gebhart/patrepeval huggingface dataset:
Nestin-Linked Green Fluorescent Protein Transgenic Nude Mouse for Imaging Human Tumor Angiogenesis (2005)

We report here a novel transgenic nude mouse for the visualization of human tumor angiogenesis. We have recently shown that the neural stem cell marker nestin is expressed in hair follicle stem cells and blood vessel networks in the skin of C57/B6 transgenic mice with nestin regulatory element-driven green fluorescent protein (ND-GFP). Others have shown ND-GFP is expressed in the brain, pancreas, and testes in these mice. In the present study, the nestin ND-GFP gene was crossed into nude mice on the C57/B6 background to obtain ND-GFP nude mice. ND-GFP was expressed in the brain, spinal cord, pancreas, stomach, esophagus, heart, lung, blood vessels of glomeruli, blood vessels of skeletal muscle, testes, hair follicles, and blood vessel network in the skin of ND-GFP nude mice. Human lung cancer, pancreatic cancer, and colon cancer cell lines as well as a murine melanoma cell line and breast cancer tumor cell line expressing red fluorescent protein were implanted orthotopically, and a red fluorescent protein-expressing human fibrosarcoma was implanted s.c. in the ND-GFP nude mice. These tumors grew extensively in the ND-GFP mice. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumors, visualized by dual-color fluorescence imaging. Results of immunohistochemical staining showed that CD31 was expressed in the ND-GFP-expressing nascent blood vessels. The ND-GFP transgenic nude mouse model enables the visualization of nascent angiogenesis in human and mouse tumor progression. These results suggest that this model is useful for the imaging of the angiogenesis of human as well as rodent tumors and visualization of the efficacy of angiogenetic inhibitors.
A new ecological method for the estimation of Nutritive Sucking Efficiency in newborns: Measurement principle and experimental assessment (2013)

The Sucking Efficiency (SEF) is one of the main parameters used to monitor and assess the sucking pattern development in infants. Since Nutritive Sucking (NS) is one of the earliest motor activity performed by infants, its objective monitoring may allow to assess neurological and motor development of newborns. This work proposes a new ecological and low-cost method for SEF monitoring, specifically designed for feeding bottles. The methodology, based on the measure of the hydrostatic pressure exerted by the liquid at the teat base, is presented and experimentally validated at different operative conditions. Results show how the proposed method allows to estimate the minimum volume an infant ingests during a burst of sucks with a relative error within the range of [3-7]% depending on the inclination of the liquid reservoir
Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion (2017)

Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure-guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy.
Progress in Methodology  Improved Reporter Gene Assays Used to Identify Ligands Acting on Orphan Seven‐Transmembrane Receptors (2003)

Seven-transmembrane G-protein-coupled receptors play a central role in physiology by facilitating cell communication through recognition of a wide range of ligands. Even more important, they represent important drug targets. Unfortunately, for many of these receptors the endogenous ligands, and hence their functions, remain to be identified. These receptors are referred to as "orphan" receptors. A pre-requisite for the identification of ligands activating orphan receptors is powerful assay systems. Until now, reporter gene assays have not been in common use in this process. Here, we summarize our development of improved reporter gene assays. We optimized reporter gene assays in respect of (i) the promoter region of the construct, (ii) the reporter enzyme used, (iii) and the assay procedure. Furthermore, an unique fluorescence-based clone selection step was introduced, allowing rapid selection of the most sensitive reporter cell clones when establishing stable reporter cell lines. Mathematical formulae are provided to enable a simple and reliable comparison between different cell lines, when tested with a compound of interest. The resulting reporter cell lines responded in a very sensitive way to the stimulation of various test receptors. The reporter system was termed HighTRACE (high-throughput reporter assay with clone election). Its high assay quality makes it suitable as a primary screening tool. Ligands for two recently unknown 7TM receptors were identified using the HighTRACE system i.e., two cell surface free fatty acid receptors, GPR40 (FFA1R) and GPR43 (FFA2R). The identification was accomplished using a reverse pharmacology approach.
Revisiting the definition of biocompatibility. (2003)

My main conclusion is that the original Williams' definition of biocompatibility still stands with respect to individual materials, but we have to move to more specific definitions within each of the varied applications of biomaterials such as those described above, and more will follow. It is time for the discussion and definition of biocompatibility to move from a materials base to an applications base.
Clinical outcomes following repair of the pars interarticularis. (2013)

Spondylolysis is a source of back pain in adolescents and young adults. The purpose of this study was to report clinical outcomes in 49 patients treated with isolated motion-sparing repair of the pars interarticularis. Patients who underwent direct repair of the pars interarticularis between 2002 and 2009 were identified. Standard demographic and radiographic data, needed for further surgeries, and radiographic evidence of healing were collected. Of 49 patients with 90 total pars defects (41 bilateral, 8 unilateral), 7 required reoperation. No serious complications were seen. None of the risk factors analyzed in our study were predictive of reoperation. The strongest preoperative predictor of Oswestry Disability Index score was Fujii chronicity (P = .041). Motion segment sparing repair of the pars is a safe and effective procedure for refractory cases of spondylolysis.
Myostatin negatively regulates satellite cell activation and self-renewal (2003)

Satellite cells are quiescent muscle stem cells that promote postnatal muscle growth and repair. Here we show that myostatin, a TGF-beta member, signals satellite cell quiescence and also negatively regulates satellite cell self-renewal. BrdU labeling in vivo revealed that, among the Myostatin-deficient satellite cells, higher numbers of satellite cells are activated as compared with wild type. In contrast, addition of Myostatin to myofiber explant cultures inhibits satellite cell activation. Cell cycle analysis confirms that Myostatin up-regulated p21, a Cdk inhibitor, and decreased the levels and activity of Cdk2 protein in satellite cells. Hence, Myostatin negatively regulates the G1 to S progression and thus maintains the quiescent status of satellite cells. Immunohistochemical analysis with CD34 antibodies indicates that there is an increased number of satellite cells per unit length of freshly isolated Mstn-/- muscle fibers. Determination of proliferation rate suggests that this elevation in satellite cell number could be due to increased self-renewal and delayed expression of the differentiation gene (myogenin) in Mstn-/- adult myoblasts. Taken together, these results suggest that Myostatin is a potent negative regulator of satellite cell activation and thus signals the quiescence of satellite cells.
Sparse LMS for system identification (2009)

We propose a new approach to adaptive system identification when the system model is sparse. The approach applies ℓ <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</inf> relaxation, common in compressive sensing, to improve the performance of LMS-type adaptive methods. This results in two new algorithms, the zero-attracting LMS (ZA-LMS) and the reweighted zero-attracting LMS (RZA-LMS). The ZA-LMS is derived via combining a ℓ <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1</inf> norm penalty on the coefficients into the quadratic LMS cost function, which generates a zero attractor in the LMS iteration. The zero attractor promotes sparsity in taps during the filtering process, and therefore accelerates convergence when identifying sparse systems. We prove that the ZA-LMS can achieve lower mean square error than the standard LMS. To further improve the filtering performance, the RZA-LMS is developed using a reweighted zero attractor. The performance of the RZA-LMS is superior to that of the ZA-LMS numerically. Experiments demonstrate the advantages of the proposed filters in both convergence rate and steady-state behavior under sparsity assumptions on the true coefficient vector. The RZA-LMS is also shown to be robust when the number of non-zero taps increases.
Inhibition of VEGF Secretion and Experimental Choroidal Neovascularization by Picropodophyllin (PPP), an Inhibitor of the Insulin-like Growth Factor-1 Receptor (2008)

PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.
Use of Non-Thermal Atmospheric Pressure Plasma Discharge for Coagulation and Sterilization of Surface Wounds (2005)

Summary form only given. Atmospheric pressure plasma discharges have recently gained interest of the medical community. Such systems have been used for sterilization of surfaces, for biochemical surface functionalization, and for many other applications. Specifically, thermal plasma discharges are applied in the field of tissue sterilization and blood coagulation as a faster alternative to normal biochemical coagulation. However, the use of thermal plasma is limited for two reasons: (a) the extremely high temperatures (2000 K up to 10000 K) cause severe tissue damage and (b) the necessity of general anesthesia makes it inconvenient for wide-spread patient use, apart from the hospital setting. Our research team has developed a novel method using non-thermal dielectric barrier discharge plasma (DBD plasma) to coagulate blood and sterilize tissues without causing thermal damage. This treatment would be safe to patients because no exposed electrodes are involved and high frequency current (about 10 KHz) is kept below milli-ampere. Our experiments have shown that such plasma treatment hastens blood coagulation and causes simultaneous wound sterilization. We suppose that these processes are stimulated by a large concentration of chemically active species in plasma that are ions, radicals (O, OH, N) and electronically-excited atoms and molecules. This novel plasma technology can find many applications in the medical field. Within the hospital setting, this technology may prove useful in the operating room for patients suffering from bleeding not amenable to other methods of coagulation (hemophilia cases, for example). Because of simultaneous sterilization, this device could also help prevent intra-operative infections. Sterilization effects of non-thermal plasma are well-known and were confirmed, for example, in our previous studies. We have determined relative time and power for blood coagulation by plasma without tissue damage as confirmed by gross and microscopic examination, and tissue cultures
Retention of antilipemic activity by periodate-oxidized non-anticoagulant heparins. (1986)

Heparin preparations with different anticoagulant and antilipemic (fat-clearing) activities were oxidized with periodate under conditions of cleavage of all the C(2)-C(3) bonds of non-sulfated uronic acid residues, while preserving the original molecular weight of the polysaccharide. Periodate-oxidised heparins (oxyheparins, O-HEP) and the corresponding borohydride-reduced products (reduced oxyheparins, RO-HEP) were compared with the original heparins for their content in trisulfated disaccharide sequences (as determined by 13C-nuclear magnetic resonance) and in active sites for antithrombin-III (as determined indirectly by affinity chromatography), and for their anticoagulant and antilipemic (lipoprotein lipase-releasing) activities. The drop of anticoagulant activity induced by periodate oxidation was paralleled by a substantial decrease of affinity for antithrombin, and is thought to arise from glycol splitting at the level of the D-glucuronic acid residue that is part of the active site for antithrombin. The trisulfated disaccharide sequences and the associated antilipemic activities were substantially unaffected by periodate oxidation. The residual anticoagulant activity of periodate-oxidized heparins obtained from preparations - such as those from beef lung - rich in trisulfated disaccharide sequences is discussed in terms of the influence of charge density on heparin-protease interactions not mediated by antithrombin.
Asymmetric Construction of 2,3-Dihydroisoxazoles via an Organocatalytic Formal [3 + 2] Cycloaddition of Enynes with N-Hydroxylamines (2016)

An organocatalytic asymmetric formal [3 + 2] cycloaddition of enynones with N-hydroxylamines has been described. A newly designed multifunctional organocatalyst was found to be highly effective, and the method allowed the synthesis of a variety of 2,3-dihydroisoxazoles in good yields with excellent enantioselectivity.
The Southern California HMO marketplace (1991)

The 1980s have been a period of rapid growth in the Southern California HMO industry. Much of this growth is related to the emergence of network-model HMOs and, more recently, IPA-model HMOs, as a major competitive force that provides an alternative to the massive and rapidly growing Kaiser plans. The growth of the industry has been made possible by and, at the same time, has facilitated the development and growth of multispecialty medical groups and hospital-based IPAs throughout Southern California. This development has brought the HMO industry and the practice of prepaid medicine into the mainstream of health care and had led to the extensive involvement of community hospitals and independent physicians and physician groups in prepaid medicine. The coming decade will be marked by further growth and by continued integration of physician practices, hospitals, and HMOs into more efficient, high quality, vertically integrated systems of health care.
Normal timing of oligodendrocyte development from genetically engineered,lineage-selectable mouse ES cells (2002)

Oligodendrocytes are post-mitotic cells that myelinate axons in the vertebrate central nervous system (CNS). They develop from proliferating oligodendrocyte precursor cells (OPCs), which arise in germinal zones, migrate throughout the developing white matter and divide a limited number of times before they terminally differentiate. Thus far, it has been possible to purify OPCs only from the rat optic nerve, but the purified cells cannot be obtained in large enough numbers for conventional biochemical analyses. Moreover, the CNS stem cells that give rise to OPCs have not been purified, limiting one's ability to study the earliest stages of commitment to the oligodendrocyte lineage. Pluripotent, mouse embryonic stem (ES) cells can be propagated indefinitely in culture and induced to differentiate into various cell types. We have genetically engineered ES cells both to positively select neuroepithelial stem cells and to eliminate undifferentiated ES cells. We have then used combinations of known signal molecules to promote the development of OPCs from selected, ES-cell-derived, neuroepithelial cells. We show that the earliest stages of oligodendrocyte development follow an ordered sequence that is remarkably similar to that observed in vivo, suggesting that the ES-cell-derived neuroepithelial cells follow a normal developmental pathway to produce oligodendrocytes. These engineered ES cells thus provide a powerful system to study both the mechanisms that direct CNS stem cells down the oligodendrocyte pathway and those that influence subsequent oligodendrocyte differentiation. This strategy may also be useful for producing human cells for therapy and drug screening.
Chemistry of the Opium Alkaloids. (1933)

As the title indicates, this is a book on pure chemistry. There is no suggestion of pharmacology or therapeutics. The material has been assembled in the course of a systematic study of the literature of the opium alkaloids and gives the impression of completeness and accuracy. The nomenclature adopted is that most commonly used in contemporary publications; in case of doubt, the German name has been accepted. This, as the authors state, leads to some unavoidable inconsistencies, but one has no difficulty in finding a discussion of the substance desired. This is a valuable source book of references on alkaloid chemistry, but especially the chemistry of opium. The authors have included a list of books on alkaloid and synthetic chemistry seldom cited in bibliographies, which in itself is of great value to chemists, research workers and others interested in chemical literature. The book is divided into two parts: 1. The
Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. (1993)

Mice homozygous for the c14CoS albino deletion die as neonates as a result of liver dysfunction. Previous mapping studies have associated this defect with a 310-kb fragment encoding the hepatocyte-specific developmental regulation locus (alf/hsdr-1). The gene encoding fumarylacetoacetate hydrolase (Fah), a metabolic enzyme that catalyzes the last step of tyrosine catabolism, also maps to the same deletion interval. To test whether the neonatal defects found in the albino deletion mutants are attributable to loss of Fah, and not to another gene mapping to the deletion, we have generated Fah mutant mice by gene targeting in embryonic stem cells. Fah-deficient mice die within 12 hr after birth from hypoglycemia and liver dysfunction. In addition, the same pattern of altered liver mRNA expression found in the albino deletion mutants was also found in affected animals. We conclude that the neonatal lethal and liver dysfunction phenotype of the alf/hsdr-1 deletion is entirely attributable to loss of Fah.
ChemInform Abstract: SYNTHESIS AND ANTISCHISTOSOMAL ACTIVITY OF CERTAIN PYRAZOLO(1,5‐A)PYRIMIDINES (1981)

Abstract Die Aminopyrazole (I) reagieren mit dem Enolat (II) und den β‐Ketocarbonsäureestern (IV) zu den Pyrazolopyrimidinonen (III) bzw. (V), die zu den Verbindungen (VI) N‐alkyliert oder auch zu den Thionen (VIII) umgesetzt werden.
The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes (1986)

Anticholinergic drugs are used to treat a number of neurologic disorders, including parkinsonism, vestibular disturbances, and dystonia. Traditionally, these drugs have been thought to act in similar fashion, as competitive antagonists at a single class of muscarinic receptors, and not to differ significantly in their therapeutic efficacy. Recently, however, pharmacologic studies have shown that the novel antagonist pirenzepine is capable of recognizing heterogeneity among muscarinic receptors; high-affinity pirenzepine sites have been classified as M1 sites and low-affinity sites as M2. This study examined whether the anticholinergics currently available for treatment of neurologic symptoms have selectivity for these subtypes and whether they differ in their degree of selectivity; the study showed that these drugs do demonstrate selectivity. All had greater affinity for the M1 site, indicated by higher affinity for rat forebrain membranes, where M1 predominates, than hindbrain preparations, where M2 predominates. The degree of selectivity varied greatly; some compounds, such as ethopropazine, had little M1 selectivity, whereas others, such as scopolamine, trihexyphenidyl, and biperiden, were quite selective, like pirenzepine. It is unknown whether these differences in selectivity have any immediate therapeutic implications. However, these results support the emerging concept of muscarinic receptor subtypes and the prospect of developing more selective agents, with enhanced therapeutic efficacy.
Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice (2011)

The complex of the serine protease factor IX (FIX) and its cofactor, factor VIII (FVIII), is crucial for propagation of the intrinsic coagulation cascade. Absence of either factor leads to hemophilia, a disabling disorder marked by excessive hemorrhage after minor trauma. FVIII is the more commonly affected protein, either by X-chromosomal gene mutations or in autoimmune-mediated acquired hemophilia. Whereas substitution of FVIII is the mainstay of hemophilia A therapy, treatment of patients with inhibitory Abs remains challenging. In the present study, we report the development of FIX variants that can propagate the intrinsic coagulation cascade in the absence of FVIII. FIX variants were expressed in FVIII-knockout (FVIII-KO) mice using a nonviral gene-transfer system. Expression of the variants shortened clotting times, reduced blood loss after tail-clip assay, and reinstalled clot formation, as tested by in vivo imaging of laser-induced vessel injury. In addition, we confirmed the therapeutic efficacy of FIX variants in mice with inhibitory Abs against FVIII. Further, mice tolerant to wild-type human FIX did not develop immune responses against the protein variants. Our results therefore indicate the feasibility of using variants of FIX to bypass FVIII as a novel treatment approach in hemophilia with and without neutralizing FVIII Abs.