Miracle-dz/UniFAR-FTUs huggingface dataset:
Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia

The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate‐risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate‐risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele‐specific matrix‐assisted laser desorption ionization time‐of‐flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms‐related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse‐free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.
Temperature-sensitive lesions in the Francisella novicida valA gene cloned into an Escherichia coli msbA lpxK mutant affecting deoxycholate resistance and lipopolysaccharide assembly at the restrictive temperature

The valAB locus of Francisella novicida has previously been found to be highly similar at the deduced amino acid level to msbA lpxK of Escherichia coli. Both ValA and MsbA are members of the superfamily of ABC transporters, and they appear to have similar functions. In this study we describe the isolation of a temperature-sensitive valAB locus. DNA sequence analysis indicates that the only changes to the ValAB deduced amino acid sequence are changes of S453 to an F and T458 to an I in ValA. E. coli strains defective in msbA and expressing temperature-sensitive ValA rapidly ceased growth when shifted from a permissive temperature to a restrictive temperature. After 1 h at the restrictive temperature, cells were much more sensitive to deoxycholate treatment. To test the hypothesis that ValA is responsible for the transport or assembly of lipopolysaccharide, we introduced gseA, a Kdo (3-deoxy-D-manno-octulosonic acid) transferase from Chlamydia trachomatis, into a strain with a temperature-sensitive valA allele and a nonfunctional msbA locus. These recombinants were defective in cell surface expression of the chlamydial genus-specific epitope within 15 min of a shift to the nonpermissive temperature. Also, there was enhanced association of the epitope with the inner membrane after a shift to the nonpermissive temperature. Thus, we propose that ValA is involved in the transport of lipopolysaccharide to the outer membrane.
Activation of nuclear factor‐κB signaling pathway by interleukin‐1 after hypoxia/ischemia in neonatal rat hippocampus and cortex

Perinatal hypoxia/ischemia (HI) is a common cause of neurological deficits in children. Interleukin‐1 (IL‐1) activity has been implicated in HI‐induced brain damage. However, the mechanisms underlying its action in HI have not been characterized. We used a 7‐day‐old rat model to elucidate the role of nuclear factor‐κB (NF‐κB) activation in HI stimulation of IL‐1 signaling. HI was induced by permanent ligation of the left carotid artery followed by 90 min of hypoxia (7.8% O2). Using ELISA assays, we observed increased cell death and caspase 3 activity in hippocampus and cortex 3, 6, 12, 24 and 48 h post‐HI. IL‐1β protein expression increased, beginning at 3 h after HI and lasting until 24 h post‐HI in hippocampus and 12 h post‐HI in cortex. Intracerebroventricular injection of 2µg IL‐1 receptor antagonist (IL‐1Ra) 2 h after HI significantly reduced cell death and caspase 3 activity. Electrophoretic mobility shift assay analyses of hippocampus and cortex after HI for NF‐κB activity showed increased p65/p50 DNA‐binding activity at 24 h post‐HI. Western blot analyses showed significant nuclear translocation of p65. Protein expression levels of two known inflammatory agents, inducible nitric oxide synthase and cycloxygenase 2, known to be transcriptionally regulated by NF‐κB, also increased at 24 h after HI. All these HI‐induced changes were reversed by IL‐1Ra blockade of IL‐1 signaling, consistent with IL‐1 triggering of inflammatory apoptotic outcomes via NF‐κB transcriptional activation. The observed increase in cytoplasmic phosphorylated inhibitor κBα (IκBα) and nuclear translocation of Bcl‐3 24 h after HI was also significantly attenuated by IL‐1Ra blockade, suggesting that HI‐induced IL‐1 activation of NF‐κB is via both the degradation of IκBα and the nuclear translocation of Bcl‐3.
Requirement of Protein Kinase Cμ Activation and Calpain-mediated Proteolysis for Arachidonic Acid-stimulated Adhesion of MDA-MB-435 Human Mammary Carcinoma Cells to Collagen Type IV*

Arachidonic acid (AA) stimulation of adhesion of human metastatic breast carcinoma cells to collagen type IV depends on the protein kinase C (PKC) pathway(s) and is associated with the translocation of PKCμ from the cytoplasm to the membrane. In the present study, we have further explored the role of PKCμ in AA-stimulated adhesion. PKCμ activation site serines 738/742 and autophosphorylation site serine 910 are rapidly phosphorylated, and in vitro PKCμ kinase activity is enhanced in response to AA treatment. Inhibition of PKCμ activation blocks AA-stimulated adhesion. A phosphorylated, truncated species of PKCμ was detected in AA-treated cells. This 77-kDa protein contains the kinase domain but lacks a significant portion of the regulatory domains. Inhibition of calpain protease activity blocks generation of the truncated protein, promotes accumulation of the activated, full-length protein in the membrane, and blocks the AA-mediated increase in adhesion. p38 MAPK activity is also required for AA-stimulated adhesion. Activation of PKCμ and p38 are independent events. However, inhibition of p38 activity reduces calpain-mediated proteolysis of PKCμ and in vivo calpain activity, suggesting a role for p38 in regulation of calpain activity and a point for cross-talk between the PKC and MAPK pathways. These results support the hypothesis that AA stimulates activation of PKCμ, which is cleaved by calpain at the cell membrane. The resulting truncated kinase, as well as the full-length kinase, may be required for increased cell adhesion to collagen type IV. Additionally, these studies present the first evidence for calpain cleavage of a non-structural protein leading to the promotion of tumor cell adhesion.
Family Functioning and Overprotection following a Natural Disaster: The Longitudinal Effects of Post-Traumatic Morbidity

The longitudinal impact of a natural disaster on the patterns of interaction in families with latency-aged children is examined. An 11-item questionnaire was developed and two factors were isolated: irritable distress and involvement. A group of 183 disaster-affected families were contrasted with 497 families who had not been exposed to the disaster. Eight months after the disaster, the interaction in the disaster-affected families was characterised by increased levels of conflict, irritability and withdrawal. Maternal overprotection was also a common feature of the pattern of care in these families. Post-traumatic morbidity in parents was the major determinant of the observed changes in family functioning and the overprotection.
Structural Basis for the Failure of the C1 Domain of Ras Guanine Nucleotide Releasing Protein 2 (RasGRP2) to Bind Phorbol Ester with High Affinity*

The C1 domain represents the recognition module for diacylglycerol and phorbol esters in protein kinase C, Ras guanine nucleotide releasing protein (RasGRP), and related proteins. RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (Kd = 2890 ± 240 nm for [3H]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn7, Ser8, Ala19, and Ile21 with the corresponding residues from RasGRP1/3 (Thr7, Tyr8, Gly19, and Leu21, respectively) conferred potent binding affinity (Kd = 1.47 ± 0.03 nm) in vitro and membrane translocation in response to phorbol 12-myristate 13-acetate in LNCaP cells. Mutant C1 domains incorporating one to three of the four residues showed intermediate behavior with S8Y making the greatest contribution. Binding activity for diacylglycerol was restored in parallel. The requirement for anionic phospholipid for [3H]phorbol 12,13-dibutyrate binding was determined; it decreased in going from the single S8Y mutant to the quadruple mutant. The full-length RasGRP2 protein with the mutated C1 domains also showed strong phorbol ester binding, albeit modestly weaker than that of the C1 domain alone (Kd = 8.2 ± 1.1 nm for the full-length protein containing all four mutations), and displayed translocation in response to phorbol ester. RasGRP2 is a guanyl exchange factor for Rap1. Consistent with the ability of phorbol ester to induce translocation of the full-length RasGRP2 with the mutated C1 domain, phorbol ester enhanced the ability of the mutated RasGRP2 to activate Rap1. Modeling confirmed that the four mutations helped the binding cleft maintain a stable conformation.
A Dynamic State Model of Migratory Behavior and Physiology to Assess the Consequences of Environmental Variation and Anthropogenic Disturbance on Marine Vertebrates

Integrating behavior and physiology is critical to formulating new hypotheses on the evolution of animal life-history strategies. Migratory capital breeders acquire most of the energy they need to sustain migration, gestation, and lactation before parturition. Therefore, when predicting the impact of environmental variation on such species, a mechanistic understanding of the physiology of their migratory behavior is required. Using baleen whales as a model system, we developed a dynamic state variable model that captures the interplay among behavioral decisions, energy, reproductive needs, and the environment. We applied the framework to blue whales (Balaenoptera musculus) in the eastern North Pacific Ocean and explored the effects of environmental and anthropogenic perturbations on female reproductive success. We demonstrate the emergence of migration to track prey resources, enabling us to quantify the trade-offs among capital breeding, body condition, and metabolic expenses. We predict that periodic climatic oscillations affect reproductive success less than unprecedented environmental changes do. The effect of localized, acute anthropogenic impacts depended on whales’ behavioral response to the disturbance; chronic, but weaker, disturbances had little effect on reproductive success. Because we link behavior and vital rates by modeling individuals’ energetic budgets, we provide a general framework to investigate the ecology of migration and assess the population consequences of disturbance, while identifying critical knowledge gaps.
The Role of Na, K-Atpase Inhibitors in Hypertension and End-Stage Renal Disease

Objective To review the role of Na, K-ATPase inhibitors in the pathogenesis of essential hypertension and hypertension associated with end-stage renal disease. Data Sources MEDLINE search, 1966 to 1997. Results There is a suggestive physiologic and epidemiologic relationship between Na, K-ATPase inhibition and hypertension. However, clearance data cannot support the hypothesis that differential metabolism of this family of compounds explains the improved hypertensive control seen in patients on peritoneal dialysis compared to those on hemodialysis. Conclusions As a result of the complex methodologies involved, it is unclear whether Na, K-ATPase inhibitors playa significant role in the hypertension of endstage renal disease in general and peritoneal dialysis in particular.
Four Week Feeding Toxicity Study with Phenylphosphinic Acid in Rats

Abstract Phenylphosphinic acid was fed in graded concentrations of either 0 (control), 100, 1,000, or 10,000 ppm to rats for 28 days. These concentrations provided average daily doses of 8, 76, and 779 mg/kg (males) and 9, 83, and 859 mg/kg (females). No signs of adverse response were detected at any concentration up to the highest levels tested, 10,000 ppm or 779 (male) or 859 (female) mg/kg. Parameters measured were clinical signs, growth, neurobehavior, ophthalmology, and clinical and anatomical pathology. Phenylphosphinic acid is very low in toxicity following 31 days of feeding to the rat.
Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles

Background information. TSEs (transmissible spongiform encephalopathies) are neurodegenerative disorders affecting humans and animals. PrPSc, a conformationally altered isoform of the normal prion protein (PrPC), is thought to be the pathogenic agent. However, the biochemical composition of the prion agent is still matter of debate. The potential transmission risk of the prion agent through biological fluids has been shown, but the development of competitive diagnostic tests and treatment for TSEs requires a more comprehensive knowledge of the agent and the cellular mechanisms by which it is disseminated. With this aim, we initiated characterization of the prion agent and the pathways by which it can be propagated using the cellular model system neuroblastoma (N2a).
Biological and molecular characterization of cellular differentiation in Tetrahymena vorax: A potential biocontrol protozoan

Tetrahymena vorax (T. vorax) is an indigenous fresh water protozoan with the natural biological potential to maintain a specific aquatic microbial flora by ingesting and eliminating specific microorganism. To investigate the molecular mechanisms controlling Tetrahymena vorax (T. vorax) cellular differentiation from a small‐mouth vegetative cell to a voracious large‐mouth carnivore capable of ingesting prey ciliates and bacteria from aquatic environments, we use DNA subtraction and gene discovery techniques to identify and isolate T. vorax differentiation‐specific genes. The physiological necessity for one newly discovered gene, SUBII‐TG, was determined in vivo using an antisense oligonucleotide directed against the 5′ SUBII‐TG DNA sequence. The barriers to delivering antisense oligonucleotides to the cytoplasm of T. vorax were circumvented by employing a new but simple procedure of processing the oligonucleotide with the differentiation stimulus, stomatin. In these studies, the antisense oligonucleotide down‐regulated SUBII‐TG mRNA expression, and blocked differentiation and ingestion of prey ciliates. The ability to down‐regulate SUBII‐TG ex‐pression with the antisense oligonucleotide suggests that the molecular mechanisms controlling the natural biological activities of T. vorax can be manipulated to further study its cellular differentiation and potential as a biocontrol microorganism.
Termination Approximation: Continuous State Decomposition for Hierarchical Reinforcement Learning

This paper presents a divide-and-conquer decomposition for solving continuous state reinforcement learning problems. The contribution lies in a method for stitching together continuous state subtasks in a near-seamless manner along wide continuous boundaries. We introduce the concept of Termination Approximation where the set of subtask termination states are covered by goal sets to generate a set of subtask option policies. The approach employs hierarchical reinforcement learning methods and exploits any underlying repetition in continuous problems to allow reuse of the option policies both within a problem and across related problems. The approach is illustrated using a series of challenging racecar problems.
Drosophila splicing factor SF2 knock‐down mutant shows altered cell‐cycle in vivo

Pioneering single gene study documents pre‐mRNA processing proteins participation in the cell‐cycle regulation of multi‐cellular animals (Andersen and Tapon, 2008, J Biol Chem 283: 31256–67). Whole‐genome RNAi screen in Drosophila tissue‐culture cell lines demonstrates that 17 genes involved in RNA‐processing are required for G2/M check‐point function (Kondo and Perrimon, 2011, Sci Signal 4: rs1). In particular, the silencing of Splicing Factor 2 (SF2) increases the number of G2(M) cells. We have measured the absolute duration of cell‐cycle phases in SF2 depleted flies with the use of flow cytometry and growth parameters of GFP marked mosaic clones. For SF2 mutant cells, G1 = 1.89 h, G2(M) = 7.22 h and S = 1.30 h compared with G1 = 2.25 h, G2(M) = 4.86 h and S = 1.28 h for control normal cells. Thus, G2(M) phase appears to be longer in SF2 silenced cells, supporting the evidence that this splicing protein participates in G2‐M check‐point function.
Reconstruction of the thermal field image from measurements in separate points

In the article gives a brief overview of the methods for recovering the thermal field image. It is proposed a computer data processing system that allows to reconstruct the complete image of the thermal field over point temperature values and which is an alternative to the use of thermal imaging technology. The problem of information loading into the computer operating system is solved by applying the electronic platform of Arduino LLC. It was proposed software environment to collect data from analog and digital temperature converters. This software provides synchronization of the device operation with a personal computer and allows displaying and recording information from primary converters. The reconstruction of the thermal field image from the temperature values obtained by a pyrometer was performed using linear, spline and cubic interpolations. A thermogram of the testing object, obtained by a thermovision camera was used as a standard field. The minimal discrepancies between the standard and reconstructed fields were obtained using spline interpolation. The proposed system can be effectively used with active thermal nondestructive testing of objects made of composite materials for visualization of thermal fields without the use of thermal imaging technology.
Tissue-Engineered Bone from BMP-2–Transduced Stem Cells Derived from Human Fat

Background: Progenitor cells capable of induction into multiple mesenchymal lineages have been isolated from human liposuction aspirates. These cells, named processed lipoaspirate cells, have previously shown in vitro osteogenic capacity. The purpose of this study was to examine the in vivo bone induction capacity of bone morphogenetic protein-2 (BMP-2)–transduced processed lipoaspirate cells using adipose tissue from multiple harvest sites. Methods: Processed lipoaspirate cells extracted from human abdominal and buttock liposuction aspirates (n = 5) and from infrapatellar fat pads (n = 5) were placed in osteogenic media containing Dulbecco’s Modified Eagle Medium with 10% fetal bovine serum supplemented with 50 &mgr;M ascorbic acid-2-phosphate and 10 mM beta-glycerol phosphate. Half of these cells were transfected with an adenovirus carrying the cDNA for bone morphogenetic protein-2 (adBMP-2). These transfected cells were then seeded onto collagen I matrices at a concentration of 2 × 106 cells/matrix and were placed into the hind limbs of severe combined immunodeficient mice (n = 10). Nontransfected processed lipoaspirate cells were placed in the contralateral limb as a control. After 6 weeks, specimens were analyzed by radiographs, densitometry, and hematoxylin and eosin and von Kossa staining. Results: The average number of cells extracted from the abdominal/buttock lipoaspirates was 3.4 × 107 cells/100 ml fat aspirate and 5.5 × 106 cells per infrapatellar fat pad (average volume, 20.6 cc). All 10 BMP-2 transfected processed lipoaspirate constructs produced abundant radiographic and histologic bone. The bone was adequately mineralized and was beginning to establish a marrow cavity. There was no quantitative difference in bone production between harvest sites [mean, 2.0 ± 0.1 aluminum units (knee) versus 2.1 ± 0.1 aluminum units (abdomen/buttock); p = 0.14]. No bone was produced in the negative controls. Conclusions: Multipotential processed lipoaspirate cells can be extracted from adipose tissue harvested from liposuction aspirates or from the infrapatellar fat pad of the knee. Processed lipoaspirate cells can be transduced with the BMP-2 gene to produce abundant in vivo bone. These cells appear to be clinically useful for bone tissue engineering applications either as osteoprogenitor cells or as delivery vehicles for BMP-2.
Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4

Activation of peroxisome proliferator-activated receptor-γ (PPARγ) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPARγ signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPARγ agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIIαCre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPARγ-protective effect. PPARγ signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [manganese(III)tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPARγ signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPARγ and PGC1α (PPARγ coactivator 1α) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed that LMO4 interacts in a ligand-dependent manner with PPARγ. LMO4 augments PPARγ-dependent gene activation, in part, by promoting RXRα (retinoid X receptor-α) binding to PPARγ and by increasing PPARγ binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPARγ signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.