gebhart/patrepeval huggingface dataset:
Inhibition of Receptor-mediated Endocytosis Demonstrates Generation of Amyloid β-Protein at the Cell Surface (2003)

Sequential cleavages of the amyloid beta-protein precursor (APP) by the beta- and gamma-secretases generate the amyloid beta-protein (A beta), which plays a central role in Alzheimer's disease. Previous work provided evidence for involvement of both the secretory and endocytic pathways in A beta generation. Here, we used HeLa cells stably expressing a tetracycline-regulated dominant-negative dynamin I (dyn K44A), which selectively inhibits receptor-mediated endocytosis, and analyzed the effects on the processing of endogenous APP. Upon induction of dyn K44A, levels of mature APP rose at the cell surface, consistent with retention of APP on the plasma membrane. The alpha-secretase cleavage products of APP were increased by dyn K44A, in that alpha-APPs in medium and the C83 C-terminal stub in the membrane both rose. The beta-secretase cleavage of APP, C99, also increased modestly. The use of specific gamma-secretase inhibitors to study the accumulation of alpha- and beta-cleavage products independent of their processing by gamma-secretase confirmed that retention of APP on the plasma membrane results in increased processing by both alpha- and beta-secretases. Unexpectedly, endogenous A beta secretion was significantly increased by dyn K44A, as detected by three distinct methods: metabolic labeling, immunoprecipitation/Western blotting, and enzyme-linked immunosorbent assay. Levels of p3 (generated by sequential alpha- and gamma-cleavage) also rose. We conclude that endogenous A beta can be produced directly at the plasma membrane and that alterations in the degree of APP endocytosis may help regulate its production. Our findings are consistent with a role for the gamma-secretase complex in the processing of numerous single-transmembrane receptors at the cell surface.
Treatment of systemic lupus erythematosus with epratuzumab (2010)

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by abnormalities in the activity of B-cells and T-cells. A novel specific treatment for autoimmune diseases is B-cell depletion with monoclonal antibodies. Epratuzumab is a monoclonal antibody that targets CD22 antigen on B-cells. Initial phase II and two terminated early phase III studies suggest that treatment of systemic lupus erythematosus with this immunomodulatory agent is effective, well tolerated and significantly improves the patient's quality of life. In vitro studies and clinical trials with non-Hodgkin lymphoma patients indicate epratuzumab can potentially serve as a complementary drug in combination therapy with another inhibitor of B-cell activity, rituximab, which is a monoclonal anti-CD20 antibody.
Characterization of Strong Promoters from an Environmental Flavobacterium hibernum Strain by Using a Green Fluorescent Protein-Based Reporter System (2006)

We developed techniques for the genetic manipulation of Flavobacterium species and used it to characterize several promoters found in these bacteria. Our studies utilized Flavobacterium hibernum strain W22, an environmental strain we isolated from tree hole habitats of mosquito larvae. Plasmids from F. hibernum strain W22 were more efficiently (approximately 1,250-fold) transferred by electroporation into F. hibernum strain W22 than those isolated from Escherichia coli, thus indicating that an efficient restriction barrier exists between these species. The strong promoter, tac, functional in proteobacteria, did not function in Flavobacterium strains. Therefore, a promoter-trap plasmid, pSCH03, containing a promoterless gfpmut3 gene was constructed. A library of 9,000 clones containing chromosomal fragments of F. hibernum strain W22 in pSCH03 was screened for their ability to drive expression of the promoterless gfpmut3 gene. Twenty strong promoters were used for further study. The transcription start points were determined from seven promoter clones by the 5' rapid amplification of cDNA ends technique. Promoter consensus sequences from Flavobacterium were identified as TAnnTTTG and TTG, where n is any nucleotide, centered approximately 7 and 33 bp upstream of the transcription start site, respectively. A putative novel ribosome binding site consensus sequence is proposed as TAAAA by aligning the 20-bp regions upstream of the translational start site in 25 genes. Our primary results demonstrate that at least some promoter and ribosome binding site motifs of Flavobacterium strains are unusual within the bacterial domain and suggest an early evolutionary divergence of this bacterial group. The techniques presented here allow for more detailed genetics-based studies and analyses of Flavobacterium species in the environment.
L’orientation scolaire et professionnelle des filles : des « choix de compromis » ? (2013)

Dans les travaux sociologiques sur l’orientation, la notion de « choix de compromis » designe la tendance qu’auraient les filles, plus que les garcons, a limiter leurs ambitions scolaires et professionnelles pour se diriger vers des metiers qui leur semblent faciles a concilier avec leurs futurs roles familiaux. Cet article se propose d’analyser la portee de cette notion et ses presupposes, a partir d’un cas limite : celui de jeunes femmes issues de familles nombreuses, qui ont souvent vu leur mere confrontee de maniere importante aux difficultes de la conciliation entre vie familiale et vie professionnelle. Constatant que les enquetees qui subordonnent leur orientation scolaire et professionnelle a l’anticipation de ces difficultes sont en fait minoritaires, l’article interroge les conditions sociales de possibilite de ces « choix de compromis ».
Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice (2002)

Nitric oxide (NO) derived from endothelial NO synthase (eNOS) is regarded as a protective factor against atherosclerosis. Therefore, augmentation of eNOS expression or NO production by pharmacological intervention is postulated to inhibit atherosclerosis. We crossed eNOS-overexpressing (eNOS-Tg) mice with atherogenic apoE-deficient (apoE-KO) mice to determine whether eNOS overexpression in the endothelium could inhibit the development of atherosclerosis. After 8 weeks on a high-cholesterol diet, the atherosclerotic lesion areas in the aortic sinus were unexpectedly increased by more than twofold in apoE-KO/eNOS-Tg mice compared with apoE-KO mice. Also, aortic tree lesion areas were approximately 50% larger in apoE-KO/eNOS-Tg mice after 12 weeks on a high-cholesterol diet. Expression of eNOS and NO production in aortas from apoE-KO/eNOS-Tg mice were significantly higher than those in apoE-KO mice. However, eNOS dysfunction, demonstrated by lower NO production relative to eNOS expression and enhanced superoxide production in the endothelium, was observed in apoE-KO/eNOS-Tg mice. Supplementation with tetrahydrobiopterin, an NOS cofactor, reduced the atherosclerotic lesion size in apoE-KO/eNOS-Tg mice to the level comparable to apoE-KO mice, possibly through the improvement of eNOS dysfunction. These data demonstrate that chronic overexpression of eNOS does not inhibit, but accelerates, atherosclerosis under hypercholesterolemia and that eNOS dysfunction appears to play important roles in the progression of atherosclerosis in apoE-KO/eNOS-Tg mice.
Renal noradrenaline spillover correlates with muscle sympathetic activity in humans. (1996)

1. To study the relationship between indices of resting sympathetic traffic in nerves to skeletal muscles and the kidneys, simultaneous measurements were made of muscle sympathetic activity in the peroneal nerve and renal noradrenaline spillover in ten healthy normotensive males aged 18-69 years (mean 42 years). 2. Group mean levels (+/-S.D.) of muscle sympathetic activity and renal spillover were 22 +/- 17 bursts min-1 and 105 +/- 49 ng min-1, respectively. There were significant positive correlations between individual values of muscle sympathetic activity and renal noradrenaline spillover (r = 0.76, P < 0.01) and similarly between muscle sympathetic activity and renal venous plasma concentration of noradrenaline(r = 0.79, P < 0.007). 3. The results indicate that, although the sympathetic system has the capacity for selective activation of different subdivisions, in healthy human subjects resting traffic is similar or proportional in sympathetic nerves to skeletal muscles and the kidney.
Atorvastatin inhibition of cytokine‐inducible nitric oxide synthase expression in native endothelial cellsin situ (2002)

Animal experimental studies have demonstrated that inducible nitric oxide synthase (iNOS) expression correlates with neointima formation and is prevented by HMG-CoA reductase inhibitors (statins). In the present study we have investigated the underlying mechanism of action of these drugs in isolated segments of the rat aorta. Western blot analysis and immunohistochemistry revealed that tumour necrosis factor alpha (TNFalpha) plus interferon-gamma (IFNgamma) synergistically induce iNOS gene expression in the endothelium but not in the smooth muscle of these segments while constitutive endothelial NO synthase (eNOS) abundance was markedly reduced. Pre-treatment with 1 - 10 microM atorvastatin, cerivastatin or pravastatin decreased TNFalpha plus IFNgamma stimulated iNOS expression in the endothelium irrespective of the presence of the HMG-CoA reductase product mevalonate (400 microM). Electrophoretic mobility shift assay experiments confirmed that the combination of TNFalpha plus IFNgamma causes activation of the transcription factors STAT-1 and NF-kappaB in native endothelial cells. Neutralization of these transcription factors by employing the corresponding decoy oligonucleotides confirmed their involvement in TNFalpha plus IFNgamma stimulated iNOS expression. Translocation of both transcription factors was attenuated by atorvastatin, and this effect was insensitive to exogenous mevalonate. The present findings thus demonstrate a specific HMG-CoA reductase-independent inhibitory effect of statins, namely atorvastatin, on cytokine-stimulated transcription factor activation in native endothelial cells in situ and the subsequent expression of a gene product implicated in vascular inflammation. This effect may be therapeutically relevant and in addition provide an explanation for the reported rapid onset of action of these drugs in humans.
Chromosomal translocation in T-cell leukemia line HUT 78 results in a MYC fusion transcript. (1988)

Primary cultures and established cell lines derived from human T-cell leukemias were analyzed for genomic rearrangements in the region 3' of the MYC locus. A T-cell leukemia line, HUT 78, whose 3' MYC region is rearranged, carries a chromosome t(2;8) juxtaposition; i.e., a locus derived from chromosome region 2q34 is attached to the 3' end of one MYC allele. The t(2;8) rearrangement in the HUT 78 cell line results in expression of a fused transcript encompassing the MYC gene and a locus designated TCL4 (T-cell leukemia/lymphoma 4), which normally resides on chromosome 2. The steady-state level of MYC-TCL4 fusion transcripts in HUT 78 cells is significantly higher than the MYC RNA level found in several other B- and T-cell lines. The production of fused MYC-TCL4 transcripts in a leukemic cell line raises the possibility that other B- and T-cell leukemias may express MYC fusion transcripts as an integral step in their pathogenesis.
Perspectives: Other ErbB2-Targeted Therapies (2010)

SUMMARY: Despite the success of individualized targeted therapies in women with breast cancer with current available compounds, new drugs - especially with different mechanisms of resistance - are under development. A range of novel targeted agents for women with tumors that overexpress ErbB2 (HER2) and progress on trastuzumab and lapatinib have entered clinical studies. Most of these agents are monoclonal antibodies or multifunctional tyrosine kinase inhibitors. Recently published data even showed encouraging synergistic effects of several new substances, which in the future could pose as a chemotherapy-free treatment option in the metastatic setting.
Recent Anti-Influenza Strategies in Multivalent Sialyloligosaccharides and Sialylmimetics Approaches (2007)

Sialic acid-containing oligosaccharides expressed on the respiratory tract epithelial cell surface are involved in influenza virus infection in both virus attaching and detaching processes. Therefore, inhibition of sialic acid-binding processes provides rational anti-influenza strategies. Previous exploring efforts using monosaccharide sialic acid-bearing macromolecules provided proof of concept for multivalent hemagglutinin inhibition. However, the monosaccharide sialic acid cannot account for the molecular determinant of virus receptor-binding specificity in the context of the whole sialyloligosaccharide receptor. On the other hand, neuraminidase inhibition efforts using sialylmimetics have resulted into two antiinfluenza drugs, zanamivir and oseltamivir, which have been shown to reduce both the severity and duration of influenza illness. Nevertheless, the usage of monomeric sialylmimetics requires relatively large amounts of expensive compounds, which may also induce virus resistance and side effect. Therefore, it is critical to develop new antiinfluenza drugs and improve the current antiinfluenza drugs. This review highlights recent explorations of multivalent sialyloligosaccharides-based influenza virus adhesion inhibition strategy and multivalent sialylmimetics-based influenza virus detachment inhibition strategy for these efforts.
Physiologic and Immunologic Hurdles to Xenotransplantation (2001)

The major problem in the field of renal transplantation is currently the shortage of available kidneys. However, the use of animals as a source of kidneys, i.e., xenotransplantation, is increasingly being viewed as a potential solution to this problem. One preeminent hurdle to xenotransplantation is the immune response of the recipient against the graft; other hurdles include the physiologic limitations of the transplant, infection, and ethical considerations. This review summarizes what is currently known regarding the obstacles to xenotransplantation and some potential solutions to those problems.
Paramyxovirus RNA Synthesis and the Requirement for Hexamer Genome Length: the Rule of Six Revisited (1998)

The template for paramyxovirus RNA synthesis is not naked RNA but the helical nucleocapsid core of the virus, in which each nucleocapsid protein (N protein) is predicted to be associated with precisely 6 nucleotides (nt) (11). Presumably as a consequence of this association, paramyxovirus genomes are replicated efficiently only when they are a multiple of 6 nt in length, and this has been dubbed the “rule of six” (4). The structure of paramyxovirus nucleocapsids is thus central to understanding how this rule might operate.
Inactivation ofStreptomycesphage ɸC31 by 405 nm light (2014)

Exposure to narrowband violet-blue light around 405 nm wavelength can induce lethal oxidative damage to bacteria and fungi, however effects on viruses are unknown. As photosensitive porphyrin molecules are involved in the microbicidal inactivation mechanism, and since porphyrins are absent in viruses, then any damaging effects of 405 nm light on viruses might appear unlikely. This study used the bacteriophage ɸC31, as a surrogate for non-enveloped double-stranded DNA viruses, to establish whether 405 nm light can induce virucidal effects. Exposure of ɸC31 suspended in minimal media, nutrient-rich media, and porphyrin solution, demonstrated differing sensitivity of the phage. Significant reductions in phage titer occurred when exposed in nutrient-rich media, with ~3-, 5- and 7-log<sub>10</sub> reductions achieved after exposure to doses of 0.3, 0.5 and 1.4 kJ/cm<sup>2</sup>, respectively. When suspended in minimal media a 0.3-log<sub>10</sub> reduction (<i>P</i> = 0.012) occurred after exposure to 306 J/cm<sup>2</sup>: much lower than the 2.7- and > 2.5-log<sub>10</sub> reductions achieved with the same dose in nutrient-rich, and porphyrin-supplemented media, suggesting inactivation is accelerated by the photo-activation of light-sensitive components in the media. This study provides the first evidence of the interaction of narrowband 405 nm light with viruses, and demonstrates that viral susceptibility to 405 nm light can be significantly enhanced by involvement of exogenous photosensitive components. The reduced susceptibility of viruses in minimal media, compared with that of other microorganisms, provides further evidence that the antimicrobial action of 405 nm light is predominantly due to the photo-excitation of endogenous photosensitive molecules such as porphyrins within susceptible microorganisms.
Manifestations of SIV-Induced Ocular Pathology in Macaque Monkeys (2004)

Simian immunodeficiency virus has been shown to cause acquired immunodeficiency syndrome in macaque monkeys. Data gathered from clinical examination and fundus photography have shown that the lentivirus is capable of the induction of choroidal lesions and retinal hemorrhages in the macaque. These findings demonstrate the potential value of the macaque monkey eye as a model of the retinal pathology routinely seen in human AIDS patients.
C2 and C3 Pain Dermatomes in Man (1991)

This report defines the C2 and C3 pain dermatomes by the distribution of: the hypalgesia clearing after surgical root decompression; the dysaesthesias produced by electrical root stimulation; and the hypalgesia produced by anaesthetic root block. The C2 pain dermatome, so defined, consists of an occipital parietal area 6-8 cm wide, ascending paramedially from the subocciput to the vertex. The C3 pain dermatome is a craniofacial area including the scalp around the ear, the pinna, the lateral cheek over the angle of the jaw, the submental region and the lateral and anterior aspects of the upper neck. These C2 and C3 pain dermatomes do not overlap and are smaller than the C2 and C3 tactile dermatomes described in the literature.
Encapsidation sequences for spleen necrosis virus, an avian retrovirus, are between the 5' long terminal repeat and the start of the gag gene. (1982)

The minimal cis-acting sequences outside the long terminal repeat (LTR) required for formation of an infectious retrovirus cloning vector were determined with recombinants of spleen necrosis virus (SNV) DNA and herpes simplex virus type 1 thymidine kinase gene. The 3' end of SNV DNA was removed to within 40 base pairs (bp) from the 3' LTR with only a 2-fold effect on the recovery of infectious recombinant virus. However, when the 5' end of SNV DNA was removed to within 100 bp from the 5' LTR, infectious recombinant virus was not recovered. Deletion mutants constructed around this latter region showed that nucleotides between 100 and 285 bp from the 5' LTR are necessary for encapsidation of genomic viral RNA. We call this region required for encapsidation E.
Isolation and characterization of functional Shiga toxin subunits and renatured holotoxin (1989)

Shiga toxin is a protein toxin produced by Shigella dysenteriae type I strains. In this report we present a procedure for the separation of functionally intact toxin A and B chains and for their reconstitution to form biologically active molecules. In agreement with the findings of others, the isolated A chain was shown to be a potent in vitro inhibitor of eukaryotic protein synthesis. The isolated B chain bound to HeLa cells and competitively inhibited the binding and cytotoxic activity of holotoxin. These findings show that the functional role of the B chain is to recognize cell surface functional receptors. By labelling the B subunit alone, prior to renaturation of holotoxin, the polypeptide chains were shown to associate noncovalently with a stoichiometry of one A chain and five B chains.
[Effect of beta-carotene on gene expression of breast cancer cells]. (2003)

beta-carotene may inhibit the growth of breast cancer cells through inducing apoptosis,breaking signal transduction,and blocking protein translation.
Methicillin-resistant Staphylococcus aureus: The Deadly Superbug (2010)

Methicillin-resistant Staphylococcus aureus (MRSA), often referred to as the superbug by the media, is currently a major epidemiological threat on a global scale. The adaptability of S. aureus to antibiotics led to the emergence of MRSA in 1961 in a hospital ward in the United Kingdom. S. aureus developed resistance to β-lactam antibiotics through the acquisition of the mecA gene, which is situated on a mobile genetic element known as staphylococcal cassette chromsome mec (SCCmec). The mecA gene encodes penicillin-binding protein 2a (PBP2a), which has a significantly reduced affinity for β-lactam antibiotics, thereby conferring β-lactam resistance. Although the first MRSA clones were hospital-associated (HA-MRSA), communityassociated MRSA (CA-MRSA) clones are now increasingly found throughout the world, affecting normally healthy individuals. MRSA accounts for greater than 50-80% of S. aureus isolates. The global emergence of MRSA has raised concern among public health officials. In fact, in year 2005, Centers for Disease Control and Prevention (CDC) estimated that the number of MRSA fatalities in the United States surpassed the number of deaths from AIDS and hurricane Katrina combined. Several preventative measures have been suggested, including: covering wounds, maintaining good personal hygiene, and avoiding sharing personal items that could facilitate the transmission of MRSA bacteria. As MRSA continues to affect individuals worldwide, it is essential that further research be conducted on the epidemiology of this deadly superbug. Although progress has been made, our current knowledge of the pathogenesis and the molecular evolution of MRSA and the number of available treatments for MRSA infections are limited. This review describes our current understanding of the key determinants of multidrug resistance, worldwide dissemination, and modes of transmission of MRSA bacteria. Also, this review highlights some of the most recent research findings, which could lead to the development of novel anti-MRSA therapeutics. In addition, some of the challenges that researchers currently face are also discussed.
Level discrimination of frozen and random noise (1990)

This paper examines how the difference limen for level, delta L, is affected by stimulus bandwidth and variability. The delta L's were measured in three normal listeners using an adaptive two-interval, forced-choice procedure. The 30-ms stimuli were a 3-kHz tone and nine noise bands with half-power bandwidths ranging from 50 Hz-12 kHz. Except for the 12-kHz bandwidth, which was a low-pass noise, the noise bands were centered at 3 kHz. The delta L's were measured for both frozen and random noises presented at 30, 60, or 90 dB SPL overall. For frozen noises, the same sample of noise was presented throughout a block of 50 trials; for the random noises, different samples of noise were used in each interval of the trials. Results show that the delta L's are higher for random than for frozen noises at narrow bandwidths, but not at wide bandwidths. The delta L's for frozen narrow-band noises decrease with increasing level and are similar to those for the pure tone, whereas the delta L's for wideband noises are only slightly smaller at 90 than at 30 dB SPL. An unexpected finding is that the delta L's are larger at 60 than at 30 dB SPL for both frozen and random noises with bandwidths greater than one critical band. The effect of bandwidth varies with level: The delta L's decrease with increasing bandwidth at low levels, but are nearly independent of bandwidth at 90 dB SPL. The interaction of bandwidth and level is consistent with the multiband excitation-pattern model, but the nonmonotonic behavior of delta L as a function of level suggests modifications to the model.