gebhart/patrepeval huggingface dataset:
Phenotype–genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence (2005)

The ability to discriminate between deleterious and neutral amino acid substitutions in the genes of patients remains a significant challenge in human genetics. The increasing availability of genomic sequence data from multiple vertebrate species allows inclusion of sequence conservation and physicochemical properties of residues to be used for functional prediction. In this study, the RET receptor tyrosine kinase serves as a model disease gene in which a broad spectrum (> or = 116) of disease-associated mutations has been identified among patients with Hirschsprung disease and multiple endocrine neoplasia type 2. We report the alignment of the human RET protein sequence with the orthologous sequences of 12 non-human vertebrates (eight mammalian, one avian, and three teleost species), their comparative analysis, the evolutionary topology of the RET protein, and predicted tolerance for all published missense mutations. We show that, although evolutionary conservation alone provides significant information to predict the effect of a RET mutation, a model that combines comparative sequence data with analysis of physiochemical properties in a quantitative framework provides far greater accuracy. Although the ability to discern the impact of a mutation is imperfect, our analyses permit substantial discrimination between predicted functional classes of RET mutations and disease severity even for a multigenic disease such as Hirschsprung disease.
Bioreducible Hyperbranched Poly(amido amine)s for Gene Delivery (2009)

A series of reducible hyperbranched poly(amido amine)s (RHB) with high transfection efficiency were designed and synthesized as nonviral gene delivery vectors. The polycations were synthesized by Michael addition copolymerization of N,N-dimethylaminodipropylenetriamine (DMDPTA) and two bisacrylamide monomers N,N'-hexamethylene bisacrylamide (HMBA) and N,N'-cystamine bisacrylamide (CBA). The density of disulfide linkages in the synthesized hyperbranched polymers was tuned by varying the feed molar ratio of the bisacrylamide monomers. The results demonstrate that disulfide content in RHB controls the molecular weight of the polycation degradation products, ease of polyplex disassembly, polycation cytotoxicity, and polyplex transfection activity. Due to their lower cytotoxicity, polyplexes based on reducible polycations could be used safely in a wider range of DNA doses than nonreducible controls. As a result, significantly increased transfection activity is achieved with optimized formulations of reducible polyplexes compared with nonreducible controls.
Homologous and heterologous regulation of alpha-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. (1994)

Specific high-affinity receptors for alpha-melanocyte-stimulating hormone (alpha-MSH) are found in variable abundance on many melanoma cell lines. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and two mouse melanoma cell lines. MSH induced up-regulation of its own receptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines. No regulation was observed in two human lines. Scatchard analysis revealed modulation of the number of receptors per cell without any change in affinity. The concentrations inducing half-maximal response for up- and down-regulation were 1.6 nM and 0.23 nM, respectively. ACTH1-17 and [Nle4,D-Phe7]-alpha-MSH were more potent, whereas ACTH1-24, desacetyl-alpha-MSH, and [Nle4]-alpha-MSH were less potent in receptor up-regulation as compared to alpha-MSH. Down-regulation but not up-regulation could be fully mimicked by Gs-protein activation and partially by elevation of cellular cAMP. Combination of different agents which increase cAMP was found to be counterregulatory. TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells. Several protein kinase inhibitors increased MSH binding in B16 cells. MSH-induced receptor down-regulation and melanin synthesis were most effectively antagonized by selective inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and negatively regulated. Whereas cAMP-dependent protein kinase activation seems to be involved in down-regulation, the mechanism responsible for up-regulation remains to be elucidated.
Fumaric acid esters (FAEs) suppress CD 15- and ODP 4-positive cells in psoriasis. (1994)

A histological-immunohistological study was conducted to investigate the effect of systemically administered fumaric acid esters (FAEs) on epidermal thickness and composition of the inflammatory infiltrate in psoriatic plaques. The very first effect of systemic therapy with FAEs is the disappearance of CD 15-positive cells in the beneath the epidermis, accompanied by a significant reduction in T-helper cells beneath the epidermis, pointing to an immunosuppressive effect. This is followed after some delay by a reduction in acanthosis and hyperkeratosis. The reduction in infiltrating T-lymphocytes corresponds to that seen after systemic or intralesional therapy with cyclosporin. However, the normalization of the psoriatic plaques takes longer under the influence of FAEs than under cyclosporin.
Generation and characterization of monospecific and bispecific hexavalent trimerbodies (2013)

Here, we describe a new class of multivalent and multispecific antibody-based reagents for therapy. The molecules, termed "trimerbodies," use a modified version of the N-terminal trimerization region of human collagen XVIII noncollagenous 1 domain flanked by two flexible linkers as trimerizing scaffold. By fusing single-chain variable fragments (scFv) with the same or different specificity to both N- and C-terminus of the trimerizing scaffold domain, we produced monospecific or bispecific hexavalent molecules that were efficiently secreted as soluble proteins by transfected mammalian cells. A bispecific anti-laminin x anti-CD3 N-/C-trimerbody was found to be trimeric in solution, very efficient at recognizing purified plastic-immobilized laminin and CD3 expressed at the surface of T cells, and remarkably stable in human serum. The bispecificity was further demonstrated in T cell activation studies. In the presence of laminin-rich substrate, the bispecific anti-laminin x anti-CD3 N-/C-trimerbody stimulated a high percentage of human T cells to express surface activation markers. These results suggest that the trimerbody platform offers promising opportunities for the development of the next-generation therapeutic antibodies, i.e., multivalent and bispecific molecules with a format optimized for the desired pharmacokinetics and adapted to the pathological context.
Hydration Behavior of Na-Smectite Crystals Synthesized at High Pressure and High Temperature (1994)

Abstract Hydration behavior of Na-smectite crystals synthesized at a pressure of 5.5 GPa and temperatures of 1400°–1500°C was examined by X-ray powder diffraction at various relative humidities (RH) in the range of 0–100%. The basal spacing of the Na-smectite crystal increased stepwise with increase in RH. The reflections observed were only normal reflections of a single or dual hydration states of smectite. No irrational, intermediate, or asymmetrical reflections were observed. The simple hydration behavior, not known for natural smectite with fine particle sizes and low crystallinity, indicates that the Na-smectite crystals are as perfect as common inorganic crystals with an ordered structure.
Identification of Functional Domains in Herpes Simplex Virus 2 Glycoprotein B (2006)

Glycoprotein B (gB) is one of four membrane proteins that are essential for the entry of herpes simplex viruses (HSV) into cells, and coexpression of the same combination of proteins in transfected cells results in cell fusion. The latter effect is reminiscent of the ability of virus infection to cause cell fusion, particularly since the degree of fusion is greatly increased by syncytial mutations in gB. Despite intensive efforts with the gB homologs of HSV and some other herpesviruses, information about functionally important regions in the 700-amino-acid ectodomain of this protein is very limited at present. This is largely due to the misfolding of the majority of the mutants examined. It was shown previously that the percentage of correctly folded mutants could be increased by targeting only predicted loop regions (i.e., not alpha-helix or beta-strand), and by using this approach new functional domains in HSV-2 gB have now been identified.
Meteorological conditions affecting electromagnetic propagation on the Arabian Peninsula (1984)

Modern U.S. Military radars and communication equipment performance will be strongly influenced by the environment it will be operating in. One of the most important atmospheric affects is ducting of electromagnetic energy by refractive layers in the atmosphere. To assess the affects of ducting on electromagnetic emissions around Dhahran, Saudi Arabia, a geometric optics model of wave propagation developed by Raymond P. Wasky was modified and utilized. This thesis also attempted to show the correlation of wind direction and wind speed to the establishment, location and heights of ducts. Finally this thesis attempted to determine if there was any correlation between the occurrence of land-sea breezes and ducting. Originator-supplied keywords: Ducting, Electromagnetic propagation, and Dhahran(Saudi Arabia).
Adenovirus E1A Directly Targets the E2F/DP-1 Complex (2011)

Deregulation of the cell cycle is of paramount importance during adenovirus infection. Adenovirus normally infects quiescent cells and must initiate the cell cycle in order to propagate itself. The pRb family of proteins controls entry into the cell cycle by interacting with and repressing transcriptional activation by the E2F transcription factors. The viral E1A proteins indirectly activate E2F-dependent transcription and cell cycle entry, in part, by interacting with pRb and family members to free the E2Fs. We report here that an E1A 13S isoform can unexpectedly activate E2F-responsive gene expression independently of binding to the pRb family of proteins. We demonstrate that E1A binds to E2F/DP-1 complexes through a direct interaction with DP-1. E1A appears to utilize this binding to recruit itself to E2F-regulated promoters, and this allows the E1A 13S protein, but not the E1A 12S protein, to activate transcription independently of interaction with pRb. Importantly, expression of E1A 13S, but not E1A 12S, led to significant enhancement of E2F4 occupancy of E2F sites of two E2F-regulated promoters. These observations identify a novel mechanism by which adenovirus deregulates the cell cycle and suggest that E1A 13S may selectively activate a subset of E2F-regulated cellular genes during infection.
Novel anion exchange membranes based on polymerizable imidazolium salt for alkaline fuel cell applications (2011)

A new polymerizable imidazolium salt monomer, 1-(4-vinylbenzyl)-3-methyl-imidazolium chloride ([VBMI]Cl), has been readily synthesized by reaction of 4-vinylbenzyl chloride with 1-methylimidazole. Novel anion exchange membranes (AEMs) based on the copolymers of [VBMI]Cl and styrene have been prepared and characterized. Excellent thermostability of the membranes is observed through the thermo-gravimetric analysis (TGA) curves. Water uptake and ion exchange capacity (IEC) of the OH− form AEMs range from 26.1% to 61.9% and from 0.95 to 1.45 mmol g−1, respectively. This type of AEM displays significant ionic conductivities over the order of 10−2 S cm−1 in deionized water at room temperature, and the membranes are stable in 10 mol L−1NaOH solution at 60 °C for 120 h. For the H2/air single fuel cell at 30 °C with this novel AEM, the peak power density of 33 mW cm−2 is obtained at a current density of 59 mA cm−2.
Cellular Delivery of siRNA Mediated by Fusion-Active Virosomes (2007)

RNA interference is expected to have considerable potential for the development of novel specific therapeutic strategies. However, successful application of RNA interference in vivo will depend on the availability of efficient delivery systems for the introduction of small-interfering RNA (siRNA) into the appropriate target cells. This paper focuses on the use of reconstituted viral envelopes ("virosomes"), derived from influenza virus, as a carrier system for cellular delivery of siRNA. Complexed to cationic lipid, siRNA molecules could be efficiently encapsulated in influenza virosomes. Delivery to cultured cells was assessed on the basis of flow cytometry analysis using fluorescently labeled siRNA. Virosome-encapsulated siRNA directed against Green Fluorescent Protein (GFP) inhibited GFP fluorescence in cells transfected with a plasmid encoding GFP or in cells constitutively expressing GFP. Delivery of siRNA was dependent on the low-pH-induced membrane fusion activity of the virosomal hemagglutinin, supporting the notion that virosomes introduce their encapsulated siRNA into the cell cytosol through fusion of the virosomal membrane with the limiting membrane of cellular endosomes, after internalization of the virosomes by receptor-mediated endocytosis. It is concluded that virosomes represent a promising carrier system for cellular delivery of siRNA in vitro as well as in vivo.
Spatial location studies on the chemical composition of human tear ferns (2000)

Tear ferns are the patterns formed when tears are allowed to dry on a clean smooth surface. The patterns have been categorised according to confluence of pattern, with less confluent ferns indicative of tear film abnormalities. Little is known about the mechanism that gives rise to this phenomenon. Previous work has concentrated on correlation of alterations in tear film composition on the ferning phenomenon. The present study takes a new approach by analysing the locations of chemical elements in the fern to understand how the ferns form. By means of SEM coupled with EDXA, Na, K and Cl were detected within the fern. Sulphur, indicative of the presence of macromolecules such as mucins and proteins, was only found at the very periphery of the dry tear drop. The results suggest that macromolecules do not play a direct role in the formation of the ferns. A model is put forward to explain the observation whereby proteins and mucins are precipitated selectively by increasing salt concentration at the drop margin. Copyright (C) 2000.
A clone screening method using mRNA levels to determine specific productivity and product quality for monoclonal antibodies (2008)

To meet increasing demands for efficient and streamlined production processes of therapeutic antibodies, improved methods of screening clones are required. In this article, we examined the potential of using antibody transcript levels as criteria for clone screening. We evaluated the QuantiGene Plex, a commercially available, high-throughput assay for simultaneously measuring multiple transcripts from cell lysate. Using the development of stable Chinese hamster ovary cell lines as examples, we investigated the relationship between transcript and antibody levels through several rounds of screening. First, we observed that measured heavy chain transcript levels are generally correlated with specific productivity, enabling the identification of high-producing clones from mRNA. Second, we observed that low ratios (< 1.5) of light to heavy chain transcript levels may be indicative of high antibody aggregation levels, allowing for the rapid identification and elimination of clones of questionable product quality. Therefore, an efficient process of identifying high-producing clones of desirable product quality is possible by using QuantiGene Plex assay to measure antibody transcript levels.
The influence of granulocyte/macrophage colony‐stimulating factor on dendritic cell levels in mouse lymphoid organs (1997)

To ascertain whether the development of dendritic cells (DC) in mouse lymphoid organs is dependent on granulocyte/macrophage colony-stimulating factor (GM-CSF), we determined the number of DC in the thymus, spleen and lymph nodes of normal mice, of mice with the genes coding for GM-CSF or its receptor inactivated, and of transgenic mice with excessive levels of GM-CSE DC were extracted from the tissues and enriched prior to flow cytometric analysis. The total DC level and the incidence of DC expressing lymphoid-related markers (CD8(hi) CD11b(lo)) and myeloid-related markers (CD8(lo) CD11b(hi)) were monitored. Both in GM-CSF null mice, and GM-CSF receptor null mice, DC of all surface phenotypes were present in all lymphoid organs; only small decreases in DC levels were recorded, except for the lymph nodes of GM-CSF receptor null mice which showed a more pronounced (threefold) decrease in DC numbers. Since the GM-CSF receptor null mice lacked the beta chain common to the GM-CSF, interleukin (IL)-3 and IL-5 receptors, the development of DC in the absence of GM-CSF was not due to common beta chain mediated developmental signals elicited by IL-3 or IL-5. In GM-CSF transgenic mice, there was only a 50 % increase in DC numbers in thymus and spleen, paralleling an increase in overall cellularity, but a more pronounced (threefold) increase in DC numbers in lymph nodes. There was no evidence that GM-CSF had a selective effect on any particular DC subpopulation defined by CD8 or CD11b expression. We conclude that the development of most lymphoid tissue DC can proceed in the absence of GM-CSF, although this cytokine can produce some elevation of DC levels. It is not clear whether the enhancing effect of GM-CSF is direct or an indirect effect mediated by other cytokines.
INDUCED MALIGNANCY IN CELLS FROM RAT MYOCARDIUM SUBJECTED TO INTERMITTENT ANAEROBIOSIS DURING LONG PROPAGATION IN VITRO (1953)

In two strains of fibroblasts originating from fragments of myocardium from a 5 day old rat of the Slonaker-Addis strain, a strain known to develop tumors but rarely, abnormal morphologic alterations took place which eventuated in neoplastic changes. This happened only after repeated exposure of the cultures to an atmosphere of nitrogen (anaerobiosis) and did not occur in the control cultures of fibroblasts originating from the same rat heart, and grown continuously throughout the same period (2 (1/2) years) without exposure to nitrogen.
Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas (2000)

Toxic bile salts induce hepatocyte apoptosis by a Fas-dependent, Fas ligand-independent mechanism. To account for this observation, we formulated the hypothesis that toxic bile salts induce apoptosis by effecting translocation of cytoplasmic Fas to the cell surface, resulting in transduction of Fas death signals. In McNtcp.24 cells the majority of Fas was cytoplasmic, as assessed by cell fractionation and immunofluorescence studies. However, cell surface Fas increased sixfold after treatment with the toxic bile salt glycochenodeoxycholate (GCDC) in the absence of increased Fas protein expression. Moreover, in cells transfected with Fas-green fluorescence protein, cell surface fluorescence also increased in GCDC-treated cells, directly demonstrating Fas translocation to the plasma membrane. Both brefeldin A, a Golgi-disrupting agent, and nocodazole, a microtubule inhibitor, prevented the GCDC-induced increase in cell surface Fas and apoptosis. In conclusion, toxic bile salts appear to induce apoptosis by promoting cytoplasmic transport of Fas to the cell surface by a Golgi- and microtubule-dependent pathway.
Synovial fluid cytokine levels in Behçet's disease. (2002)

The arthritis of BD is non-erosive and accordingly, its synovial fluid contains lower levels of cytokines primarily involved in cartilage destruction, namely IL-1 beta and TNF-alpha, than RA. IL-1ra and TGF might serve as protective factors against erosion in the inflamed joints. High synovial fluid levels of sIL-2r and IL-8 probably reflect a non-specific inflammatory process.
Synthesis of oxygen‐substituted N‐alkyl 1‐deoxynojirimycin derivatives: Aza sugar α‐glucosidase inhibitors showing antiviral (HIV‐1) and immunosuppressive activity (1994)

Abstract The synthesis of a series of six less‐lipophilic analogues of the α‐glucosidase inhibitor N ‐decyl‐1‐deoxynojirimycin ( N ‐decyl‐dNM, 5 ) is described. With the incorporation of a single oxygen atom, particularly at position seven in the N ‐decyl side‐chain to give N ‐(7‐oxadecyl)‐dNM ( 8 ), the therapeutic ratio (α‐glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. Compound 8 inhibits purified porcine liver α‐glucosidase I with an IC 50 value of 0.28 μM. The position of the oxygen atom in the N ‐decyl side‐chain is of importance since N‐(3‐oxadecyl)‐dNM ( 7 ) is less active than 8 and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of eight ester derivatives of N ‐(7‐oxadecyl)‐dNM is described. All of these ester analogues are less active α‐glucosidase inhibitors than the parent compound 8 in HepG2 cells. The compounds were further analyzed for antiviral and immunomodulatory activity in vitro . It is found that the most potent α‐glucosidase I inhibitor from this study N ‐(7‐oxadecyl)‐dNM ( 8 ) inhibits HIV‐1‐induced syncytia formation and lymphocyte proliferation in vitro . Finally, compound 8 was investigated in vivo . N ‐(7‐Oxadecyl)‐dNM ( 8 ) reduced adjuvant‐induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.
Strategies and Tools for Whole-Genome Alignments (2003)

The availability of the assembled mouse genome makes possible, for the first time, an alignment and comparison of two large vertebrate genomes. We investigated different strategies of alignment for the subsequent analysis of conservation of genomes that are effective for assemblies of different quality. These strategies were applied to the comparison of the working draft of the human genome with the Mouse Genome Sequencing Consortium assembly, as well as other intermediate mouse assemblies. Our methods are fast and the resulting alignments exhibit a high degree of sensitivity, covering more than 90% of known coding exons in the human genome. We obtained such coverage while preserving specificity. With a view towards the end user, we developed a suite of tools and Web sites for automatically aligning and subsequently browsing and working with whole-genome comparisons. We describe the use of these tools to identify conserved non-coding regions between the human and mouse genomes, some of which have not been identified by other methods.
Nanoencapsulation for drug delivery (2014)

Nanoencapsulation of drug/small molecules in nanocarriers (NCs) is a very promising approach for development of nanomedicine. Modern drug encapsulation methods allow efficient loading of drug molecules inside the NCs thereby reducing systemic toxicity associated with drugs. Targeting of NCs can enhance the accumulation of nanonencapsulated drug at the diseased site. This article focussed on the synthesis methods, drug loading, drug release mechanism and cellular response of nanoencapsulated drugs on liposomes, micelles, carbon nanotubes, dendrimers, and magnetic NCs. Also the uses of these various NCs have been highlighted in the field of nanotechnology.
Bonding/barrier layers on bismuth telluride (Bi2Te3) for high temperature applications (2010)

In this research, a fundamental study is conducted to identify the materials and processes for producing bonding/barrier composites on Bi <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> Te <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> for high temperature thermoelectric applications. Pd, Ni, Ni/Au, Ag, and Ti/Au were deposited and evaluated using scanning electron microscope (SEM) and energy dispersive X-ray (EDX). A thermal evaporated, 100nm Ti/100nm Au composite gave the most promising.