gebhart/patrepeval huggingface dataset:
Recent Developments in Cholinesterases Inhibitors for Alzheimers Disease Treatment (2007)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) which is the most common cause of dementia in the elderly. It is characterized by the deficits in the cholinergic system and presence of characteristic hallmarks: neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes it became a target for the design of anti-alzheimer drugs. Cholinesterase inhibitors enhance cholinergic transmission indirectly, by inhibiting the enzyme which hydrolyses acetylcholine. It has been also demonstrated that acetylcholinesterase (AChE) is involved in the development of amyloid plaques. Therefore, substances which are AChE inhibitors (AChEI) are the only drugs approved for the symptomatic treatment of AD. This review presents the main classes of cholinesterase inhibitors developed recently for the treatment of AD. We have started with the analogues of the existing drugs: tacrine, donepezil, rivastigmine and galantamine which are still of interest for many research groups. Among them there is a very interesting group--dual binding site inhibitors characterized by increased inhibitory potency against AChE and amyloid plaques formation. There is also a group of compounds with additional properties such as: antioxidant activity, affinity to 5-HT(3) receptors, inhibition of N-methyltransferase that metabolize histamine, which can be beneficial for the treatment of AD. Furthermore there are some interesting compounds which belong to different chemical groups also of natural origin. In this review we sum up current research concerned with development of AChEIs which can be more effective in the future treatment of AD.
Distribution of GABA‐immunoreactive neurons in the basal ganglia of the squirrel monkey (Saimiri sciureus) (1987)

The distribution of GABA-immunoreactive neurons was visualized in the basal ganglia of the squirrel monkey (Saimiri sciureus), by using a highly specific antiserum raised against GABA-glutaraldehyde-lysyl-protein conjugate and revealed by the indirect peroxidase-antiperoxidase immunohistochemical method. In the dorsal striatum, GABA-immunoreactive nerve cell bodies were small to medium in size (sectional area ranging from 90 to 125 microns2), but some larger ones (500-600 microns2) were also found. These cells displayed no obvious clustering but were significantly more numerous in the caudate nucleus than in the putamen; their number was also markedly greater at caudal than at rostral striatal levels. A moderate number of evenly distributed positive axon terminals were visible in both the caudate nucleus and the putamen. In the ventral striatum, GABA-immunoreactive nerve cell bodies and axon terminals were seen in fair number within the nucleus accumbens and in the deep layers of the olfactory tubercle. Many positive terminals but no somata were found in the islands of Calleja. In the globus pallidus, virtually all nerve cell bodies were GABA-immunoreactive and the neuropil exhibited a multitude of positive terminals. In the substantia innominata, clusters of small, globular GABA-immunoreactive somata were scattered among aggregates of larger, nonimmunoreactive neurons belonging to the nucleus basalis, and the whole region showed a low to moderate number of evenly spread GABA-positive terminals. In the subthalamic nucleus, nerve cell bodies were generally surrounded by several GABA-positive terminals but were not themselves immunoreactive. The substantia nigra showed many GABA-immunoreactive somata, which predominated in the pars lateralis and diminished progressively in number along the lateromedial axis of the pars reticulata. These cells formed a rather pleomorphic group comprising round, fusiform, or polygonal elements of relatively large size (sectional area ranging from 200 to 800 microns2). In the pars compacta and ventral tegmental area, a few GABA-immunoreactive neurons of small size were dispersed among larger, unreactive neurons. In both pars lateralis and pars reticulata of the substantia nigra, the number of GABA-positive terminals was high and their distribution was rather uniform; a smaller number were visible in the pars compacta of the substantia nigra and in the ventral tegmental area. The present results demonstrate that GABA-containing neurons are widely and heterogeneously distributed in the various components of the squirrel monkey's basal ganglia.(ABSTRACT TRUNCATED AT 400 WORDS)
Transient Receptor Potential Vanilloid 4–Mediated Disruption of the Alveolar Septal Barrier (2006)

Disruption of the alveolar septal barrier leads to acute lung injury, patchy alveolar flooding, and hypoxemia. Although calcium entry into endothelial cells is critical for loss of barrier integrity, the cation channels involved in this process have not been identified. We hypothesized that activation of the vanilloid transient receptor potential channel TRPV4 disrupts the alveolar septal barrier. Expression of TRPV4 was confirmed via immunohistochemistry in the alveolar septal wall in human, rat, and mouse lung. In isolated rat lung, the TRPV4 activators 4alpha-phorbol-12,13-didecanoate and 5,6- or 14,15-epoxyeicosatrienoic acid, as well as thapsigargin, a known activator of calcium entry via store-operated channels, all increased lung endothelial permeability as assessed by measurement of the filtration coefficient, in a dose- and calcium-entry dependent manner. The TRPV antagonist ruthenium red blocked the permeability response to the TRPV4 agonists, but not to thapsigargin. Light and electron microscopy of rat and mouse lung revealed that TRPV4 agonists preferentially produced blebs or breaks in the endothelial and epithelial layers of the alveolar septal wall, whereas thapsigargin disrupted interendothelial junctions in extraalveolar vessels. The permeability response to 4alpha-phorbol-12,13-didecanoate was absent in TRPV4(-/-) mice, whereas the response to thapsigargin remained unchanged. Collectively, these findings implicate TRPV4 in disruption of the alveolar septal barrier and suggest its participation in the pathogenesis of acute lung injury.
Synthesis of Pentaantennary N‐Glycans with Bisecting GlcNAc and Core Fucose (2007)

Always use protection? The omission of a single protecting group led to the convergent synthesis of the highly branched dodecasaccharide N-glycan that contains two neighboring tetrasubstituted mannoside groups. A serendipitous finding led to the identification of the key protecting group in oligosaccharide building blocks for the optimized synthesis of N-glycans. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z604788_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
To see, or not to see— is That the query? (1991)

Article To see, or not to see— is That the query? Share on Author: Robert R. Korfhage Department of Information Science, University of Pittsburgh Department of Information Science, University of PittsburghView Profile Authors Info & Claims SIGIR '91: Proceedings of the 14th annual international ACM SIGIR conference on Research and development in information retrievalSeptember 1991 Pages 134–141https://doi.org/10.1145/122860.122873Online:01 September 1991Publication History 56citation664DownloadsMetricsTotal Citations56Total Downloads664Last 12 Months9Last 6 weeks1 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteGet Access
The Origins of Eukaryotic Gene Structure (2005)

Most of the phenotypic diversity that we perceive in the natural world is directly attributable to the peculiar structure of the eukaryotic gene, which harbors numerous embellishments relative to the situation in prokaryotes. The most profound changes include introns that must be spliced out of precursor mRNAs, transcribed but untranslated leader and trailer sequences (untranslated regions), modular regulatory elements that drive patterns of gene expression, and expansive intergenic regions that harbor additional diffuse control mechanisms. Explaining the origins of these features is difficult because they each impose an intrinsic disadvantage by increasing the genic mutation rate to defective alleles. To address these issues, a general hypothesis for the emergence of eukaryotic gene structure is provided here. Extensive information on absolute population sizes, recombination rates, and mutation rates strongly supports the view that eukaryotes have reduced genetic effective population sizes relative to prokaryotes, with especially extreme reductions being the rule in multicellular lineages. The resultant increase in the power of random genetic drift appears to be sufficient to overwhelm the weak mutational disadvantages associated with most novel aspects of the eukaryotic gene, supporting the idea that most such changes are simple outcomes of semi-neutral processes rather than direct products of natural selection. However, by establishing an essentially permanent change in the population-genetic environment permissive to the genome-wide repatterning of gene structure, the eukaryotic condition also promoted a reliable resource from which natural selection could secondarily build novel forms of organismal complexity. Under this hypothesis, arguments based on molecular, cellular, and/or physiological constraints are insufficient to explain the disparities in gene, genomic, and phenotypic complexity between prokaryotes and eukaryotes.
Inverted Repetitions in the Chromosome of Herpes Simplex Virus (1974)

Single DNA strands will sometimes fold back on themselves and form duplex regions by base pairing. This behavior is diagnostic of repeated, complementary nucleotide sequences in the strand, which are inverted with respect to one another. Examples of such inverted repetitions (ABC … C′B′A′) have been found by electron microscopy in DNA from bacterial plasmids (Sharp et al. 1973), bacteriophage Mu (Hsu and Davidson 1974), eukaryotic chromatin (Thomas et al. 1974) and two animal viruses, adenovirus (Garon et al. 1972; Wolfson and Dressier 1972) and adeno-associated virus (Koczot et al. 1973; Gerry et al. 1973).
Realistic absorption coefficient of ultrathin films (2012)

Both a theoretical algorithm and an experimental procedure are discussed of a new route to determine the absorption/scattering properties of thin films deposited on transparent substrates. Notably, the non-measurable contribution of the film–substrate interface is inherently accounted for. While the experimental procedure exploits only measurable spectra combined according to a very simple algorithm, the theoretical derivation does not require numerical handling of the acquired spectra or any assumption on the film homogeneity and substrate thickness. The film absorption response is estimated by subtracting the measured absorption spectrum of the bare substrate from that of the film on the substrate structure but in a non-straightforward way. In fact, an assumption about the absorption profile of the overall structure is introduced and a corrective factor accounting for the relative film-to-substrate thickness. The method is tested on films of a well known material (ITO) as a function of the film structural quality and influence of the film–substrate interface, both deliberately changed by thickness tuning and doping. Results are found fully consistent with information obtained by standard optical analysis and band gap values reported in the literature. Additionally, comparison with a conventional method demonstrates that our route is generally more accurate even if particularly suited for very thin films.
Mechanisms involved in synergistic anticancer effects of anti-4-1BB and cyclophosphamide therapy (2009)

Chemotherapy can precondition for immunotherapy by creating an environment for homeostatic lymphoproliferation and eliminating some of the suppressive immune networks. We found that combination therapy with anti-4-1BB and cyclophosphamide (CTX) produced synergistic anticancer effects in the poorly immunogenic B16 melanoma model in mice. The antitumor effect of the combination therapy depended mainly on CD8(+) T cells, the 4-1BB-dependent expansion and differentiation of which into IFN-gamma-producing CD11c(+)CD8(+) T cells was enhanced by CTX. Anti-4-1BB induced a rapid repopulation of T and B cells from CTX-mediated lymphopenia. Anti-4-1BB protected naïve T cells from CTX and promoted proliferation of memory/effector and memory T cells. The combination treatment produced approximately 60- and 2.2-fold more CTLs per tumor-associated antigen compared with CTX or anti-4-1BB alone, respectively. This indicates that anti-4-1BB promoted a preferential expansion of tumor-specific CD8(+) T cells among the repopulated lymphocytes following CTX-mediated lymphopenia. CTX treatment enhanced 4-1BB expression on CD4 and CD8 T cells, and CTX alone or in combination with anti-4-1BB effectively suppressed peripheral regulatory T cells. Our results indicate that anti-4-1BB and CTX can be practical partners in cancer therapy because CTX creates an environment in which anti-4-1BB actively promotes the differentiation and expansion of tumor-specific CTLs.
Markers of bone metabolism (1995)

A suitable marker of bone metabolism is either a measurable enzymatic activity specific for osteoblasts or osteoclasts or a bone matrix component released into the circulation and excreted in the urine during bone formation or bone resorption. Testing such bone markers is the most sensitive method for monitoring acute changes in bone metabolism. Guidelines for the use of assays in patient care are not yet established, largely because of the large intrapatient variation seen with the results of most assays. Bone markers also can be used as predictors of bone turnover, bone loss, and fracture risk. During the past year, bone markers have been intensively studied in the context of these issues.
An Arabidopsis thaliana protein interacts with a movement protein of Turnip crinkle virus in yeast cells and in vitro (2001)

Plant virus movement proteins bind host components to promote virus movement from initially infected cells to neighbouring cells. In this study, cDNA clones encoding p8 and p9, two small proteins required for the movement of Turnip crinkle virus, were used as 'bait' in a yeast two-hybrid system to screen an Arabidopsis thaliana cDNA library for interactive proteins. One A. thaliana clone was identified that encodes a protein, designated Atp8, which interacted with p8 in yeast cells and in vitro. The apparent full-length of Atp8 mRNA was sequenced and shown to encode a protein with two possible transmembrane helices, several potential phosphorylation sites and two 'RGD' sequences.
2016년 미국 대선의 예비선거: 제도, 과정, 결과 및 함의 (2016)

이 글은 2016년 미국 대선의 예비선거를 과정, 제도, 과정, 결과로 나누어 설명하고자 한다. 첫째, 예비선거의 역사적 기원을 짧게 살펴본 후 제도의 내용을 대의원 할당 규칙, 경선의 유형 및 대의원 배분 규칙을 중심으로 설명한다. 둘째, 경선의 과정을 세 가지 특징－아웃사이더 현상, 정책 쟁점, 경합전당대회－을 중심으로 설명한다. 마지막으로 본선의 서막을 알리는 전당대회의 모습을 묘사한다. 결론에서는 미국 예비선거가 한국 정치에 지니는 함의를 짧게 토론한다.
TLR9 stimulation drives naïve B cells to proliferate and to attain enhanced antigen presenting function (2007)

Mechanisms that regulate naïve B cell proliferation and function are incompletely defined. In this study, we test the hypothesis that naïve B cell expansion, survival and ability to present antigen to T lymphocytes can be directly modulated by Toll-like receptor (TLR) agonists. In the absence of B cell receptor stimulation, CpG oligonucleotide, a TLR9 agonist, was particularly efficient in inducing naïve B cell proliferation and survival. Although the expanded naïve B cells did not mature into CD27+ or IgG+ memory B cells, these cells did differentiate into IgM-secreting cells with increased surface expression of HLA-DR, CD40 and CD80. This was associated with an increased potential for these B cells to activate allogeneic T cells. We propose that the activation and expansion of naïve B cells induced by TLR9 agonists could enhance the potential of these cells to interact with cognate antigens and facilitate cell-mediated immune responses.
Mutational trends in V3 loop protein sequences observed in different genetic lineages of human immunodeficiency virus type 1 (1994)

Highly variable international human immunodeficiency virus type 1 envelope sequences can be assigned to six major clades, or phylogenetically defined subtypes, designated A through F. These subtypes are approximately equidistant in terms of evolutionary distance measured by nucleotide sequences. This radiation from a common ancestral sequence may have been in step with the spread of the pandemic. In this study, V3 loop protein sequence relationships within these major clades are analyzed to determine how the different lineages might be evolving with respect to this biologically important domain. The V3 loop has been shown to influence viral phenotype and to elicit both humoral and cellular immune responses. To identify patterns in V3 loop amino acid evolution, we cluster the sequences by a phenetic principle which evaluates protein similarities on the basis of amino acid identities and similarities irrespective of evolutionary relationships. When phenetic clustering patterns are superimposed upon phylogenetic subtype classifications, two interesting mutational trends are revealed. First, a set of identical, or highly similar, V3 loop protein sequences can be identified within two otherwise dissimilar genetic subtypes, A and C. Second, the D subtype sequences are found to possess the most radically divergent set of V3 loop sequences. These and other patterns characteristic of the V3 loop reflect the acquisition of specific biological properties during the apparently recent evolution of the human immunodeficiency virus type 1 lineages.
Protein disulfides and protein disulfide oxidoreductases in hyperthermophiles (2006)

Disulfide bonds are required for the stability and function of a large number of proteins. Recently, the results from genome analysis have suggested an important role for disulfide bonds concerning the structural stabilization of intracellular proteins from hyperthermophilic Archaea and Bacteria, contrary to the conventional view that structural disulfide bonds are rare in proteins from Archaea. A specific protein, known as protein disulfide oxidoreductase (PDO) is recognized as a potential key player in intracellular disulfide-shuffling in hyperthermophiles. The structure of this protein shows a combination of two thioredoxin-related units with low sequence identity which together, in tandem-like manner, form a closed protein domain. Each of these units contains a distinct CXXC active site motif. Due to their estimated conformational energies, both sites are likely to have different redox properties. The observed structural and functional characteristics suggest a relation to eukaryotic protein disulfide isomerase. Functional studies have revealed that both the archaeal and bacterial forms of this protein show oxidative and reductive activity and are able to isomerize protein disulfides. The physiological substrates and reduction systems, however, are to date unknown. The variety of active site disulfides found in PDOs from hyperthermophiles is puzzling. Nevertheless, the catalytic function of any PDO is expected to be correlated with the redox properties of its active site disulfides CXXC and with the distinct nature of its redox environment. The residues around the two active sites form two grooves on the protein surface. In analogy to a similar groove in thioredoxin, both grooves are suggested to constitute the substrate binding sites of PDO. The direct neighbourhood of the grooves and the different redox properties of both sites may favour sequential reactions in protein disulfide shuffling, like reduction followed by oxidation. A model for peptide binding by PDO is proposed to be derived from the analysis of crystal packing contacts mimicking substrate binding interactions. It is assumed, that PDO enzymes in hyperthermophilic Archaea and Bacteria may be part of a complex system involved in the maintenance of protein disulfide bonds. The regulation of disulfide bond formation may be dependent on a distinct interplay of thermodynamic and kinetic effects, including functional asymmetry and substrate-mediated protection of the active sites, in analogy to the situation in protein disulfide isomerase. Numerous questions related to the function of PDO enzymes in hyperthermophiles remain unanswered to date, but can probably successfully be studied by a number of approaches, such as first-line genetic and in vivo studies.
Design Synthesis of Advanced Technology, Flying Wing Seaplanes (2011)

Over the past decades there has been increasing pressure for ever more efficient and environmentally friendly aircraft to be designed. The use of waterborne aircraft could be a means of satisfying those requirements in the future. The aim of the PhD research program presented in this thesis was to develop the methodologies necessary for the preliminary design of large passenger seaplanes and evaluate the performance of such an aircraft compared to the current state of the art. The major technological and operational constraints in designing large waterborne aircraft were identified through an extensive feasibility study. A number of subject areas necessitating further investigation were also identified. To ensure that waterborne takeoff distance requirements are met, a novel initial sizing methodology was generated, relating the aircraft's thrust and lifting characteristics to the takeoff Balanced Field Length. To allow the design of a broad family of aircraft based on a predefined baseline configuration, the seaplane geometry was fully parameterized. The aerodynamic properties of the entire aircraft were determined using a vortex-lattice potential flow solver, written specifically for the configuration being investigated, combined with other commonly used empirical methods. Novel methodologies for estimating the hydrodynamic characteristics of a broad range of parametric hulls were developed using the wealth of experimental hydrodynamic test data available. These methods can be used not only to predict the resistance and trim characteristics of a seaplane throughout the entire takeoff and landing manoeuvre but also give an initial estimate of the attitudes where hydrodynamic instabilities may be encountered. The airborne and waterborne performance characteristics of each resulting aircraft design were estimated using the aforementioned methods. The resulting design synthesis has been integrated into a single algorithm, written in FORTRAN, intended to allow the easy and prompt analysis of any parametric variant of the baseline configuration.