gebhart/patrepeval huggingface dataset:
Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis (1998)

Programmed cell death, or apoptosis, has been implicated in Alzheimer's disease (AD). DNA damage was assessed in primary cortical neurons infected with herpes simplex virus (HSV) vectors expressing the familial Alzheimer's disease (FAD) gene presenilin-1 (PS-1) or an FAD mutant of this gene, A246E. After infection, immunoreactivity for PS-1 was shown to be enhanced in infected cells. The infected cells exhibited no cytotoxicity, as evaluated by trypan blue exclusion and mitochondrial function assays. Quantitative analysis of cells that were immunohistochemically labeled using a Klenow DNA fragmentation assay or the TUNEL method revealed no enhancement of apoptosis in PS-1-infected cells. This result was confirmed using assays for chromatin condensation and for DNA fragmentation. Expression of PS-1 protected against induction of apoptosis in the cortical neurons by etoposide or staurosporine. The specificity of this phenotype was demonstrated by the fact that cortical cultures infected with recombinant HSV vectors expressing the amyloid precursor protein (APP-695) showed, in contrast, a significant increase in the number of apoptotic cells and an increase in DNA fragmentation for all parameters tested. Our results indicate that overexpression of wild-type or A246E mutant PS-1 does not enhance apoptosis in postmitotic cortical cells and suggest that the previously reported enhancement of apoptosis by presenilins may be dependent on cell type.
α-Human Atrial Natriuretic Peptide, Carperitide, Reduces Infarct Size But Not Arrhythmias After Coronary Occlusion/Reperfusion in Dogs (2000)

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.
Clinical challenges associated with bortezomib therapy in multiple myeloma and Waldenströms Macroglobulinemia (2009)

Rapid development of the small molecule proteasome inhibitor bortezomib has yielded important clinical benefit for patients with multiple myeloma. Early phase clinical trials suggest the agent has similar efficacy in Waldenströms Macroglobulinemia. Optimization of bortezomib-based therapy, though, requires an understanding of the various challenges associated with use of the drug. This review highlights the rationale for bortezomib therapy in patients with multiple myeloma and Waldenströms Macroglobulinemia, mechanisms of bortezomib resistance, important therapy-related side effects, and new directions for the use of proteasome inhibitors in these disorders.
Comorbidity Patterns of Anxiety and Depressive Disorders in a Large Cohort Study (2011)

Comorbidity rates in anxiety and depressive disorders were very high, indicating that it is advisable to assess both disorders routinely regardless of the primary reason for consultation. This is especially important since comorbid patients showed a specific vulnerability pattern, with more childhood trauma, neuroticism, and higher severity and duration of symptoms.
Targeting PIM Kinases Impairs Survival of Hematopoietic Cells Transformed by Kinase Inhibitor–Sensitive and Kinase Inhibitor–Resistant Forms of Fms-Like Tyrosine Kinase 3 and BCR/ABL (2006)

Previous studies have shown that activation of the signal transducer and activator of transcription 5 (STAT5) plays an essential role in leukemogenesis mediated through constitutive activated protein tyrosine kinases (PTK). Because PIM-1 is a STAT5 target gene, we analyzed the role of the family of PIM serine/threonine kinases (PIM-1 to PIM-3) in PTK-mediated transformation of hematopoietic cells. Ba/F3 cells transformed to growth factor independence by various oncogenic PTKs (TEL/JAK2, TEL/TRKC, TEL/ABL, BCR/ABL, FLT3-ITD, and H4/PDGFbetaR) show abundant expression of PIM-1 and PIM-2. Suppression of PIM-1 activity had a negligible effect on transformation. In contrast, expression of kinase-dead PIM-2 mutant (PIM-2KD) led to a rapid decline of survival in Ba/F3 cells transformed by FLT3-ITD but not by other oncogenic PTKs tested. Coexpression of PIM-1KD and PIM-2KD abrogated growth factor-independent growth of Ba/F3 transformed by several PTKs, including BCR/ABL. Targeted down-regulation of PIM-2 by RNA interference (RNAi) selectively abrogated survival of Ba/F3 cells transformed by various Fms-like tyrosine kinase 3 (FLT3)-activating mutants [internal tandem duplication (ITD) and kinase domain] and attenuated growth of human cell lines containing FLT3 mutations. Interestingly, cells transformed by FLT3 and BCR/ABL mutations that confer resistance to small-molecule tyrosine kinase inhibitors were still sensitive to knockdown of PIM-2, or PIM-1 and PIM-2 by RNAi. Our observations indicate that combined inactivation of PIM-1 and PIM-2 interferes with oncogenic PTKs and suggest that PIMs are alternative therapeutic targets in PTK-mediated leukemia. Targeting the PIM kinase family could provide a new avenue to overcome resistance against small-molecule tyrosine kinase inhibitors.
Overexpression of HMGA2 Promotes Metastasis and Impacts Survival of Colorectal Cancers (2011)

Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy.
Solution structure of P01, a natural scorpion peptide structurally analogous to scorpion toxins specific for apamin-sensitive potassium channel (1996)

The venom of the North African scorpion Androctonus mauretanicus mauretanicus possesses numerous highly active neurotoxins that specifically bind to various ion channels. One of these, P05, has been found to bind specifically to calcium-activated potassium channels and also to compete with apamin, a toxin extracted from bee venom. Besides the highly potent ones, several of these peptides (including that of P01) have been purified and been found to possess only a very weak, although significant, activity in competition with apamin. The amino acid sequence of P01 shows that it is shorter than P05 by two residues. This deletion occurs within an alpha-helix stretch (residues 5-12). This alpha-helix has been shown to be involved in the interaction of P05 with its receptor via two arginine residues. These two arginines are absent in the P01 sequence. Furthermore, a proline residue in position 7 of the P01 sequence may act as an alpha-helix breaker. We have determined the solution structure of P01 by conventional two-dimensional 1H nuclear magnetic resonance and show that 1) the proline residue does not disturb the alpha-helix running from residues 5 to 12; 2) the two arginines are topologically replaced by two acidic residues, which explains the drop in activity; 3) the residual binding activity may be due to the histidine residue in position 9; and 4) the overall secondary structure is conserved, i.e., an alpha-helix running from residues 5 to 12, two antiparallel stretches of beta-sheet (residues 15-20 and 23-27) connected by a type I' beta-turn, and three disulfide bridges connecting the alpha-helix to the beta-sheet.
ChemInform Abstract: Low‐Energy Electron Impact Spectroscopy of (1.1.1)Propellane: Electron Attachment Energies and Singlet and Triplet Excited States (1993)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Computers under attack: intruders, worms, and viruses (1991)

This book is broken down into 6 parts. The first describes the emergence of a worldwide network of computers, here called Worldnet, and the practices that people have engaged in as a result. The second part describes the problem of electronic breakins. The third part deals with the phenomenon of worms. The fourth part deals with viruses. The fifth part of the book gives a glimpse of the worlds in which hackers live. The final part deals with the social context in which people make ethical and moral interpretations and propose new laws.
ATR disruption leads to chromosomal fragmentation and early embryonic lethality (2000)

Although a small decrease in survival and increase in tumor incidence was observed in ATR(+/-) mice, ATR(-/-) embryos die early in development, subsequent to the blastocyst stage and prior to 7.5 days p.c. In culture, ATR(-/-) blastocysts cells continue to cycle into mitosis for 2 days but subsequently fail to expand and die of caspase-dependent apoptosis. Importantly, caspase-independent chromosome breaks are observed in ATR(-/-) cells prior to widespread apoptosis, implying that apoptosis is caused by a loss of genomic integrity. These data show that ATR is essential for early embryonic development and must function in processes other than regulation of p53.
Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. (1988)

Screening of cDNA libraries prepared from the frontal cortex of an Alzheimer disease patient and from fetal human brain has led to isolation of the cDNA for a core protein of the paired helical filament of Alzheimer disease. The partial amino acid sequence of this core protein was used to design synthetic oligonucleotide probes. The cDNA encodes a protein of 352 amino acids that contains a characteristic amino acid repeat in its carboxyl-terminal half. This protein is highly homologous to the sequence of the mouse microtubule-associated protein tau and thus constitutes the human equivalent of mouse tau. RNA blot analysis indicates the presence of two major transcripts, 6 and 2 kilobases lon g, with a wide distribution in normal human brain. Tau protein mRNAs were found in normal amounts in the frontal cortex from patients with Alzheimer disease. The proof that at least part of tau protein forms a component of the paired helical filament core opens the way to understanding the mode of formation of paired helical filaments and thus, ultimately, the pathogenesis of Alzheimer disease.
Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway (2003)

Stimulation of Toll-like receptors (TLRs) triggers activation of a common MyD88-dependent signaling pathway as well as a MyD88-independent pathway that is unique to TLR3 and TLR4 signaling pathways leading to interferon (IFN)-beta production. Here we disrupted the gene encoding a Toll/IL-1 receptor (TIR) domain-containing adaptor, TRIF. TRIF-deficient mice were defective in both TLR3- and TLR4-mediated expression of IFN-beta and activation of IRF-3. Furthermore, inflammatory cytokine production in response to the TLR4 ligand, but not to other TLR ligands, was severely impaired in TRIF-deficient macrophages. Mice deficient in both MyD88 and TRIF showed complete loss of nuclear factor kappa B activation in response to TLR4 stimulation. These findings demonstrate that TRIF is essential for TLR3- and TLR4-mediated signaling pathways facilitating mammalian antiviral host defense.
Flexibility and molecular recognition in the immune system (2002)

Photon echo spectroscopy has been used to measure the response of three antibody-binding sites to perturbation from electronic excitation of a bound antigen, fluorescein. The three antibodies show motions that range in time scale from tens of femtoseconds to nanoseconds. Relative to the others, one antibody, 4-4-20, possesses a rigid binding site that likely results from a short and inflexible heavy chain complementarity-determining region 3 (HCDR3) loop and a critical Tyr that acts as a "molecular splint," rigidifying the antigen across its most flexible internal degree of freedom. The remaining two antibodies, 34F10 and 40G4, despite being generated against the same antigen, possess binding sites that are considerably more flexible. The more flexible combining sites likely result from longer HCDR3 loops and a deletion in the light chain complementarity-determining region 1 (LCDR1) that removes the critical Tyr residue. The binding site flexibilities may result in varying mechanisms of antigen recognition including lock-and-key, induced-fit, and conformational selection.
Human Monocytes Infected with Yersinia pestis Express Cell Surface TLR9 and Differentiate into Dendritic Cells (2004)

TLR9 recognizes DNA sequences containing hypomethylated CpG motifs and is a component of the innate immune system highly conserved during eukaryotic evolution. Previous reports suggested that the expression of TLR9 is restricted to plasmacytoid dendritic cells and B lymphocytes. Our results indicate that low levels of TLR9 are present on the cell surface of freshly isolated human monocytes, and expression is greatly increased by infection with Yersinia pestis. Enhanced cell surface TLR9 coincided with elevated levels of cytoplasmic TLR9 and recruitment of MyD88. Infected monocytes differentiated into mature dendritic cells, expressed IFN-alpha, and stimulated proliferative and cytotoxic T cell responses specific to Y. pestis. Furthermore, uninfected B cells and monocytes both increased cell surface TLR9, CD86, and HLA-DR in response to treatment with CpG-containing oligonucleotides, whereas cell surface TLR9 was down-modulated on infected dendritic cells by the addition of agonist oligonucleotide. Our results suggest that increased expression of TLR9 on the surface of infected cells may serve a role as an activation signal to other cells of the immune system.
Differential responses of human B‐lymphocyte subpopulations to graded levels of CD40–CD154 interaction (2005)

Naïve and memory B-lymphocyte populations are activated by CD154 interaction through cell-surface CD40. This interaction plays an important role in the regulation of the humoral immune response, and increasing evidence indicates that fine variation in CD40 binding influences B lymphocytes, macrophages and dendritic cells in murine models. Here we have investigated whether and how variations in the intensity of the CD40-CD154 interaction could contribute to differential regulation of human B-lymphocyte populations. Proliferation and differentiation of B lymphocytes were monitored in response to graded levels of CD40 stimulation in the presence of interleukin (IL)-2, IL-4 and IL-10. Our results show that the level of CD154 binding to CD40 on B lymphocytes can directly influence the evolution of CD19(+) CD27(-) and CD19(+) CD27(+) cell populations. Furthermore, proliferation, global expansion of CD19(+) cells and emergence of CD38(++) CD138(+) cells, as well as immunoglobulin G (IgG) and IgM secretion, were affected by the level of exposure of B lymphocytes to CD154. These results suggest that the CD40-CD154 interaction is more like a rheostat than an on/off switch, and its variation of intensity may play a role in the regulation of B-lymphocyte activation following the primary and/or secondary humoral immune response.
Asymmetric Organocatalytic Epoxidation of α,β-Unsaturated Aldehydes with Hydrogen Peroxide (2005)

The first asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes is presented. A chiral bisaryl-silyl-protected pyrrolidine acts as a very selective epoxidation organocatalyst using simple oxidation agents, such as hydrogen peroxide and tert-butyl hydroperoxide. The asymmetric epoxidation reactions proceed under environmental friendly reaction condition in, for example, water mixtures of alcohols, and the scope of the reaction is demonstrated by the formation of optically active alpha,beta-epoxy aldehydes in high yields and enantioselectivities >94% ee. Furthermore, the direct synthesis of the sex pheromone from an acaric mite by asymmetric epoxidation of citral is presented.
Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo (2000)

Peripheral blood stem cell (PBSC) transplantation is successful in improving engraftment without increasing acute graft-versus-host disease (GVHD), despite much larger numbers of T cells in unmanipulated PBSCs than in bone marrow grafts. In mouse models and retrospective human studies, granulocyte colony-stimulating factor (G-CSF) therapy has been associated with less acute GVHD. We studied the effect of G-CSF on interferon (IFN)-gamma and IL-4 expression in CD4(+) lymphocytes. CD4(+) cells co-cultivated with G-CSF and stimulated with PHA or CD3 monoclonal antibodies showed significant decreases in IFN-gamma and increases in IL-4 expression (n = 13; P <. 01). G-CSF appeared to have a direct effect on CD4(+) cells independent of monocytes present in the culture because purified CD4(+) cells exposed to G-CSF, washed, and cocultivated with untreated monocytes demonstrated similar changes in IFN-gamma and IL-4 expression, whereas untreated CD4(+) cells cocultured with G-CSF-stimulated monocytes behaved as controls. We then studied peripheral blood mononuclear cells (PBMCs) from G-CSF-mobilized PBSC donors. When their PBMCs were cultured with PHA or CD3 monoclonal antibody, the percent of IFN-gamma-expressing cells decreased by a mean of 55% and 42%, respectively, whereas the percent of IL-4-containing cells increased by a mean of 39% and 58%, respectively, following G-CSF stimulation. Increased apoptosis of IFN-gamma-producing CD4(+) cells was not responsible for the shift in TH1/TH2 subsets. G-CSF-R mRNA was present in both CD4(+) and CD8(+) cells. These results suggest that G-CSF decreases IFN-gamma and increases IL-4 production in vitro and in vivo and likely modulates a balance between TH1 and TH2 cells, an effect that may be important in PBSC transplantation.
Antifungal activity of saperconazole (R 66 905) in vitro (1989)

Saperconazole, a novel orally active triazole antifungal, inhibited Candida spp., Aspergillus spp. and dermatophyte fungi in vitro. Its minimal inhibitory concentrations for Candida spp. and dermatophytes were relatively high, like those of comparable triazole antifungals, but all of the Aspergillus isolates tested were inhibited by less than 0.1 mg/l. Relative inhibition factors of saperconazole were in the range 31-76% for Candida isolates, 6-18% for Aspergillus isolates and 5-10% for dermatophytes. These figures predict a good inhibitory activity of saperconazole for all the fungi tested, with particularly strong activity against Aspergillus spp. and dermatophytes. Saperconazole inhibited hyphal branch formation in C. albicans at concentrations as low as 10(8) M.
Human milk oligosaccharides and their potential benefits for the breast-fed neonate. (2012)

Human milk oligosaccharides (HMO), unconjugated complex carbohydrates that are highly abundant in human milk but not in infant formula, have recently received much attention due to their potential benefits for the breast-fed neonate. While it is becoming evident that HMO structure determines their specific function, understanding the metabolic fate of ingested HMO is key in assessing their biological roles. Remarkably little is known about how, when and where they are metabolized. HMO have long been regarded as metabolically "inert" to the host, as significant amounts are excreted with the fe-ces. HMO reach the colon intact where their prebiotic effects promote healthy gut colonization. HMO can also function as soluble decoy receptors and block adhesion of microbial pathogens to epithelial surfaces. Local effects at the mucosal lining include differential cell responses or modulation of the innate immune system. A small percentage of HMO is believed to be absorbed intact in the small intestine and later excreted with the urine, which opens speculations on possible systemic effects, e.g. in the immune system or in the context of neuronal development. Oligosaccharides currently added to infant formula are structurally different from HMO and therefore most likely not functionally equivalent. Selected "authentic" HMO might soon become available for the supplementation of infant formula, but additional preclinical and clinical studies are required to demonstrate efficacy. This review provides an overview about the structural and functional properties of HMO with emphasis on recent findings in metabolism studies.