gebhart/patrepeval huggingface dataset:
Bisphosphonates: Preclinical Review (2004)

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.
Endophytic fungi alter sucking bug responses to cotton reproductive structures (2017)

All plants including cotton host a wide range of microorganisms as endophytes. There is a growing appreciation of the prevalence, ecological significance and management potential of facultative fungal endophytes in protecting plants from pests, pathogens and environmental stressors. Hemipteran sucking bugs have emerged as major pests across the U.S. cotton belt, reducing yields directly by feeding on developing reproductive structures and indirectly by vectoring plant pathogens. We used no-choice and simultaneous choice assays to examine the host selection behavior of western tarnished plant bugs (Lygus hesperus) and southern green stink bugs (Nezara viridula) in response to developing flower buds and fruits from cotton plants colonized by 1 of 2 candidate beneficial fungal endophytes, Phialemonium inflatum or Beauveria bassiana. Both insect species exhibited strong negative responses to flower buds (L. hesperus) and fruits (N. viridula) from plants that had been colonized by candidate endophytic fungi relative to control plants under both no-choice and choice conditions. Behavioral responses of both species indicated that the insects were deterred prior to contact with plant tissues from endophyte-colonized plants, suggesting a putative role for volatile compounds in mediating the negative response. Our results highlight the role of fungal endophytes as plant mutualists that can have positive effects on plant resistance to pests.
EXPRESSION OF ADHESION MOLECULES IN ALLOGRAFT RENAL DYSFUNCTION (1993)

MAMPASO, FRANCISCO; SANCHEZ-MADRID, FRANCISCO; MARCEN, ROBERTO; MOLINA, ANA; PASCUAL, JULIO; BRICIO, TERESA; MARTIN, ANA; ALVAREZ, VINCENTE Author Information
Two pairs of oppositely charged amino acids from Jun and Fos confer heterodimerization to GCN4 leucine zipper. (1994)

The preferential assembly of Jun and Fos into heterodimers has been shown to be mainly driven by 16 amino acids (8 from each protein) situated in positions e and g of the leucine zipper coiled-coil structures of the two proteins (O'Shea, E. K., Rutkowski, R., and Kim, P. S. (1992) Cell 68, 699-708). Using a similar approach, we show that among these residues two pairs of oppositely charged amino acids account in fact for most of the additional free energy of heterodimerization in this system. These residues are 2 glutamic acid side chains in positions g1 and e2 of the Fos leucine zipper and 2 lysine residues in the equivalent positions of the Jun zipper. These amino acids were placed in the context of a GCN4 leucine zipper using peptide synthesis. These peptides contain unique cysteine residues enabling the formation of covalent dimers. The gain in heterodimer free energy has been determined both by cysteine-linked dimer formation under redox conditions and by thermal melting experiments of covalent dimers using circular dichroism experiments. The two pairs of oppositely charged residues (Glu,Glu and Lys,Lys) in positions g1 and e2 contribute at least -1.9 kcal/mol of additional free energy, accounting for a 50-fold excess of the heterodimer with respect to one of the homodimers. Thermal denaturation studies as a function of pH and ionic strength suggest that electrostatic effects should indeed be a major driving force for heterodimerization. On the contrary, peptides harboring the 12 amino acids from Jun and Fos in the other e and g positions (i.e. in e1, g2, e3, g3, e4, and g4) show only a moderate tendency to form heterodimers.
Omega-3 Eicosapentaenoic Acid in Bipolar Depression (2005)

Although the ultimate utility of omega-3 fatty acids in bipolar depression is still an open question, we believe that these initial results are encouraging, especially for mild to moderate bipolar depression, and justify the continuing exploration of its use.
Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock (2002)

Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-kappaB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.
EMOTIONAL AND NON-EMOTIONAL PERSUASION (2006)

The paper presents a model of persuasion in general and o the cases and types of persuasion that make an appeal to emotion, by making reference to relations between emotions and goals. Some persuasion strategies are described and formalized in terms of oriented graphs, while showing how emotional and non emotional strategies may interact, and strengthen each other. The role of uncertainty in persuasion strategies is also addressed. -
The Data Warehouse Toolkit: The Complete Guide to Dimensional Modeling (1996)

From the Publisher:
The latest edition of the single most authoritative guide on dimensional modeling for data warehousing!
Dimensional modeling has become the most widely accepted approach for data warehouse design. Here is a complete library of dimensional modeling techniques the most comprehensive collection ever written. Greatly expanded to cover both basic and advanced techniques for optimizing data warehouse design, this second edition to Ralph Kimballs classic guide is more than sixty percent updated. 
The authors begin with fundamental design recommendations and gradually progress step-by-step through increasingly complex scenarios. Clear-cut guidelines for designing dimensional models are illustrated using real-world data warehouse case studies drawn from a variety of business application areas and industries, including:

Retail sales and e-commerce 
Inventory management 
Procurement
Order management
Customer relationship management (CRM)
Human resources management
Accounting
Financial services
Telecommunications and utilities
Education
Transportation
Health care and insurance


By the end of the book, you will have mastered the full range of powerful techniques for designing dimensional databases that are easy to understand and provide fast query response. You will also learn how to create an architected framework that integrates the distributed data warehouse using standardized dimensions and facts. 
Author Biography: Ralph KimbalL, PhD, has been a leading visionary in the data warehouse industry since 1982 and is one of todays most well- known speakers, consultants, and teachers. He writes the Warehouse Designer column for Intelligent Enterprise magazine and is also the author of the bestselling books The Data Warehouse Lifecycle Toolkit and The Data Webhouse Toolkit (both from Wiley).
Margy Ross is President of DecisionWorks Consulting and a Ralph Kimball Associate. She has focused exclusively on decision support and data warehousing since 1982. Margy coauthored the highly acclaimed The Data Warehouse Lifecycle Toolkit, consults on data warehouse projects worldwide, and teaches data warehouse design for Kimball University.
Effective strategies to reduce commercial tobacco use in Indigenous communities globally: A systematic review (2015)

The extent of this research in Indigenous communities globally suggests a growing prioritization and readiness to address the high rates of commercial tobacco use through the use of both comprehensive and tailored interventions. A comprehensive approach that uses multiple activities, the centring of Aboriginal leadership, long term community investments, and the provision of culturally appropriate health materials and activities appear to have an important influence in producing desired change.
Repression of Beta Interferon Gene Expression in Virus-Infected Cells Is Correlated with a Poly(A) Tail Elongation (1996)

Expression of beta interferon (IFN-beta) is transiently induced when Namalwa B cells (Burkitt lymphoma cell line) are infected by Sendai virus. In this study, we found that an elongation of the IFN-beta mRNA could be detected in virus-infected cells and that such a modification was not observed when the IFN-beta transcript was induced by a nonviral agent, poly(I-C). Treatment of the cells with a transcriptional inhibitor (actinomycin D or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) resulted in further elongation of the transcript. Characterization of the elongated IFN-beta transcript by primer extension and RNase H treatment showed that the modification was a result of an elongated poly(A) tail of up to 400 nucleotides. We conclude that the poly(A) tail elongation of the IFN-beta transcript is associated with the viral infection. Furthermore, the presence of the elongated IFN-beta transcript correlated with a decrease of IFN-beta protein in the medium and in cell extracts. Sucrose gradient analysis of cytoplasmic extracts showed that IFN-beta transcripts with elongated poly(A) tails were found in the nonpolysomal fractions, whereas the shorter transcripts could be detected in both polysomal and nonpolysomal fractions. A longer form of the IFN-beta mRNA was also found in the nonpolysomal fractions of cells not treated with transcriptional inhibitors. Thus, the observed regulation of IFN-beta mRNA is not entirely dependent on the inhibition of transcription. To our knowledge, this study provides the first example of a poly(A) tail elongation in somatic cells that negatively influences gene expression in vivo.
Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. (1992)

The effect of endogenous glucocorticoids on the expression of the cyclooxygenase enzyme was studied by contrasting cyclooxygenase expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice with or without the concurrent administration of endotoxin. Peritoneal macrophages obtained from adrenalectomized mice showed a 2- to 3-fold induction in cyclooxygenase synthesis and activity when compared to sham controls. Intravenous injection of a sublethal dose of endotoxin (5 micrograms/kg) further stimulated cyclooxygenase synthesis, resulting in a 4-fold increase in prostaglandin production. Similar cyclooxygenase induction can be achieved in macrophages obtained from normal mice but only after high doses of endotoxin (2.5 mg/kg) that are 100% lethal to adrenalectomized mice. Restoration of glucocorticoids in adrenalectomized animals with dexamethasone completely inhibited the elevated cyclooxygenase and protected these animals from endotoxin-induced death. In contrast, no signs of cyclooxygenase induction were observed in the kidneys of the adrenalectomized mice, even when treated with endotoxin. Dexamethasone did not affect the constitutive cyclooxygenase activity and prostaglandin production present in normal and adrenalectomized kidneys. These data indicate the existence of a constitutive cyclooxygenase that is normally present in most cells and tissues and is unaffected by steroids and of an inducible cyclooxygenase that is expressed only in the context of inflammation by proinflammatory cells, like macrophages, and that is under glucocorticoid regulation. Under normal physiological conditions glucocorticoids maintain tonic inhibition of inducible cyclooxygenase expression. Depletion of glucocorticoids or the presence of an inflammatory stimulus such as endotoxin causes rapid induction of this enzyme, resulting in an exacerbated inflammatory response that is often lethal.
Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin (2015)

Murine NLR family, apoptosis inhibitory protein (Naip)1, Naip2, and Naip5/6 are host sensors that detect the cytosolic presence of needle and rod proteins from bacterial type III secretion systems and flagellin, respectively. Previous studies using human-derived macrophage-like cell lines indicate that human macrophages sense the cytosolic needle protein, but not bacterial flagellin. In this study, we show that primary human macrophages readily sense cytosolic flagellin. Infection of primary human macrophages with Salmonella elicits robust cell death and IL-1β secretion that is dependent on flagellin. We show that flagellin detection requires a full-length isoform of human Naip. This full-length Naip isoform is robustly expressed in primary macrophages from healthy human donors, but it is drastically reduced in monocytic tumor cells, THP-1, and U937, rendering them insensitive to cytosolic flagellin. However, ectopic expression of full-length Naip rescues the ability of U937 cells to sense flagellin. In conclusion, human Naip functions to activate the inflammasome in response to flagellin, similar to murine Naip5/6.
Alphavirus-Based Vaccines in Melanoma: Rationale and Potential Improvements in Immunotherapeutic Combinations (2015)

Immune checkpoint blockade has formally demonstrated the clinical benefit of immunotherapy against melanoma. New immunotherapeutic modalities are currently explored to improve the management of relapsing/refractory patients. Potent antitumor vaccines would have the advantage to promote long-lasting tumor control while limiting autoimmunity. Alphavirus vectors and nonreplicating particles offer versatile platforms to deliver antigen expression and immunize against cancer. They have shown promising preclinical results and initial proof of clinical activity in melanoma. The growing number of clinically available immunomodulatory agents provides a tremendous opportunity to exploit and revisit anticancer vaccines in the setting of powerful immunotherapeutic combinations. Accelerating the evaluation of alphavirus-based vaccines in patients with immune sensitive, but still very deadly malignancies, such as melanoma, is thus extremely important.
Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Stimulated by Hypoxia Promote Angiogenesis Both In Vitro and In Vivo (2012)

Although mesenchymal stem cells (MSCs) have been increasingly trialed to treat a variety of diseases, the underlying mechanisms remain still elusive. In this study, human umbilical cord (UC)-derived MSCs were stimulated by hypoxia, and the membrane microvesicles (MVs) in the supernatants were collected by ultracentrifugation, observed under an electron microscope, and the origin was identified with the flow cytometric technique. The results showed that upon hypoxic stimulus, MSCs released a large quantity of MVs of ~100 nm in diameter. The MVs were phenotypically similar to the parent MSCs, except that the majority of them were negative for the receptor of platelet-derived growth factor. DiI-labeling assay revealed that MSC-MVs could be internalized into human UC endothelial cells (UC-ECs) within 8 h after they were added into the culture medium. Carboxyfluorescein succinimidyl ester-labeling technique and MTT test showed that MSC-MVs promoted the proliferation of UC-ECs in a dose-dependent manner. Further, MVs could enhance in vitro capillary network formation of UC-ECs in a Matrigel matrix. In a rat hindlimb ischemia model, both MSCs and MSC-MVs were shown to improve significantly the blood flow recovery compared with the control medium (P<0.0001), as assessed by laser Doppler imaging analysis. These data indicate that MV releasing is one of the major mechanisms underlying the effectiveness of MSC therapy by promoting angiogenesis.
Characterization of the stimulatory action of insulin on insulin-like growth factor II binding to rat adipose cells. Differences in the mechanism of insulin action on insulin-like growth factor II receptors and glucose transporters. (1988)

Insulin is known to increase the number of cell surface insulin-like growth factor II (IGF-II) receptors in isolated rat adipose cells through a subcellular redistribution mechanism similar to that for the glucose transporter. The effects of insulin on these two processes, therefore, have now been directly compared in the same cell preparations. 1) Insulin increases the steady state number of cell surface IGF-II receptors by 7-13-fold without affecting receptor affinity; however, insulin stimulates glucose transport activity by 25-40-fold. 2) The insulin concentration required for half-maximal stimulation of cell surface IGF-II receptor number is approximately 30% lower than that for the stimulation of glucose transport activity. 3) The half-time for the achievement of insulin's maximal effect at 37 degrees C is much shorter for IGF-II receptor number (approximately 0.8 min) than for glucose transport activity (approximately 2.6 min). 4) Reversal of insulin's action at 37 degrees C occurs more rapidly for cell surface IGF-II receptors (t1/2 congruent to 2.9 min) than for glucose transport activity (t1/2 congruent to 4.9 min). 5) When the relative subcellular distribution of IGF-II receptors is examined in basal cells, less than 10% of the receptors are localized to the plasma membrane fraction indicating that most of the receptors, like glucose transporters, are localized to an intracellular compartment. However, in response to insulin, the number of plasma membrane IGF-II receptors increases only approximately 1.4-fold while the number of glucose transporters increases approximately 4.5-fold. Thus, while the stimulatory actions of insulin on cell surface IGF-II receptors and glucose transport activity are qualitatively similar, marked quantitative differences suggest that the subcellular cycling of these two integral membrane proteins occurs by distinct processes.
Structural and functional insights into human Tudor-SN, a key component linking RNA interference and editing (2008)

Human Tudor-SN is involved in the degradation of hyper-edited inosine-containing microRNA precursors, thus linking the pathways of RNA interference and editing. Tudor-SN contains four tandem repeats of staphylococcal nuclease-like domains (SN1-SN4) followed by a tudor and C-terminal SN domain (SN5). Here, we showed that Tudor-SN requires tandem repeats of SN domains for its RNA binding and cleavage activity. The crystal structure of a 64-kD truncated form of human Tudor-SN further shows that the four domains, SN3, SN4, tudor and SN5, assemble into a crescent-shaped structure. A concave basic surface formed jointly by SN3 and SN4 domains is likely involved in RNA binding, where citrate ions are bound at the putative RNase active sites. Additional modeling studies provide a structural basis for Tudor-SN's preference in cleaving RNA containing multiple I.U wobble-paired sequences. Collectively, these results suggest that tandem repeats of SN domains in Tudor-SN function as a clamp to capture RNA substrates.
The human umbilical cord: A novel substitute for reconstruction of the extrahepatic bile duct (2012)

Reconstruction of the extrahepatic bile duct following bile duct injury or defect is one of the most common challenges for hepatobiliary surgeons. There are currently a number of surgical strategies such as biliary-enteric anastomosis, end-to-end anastomosis and autologous tissue substitute. However, sphincter of Oddi dysfunction as well as biliary stricture may occur after surgical anastomosis. Also, insufficient tissue quantity remains a problem associated with the application of tissue substitute. Therefore, considerable attention has been attracted to explore a new replacement material of the bile duct for biliary reconstruction. The human umbilical cord (HUC) is abundant in resource and is convenient to collect, including two arteries and one vein, whose diameters are close to that of the common bile duct. In order to reduce immunogenicity (foreign-body reaction), cells and major histocompatibility complex (MHC) antigens can be removed from the HUC and the remaining tissue (extracellular matrix, ECM) can be used as a scaffold. The HUC provides a rich source of mesenchymal stem cells (MSCs). A current study has demonstrated that MSCs are able to differentiate into biliary epithelial cells in vivo and in vitro with low immunogenicity, which can be used as seed cells. The HUC might be a promising composite material of a scaffold (ECM) and seed cells (biliary epithelial cells), for bile duct replacement in situ without removal of sphincter of Oddi, or biliary stricture. In addition, the patients’ own umbilical cord without any foreign-body reaction can be directly banked for possible future use in bile duct reconstruction. Therefore, we hypothesise that the HUC may be a novel substitute for reconstruction of the extrahepatic bile duct.