gebhart/patrepeval huggingface dataset:
Optimizing oral vaccines: induction of systemic and mucosal B-cell and antibody responses to tetanus toxoid by use of cholera toxin as an adjuvant (1993)

Cholera toxin (CT) is an effective mucosal antigen and acts as an adjuvant when given orally with various antigens; however, few studies have compared the levels of antibody responses to CT and coadministered protein in systemic and mucosal tissues. In this study, we used tetanus toxoid (TT) for assessment of immune responses. Time course and dose-response studies established that 250 micrograms of TT given orally with 10 micrograms of CT three times at weekly intervals induced high serum and gastrointestinal tract anti-TT and anti-CT antibody responses. Oral immunization with TT alone induced no detectable mucosal immunoglobulin A (IgA) antibodies in fecal extracts and only weak serum IgG anti-TT responses. The coadministration of CT and TT induced peak serum IgG anti-TT responses following two oral doses that remained constant after the third oral immunization, while optimal mucosal IgA responses were seen after the third oral immunization. The serum anti-TT response obtained with CT and TT proved protective against TT challenge (100 minimum lethal doses), whereas mice orally given CT or TT alone died. Antigen-specific B-cell responses were assessed with an isotype-specific Elispot assay of isolated lymphoid cells from the spleen, Peyer's patches, and the small intestinal lamina propria. Interestingly, approximately fourfold-higher numbers of IgA anti-CT than of anti-TT antibody-producing (spot-forming) cells occurred in lymphocytes from the lamina propria of mice orally immunized with both TT and CT. The adjuvant CT did not induce polyclonal B-cell responses in mice given CT by the oral route, since no significant differences in total numbers of B cells producing IgA, IgG, or IgM were found compared with the numbers in mice given TT alone. The results clearly indicate that serum and mucosal antibody responses develop with different kinetics and that protective TT-specific antibody responses are generated in the systemic compartment when TT is administered with CT via the oral route.
Infection following soft tissue injury: its role in wound healing (2007)

Purpose of review Wound infection has always been an unconquered problem temporarily improved with the discovery of antibiotics but now struggling with an epidemic of resistant organisms. Wound healing has become a popular sub-speciality for the doctor and allied health professional working in the laboratory or at the bedside. It is a field with many new journals and frequent congresses that publish elaborate proceedings. These have been examined for this review. Recent findings Measurement of infection remains elusive. A clear difference between contamination and infection is difficult to delineate. In the era of the HIV/AIDS epidemic attention is drawn to host factors, which when attended to are as effective in suppressing infection as antisepsis. The bacterial capacity to put on a protective coat known as biofilm is a newly investigated system. Summary Antisepsis and antibiotics continue to provide a wealth of studies and some new technology. The evidence base, as examined by Cochrane systematic reviews, suggests that our strategy for preventing and dealing with infection of wounds needs further refinement.
Plant Breeding and Drought in C3 Cereals: What Should We Breed For? (2002)

Drought is the main abiotic constraint on cereal yield. Analysing physiological determinants of yield responses to water may help in breeding for higher yield and stability under drought conditions. The traits to select (either for stress escape, avoidance or tolerance) and the framework where breeding for drought stress is addressed will depend on the level and timing of stress in the targeted area. If the stress is severe, breeding under stress-free conditions may be unsuccessful and traits that confer survival may become a priority. However, selecting for yield itself under stress-alleviated conditions appears to produce superior cultivars, not only for optimum environments, but also for those characterized by frequent mild and moderate stress conditions. This implies that broad avoidance/tolerance to mild-moderate stresses is given by constitutive traits also expressed under stress-free conditions. In this paper, we focus on physiological traits that contribute to improved productivity under mild-moderate drought. Increased crop performance may be achieved through improvements in water use, water-use efficiency and harvest index. The first factor is relevant when soil water remains available at maturity or when deep-rooted genotypes access water in the soil profile that is not normally available; the two latter conditions become more important when all available water is exhausted by the end of the crop cycle. Independent of the mechanism operating, a canopy able to use more water than another would have more open stomata and therefore higher canopy temperature depression, and 13C discrimination (delta13C) in plant matter. The same traits would also seem to be relevant when breeding for hot, irrigated environments. Where additional water is not available to the crop, higher water-use efficiency (WUE) appears to be an alternative strategy to improve crop performance. In this context delta13C constitutes a simple but reliable measure of WUE. However, in contrast to lines performing better because of increased access to water, lines producing greater biomass due to superior WUE will have lower delta13C values. WUE may be modified not only through a decrease in stomatal conductance, but also through an increase in photosynthetic capacity. Harvest index is strongly reduced by terminal drought (i.e. drought during grain filling). Thus, phenological traits increasing the relative amount of water used during grain filling, or adjusting the crop cycle to the seasonal pattern of rainfall may be useful. Augmenting the contribution of carbohydrate reserves accumulated during vegetative growth to grain filling may also be worthwhile in harsh environmcnts. Alternatively, extending the duration of stem elongation without changing the timing of anthesis would increase the number of grains per spike and the harvest index without changing the amount of water utilized by the crop.
Lipoprotein(a) is an independent risk factor for myocardial infarction at a young age (1990)

We quantified lipoprotein(a) [Lp(a)] immunochemically in young (less than 46 y) male survivors of myocardial infarction and in age-matched controls recruited from participants of the Prospective Cardiovascular Münster (PROCAM) study. We further determined apolipoprotein E polymorphism and measured triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol (HDL and LDL), and apolipoproteins AI, AII, and B in the serum of these subjects. Lp(a) concentrations in serum were not correlated with other well-recognized risk factors for early myocardial infarction such as apolipoproteins AI and B, LDL cholesterol, and HDL cholesterol. Apolipoprotein E polymorphism did not affect Lp(a) concentrations, but had a major influence on apolipoprotein B concentration. Lp(a) concentrations were not influenced by age. Our data suggest that (a) an increased concentration of Lp(a) constitutes an independent risk factor for early myocardial infarction and (b) the concentrations of Lp(a) and LDL cholesterol (apolipoprotein B) in serum are under separate metabolic control.
Infantile neuronal degeneration masquerading as werdnig‐hoffmann disease (1980)

We investigated two infants whose clinical illness resembled Werdnig-Hoffmann disease (WHD). Motor nerve conduction velocities in one infant were markedly decreased, suggesting a demyelinative neuropathy. Pathological examination of the central nervous system in both patients revealed the expected loss of cell bodies in the anterior horn and motor cranial nerves. In addition, there was widespread neuron loss and gliosis in both gray and white matter of the thalamus, cerebellum, pons, and spinal cord. Motor sensory, and mixed peripheral nerves of one infant showed evidence of segmental demyelination with only mild fiber loss. These and similar patients previously described have a disorder that should be separated from WHD and can be termed infantile neuronal degeneration.
Adenovirus‐mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer (1997)

It is critical to develop new therapies, such as gene therapy, which can impact on both local and metastatic prostate cancer progression. We have developed an orthotopic mouse model of metastatic prostate cancer using a cell line (RM-1) derived from the mouse prostate reconstitution (MPR) model system. This mouse model closely simulates the anatomical and biological milieu of the prostate and allows for realistic testing of experimental gene therapy protocols. Adenovirus (ADV)-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) gene in conjunction with ganciclovir (GCV) in this model led to significant suppression of growth and of spontaneous metastasis at 14 days post-tumor inoculation. Longer-term studies produced a significant survival advantage and a continued suppression of metastatic activity for treatment animals despite regrowth of the primary tumor. Challenge by injection of tumor cells into the tail vein following excision of treated and control s.c. primary tumors resulted in 40% reduction in lung colonization in the treatment group, indicating the possible production of systemic anti-metastatic activity following a single in situ treatment with ADV/HSV-tk + GCV in this model system. Int. J. Cancer, 70:183–187, 1997. © 1997 Wiley-Liss, Inc.
Subunit identity of the dimeric 17 beta-hydroxysteroid dehydrogenase from human placenta. (1992)

Human placental 17 beta-hydroxysteroid dehydrogenase has been purified with a new rapid procedure based on fast protein liquid chromatography, yielding quantitatively a homogeneous preparation with high specific activity catalyzing the oxidation of 7.2 mumol of estradiol/min/mg of enzyme protein at 23 degrees C, pH 9.2. This preparation was shown to have a subunit mass of 34.5 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis while having a molecular mass of 68 kDa by both Superose-12 gel-filtration and native pore gradient gel electrophoresis. When 17 beta-hydroxysteroid dehydrogenase was expressed in HeLa cells or overproduced in insect cells using the baculovirus expression system, both from its cDNA encoding a protein of 34 kDa, the enzyme had the same migration in native and sodium dodecyl sulfate-gel electrophoresis as the purified one from human placenta and eluted from the Superose-12 column at the same elution volume. Moreover, all the above forms of this enzyme have similar specific activity. These results clearly demonstrate the identity of the three enzyme forms. The enzyme produced from the cDNA is expressed as a dimer, and its two subunits are identical. 17 beta-Hydroxysteroid dehydrogenase subunit identity is thus proved. The NH2-terminal analysis revealed a unique sequence of Ala-Arg-Thr-Val-Val-Leu-Ile for the purified enzyme from placenta, further confirming the above conclusion.
Determining the Binding Affinity of Therapeutic Monoclonal Antibodies towards Their Native Unpurified Antigens in Human Serum (2013)

Monoclonal antibodies (mAbs) are a growing segment of therapeutics, yet their in vitro characterization remains challenging. While it is essential that a therapeutic mAb recognizes the native, physiologically occurring epitope, the generation and selection of mAbs often rely on the use of purified recombinant versions of the antigen that may display non-native epitopes. Here, we present a method to measure both, the binding affinity of a therapeutic mAb towards its native unpurified antigen in human serum, and the antigen's endogenous concentration, by combining the kinetic exclusion assay and Biacore's calibration free concentration analysis. To illustrate the broad utility of our method, we studied a panel of mAbs raised against three disparate soluble antigens that are abundant in the serum of healthy donors: proprotein convertase subtilisin/kexin type 9 (PCSK9), progranulin (PGRN), and fatty acid binding protein (FABP4). We also determined the affinity of each mAb towards its purified recombinant antigen and assessed whether the interactions were pH-dependent. Of the six mAbs studied, three did not appear to discriminate between the serum and recombinant forms of the antigen; one mAb bound serum antigen with a higher affinity than recombinant antigen; and two mAbs displayed a different affinity for serum antigen that could be explained by a pH-dependent interaction. Our results highlight the importance of taking pH into account when measuring the affinities of mAbs towards their serum antigens, since the pH of serum samples becomes increasingly alkaline upon aerobic handling.
Photo‐controlled Growth of Telechelic Polymers and End‐linked Polymer Gels (2013)

Growing pores: Exposure of a bis-norbornene trithiocarbonate to long-wavelength UV light, or sunlight, in the presence of N-isopropylacrylamide (NiPAAm) led to well-defined norbornene–telechelic poly(NiPAAm) macromers. The macromers were end-linked with a tris-tetrazine via inverse-electron-demand Diels–Alder cycloaddition to generate polymer gels. Addition of new monomer, followed by exposure to sunlight, led to “photo-growth” of the network pores.
Resolution improved optical coherence-gated tomography for imaging through biological tissues (1999)

Abstract A mathematical model for the process of optical coherence-gated tomography (OCT) is described for the first time. It shows that the recorded signal of OCT is the cross-correlation of the self-coherence function of the light source with the impulse response of biological tissue to be measured. A deconvolution technique is then introduced to improve the longitudinal resolution of the system by recording the self-coherence function of the light source before the actual measurement is made. The technique could improve the resolution by a factor of 2–3, but with a penalty of a reduced signal-to-noise ratio; however, this penalty could be compromised by a spectral filtering technique. A proof-of-concept experiment is presented.
Material Considerations for Avalanche Photodiodes (2008)

Avalanche photodiodes (APDs) are widely used to detect and amplify weak optical signals by utilizing the impact ionization process. The choice of material is critical for the detection of a particular wavelength, and it is often expedient to use a combination of different materials to optimize the overall device performance. The APDs are now capable of covering a wide spectrum from the infrared down to the ultraviolet wavelengths. This paper will review the material requirements to achieve high gain with low excess noise at the different wavelength regions.
Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors (2012)

The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting the Wnt pathway with a monoclonal antibody, OMP-18R5. This antibody, initially identified by binding to Frizzled 7, interacts with five Fzd receptors through a conserved epitope within the extracellular domain and blocks canonical Wnt signaling induced by multiple Wnt family members. In xenograft studies with minimally passaged human tumors, this antibody inhibits the growth of a range of tumor types, reduces tumor-initiating cell frequency, and exhibits synergistic activity with standard-of-care chemotherapeutic agents.
Expression of functional interleukin‐21 receptor on adult T‐cell leukaemia cells (2004)

Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I). It has been suggested that cytokines play a role in the development and in the neoplastic cell growth of ATL. However, the precise mechanism involved in this process still remains unclear. Interleukin-21 (IL-21) and its receptor (IL-21R) have been recently described. In this study, we examined the expression of IL-21R and the effect of IL-21 on ATL cells. Real-time reverse transcription polymerase chain reaction showed that HTLV-I-infected cell lines and primary ATL cells expressed IL-21R mRNA. Cell surface expression of IL-21R on these cells was confirmed by flow cytometric analysis using a newly developed monoclonal antibody against human IL-21R. In contrast to the expression of IL-21R, IL-21 mRNA was scarcely detectable in these cells. Notably, IL-21 induced the proliferation of ATL-43T and ED-40515(+) cells, both of which were derived from leukaemic cell clones of ATL. Concerning the intracellular signalling pathways, IL-21 activated the phosphorylation of the signal transducers and activators of transcription (STAT)3 and STAT5. Taken together, these findings provide the first evidence that ATL cells express functional IL-21R, suggesting that it may contribute to the pathophysiology of ATL. In addition, the IL-21/IL-21R system may represent a new target for the treatment of ATL.
Effect of zinc gluconate on propionibacterium acnes resistance to erythromycin in patients with inflammatory acne: in vitro and in vivo study. (2005)

Tetracyclines and macrolide antibiotics have been in use for acne treatment for more than 20 years. Since 1992 increasing resistance to these antibiotics, and especially to erythromycin, is reported with Propionibacterium acnes. Zinc salts have demonstrated their efficacy in inflammatory acne treatment as well as their bacteriostatic activity against Propionibacterium acnes. The objective of our work was firstly to determine whether the clinical anti-inflammatory efficacy of zinc salts was altered in the presence of erythromycin resistant strains in vivo, and secondly to study the in vitro and in vivo effect of zinc on the sensitivity of Propionibacterium acnes strains to erythromycin. Thirty patients with inflammatory acne were treated by zinc gluconate with a daily dose of 30 mg for two months and bacteriologic samples were taken at D0, D30 and D60. In vivo, this study displayed a reduction in the number of inflammatory lesions after a 2-month treatment whether or not Propionibacterium acnes carriage was present. Concurrently, in vitro addition of zinc salts in the culture media of Propionibacterium acnes reduced resistance of Propionibacterium acnes strains to erythromycin. Thus, association of zinc salts via a systemic route and topical erythromycin treatment seems an interesting option in the light of an increasing number of patients carrying erythromycin resistant Propionibacterium acnes strains.
Inhibition of cholesterol absorption in rats by plant sterols. (1988)

The extent and site(s) of inhibition of cholesterol absorption by plant sterols, sitosterol and fucosterol, were studied in rats. The intragastric administration of a single emulsified lipid meal containing 25 mg [3H]cholesterol and 25 mg of either sitosterol or fucosterol inhibited the lymphatic absorption of cholesterol by 57% and 41%, respectively, in 24 hr. Less than 2% of each plant sterol was absorbed in the 24-hr period. In contrast, neither plant sterol (50 microM) inhibited cholesterol absorption when co-administered with equimolar amounts of cholesterol in phospholipid-bile salt micelles nor was either absorbed from the micellar solution. A series of in vitro studies was conducted to identify the site(s) of plant sterol inhibition of cholesterol absorption and to account for the difference in inhibitory effectiveness of sitosterol and fucosterol. A comparison of the micellar solubility of each sterol alone and in equimolar binary mixtures (to 2.0 mM) revealed that the solubility of individual sterols decreased in the following order: cholesterol, fucosterol, sitosterol, and that in binary mixtures cholesterol solubility was decreased by sitosterol and, to a lesser extent, by fucosterol relative to its solubility alone. A comparison between micellar-solubilized cholesterol and either sitosterol or fucosterol for binding to isolated brush border membranes, intestinal mucin, or for esterification by either cholesterol esterase or acyl coenzyme A:cholesterol acyltransferase revealed moderate to no competition. The data suggest that plant sterols displace cholesterol from bile salt (taurocholate) micelles and that sitosterol is more effective than fucosterol in this capacity.
Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1 H -pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid) A Receptor (2017)

Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABA<sub>A</sub> receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1'-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABA<sub>A</sub> receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
Cosegregation of blood pressure with a kallikrein gene family polymorphism. (1991)

It has recently been proposed that sequence variation in the gene coding for tissue kallikrein might be involved in the pathogenesis of hypertension. However, molecular evidence of an association between a sequence alteration in the kallikrein gene family and the transmission of increased blood pressure has never been reported. In 32 recombinant inbred (RI) strains derived from the spontaneously hypertensive rat (SHR) and the normotensive Brown Norway rat (BN), we investigated whether a restriction fragment length polymorphism (RFLP) marking the kallikrein gene family cosegregated with blood pressure. In the RI strains that inherited the kallikrein RFLP from the SHR progenitor strain, the median systolic, diastolic, and mean arterial pressures were significantly greater than in the RI strains that inherited the kallikrein RFLP from the BN progenitor strain. These findings suggest that in the rat, sequence variation in the kallikrein gene family, or in closely linked genes, may have the capacity to affect blood pressure.