Miracle-dz/UniFAR-FTUs huggingface dataset:
Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia

Activation of the Hedgehog pathway has been implicated in the pathogenesis of several tumor types including myeloid leukemia. Previously we demonstrated that overexpression of Hedgehog downstream mediators GLI1/2 confers an adverse prognosis to patients with acute myeloid leukemia (AML) and is correlated with a FLT3 mutated status. To analyze a possible non-canonical activation of the Hedgehog pathway via FLT3 and PI3K, we performed blocking experiments utilizing inhibitors for FLT3 (sunitinib), PI3K (PF-04691502) and GLI1/2 (GANT61) in FLT3-mutated and FLT3 wildtype AML cell lines and primary blasts. Combination of all three compounds had stronger anti-leukemic effects in FLT3-mutated compared to FLT3 wildtype AML cells in vitro. Interestingly, the colony growth of normal CD34+ cells from healthy donors was not impeded by the triple inhibitor combination possibly opening a therapeutic window for the clinical use of inhibitor combinations. Besides, combined treatment with sunitinib, PF-04691502 and GANT61 significantly prolonged the survival of mice transplanted with FLT3-mutated MV4-11 cells compared to the single agent treatments. Furthermore, the inhibition of FLT3 and PI3K resulted in reduced GLI protein expression and promotor activity in FLT3-mutated but not in FLT3 wildtype AML cell lines in western blotting and GLI1/2 promoter assays supporting our hypothesis of non-canonical GLI activation via FLT3. In summary, FLT3-mutated in contrast to FLT3 wildtype cells or normal human hematopoietic progenitor cells are exquisitely sensitive to combined inhibition by FLT3, PI3K and GLI1/2 overcoming some of the limitations of current FLT3 directed therapy in AML. The development of GLI1/2 inhibitors is highly desirable.
Probing the Flavivirus Membrane Fusion Mechanism by Using Monoclonal Antibodies

ABSTRACT In this study, we investigated in a flavivirus model (tick-borne encephalitis virus) the mechanisms of fusion inhibition by monoclonal antibodies directed to the different domains of the fusion protein (E) and to different sites within each of the domains by using in vitro fusion assays. Our data indicate that, depending on the location of their binding sites, the monoclonal antibodies impaired early or late stages of the fusion process, by blocking the initial interaction with the target membrane or by interfering with the proper formation of the postfusion structure of E, respectively. These data provide new insights into the mechanisms of flavivirus fusion inhibition by antibodies and their possible contribution to virus neutralization.
Tuberculosis associated with household crowding in a developed country

Background: Tuberculosis (TB) remains an important infectious disease in New Zealand (NZ) and globally, but risk factors for transmission are still poorly understood. This research aimed to identify whether household crowding contributes to TB transmission in NZ. Methods: This ecological study used TB surveillance and census data to calculate TB incidence rates by census area unit (CAU). Census data were used to determine CAU characteristics including proportion of household crowding (a bedroom deficit of one or more), proportion of population who are migrants born in high-TB-incidence countries, median household income, and deprivation level. A negative binomial regression model was used to estimate the association between TB incidence and household crowding. Results: The analysis included 1898 notified TB cases for the 2000–4 period. Univariate analysis showed TB incidence at the CAU level was associated with household crowding, for the total population and for all ethnic and age groups. After adjusting for the covariates of household income, existing TB burden, and proportion of migrants from high-TB-incidence countries, multivariate analysis showed statistically significant associations between TB incidence and household crowding. The incidence rate ratio (IRR) was 1.05 (95% CI 1.02 to 1.08) in the total population and 1.08 (95% CI 1.04 to 1.12) for NZ-born people <40 years. Conclusion: At the CAU level, TB incidence in NZ is associated with household crowding. An individual-based study (e.g. case–control) in recently infected cases (detected by molecular epidemiology techniques) is suggested to complement these findings. Reducing or eliminating household crowding could decrease TB incidence in NZ and globally.
Effect of aminophylline on plasma [K+] and hypoxic ventilatory response during mild exercise in men.

To examine the role of endogenous adenosine on the hypoxic ventilatory response (HVR) enhanced during exercise, we measured HVR at rest and during mild exercise (12.5 W) in nine healthy men in a supine position after pretreatment with aminophylline (5 mg/kg), an adenosine receptor blocker, or dipyridamole (0.6 mg/kg), an adenosine uptake blocker, by using a 3-day double-blind placebo-controlled design. Although HVR was enhanced during exercise on all occasions, HVR with aminophylline [0.42 +/- 0.07 (SE) l.min-1. %fall-1 of arterial O2 saturation] was significantly lower than that with placebo (0.64 +/- 0.13 l.min-1.%fall-1) or dipyridamole (0.64 +/- 0.08 l.min-1.%fall-1) during exercise (P < 0.05 for both) at similar end-tidal PCO2 on the 3 days but not at rest. We then examined the changes in plasma K+ concentration ([K+]) and catecholamines, the other possible endogenous potentiators of the carotid body activity. The exercise- and hypoxia-induced increases in plasma [K+] were significantly lower with aminophylline (0.23 +/- 0.09 meq/l) than with the placebo (0.51 +/- 0.10 meq/l) or dypyridamole (0.58 +/- 0.13 meq/l) (P < 0.05 for both). We therefore conclude that aminophylline attenuates the enhancement of HVR during mild exercise and that this might be due to its attenuating effect on exercise- and hypoxia-associated increases in plasma [K+] rather than due to its antagonizing effect on endogenous adenosine.
A prospective study of the outcome for fetuses with diaphragmatic hernia.

OBJECTIVE To establish the natural history and outcome of isolated congenital diaphragmatic hernia (CDH) diagnosed before birth. The mortality of CDH with currently available postnatal care, including extracorporeal membrane oxygenation (ECMO), reported in retrospective studies ranges from less than 25% to greater than 75%. This variation is attributable to a "hidden mortality" (infants who die with CDH that is not recognized) of unknown magnitude. DESIGN Prospectively followed case series. SETTING Patients were referred from practitioners in 18 states and evaluated and followed up by the University of California, San Francisco, Fetal Treatment Center. Arrangements were made for planned delivery at tertiary perinatal centers with ECMO capability. PATIENTS All 83 fetuses with isolated, potentially correctable CDH diagnosed prior to 24 weeks' gestation referred to the University of California, San Francisco, Fetal Treatment Center between January 1989 and October 1993. MAIN OUTCOME MEASURES Survival beyond 2 months after optimal postnatal care. RESULTS Fifty-eight percent (48 of 83) died despite optimal postnatal care (95% confidence interval, 41% to 75%). Of the 48 nonsurvivors, seven suffered intrauterine fetal demise, four were too premature for ECMO, 16 died before ECMO could be started, and 21 died despite ECMO therapy. Twenty-two of the 35 survivors received ECMO, and nine of these have severe chronic illness attributable to the intensive management. CONCLUSIONS In this study, the mortality for potentially correctable CDH diagnosed before 24 weeks' gestation is 58%, despite optimal care presently available after birth. Infants who die in utero and soon after birth constitute a substantial hidden mortality.
Reactivity pattern and cytokine profile of T cells primed by myelin peptides in multiple sclerosis and healthy individuals

Autoreactive T cells specific for candidate myelin antigens, including myelin basic protein (MBP) and proteolipid protein (PLP), are thought to play an important role in the pathogenesis of multiple sclerosis (MS). Myelin‐reactive T cells primed in vivo by myelin breakdown products or microbial cross‐reactive antigens during the disease processes may exhibit a reactivity pattern and cytokine profile different from those in the normal T cell repertoire. In this study, we examined the precursor frequency, the reactivity pattern and cytokine profile of myelin‐reactive T cells that were primed in vitro with overlapping peptides of MBP and PLP in patients with MS and healthy individuals. The results revealed that T cells specific for peptides of MBP and PLP occurred at a relatively higher precursor frequency in patients with MS than that in healthy individuals. We identified a number of dominant T cell epitopes within MBP and PLP, some of which were not previously detected using whole myelin antigens as the primary stimuli. Some residues represented common immunodominant regions that were detected in both MS patients and healthy controls while others were associated only with MS. MBP‐reactive T cell lines generally exhibited a Th0‐like cytokine profile. There was significantly increased Th1 cytokine production (i. e. TNF and IFN‐γ) among MS‐derived T cell lines. PLP‐reactive T cell lines had a distinct cytokine profile, producing predominantly TNF‐α and little or not IFN‐γ and IL‐4. The findings have important implications in the understanding of the role of myelin‐reactive T cells in MS.
Adverse Selection or Moral Hazard, an Empirical Study

Markets prone to asymmetric information employ reputation mechanisms to address adverse selection and moral hazard. In this paper, we use a change in such a reputation mechanism to examine its effect on improving adverse selection and moral hazard. In May, 2008, eBay changed its reputation mechanism to prevent sellers from giving negative feedback to buyers. This change was intended to prevent sellers from retaliating against buyers who gave them negative feedback. We observe an improvement in the overall quality of the marketplace as a result of this change. We attribute 49%–77% of this improvement to reduced adverse selection as low‐quality sellers exit the market or their market share drops, and the rest to a reduction in moral hazard as sellers improve the quality of their service.
Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives

Retinal neovascularization and macular edema are central features of diabetic retinopathy, the major cause of blindness in the developed world. Current treatments are limited in their efficacy and are associated with significant adverse effects. Characterization of the molecular and cellular processes involved in vascular growth and permeability has led to the recognition that the angiogenic growth factor and vascular permeability factor vascular endothelial growth factor (VEGF) plays a pivotal role in the retinal microvascular complications of diabetes. Therefore, VEGF represents an exciting target for therapeutic intervention in diabetic retinopathy. This review highlights the current understanding of the mechanisms that regulate VEGF gene expression and mediate its biological effects and how these processes may become altered during diabetes. The cellular and molecular alterations that characterize experimental models of diabetes are considered in relation to the influence of high glucose‐mediated oxidative stress on VEGF expression and on the mechanisms of VEGF's actions under hyperglycemic induction. Finally, potential therapeutic strategies for preventing VEGF overexpression or blocking its pathological effects in the diabetic retina are considered. Copyright © 2003 John Wiley & Sons, Ltd.
Increased plasma histamine concentrations after food challenges in children with atopic dermatitis.

Thirty-three patients with atopic dermatitis underwent double-blind placebo-controlled food challenges for evaluation of the role of histamine in hypersensitivity to food. After suspect foods were eliminated for 10 days, oral challenges were performed with up to 8 g of dehydrated food. A total of 35 positive challenges elicited symptoms that were cutaneous (31), gastrointestinal (17), nasal (8), and respiratory (6) within 10 to 90 minutes. Forty-one food challenges were negative, and all 60 placebo challenges were negative. Only the group of patients with positive food challenges had a significant mean (+/- S.E.M.) rise in the plasma histamine concentration, from 296 +/- 80 pg per milliliter before challenge to 1055 +/- 356 after challenge (P less than 0.001). Rises in plasma histamine that were seen after these positive oral food challenges implicate mast-cell or basophil mediators in the pathogenesis of food allergy, including cutaneous changes in patients with atopic dermatitis.
Decision Determinants of Tourist’s Intention to Revisit a Coastal Tourism Object by Using ROS Model: A Case of Kelapa Dua Islands Jakarta

This study examines factors in decision making of tourist to revisit Kelapa Dua Island, Thousand Islands, DKI Jakarta, Indonesia. The objectives of this study were: (1) To know the socio-demographic characteristics of the visitors in order to understand the relationship on their decision making to revisit the island, (2) To know the preferred activity preference attributes of the visitors in order to understand the relationship on their decision making to revisit the island, (3) To know the specific role of beach settings / attributes in the visitors‟ view in order to understand the relationship on their decision making to revisit the island, and (4) To define the expected desired experiences of the visitors in order to understand the relationship on their decision making to revisit the island. The data collection used was primary data, taken by spreading questionnaire to 100 visitors on the exit gate of Kelapa Dua Island, DKI Jakarta, Indonesia. An accidental sampling was used to select the respondent surveyed for this study. Sampling will be rotated on different days of the week and between morning, afternoon, and evening in attempts to acquire a more accurate and representative population.
Activation of protein kinase C and protein kinase D in human natural killer cells: effects of tributyltin, dibutyltin, and tetrabromobisphenol A

Abstract Up to now, the ability of target cells to activate protein kinase C (PKC) and protein kinase D (PKD) (which is often a downstream target of PKC) has not been examined in natural killer (NK) lymphocytes. Here we examined whether exposure of human NK cells to lysis sensitive tumor cells activated PKC and PKD. The results of these studies show for the first time that activation of PKC and PKD occurs in response to target cell binding to NK cells. Exposure of NK cells to K562 tumor cells for 10 and 30 min increased phosphorylation/activation of both PKC and PKD by roughly 2-fold. Butyltins (tributyltin (TBT), dibutyltin (DBT)) and brominated compounds (tetrabromobisphenol A (TBBPA)) are environmental contaminants that are found in human blood. Exposures of NK cells to TBT, DBT, or TBBPA decrease NK cell lytic function in part by activating the mitogen-activated protein kinases (MAPKs) that are part of the NK lytic pathway. We established that PKC and PKD are part of the lytic pathway upstream of MAPKs and thus we investigated whether DBT, TBT, and TBBPA exposures activated PKC and PKD. TBT-activated PKC by 2–3-folds at 10 min at concentrations ranging from 50 to 300 nM while DBT caused a 1.3-fold activation at 2.5 µM at 10 min. Both TBT and DBT caused an approximately 2-fold increase in phosphorylation/activation of PKC. Exposures to TBBPA caused no statistically significant changes in either PKC or PKD activation.
Mixed Lineage Kinase 2 Interacts with Clathrin and Influences Clathrin-coated Vesicle Trafficking*

Mixed lineage kinase 2 (MLK2) is a protein kinase that signals in the stress-activated Jun N-terminal kinase signal transduction pathway. We used immunoprecipitation and mass spectrometric analysis to identify MLK2-binding proteins in cell lines with inducible expression of green fluorescent protein-tagged MLK2. Here we report the identification of clathrin as a binding partner for MLK2 in both cultured cells and mammalian brain. We demonstrate that clathrin binding requires a motif (LLDMD) located near the MLK2 C terminus, which is similar to “clathrin box” motifs important for binding of clathrin coat assembly and accessory proteins to the clathrin heavy chain. A C-terminal fragment of MLK2 containing this motif binds strongly to clathrin, and mutation of the LLDMD sequence to LAAAD completely abrogates clathrin binding. We isolated clathrin-coated vesicles from green fluorescent protein-MLK2-expressing cells and from mouse brain lysates and found that MLK2 is enriched along with clathrin in these vesicles. In addition, we demonstrated that endogenous MLK2 co-immunoprecipitates with clathrin heavy chain from the vesicle-enriched fraction of mouse brain lysate. Furthermore, overexpression of MLK2 in cultured cells inhibits accumulation of labeled transferrin in recycling endosomes during receptor-mediated endocytosis. These findings suggest a role for MLK2 and the stress-signaling pathway at sites of clathrin activity in vesicle formation or trafficking.
Neonatal diabetes mellitus: Insulin pump as an alternative management strategy

Abstract: Neonatal diabetes mellitus (hyperglycaemia within the first month of life, with an insulin requirement) may be transient or permanent. Management is complex, due to lack of subcutaneous fat and the need for small doses of insulin, and may be complicated by additional medical problems. Three cases are presented, the first of which was treated with conventional insulin therapy. The latter two were successfully treated with subcutaneous insulin pump therapy. We present suggested guidelines for treatment of neonatal diabetes, using this novel approach to management.
V*-Algebras, Independence Algebras and Logic

Independence algebras were introduced in the early 1990s by specialists in semigroup theory, as a tool to explain similarities between the transformation monoid on a set and the endomorphism monoid of a vector space. It turned out that these algebras had already been defined and studied in the 1960s, under the name of v*-algebras, by specialists in universal algebra (and statistics). Our goal is to complete this picture by discussing how, during the middle period, independence algebras began to play a very important role in logic.
Construction of a Low-Temperature Protein Expression System Using a Cold-Adapted Bacterium, Shewanella sp. Strain Ac10, as the Host

ABSTRACT A recombinant protein expression system working at low temperatures is expected to be useful for the production of thermolabile proteins. We constructed a low-temperature expression system using an Antarctic cold-adapted bacterium, Shewanella sp. strain Ac10, as the host. We evaluated the promoters for proteins abundantly produced at 4°C in this bacterium to express foreign proteins. We used 27 promoters and a broad-host-range vector, pJRD215, to produce β-lactamase in Shewanella sp. strain Ac10. The maximum yield was obtained when the promoter for putative alkyl hydroperoxide reductase (AhpC) was used and the recombinant cells were grown to late stationary phase. The yield was 91 mg/liter of culture at 4°C and 139 mg/liter of culture at 18°C. We used this system to produce putative peptidases, PepF, LAP, and PepQ, and a putative glucosidase, BglA, from a psychrophilic bacterium, Desulfotalea psychrophila DSM12343. We obtained 48, 7.1, 28, and 5.4 mg/liter of culture of these proteins, respectively, in a soluble fraction. The amounts of PepF and PepQ produced by this system were greater than those produced by the Escherichia coli T7 promoter system.
Quality of Work Life in Higher Education Institutions

The quality of work life, whether in the public or private institution, aims to promote well-being for employees, so that they can perform their activities satisfied and motivated, thus contributing to an excellent organizational performance. This study is a review of the literature on the quality of life at work, in which approaches and applications were sought from public servants, especially from Higher Education Institutions. For that, bibliographic research was carried out, with an exploratory and descriptive character, with a qualitative approach and deductive method. The collection of data in front of the compiled and localized scientific works focused on the identification of existing models, among which Walton was considered the most adequate and therefore, with higher utility for the future study of deepening in an application with public servants of Higher education institutions. This model includes a structured questionnaire with eight criteria: social relevance of work life, use of skills, working conditions, social integration in the organization, work, and total living space and constitutionalism, fair and adequate compensation and opportunity for growth. It is understood that new research applied in this sense, help the managers of the HEIs studied in the decision making aimed at promoting improvements to the Quality of Life at Work.
Hereditary sacral agenesis with presacral mass and anorectal stenosis: The Currarino triad

A family with autosomal dominant inheritance of sacral agenesis is described. Ten members were affected; four had associated presacral teratomas and anterior sacral meningoceles, giving rise to serious complications in three, including bacterial meningitis, local recurrence of teratoma and perianal sepsis. Three of those with presacral masses presented initially with anorectal anomalies. Other associated abnormalities included tethering of the cord, hydrocephalus, duplex ureter, hydronephrosis, vesicoureteric reflux, neurogenic bladder, bicornuate uterus, rectovaginal fistula and hereditary spherocytosis. Early diagnosis and surgical excision of a presacral mass is advised to prevent future morbidity and mortality.
The Role of e-Commerce in the Success of Low-cost Carriers

Abstract This research aims to answer the question if e-commerce favoured in a special way the growth of low-cost carriers within the civil aviation market. After defining low-cost and traditional carriers’ business models, data on transported passengers were collected for three countries (Italy, Germany and Spain) and confronted with the number of e-consumers. Despite a significant correlation in all the three markets, only in Italy our hypothesis has been supported by Granger causality, and the regression analysis allows to forecast a future characterized by a growing dominance of LCCs. Although the definition of an econometric model will require further studies, the distinctive features of the Italian market might represent a starting point for future research on the complex relationship between e-commerce and air transport.