gebhart/patrepeval huggingface dataset:
Isolation and functional characterization of the proenzyme form of the catalytic domains of human C1r (1989)

The proenzyme form of C1r catalytic domains was generated by limited proteolysis of native C1r with thermolysin in the presence of 4-nitrophenyl-4'-guanidinobenzoate. The final preparation, isolated by high-pressure gel permeation in the presence of 2 M-NaCl, was 70-75% proenzyme and consisted of a dimeric association of two gamma B domains, each resulting from cleavage of peptide bonds at positions 285 and 286 of C1r. Like native C1r, the isolated domains autoactivated upon incubation at 37 degrees C. Activation was inhibited by 4-nitrophenyl-4'-guanidinobenzoate but was nearly insensitive to di-isopropyl phosphorofluoridate; likewise, compared to pH 7.4, the rate of activation was decreased at pH 5.0, but was not modified at pH 10.0. In contrast, activation of the (gamma B)2 domains was totally insensitive to Ca2+. Activation of the catalytic domains, which was correlated with an irreversible increase of intrinsic fluorescence, comparable with that previously observed with native C1r [Villiers, Arlaud & Colomb (1983) Biochem. J. 215, 369-375], was reversibly inhibited at high ionic strength (2 M-NaCl), presumably through stabilization of a non-activatable conformational state. Detailed comparison of the properties of native C1r and its catalytic domains indicates that the latter contain all the structural elements that are necessary for intramolecular activation, but probably lack a regulatory mechanism associated with the N-terminal alpha beta region of C1r.
Genetic predisposition and parameters of malignant progression in K14-HPV16 transgenic mice. (1996)

Reproducible multi-stage progression to invasive squamous carcinoma of the epidermis has been achieved in transgenic mice expressing the HPV16 early-region genes, including the E6/E7 oncogenes, under the control of the human keratin-14 promoter/enhancer. Although 100% of K14-HPV16 transgenic animals develop hyperplastic and/or dysplastic lesions in several inbred backgrounds, including C57BL/6, BALB/c, and SSIN/SENCAR, only mice backcrossed into the FVB/n background progress to malignant squamous cell carcinomas of two pathological grades, well differentiated and moderate/poorly differentiated (WDSC or MPDSC, respectively), each displaying characteristic patterns of malignant behavior. WDSCs typically arise within the epidermis of the ear and invade deeply into the underlying dermis but fail to metastasize, whereas MPDSCs develop on the chest and truncal skin and invariably metastasize to regional lymph nodes. The transition to the malignant state, in 21% of FVB/n transgenic mice, is characterized by alteration of the repertoire of keratin intermediate filament proteins expressed within neoplastic epidermis, such that WDSCs maintain expression of keratins common to terminally differentiating stratified keratinocytes (K10), whereas MPDSCs are distinguished from WDSCs by activation of embryonic and mucosal keratins (K13, K8, and K19). Precursor hyperplastic and dysplastic lesions are characterized by a progressively increased proliferative index, striking morphological alterations in keratinocyte cell-cell and cell-matrix interactions, and extensive remodeling of the underlying dermal stroma. Remarkably, this extensive stromal remodeling, which may facilitate both angiogenesis and eventual tumor cell invasion, develops early at the dysplastic stage in all animals well before malignant conversion.
Monoclonal antibody therapy of inflammatory bowel disease. (1996)

Several anti-inflammatory drugs have therapeutic efficacy in inflammatory bowel disease, but their targets remain incompletely characterized. The development of monoclonal antibodies that either recognize epitopes on immune-competent cells, or neutralize pro-inflammatory cytokines, has helped to define the importance of inflammatory mediators and their cellular sources in experimental inflammatory bowel disease. Moreover, two monoclonal antibodies, directed against CD4 and tumour necrosis factor, have been used to treat patients with steroid-refractory Crohn's disease. Preliminary data suggest that immune-modulatory monoclonal antibodies may have beneficial effects in selected patients with severe Crohn's disease.
Transforming growth factor-beta 1 inhibits murine immediate and delayed type hypersensitivity (1992)

Transforming growth factor beta 1 (TGF-beta 1) is a member of a gene superfamily that regulates growth, differentiation, and function of cells including several in vitro immune functions. Our study examined the systemic effect of TGF-beta 1 on murine delayed-type hypersensitivity (DTH), a model of T cell-mediated immunity that may depend on mast cells. Mice were immunized by i.v. injection of SRBC or by topical application of picryl chloride, and the responses were elicited by cutaneous challenge with the appropriate Ag. Systemic administration of TGF-beta 1 at the time of Ag challenge significantly reduced both the early and late phases of DTH. The effect of TGF-beta 1 on the release of serotonin from mouse peritoneal mast cells was examined. Results indicated that in vivo treatment with TGF-beta 1 24 h before mast cell harvest inhibited the in vitro release of serotonin in response to challenge with compound 48/80, or anti-IgE antibody. In contrast, treatment with TGF-beta 1 24 h before Ag challenge did not inhibit DTH indicating that mast cells may not be the direct target for TGF-beta 1 in the DTH models. In vivo treatment with TGF-beta 1 inhibited the IgE-mediated, mast cell-dependent, immediate hypersensitivity skin swelling response when injected at the time of, or 24 h before challenge. This suggests an effect on mast cells and a regulatory role for TGF-beta 1 in IgE-mediated responses.
Maternal dietary fat alters amniotic fluid and fetal intestinal membrane essential n-6 and n-3 fatty acids in the rat (2005)

We investigated whether maternal fat intake alters amniotic fluid and fetal intestine phospholipid n-6 and n-3 fatty acids. Female rats were fed a 20% by weight diet from fat with 20% linoleic acid (LA; 18:2n-6) and 8% alpha-linolenic acid (ALA; 18:3n-3) (control diet, n = 8) or 72% LA and 0.2% ALA (n-3 deficient diet, n = 7) from 2 wk before and then throughout gestation. Amniotic fluid and fetal intestine phospholipid fatty acids were analyzed at day 19 gestation using HPLC and gas-liquid chromotography. Amniotic fluid had significantly lower docosahexaenoic acid (DHA; 22:6n-3) and higher docosapentaenoic acid (DPA; 22:5n-6) levels in the n-3-deficient group than in the control group (DHA: 1.29 +/- 0.10 and 6.29 +/- 0.33 g/100 g fatty acid; DPA: 4.01 +/- 0.35 and 0.73 +/- 0.15 g/100 g fatty acid, respectively); these differences in DHA and DPA were present in amniotic fluid cholesterol esters and phosphatidylcholine (PC). Fetal intestines in the n-3-deficient group had significantly higher LA, arachidonic acid (20:4n-6), and DPA levels; lower eicosapentaenoic acid (EPA; 20:5n-3) and DHA levels in PC; and significantly higher DPA and lower EPA and DHA levels in phosphatidylethanolamine (PE) than in the control group; the n-6-to-n-3 fatty acid ratio was 4.9 +/- 0.2 and 32.2 +/- 2.1 in PC and 2.4 +/- 0.03 and 17.1 +/- 0.21 in PE in n-3-deficient and control group intestines, respectively. We demonstrate that maternal dietary fat influences amniotic fluid and fetal intestinal membrane structural lipid essential fatty acids. Maternal dietary fat can influence tissue composition by manipulation of amniotic fluid that is swallowed by the fetus or by transport across the placenta.
Cluster headache in primary care: unmissable, underdiagnosed and undertreated. (2006)

Despite the substantial disability caused by headache disorders, they remain underdiagnosed and undertreated and in many cases the needs of the sufferer remain unmet. Cluster headache is one of the most painful conditions a GP will ever see and cluster sufferers may find themselves passing through ENT, ophthalmic or maxillo-facial departments with many years of intense suffering before a diagnosis is finally made.

Cluster headache is a syndrome with a prevalence of approximately 0.1% characterised by a trigeminal distribution of pain, ipsilateral cranial autonomic features and a striking tendency to circadian and circannual periodicity. Unlike migraine where females predominate there is a male:female ratio 5:1.1 The most common age of onset is the third or fourth decade of life and available evidence suggests that it is a lifelong disorder in the majority of sufferers, but with longer remission periods over time.2 Although the exact pathogenesis remains unclear, the underlying abnormality is in the posterior hypothalamus with subsequent trigeminovascular and cranial autonomic activation.3 Alcohol, nitroglycerine, exercise, and elevated environmental temperature are recognised precipitants but allergies, food sensitivities, reproductive hormonal changes and stress do not appear to have any significant role.

There are three significant features of cluster …
Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy (2018)

The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.
Expanding Cytotoxic T Lymphocytes from Umbilical Cord Blood that Target Cytomegalovirus, Epstein-Barr Virus, and Adenovirus (2012)

Virus infections after stem cell transplantation are among the most common causes of death, especially after cord blood (CB) transplantation (CBT) where the CB does not contain appreciable numbers of virus-experienced T cells which can protect the recipient from infection. We and others have shown that virus-specific CTL generated from seropositive donors and infused to the recipient are safe and protective. However, until recently, virus-specific T cells could not be generated from cord blood, likely due to the absence of virus-specific memory T cells. In an effort to better mimic the in vivo priming conditions of naïve T cells, we established a method that used CB-derived dendritic cells (DC) transduced with an adenoviral vector (Ad5f35pp65) containing the immunodominant CMV antigen pp65, hence driving T cell specificity towards CMV and adenovirus. At initiation, we use these matured DCs as well as CB-derived T cells in the presence of the cytokines IL-7, IL-12, and IL-15. At the second stimulation we used EBV-transformed B cells, or EBV-LCL, which express both latent and lytic EBV antigens. Ad5f35pp65-transduced EBV-LCL are used to stimulate the T cells in the presence of IL-15 at the second stimulation. Subsequent stimulations use Ad5f35pp65-transduced EBV-LCL and IL-2. From 50x10(6) CB mononuclear cells we are able to generate upwards of 150 x 10(6) virus-specific T cells that lyse antigen-pulsed targets and release cytokines in response to antigenic stimulation. These cells were manufactured in a GMP-compliant manner using only the 20% fraction of a fractionated cord blood unit and have been translated for clinical use.
Reductions of Organic Functional Groups Using NaBH4OR NaBH4/LiCl in Diglyme at 125 TO 162 °C (1998)

Abstract Reduction of nitro, amide, carboxylate, ester and nitrile functional groups to -NH2, -CH2NH2, -CH2OH, -CH2OH and -CH2NCHPh, respectively were achieved using NaBH4 or NaBH4/LiCl in diglyme at 125—162 °C. This greatly extends the range of functional group types which can be considered generally reducible by borohydride.
Controlled ink-jet printing and deposition of organic polymers and solid particles (1998)

In this letter, we present a technique for the deposition of inks, organic polymers and solid particles, using a fluid ejector. The ejector design is based on a flextensional transducer that excites axisymmetric resonant modes in a clamped circular membrane. It is constructed by bonding a thin piezoelectric annular ring to a thin, edge supported, circular membrane. Liquids or solid particles are placed behind one face of the membrane which has a small orifice (50–200 μm diam) at its center. By applying an ac signal across the piezoelectric element, continuous or drop-on-demand ejection of photoresist (Shipley Microposit S1400-21, S1400-27, S1805, and S1813), oil-based ink, water, or talcum powder [Mg3Si4O10(OH)2] has been achieved. Successful deposition of photoresist has been accomplished without spinning, and thus without waste. Patterning of 10 μm features, by baking, exposure, and developing, has revealed no defects in the deposition process. A boundary integral method was used to numerically simulate drop formation from the vibrating orifice. Simulations have been used to optimize ejection performance.
Control of Yeast Mating Signal Transduction by a Mammalian β 2 -adrenergic Receptor and G s α Subunit (1990)

To facilitate functional and mechanistic studies of receptor-G protein interactions, [corrected] the human beta 2-adrenergic receptor (h beta-AR) has been expressed in Saccharomyces cerevisiae. This was achieved by placing a modified h beta-AR gene under control of the galactose-inducible GAL1 promoter. After induction by galactose, functional h beta-AR was expressed at a concentration several hundred times as great as that found in any human tissue. As determined from competitive ligand binding experiments, h beta-AR expressed in yeast displayed characteristic affinities, specificity, and stereoselectivity. Partial activation of the yeast pheromone response pathway by beta-adrenergic receptor agonists was achieved in cells coexpressing h beta-AR and a mammalian G protein (Gs) alpha subunit-demonstrating that these components can couple to each other and to downstream effectors when expressed in yeast. This in vivo reconstitution system provides a new approach for examining ligand binding and G protein coupling to cell surface receptors.
Transbilayer distribution of phosphatidylethanolamine in large and small unilamellar vesicles (1981)

There is much evidence which strongly suggests that most constituents of biological membranes display a transbilayer compositional asymmetry. The tendency of binary mixtures of phospholipids to form compositionally asymmetric bilayers spontaneously has been studied extensively. In small unilamellar vesicles, most mixtures of phospholipids with different head groups have been reported to be nonrandomly arranged across the bilayer. In this study, the influence of the radius of curvature on the transbilayer phospholipid distribution has been investigated. The distribution of egg phosphatidylethanolamine in large unilamellar vesicles comprised of egg phosphatidylethanolamine and egg was determined by 2,4,6-trinitrobenzenesulfonic acid labeling. These large vesicles were obtained by modifying the ethanol injection procedure originally described by Batzri & Korn (1973) [Batzri, S., & Korn, E. D. (1973) Biochim. Biophys. Acta 298, 1015] by using a slow injection rate. After injection, the ethanol was removed by molecular sieve chromatography and the vesicle dispersion centrifuged. This results in a population of large, homogeneous, and unilamellar vesicles as determined by molecular sieve chromatography, 32P NMR, and electron microscopy. The phosphatidylethanolamine component in unilamellar vesicles of this type is equally distributed between the two monolayers. In contrast, phosphatidylethanolamine in small unilamellar vesicles is known to be preferentially localized in the outer monolayer at low phosphatidylethanolamine concentrations and in the inner monolayer at high phosphatidylethanolamine concentrations. These results suggest that while phospholipids may form asymmetric bilayers spontaneously in highly curved regions of biological membranes, other factors must be responsible for the generalized phospholipid asymmetry seen in these systems.
Elevated tissue inhibitor of metalloproteinase 1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases. (1995)

Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tumor invasion and metastases. The purpose of this study was to determine the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationships between TIMP-1 RNA expression and standard clinicopathological variables of CRC. Total cellular RNA, extracted from 56 CRC and 10 liver metastases, were examined by Northern blot hybridization. The mean/normal mucosa fold increase of TIMP-1 RNA was significantly elevated in both CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6). No relationship was noted between TIMP-1 expression and tumor size, location nor differentiation. Based on lymph node metastases status, significantly higher TIMP-1 RNA levels were found in CRC with metastases than in those without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04). Similarly, TIMP-1 RNA levels were higher in primary CRC with distant metastases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0. 04). In situ hybridization localized TIMP-1 mRNA predominantly in tumor stroma within spindle fibroblast-like cells rather than in cancer cells themselves. The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.
Active efflux of bile salts by Escherichia coli (1997)

Enteric bacteria such as Escherichia coli must tolerate high levels of bile salts, powerful detergents that disrupt biological membranes. The outer membrane barrier of gram-negative bacteria plays an important role in this resistance, but ultimately it can only retard the influx of bile salts. We therefore examined whether E. coli possessed an energy-dependent efflux mechanism for these compounds. Intact cells of E. coli K-12 appeared to pump out chenodeoxycholate, since its intracellular accumulation increased more than twofold upon deenergization of the cytoplasmic membrane by a proton conductor. Growth inhibition by bile salts and accumulation levels of chenodeoxycholate increased when mutations inactivating the acrAB and emrAB gene clusters were introduced. The AcrAB system especially appeared to play a significant role in bile acid efflux. However, another efflux system(s) also plays an important role, since the accumulation level of chenodeoxycholate increased strongly upon deenergization of acrA emrB double mutant cells. Everted membrane vesicles accumulated taurocholate in an energy-dependent manner, apparently consuming delta pH without affecting delta psi. The efflux thus appears to be catalyzed by a proton antiporter. Accumulation by the everted membrane vesicles was not decreased by mutations in acr and emrB genes and presumably reflects activity of the unknown system seen in intact cells. It followed saturation kinetics with Vmax and Km values in the neighborhood of 0.3 nmol min(-1) mg of protein(-1) and 50 microM, respectively.
Pulmonary deposition and clearance of aerosolized alpha-1-proteinase inhibitor administered to dogs and to sheep. (1989)

Augmentation of lung antiprotease levels may be an important therapeutic intervention in the prevention of pulmonary emphysema. We have administered aerosols of plasma-derived human alpha 1 proteinase inhibitor (A1PI) to the lungs of dogs and sheep to investigate (a) delivery of the protein to the distal air spaces of the lung; (b) maintenance of functional activity of the protein; and (c) flux of the protein across the components of the alveolar-capillary membrane. A1PI (26.4 mg/kg body weight) was administered as an aerosol to anesthetized animals; sheep were prepared for the chronic collection of lung lymph. Immunoperoxidase staining of lung tissue obtained 2 h after administration of A1PI demonstrated the presence of human A1PI on the surface of alveoli and distal bronchioles. Bronchoalveolar lavage fluid recovered at intervals after A1PI administration demonstrated time-dependent elevations of human A1PI levels with augmentation of lavage fluid antielastase activity in proportion to the content of human A1PI. Using radiolabeled A1PI as a tracer, we found that 32% of the aerosol was retained in the animals' lungs. Measurements of the rate of loss of A1PI from the lung and of the rate of appearance of human A1PI in plasma resulted in a calculated permeability of the alveolar-capillary membrane to A1PI of 3.49-6.39 X 10(-10) cm/s. Experiments using instrumented sheep allowed independent calculation of endothelial permeability to A1PI of 122-236 X 10(-10) cm/s and calculation of epithelial permeability of 4.70-4.81 X 10(-10) cm/s. Modeling of aerosol delivery of A1PI to humans using the results of these studies predicts that the ratio of plasma/alveolar levels of delivered A1PI will be 0.024, and that aerosolization of 175 mg A1PI/d will result in an A1PI alveolar fluid level of 1.0 mg/ml. Aerosol administration of A1PI may provide an efficient method of augmenting alveolar antiprotease levels.
[Evaluation of serum IgG sub-classes in children with recurrent respiratory infections]. (1996)

Serum IgG sub-classes levels were measured by radial immunodiffusion with policlonal antibodies in 26 children aged 2 years to 8 years, affected with respiratory recurrent infections. These subjects were controlled and compared with normal children values for age groups. In 10 patients a deficit of IgG sub-classes levels was found, in 7 patients an increase level for IgG1 was detected. These data must be taken in account defining IgG-sub-classes deficiencies in children with respiratory recurrent infection.
Saturation spectroscopy for optically thick atomic samples (1987)

Doppler-free saturation spectroscopy in the regime of strong pumping intensities and optically thick atomic samples is investigated experimentally and theoretically. It is shown that a very high signal-to-background ratio can be obtained and, at the same time, subnatural linewidths can be reached. Further contrast and linewidth improvements can be attained by supplementing the primary depleted pumping beam with a second pumping beam. By using the signal beam from a first setup as the pumping beam for a second identical arrangement, extreme values for contrast and linewidth should be attainable.
Bupivacaine Inhibits Cyclic-3', 5'-Adenosine Monophosphate Production A Possible Contributing Factor to Cardiovascular Toxicity (1993)

Inhibition of basal and epinephrine-stimulated cAMP production may contribute to local anesthetic cardiovascular toxicity. Inhibition of cAMP production may limit the success of resuscitative measures and drugs administered for bupivacaine cardiovascular toxicity. Increasing the resuscitation dose of epinephrine may be required to restore cardiac contractile function after bupivacaine intoxication.