gebhart/patrepeval huggingface dataset:
Parathyroid Hormone Controls Receptor Activator of NF-κB Ligand Gene Expression via a Distant Transcriptional Enhancer (2006)

RANKL, a protein essential for osteoclast development and survival, is stimulated by parathyroid hormone (PTH) via a PTH receptor 1/cyclic AMP (cAMP)/protein kinase A (PKA)/CREB cascade, exclusively in osteoblastic cells. We report that a bacterial artificial chromosome-based transcriptional reporter construct containing 120 kb of RANKL 5'-flanking region was stimulated by dibutyryl-cAMP in stromal/osteoblastic cells, but not other cell types. Full cAMP responsiveness was dependent upon a conserved 715-bp region located 76 kb upstream from the transcription start site, which we identified by sequential deletion analysis and by comparison of human and mouse genomic sequences in silico. This region contained conserved consensus sequences which bound CREB and the osteoblast-specific transcription factor Runx2, and when mutated blunted cAMP responsiveness. Overexpression of Runx2 potentiated cAMP responsiveness of the endogenous RANKL gene in a cell-type-specific manner. Lastly, PTH responsiveness of the endogenous RANKL gene was abrogated in mice from which we deleted this conserved upstream region. Thus, PTH responsiveness of the RANKL gene is determined by a distant regulatory region that responds to cAMP in a cell-type-specific manner and Runx2 may contribute to such cell-type specificity.
A convenient multiplex PCR system for the detection of dystrophin gene deletions: a comparative analysis with cDNA hybridisation shows mistypings by both methods. (1991)

Existing reactions for the multiplex PCR amplification of exons in the dystrophin gene have been modified to produce two multiplex reactions which separately cover the 5' and 3' major deletion 'hotspots' in the gene, and together detect approximately 98% of all deletions detectable by Southern cDNA hybridisation. A comparative study of 148 patients showed mistypings in both the cDNA hybridisation data (4%) and the PCR analysis (1.2%). We suggest means of circumventing the underlying problems in order to avoid mistyping and subsequent misdiagnosis, and conclude that, with appropriate precautions, multiplex PCR amplification can be the method of choice for detecting deletions in the dystrophin gene.
An attempt to categorize yield stress fluid behaviour (2009)

We propose a new view on yield stress materials. Dense suspensions and many other materials have a yield stress-they flow only if a large enough shear stress is exerted on them. There has been an ongoing debate in the literature on whether true yield stress fluids exist, and even whether the concept is useful. This is mainly due to the experimental difficulties in determining the yield stress. We show that most if not all of these difficulties disappear when a clear distinction is made between two types of yield stress fluids: thixotropic and simple ones. For the former, adequate experimental protocols need to be employed that take into account the time evolution of these materials: ageing and shear rejuvenation. This solves the problem of experimental determination of the yield stress. Also, we show that true yield stress materials indeed exist, and in addition, we account for shear banding that is generically observed in yield stress fluids.
Liquid−Liquid Slug Flow in a Capillary:  An Alternative to Suspended Drop or Film Contactors (2007)

The widely used separation process of liquid−liquid extraction is performed in a variety of contactors. The interfacial area in these conventional contactors is often poorly defined, because of the complex hydrodynamics involved, and the intensity of mass transfer is limited by the constraints imposed by the underlying buoyancy or gravitational effects being exploited. Similar shortcomings are apparent in most of the laboratory equipment presently used for investigating extraction and biphasic reactions. In the present work, a new contactor concept, liquid−liquid slug flow in a capillary, is presented as an alternative to conventional equipment. Experiments were performed to investigate the effect of operating conditions on mass-transfer coefficients for different nonreacting systems. In addition, a flow splitter was developed for downstream separation of two liquid phases. The combination of this flow splitter with the capillary provides miniature mixer−settler modules, which can be networked in a wide variety of configurations. Finally, the results obtained were compared with the literature data, and it was determined that such a microextractor−reactor offers superior performance and greater efficiency, in comparison to conventional equipment for liquid−liquid extraction. The results also show that such equipment can be exploited to enhance mass-transfer- and heat-transfer-limited liquid-phase reactions.
Mechanism based chemotherapy for prostate cancer. (1991)

Estramustine offers a mechanistically novel therapy for the treatment of prostatic cancer. The drug is composed of oestradiol coupled to nor-nitrogen mustard. The cytotoxic properties of estramustine act independently of its constituent molecules. In vivo and in vitro studies indicate that the drug binds microtubule associated proteins and inhibits microtubule regulated processes. We have lately shown that micromolar levels of estramustine inhibit selected processes in mitosis, suggesting that certain classes of microtubules and/or MAPs are differentially sensitive to the drug. New clinical trials using estramustine and vinblastine on patients with advanced hormone refractory disease suggest that the combination of two antimicrotubule agents acting by means of different target molecules may be important clinically.
Phosphosulindac (OXT-328) Selectively Targets Breast Cancer Stem Cells In Vitro and in Human Breast Cancer Xenografts (2012)

Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p = .06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p < .05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling.
Over-Determined Source Separation and Localization Using Distributed Microphones (2016)

We propose an overdetermined source separation and localization method for a set of M microphones distributed around an unknown number, N <; M, of sources. We reformulate the overdetermined acoustic mixing procedure with a new determined mixing model and apply a determined M × M independent component analysis ('CA) in each frequency bin directly. The reformulated 'CA operates without knowing N and also leads to better separation in reverberant scenarios. To solve the challenging permutation ambiguity problem, we first employ a time activity-based clustering approach to cluster the separated frequency components into M channels. We then propose a remixing procedure to detect and merge channels from the same source. The detection is done by analyzing time and frequency activities, spectral likeliness, and spatial location. To estimate the spatial location, we propose a time-frequency masking-based steered response power algorithm. Simulated and real-data experiments in a very challenging reverberant scenario confirm the effectiveness of the proposed method in obtaining the number of sources, the separated signals, and the location and spatial likelihood of each source.
Regulation of lipid metabolism via angiopoietin-like proteins (2005)

Regulation of mammalian energy metabolism is an intricate process involving numerous hormones, transcription factors and signal transduction cascades. Much of the regulation occurs via secreted factors that relay information from one organ to another. One group of secreted factors that recently emerged as having a major impact on lipid and possibly glucose metabolism are the ANGPTLs (angiopoietin-like proteins). This includes ANGPTL3, ANGPTL4/FIAF (fasting-induced adipose factor), and ANGPTL6/AGF (angiopoietin-related growth factor). Although the receptors for these proteins have yet to be identified, it is nevertheless increasingly clear that these proteins have important effects on plasma triacylglycerol clearance, adipose tissue lipolysis, and adiposity. This review summarizes contemporary data on ANGPTLs with emphasis on the connection with energy metabolism.
VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet‐induced nonalcoholic steatohepatitis model in mice† (2008)

Nonalcoholic fatty liver disease (NAFLD) and its advanced stage, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease in the United States. NASH features the metabolic syndrome, inflammation, and fibrosis. Probiotics exhibit immunoregulatory and anti-inflammatory activity. We tested the hypothesis that probiotic VSL#3 may ameliorate the methionine-choline-deficient (MCD) diet-induced mouse model of NASH. MCD diet resulted in NASH in C57BL/6 mice compared to methionine-choline-supplemented (MCS) diet feeding evidenced by liver steatosis, increased triglycerides, inflammatory cell accumulation, increased tumor necrosis factor alpha levels, and fibrosis. VSL#3 failed to prevent MCD-induced liver steatosis or inflammation. MCD diet, even in the presence of VSL#3, induced up-regulation of serum endotoxin and expression of the Toll-like receptor 4 signaling components, including CD14 and MD2, MyD88 adaptor, and nuclear factor kappaB activation. In contrast, VSL#3 treatment ameliorated MCD diet-induced liver fibrosis resulting in diminished accumulation of collagen and alpha-smooth muscle actin. We identified increased expression of liver peroxisome proliferator-activated receptors and decreased expression of procollagen and matrix metalloproteinases in mice fed MCD+VSL#3 compared to MCD diet alone. MCD diet triggered up-regulation of transforming growth factor beta (TGFbeta), a known profibrotic agent. In the presence of VSL#3, the MCD diet-induced expression of TGFbeta was maintained; however, the expression of Bambi, a TGFbeta pseudoreceptor with negative regulatory function, was increased. In summary, our data indicate that VSL#3 modulates liver fibrosis but does not protect from inflammation and steatosis in NASH. The mechanisms of VSL#3-mediated protection from MCD diet-induced liver fibrosis likely include modulation of collagen expression and impaired TGFbeta signaling.
The Biochemistry and Physiology of Metallic Fluoride: Action, Mechanism, and Implications (2003)

Fluoride is a well-known G protein activator. Activation of heterotrimeric GTP-binding proteins by fluoride requires trace amounts of Al3+ or Be2+ ions. AlFx mimics a gamma-phosphate at its transition state in a Galpha protein and is therefore able to inhibit its GTPase activity. AlFx also forms complexes with small GTP-binding proteins in the presence of their GTPase-activating proteins (GAP). As phosphate analogs, AlFx or BeFx affect the activity of a variety of phosphoryl transfer enzymes. Most of these enzymes are fundamentally important in cell signal transduction or energy metabolism. Al3+ and F- tend to form stable complexes in aqueous solution. The exact structure and concentration of AlFx depend on the pH and the amount of F- and Al3+ in the solution. Humans are exposed to both F and Al. It is possible that Al-F complexes may be formed in vivo, or formed in vitro prior to their intake by humans. Al-F complexes may play physiological or pathological roles in bone biology, fluorosis, neurotoxicity, and oral diseases such as dental caries and periodontal disease. The aim of this review is to discuss the basic chemical, biochemical, and toxicological properties of metallic fluoride, to explore its potential physiological and clinical implications.
Molecular interactions between thyroid hormone analogs and the rat liver nuclear receptor. Partitioning of equilibrium binding free energy changes into substituent group interactions. (1980)

Chromatin-localized non-histone proteins, which may mediate the actions of thyroid hormones, are present in rat liver nuclei.A study of the binding affinities of ~-3,6-[3'-'~~1]triiodothyronine (['261]T,) and a series of thyroid hormone analogs to the solubilized nuclear receptor has provided information about the structural and stereochemical nature and magnitude of interactions in the hormone receptor complex.The receptor binding affinities of 67 thyroid hormone anaIogs were determined in a competitive binding assay with I'*'IJTS (& = 1.2 & 0.4 X loB "l).These results were used to calculate the free energy of binding (AGO)for each analog in order to determine, by first order partitioning of free energies, the nature and magnitude of specific substituent interactions with the receptor.The binding of ['"IJT3 to the solubilized receptor is associated with a change in free energy.AGO = -12.4(-t 0.2) kcal/mol.The individual substituent group contributions are: 1) The 4"hydroxyl participates in a donor hydrogen bond oriented toward the 6' side of the outer ring and adds -1.2 (2 0.2) kcal/mol of binding free energy.2) The 3' substituent participates in direct hydrophobic and van der Waals bonding with a size limit at isopropyl.The 3' substituent also enhances the strength of the 4'-hydroxyl interaction.The contribution to the binding free energy of a 3"iodine in TI is -4.1 (& 0.4) kcal/mol.3) The optimal 3,6 substituents are iodine atoms which can each contribute an average of -3.4 ( 2 0.7) kcal/mol.T h i s value contains the interactive effect on orientation of the outer ring, as well as the direct contribution to binding by the 3,S-iodine atoms and the aromatic rings.4) The alanine side chain probably participates in an electrostatic attraction between the carboxylate anion and a positively charged amino acid residue in the receptor but due to the presence of the a-ammonio group adds a negligible -0.2 (& 0.8) kcal/mol.The thyroid hormones show a wide variety of biological
Outer membrane porin protein of Campylobacter jejuni (1986)

Protein e, a 43-kDa protein from the outer membrane of Campylobacter jejuni UA580, was purified and reconstituted into lipid bilayer membranes. It was shown to form small channels with a single channel conductance of 8.82 nS in 1M KCl. Zero current potential measurements demonstrated that the channel was approx. 10-fold selective for K+ over Cl− ions. A porin with a similar single channel conductance was observed in fractions from the outer membrane of Campylobacter fetus UA60.
Pubertal development among girls with classical congenital adrenal hyperplasia initiated on treatment at different ages (2012)

There was a delay in HPO axis maturation (as evidenced by delayed pubertal development) in the absence of treatment in girls with CAH. This could be corrected with steroid supplementation.
Production of sterile transcripts of Cγ genes in an IgM-producing human neoplastic B cell line that switches to IgG-producing cells (1989)

A human neoplastic B cell line SSK41 that expresses IgM on its surface switches spontaneously to IgG-producing cells. The SSK41 line contains a single immunoglobulin heavy-chain locus, the constant region (C) genes of which retain the germline configuration. The IgG-producing SSK41 line was purified by sorting, and shown to have undergone S-S recombination with deletion of the C mu gene. This line produced secretory and membrane-bound forms of gamma-chain mRNA. From cDNA libraries of a mixed population of IgM+/IgG+ SSK41 cells, we have isolated cDNA clones encoding the mature membrane-bound and secretory forms of the mu and gamma 1 heavy chains, all of which share the same variable region sequence. cDNA clones containing the mature gamma 3 chain were identified as well. We also isolated cDNA clones containing C gamma 1 and C gamma 3 sterile transcripts from the SSK41 line. These sterile transcripts contained additional exon sequences designated 'I' which were localized upstream of the C gamma 1 and C gamma 3 switch regions and homologous to murine counterparts. The I sequences were precisely spliced to the 5' ends of the corresponding C gamma exon sequences. These features of germline CH transcripts, i.e. the isotype specificity to class switching, location of exons, and sequences per se, are highly conserved between man and mouse.
Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes (2003)

A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.
Quantitative RT-PCR: Pitfalls and Potential (1999)

Reverse transcription PCR (RT-PCR) represents a sensitive and powerful tool for analyzing RNA. While it has tremendous potential for quantitative applications, a comprehensive knowledge of its technical aspects is required. Successful quantitative RT-PCR involves correction for experimental variations in individual RT and PCR efficiencies. This review addresses the mathematics of RT-PCR, choice of RNA standards (internal vs. external) and quantification strategies (competitive, noncompetitive and kinetic [real-time] amplification). Finally, the discussion turns to practical considerations in experimental design. It is hoped that this review will be appropriate for those undertaking these experiments for the first time or wishing to improve (or validate) a technique in what is frequently a confusing and contradictory field.
Is Panton‐Valentine Leukocidin the Major Virulence Determinant in Community‐Associated Methicillin‐Resistant Staphylococcus aureus Disease? (2006)

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiological studies to community-associated MRSA (CA-MRSA) disease. However, the role that PVL plays in the pathogenesis of CA-MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL-positive with that of PVL-negative CA-MRSA representing the leading disease-causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL-negative (lukS/F-PV knockout) strains of USA300 and USA400 were as lethal as wild-type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild-type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA-MRSA strains, we conclude that PVL is not the major virulence determinant of CA-MRSA.
CapE, a 47-Amino-Acid Peptide, Is Necessary for Bacillus anthracis Polyglutamate Capsule Synthesis (2005)

Polyglutamate is found in various bacteria, but displays different functions depending on the species and their environment. Here, we describe a minimal polyglutamate synthesis system in Bacillus anthracis. In addition to the three genes previously described as sufficient for polyglutamate synthesis, this system includes a small open reading frame, capE, belonging to the cap operon. The polyglutamate system's requirement for the five cap genes, for capsulation and anchoring, was assayed in nonpolar mutants. The capA, capB, capC, and capE genes are all necessary and are sufficient for polyglutamate synthesis by B. anthracis. capD is required for polyglutamate anchoring to the peptidoglycan. The 47-amino-acid peptide encoded by capE is localized in the B. anthracis membrane. It is not a regulator and it is required for polyglutamate synthesis, suggesting that it has a structural role in polyglutamate synthesis. CapE appears to interact with CapA. Bacillus subtilis ywtC is similar to capE and we named it pgsE. Genes similar to capE or pgsE were found in B. subtilis natto, Bacillus licheniformis, and Staphylococcus epidermidis, species that produce polyglutamate. All the bacterial polyglutamate synthesis systems analyzed show a similar genetic organization and, we suggest, the same protein requirements.