gebhart/patrepeval huggingface dataset:
Differential Allosteric Regulation of Prostaglandin H Synthase 1 and 2 by Arachidonic Acid (1997)

Prostaglandins are synthesized by prostaglandin H synthase (PGHS) 1 and 2. PGHS2 is regulated through inducible expression. We report here the regulation of PGHS1 activity by substrate-dependent cooperative activation. The cooperativity is characterized by a Hill coefficient of 1.29 +/- 0.06, a curved Eadie-Scatchard plot, and activation by low concentrations of competitive inhibitors. The activation also appears to induce a conformational change in the cyclooxygenase site. The cooperativity produces a 2-4-fold greater rate of PGHS2-dependent prostaglandin formation compared with PGHS1-dependent prostaglandin formation at arachidonic acid concentrations below 0.5 microM. A consequence of the PGHS1 cooperativity is that the affinity of many cyclooxygenase inhibitors for PGHS1 decreases in parallel to the activation by arachidonic acid. In contrast, the affinity of these inhibitors for PGHS2 is unaffected by the changes in arachidonic acid concentration. This results in a dramatic difference in PGHS2/PGHS1 selectivity at different arachidonic acid concentrations.
Human Natural Killer T Cells Are Heterogeneous in Their Capacity to Reprogram Their Effector Functions (2006)

Together, these results suggest that neonatal CD4+, adult CD4+, and adult CD4- NKT may represent unique states of maturation and that some functions of human NKT cells may be developmentally imprinted, while others are acquired similar to conventional T cell subsets during peripheral maturation and differentiation. Given the potent immuno-regulatory functions of NKT cells, these findings have important implications for the development of novel NKT cell-based therapeutics and vaccines.
Application of 3D tumoroid systems to define immune and cytotoxic therapeutic responses based on tumoroid and tissue slice culture molecular signatures (2017)

We have developed 3D-tumoroids and tumor slice <i>in vitro</i> culture systems from surgical tumor specimens derived from patients with colorectal cancer (CRC) or lung cancer to evaluate immune cell populations infiltrating cultured tissues. The system incorporates patient's peripherally and tumor-derived immune cells into tumoroid <i>in vitro</i> cultures to evaluate the ability of the culture to mimic an immunosuppressive tumor microenvironment (ITM). This system enables analysis of tumor response to standard therapy within weeks of surgical resection. Here we show that tumoroid cultures from a CRC patient are highly sensitive to the thymidylate synthase inhibitor 5-fluorouracil (adrucil) but less sensitive to the combination of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (Lonsurf). Moreover, re-introduction of isolated immune cells derived from surrounding and infiltrating tumor tissue as well as CD45+ tumor infiltrating hematopoietic cells displayed prolonged (>10 days) survival in co-culture. Established tumor slice cultures were found to contain both an outer epithelial and inner stromal cell compartment mimicking tumor structure <i>in vivo</i>. Collectively, these data suggest that, 3D-tumoroid and slice culture assays may provide a feasible <i>in vitro</i> approach to assess efficacy of novel therapeutics in the context of heterogeneous tumor-associated cell types including immune and non-transformed stromal cells. In addition, delineating the impact of therapeutics on immune cells, and cell types involved in therapeutic resistance mechanisms may be possible in general or for patient-specific responses.
Introduzione: perché raccontare la storia della relatività generale? (2016)

European Union’s Horizon 2020 research and innovation programme, under the Marie Skłodowska-Curie grant agreement n. 656139
Spin Hall Effect (1999)

It is proposed that when a charge current circulates in a paramagnetic metal a transverse spin imbalance will be generated, giving rise to a ``spin Hall voltage.'' Similarly, it is proposed that when a spin current circulates a transverse charge imbalance will be generated, giving rise to a Hall voltage, in the absence of charge current and magnetic field. Based on these principles we propose an experiment to generate and detect a spin current in a paramagnetic metal.
Protective and Destructive Innate Immune Responses to Enteropathogenic Escherichia Coli and Related A/E Pathogens (2008)

Enteropathogenic Escherichia coli, enterohemorrhagic E. coli (O157:H7) and Citrobacter rodentium are classified as attaching and effacing (A/E) pathogens based on their ability to adhere to intestinal epithelium, destroy microvilli and induce pedestal formation at the site of infection. A/E bacterial infections also cause acute diarrheal episodes and intestinal inflammation. The use of model systems has led to an understanding of the innate immune response to A/E pathogens. The innate immune system plays a protective role, initiating a productive antibody response, directly killing bacteria and inducing repair mechanisms following tissue damage caused by infection. However, hyperactivation of the innate immune system can have negative consequences, including exacerbated tissue destruction following neutrophil infiltration. Here we review how innate immune cell types, including neutrophils, macrophages and dendritic cells, orchestrate both protective and destructive responses. Such information is crucial for the development of therapeutics that can mitigate destructive inflammatory responses while accentuating those that are protective.
Preparation of Macromolecule-Containing Dry Powders for Pulmonary Delivery (2008)

Drug delivery by inhalation is routine for the treatment of local pulmonary conditions like asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Only recently, though, has the inhalation route been considered for administering drugs for systemic diseases. The pulmonary route is attractive for several reasons. It is non-invasive, it avoids first-pass metabolism, and it allows drug absorption from a large, highly vascularized surface area. However, consistent delivery to the deep lung requires drug particles within a very narrow size range. Several particle engineering approaches have been used to produce dry powders that will reach the alveolar space. Some of these methods, such as spray drying from solution, the formation of drug-containing liposomes, and the controlled crystallization of particles, are described here.
Biochemical engineering and biotechnology handbook (1992)

Part One Properties of industrially important microorganisms: general classification of microorganisms macrocomposition of microorganisms examples of substances produced by microbial activity. Part Two Thermodynamic aspects of microbial metabolism: flow of energy in the biological world classification ofmicroorganisms by their carbon and energy sources cycling of matter in the biological world thermodynamic concepts in the analysis of biological systems. Part Three Stoichiometric aspects of microbial metabolism: importance of yield and yield coefficients relationship between amount of growth and substrate utilization composition of various microorganisms material balances for growth and product formation (stoichiometry). Part Four Microbial activity: monod equation time course of fermentation substrate utilization and nutrient requirements effect of oxygen on metabolism and stoichiometry. Part Five Product information: acetone butanol amino acids antibiotics butanediol/acetoin. Part Six Enzyme activity: nomenclature and classification general characteristics enzyme properties uses sources immobilized enzymes. Part Seven Reactors: design methodology batch reactors tinuous reactors containing freely suspended biomass. Part Eight Flow behaviour of fermentation fluids. Part Nine Gas-liquid mass transfer: solubility data experimental determination of dissolved oxygen concentrations stirred tanks. Part Ten Solid and liquid-phase mass transfer: nature of diffusional limitations biological rate equation lineweaver-burk plot of the biological rate equation. Part Eleven Heat transfer: importance of heat effects in biochemical processes general energy balance equation experimental determination of heat evolution during microbial reaction. Part Twelve Downstream process engineering: downstream processing problems broth processing product isolation. Part Thirteen Product recovery processes and unit operations: broth handling stages product recovery stages examples of innovation. Part Fourteen Processes: acetone butanol antibiotics carotenoids.
Meta-analysis on the association between environmental tobacco smoke (ETS) exposure and the prevalence of lower respiratory tract infection in early childhood (1999)

The aim of this study was to obtain quantitative information from published data on the association between environmental tobacco smoke (ETS) exposure and the prevalence of serious lower respiratory tract infections (LRTI) in infancy and early childhood. We identified 21 relevant publications on the relation between ETS and the prevalence of serious LRTI by reviewing reference lists in relevant reports and by conducting manual and computer searches (Medline database; Dissertation abstracts index of Xerox University Microfilms) of published reports between 1966 and 1995. Thirteen studies were included in a quantitative overview using random effects modeling to derive pooled odds ratios. Sensitivity analyses were conducted to test the decision rules used in extracting odds ratio data. The results of community and hospital studies are broadly consistent and show that the child of a parent who smokes is at approximately twice the risk of having a serious respiratory tract infection in early life that requires hospitalization. This association was pronounced in children younger than age two and diminished after the age of two. The combined odds ratio for hospitalization for lower respiratory tract infections in infancy or early childhood is 1.93 (95% CI 1.66-2.25); the combined odds ratio of prevalence of serious LRTI at age less than 2 years, between 0 and 6 years, and between 3 and 6 years were 1.71 (95% CI 1.33-2.20); 1.57 (1.28-1.91), and 1.25 (0.88-1.78), respectively. There was no evidence of heterogeneity across the studies in these combined odds ratios. We conclude that this meta-analysis provides strong evidence that exposure to ETS causes adverse respiratory health outcomes such as either a serious LRTI or hospitalization for LRTI. New public health campaigns are urgently needed to discourage smoking in the presence of young children.
Sagittal suture as an external landmark for the superior sagittal sinus (2001)

This information should be useful to the neurosurgeon who must be aware of the SSS and its relationship with superficial skull landmarks.
Optical stability of gossypol (1992)

Abstract The optical stability of gossypol [1,1',6,6',7,7'‐hexahydroxy‐3,3'‐dimetyl‐5,5'‐bis(1‐methylethyl)‐2,2'‐binaphthalene‐8,8'‐dicarboxaldehyde], a natural product exhibiting profoundly enantiospecific antitumor and male antifertility action, was investigated by means of computational methods and thermal racemization experiments. The calculations on gossypol and several derivatives and model compounds were carried out using the MM2 force field; energies and geometries of minimum energy conformations, as well as structures along various inversion pathways, were calculated. According to the calculations, gossypol (the dialdehyde form) and its simple analogues are not thermally racemizable (energy barriers for rotational inversion above 50 kcal/mol). By contrast, the calculations suggest that the acetal tautomer of gossypol and its dehydration product (anhydrogossypol) are thermally racemizable, although the energy barriers are still relatively high (35–40 kcal/mol). Optically pure (+)‐anhydrogossypol was prepared and characterized; its racemization became rapid only at high temperatures (180–200°C). When dehydration of gossypol was hindered (in aqueous solution), no racemization of gossypol was observed after prolonged heating at 90°C. © 1992 Wiley‐Liss, Inc.
Traumatic Endotheliopathy (2016)

We confirmed that sympathoadrenal activation was strongly and independently associated with endothelial glycocalyx and cell damage (ie, endotheliopathy) and furthermore that sympathoadrenal activation and endotheliopathy were independent predictors of mortality in trauma patients.
Brain site-specific proteome changes in aging-related dementia (2013)

This study is aimed at gaining insights into the brain site-specific proteomic senescence signature while comparing physiologically aged brains with aging-related dementia brains (for example, Alzheimer's disease (AD)). Our study of proteomic differences within the hippocampus (Hp), parietal cortex (pCx) and cerebellum (Cb) could provide conceptual insights into the molecular mechanisms involved in aging-related neurodegeneration. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-LC-MS/MS) brain site-specific proteomic strategy, we identified 950 proteins in the Hp, pCx and Cb of AD brains. Of these proteins, 31 were significantly altered. Most of the differentially regulated proteins are involved in molecular transport, nervous system development, synaptic plasticity and apoptosis. Particularly, proteins such as Gelsolin (GSN), Tenascin-R (TNR) and AHNAK could potentially act as novel biomarkers of aging-related neurodegeneration. Importantly, our Ingenuity Pathway Analysis (IPA)-based network analysis further revealed ubiquitin C (UBC) as a pivotal protein to interact with diverse AD-associated pathophysiological molecular factors and suggests the reduced ubiquitin proteasome degradation system (UPS) as one of the causative factors of AD.
A hybrid number system processor with geometric and complex arithmetic capabilities (1991)

The architecture, design, and performance of a hybrid number system processor are described. The processor performs multiplication, division, square root, and square in the logarithmic number system (LNS) domain. However, the input, output, addition, and subtraction are all executed in the 32-b IEEE standard floating-point number system. With the LNS multiplier and pipelined architecture, the processor is able to perform the geometric and complex arithmetic very effectively. The processor is also shown to compare well to an existing 32-b floating-point DSP (digital signal processor) chip. For the same level of CMOS technology, the performance ratios between the hybrid number system and the floating-point processor are shown to be 6.4:1 and 8:1 for division and square root, respectively; for the complex FFT (fast Fourier transform) algorithm, the ratio is around 2:1.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Assessment of K‐ras mutation (2009)

Some of the most significant therapeutic advances in the treatment of cancer have occurred in the management of colorectal metastases. The introduction of new cytotoxic chemotherapeutic and biologic agents has changed the approach to these patients from both an oncologic and a surgical perspective. In addition, an understanding of the molecular mechanisms by which these agents affect tumors is developing. This molecular information will be critical in the future in designing therapeutic regimens based on an individual tumor's genetic profile rather than treatment for a specific tumor type. The rapidly evolving treatment of colon cancer has provided several interesting genetic biomarkers/pathways/genes-/kinases that have been targeted or seem to play an important role. Of particular interest is the blockade of epidermal growth factor receptor (EGFR) with monoclonal antibodies. This treatment is efficacious when used alone or combined with chemotherapy. However, recent data revealed that patients with tumors positive for the K-ras mutation do not benefit from EGFR blockade. Compelling evidence has indicated that mutated K-ras is an important oncogene involved at the early stage of the development of colorectal cancer. Furthermore, mutations in the K-ras gene have been associated with aggressive tumor biology. K-ras mutational analysis is an important step in the overarching goal of developing personalized medicine. New treatment strategies are needed to more effectively treat patients with the K-ras mutation.
Control of dendritic development by theDrosophila fragile X-relatedgene involves the small GTPase Rac1 (2003)

Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 gene. How these mutations affect neuronal development and function remains largely elusive. We generated specific point mutations or small deletions in the Drosophila fragile X-related (Fmr1) gene and examined the roles of Fmr1 in dendritic development of dendritic arborization (DA) neurons in Drosophila larvae. We found that Fmr1 could be detected in the cell bodies and proximal dendrites of DA neurons and that Fmr1 loss-of-function mutations increased the number of higher-order dendritic branches. Conversely, overexpression of Fmr1 in DA neurons dramatically decreased dendritic branching. In dissecting the mechanisms underlying Fmr1 function in dendrite development, we found that the mRNA encoding small GTPase Rac1 was present in the Fmr1-messenger ribonucleoprotein complexes in vivo. Mosaic analysis with a repressor cell marker (MARCM) and overexpression studies revealed that Rac1 has a cell-autonomous function in promoting dendritic branching of DA neurons. Furthermore, Fmr1 and Rac1 genetically interact with each other in controlling the formation of fine dendritic branches. These findings demonstrate that Fmr1 affects dendritic development and that Rac1 is partially responsible for mediating this effect.
Enzymatic Method for the Synthesis of Blockbuster Drug Intermediates – Synthesis of Five‐Membered Cyclic γ‐Amino Acid and γ‐Lactam Enantiomers (2008)

Abstract A very efficient enzymatic method was developed for the synthesis of cyclic γ‐lactam and γ‐amino acid enantiomers, intermediates for drugs with a prominent turnover (e.g., abacavir and carbovir), through the CAL‐B‐catalysed enantioselective ( E &gt; 200) hydrolysis of the corresponding N ‐Boc protected and unprotected racemic γ‐lactams with H 2 O in i Pr 2 O. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2008)
Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL (2014)

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental factors for proliferation and survival. In particular, tissue-resident CLL cells show prominent activation of both B-cell receptor (BCR) and NF-κB pathways. We evaluated the in vivo effects of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor on tumor cell activation and proliferation in the blood, lymph node, and bone marrow of patients with CLL. Applying validated pathway-specific gene signatures, we detected a rapid and sustained downregulation of BCR and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment. Ibrutinib reduced phosphorylation of PLCγ2 and ERK and decreased nuclear protein expression of NF-κB p50. Ibrutinib significantly decreased tumor proliferation and expression of surface activation markers CD69 and CD86, independent of prognostic factors such as IGHV mutational status, chromosome 17p deletion, or prior treatment history. Interestingly, stronger inhibition of BCR signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2. Together, these data validate on-target effects of BTK inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo. This study is registered at www.clinicaltrials.gov as #NCT01500733.
Essential role for the p110 isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia (2005)

The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been shown to be frequently activated in blast cells from patients with acute myeloid leukemia (AML) and to contribute to survival and proliferation of these cells. Of the 8 distinct mammalian isoforms of PI3K, it is the class I PI3Ks (p110alpha, p110beta, p110gamma, and p110delta) that are responsible for Akt activation. It is not known which PI3K isoform is critical in AML. Here we show that the p110delta isoform of PI3K is consistently expressed at a high level in blast cells from AML, in contrast to the other class I isoforms, the expression of which was very variable among patients. IC87114, a p110delta-selective inhibitor, suppressed both constitutive and Flt-3-stimulated Akt activation in blasts to the same extent as Ly294002, an inhibitor of all PI3K isoforms. Moreover, IC87114 inhibited AML cell proliferation without affecting the proliferation of normal hematopoietic progenitor cells. These observations identify p110delta as a potential therapeutic target in AML.
Prevention of inhibitory effects of alpha-difluoromethylornithine on rat urinary bladder carcinogenesis by exogenous putrescine. (1986)

We previously demonstrated that repeated instillation of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), inhibits (or retards) urinary bladder carcinogenesis in rats. Since ODC catalyzes the first step in polyamine synthesis, the inhibition of polyamine formation may be responsible for tumor inhibition by DFMO. The present experiment was conducted using male Fischer rats with a heterotopically transplanted urinary bladder (HTB) to determine whether the effects of DFMO are prevented by exogeneous Pu. HTBs were treated with 0.25 mg of N-methyl-N-nitrosourea (MNU) once a week for 3 weeks and the animals were then arbitrarily divided into 6 groups. Beginning one week following the last MNU treatment, all rats received twice a week instillation (0.5 ml each) as follows: Group 1 rats, normal rat urine; Group 2, 2% DFMO in urine; Group 3, 250 microM Pu and 2% DFMO in urine; Group 4, 250 microM Pu in urine; Group 5, urine for 10 weeks followed by 2% DFMO in urine; and Group 6, urine for 10 weeks followed by 250 microM Pu and 2% DFMO in urine. At 10 weeks following the last MNU instillation 5 rats from each of Groups 1 through 4 were killed for determination of urothelial polyamine levels. An additional 4 rats of Group 1 were killed at 10 weeks for histological examination. All remaining rats were killed 20 weeks after the last MNU instillation. Polyamine levels showed no significant difference among the 4 groups. The incidence of carcinoma was significantly lower in the group treated with DFMO (p less than 0.001, Group 1 vs Group 2), confirming our previous observation.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulation of Gelatin-Binding Protein 28 (GBP28) Gene Expression by C/EBP. (1999)

We have previously reported the isolation of human gelatin-binding protein 28 (GBP28) gene which is specifically expressed in adipose tissue. The transcriptional activity of the flanking region of the GBP28 gene was examined by the transient transfection of promoter-luciferase reporter constructs into 3T3 adipocytes and electrophoretic mobility shift assay. This revealed the existence of a protein which binds to the 5'-flanking region of the GBP28 gene in nuclear extracts from human adipose tissue, but not in nuclear extracts from mouse liver. The C/EBP sites contained in this region are thought to take part in the regulation of GBP28 gene expression.
o-Phenylene-Bridged Cp/Amido Titanium Complexes for Ethylene/1-Hexene Copolymerizations (2006)

o-Phenylene-bridged Me3Cp/amido titanium complexes have been prepared via the Suzuki coupling reaction. Some of them show reactivity comparable to that of the CGC [Me2Si(η5-Me4Cp)(NtBu)]TiCl2 in ethylene/1-hexene copolymerization in terms of activity, molecular weight, and comonomer incorporation.