gebhart/patrepeval huggingface dataset:
Natural Killer Cell Function in Patients With Acquired Immunodeficiency Syndrome and Related Diseases (1989)

This review describes current knowledge of changes in natural killer (NK) cell function in acquired immunodeficiency syndrome (AIDS)-related disorders, vis-à-vis associated abnormalities in NK cytolytic function, NK cell subset distribution, NK cytopathology, and lymphokine regulation. NK cells, which are closely associated with large granular lymphocytes, are spontaneously cytotoxic to tumor and virally infected targets. As such, they may play a role in natural resistance to human immunodeficiency virus type 1 (HIV-1)-associated disorders and other opportunistic infections. Yet, peripheral blood NK activity is frequently reduced in patients with HIV-1-induced disease. NK cells are heterogeneous both with respect to their expression of serologically defined membrane antigens and functional activity. In AIDS-related syndromes, there appears to be a diminution of the NK pool (CD16+ cells) involved in cytolytic function, while there is an elevation of the NK pool that coexpresses NK (Leu 7+) and T (CD8+) cell markers, which show little or no involvement in cytolytic function. The impairment of in vitro NK function is not associated with a reduced frequency of lytic conjugates of effectors and target cells nor with the recycling capacity of these effector cells but rather is associated with defects in the NK cell lytic machinery following formation of such conjugates. NK cells in AIDS patients show an impairment in effector cell microtubule rearrangement following target cell interaction. The causes of NK cell dysfunction in AIDS-related disorders remain unknown. NK cells do not appear to express the CD4 epitope of the HIV receptor, nor have they been demonstrated to be susceptible to infection by HIV-1. There appears to be a preponderance of immature NK cells and a lymphokine imbalance in patients with HIV-1 associated disease. Interleukin-2 can partially restore diminished in vitro NK function. Elucidation of the involvement of the NK compartment in natural resistance to HIV-1 merits further investigation.
Adenovirus Vector-Induced Innate Inflammatory Mediators, MAPK Signaling, As Well As Adaptive Immune Responses Are Dependent upon Both TLR2 and TLR9 In Vivo (2008)

Adenovirus (Ad) vectors are promising candidates for both gene transfer and vaccine applications. In this study, we investigated the role of TLR2 in innate and adaptive immune responses to Ad and/or the transgene it expresses following systemic injection. We found that Ad directly activates ERK1/2 in vivo, but that initiation of ERK1/2 activation is primarily a MyD88/TLR2-independent, but Kupffer cell-dependent, event. The complexity of Ad-induced innate immune responses was confirmed when we also found that both TLR2 and MyD88 functions are required for the sustained activation of ERK1/2. Although we found that the initial activation of NF-kappaB by Ads is dependent upon MyD88, but independent of TLR2 in (non-Kupffer cells) the liver, TLR2 significantly influenced the Ad-induced late phase NF-kappaB activation. These very rapid responses were positively correlated with subsequent innate immune responses to the Ad vector, as our results confirmed that the induction of several cytokines and chemokines, and the expression of innate immune response genes following Ad injection were TLR2 dependent in vivo. The requirement of TLR2 in Ad-induced innate responses also correlated with significantly altered adaptive immune responses. For example, our results demonstrate that the generation of Ad-neutralizing Abs, and anti-transgene-specific Abs elicited subsequent to Ad vector treatments, are both dependent upon TLR2 functionality. Finally, we found that several Ad-induced innate immune responses are dependent on both TLR2 and TLR9. Therefore, this study confirms that several (but not all) Ad-induced innate and adaptive immune responses are TLR dependent.
The Subjective Experience of Acute Pain An Assessment of the Utility of 10 Indices (1989)

Sixty-nine postoperative patients indicated the severity of their pain using eight measures designed to assess pain intensity and two designed to measure pain affect. The utility and validity of the 10 measures were evaluated according to two criteria: (a) the magnitude of the relationship between each scale and a linear combination of the pain measures, and (b) relative rates of incorrect responding. The results indicate that each of the measures of pain intensity is adequately valid. In addition, this sample of patients failed to differentiate pain intensity and pain affect using the present measures, suggesting the need for additional research to explore the validity of the affective measures employed in the study. The 11-point Box Scale (BS-11) of pain intensity demonstrated the strongest relationship to a linear combination of all of the measures employed and was responded to correctly by each subject in the sample. All else being equal, these results suggest that the BS-11 scale may be the most useful clinical index of pain intensity among postoperative patients.
Instruction scheduling for the IBM RISC System/6000 processor (1990)

For fast execution on the IBM RISC System/6000* processor, instructions should be arranged in an order that uses the arithmetic units as efficiently as possible. This paper describes the scheduling requirements of the machine, and a scheduling algorithm for it that is used in two compilers.
7T vs. 4T: RF power, homogeneity, and signal‐to‐noise comparison in head images (2001)

Signal-to-noise ratio (SNR), RF field (B(1)), and RF power requirement for human head imaging were examined at 7T and 4T magnetic field strengths. The variation in B(1) magnitude was nearly twofold higher at 7T than at 4T ( approximately 42% compared to approximately 23%). The power required for a 90 degrees pulse in the center of the head at 7T was approximately twice that at 4T. The SNR averaged over the brain was at least 1.6 times higher at 7T compared to 4T. These experimental results were consistent with calculations performed using a human head model and Maxwell's equations. Magn Reson Med 46:24-30, 2001.
Synthesis and Breakdown of pppA2′p5′A2′p5′A and Transient Inhibition of Protein Synthesis in Extracts from Interferon‐Treated and Control Cells (1978)

Incubation of the mouse L-cell-free system with a concentration of pppA2'p5'A2'p5'A [(2'-5')An] just sufficient to inhibit protein synthesis results in formation of a high-molecular-weight, heatlabile inhibitor and enhanced ribonuclease activity and in the rapid breakdown of (2'-5')An to ATP. The (2'-5')An-enhanced ribonuclease activity is also unstable and in the absence of a (2'-5')-An-regenerating system inhibiton of protein synthesis is transient. Although interferon treatment enhances the synthesis of (2'-5')An, the rates of degradation of (2'-5')An and levels of activatible nuclease are similar in extracts prepared from control or interferon-treated cells. Interestingly, the sensitivity of different cell-free systems to (2'-5')An, varies with the source of the cell-free systems and with the methods used in their preparation. There is, however, no obvious correlation between the sensitivities of the system and the rate of breakdown of (2'-5')An. The significance of these results is discussed in relation to a possible control function for the (2'-5')An system in both interferon-treated and control cells.
The human complement fragment receptor, C5L2, is a recycling decoy receptor (2008)

C5L2 is a 7 transmembrane domain receptor for complement fragment C5a that, unlike the classical C5a receptor, C5aR, does not couple to G proteins. However, in mice where C5L2 has been deleted, the response to C5a is altered, suggesting that C5L2 may have a signaling function. In order to investigate whether human C5L2 also has some capacity to transduce signals, we have attempted to produce a signaling competent form of human C5L2 by inserting C5aR sequences at three key G protein activation motifs. However, we detected neither an intracellular Ca(2+) response nor beta-arrestin redistribution in mutated C5L2, suggesting that the potential for G protein coupling is completely absent in this receptor and that, in humans, C5L2 may have functions that are unrelated to signaling. In confirmation of this, we detected constitutive ligand-independent internalization of C5L2 that resulted in the rapid accumulation of C5a and its stable metabolite, C5a des Arg, within the cell with only a small net change in cell surface receptor levels. Internalization was found to be through a clathrin-dependent mechanism that led to the retention and, in cells natively expressing C5L2, the degradation of the ligand within an intracellular compartment. In contrast, the classical C5a receptor, C5aR, internalized ligand much more slowly and a majority of this ligand was released back into the extracellular environment in an apparently undegraded form. These data suggest that a major function of human C5L2 is to remove active complement fragments from the extracellular environment.
Luteinising hormone, follicle stimulating hormone and gonadotropin releasing hormone immunoreactivity in two insects: Locusta migratoria migratoroides R&F andSarcophaga bullata(Parker) (1989)

Summary Materials immunologically related to luteinising hormone (LH), follicle stimulating hormone (FSH) and the gonadotropin releasing hormone (GnRH) were localised in cerebral tissue of Locusta migratoria and Sarcophaga bullata by means of the peroxidase-antiperoxidase method. Several polyclonal and a monoclonal antisera were used. From the third larval instar a positive reaction was observed in cells located in several parts of the brain. Each antiserum reacted with a constant number of well defined cells and nerve fibers. No differences between sexes were observed.
Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. (1996)

Porcine pancreatic islets were microencapsulated in alginate-polylysine-alginate capsules and transplanted intraperitoneally into nine spontaneously diabetic monkeys. After one, two, or three transplants of 3-7 x 10(4) islets per recipient, seven of the monkeys became insulin independent for periods ranging from 120 to 804 d with fasting blood glucose levels in the normoglycemic range. Glucose clearance rates in the transplant recipients were significantly higher than before the graft administration and the insulin secretion during glucose tolerance tests was significantly higher compared with pretransplant tests. Porcine C-peptide was detected in all transplant recipients throughout their period of normoglycemia while none was found before the graft administration. Hemoglobin A1C levels dropped significantly within 2 mo after transplantation. While ketones were detected in the urine of all recipients before the graft administration, all experimental animals became ketone free 2 wk after transplantation. Capsules recovered from two recipients 3 mo after the restoration of normoglycemia were found physically intact with enclosed islets clearly visible. The capsules were free of cellular overgrowth. Examination of internal organs of two of the animals involved in our transplantation studies for the duration of 2 yr revealed no untoward effect of the extended presence of the microcapsules.
Nucleotide sequence of thetetMtetracycline resistance determinant of the streptococcal conjugative shuttle transposon Tn1545 (1986)

The nucleotide sequence of the tetracycline resistance gene tetM encoded by streptococcal conjugative shuttle transposon Tn1545 has been determined. The resistance gene was identified as a coding sequence of 1917 base pairs corresponding to a protein with a Mr of 72,500 daltons. This value is in good agreement with that, 68,000 daltons, estimated by SDS-polyacrylamide gel electrophoresis of Escherichia coli minicell extracts. The tetM gene product does not exhibit any sequence homology with either the Gram-negative (tetA, tetB and tetC), or the Bacillus and Staphylococcus tetracycline resistance proteins. The average hydropathy value of the tetM gene product (-0.21) contrasts with those calculated for the other TET proteins which are markedly hydrophobic (0.76 to 0.93). Hybridization experiments performed with an intragenic tetM probe do not support the claim [Taylor, D. (1986), J. Bact. 165, 1037-1039)] that tetracycline resistance in Campylobacter is due to acquisition of tetM.
Total Negative Refraction in Real Crystals for Ballistic Electrons and Light (2003)

It is found that there exists a category of material interfaces, readily available, that not only can provide total refraction (i.e., zero reflection) but can also give rise to amphoteric refraction (i.e., both positive and negative refraction) for electromagnetic waves in any frequency domain as well as for ballistic electron waves. These two unusual phenomena are demonstrated experimentally for the propagation of light through such an interface.
Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency (2013)

Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN₅₈₈₋₅₉₃, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.
True green semipolar InGaN-based laser diodes beyond critical thickness limits using limited area epitaxy (2013)

Semipolar oriented laser diodes (LDs) have fundamental advantages over c-plane oriented LDs, however, the thickness and composition of InGaN waveguiding layers and AlGaN cladding are limited by the onset of stress relaxation via threading dislocation glide on the c-plane slip system. Limited area epitaxy minimizes misfit dislocation (MD) formation by preventing pre-existing TDs from entering a patterned mesa. We examine the effects of mesa height and facet evolution for LAE grown strained layers. Significant MD formation was suppressed by at least a factor of four for Al0.1Ga0.9N/GaN superlattices, enabling AlGaN-clad structures similar to those used in c-plane LDs. We then demonstrate AlGaN-clad blue (456 nm) LDs with threshold current density (Jth) of 4.5 kA/cm2 and GaN-clad true green (523 nm) LDs with Jth of 12 kA/cm2. TEM measurements of the green LD confirm reduction of MD densities with reduction of MD run length. LAE is effective for improving the optical confinement factor of semipolar LDs and offers a glimpse of the design space that may soon be available using low TD density bulk GaN substrates.
The role of vascular cell integrins αvß3 and αvß5 in angiogenesis (1997)

Six hundred thousand new cases of lung, colon, breast and prostate cancer will be diagnosed in the United States this year, accounting for 75% of new solid tumor cancers and 77% of solid tumor cancer deaths (Fraumeni et al, 1993). Although advances in therapy and in our understanding of cancer causes and risk factors have led to improved outcomes overall, many cancers will have low five year survival rates. Despite these advances in primary tumor management, 50% of patients will ultimately die of their disease, largely due to the metastatic spread of tumors to numerous or inoperable sites through the tumor-associated vasculature (Fraumeni et al., 1992; Weinstat-Saslow, 1994). It is now known that the growth and spread of solid tumor cancer depends on the development of a tumor-associated vasculature by a process known as angiogenesis.
The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2‘,3‘-dideoxycytidine. (1992)

2',3'-Dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and shows beneficial effects in AIDS therapy. The compound inhibits mitochondrial DNA (mtDNA) synthesis at a clinically relevant concentration, which could be responsible for the side effects of ddC observed in the clinic. Thymidine (dThd), one of the substrates of mitochondrial deoxypyrimidine kinase (dPyd kinase), was not able to reverse the mitochondrial toxicity of ddC in CEM cells. Furthermore, the cytoplasmic deoxycytidine kinase (dCyd kinase)-deficient CEM cells were highly resistant to the mitochondrial toxicity of ddC. These data suggest a critical role for cytoplasmic dCyd kinase in the mitochondrial toxicity of ddC. The metabolites of ddC, but not ddC itself, were able to inhibit mtDNA synthesis in isolated mitochondria. The potency of the inhibitory effect was in the order of ddCTP greater than ddCDP greater than ddCMP greater than ddC. The lack of inhibition by ddC of mtDNA synthesis could be due to the inefficient ddC phosphorylation in mitochondria. Although the mitochondrial dPyd kinase was reported to phosphorylate ddC, the phosphorylation of ddC in isolated mitochondria was not detectable. The data suggest that ddC is phosphorylated to ddCTP in the cytoplasm and then transported into mitochondria to exert its inhibitory effect on mtDNA synthesis.
Biologically Engineered Protein-graft-Poly(ethylene glycol) Hydrogels:  A Cell Adhesive and Plasmin-Degradable Biosynthetic Material for Tissue Repair (2002)

To address the need for bioactive materials toward clinical applications in wound healing and tissue regeneration, an artificial protein was created by recombinant DNA methods and modified by grafting of poly(ethylene glycol) diacrylate. Subsequent photopolymerization of the acrylate-containing precursors yielded protein-graft-poly(ethylene glycol) hydrogels. The artificial protein contained repeating amino acid sequences based on fibrinogen and anti-thrombin III, comprising an RGD integrin-binding motif, two plasmin degradation sites, and a heparin-binding site. Two-dimensional adhesion studies showed that the artificial protein had specific integrin-binding capability based on the RGD motif contained in its fibrinogen-based sequence. Furthermore, heparin bound strongly to the protein's anti-thrombin III-based region. Protein-graft-poly(ethylene glycol) hydrogels were plasmin degradable, had Young's moduli up to 3.5 kPa, and supported three-dimensional outgrowth of human fibroblasts. Cell attachment in three dimensions resulted from specific cell-surface integrin binding to the material's RGD sequence. Hydrogel penetration by cells involved serine-protease mediated matrix degradation in temporal and spatial synchrony with cellular outgrowth. Protein-graft-poly(ethylene glycol) hydrogels represent a new and versatile class of biomimetic hybrid materials that hold clinical promise in serving as implants to promote wound healing and tissue regeneration.
Anti-Interleukin 6 Receptor Monoclonal Antibody Therapy Reduced Serum Interleukin 4 and IgE Production in Castleman’s Disease. (2005)

Abstract Multicentric Castleman’s disease (MCD) is an atypical lympho- proliferative disorder which is closely associated with dysregulated overproduction of interleukin-6 (IL-6). In the previous report, we showed that the humanized anti-IL-6 receptor monoclonal antibody, tocilizumab (formerly called MRA), was therapeutically effective for the patients with MCD and the safety profile was acceptable relative to the clinical benefit. We also found that serum IgE levels were elevated in some patients with Castleman’s disease, which also decreased by IL-6 blocking therapy, suggesting that IL-6 may be involved in IgE production in vivo. To examine whether or not IL-6 serves as a regulator for IL-4, a major class switching factor for IgE, in vivo, we analyzed serum IL-4 as well as IgE levels in patients with MCD before and after the blockade of IL-6 actions utilizing humanized anti-IL-6 receptor monoclonal antibody in the 4-month clinical trial. Twenty-eight patients with MCD were enrolled and received intravenously 8 mg/kg of tocilizumab every two weeks for a total of 4 months. In fifteen of twenty-eight patients, 5–20 mg/day of prednisolone was used 4 weeks prior to study dosing, but the dosage of each patient was not changed during treatment. Serum IL-4 and IgE levels as well as inflammatory markers were monitored. This study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice guidelines. All patients gave written informed consent before participating in this study. Tocilizumab treatment improved the systemic inflammatory manifestations and laboratory markers such as CRP and fibrinogen as we previously reported. Before tocilizumab treatment, serum IL-4 and IgE levels were elevated (median 14.9 pg/mL, range 2.8–228 pg/mL and median 995 IU/mL, range 12–8000 IU/mL, respectively, n=28). Serum IL-4 levels gradually decreased by tocilizumab treatment (median 8.0 pg/mL, range 2.0–257 pg/mL at 6 weeks, n=28, p&lt;0.005 vs. pretreatment; median 6.0 pg/mL, range 2.0–75.6 pg/mL at 16 weeks, n=28, p&lt;0.0001, respectively). Serum IgE levels also significantly decreased at 6 weeks but not at 16 weeks (median 590 IU/mL, range 6–7000 IU/mL at 6 weeks, p&lt;0.005; median 605 IU/mL, range 5.9–16000 IU/mL at 16 weeks, n.s, respectively). In association with the decrease in serum IL-4 and IgE levels, disease activity of atopic dermatitis improved in the patients with atopic dermatitis. IgE RAST scores for Japanese cedar also significantly decreased. IL-6 has been reportedly to direct the differentiation of IL-4-producing T helper cell 2 (Th2), in vitro, but the in vivo action of IL-6 has been controversial. Our findings clearly indicate that IL-6 regulates the IL-4 production, in vivo, and may serve as a regulator not only for B cell differentiation but also for class switching to IgE.
Pooling in high-throughput drug screening. (2009)

Pooling in HTS refers to the act of testing mixtures of compounds in a primary screen to accurately identify hits for secondary screening. The reduction in the number of tests needed to screen a compound library by pooling can also be extended to achieve much-needed error tolerance in HTS. Despite the success of HTS in other biological experiments, pooling in high-throughput drug screening has been a controversial and often marginalized paradigm. At first appearance, pooling appears to promise gains from reduced effort, or possibly could create more problems than solutions. However, this article demonstrates that pooling is a practical and necessary part of HTS: discussions include the rationale for pooling compounds in HTS, a unifying view of pooling design theory, a review of past attempts at pooling and their success, and recent advances in the field.