gebhart/patrepeval huggingface dataset:
Platelet-derived microparticles express high affinity receptors for factor VIII. (1991)

Factor VIII is a cofactor in the tenase enzyme complex which assembles on the membrane of activated platelets. A critical step in tenase assembly is membrane binding of factor VIII. Platelet membrane factor VIII-binding sites were characterized by flow cytometry using either fluorescein maleimide-labeled recombinant factor VIII or a fluorescein-labeled monoclonal antibody against factor VIII. Following activation by thrombin, most platelets bound factor VIII within 90 s. In addition, over the course of several minutes, membranous vesicles (microparticles) were shed from the platelet plasma membrane and each microparticle bound as much factor VIII as a stimulated platelet. Over 30 min, stimulated platelets (but not microparticles) lost the capacity to bind factor VIII. Factor VIII bound saturably to microparticles from platelets stimulated with thrombin, thrombin plus collagen, or the complement proteins C5b-9. The binding of factor VIII was compared to factor V, a structurally homologous coagulation cofactor. Analysis of microparticle binding kinetics yielded similar on and off rates for factor VIII and factor Va and KD values of 2-10 nM. In the presence of 20 nM factor Va, the binding of factor VIII to microparticles was increased, and there was a comparable increase in platelet tenase activity. At higher factor Va concentrations, factor VIII binding and tenase activity were inhibited. Conversely, factor VIII had a similar dose-dependent effect on factor Va binding and platelet prothrombinase activity. Synthetic phospholipid vesicles containing phosphatidylserine competed with microparticles for binding of factor VIII and factor Va. These studies indicate that activated platelets express a transient increase in high affinity receptors for factor VIII, whereas platelet-derived microparticles express a sustained increase in receptors. The binding characteristics of platelet membrane receptors for factor VIII are similar to those for factor Va.
Treatment of Clostridium difficile colitis in hamsters with a lipopeptide antibiotic, LY146032 (1987)

LY146032, an acidic lipopeptide antibiotic which inhibits the biosynthesis of cell wall peptidoglycan, was found to be effective in delaying death in a hamster model of pseudomembranous colitis. A dose of 0.05 mg/day was effective. The equivalent protection with vancomycin required a dose 100-fold higher, i.e., 5 mg/day.
State-dependent M/G/1 type queueing analysis for congestion control in data networks (2000)

We study in this paper a TCP-like linear-increase multiplicative-decrease flow control mechanism. We consider congestion signals that arrive in batches according to a Poisson process. We focus on the case when the transmission rate cannot exceed a certain maximum value. We write the Kolmogorov equations and we use Laplace transforms to calculate the distribution of the transmission rate in the steady state as well as its moments. Our model is particularly useful to study the behavior of TCP, the congestion control mechanism in the Internet. By a simple transformation, the problem can be reformulated in terms of an equivalent M/G/1 queue, where the transmission rate in the original model corresponds to the workload in the 'dual' queue. The service times in the queueing model are not i.i.d., and they depend on the workload in the system.
Oncological applications of gene therapy. (2000)

Despite the rapid technological advances that continue to sustain the field of cancer gene therapy, few individual patients have benefited from the revolution so far. The plethora of clinical trials described confirms that each malignancy will have its own ideal strategy based on the associated molecular defects, and there has been rapid progress from this viewpoint. At the same time, there has been a renewed appreciation for the limitations to gene therapy, which include low efficiency of gene transfer, poor specificity of response and methods to accurately evaluate responses, and lack of truly tumor-specific targets at which to aim. As with all new therapies, we are climbing a steep learning curve in terms encountering treatment-related toxicities, as well as profound ethical and regulatory issues.
Bridging Disulfides for Stable and Defined Antibody Drug Conjugates (2014)

To improve both the homogeneity and the stability of ADCs, we have developed site-specific drug-conjugating reagents that covalently rebridge reduced disulfide bonds. The new reagents comprise a drug, a linker, and a bis-reactive conjugating moiety that is capable of undergoing reaction with both sulfur atoms derived from a reduced disulfide bond in antibodies and antibody fragments. A disulfide rebridging reagent comprising monomethyl auristatin E (MMAE) was prepared and conjugated to trastuzumab (TRA). A 78% conversion of antibody to ADC with a drug to antibody ratio (DAR) of 4 was achieved with no unconjugated antibody remaining. The MMAE rebridging reagent was also conjugated to the interchain disulfide of a Fab derived from proteolytic digestion of TRA, to give a homogeneous single drug conjugated product. The resulting conjugates retained antigen-binding, were stable in serum, and demonstrated potent and antigen-selective cell killing in in vitro and in vivo cancer models. Disulfide rebridging conjugation is a general approach to prepare stable ADCs, which does not require the antibody to be recombinantly re-engineered for site-specific conjugation.
Turbo Linearizer for High Power Amplifier (2011)

Often, to increase the efficiency of high-power amplifiers (HPAs), these amplifiers are driven into a nonlinear region. The nonlinearities in HPAs warp the signal constellation, increasing out-of-band radiation and causing both EVM and BER degradation. Digital predistortion (DPD) is one of the most promising linearization techniques that could lead to more efficient and cost-effective HPAs. The DPD approach works in many practical cases; however, as the bandwidth of the transmitted signal increases, the memory effect in HPAs arises. The performance of DPD algorithms that do not take the memory effect into account severely deteriorate as the bandwidth of the input signal increases. On the other hand, the DPD algorithms that do take the memory effect into account require computational complexity significantly higher than the complexity of DPD for memoryless HPA. In this paper, we propose an exact solution (turbo linearizer) that minimizes the in-band distortion caused by HPA nonlinearity with memory. In contrast to the conventional techniques, the proposed approach places the linearizer on the receiver side. The simulation results show that under certain conditions, the proposed 'turbo scheme' placed on the receiver side provides better BER performance for a given complexity than conventional DPD placed in a transmitter, especially at higher signal-to-noise ratios.
Microfabrication Techniques for Integrated Sensors and Microsystems (1991)

Integrated sensors and actuators are rapidly evolving to provide an important link between very large scale integrated circuits and nonelectronic monitoring and control applications ranging from biomedicine to automated manufacturing. As they continue to expand, entire microsystems merging electrical, mechanical, thermal, optical, magnetic, and perhaps chemical components should be possible on a common substrate.
Structural and functional characterization of tissue factor pathway inhibitor following degradation by matrix metalloproteinase-8 (2002)

Vascular injury results in the activation of coagulation and the release of proteolytic enzymes from neutrophils and connective- tissue cells. High concentrations of these inflammatory proteinases may destroy blood coagulation proteins, contributing to coagulation and bleeding disorders associated with severe inflammation. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils at sites of inflammation and vascular disease. We have investigated the effect of MMP-8 degradation on the anticoagulant function of tissue factor pathway inhibitor (TFPI) as a potential pathological mechanism contributing to coagulation disorders. MMP-8 cleaves TFPI following Ser(174) within the connecting region between the second and third Kunitz domains ( k (cat)/ K (m) approximately 75 M(-1).s(-1)) as well as following Lys(20) within the NH(2)-terminal region. MMP-8 cleavage of TFPI decreases the anticoagulant activity of TFPI in factor Xa initiated clotting assays as well as the ability of TFPI to inhibit factor Xa in amidolytic assays. Yet, MMP-8 cleavage does not alter the ability of TFPI to inhibit trypsin. Since the inhibition of both factor Xa and trypsin is mediated by binding to the second Kunitz domain, these results suggest that regions of TFPI other than the second Kunitz domain may directly interact with factor Xa. (125)I-factor Xa ligand blots of TFPI fragments generated following MMP-8 degradation were used for probing binding interactions between factor Xa and regions of TFPI, other than the second Kunitz domain. In experiments performed under reducing conditions that disrupt the Kunitz domain structure, (125)I-factor Xa binds to the C-terminal fragment of MMP-8-degraded TFPI. This fragment contains portions of TFPI distal to Ser(174), which include the third Kunitz domain and the basic C-terminal region. An altered form of TFPI lacking the third Kunitz domain, but containing the C-terminal region, was used to demonstrate that the C-terminal region directly interacts with factor Xa.
Comparison of fermentation reactions in different regions of the human colon (1992)

Colonic contents were obtained from two human sudden-death victims within 3 h of death. One of the subjects (1) was methanogenic, the other (2) was a non-CH4 producer. Measurements of bacterial fermentation products showed that in both individuals short-chain fatty acids, lactate and ethanol concentrations were highest in the caecum and ascending colon. In contrast, products of protein fermentation, such as ammonia, branched chain fatty acids and phenolic compounds, progressively increased from the right to the left colon, as did the pH of gut contents. In Subject 1, cell population densities of methanogenic bacteria (MB) increased distally through the gut and methanogenic activity was lower in the right (0.78-1.18 mumol CH4 produced/h/g dry wt contents) than in the left colon (1.34 mumol CH4 produced/h/g dry wt contents). Methane production rates did not correlate with MB numbers. Sulphate-reducing bacteria (SRB) were not found and dissimilatory sulphate reduction was not detected in any region of the colon. Methanogenic bacteria did not occur in subject 2, but high numbers of SRB were present throughout the gut (ca 10(9)/g dry wt contents). Sulphate reduction rates were maximal in the ascending and transverse colons (0.24 and 0.22 mumol 35SO4(2-) reduced/h/g dry wt contents, respectively). Short-chain fatty acid production by caecal contents was up to eight-fold higher than contents from the sigmoid/rectum. These findings demonstrate significant differences in fermentation reactions in different regions of the large gut.
Comorbidities in Chronic Neuropathic Pain (2004)

Neuropathic pain arises from a lesion or dysfunction within the nervous system; the specific mechanisms that elicit neuropathic pain symptoms are the subject of ongoing research. It is generally acknowledged that neuropathic pain is extremely difficult to treat, and a major factor impacting outcomes is the presence of comorbidities such as poor sleep, depressed mood, and anxiety. Patients who suffer from chronic pain experience difficulties in initiating and maintaining sleep. Sleep deprivation has been associated with a decreased pain threshold, muscle aches, and stiffness in normal volunteers. The interrelationship of these factors is complex: Many chronic pain patients are depressed and anxious; sleep deprivation can lead to anxiety; and depression can be both the cause and the result of sleep disturbances. Thus, physicians must evaluate all aspects of pain, sleep, and mood in chronic pain patients. Several instruments have been developed to aid physicians in gathering qualitative and quantitative information from chronic pain patients. This triad of chronic pain, sleep disturbances, and depression/anxiety must be fully addressed if the patient is to be restored to optimal functionality. A multidisciplinary team approach allows for treatment of the whole patient. Nonpharmacologic interventions include relaxation therapy, sleep restriction therapy, and cognitive therapy. Strategies for pharmacologic interventions should attempt to maximize outcomes by employing, where possible, agents that address both the pain and the comorbidities. In this way, functionality may be restored and the patient's quality of life improved.
IRAK-4 Kinase Activity Is Required for Interleukin-1 (IL-1) Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression (2007)

IRAK-4 is an essential component of the signal transduction complex downstream of the IL-1- and Toll-like receptors. Although regarded as the first kinase in the signaling cascade, the role of IRAK-4 kinase activity versus its scaffold function is still controversial. To investigate the role of IRAK-4 kinase function in vivo, "knock-in" mice were generated by replacing the wild type IRAK-4 gene with a mutant gene encoding kinase-deficient IRAK-4 protein (IRAK-4 KD). IRAK-4 kinase was rendered inactive by mutating the conserved lysine residues in the ATP pocket essential for coordinating ATP. Analyses of embryonic fibroblasts and macrophages obtained from IRAK-4 KD mice demonstrate lack of cellular responsiveness to stimulation with IL-1beta or a Toll-like receptor 7 (TLR7) agonist. IRAK-4 kinase deficiency prevents the recruitment of IRAK-1 to the IL-1 receptor complex and its subsequent phosphorylation and degradation. IRAK-4 KD cells are severely impaired in NFkappaB, JNK, and p38 activation in response to IL-1beta or TLR7 ligand. As a consequence, IL-1 receptor/TLR7-mediated production of cytokines and chemokines is largely absent in these cells. Additionally, microarray analysis identified IL-1beta response genes and revealed that the induction of IL-1beta-responsive mRNAs is largely ablated in IRAK-4 KD cells. In summary, our results suggest that IRAK-4 kinase activity plays a critical role in IL-1 receptor (IL-1R)/TLR7-mediated induction of inflammatory responses.
How to improve the effectiveness of transurethral resection in nonmuscle invasive bladder cancer? (2009)

The currently available techniques of re-TUR and photodynamic diagnosis have demonstrated potential to improve effectiveness of TUR and should be used in selected cases. New techniques such as narrow-band imaging and optical coherence tomography seem promising, but more evidence is needed before these methods can be implemented in daily practice.
Multicentric evaluation of the DiaMed enzyme‐linked immunosorbent assay malaria antibody test for screening of blood donors for malaria (2007)

The performance of the ELISA test in this study has confirmed its potential as a new screening test for use in blood banks, as an alternative to the IFAT in prevention of transfusion-transmitted malaria in non-endemic countries.
Alternative Transcripts of <i>Dclk</i>1 and <i>Dclk</i>2 and Their Expression in <i>Doublecortin</i> Knockout Mice (2007)

The doublecortin (DCX) gene, mutated in X-linked human lissencephaly, has 2 close paralogs, doublecortin-like kinase 1 and 2 (Dclk1 and 2). In this study we attempted to better understand the dramatic differences between human and mouse DCX/Dcx-deficient phenotypes, focusing on the Dclk genes which are likely to compensate for Dcx function in the mouse. Using sequence database screens, Northern blot analyses and in situ hybridization experiments, we characterized the developmental transcripts of Dclk1 and 2, questioning their conservation between mouse and human, and their similarity to Dcx. Like Dcx, Dcx-like transcripts of the Dclk1 gene are expressed in postmitotic neurons in the developing cortex. No changes of expression were observed at the RNA level for these transcripts in Dcx knockout mice. However, a minor change in expression at the protein level was detected. The Dclk2 gene is less well characterized than Dclk1 and we show here that it is expressed both in proliferating cells and postmitotic neurons, with a notably strong expression in the ventral telencephalon. No major differences in Dclk2 expression at the RNA and protein levels were identified comparing Dcx knockout and wild-type brains. We also analyzed Dclk1 and 2 expression in the hippocampal CA3 region which, unlike the neocortex, is abnormal in Dcx knockout mice. Interestingly, each transcript was expressed in CA3 neurons, including in the heterotopic pyramidal layer of Dcx knockout animals, but is presumably not able to compensate for a lack of Dcx. These results, in addition to characterizing the transcript diversity of an important family of genes, should facilitate further studies of compensation in Dcx-deficient mice.
An approach to gene-specific transcription inhibition using oligonucleotides complementary to the template strand of the open complex (2000)

The single-stranded region of DNA within the open complex of transcriptionally active genes provides a unique target for the design of gene-specific transcription inhibitors. Using the Escherichia coli lac UV5 and trp EDCBA promoters as in vitro models of open complex formation, we have identified the sites inside these transcription bubbles that are accessible for hybridization by short, nuclease-resistant, non-extendable oligoribonucleotides (ORNs). Binding of ORNs inside the open complex was determined by linking the chemical nuclease bis(1,10-phenanthroline) cuprous chelate [(OP)(2)Cu(+)] to the ORN and demonstrating template-specific DNA scission. In addition, these experiments were supported by in vitro transcription inhibition. We find that the most effective inhibitors are 5 nt long and have sequences that are complementary to the DNA template strand in the region near the transcription start site. The ORNs bind to the DNA template strand, forming an antiparallel heteroduplex inside the open complex. In this system, RNA polymerase is essential not only to melt the duplex DNA but also to facilitate hybridization of the incoming ORN. This paradigm for gene-specific inactivation relies on the base complementarity of the ORN and the catalytic activity and sequence specificity of RNA polymerase for the site- and sequence-specific recognition and inhibition of transcriptionally active DNA.
A two‐dimensional gel database of human plasma proteins (1991)

An updated two-dimensional electrophoretic map of human plasma proteins is presented, together with a complete listing of the individual protein spots, their locations, size and isoelectric points relative to internal charge standards. Forty-nine polypeptide species are identified, many consisting of multiple spots differing in glycosylation or sequence (e.g., immunoglobulins). A further series of 35 as yet uncharacterized proteins is indicated.
Efficacy against lung metastasis with a tumor-targeting mutant of Salmonella typhimurium in immunocompetent mice (2012)

Salmonella typhimurium double leu-arg auxotrophs have been shown to be highly effective as antitumor agents in nude mouse models of human metastatic cancer. In order to proceed to clinical development of the S. typhimurium double auxotroph, termed A1-R, it is necessary to evaluate antitumor efficacy in immunocompetent mice. In the present study, we have observed the efficacy of A1-R on the Lewis lung (LLC) carcinoma in vitro as well as in C57BL/6 (C57) immunocompetent mice. In vitro, A1-R treatment of LLC began to induce cell death within one hour. Various doses and schedules of A1-R were administered to C57 mice implanted with LLC, including bolus single intravenous injection; medium dose with weekly intravenous administration and metronomic treatment with small intravenous doses twice a week. Bolus treatment was toxic to the immunocompetent host, in contrast to nude mice. Lower-dose weekly doses and metronomic doses were well tolerated by the immunocompetent host. Weekly intravenous injection with 2 × 10(7) bacteria and twice a week intravenous injection with 10(7) bacteria significantly inhibited metastasis formation, while bolus injection was toxic. Intra-thoracic administration was carried out with 10(8) bacteria A1-R injected into Lewis lung-bearing C57 mice weekly for three weeks. Lung metastasis was significantly inhibited by intrathoracic bacterial administration, without toxicity. The results in this report, demonstrating the anti-metastatic efficacy of S. typhimurium A1-R in immunocompetent mice, indicate the clinical potential of bacterial therapy of cancer.
Quantum computers that can be simulated classically in polynomial time (2001)

A model of quantum computation based on unitary matrix operations was introduced by Feynman and Deutsch. It has been asked whether the power of this model exceeds that of classical Turing machines. We show here that a significant class of these quantum computations can be simulated classically in polynomial time. In particular we show that two-bit operations characterized by 4 \times 4 matrices in which the sixteen entries obey a set of five polynomial relations can be composed according to certain rules to yield a class of circuits that can be simulated classically in polynomial time. This contrasts with the known universality of two-bit operations, and demonstrates that efficient quantum computation of restricted classes is reconcilable with the Polynomial Time Turing Hypothesis. In other words it is possible that quantum phenomena can be used in a scalable fashion to make computers but that they do not have superpolynomial speedups compared to Turing machines for any problem. The techniques introduced bring the quantum computational model within the realm of algebraic complexity theory. In a manner consistent will one view of quantum physics, the wave function is simulated deterministically, and randomization arises only in the course of making measurements. The results generalize the quantum model in that they do not require the matrices to be unitary. In a different direction these techniques also yield deterministic polynomial time algorithms for the decision and parity problems for certain classes of read-twice Boolean formulae. All our results are based on the use of gates that are defined in terms of their graph matching properties.
MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes (2004)

MolProbity is a general-purpose web service offering quality validation for three-dimensional (3D) structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis of any steric problems within the molecules and can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. The results are reported in multiple forms: as overall numeric scores, as lists, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown on-line in the KiNG viewer. This service is available free to all users at http://kinemage.biochem.duke.edu.