gebhart/patrepeval huggingface dataset:
Dimerization of simian virus 40 T-antigen hexamers activates T-antigen DNA helicase activity (1997)

Chromosomal DNA replication in higher eukaryotes takes place in DNA synthesis factories containing numerous replication forks. We explored the role of replication fork aggregation in vitro, using as a model the simian virus 40 (SV40) large tumor antigen (T antigen), essential for its DNA helicase and origin-binding activities. Previous studies have shown that T antigen binds model DNA replication forks primarily as a hexamer (TAgH) and to a lesser extent as a double hexamer (TAgDH). We find that DNA unwinding in the presence of ATP or other nucleotides strongly correlates with the formation of TAgDH-DNA fork complexes. TAgH- and TAgDH-fork complexes were isolated, and the TAgDH-bound fork was denatured at a 15-fold-higher rate during the initial times of unwinding. TAgDH bound preferentially to a DNA substrate containing a 50-nucleotide bubble, indicating the bridging of each single-stranded DNA/duplex DNA junction, and this DNA molecule was also unwound at a high rate. Both the TAgH- and TAgDH-fork complexes were relatively stable, with the half-life of the TAgDH-fork complex greater than 40 min. Our data therefore indicate that the linking of two viral replication forks serves to activate DNA replication.
Basic and clinical aspects of visceral sensation: transmission in the CNS (2005)

Pain and discomfort are the leading cause for consultative visits to gastroenterologists. Acute pain should be considered a symptom of an underlying disease, thereby serving a physiologically important function. However, many patients experience chronic pain in the absence of potentially harmful stimuli or disorders, turning pain into the primary problem rather than a symptom. Vagal and spinal afferents both contribute to the sensory component of the gut-brain axis. Current evidence suggests that they convey different elements of the complex sensory experience. Spinal afferents play a key role in the discriminatory dimension, while vagal input primarily affects the strong emotional and autonomic reactions to noxious visceral stimuli. Drugs, surgical and non-pharmacological treatments can target these pathways and provide therapeutic options for patients with chronic visceral pain syndromes.
Pain alleviation by vibratory stimulation (1984)

In the present study 366 patients suffering acute or chronic musculoskeletal pain of different origin were given vibratory stimulation for the pain. Many of the patients had previously had treatments of various kinds without satisfactory relief. The effect of vibratory stimulation was assessed during and after stimulation using a graphic rating scale. Sixty-nine per cent of the patients reported a reduction of pain during vibratory stimulation. The best pain reducing site was found to be either the area of pain, the affected muscle or tendon, the antagonistic muscle or a trigger point outside the painful area. In most patients the best pain reducing effect was obtained when the vibratory stimulation was applied with moderate pressure. To obtain a maximal duration of pain relief the stimulation had to be applied for about 25-45 min.
Combined DNA Methyltransferase and Histone Deacetylase Inhibition in the Treatment of Myeloid Neoplasms (2006)

Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials.
miR-155 : On the Crosstalk Between Inflammation and Cancer (2009)

MicroRNAs are short non-coding RNAs that posttranscriptionally modulate the expression of multiple target genes and are thus implicated in a wide array of cellular and developmental processes. miR-155 is processed from BIC, a non-coding transcript highly expressed in both activated B and T cells and in monocytes/macrophages. miR-155 levels change dynamically during both hematopoietic lineage differentiation and the course of the immune response. Different mouse models developed recently indicate that miR-155 plays a critical role during hematopoiesis and regulates lymphocyte homeostasis and tolerance. A moderate increase of miR-155 levels is observed in many types of malignancies of B cell or myeloid origin, and transgenic over-expression of miR-155 in mice results in cancer. While the high levels of miR-155 reached transiently during the course of the immune response remain unharmful for the organism, the reason why a moderate up-regulation of miR-155 can lead to cancer remains obscure. As prolonged exposure to inflammation can lead to cancer, the permanent up-regulation of miR-155 might be a link between the two. Therefore, designing miR-155 based therapies will require a better understanding of the molecular basis of its action as well as of how miR-155 levels are regulated in a cell-specific manner.
Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating (2008)

Fibrotic rigidification following a myocardial infarct is known to impair cardiac output, and it is also known that cardiomyocytes on rigid culture substrates show a progressive loss of rhythmic beating. Here, isolated embryonic cardiomyocytes cultured on a series of flexible substrates show that matrices that mimic the elasticity of the developing myocardial microenvironment are optimal for transmitting contractile work to the matrix and for promoting actomyosin striation and 1-Hz beating. On hard matrices that mechanically mimic a post-infarct fibrotic scar, cells overstrain themselves, lack striated myofibrils and stop beating; on very soft matrices, cells preserve contractile beating for days in culture but do very little work. Optimal matrix leads to a strain match between cell and matrix, and suggests dynamic differences in intracellular protein structures. A 'cysteine shotgun' method of labeling the in situ proteome reveals differences in assembly or conformation of several abundant cytoskeletal proteins, including vimentin, filamin and myosin. Combined with recent results, which show that stem cell differentiation is also highly sensitive to matrix elasticity, the methods and analyses might be useful in the culture and assessment of cardiogenesis of both embryonic stem cells and induced pluripotent stem cells. The results described here also highlight the need for greater attention to fibrosis and mechanical microenvironments in cell therapy and development.
Comparison between carbon nanoparticles and methylene blue on cell tracking of sentinel lymph node for papillary thyroid carcinoma (2017)

Objective
To evaluate the value of methylene blue and carbon nanoparticles as cell tracer in the sentinel lymph node (SLN) for papillary thyroid carcinoma.


Methods
130 patients with papillary thyroid carcinoma were enrolled in the study. The patients were divided into two groups randomly, which were given sentinel lymph node biopsy with either methylene blue or carbon nanoparticles. The sentinel lymph node location and number were recorded, followed by ipsilateral functional cervix lymph node dissection. Then the sentinel lymph node and dissected cervix lymph nodes were subject to pathology examination respectively. Experimental data were statistically analyzed byttest, chi-square test and fisher exact probability test when appropriate.


Results
In 65 patients in the methylene blue group, SLN were identified in 52 patients, with 27 having histopathologically positive lymph nodes. The detection rate, sensitivity, accuracy rate and false negative rate were 80﹪, 84.38﹪, 90.38﹪, and 15.62﹪, respectively. Whereas in the carbon nanoparticles group, SLN were identified in 61 patients, with 30 having histopathologically positive lymph nodes.The detection rate, sensitivity, accuracy rate and false negative rate were 93.84﹪, 90.91﹪, 95.08﹪, and 9.09﹪, respectively.The difference of the detection rate was significant (χ2= 5.482, P= 0.019) . There was no significantly difference on the distribution of the detected SLN in regions between the two groups (χ2= 1.043,P= 0.791) .The detection rate and positive rate of SLN were both highest in regionⅣandⅥin the two groups.And there was no significantly difference between the two groups (χ2= 1.043, P= 0.425; χ2= 0.012, P= 0.914) .


Conclutions
Methylene blue and cabon nanoparticles are both feasible in intraoperative SLN identification. They could reflect lymphatic metastasis accurately and be instructive to cervix lymph nodes dissection. Carbon nanoparticles tracer provides clearer surgery field and has higher detection rate.


Key words: 
Thyroid neoplasms; Sentinel lymph node; Nanostructures; Carbon; Methylene blue; Cell tracking
Depletion of CD4+CD25+ human regulatory T cells in vivo: Kinetics of Treg depletion and alterations in immune functions in vivo and in vitro (2007)

The aim of this study was to investigate whether depletion of CD4(+)CD25(+) regulatory T cells (Treg) from melanoma patients affects immune responses against tumors. By application of recombinant IL-2-diphteria toxin fusion protein, also known as ONTAK, we were able to significantly reduce the frequency of Treg in peripheral blood, whereas other cell populations remained unaffected. The reduction of Treg started immediately after the first bolus of ONTAK with a dose of 5 microg ONTAK per kg bodyweight and lasted for 13 days with subsequent recovery thereafter. Successive ONTAK treatments further reduced the number of circulating Treg. Using the contact sensitizer DCP we show that all patients developed vast eczema after Treg depletion, whereas no or only mild eczematous reactions were detectable before ONTAK treatment. Corresponding induction of DCP-specific CD4(+) and CD8(+) T cells were detectable. Moreover, after immunization of ONTAK treated patients with tumor antigen peptides, MelanA/MART-1 and gp100, significant induction of peptide specific CD8(+) T cells could be observed in 90% of the patients treated. These cells displayed effector functions, as they were able to lyse peptide-pulsed target cells and secreted IFNgamma upon restimulation. In aggregate, our data indicate that ONTAK depletes Treg in vivo significantly, resulting in enhanced immune functions and substantial development of antigen-specific CD8(+) T cells in vaccinated individuals.
Using structural analysis to generate parasite‐selective monoclonal antibodies (2008)

Diagnosis of eukaryotic parasitic infection using antibody-based tests such as ELISAs (enzyme-linked immunosorbent assays) is often problematic because of the need to differentiate between homologous host and pathogen proteins and to ensure that antibodies raised against a peptide will also bind to the peptide in the context of its three-dimensional protein structure. Filariasis caused by the nematode, Brugia malayi, is an important worldwide tropical disease in which parasites disappear from the bloodstream during daylight hours, thus hampering standard microscopic diagnostic methods. To address this problem, a structural approach was used to develop monoclonal antibodies (mAbs) that detect asparaginyl-tRNA synthetase (AsnRS) secreted from B. malayi. B. malayi and human AsnRS amino acid sequences were aligned to identify regions that are relatively unconserved, and a 1.9 A crystallographic structure of B. malayi AsnRS was used to identify peptidyl regions that are surface accessible and available for antibody binding. Sequery and SSA (Superpositional Structural Analysis) software was used to analyze which of these peptides was most likely to maintain its native conformation as a synthetic peptide, and its predicted helical structure was confirmed by NMR. A 22-residue peptide was synthesized to produce murine mAbs. Four IgG(1) mAbs were identified that recognized the synthetic peptide and the full-length parasite AsnRS, but not human AsnRS. The specificity and affinity of mAbs was confirmed by Western blot, immunohistochemistry, surface plasmon resonance, and enzyme inhibition assays. These results support the success of structural modeling to choose peptides for raising selective antibodies that bind to the native protein.
Comparison of Various Envelope Proteins for Their Ability to Pseudotype Lentiviral Vectors and Transduce Primitive Hematopoietic Cells from Human Blood (2002)

Substantial effort has been invested in developing methodologies for efficient gene transfer into human, repopulating, hematopoietic stem cells. Oncoretroviral vectors are limited by the lack of nuclear mitosis in quiescent stem cells during ex vivo transduction, whereas the preintegration complex of lentiviral vectors contains nuclear-localizing signals that permit genome integration without mitosis. We have developed a flexible and versatile system for generating lentiviral vector particles and have pseudotyped such particles with amphotropic, ecotropic, feline endogenous virus (RD114) or vesicular stomatitis virus (VSV-G) envelope proteins. Particles of all four types could be concentrated approximately 100-fold by ultracentrifugation or ultrafiltration. RD114 or amphotropic particles were more efficient than VSV-G-pseudotyped particles at transducing human cord blood CD34(+) cells and clonogenic progenitors within that population. Amphotropic particles transduced cytokine-mobilized, human peripheral blood CD34(+) cells capable of establishing hematopoiesis in immunodeficient mice more efficiently than the other two types of particles. We conclude that the use of amphotropic pseudotyped lentiviral vector particles rather than the commonly used VSV-G-pseudotyped particles should be considered in potential applications of lentiviral vectors for gene transfer into this therapeutically relevant target cell population.
Melanophilin and myosin Va track the microtubule plus end on EB1 (2005)

In mouse melanocytes, myosin Va is recruited onto the surface of melanosomes by a receptor complex containing Rab27a that is present in the melanosome membrane and melanophilin (Mlp), which links myosin Va to Rab27a. In this study, we show that Mlp is also a microtubule plus end–tracking protein or +TIP. Moreover, myosin Va tracks the plus end in a Mlp-dependent manner. Data showing that overexpression and short inhibitory RNA knockdown of the +TIP EB1 have opposite effects on Mlp–microtubule interaction, that Mlp interacts directly with EB1, and that deletion from Mlp of a region similar to one in the adenomatous polyposis coli protein involved in EB1 binding blocks Mlp's ability to plus end track argue that Mlp tracks the plus end directly by hitchhiking on EB1. These results identify a novel +TIP and indicate that vertebrate cells possess a +TIP complex that is similar to the Myo2p–Kar9p–Bim1p complex in yeast. We suggest that the +TIP complex identified in this study may serve to focus the transfer of melanosomes from microtubules to actin at the microtubule plus end.
Survival of adult bone marrow transplant patients receiving mechanical ventilation: a case for restricted use. (1993)

A retrospective study of all adults receiving BMT over a 13 year period at a large transplant center was performed to determine overall survival and prognostic indicators of poor outcome among patients receiving mechanical ventilation (MV). Of 653 adult BMT patients, 191 (29%) received MV after transplant. Of these 191, 161 (84%) died on the ventilator or within hours of extubation; 18 (10%) survived 1 week after extubation and 6 (3%) survived 6 months. Survival was not predicted by type of graft, use of total body irradiation (TBI) or reason for intubation. The patient's age and the timing of intubation were predictive of survival. Of patients > or = 40 years, 98% died within a week of extubation and all died within 30 days. Similarly, of those intubated within 90 days of transplant, 94% died within a week of extubation and all died by day 100. These results suggest that MV is rarely effective in achieving long-term survival in adult BMT recipients, especially older patients and those early in their transplant course. An argument, based on cost/benefit considerations and medical futility, can be developed to withhold MV in certain patient subsets apart from a clinical research trial.
Aqueous-Phase Hydrodechlorination of 2,4-Dichlorophenol over Pd/Al2O3:  Reaction under Controlled pH (2007)

The aqueous-phase hydrodechlorination (HDC) of 2,4-dichlorophenol (2,4-DCP) over a Pd/Al2O3 catalyst has been studied with adjustment of the bulk solution pH either by base (NaOH and NH4OH) addition prereaction or with a continual supply of base during HDC. With a starting pH in the range 7−11.6, the solution pH can be controlled to within ±0.1 with an external supply of NaOH during HDC. A preliminary kinetic analysis suggests that 2,4-DCP HDC is predominately stepwise, yielding 2-chlorophenol (2-CP) as the partially dechlorinated product, which is further converted to phenol and ultimately to cyclohexanone. Pd/Al2O3, operating under controlled pH, delivered maximum HDC activity in the pH range 7−8, where the selectivity with respect to 2-CP was lower than that associated with pH = 11.6. In the absence of mass transport constraints, initial HDC rate as a function of 2,4-DCP concentration exhibits Langmuir−Hinshelwood mechanistic behavior involving competitive adsorption of H2 and 2,4-DCP with the surface addition of two H atoms as rate limiting. The pH effect on initial HDC rate can be represented by a generic correlation that demonstrates a 4-fold increase in 2,4-DCP adsorption, where solution pH was lowered from 13 to 7 but there was a pH insensitivity with respect to the rate constant for surface reaction.
Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women (1983)

A comparative study was done in women and men of the effects of delta 9-tetrahydrocannabinol (delta 9-THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. delta 9-THC is converted by microsomal hydroxylation to 11-hydroxy-delta 9-THC (11-OH-delta 9-THC), which is both a key intermediate for further metabolism to 11-nor-delta 9-THC-9-carboxylic acid (11-nor-acid) by liver alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11-OH-delta 9-THC to that of delta 9-THC in plasma were found after intravenous dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11-nor-acids and the related, more polar acids. Urinary excretion of delta 9-THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11-OH-delta 9-THC were particularly noteworthy. Kinetics of delta 9-THC and metabolites were much the same for female and male subjects. For delta 9-THC, terminal-phase t1/2s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AUC/dose (delta 9-THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous delta 9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).
Conotoxins as selective inhibitors of neuronal ion channels, receptors and transporters (2004)

Cone snails have evolved a vast array of peptide toxins for prey capture and defence. These peptides are directed against a wide variety of pharmacological targets, making them an invaluable source of ligands for studying the properties of these targets in normal and diseased states. A number of these peptides have shown efficacy in vivo, including inhibitors of calcium channels, the norepinephrine transporter, nicotinic acetylcholine receptors, NMDA receptors and neurotensin receptors, with several having undergone pre-clinical or clinical development for the treatment of pain.
Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. (1976)

The prostaglandin synthetase system of bovine vesicular gland microsomes was solubilized and separated into Fractions I and II. The former fraction catalyzed the conversion of 8,11,14-eicosatrienoic acid to prostaglandin H1 (9 alpha, 11alpha-epidioxy-15(S)-hydroxy-13-trans-prostenoic acid). This compound was isomerized to prostaglandin E1 (11alpha, 15(S)-dihydroxy-9-keto-13-trans-prostenoic acid) by the action of Fraction II (Miyamoto, T., Yamamoto, S., and Hayaishi, O. (1974) Proc. Natl. Acad. Sci. U.S.A. 71, 3645-3648). Fraction I was further purified by isoelectric focusing and about a 700-fold purification was achieved starting from the microsomes. When the enzyme was incubated with 8,11,14-eicosatrienoic acid in the presence of hematin, an unstable compound which was distinguishable from prostaglandin H1 accumulated. The chemical properties of this compound were identical with those of prostaglandin G1 (9 alpha, 11 alpha-epidioxy-15(S)-hydroperoxy-13-trans-prostenoic acid). The enzyme also catalyzed the conversion of prostaglandin G1 to H1 when heme and tryptophan were supplied. Thus, the purified enzyme, which was provisionally referred to as prostaglandin endoperoxide synthetase, exhibited two enzyme activities: the synthesis of prostaglandin G1 and its conversion to prostaglandin H1. Either free or protein-bound heme was required for both reactions, and only protoheme was active. Tryptophan stimulated the conversion of prostaglandin G1 to H1, and this stimulatory effect was also observed with various other aromatic compounds. Indomethacin and aspirin inhibited prostaglandin G1 synthesis, but not the other steps of prostaglandin biosynthesis.