gebhart/patrepeval huggingface dataset:
Role of E2F in cell cycle control and cancer (1998)

E2F transcription factors regulate the expression of a number of genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. The activity of E2F factors is regulated through association with the retinoblastoma tumor suppressor protein (Rb) and the other pocket proteins, p107 and p130. Binding of Rb, p107 or p130 converts E2F factors from transcriptional activators to transcriptional repressors. The interplay among G1 cyclins (D-type cyclins and cyclin E), cyclin-dependent kinases (cdk4, 6, and 2), cdk inhibitors, and protein phosphatases determines the phosphorylation state of the pocket proteins which in turn regulates the ability of the pocket proteins to complex with E2F. E2F activity is further regulated through direct interactions with other factors, such cyclin A, Sp1, p53 and the ubiquitin-proteasome pathway. Deregulated expression of E2F family member genes has been shown to induce both inappropriate S phase entry and apoptosis. An important role for E2F in the development of cancer is suggested by the finding that in most human neoplasias, genetic or epigenetic alterations occur that ultimately result in the deregulation of E2F-dependent transcription. This review will highlight recent findings on the specific roles of the individual E2F species in regulating transcription, proliferation and apoptosis, and discuss the growing link between E2F and cancer.
X‐ray diffraction study of gallium nitride grown by MOCVD (1996)

Abstract An X‐ray diffraction study of gallium nitride grown on the c‐plane (0001) and r‐plane (0112) of sapphire substrates by metal organic chemical vapour deposition using triethylgallium and ammonia was performed. By measuring asymmetric reflections with a ω‐2θ two‐circle diffractometer, lattice constants of α‐GaN could be resolved for both substrate orientations and the epitaxial relationships could be confirmed. Additionally, the existence of β‐GaN on the r‐plane sapphire substrate could be determined. Pole figure measurements show different qualities of in‐plane orientation of the α‐GaN layers for the two substrate orientations.
A Proof of the Strong Converse Theorem for Gaussian Multiple Access Channels (2016)

We prove the strong converse for the N -source Gaussian multiple access channel. In particular, we show that any rate tuple that can be supported by a sequence of codes with asymptotic average error probability <;1 must lie in the Cover-Wyner capacity region. Our proof consists of the following. First, we perform an expurgation step to convert any given sequence of codes with asymptotic average error probability <;1 to codes with asymptotic maximal error probability <;1. Second, we quantize the input alphabets with an appropriately chosen resolution. Upon quantization, we apply the wringing technique (by Ahlswede) on the quantized inputs to obtain further subcodes from the subcodes obtained in the expurgation step, so that the resultant correlations among the symbols transmitted by the different sources vanish as the blocklength grows. Finally, we derive upper bounds on achievable sum-rates of the subcodes in terms of the type-II error of a binary hypothesis test. These upper bounds are then simplified through judicious choices of auxiliary output distributions. Our strong converse result carries over to the Gaussian interference channel under strong interference as long as the sum of the two asymptotic average error probabilities <;1.
Treatment of experimental stroke (1982)

The effects of naloxone and thyrotropin releasing hormone (TRH) were compared in an incremental air embolization model of experimental stroke in dogs. Naloxone treatment significantly improved the cortical somatosensory evoked response and had a beneficial effect on local cerebral blood flow, whereas TRH treatment had no effect on these variables. These findings may implicate endorphins in the pathophysiology of stroke and indicate that naloxone may have a therapeutic role in this condition. Moreover, the lack of effect of TRH in this model, in contrast to its therapeutic effect in experimental spinal injury, indicates that the pathophysiologic responses to ischemic cerebral injury and traumatic spinal injury may differ.
Reversible acetylation of chromatin: Implication in regulation of gene expression, disease and therapeutics (2009)

The eukaryotic genome is a highly dynamic nucleoprotein complex that is comprised of DNA, histones, nonhistone proteins and RNA, and is termed as chromatin. The dynamic of the chromatin is responsible for the regulation of all the DNA-templated phenomena in the cell. Several factors, including the nonhistone chromatin components, ATP-dependent remodeling factors and the chromatin-modifying enzymes, mediate the combinatorial post-translational modifications that control the chromatin fluidity and, thereby, the cellular functions. Among these modifications, reversible acetylation plays a central role in the highly orchestrated network. The enzymes responsible for the reversible acetylation, the histone acetyltransferases (HATs) and histone deacetylases (HDACs), not only act on histone substrates but also on nonhistone proteins. Dysfunction of the HATs/HDACs is associated with various diseases like cancer, diabetes, asthma, cardiac hypertrophy, retroviral pathogenesis and neurodegenerative disorders. Therefore, modulation of these enzymes is being considered as an important therapeutic strategy. Although substantial progress has been made in the area of HDAC inhibitors, we have focused this review on the HATs and their small-molecule modulators in the context of disease and therapeutics. Recent discoveries from different groups have established the involvement of HAT function in various diseases. Furthermore, several new classes of HAT modulators have been identified and their biological activities have also been reported. The scaffold of these small molecules can be used for the design and synthesis of better and efficient modulators with superior therapeutic efficacy.
Kinetic Consequences of Covalent Linkage of DNA Binding Polyamides (2000)

Creatine action on the activity of creatine kinase (ATP: creatine-phosphotransferase; EC 2.7.3.2) and the content of water-soluble proteins in the developing monolayer culture of chick myoblasts are studied. Creatine at concentrations of 1.9-10- minus 3-3.8-10- minus 3 M is shown to increase reliably the creatine kinase activity by 1,1--2,9 times and to reduct considerably the content of water-soluble proteins. Lower concentrations of creatine (3.8-10- minus 5 M) also increased the creatine kinase activity but did not change the contents of water-soluble proteins. The creatine effect was maximal at the period preceding the termination of tissue cells differentiation. In the course of the combined effect of both actinomycin D (50 mcg/plate) and creatine (3.8-10- minus 3 M) the creatine kinase activity was much higher than that in the presence of actinomycin D alone which considerably reduced the enzyme activity as well as the contents of water-soluble proteins.
Visual comparison for information visualization (2011)

Data analysis often involves the comparison of complex objects. With the ever increasing amounts and complexity of data, the demand for systems to help with these comparisons is also growing. Increasingly, information visualization tools support such comparisons explicitly, beyond simply allowing a viewer to examine each object individually. In this paper, we argue that the design of information visualizations of complex objects can, and should, be studied in general, that is independently of what those objects are. As a first step in developing this general understanding of comparison, we propose a general taxonomy of visual designs for comparison that groups designs into three basic categories, which can be combined. To clarify the taxonomy and validate its completeness, we provide a survey of work in information visualization related to comparison. Although we find a great diversity of systems and approaches, we see that all designs are assembled from the building blocks of juxtaposition, superposition and explicit encodings. This initial exploration shows the power of our model, and suggests future challenges in developing a general understanding of comparative visualization and facilitating the development of more comparative visualization tools.
Discovery of NovelN-Phenylglycine Derivatives as Potent and Selective β3-Adrenoceptor Agonists for the Treatment of Frequent Urination and Urinary Incontinence (2001)

With a novel assay using isolated ferret detrusor to estimate β3-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a β2-adrenoceptor agonist, are potent β3-adrenoceptor agonists, with excellent selectivity versus β1 and β2 subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the β3-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f−i exhibited potent β3-adrenoceptor-mediated relaxation of ferret detrusor (EC50 = 0.93, 11, 14, and 160 nM) and higher potency at β3-adrenoceptors than at β1 or β2. The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED50 = 48 μg/kg) without cardiovascular side effects. This article is the first report of structure−activity relationships (SAR) concerning β3-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
A 2-kW Single-Phase Seven-Level Flying Capacitor Multilevel Inverter With an Active Energy Buffer (2017)

High-efficiency and compact single-phase inverters are desirable in many applications such as solar energy harvesting and electric vehicle chargers. This paper presents a 2-kW, 60-Hz, 450-VDC-to-240-VAC power inverter, designed and tested subject to the specifications of the Google/IEEE Little Box Challenge. The inverter features a seven-level flying capacitor multilevel converter, with low-voltage GaN switches operating at 120 kHz. The inverter also includes an active buffer for twice-line-frequency power pulsation decoupling, which reduces the required capacitance by a factor of 8 compared to conventional passive decoupling capacitors, while maintaining an efficiency above 99%. The inverter prototype is a self-contained box that achieves a high power density of 216 W/in <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> and a peak overall efficiency of 97.6%, while meeting the constraints including input current ripple, load transient, thermal, and FCC Class B EMC specifications.
Polymorphisms of cardiac presynaptic α 2C adrenergic receptors: Diverse intragenic variability with haplotype-specific functional effects (2004)

The presynaptic alpha2C adrenergic receptors (AR) act to inhibit norepinephrine release in cardiac and other presynaptic nerves. We have recently shown that a genetic variant in the alpha2CAR coding region (Del322-325), which renders the receptor partially uncoupled from Gi, is a risk factor for heart failure. However, variability of heart failure phenotypes and a dominance of Del322-325 in those of African descent led us to hypothesize that other regions of this gene have functional polymorphisms. In a multiethnic population, we found 20 polymorphisms within 4,625 bp of contiguous sequence of this intronless gene encompassing the promoter, 5' UTR, coding, and 3' UTR. These polymorphisms occur in 24 distinct haplotypes with complex organizations, including multiple 5'-upstream polymorphisms in regions known to direct expression, a 3' UTR substitution polymorphism within an insertion/deletion sequence, and the radical coding polymorphism that deletes four amino acids. Relatively low linkage disequilibrium between many polymorphisms, few cosmopolitan haplotypes, prevalent ethnic-specific haplotypes, and substantial genetic divergence among haplotypes was noted. The dysfunctional Del322-325 allele was partitioned into multiple haplotypes, with frequencies of 48% to 2%. The functional implications of the haplotypes were ascertained by whole-gene transfections of human neuronal cells, where haplotype was significantly related (P < 0.001) to expression levels of receptor transcript and protein. Expression varied by as much as approximately 50% by haplotype, and such studies enabled haplotype clustering by phenotypic, rather than genotypic, similarities. Thus, depending on phenotype, expression-specific haplotypes may amplify, attenuate, or dominate the cardiomyopathic effect attributed to the alpha2CDel322-325 marker.
Characterization of mutants within the gene for the adenovirus E3 14.7-kilodalton protein which prevents cytolysis by tumor necrosis factor (1993)

The 14,700-Da protein (14.7K protein) encoded by the E3 region of adenovirus has previously been shown to protect mouse cells from cytolysis by tumor necrosis factor (TNF). Delineating the sequences in the 14.7K protein that are required for this activity may provide insight into the mechanism of protection from TNF by 14.7K as well as the mechanism of TNF cytolysis. In the present study, we examined the ability of 14.7K mutants to protect cells from lysis by TNF. In-frame deletions as well as Cys-to-Ser mutations in the 14.7K gene were generated by site-directed mutagenesis and then built into the genome of a modified adenovirus type 5 (dl7001) that lacks all E3 genes. dl7001, which replicates to the same titers as does adenovirus type 5 in cultured cells, has the largest E3 deletion analyzed to date. 51Cr release was used to assay TNF cytolysis. Our results indicate that most mutations in the 14.7K gene result in a loss of function, suggesting that nearly the entire protein rather than a specific domain functions to prevent TNF cytolysis.
The Contribution of the N-Terminal Structure of Polymyxin B Peptides to Antimicrobial and Lipopolysaccharide Binding Activity (2004)

Abstract To elucidate the N-terminal structure–activity relationships of polymyxin B peptides, seven polymyxin B component peptides, the structures of which having been elucidated, and seven N-terminal fatty acid and/or amino acid deletion analogs were synthesized, and their antimicrobial activities determined. The lipopolysaccharide (LPS) binding activities of synthetic peptides were evaluated using [Dab(Dansyl-Gly)1]-polymyxin B3 (Dab; l-α,γ-diaminobutyric acid) as a fluorescent probe. The results indicated that the fatty acyl moiety was not indispensable for LPS binding, but the C9 fatty acyl groups of polymyxin B peptides contributed to the binding affinity to a slightly greater extent than C8 or C7. The fatty acyl moieties of polymyxin B contributed greatly to the antimicrobial activity, while the distinct N-terminal structures of polymyxin B1–B6, bearing normal-, iso-, or anteiso-fatty acids, or 3-hydroxy-fatty acid with chain lengths between C7 and C9, did not affect bactericidal potency.
IL-8 responsiveness defines a subset of CD8 T cells poised to kill (2004)

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)-responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-gamma (IFNgamma), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1-specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.
Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study (2015)

NCT02061293.
Combined transgenic expression of α-galactosidase and α1,2-fucosyltransferase leads to optimal reduction in the major xenoepitope Galα(1,3)Gal (1997)

Hyperacute rejection of pig organs by humans involves the interaction of Galalpha(1,3)Gal with antibodies and complement. Strategies to reduce the amount of xenoantigen Galalpha(1,3)Gal were investigated by overexpression of human lysosomal alpha-galactosidase in cultured porcine cells and transgenic mice. The overexpression of human alpha-galactosidase in cultured porcine endothelial cells and COS cells resulted in a 30-fold reduction of cell surface Galalpha(1,3)Gal and a 10-fold reduction in cell reactivity with natural human antibodies. Splenocytes from transgenic mice overexpressing human alpha-galactosidase showed only a 15-25% reduction in binding to natural human anti-Galalpha(1,3)Gal antibodies; however, this decrease was functionally significant as demonstrated by reduced susceptibility to human antibody-mediated lysis. However, because there is residual Galalpha(1,3)Gal and degalactosylation results in the exposure of N-acetyllactosamine residues and potential new xenoepitopes, using alpha-galactosidase alone is unlikely to overcome hyperacute rejection. We previously reported that mice overexpressing human alpha1,2-fucosyltransferase as a transgene had approximately 90% reduced Galalpha(1,3)Gal levels due to masking of the xenoantigen by fucosylation; we evaluated the effect of overexpressing alpha-galactosidase and alpha1,2-fucosyltransferase on Galalpha(1,3)Gal levels. Galalpha(1, 3)Gal-positive COS cells expressing alpha1,3-galactosyltransferase, alpha1,2-fucosyltransferase, and alpha-galactosidase showed negligible cell surface staining and were not susceptible to lysis by human serum containing antibody and complement. Thus, alpha1, 2-fucosyltransferase and alpha-galactosidase effectively reduced the expression of Galalpha(1,3)Gal on the cell surface and could be used to produce transgenic pigs with negligible levels of cell surface Galalpha(1,3)Gal, thereby having no reactivity with human serum and improving graft survival.
Regulation of Caspase 9 through Phosphorylation by Protein Kinase C Zeta in Response to Hyperosmotic Stress (2005)

Caspase 9 is a critical component of the mitochondrial or intrinsic apoptotic pathway and is activated by Apaf-1 following release of cytochrome c from mitochondria in response to a variety of stimuli. Caspase 9 cleaves and activates effector caspases, mainly caspase 3, leading to the demise of the cell. Survival signaling pathways can impinge on this pathway to restrain apoptosis. Here, we have identified Ser144 of human caspase 9as an inhibitory site that is phosphorylated in a cell-free system and in cells in response to the protein phosphatase inhibitor okadaic acid. Inhibitor sensitivity and interactions with caspase 9 indicate that the predominant kinase that targets Ser144 is the atypical protein kinase C isoform zeta (PKCzeta). Prevention of Ser144 phosphorylation by inhibition of PKCzeta or mutation of caspase 9 promotes caspase 3 activation. Phosphorylation of serine 144 in cells is also induced by hyperosmotic stress, which activates PKCzeta and regulates its interaction with caspase 9, but not by growth factors, phorbol ester, or other cellular stresses. These results indicate that phosphorylation and inhibition of caspase 9 by PKCzeta restrain the intrinsic apoptotic pathway during hyperosmotic stress. This work provides further evidence that caspase 9 acts as a focal point for multiple protein kinase signaling pathways that regulate apoptosis.
Protein kinases in divergent eukaryotes: identification of protein kinase activities regulated during trypanosome development. (1993)

The role of protein kinases in organisms that diverged early in the eukaryotic lineage is relatively unexplored. In this study, we determined that primitive parasitic protozoa possess multiple protein-serine kinases and inferred the presence of protein-tyrosine kinases through sensitive immunoblotting techniques. To further explore the role of protein kinases in parasite development, we examined the activity of eight renaturable protein kinases during the life cycle of the protozoan parasite Trypanosoma brucei. The activities of six protein-serine/threonine kinases were regulated during development, with several distinct patterns of regulation. In addition, an 89-kDa protein kinase was detected in dividing cells but not in nondividing cells. Our data indicate that even the most primitive eukaryotes possess a large complement of protein kinases, including protein-tyrosine kinases as well as protein-serine/threonine kinases. The data further suggest that protein kinases may play a pivotal role in regulation of proliferation and differentiation in protozoa.
[Magnifying endoscopic observation on the effect of a proton pump inhibitor on the healing process of gastric ulcer]. (1992)

The effect of a proton pump inhibitor on the healing process of gastric ulcer was investigated through magnifying endoscopic observation of the regenerated mucosa. The findings were the same obtained as those by stereoscopic microscopic observation of the effect of conventional drugs. Namely, a structureless red area consisting of one layer of regenerated epithelium was the first to procede forward the ulcer base, and a radially arranged roughly striated pattern of regenerated mucosa, in which gastric glands were formed. The regenerated mucosa changed from a striated to a granular pattern. In a shallow ulcer, the ulcer scar showed a fine gastric mucosal pattern similar to that of the surrounding area. The strong inhibition of gastric acid secretion by a proton pump inhibitor is believed to raise no problems in the healing process of peptic ulcer. The magnifying endoscopic observation also disclosed that the protruding granulation disappeared gradually and changed to concave regenerated epithelium, suggesting that the ulcer base protrusion, which has been considered as an adverse effect of strong acid secretion inhibitors, has no influence on the healing of the ulcer.