Miracle-dz/UniFAR-FTUs huggingface dataset:
RIP1 Protein-dependent Assembly of a Cytosolic Cell Death Complex Is Required for Inhibitor of Apoptosis (IAP) Inhibitor-mediated Sensitization to Lexatumumab-induced Apoptosis*

Background: Rhabdomyosarcomas (RMS) are often resistant to TRAIL-induced apoptosis. Results: IAP inhibitors prime RMS cells to TRAIL receptor 2-induced apoptosis in a RIP1-dependent but TNFα-independent manner. Conclusion: RIP1 is a critical regulator of IAP inhibitor/TRAIL receptor 2-triggered apoptosis. Significance: These findings have important implications for the development of novel treatment strategies for RMS. Searching for new strategies to trigger apoptosis in rhabdomyosarcoma (RMS), we investigated the effect of two novel classes of apoptosis-targeting agents, i.e. monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (mapatumumab) and TRAIL receptor 2 (lexatumumab) and small-molecule inhibitors of inhibitor of apoptosis (IAP) proteins. Here, we report that IAP inhibitors synergized with lexatumumab, but not with mapatumumab, to reduce cell viability and to induce apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1). Cotreatment-induced apoptosis was accompanied by enhanced activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and caspase-dependent apoptosis. In addition, IAP inhibitor and lexatumumab cooperated to stimulate the assembly of a cytosolic complex containing RIP1, FADD, and caspase-8. Importantly, knockdown of RIP1 by RNA interference prevented the formation of the RIP1·FADD·caspase-8 complex and inhibited subsequent activation of caspase-8, -9, and -3; loss of mitochondrial membrane potential; and apoptosis upon treatment with IAP inhibitor and lexatumumab. In addition, RIP1 silencing rescued clonogenic survival of cells treated with the combination of lexatumumab and IAP inhibitor, thus underscoring the critical role of RIP1 in cotreatment-induced apoptosis. By comparison, the TNFα-blocking antibody Enbrel had no effect on IAP inhibitor/lexatumumab-induced apoptosis, indicating that an autocrine TNFα loop is dispensable. By demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent but TNFα-independent manner in RMS cells, our findings substantially advance our understanding of IAP inhibitor-mediated regulation of TRAIL-induced cell death.
INTRAVITREAL RANIBIZUMAB INJECTION FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN PHAKIC VERSUS PSEUDOPHAKIC EYES

Purpose: To compare the effect of intravitreal ranibizumab injections for the treatment of neovascular age-related macular degeneration between phakic and pseudophakic eyes. Methods: We retrospectively reviewed the medical records of 110 patients with neovascular age-related macular degeneration receiving intravitreal ranibizumab therapy and categorized them into 2 subgroups: phakic group (75 eyes) and pseudophakic group (45 eyes). For all patients, the initial three loading injections were performed by month, and reinjection was performed as needed. Main outcome measures included best-corrected visual acuity and central macular thickness as assessed by optical coherence tomography. Results: The mean age of the patients was 72 ± 4.2 years, and the patients were followed up for an average of 18 ± 3.6 months. At the last visit, the average number of injections was 3.87 ± 1.18 in the phakic group and 3.62 ± 1.17 in the pseudophakic group. After injection, the mean logarithm of the minimum angle of resolution of best-corrected visual acuity improved from 0.88 ± 0.65 to 0.75 ± 0.66 in the phakic group and from 0.86 ± 0.54 to 0.74 ± 0.09 in the pseudophakic group. Average central macular thickness decreased from 561 ± 289 &mgr;m to 419 ± 216 &mgr;m in the phakic group and from 559 ± 232 &mgr;m to 429 ± 166 &mgr;m in the pseudophakic group. There was no statistically significant difference in the injection number, best-corrected visual acuity improvement was achieved, and central macular thickness improvement was achieved between the phakic group and pseudophakic group. Conclusion: The therapeutic effect of intravitreal ranibizumab injection for neovascular age-related macular degeneration did not show differences between phakic and pseudophakic eyes.
Fungal metabolism and detoxification of fluoranthene

Five metabolites produced by Cunninghamella elegans from fluoranthene (FA) in biotransformation studies were investigated for mutagenic activity towards Salmonella typhimurium TA100 and TA104. Whereas FA displayed positive, dose-related mutagenic responses in both tester strains in the presence of a rat liver homogenate fraction, 3-FA-beta-glucopyranoside, 3-(8-hydroxy-FA)-beta-glucopyranoside, FA trans-2,3-dihydrodiol, and 8-hydroxy-FA trans-2,3-dihydrodiol were negative. 9-Hydroxy-FA trans-2,3-dihydrodiol showed a weak positive response in S. typhimurium TA100. Mutagenicity assays performed with samples extracted at 24-h intervals during incubation of C. elegans with FA for 120 h showed that mutagenic activity decreased with time. Comparative studies with rat liver microsomes indicated that FA trans-2,3-dihydrodiol, the previously identified proximal mutagenic metabolite of FA, was the major metabolite. The circular dichroism spectrum of the rat liver microsomal FA trans-2,3-dihydrodiol indicated that it was optically active. In contrast, the circular dichroism spectrum of the fungal FA trans-2,3-dihydrodiol showed no optical activity. These results indicate that C. elegans has the potential to detoxify FA and that the stereochemistry of its trans-2,3-dihydrodiol metabolite reduces its mutagenic potential.
Oxytocin Involvement in Male and Female Sexual Behavior

Oxytocin is a fine example of a molecule used by the organism for multiple purposes. The oxytocin produced by the classic magnocellular neurons that project from the supraoptic and paraventricular n~cleil-~--and also from other nuclei in and near the hypothalamus (forebrain bundle, bed stria terminalis, zona incerta, substantia innominata, et~.)&~-to the posterior pituitary gland is secreted into the systemic circulation and behaves as a classic hormone, acting on distant target organs (myometrium, mammary gland, seminiferous tubules) (for review, see Zimmerman5 and Ivell? . On the other hand, the oxytocin produced by smaller (parvocellular) neurons in the caudal paraventricular nucleus of the hypothalamus behaves as a classic neurotransmitter. These neurons send oxytocinergic projections to the forebrain (cortex, medial septum, amygdala, ventral hippocampus), the brain stem (substantia nigra, mesencephalic gray, dorsal raphe, parabrachial nucleus, raphe magnus, tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, lateral reticular and commissural nuclei), and the spinal cord (lamina I [dorsal horn], lamina X [central gray], intermediolatera1 gray). In these areas, oxytocinergic projections form synapses with other neurons.6s8 In these same areas, high-affinity oxytocin receptors are f~und,~l ' and oxytocin proteolytic enzymes have been well characterized (for a review, see Burbach12). Finally, oxytocin is a precursor of other shorter but even more potent neuropeptides in the brain,l2.l3 behaves as an autacoid in ovaries and testes (for a review, see WathesI4), and is of primary importance in the functional and structural plasticity of its own hypothalamic system.L5. 16 Oxytocin has long been associated with maternity, for its importance in parturition and its fundamental role in milk ejection and lactation. This view has been further strengthened by the finding that oxytocin might play a role in the induction of maternal care.I7 However, oxytocin-synthesizing cells are equally present in females and in males; there is no sexual dimorphism in supraoptic and paraventricular nuclei; and basal cerebrospinal fluid and plasma levels of oxytocin in males are not dissimilar to those found in female^. ^^'*-*^ At present it is well recognized that oxytocin-derived neuropeptides have potent effects on many different behaviors common to either sex, and such effects have been extensively studied and characterized (for review, see Kovacs21). However, although the longest and best known roles of oxytocin are related to mammalian reproductive function, and although many of the most effective stimuli for oxytocin
Characterization of embryonic stem cells: A special focus on farm animals

Embryonic stem (ES) cells are derived from the inner cell mass of blastocysts. They grow indefinitely while maintaining the pluripotency in the presence of specific growth factors such as leukemia inhibitory factor. The molecular mechanisms for self-renewal of pluripotent cells and the role of various growth factors involved in self-renewal as well as differentiation are being deciphered. ES cells, in their undifferentiated state, are characterized by a distinct morphology and by the presence of a set of markers classified into intracellular and extracellular types. Expression of specific markers (surface and transcription based) is an important criterion for pluripotent or undifferentiated state of cells. The expression of these markers is found to be exclusive to a particular species. A thorough understanding of the expression of these markers and of factors or conditions for the long-term culture of ES cells, without compromising their pluripotency and a stable genetic make-up is very important for the production and maintenance of ES cells from different species of farm animals. In this review, we present an overview of characterization of embryonic stem cells in farm animals.
Charge immobilization of the voltage sensor in domain IV is independent of sodium current inactivation

Recovery from fast inactivation in voltage‐dependent Na+ channels is associated with a slow component in the time course of gating charge during repolarization (i.e. charge immobilization), which results from the slow movement of the S4 segments in domains III and IV (S4‐DIII and S4‐DIV). Previous studies have shown that the non‐specific removal of fast inactivation by the proteolytic enzyme pronase eliminated charge immobilization, while the specific removal of fast inactivation (by intracellular MTSET modification of a cysteine substituted for the phenylalanine in the IFM motif, ICMMTSET, in the inactivation particle formed by the linker between domains III and IV) only reduced the amount of charge immobilization by nearly one‐half. To investigate the molecular origin of the remaining slow component of charge immobilization we studied the human cardiac Na+ channel (hH1a) in which the outermost arginine in the S4‐DIV, which contributes ∼20% to total gating charge (Qmax), was mutated to a cysteine (R1C‐DIV). Gating charge could be fully restored in R1C‐DIV by exposure to extracellular MTSEA, a positively charged methanethiosulphonate reagent. The RIC‐DIV mutation was combined with ICMMTSET to remove fast inactivation, and the gating currents of R1C‐DIV‐ICMMTSET were recorded before and after modification with MTSEAo. Prior to MTSEAo, the time course of the gating charge during repolarization (off‐charge) was best described by a single fast time constant. After MTSEA, the off‐charge had both fast and slow components, with the slow component accounting for nearly 35% of Qmax. These results demonstrate that the slow movement of the S4‐DIV during repolarization is not dependent upon the normal binding of the inactivation particle.
Clinical studies with tubercidin administered by direct intravenous injection.

Summary Tubercidin (NSC 56408), a cytotoxic antibiotic, was used in the treatment of 93 patients with various types of advanced neoplastic disease in a Phase I study to determine human toxicity. Significant toxicity was limited to the observation of nephrotoxicity in 18 cases and local irritation of veins in 12. Tumor response was suggested in only 3 cases, all of which were cases of primary carcinoma of the pancreas.
Monitoring jaguar populations Panthera onca with non-invasive genetics: a pilot study in Brazilian ecosystems

Abstract The global population of jaguars Panthera onca has decreased significantly since the beginning of the 20th century. Given the scarcity of demographic and biological information, estimating population parameters is critical for the design of conservation measures. The jaguar's elusive behaviour makes it impossible to estimate and monitor populations by direct observation. We propose a non-invasive genetic sampling approach and demonstrate its potential for large-scale monitoring. Sex identification was optimized for faecal samples of jaguars and other felids. We also optimized a set of 11 microsatellite markers for reliable identification of individuals. We estimated the effectiveness of faecal sample genotyping in two distinct Brazilian biomes: the Pantanal and the semi-arid Caatinga. Almost 90% of the samples that were molecularly identified as jaguar (n = 90) were successfully genotyped and were assigned to 30 individuals. Genetic diversity was generally high but was significantly lower in the Caatinga population. We show that non-invasive genetic sampling can be a reliable tool to study population parameters and to monitor the genetic status of jaguar populations in different habitats. It may also be useful for future surveys of jaguars that address ecological, behavioural and conservation issues, and could provide a baseline for non-invasive genetic studies of other wild felid populations.
Evolution of the Outgassing of Comet Hale-Bopp (C/1995 O1) from Radio Observations

Spectra obtained from ground-based radio telescopes show the progressive release of CO, CH3OH, HCN, H2O (from OH), H2S, CS, H2CO, CH3CN, and HNC as comet Hale-Bopp (C/1995 O1) approached the sun from 6.9 to 1.4 astronomical units (AU). The more volatile species were relatively more abundant in the coma far from the sun, but there was no direct correlation between overabundance and volatility. Evidence for H2O sublimation from icy grains was seen beyond 3.5 AU from the sun. The change from a CO-driven coma to an H2O-driven coma occurred at about 3 AU. The gas outflow velocity and temperature increased as Hale-Bopp approached the sun.
Accelerated Rehabilitation after Anterior Cruciate Ligament Reconstruction : Comparison of Closed Kinetic Chain ( CKC ) Versus Open Kinetic Chain ( OKC ) Exercises

Background: Anterior cruciate ligament (ACL) is one of the most commonly injured ligaments of the knee. ACL reconstruction (ACL-R) is the treatment of choice in cases of severe knee instability to avoid recurrent knee injuries and subsequent degenerative changes. Accelerated rehabilitation after ACL-R greatly affects the healing response and significantly helps patients to gain dynamic stability in the knee joint. Much debate surrounds the difference between open kinetic chain (OKC) and closed kinetic chain (CKC) exercises during ACL-R rehabilitation. Objective: It was the aim of this study to compare the effects of a comprehensive rehabilitation program with quadriceps strengthening in closed kinetic chain (CKC) exercises with the same rehabilitation program with quadriceps strengthening in open kinetic chain (OKC) exercises in patients with ACL reconstruction and to evaluate the effects on knee functions. Subjects and Methods: Forty consecutive patients with ACL reconstruction for isolated ACL injury were included in this study. They were subjected to a rehabilitation program for 4 months supplemented with OKC exercises in one group and CKC exercises in the second group. Results: Patients in CKC exercise group showed at the end of the four months’ rehabilitation programs, a statistically significant increase in passive range of motion (PROM) (p<0.001), in Lysholm score (p=0.002) and a significant decrease in number of patients with extension deficit ≥5o (p= 0.008), all indicating improvement in knee functions, while OKC group only showed improvement in PROM as regards knee functions (p=0.049). Comparing both groups as regards the outcome of rehabilitation program on knee functionsshowed that there was a non significant difference between the two groups concerning PROM, Lysholm score or improvement of extension deficit and thigh atrophy ( p=0.463, p= 0.757, p=0.085, p=0.430 respectively). At the end of the 4 months, there was statistically significant more improvement of knee pain in CKC group than OKC groups (p=0.018) and more number of patients who gave a response of "satisfied" in CKC group than OKC groups (p=0.027). Conclusion: We conclude that both CKC and OKC exercises appear to be suitable for rehabilitation after ACL reconstruction; however, CKC exercises showed better outcome after rehabilitation than OKC exercises as regards knee function, knee pain and patient satisfaction.
Fuchs’ corneal dystrophy

Fuchs’ corneal dystrophy (FCD) is a progressive, hereditary disease of the cornea first described a century ago by the Austrian ophthalmologist Ernst Fuchs. Patients often present in the fifth to sixth decade of life with blurry morning vision that increases in duration as the disease progresses. Primarily a condition of the posterior cornea, characteristic features include the formation of focal excrescences of Descemet membrane termed ‘guttae’, loss of endothelial cell density and end-stage disease manifested by corneal edema and the formation of epithelial bullae. Recent advances in our understanding of the genetic and pathophysiological mechanisms of the disease, as well as the application of new imaging modalities and less invasive surgical procedures, present new opportunities for improved outcomes among patients with FCD.
Estimating the spatial pattern of human-caused forest fires using a generalized linear mixed model with spatial autocorrelation in South Korea

Most forest fires in Korea are spatially concentrated in certain areas and are highly related to human activities. These site-specific characteristics of forest fires are analyzed by spatial regression analysis using the R-module generalized linear mixed model (GLMM), which can consider spatial autocorrelation. We examined the quantitative effect of topology, human accessibility, and forest cover without and with spatial autocorrelation. Under the assumption that slope, elevation, aspect, population density, distance from road, and forest cover are related to forest fire occurrence, the explanatory variables of each of these factors were prepared using a Geographic Information System-based process. First, we tried to test the influence of fixed effects on the occurrence of forest fires using a generalized linear model (GLM) with Poisson distribution. In addition, the overdispersion of the response data was also detected, and variogram analysis was performed using the standardized residuals of GLM. Second, GLMM was applied to consider the obvious residual autocorrelation structure. The fitted models were validated and compared using the multiple correlation and root mean square error (RMSE). Results showed that slope, elevation, aspect index, population density, and distance from road were significant factors capable of explaining the forest fire occurrence. Positive spatial autocorrelation was estimated up to a distance of 32 km. The kriging predictions based on GLMM were smoother than those of the GLM. Finally, a forest fire occurrence map was prepared using the results from both models. The fire risk decreases with increasing distance to areas with high population densities, and increasing elevation showed a suppressing effect on fire occurrence. Both variables are in accordance with the significance tests.
Relocation of the radial head with minimal invasive approach using the Ilizarov technique in neglected Monteggia fracture

Introduction: Missed or Neglected Monteggia fracture dislocation classically implies a duration of more than 4 weeks. Two factors of significant deformity and delayed presentation constitute the problem of management of old Monteggia fracture-dislocation in paediatric age group. Restoration of radiocapitellar joint and biomechanics of the elbow joint is of paramount importance for favourable long term functional outcome. Long-term follow-up of untreated Monteggia fracture dislocations reveals development of premature arthritis, pain, instability, loss of pronation and supination, valgus deformity and a prominence on the anterior aspect of the elbow. Tardy nerve palsies have been reported subsequent to long-standing unrecognized Monteggia lesions. Thus, it is imperative to treat the neglected fracture as soon as it is diagnosed. We used the Ilizarov method using ulnar osteotomy with distraction osteogenesis to produce controlled lengthening to restore the radiocapitellar articulation Aims and Objectives: To evaluate the outcome of relocation of the radial head with minimal invasive approach using the Ilizarov technique in neglected Monteggia fracture in respect to mean increase in Mayo Elbow Performance Index (MEPI). Conclusion: Neglected Monteggia fracture dislocation in children can produce significant orthopaedic complications with gross restriction of activities of daily living. Early diagnosis and prompt management results in favourable long term outcome. Restoration of ulnar length and reduction of the radial head with minimal invasive approach using the Ilizarov technique and transcapitellar pinning is a more biological option for the restoration of the elbow biomechanics and increase in the Mayo Elbow Performance Index.
Impacts of International Migration and Remittances on Source Country Household Incomes in Small Island States; Fiji and Tonga

We use original 2005 survey data from Fiji and Tonga on remittances and household income to estimate the combined impact of migration and remittances on the composition of household income. A two-stage methodology is followed. A variable for the predicted number of migrants in each household is generated to control for selectivity in migration. This variable is then used in a 3SLS remittances and income equation system. In neither country do we observe significant impacts on agricultural cash income, but, in relation to other income sources, including subsistence agriculture, wages and non-agricultural business activities, some significant and different effects are found, both positive and negative. These findings suggest that the duration and intensity of remittance-driven migration, and the structure of economic activity within a community are important in understanding the influences of migration and remittances on household resource allocation and production decisions and on the community’s economic transformation.
Paracetamol (acetaminophen) poisoning.

INTRODUCTION Paracetamol directly causes around 150 deaths per year in UK. METHODS AND OUTCOMES We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS At this update, searching of electronic databases retrieved 127 studies. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 46 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review was updated and one RCT was added at this update. In addition, two systematic reviews and three RCTs not meeting our inclusion criteria were added to the Comment sections. We performed a GRADE evaluation for three PICO combinations. CONCLUSIONS In this systematic overview we categorised the efficacy for six interventions, based on information about the effectiveness and safety of activated charcoal (single or multiple dose), gastric lavage, haemodialysis, liver transplant, methionine, and acetylcysteine.