate with changes in disease activity in individual patients. Serum BLyS phenotype did not associate with specific organ system involvement. CONCLUSION Dysregulation of BLyS over extended periods of time is common in patients with SLE. Neutralization of BLyS activity with an appropriate BLyS antagonist may be therapeutically beneficial.
Correlation between multiple climbing fibre regression and parallel fibre response development in the postnatal mouse cerebellum

At the neuromuscular junction elimination of supernumerary synaptic connections during development is owing to a competitive process between single neuronal populations, whereas in the central nervous system the interaction of different types of input could affect the process. In the cerebellum, the regression from multiple‐ to mono‐innervation of the Purkinje cells by climbing fibres is virtually completed during the first two weeks of postnatal development. While it is clear that parallel fibres are important in the control of the regression, there are conflicting results in relation to whether an early phase of regression is independent of parallel fibre effects. We studied the precise timing of climbing fibre synapse development and decline and the relationship with the functional maturation of parallel fibres. Until postnatal day (P) 6 or 7, the synaptic currents generated by different climbing fibres become progressively more uniform in amplitude. However, between P7 and 14, the amplitudes of the currents increasingly diverge until only one fibre remains connected. These data are taken as evidence that, in multiply innervated Purkinje cells, competition between different climbing fibres appears at P7 and continues during the second postnatal week. Morphological and electrophysiological data demonstrate that parallel fibres synapses appear at P7 and their development is significantly correlated with the time course of the climbing fibre regression. These results provide no evidence for climbing fibre regression independent of parallel fibres before P7 and also suggest a dominant role of the parallel fibre input in the later phase.
Raising search costs to deter window shopping can increase profits and welfare

Consumers tend to browse products they are interested in and firms often invest resources in selling to them. A consequence, I show, is that it is optimal for a firm to increase the cost of browsing (even though this drives away potential customers) because doing so allows it to target sales efforts at those consumers most likely to buy. Despite representing pure waste, this can increase welfare by facilitating efficient allocation of sales or marketing resources. For a similar reason, consumers often benefit from search costs in aggregate, and prefer them to other means of screening, such as price increases.
Microgrids emergency management exploiting EV, demand response and energy storage units

Within the Smart Grid paradigm, the MicroGrid concept (MG) presents an adequate framework to monitor and manage the low voltage network and coordinate the resources connected to it, including the smart grid new players, namely the consumers, prosumers and the Electric Vehicles (EV). The coordinated management and control of the MG resources, enables the operation both connected to the main power network or autonomously, due to planned or unplanned outages. In order to operate autonomously, the MG relies in its storage capacity to provide some form of energy buffering capabilities to balance load and generation. This paper presents innovative methodology to coordinate the microgrid storage capacity with EV smart charging strategies and demand response schemes, in order to improve microgrid resilience in the moments subsequent to islanding and reduce the non-served load. The effectiveness of the proposed algorithms are validated though extensive numerical simulations.
Early High Pulse Pressure is Associated With Graft Dysfunction and Predicts Poor Kidney Allograft Survival

Background. Pulse pressure (PP), which reflects the pulsatile component of the blood pressure (BP), is known as a major predictor of cardiovascular events and death. In the elderly and type 2 diabetic patients, PP is associated with low glomerular filtration rate and albuminuria. Because kidney allograft survival is closely related to BP levels, we investigated the impact of early high PP, systolic, diastolic, and mean arterial BP on kidney allograft survival. Methods. Renal hemodynamic and function studies using isotopic methods were prospectively performed in 493 renal transplant patients at 3 months posttransplantation to determine the impact of the different BP components on allograft survival using a proportional hazard model. Results. After a median follow-up of 6.3 years, 91 allografts were lost. High PP was associated with high systolic, diastolic, and mean arterial pressure, heart rate, recipient age, glycemia, and low glomerular filtration rate. Moreover, PP emerged as the strongest BP component influencing overall and death-censored kidney allograft survival. Conclusion. High PP is an early marker of poor allograft outcome that could be corrected by therapeutic intervention.
Understanding public performance measurement through theoretical pluralism

Purpose The purpose of this paper is to investigate, through different interpretative theories, the implementation and operation of performance measurement systems (PMS) considering the factors crucial in influencing the development and the operational difficulties of the PMS in a context such as Italy, which is typically unresponsive to new public management-inspired ideas. Design/methodology/approach A theoretical framework is developed through the use of new institutional sociology and management control theory. The empirical study involves the whole ministerial sector, and explores some strategic documents belonging to the new PMS introduced in Italy in 2009. Findings The research illustrates a widespread dissemination of the reform in ministries. However, it has also shown the ceremonial and superficial implementation of the PMS. In addition, the findings confirm that the operation and the actual development of a PMS is strongly affected by the characteristics of the activity under examination. Research limitations/implications The peculiarity of the Italian context limits the generalizability of the findings to countries with similar public sector management and culture. Further studies may investigate the system through an individual perspective, i.e. exploring the role of individual managers in slowing down the operations of the evaluation systems. Originality/value This paper contributes to the debate on the implementation and operation of administrative reforms in legalistic countries also known as Rechtsstaat countries. The use of multiple theories allows investigating the subject matter by considering its complexity in a holistic way.
Mesendodermal signals required for otic induction: Bmp‐antagonists cooperate with Fgf and can facilitate formation of ectopic otic tissue

Induction of otic placodes requires Fgf from surrounding tissues. We tested the hypothesis that mesendodermally derived Bmp‐antagonists Chordin, Follistatin‐a, and Crossveinless‐2 cooperate in this process. Injecting morpholinos for all three genes, or treatment with the Nodal inhibitor SB431542 to block mesoderm‐formation, reduces otic induction and strongly enhances the effects of disrupting fgf3 or fgf8. In contrast, using a lower dose of SB431542, combined with partial loss of Fgf, causes a dramatic medial expansion of otic tissue and formation of a single, large otic vesicle spanning the width of the hindbrain. Under these conditions, paraxial cephalic mesoderm forms ectopically at the midline, migrates into the head, and later transfates to form otic tissue beneath the hindbrain. Blocking expression of Bmp‐antagonists blocks formation of medial otic tissue. These data show the importance of mesendodermal Bmp‐antagonists for otic induction and that paraxial cephalic mesendoderm can facilitate its own otic differentiation under certain circumstances. Developmental Dynamics 238:1582–1594, 2009. © 2009 Wiley‐Liss, Inc.
[Antiestrogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the gene expression of insulin-like growth factors family in osteoblast cells].

OBJECTIVE To investigate the antiestrogenic effect of environment teratogen on the gene expression of insulin-like growth factors (IGFs) family in osteoblast cells during rat skeleton development. METHODS The fetal rat models with congenital skeleton malformation were constructed by treating 20 female Wistar rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on pregnant day 10. The MC-3T3-E1 cells were cultured with estrogen, TCDD, or a combination of the two chemicals for 24 hours. The IGF-II and IGFBP-6 mRNA levels in rat calvaria bone tissue and MC-3T3-E1 cells were detected by reverse transcription-polymerase chain reaction. Flow cytometer was used to determine the cell proliferation. RESULTS TCDD at the concentration of 5-15 microg/kg induced developmental skeleton defect of fetal rat, and the effect was dose-dependent. The expression of IGF-II mRNA gene was enhanced by estrogen in rat calvaria bone tissue and MC-3T3-E1 cells, whereas IGFBP-6 mRNA was decreased. Estrogen increased the cell proliferation in MC-3T3-E1 cells. TCDD, however, inhibited the effect of estrogen on regulation of IGF-II gene and IGFBP-6 gene as well as MC-3T3-E1 cell proliferation. CONCLUSION These findings provide the evidence that TCDD can induce congenital fetal skeleton malformation under the condition of high estrogen level in pregnant Wistar rats. TCDD has antiestrogenic effect and hence exerts negative influence on the osteoblast cells through target IGF-II and IGFBP-6 of IGFs family.
Superinduction of the human gene encoding immune interferon.

Mitogen‐induced interferon‐gamma (IFN‐gamma) gene expression was analyzed in human tonsil cells by titration of IFN‐gamma activity and by quantitation of IFN‐gamma mRNA. Expression of the IFN‐gamma gene can be superinduced extensively by two distinct methods: exposure to various inhibitors of translation, or to low doses of gamma‐irradiation. gamma‐Irradiated cells produce, after exposure to cycloheximide, up to 12‐fold greater amounts of IFN‐gamma activity. Within as little as 4 h after the addition of translation inhibitors, IFN‐gamma mRNA levels rise 3‐ to 5‐fold. Superinduction acts to increase the size of the wave of IFN‐gamma mRNA. Primary transcription of the IFN‐gamma gene does not increase in cells superinduced by cycloheximide, nor can superinduction be explained by stabilization of IFN‐gamma mRNA sequences. These findings show that, during normal induction, a labile protein acts post‐transcriptionally to repress the accumulation of mature IFN‐gamma mRNA sequences. The superinductive effects of cycloheximide and gamma‐irradiation on levels of IFN‐gamma are additive, suggesting that they affect different aspects of IFN‐gamma gene expression. Superinduction by gamma‐irradiation also has a post‐transcriptional basis and is consistent with the possibility that expression of the IFN‐gamma gene is normally controlled by the action of suppressor T cells. Even though the genes for human IFN‐gamma and for interleukin‐2 are both superinducible, a striking difference in the regulation of expression of these lymphokine genes is observed. Superinduction of IFN‐gamma mRNA is not due to superinduction of interleukin‐2.
Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept

Purpose of reviewDrug allergies are examples of immune reactions to small molecular compounds. In many drug allergies drug specific CD4+ and CD8+ T-cells can be detected, which recognize small chemicals via their αβ-T-cell receptor in a major histocompatibility complex dependent way. In this review a new concept of drug presentation to T-cells is presented. Recent findingsDrugs were stimulatory for T-cells if they bound covalently to peptides or proteins, but also if the drug had structural features allowing it to bind in a labile way (noncovalently) to the major histocompatibility peptide complex. This latter binding method has some similarities to superantigen stimulations and can explain allergies to drugs that are not metabolized. It has been described in patients with maculopapular, bullous and neutrophilic drug eruption, as well as in contact dermatitis. SummaryNoncovalent drug presentation leads to the stimulation of immune cells, namely T-cells. The drug needs two surface molecules (one inert serving as a scaffold, major histocompatibility complex, and one reactive, T-cell receptor) to exert its function. Although two receptor structures are involved, the process is reminiscent of a pharmacological interaction between a drug and its receptors and, from the phrase pharmacological interaction with immune receptors, was thus termed the p-i concept.
Expression of Steroidogenic Factor 1 in the Testis Requires an E Box and CCAAT Box in its Promoter Proximal Region1

Abstract Steroidogenic factor 1 (SF-1), also known as adrenal 4-binding protein, is a member of the nuclear hormone receptor family that regulates transcription of genes encoding hormones and steroidogenic enzymes important to the function of the hypothalamic-pituitary-gonadal axis. The mammalian Ftz-F1 gene encodes SF-1 and is required for development of adrenal glands and gonads. To better understand the mechanisms regulating this gene in the gonads, we have examined its expression in the testis and characterized the promoter region for SF-1 in two testicular cell types. SF-1 promoter activity was examined in primary cultures of Sertoli cells and cell lines representative of Sertoli and Leydig cells. Deletion mutagenesis of the promoter identified several regions: both 5′ and 3′ to the transcriptional start sites that are important for transcriptional activity. Two elements, an E box and a CCAAT box, were found to be important for SF-1 transcription in the testis. An oligodeoxynucleotide containing both of these elements bound three specific protein complexes. The binding of one complex required only sequences within the E box and cross-reacted with antibodies against the basic helix-loop-helix ZIP proteins USF1 and USF2. A second specific complex required sequences within both the E box and CCAAT box for efficient binding, while a third complex predominantly interacted with sequences within the CCAAT motif. The presence of multiple protein complexes binding these sites suggests that regulation through these elements may involve interactions with different factors that depend on the state of the cell and its environment.
Modeling Kick-Kill Strategies toward HIV Cure

Although combinatorial antiretroviral therapy (cART) potently suppresses the virus, a sterile or functional cure still remains one of the greatest therapeutic challenges worldwide. Reservoirs are infected cells that can maintain HIV persistence for several years in patients with optimal cART, which is a leading obstacle to eradicate the virus. Despite the significant progress that has been made in our understanding of the diversity of cells that promote HIV persistence, many aspects that are critical to the development of effective therapeutic approaches able to purge the latent CD4+ T cell reservoir are poorly understood. Simultaneous purging strategies known as “kick-kill” have been pointed out as promising therapeutic approaches to eliminate the viral reservoir. However, long-term outcomes of purging strategies as well as the effect on the HIV reservoir are still largely fragmented. In this context, mathematical modeling can provide a rationale not only to evaluate the impact on the HIV reservoir but also to facilitate the formulation of hypotheses about potential therapeutic strategies. This review aims to discuss briefly the most recent mathematical modeling contributions, harnessing our knowledge toward the uncharted territory of HIV eradication. In addition, problems associated with current models are discussed, in particular, mathematical models consider only T cell responses but HIV control may also depend on other cell responses as well as chemokines and cytokines dynamics.
The evolution of the Polish central bank’s views on Eurozone membership

Abstract This article analyses the reports published by the National Bank of Poland (NBP – Narodowy Bank Polski) between 2004 and 2014. These reports shed light on the evolution of official thinking on the possibility of Polish participation in the Eurozone, revealing a decline in enthusiasm over time. This change has taken place against a backdrop of a shift in general public attitudes (in Poland) towards the European Union, and a more specific shift in public opinion on the desirability of monetary integration on the supranational level caused by the economic crisis. These two factors explain the shift in conclusions and arguments contained in the official reports of the National Bank of Poland.
Continuity of care: when do patients visit community healthcare providers after leaving hospital?

Background/Aims: Enhanced communication and transfer of information between healthcare providers and healthcare settings can reduce medication and healthcare errors post‐hospital discharge. The timeframes within which patients access community healthcare providers post‐hospital discharge are not well studied. This study aimed to determine length of time from hospital discharge until a general practice, pharmacy or specialist visit, or care planning service.
Ionic conductances underlying the activity of interneurons that control heartbeat in the medicinal leech

Electrical properties of interneurons that control heartbeat in the leech (HN cells) were studied using intracellular recording and stimulation in isolated ganglia bathed by salines of various ionic compositions. Substitution of Na+ ions in the bath by Tris stopped the spontaneous firing of HN cells and led to their gradual hyperpolarization by 15–20 mV. In the absence of Na+, HN neurons produced long-lasting regenerative plateau potentials with thresholds near -55 mV and peaks near -30 mV that were accompanied by an increase in membrane conductance. Elevation of Ca2+ concentration enhanced plateaus, as did replacement of Ca2+ by Ba2+. Plateaus were formed when Sr2+ replaced Ca2+, but were blocked by addition of Mg2+ or Co2+ to the bath, Co2+ being effective at lower concentrations than Mg2+. Hyperpolarization of HN neurons with injected currents revealed a time- dependent change in membrane potential, whereby initial maximum hyperpolarization was followed by a “sag” in potential towards more depolarized values. The sag showed dual voltage dependence, being diminished when HN neurons were hyperpolarized or depolarized outside the normal range of oscillation. The sag was found to depend on the presence of Na+ ions and to be blocked by Cs+ but not by Ba2+. This time-dependent change in membrane potential counters hyperpolarizations of HN neuron membrane potential and may contribute to the escape of these neurons from synaptic inhibition.
Entrepreneurship Education: Can Business Schools Meet the Challenge?

Examines the characteristics and role of the entrepreneur and the challenges for business schools posed by the need to develop more enterprising individuals. Argues that the traditional education system stultifies rather than develops the requisite attributes and skills to produce entrepreneurs, and proposes that if entrepreneurs are to be developed, considerable changes are required in both the content and process of learning. In particular it suggests that there needs to be a shift in the emphasis from educating "about" entrepreneurship to educating "for" it. Stresses equally that entrepreneurship should not be equated with new venture creation or small business management, but with creativity and change. In this context proposes that educational institutions need to change the process of learning to enable their students to develop their right brain entrepreneurial capabilities as well as their left-brain analytical skills. As Chia argues, business schools need to weaken the thought processes so as to encourage and stimulate the entrepreneurial imagination. (Publication abstract)
Soft‐Tissue Sarcomas of the Head and Neck: A Retrospective Analysis of the Alberta Experience 1974 to 1999

Background: Soft‐tissue sarcomas (STS) of the head and neck constitute a heterogeneous group of rare malignant tumors occurring in an uncommon site. The most common subtypes of STS in the head and neck are malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, and fibrosarcoma. Evidence based subtype‐specific treatment decisions are often not possible.