gebhart/patrepeval huggingface dataset:
Long‐term efficacy and safety of safinamide as add‐on therapy in early Parkinson's disease (2012)

The pooled data from the safinamide groups failed to reach statistical significance for the primary endpoint of median time from baseline to additional drug intervention. Post hoc analyses indicate that safinamide 100 mg/day may be effective as add-on treatment to DA in PD.
Mechanistic studies with general acyl-CoA dehydrogenase and butyryl-CoA dehydrogenase: evidence for the transfer of the .beta.-hydrogen to the flavin position N(5) as a hydride (1984)

Butyryl-CoA dehydrogenase from Megasphera elsdenii catalyzes the exchange of the alpha- and beta-hydrogens of substrate with solvent [Gomes, B., Fendrich, G., & Abeles, R. H. (1981) Biochemistry 20, 1481-1490]. The stoichiometry of this exchange was determined by using 3H2O label as 1.94 +/- 0.1 per substrate molecule. The rate of 3H label incorporation into substrate under anaerobic conditions is monophasic, indicating that both the alpha- and beta-hydrogens exchange at the same rate. The exchange in 2H2O leads to incorporation of one 2H each into the alpha- and the beta-positions of butyryl-CoA, as determined by companion 1H NMR experiments and confirmed by mass spectroscopic analysis. In contrast, with general acyl-CoA dehydrogenase from pig kidney, only exchange of the alpha-hydrogen was found. The beta-hydrogen is the one that is transferred (reversibly) to the flavin 5-position during substrate dehydrogenation. This was demonstrated by reacting 5-3H- and 5-2H-reduced 5-deaza-FAD-general acyl-CoA dehydrogenase with crotonyl-CoA. Only one face of the reduced flavin analogue is capable of transferring hydrogen to substrate. The rate of this reaction is 11.1 s-1 for 5-deaza-FAD-enzyme and 2.2 s-1 for [5-2H]deaza-FAD-enzyme, yielding an isotope effect of 5. These values compare with a rate of 2.6 s-1 for the reaction of native reduced enzyme with crotonyl-CoA. The two reduced enzymes (normal vs. 5-deaza-FAD-enzyme) thus react at similar rates, indicating a similar mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Nasal Colonization with Streptococcus pneumoniae Includes Subpopulations of Surface and Invasive Pneumococci (2005)

We demonstrated that during colonization with Streptococcus pneumoniae the nasal mucosal tissues of mice support two populations of pneumococci. Transparent-phase pneumococci can be readily washed from the outer surface, while a second population composed of primarily opaque-phase pneumococci is released only by homogenization of the nasal tissue. The fact that the opaque phase has previously been associated with invasion and the fact that opaque-phase pneumococci were released by homogenization of previously washed nasal tissue suggest that the opaque-phase pneumococci may have invaded the nasal tissue. Consistent with this hypothesis was our observation that there was inflammation in portions of the nasal mucosa of the colonized mice but not in the mucosa of noncolonized mice, but this observation did not prove the hypothesis. If the opaque-phase pneumococci released from the nasal tissue were from within the tissue and/or if resistance of the opaque-phase subpopulation to antibody, complement, and phagocytes is essential for long-term carriage, it seems likely that the virulence factors of S. pneumoniae that are necessary for killing humans exist to facilitate carriage. Although this speculation is unproven, the observation that there are separate populations of pneumococci during colonization may help guide future attempts to understand the biology of nasal colonization by this pathogen.
Isolation of Plasma Kallikrein by High Efficiency Affinity Chromatography and Its Characterization. (2001)

We established a simple method for the purification of human plasma kallikrein (PK) by affinity chromatography and characterized it by analytical reverse phase-HPLC and Time of Flight Mass Spectroscopy (TOF-MS). The affinity resin (PKSI-Toyopearl) was synthesized using a selective synthetic inhibitor of plasma kallikrein (PKSI-527) as a ligand. The resin was found to have the highest efficiency in PK purification when the coupling ratio of PKSI-527 per resin was 9-14 micromol/g. PK was purified 466-fold with a yield of 83% from acetone-activated human plasma by affinity chromatography. The purity of PK thus obtained was confirmed by reverse phase-HPLC with a linear gradient of acetonitrile. The molecular weight of the purified PK was determined to be 86,151 by TOF-MS.
Membrane Raft-Dependent Regulation of Phospholipase Cγ-1 Activation in T Lymphocytes (2001)

Numerous signaling molecules associate with lipid rafts, either constitutively or after engagement of surface receptors. One such molecule, phospholipase Cgamma-1 (PLCgamma1), translocates from the cytosol to lipid rafts during T-cell receptor (TCR) signaling. To investigate the role played by lipid rafts in the activation of this molecule in T cells, an influenza virus hemagglutinin A (HA)-tagged PLCgamma1 was ectopically expressed in Jurkat T cells and targeted to these microdomains by the addition of a dual-acylation signal. Raft-targeted PLCgamma1 was constitutively tyrosine phosphorylated and induced constitutive NF-AT-dependent transcription and interleukin-2 secretion in Jurkat cells. Tyrosine phosphorylation of raft-targeted PLCgamma1 did not require Zap-70 or the interaction with the adapters Lat and Slp-76, molecules that are necessary for TCR signaling. In contrast, the Src family kinase Lck was required. Coexpression in HEK 293T cells of PLCgamma1-HA with Lck or the Tec family kinase Rlk resulted in preferential phosphorylation of raft-targeted PLCgamma1 over wild-type PLCgamma1. These data show that localization of PLCgamma1 in lipid rafts is sufficient for its activation and demonstrate a role for lipid rafts as microdomains that dynamically segregate and integrate PLCgamma1 with other signaling components.
Genetic and Epidemiological Studies of Dengue Type 2 Viruses by Hybridization Using Synthetic Deoxyoligonucleotides as Probes (1986)

A rapid nucleic acid hybridization procedure was developed for examining the genotypic variation of dengue type 2 viruses (DEN 2) having distinct RNase T1 fingerprints and isolated from different geographical areas. Synthetic DNA hybridization probes were constructed complementary in nucleotide sequence to common and unique RNase T1 oligonucleotides of topotype viruses from Puerto Rico/South Pacific, Jamaica, the Seychelles, Thailand/Burma and Africa. Hybridization probes with both type- and topotype-specific reactivities were observed, as were probes specific for two or more of the DEN 2 topotypes. These results confirm geographical movement of topotype virus strains and suggest possible origins. Detection of DEN 2 RNA by hybridization is a rapid and reproducible method that can be modified and applied as a viable alternative to the laborious T1 oligonucleotide fingerprinting.
Differential expression of tissue inhibitor of metalloproteinases‐3 in cultured astrocytes and neurons regulates the activation of matrix metalloproteinase‐2 (2007)

Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in the pathogenesis of several neurological diseases. Secreted in proforms, the MMPs require activation. Tissue inhibitors of matrix metalloproteinases (TIMPs) regulate the activity of MMPs. We investigated the expression of MMP-2 and -9, and the role of the TIMP-3 in MMP-2 activation, using cultures of cortical neurons and astrocytes. Under basal conditions, astrocytes and neurons produced low levels of pro-MMP-2, and -9. Stimulation with lipopolysaccharide (LPS) markedly increased pro-MMP-9 production in astrocytes, with only a slight increase in neurons. Pro-MMP-2 were constitutively expressed in both cell types, but with a much higher level in the astrocytes. Real-time RT-PCR showed that the mRNA levels of MMP-2 and -9 paralleled their gelatinolytic activities in the gelatin zymograms. Interestingly, active MMP-2 was observed only in neuronal cultures. TIMP-2 and TIMP-3 are constitutively expressed in astrocytes and neurons. However, astrocytes expressed much higher levels of TIMP-3 mRNA and protein than neurons. Knockdown of TIMP-3 with small interfering RNA (siRNA) significantly increased MMP-2 activation in astrocytes. These results indicate that astrocytes are a more important intrinsic cellular source of MMP-2 and -9 than neurons under normal and neuroinflammatory conditions. TIMP-3 may be the key factor determining the differential activation of MMP-2 in astrocytes and neurons.
Lignin—Polysaccharide Interactions in Woody Plants (1999)

Hemicellulose and lignin are theorized to be linked to one another through covalent bonds, and these bonds are thought to limit rapid chemical and biochemical breakdown of woody biomass. After years of study, the mechanism by which lignin and hemicellulose interact with one another is still not clear. This information is crucial to our understanding of wood biosynthesis and the organization of the cell wall three-dimensional matrix. An overview of what is known about these interactions is presented, and bonding patterns are suggested to support the chemical and spectroscopic data reported in the literature.
Cell surface expression of human cytomegalovirus (HCMV) gp55-116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response (1990)

Cell surface expression of the human cytomegalovirus (HCMV) major envelope glycoprotein complex, gp55-116 (gB), was studied by using monoclonal antibodies and an HCMV gp55-116 (gB) recombinant vaccinia virus. HCMV-infected human fibroblasts and recombinant vaccinia virus-infected HeLa cells expresses three electrophoretically distinct proteins of Mr 170,000, 116,000, and 55,000 on their surface. These species have been previously identified within infected cells and purified virions. Two unique neutralizing epitopes were shown to be present on the cell surface gp55-116 (gB). Utilizing HeLa cells infected with the gp55-116 recombinant vaccinia virus as a specific immunosorbent, we have shown that approximately 40 to 70% of the total serum virus-neutralizing activity of a group of individuals with past HCMV infections was directed against this single envelope glycoprotein. The implications of this finding for vaccine development are discussed.
Mechanical and Electrical Properties of Multiwall Nanotube under Interlayer Sliding (2005)

We have successfully measured the sliding force for an interlayer of individual multiwall carbon nanotubes using a combination of a well-controlled electrical breakdown process and a manipulation process using a scanning electron microscope. A sliding force of ∼4 nN for an inner layer diameter of 5 nm is maintained constant during a sliding process. This result agrees well with the theoretical calculation. This agreement indicates that the layered structure exhibits ideal characteristics even after the electrical breakdown process. We have also proposed nanoscale variable resistors using the sliding mechanism of the interlayer of individual multiwall carbon nanotubes. The two-terminal resistance of the processed nanotube increases exponentially with the sliding distance under a low bias voltage and is proportional to the sliding distance under a high bias voltage. The variation of the resistance under the low bias voltage can be explained as a one dimensional localized system, with a characteristic localization length around 840 nm. On the contrary, the sliding nanotube acts as the diffusive conductor under a high bias voltage. [DOI: 10.1380/ejssnt.2005.86]
Hyper-Reactivity to Atropine in Down's Syndrome (1968)

Patients with Down's syndrome respond with abnormally great mydriasis to conjunctivally instilled atropine. This finding has been attributed to a structural anomaly of the Iris. To define the systemic reactivity to atropine in mongolism, the effects of intravenous atropine on heart rate were determined in three age-matched groups: 12 patients with Down's syndrome; 10 retardates without the syndrome; and 10 normal subjects. The patients with Down's syndrome, although reacting normally to atropine's bradycrotic or vagotonic action, had a markedly increased (twice normal or greater) sensitivity to the cardioacceleratory effects of atropine. This increased sensitivity, a pharmacogenetic abnormality, may result from the genetic imbalance imposed by an extra chromosome 21 in Down's syndrome.
Hypothermia and Acute Pancreatitis: Myth or Reality? (2003)

Among the rarer causes of acute pancreatitis listed in surgical texts is hypothermia. To assess the evidence for cause and effect, we questioned selected consultants about their experience and examined the case-notes of patients admitted with hypothermia. The 31 consultants who returned our questionnaire (69% response rate; 317 consultant-years’ experience) could recall only 5 cases of pancreatitis associated with hypothermia, in 2 of which other aetiological factors were judged primary. In case-notes for 100 months of emergency admissions at a single hospital we identified 310 patients with hypothermia and 1153 with acute pancreatitis; none had the dual diagnosis. Of the hypothermic patients, none had abdominal pain typical of acute pancreatitis. In 43 serum amylase was measured because the patient was unable to give a full history and in 2 of these the enzyme was slightly raised; both had experienced a cerebrovascular accident, which is a known cause of hyperamylasaemia. Considered alongside the weak evidence from previous studies, these findings offer negligible support for the idea that hypothermia is a clinically relevant risk factor for acute pancreatitis.
Intracellular Signals as Molecular Biomarkers for Therapeutic Responses in Kras Mutant Myeloid Cells. (2007)

Abstract Somatic RAS mutations are found in many human cancers, including lung, pancreas, and colon carcinomas, melanoma, and myeloid malignancies. Most of these diseases respond poorly to current treatments. Mutant RAS alleles found in leukemia and other cancers encode proteins that accumulate in a constitutively active GTP-bound conformation, and aberrantly activate downstream effectors such as Raf/MEK/ERK, PI-3K/Akt, and Ral-GDS pathways. To investigate the mechanisms by which hyperactive Ras deregulates myeloid growth, we generated Mx1-Cre , LSL-KrasG12D mice, which harbor a conditional oncogenic KrasG12D allele and uniformly develop a fatal myeloproliferative disease (MPD) after induction of KrasG12D expression (Braun et al., PNAS 10, 597, 2004). In contrast to acute myeloid leukemia (AML), which typically demonstrates multiple mutations, MPD are caused by fewer and even single mutations narrowing the window for targeted therapies. We are exploiting multiparametric FACS analysis as a general strategy to obtain a comprehensive biochemical understanding of mutant signaling networks and to identify and interrogate relevant populations mediating disease initiation and progression. This technique allows us to simultaneously measure intracellular phosphoproteins in phenotypically characterized subpopulations of cells. We have focused on comparing c-kit-positive, lineage-negative (c-kit+/lin-) cells in KrasG12D and normal marrow. This population, which comprises only 2–3% of total bone marrow cells, accounts for 85–90% of progenitors cells. Primary bone marrow from normal and KrasG12D mice with MPD were extracted, serum starved, and stimulated at different time points with granulocyte-macrophage colony stimulating factor (GM-CSF). Kras mutant cells exhibited hyper-phosphorylation not only of MAP kinase effectors (e.g. ERK and Mnk) but also of downstream components of the PI3 kinase cascades such as Akt and S6. We also detected elevated levels of phosphorylated STAT3 and 5 at baseline and after exposure to GM-CSF. In addition, KrasG12D mutant cells showed a more sustained activation of pERK and pS6 over time. Paradoxically, Kras mutant cells showed an intriguing attenuation of the same effectors upon SCF stimulation. Parallel studies showed that inhibiting PI3 kinase interferes with ERK activation, thus revealing crosstalk among pathways. These effects are most evident in defined subsets of stem/progenitor cells that exhibit aberrant proliferation and differentiation in vitro. Finally, we observe dramatic differences in Ras signaling networks with progression from MPD to AML. Our data suggest that oncogenic hyperactive Ras induces rewiring in cellular signaling networks that are not static, but are strongly modulated by secondary mutations. Multiparameter flow cytometry is a robust methodology for analyzing the biochemical profiles of primary cells that can be used to monitor biochemical responses to targeted therapeutics in disease-relevant populations of hematopoietic stem and progenitor cells.
Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. (1997)

BRCA1 and BRCA2 mutations confer increased risk for development of breast cancer, but a number of additional, currently largely unknown, somatic genetic defects must also accumulate in the breast epithelial cells before malignancy develops. To evaluate the nature of these additional somatic genetic defects, we performed a genome-wide survey by comparative genomic hybridization on breast cancers from 21 BRCA1 mutation carriers, 15 BRCA2 mutation carriers, and 55 unselected controls. The total number of genetic changes was almost two times higher in tumors from both BRCA1 and BRCA2 mutation carriers than in the control group. In BRCA1 tumors, losses of 5q (86%), 4q (81%), 4p (64%), 2q (40%), and 12q (40%) were significantly more common than in the control group (7-13%). BRCA2 tumors were characterized by a higher frequency of 13q (73%) and 6q (60%) losses and gains of 17q22-q24 (87%) and 20q13 (60%) as compared to the prevalence of these changes in the control group (12-18%). In conclusion, accumulation of somatic genetic changes during tumor progression may follow a unique pathway in individuals genetically predisposed to cancer, especially by the BRCA1 gene. Activation or loss of genes in the affected chromosomal regions may be selected for during tumor progression in cells lacking functional BRCA1 or BRCA2. Identification of such genes could provide targets for therapeutic intervention and early diagnosis.
Treatment of Non-Hodgkin's Lymphoma (1993)

The disorders classified as non-Hodgkin's lymphoma are increasing in frequency in the United States, with more than 35,000 cases diagnosed annually. In recent years, there have been numerous advances in our understanding of the biology of these disorders and in their treatment. In this article, these advances will be reviewed in the same order as a physician should consider them when seeing a new patient with non-Hodgkin's lymphoma: the diagnosis is considered first, followed by the prognosis, choice of treatment, and treatment itself.Clinically Important Subtypes of Non-Hodgkin's LymphomaUnlike the related disorder Hodgkin's disease, non-Hodgkin's lymphoma has a firmly . . .
Dynamic-effect compensating technique for stable a-Si:H AMOLED displays (2005)

A reliable driving scheme that can compensate for temporal instability of hydrogenated amorphous silicon (a-Si:H) backplane and OLED degradation is a prerequisite for the operation of a-Si:H AMOLED displays. In particular, for large-area and high-resolution displays, the technique should be accurate and fast. Although several driving schemes have been proposed to compensate for the static effect of the V/sub T/-shift, they are prone to the dynamic effects associated with charge injection and clock feed-through. The simulation results show that the dynamic effects can induce up to 10% error in the pixel current. A new driving scheme that enables control of the static and dynamic effects of the V/sub T/-shift is presented.
Myoblast and Fibroblast Therapy for Post-Prostatectomy Urinary Incontinence: 1-Year Followup of 63 Patients (2007)

The use of myoblast and fibroblast therapy represents a minimally invasive, safe and effective treatment for post-prostatectomy incontinence after a followup of 1 year.
Bcl-2 Expression in Neural Cells Blocks Activation of ICE/CED-3 Family Proteases during Apoptosis (1996)

The ICE/CED-3 family of proteases has been implicated in playing a fundamental role in programmed cell death. Bcl-2 protein represses a number of apoptotic death programs, but the biochemical mechanism of its action is not known. We investigated the activation of ICE/CED-3 proteases induced by three apoptotic stimuli (staurosporine, ceramide, and serum withdrawal) in the neuronal cell line GT1-7 and in cells overexpressing Bcl-2. Rapid activation of a 17 kDa subunit of an activated member of the ICE/CED-3 family is demonstrated by affinity-labeling GT1-7 extracts from apoptotic controls cells with a biotinylated ICE/CED-3 inhibitor. This activation corresponds to an increased ICE/CED-3-like protease activity in extracts measured by a fluorogenic substrate assay. In a cell-free system, these extracts induce apoptotic morphological changes in intact nuclei. All three activities are readily inhibited by treatment of control extracts with ICE/CED-3-like protease inhibitors. Overexpressed Bcl-2 inhibits the activation of the 17 kDa protein, the ICE/CED-3-like protease activity in the fluorogenic assay, and the induction of apoptotic morphological changes in HeLa nuclei in the cell-free system, similar to results obtained with ICE/CED-3 protease inhibitors. At the mRNA level, overexpression of Bcl-2 did not alter expression of five members of the ICE/CED-3 family: CPP32, ICE, Mch 2, Nedd 2, and TX. Overexpression of Bcl-2 prevented the apoptosis-induced processing of pro-Nedd 2 to the cleaved form. These data suggest that Bcl-2 participates upstream from the function of ICE/CED-3 proteases and may inhibit apoptosis by preventing the post-translational activation of ICE/CED-3 proteases.
HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis (2015)

Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.