gebhart/patrepeval huggingface dataset:
Modeling and analysis of dynamic coscheduling in parallel and distributed environments (2002)

Scheduling in large-scale parallel systems has been and continues to be an important and challenging research problem. Several key factors, including the increasing use of off-the-shelf clusters of workstations to build such parallel systems, have resulted in the emergence of a new class of scheduling strategies, broadly referred to as dynamic coscheduling. Unfortunately, the size of both the design and performance spaces of these emerging scheduling strategies is quite large, due in part to the numerous dynamic interactions among the different components of the parallel computing environment as well as the wide range of applications and systems that can comprise the parallel environment. This in turn makes it difficult to fully explore the benefits and limitations of the various proposed dynamic coscheduling approaches for large-scale systems solely with the use of simulation and/or experimentation.To gain a better understanding of the fundamental properties of different dynamic coscheduling methods, we formulate a general mathematical model of this class of scheduling strategies within a unified framework that allows us to investigate a wide range of parallel environments. We derive a matrix-analytic analysis based on a stochastic decomposition and a fixed-point iteration. A large number of numerical experiments are performed in part to examine the accuracy of our approach. These numerical results are in excellent agreement with detailed simulation results. Our mathematical model and analysis is then used to explore several fundamental design and performance tradeoffs associated with the class of dynamic coscheduling policies across a broad spectrum of parallel computing environments.
Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia (2019)

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior–posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an “undruggable” target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.
Synthesis of analogues of peptide YY with modified N‐terminal regions: Relationships of amphiphilic secondary structures and activity in rat vas deferens (1990)

Peptide YY (PYY) not only has distinct sequence homology with neuropeptide Y (NPY) and avian pancreatic polypeptide (APP), but it also exhibits both NPY- and APP-like biological activities. We synthesized two analogues of PYY, A1 and A2, with modified N-terminal regions, and compared their chemical and biological properties to those of PYY and the C-terminal fragment of PYY, (13-36)PYY. This study shows that there is a good correlation between the stability of amphiphilic alpha-helical structure and the biological activity of these peptides. A CD study of (13-36)PYY in mixed H2O and trifluoroethanol (TFE) solutions indicated a significant increase in alpha-helical segments (26-79%) with increasing TFE proportions. Since the fragment (13-36)PYY had potent activity in the rat vas deferens (RVD) assay, the secondary structure is possibly required on the RVD cell surface receptors. The analogues, A1 and A2, were designed to increase the stability of the alpha-helical structures by incorporation of modified N-terminal regions. The CD studies and the RVD assays of A1 and A2, suggest that the amphiphilic alpha-helical structures are stabilized by intramolecular hydrophobic interactions with the N-terminal regions and/or by intermolecular hydrophobic interactions in the self-association process, and subsequently potentiate the activities of the peptides compared to those of PYY and (13-36)PYY.
Nucleoprotein viral RNA and mRNA of Thogoto virus: a novel "cap-stealing" mechanism in tick-borne orthomyxoviruses? (1996)

Tick-borne Thogoto virus (THOV) represents the prototype virus of a new genus in the Orthomyxoviridae family. Its genome consists of six segments of negative-sense, single-stranded RNA. We have cloned and sequenced the fifth genomic segment, which codes for the viral nucleoprotein (NP). The deduced amino acid sequence shows 43% similarity to the NP of Dhori virus, a related tick-transmitted orthomyxovirus, and about 14% sequence similarity to those of the influenza viruses. To reveal the mechanism by which THOV initiates mRNA synthesis, we characterized the 5' ends of the NP mRNAs. Transcripts were recognized by a cap-specific monoclonal antibody, indicating that THOV mRNAs are capped. Surprisingly, no large heterogeneous extensions were found at the 5' end, as would have been expected if THOV were using a classical "cap-stealing" mechanism. We therefore propose that THOV is stealing only the cap structure with one or two additional nucleotides from cellular mRNAs to generate appropriate primers for initiation of viral mRNA transcription.
The structure of a subterminal repeated sequence present on many human chromosomes (1990)

All telomeres which have been studied consist of an array of simple G/C rich repeats. Human telomeres were shown to share sequence similarity with those of lower eukaryotes by cross-hybridization and human telomeric sequences have been cloned by complementation of telomere function in yeast. Analysis of human telomeric sequences cloned in this way is described here. The terminal part of the cloned human telomeric DNA consists of an array of simple repeats, principally of the sequence TTAGGG and derivatives. The very terminal part consists of yeast-type telomeric repeats which suggests that the human telomeric sequences have acted as a primer for the addition of additional telomeric repeats in the yeast. Subterminal sequences are shared between a number of clones and in situ data shows that these subterminal sequences are present at several different chromosomal ends. Related sequences are present at internal as well as telomeric positions. Differences in the hybridization patterns of subterminal sequences in somatic compared to germ-line tissues are described which indicate differential modification of these sequences during development.
The CD8+ T cell repertoire in beta 2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I. (1994)

Beta 2-Microglobulin-deficient (beta 2m -/-) mice are reported to lack cell surface expression of major histocompatibility complex (MHC) class I molecules, CD8+ T cells, and the ability to mount MHC class I-specific T cell responses. We have observed that beta 2m -/- mice possess CD8+ T cells that can be induced to perform strong allospecific cytotoxic responses against nonself-MHC class I by in vivo priming. We report that these beta 2m -/- cytotoxic T lymphocyte (CTL) differ from those induced in beta 2m-positive littermates in that they cross-react and kill cells expressing self-MHC class I at normal ligand density with beta 2m. beta 2m -/- CTL could even be induced in primary mixed lymphocyte culture by self-MHC class I expressing stimulator cells, whereas allogeneic stimulator cells failed to elicit a response under similar conditions. Cells with a reduced cell surface MHC class I expression were less sensitive, while syngeneic beta 2m -/- cells were resistant to the beta 2m -/- CTL. This antiself-MHC reactivity could not be induced when beta 2m -/- T cells matured in an environment with normal MHC class I expression in bone marrow chimeric mice. Antiself-MHC reactivity was also observed against human peptide loading-deficient cells expressing the appropriate murine class I molecules, suggesting that affinity to self-MHC class I may occur irrespective of peptide content. The results fit with a model where positive and negative selection of CD8+ T cells in beta 2m -/- mice is mediated by low levels of MHC class I free heavy chains. In this model, low ligand density on selecting cells leads to positive selection of rare T cells that bind to low levels of MHC class I free heavy chains, resulting in a very small peripheral CD8+ compartment. Due to low density of the selecting ligand, negative selection does not remove T cells recognizing beta 2m-positive cells expressing self-MHC class I at normal ligand density, which generates a T cell repertoire that would be autoreactive in a beta 2m-positive littermate. The first "MHC deficient" animals thus paradoxically provide a tool for direct demonstration and analysis of self MHC bias in the T cell repertoire.
Abstract 1783: Pro-Apoptotic Bnip3 Mediates Permeabilization of Mitochondria and Release of Cytocrome c via a Novel Mechanism (2008)

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. The pro-apoptotic Bcl-2 proteins mediate mitochondrial dysfunction independent of the mitochondrial permeability transition pore (mPTP). However, Bnip3 has been reported to mediate cell death via the mPTP. In this study, we investigated the mechanism(s) by which Bnip3 causes mitochondrial dysfunction. Using a mitochondrial swelling assay to assess pore opening, we found that addition of 200 microM Ca2+ to mitochondria isolated from rat hearts induced rapid swelling of mitochondria and release of cytochrome c (cyto c). Bnip3 also induced mitochondrial swelling and cyto c release, but always at a slower rate and to a greater degree, suggesting that Bnip3 mediates swelling via a different mechanism. Cyclosporin A (CsA), an inhibitor of mPTP opening, prevented Ca2+-induced swelling and cyto c release, but had no effect on Bnip3. Another BH3-only protein, tBid, caused release of cyto c but failed to induce swelling of mitochondria. Interestingly, Bnip3, but not Ca2+ and tBid, induced release of the matrix protein MnSOD. Cyclophilin D (cycD) is an essential component of the mPTP and heart mitochondria isolated from cycD−/− mice were resistant to Ca2+-, but not to Bnip3-induced swelling and cyto c release. Also, tBid caused cyto c release without mitochondrial swelling in the absence of cycD. To further explore the mPTP as a downstream effector of Bnip3-mediated cell death, we assessed cell death in mouse embryonic fibroblasts (MEFs) isolated from wild type (wt) and cycD−/− mice. Infection with an adenovirus expressing Bnip3 caused significant cell death in wt (52.8±1.8%) and cycD−/− (61.8±6.1%) MEFs as measured by LDH release. In addition, both Bnip3 and opening of the mPTP have been reported to initiate upregulation of autophagy. Monitoring of GFP-LC3 incorporation into autophagosomes by fluorescence microscopy revealed that Bnip3 infection induced autophagy in wt (86.5±6.6%) and cycD−/− (96.4±1.4%) MEFs (n=3, p&lt;0.05). Thus, these studies suggest that Bnip3 mediates permeabilization of the inner and outer mitochondrial membranes via a novel mechanism that is different from other BH3-only proteins. This research has received full or partial funding support from the American Heart Association, AHA National Center.
Heterologous Expression in Yeast (2003)

The complex nature of plant metabolism often can seriously hinder the functional analysis of many proteins; and this has led some researchers to attempt to express such proteins in less sophisticated organisms. Unfortunately, the obvious choice, Escherichia coli, is less than ideal with many foreign peptides being misfolded and subsequently sequestered in insoluble protein bodies. The yeast Saccharomyces cerevisiae, however, has a combination of properties that make it a particularly attractive system for the functional expression of plant proteins.
Feedforward control of flexible manipulators (2003)

The design of feedforward controllers to control the tip position of single-link flexible arms is developed. The objective is to drive the tip position along a commanded trajectory without any oscillations at the tip. The method is based on the well-known dynamics model inversion technique. Since the controllers are implemented on a computer, the dynamic inversion of the single-link flexible arms is studied from a discrete point of view. A general method to obtain a feedforward controller is developed, even in the case when the system transfer function is of nonminimum phase. The method is general in the sense that it removes oscillation in the arm with any number of vibration modes. It is shown that the input preshaping scheme developed by N.C. Singer and W.P. Seering (1990) is a special case of this method. The design technique is illustrated with numerical examples, and a comparison with the input preshaping method is carried out.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Low‐dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis (1995)

A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.
Availability of rhenium-188 from the alumina-based tungsten-188/rhenium-188 generator for preparation of rhenium-188-labeled radiopharmaceuticals for cancer treatment. (1997)

Rhenium-188 (beta- = 2.2 MeV; gamma = 155 keV; T1/2 16.9 hours) is an attractive therapeutic radioisotope which is produced from decay of the reactor-produced tungsten-188 parent (T1/2 69 days) and thus conveniently obtained on demand by elution from the alumina-based tungsten-188 /rhenium-188 generator system. The rhenium-188 is obtained as sodium perrhenate by elution of the generator with 0.9% saline. The post elution use of disposable tandem, ion-exchange columns is a simple method for the concentration of rhenium-188 saline solutions with specific volumes > 500 mCi/ml. This method can also extend the useful shelf-life of the generator, which can be as long as one year. The long useful shelf-life of the generator is expected to provide rhenium-188 at very reasonable costs for routine preparation of a variety of radiopharmaceuticals for the treatment of a variety of cancers including breast cancer. We are evaluating two types of Re-188-labeled agents under investigation which have potential for the treatment of breast cancer. Rhenium-188-labeled hydroxyethylidenediphosphonate (HEDP) and Re-188-dimercaptosuccinic acid (DMSA) are being applied for palliative treatment of pain associated with skeletal metastases, and the Re-188-RC-160 somatostatin analogue [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Lys-Val-Cys-Trp-NH2] for somatostatin-receptor-positive tumors. The results of initial clinical studies with the two bone pain agents demonstrate good targeting to skeletal metastases, and use of Re-188-HEDP has resulted in pain palliation with minimal bone marrow suppression in the initial patient studies. While these initial studies have been conducted in patients with prostate cancer, similar results are expected in planned studies in breast cancer patients. In animal studies, Re-188-RC-160 has been successfully used for the local/regional treatment of experimental breast cancer and other cancers. Re-188-RC-160 binds to somatostatin-receptor-positive cells both in vitro and in vivo, including breast cancer cells (ZR-75-1 breast carcinoma and NCI-H69 human small cell ling carcinoma), but not to binding-negative cells (Raji, Burkitt's lymphoma). A structurally similar Re-188-cyclic peptide with different binding specificity (CTOP [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Orn-Thr-Pen-Thr-ol]; an opiate-receptor antagonist) did not bind to target cells. Both gentisic acid and ascorbic acid are present in the Re-188-HEDP and Re-188-RC-160 formulations, and have been found to also significantly reduce radiolytic degradation of the somatostatin peptide analogues, and may have general application in the stabilization of Re-188-labeled radio-pharmaceuticals.
Tracking contact and free gesture across large interactive surfaces (2003)

Built into store windows, museum exhibits, and other communal spaces, these surfaces entice even casual passersby to playfully interact with information---and each other---by knocking on the glass.
Enhanced Therapeutic Epidermal Growth Factor Receptor (EGFR) Antibody Delivery via Pulsed Ultrasound with Targeting Microbubbles for Glioma Treatment (2015)

Pulsed-mode ultrasound (pUS) in combination with intravenously (IV) administered microbubbles (MBs) can enhance local drug delivery by temporarily enhancing capillary permeability. This study evaluates the use of epidermal growth factor receptor (EGFR)-targeting MBs after pUS treatment to enhance the effects of therapeutic-EGFR antibody delivery to glioma tumor cells in mice. Three animal groups were compared: (1) IV-injected non-targeting MBs, (2) IV-injected targeting MBs, and (3) IV-injected targeting MBs combined with pUS treatment. All animals were analyzed using high-frequency small-animal US imaging. The mean halftime of circulating targeting MBs was significantly increased from 3.13 min of targeting bubble alone to 5.86 min by targeting MBs combined with pUS treatment, compared to 2.34 min for non-targeting MBs. Compared to targeting bubble administration alone, pUS exposure prior to injection of targeting MBs was also significantly better at suppressing tumor growth when monitored for up to 35 days (<i>p</i> < 0.05). The final relative tumor volumes were 2664, 700, and 188 mm<sup>3</sup> for non-targeting MBs, targeting MBs, and targeting MBs combined with pUS treatment, respectively. pUS treatment prolonged the mean circulatory halftime of targeting MBs and enhanced the anti-tumor effect of EGFR antibodies in a human glioma model in mice. Targeting MBs combined with pUS treatment thus has potential for enhanced therapeutic antibody delivery for facilitating anti-glioma treatment.
Dynamic structures of phosphodiesterase‐5 active site by combined molecular dynamics simulations and hybrid quantum mechanical/molecular mechanical calculations (2007)

Abstract Various quantum mechanical/molecular mechanical (QM/MM) geometry optimizations starting from an x‐ray crystal structure and from the snapshot structures of constrained molecular dynamics (MD) simulations have been performed to characterize two dynamically stable active site structures of phosphodiesterase‐5 (PDE5) in solution. The only difference between the two PDE5 structures exists in the catalytic, second bridging ligand (BL2) which is HO − or H 2 O. It has been shown that, whereas BL2 (i.e. HO − ) in the PDE5(BL2 = HO − ) structure can really bridge the two positively charged metal ions (Zn 2+ and Mg 2+ ), BL2 (i.e. H 2 O) in the PDE5(BL2 = H 2 O) structure can only coordinate Mg 2+ . It has been demonstrated that the results of the QM/MM geometry optimizations are remarkably affected by the solvent water molecules, the dynamics of the protein environment, and the electronic embedding charges of the MM region in the QM part of the QMM/MM calculation. The PDE5(BL2 = H 2 O) geometries optimized by using the QM/MM method in different ways show strong couplings between these important factors. It is interesting to note that the PDE5(BL2 = HO ‐ ) and PDE5(BL2 = H 2 O) geometries determined by the QM/MM calculations neglecting these three factors are all consistent with the corresponding geometries determined by the QM/MM calculations that account for all of these three factors. These results suggest the overall effects of these three important factors on the optimized geometries can roughly cancel out. However, the QM/MM calculations that only account for some of these factors could lead to considerably different geometries. These results might be useful also in guiding future QM/MM geometry optimizations on other enzymes. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008
Systemic Delivery of Antiangiogenic Adenovirus AdmATF Induces Liver Resistance to Metastasis and Prolongs Survival of Mice (1999)

Systemic administration of Ad5-based recombinant adenovirus leads to preferential transduction of the liver. Using this property, we have assessed the potential of venous viral injection to deliver a recombinant antiangiogenic adenovirus to treat cancer dissemination and improve survival. The results demonstrate that venous injection of adenovirus AdmATF, which encodes a secretable mouse ATF (amino-terminal fragment of urokinase) known to inhibit angiogenesis, suppressed angiogenesis induced by colon cancer metastasis growth in mice liver and improved survival. Nude mice were injected intravenously with 5 X 10(9) PFU of AdmATF and subsequently challenged after a 3-day interval by intrasplenically injected human colon carcinoma cells (LS174T, 3 x 10(6)) that home to liver. Microscopic inspection revealed that, within the AdmATF-pretreated mice (n = 8), the size and number of liver-metastasized nodules on day 30 were remarkably reduced (80% in number, p < 0.05) compared with control mice (n = 7) pretreated in parallel with a control adenovirus. Metastatic growth-related liver weight gain was also inhibited up to 90%. AdmATF-specific capability that offers liver resistance to the apparition and growth of liver metastasis was shown to correlate with the inhibition of peritumoral and intratumoral angiogenesis (reduced by 79%, p < 0.01 as shown by anti-vWF immunostaining of liver sections) and a twofold increase in tumor necrotic area and an eightfold increase in apoptotic tumor cell number. This protective effect was still observed when the mice were challenged 10 days after venous AdmATF injection (visible metastasis nodules: 6.3+/-3.1, n = 7 for control mice versus 2.7+/-2.9, n = 10 for treated mice, p < 0.05). More importantly, the mean survival has been prolonged from 45.1 days (n = 9) to 83.3 days (n = 10, p < 0.05). Altogether, the high efficacy, although transient, in this experimental mice model strongly advocates the plausibility of transforming the liver into a dissemination resistant organ by antiangiogenic gene therapy through systemic delivery approach.