gebhart/patrepeval huggingface dataset:
Characterization of a Novel Tripartite Nuclear Localization Sequence in the EGFR Family (2007)

Aberrant expression of epidermal growth factor receptor (EGFR) is present in many human tumors. Several reports have shown that EGFR is translocated into the nucleus during liver regeneration and in several types of cells and tissues such as placenta and thyroid. Nuclear EGFR is associated with transcription, DNA synthesis, and DNA repair activity and serves as a prognostic marker in breast carcinoma and oropharyngeal squamous cell cancer. However, the nuclear localization sequence (NLS) of EGFR has not been extensively examined. In this study, we have shown that the juxtamembrane region of EGFR harbors a putative NLS with three clusters of basic amino acids (RRRHIVRKRTLRR (amino acids 645-657)) that mediates the nuclear localization of EGFR. We found that this newly characterized tripartite NLS is conserved among the EGFR family members (EGFR, ErbB2, ErbB3, and ErbB4) and is able to move each to the nucleus. Further, this tripartite NLS could also mediate the nuclear localization of other known cytoplasmic proteins such as pyruvate kinase. We have demonstrated that mutating one of the three basic amino acid clusters (R or K --> A) leads to significant impairment of the nuclear localization of EGFR and that of a green fluorescent protein-pyruvate kinase-NLS reporter protein. Our results show that this tripartite NLS is distinct from the traditional mono- and bipartite NLS and reveal a mechanism that could account for the nuclear localization of membrane receptors.
New Interleukin-15 Superagonist (IL-15 SA) Combined with Donor Lymphocyte Infusion (DLI) Significantly Enhances Graft-Versus-Tumor Activity after Allogeneic Hematopoietic Stem Cell Transplantation (2014)

Abstract Donor lymphocyte infusion (DLI) has been successfully used clinically to augment the graft-versus-tumor (GVT) effect following hematopoietic stem cell transplantation (HSCT) in relapsed patients. However, improvements can still be made in enhancing anti-tumor activity, reducing graft-versus-host disease (GVHD) and decreasing complications from opportunistic infections. Our studies present clear evidence of increased tumor clearance via cytokine therapy in combination with DLI as a way to “boost” the infused cells function. Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cells number and function in normal mice and recipients of stem cell transplantation. Despite this, obstacles remain for use of IL-15 therapeutically, specifically its low potency and short in vivo half-life. To overcome this, a new IL-15 superagonist (IL-15 SA-(ALT-803)) has been developed with a longer half-life and increased potency. Administration of IL-15 SA to recipients of CFSE labeled T cells increases proliferation of CD8+T cells and IFN-γ and TNF-α secretion from CD8+T cells. We developed a murine DLI model by titrating the dose of infused T cells in a parent-F1 model, and then combined IL-15 SA administration with DLI in murine recipients of allogeneic HSCT. In this model, lethally irradiated CB6F1 (H2Kb/d) mice were transplanted with T- cell depleted bone marrow cells from C57BL6 mice (H2Kb). All recipients of HSCT were also co-injected A20 B-cell lymphoma cells transfected with a luciferase-producing gene, which allows bioluminescent imaging and tracking of tumor progress in vivo. Mice receiving DLI (2.5 X 105 T cells) with IL-15 SA injections given at 1μg/mouse on days 17 and 24 post-BMT show less tumor burden and increased overall survival (p = 0.04) and decreased tumor growth (p = 0.02) (Figure 1). The IL-15 SA treated group had a significantly less weight loss than the control group (p = 0.007). No GVHD symptoms were noted via weekly clinical scoring, highlighting both the efficacy and overall safety of the IL-15 SA therapy. Furthermore, we evaluated T- cell exhaustion markers on CD8+ T cells in surviving mice. We found increased programmed death-1 (PD-1) expression on T cells even when the tumor burden is cleared. Treatment with IL-15 SA reduced PD-1 expression on donor CD8+ T-cells in mice surviving more than 120 days post-transplant. We conclude that IL-15 SA enhances CD8+ T cell function by increasing cytokine secretion and proliferation of T cells whereas could also prevent T cell exhaustion. We suggest that IL-15 SA is a long-waited lymphoid growth factor and has the potential to use in combination with DLI for the treatment of recurrent disease after HSCT. Disclosures No relevant conflicts of interest to declare.
Promoters largely determine the efficiency of repressor action. (1988)

Operator sequence and repressor protein regulate the activity of the lac promoter over a greater than 1000-fold range. Combinations of the lac operator with other promoter sequences, however, differ vastly in the level of repression. The data presented show that the extent of repression is determined largely by the rates of complex formation of the competing systems operator-repressor and promoter-RNA polymerase and by the rate at which RNA polymerase clears the promoter. Moreover, up to 70-fold differences in the level of repression were found when the operator was placed in different positions within the promoter sequence. A kinetic model is proposed that explains the observed effects and that allows predictions on promoters controlled by negatively acting elements.
BLNK mediates Syk-dependent Btk activation (2001)

Btk is a critical molecule in B cell antigen receptor (BCR)-coupled signaling, and its activity is regulated by Lyn and Syk. Although the molecular mechanism of Lyn-dependent Btk activation has been investigated, that of Syk-dependent Btk activation has remained unidentified. We have demonstrated that BLNK mediates Syk-dependent Btk activation. In a reconstitution cell system, coexpression of BLNK allows Syk to phosphorylate Btk on its tyrosine 551, leading to the enhancement of Btk activity. This phosphorylation depends on the interaction of Btk and BLNK by means of the Btk-Src homology 2 domain. The existence of such an activation mechanism is supported by the observation that the BCR-induced Btk phosphorylation and activation are significantly reduced in BLNK-deficient B cells as well as in Syk-deficient B cells. Although previous observations have identified the function of BLNK as the linker that integrates the action of Btk and Syk into downstream effectors such as phospholipase Cgamma2, our present study indicates another function of BLNK that connects the activity of Syk to that of Btk.
Activation of c-Src in cells bearing v-Crk and its suppression by Csk. (1992)

The protein product of the CT10 virus, p47gag-crk (v-Crk), which contains Src homology region 2 (SH2) and 3 (SH3) domains but lacks a kinase domain, is believed to cause an increase in cellular protein tyrosine phosphorylation. A candidate tyrosine kinase, Csk (C-terminal Src kinase), has been implicated in c-Src Tyr-527 phosphorylation, which negatively regulates the protein tyrosine kinase of pp60c-src (c-Src). To investigate how c-Src kinase activity is regulated in vivo, we first looked at whether v-Crk can activate c-Src kinase. We found that cooverexpression of v-Crk and c-Src caused elevation of c-Src kinase activity, resulting in an increase of tyrosine phosphorylation of cellular proteins and morphological transformation of rat 3Y1 fibroblasts. v-Crk and c-Src complexes were not detected, although v-Crk bound to a variety of tyrosine-phosphorylated proteins in cells overexpressing v-Crk and c-Src. Overexpression of Csk in these transformed cells caused reversion to normal phenotypes and also reduced the level of c-Src kinase activity. However, Csk did not cause reversion of cells transformed by v-Src or c-Src527F, in which Tyr-527 was changed to Phe. These results strongly suggest that Csk acts on Tyr-527 of c-Src and suppresses c-Src kinase activity in vivo. Because Csk can suppress transformation by cooverexpression of v-Crk and c-Src, we suggest that v-Crk causes activation of c-Src in vivo by altering the phosphorylation state of Tyr-527.
Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma (2004)

Patients with relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) who achieve complete response (CR) before autologous stem cell transplantation (ASCT) generally have better outcomes than those who achieve only partial response (PR). We investigated whether adding rituximab to the ifosfamide-carboplatin-etoposide (ICE) chemotherapy regimen (RICE) could increase the CR rate of patients with DLBCL under consideration for ASCT. Thirty-six eligible patients were treated with RICE, and 34 received all 3 planned cycles. The CR rate was 53%, significantly better than the 27% CR rate (P =.01) achieved among 147 similar consecutive historical control patients with DLBCL treated with ICE; the PR rate was 25%. Febrile neutropenia was the most frequent grade 3 or 4 nonhematologic toxicity; it occurred in 7.5% of delivered cycles. No patient had RICE-related toxicity that precluded ASCT. The median number of CD34(+) cells per kilogram mobilized was 6.3 x 10(6). Progression-free survival rates of patients who underwent transplantation after RICE were marginally better than those of 95 consecutive historical control patients who underwent transplantation after ICE (54% vs 43% at 2 years; P =.25). RICE appears to induce very high CR rates in patients with relapsed and refractory DLBCL; however, further studies are necessary to determine whether this treatment regimen will improve outcomes after ASCT.
3D Computer Graphics (1993)

The third edition of Alan Watt's 3D Computer Graphics, a bible of computer graphics, includes a CD-ROM full of examples and updated information on graphics and rendering algorithms. The book discusses many of the techniques that have evolved in the seven years since the previous edition was published. 3D Computer Graphics is a textbook, and it's designed for serious programmers creating graphics applications (not end users). Over the course of 16 sections, Watt introduces the concepts and implementation of computer imaging, from “Mathematical Fundamentals of Computer Graphics” to “Representation and Rendering” and ending with “Image-Based Rendering and Photo-Modelling.” The last section, devoted to computer animation, includes methods for linked structures, collision detection, and particle animation (to name a few). Although the topics are sometimes hard to grasp, Mr. Watt writes clearly and concisely, making generous use of diagrams to help convey the principles described in the text. The accompanying CD-ROM includes over a dozen studies of computer graphics techniques and rendering algorithms. Presented in HTML, the exhaustive studies, each with a matrix of thumbnails, demonstrates the varied achievable results. One minor complaint here: although the thumbnails can be clicked to view a much larger image, the larger versions come in.tif format, which few (if any) Web browsers can view. Users will need another application to view them. Having the large image in.jpg format would have enabled the reader to view it in the already-open Web browser.
Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline (2014)

On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.
Pseudomonas aeruginosa LPS or Flagellin Are Sufficient to Activate TLR-Dependent Signaling in Murine Alveolar Macrophages and Airway Epithelial Cells (2009)

The results clearly demonstrate that only two ligand/receptor pairs are necessary for the induction of KC, TNF-alpha, and IL-6 synthesis by P. aeruginosa-activated cells, i.e. TLR2,4/LPS and TLR5/flagellin. Either ligand/receptor pair is sufficient to sense the bacterium and to trigger cell activation, and when both are missing lung EC and AM are unable to produce such a response as were cells from MyD88(-/-) mice.
An obstacle detection method by fusion of radar and motion stereo (2002)

In order to avoid collision with an object that blocks the course of a vehicle, measuring the distance to it and detecting positions of its side boundaries, are necessary. In the paper, an object detection method achieved by the fusion of millimeter-wave radar and a single video camera is proposed. We consider the method as the least expensive solution because at least one camera is necessary for lane marking detection. In the method, the distance is measured by the radar, and the boundaries are found from an image sequence, based on a motion stereo technique with the help of the distance measured by the radar. Since the method does not depend on the appearance of objects, it is capable of detecting not only an automobile but also other objects. Object detection by the method was confirmed through an experiment. In the experiment, both a stationary and a moving object were detected and a pedestrian as well as a vehicle was detected.
Longitudinal positron emission tomography imaging for monitoring myelin repair in the spinal cord (2013)

[11C]MeDAS-PET is a promising imaging marker for monitoring myelin pathology in vivo, future applications of which in humans should be achievable.
Synthesis and Characterization of a Homogeneous Chemical Conjugate Between Basic Fibroblast Growth Factor and Saporin (1995)

Basic fibroblast growth factor (FGF-2) and saporin were chemically conjugated using the crosslinker, N-succinimidyl-3(2-pyridyldithio)-propionate. When purified, the conjugate was found to be heterogeneous as analyzed by SDS/PAGE, size-exclusion HPLC and reverse-phase HPLC. Therefore, we sought to synthesize a molecule that would be homogeneous and thus easier to characterize and evaluate its efficacy and toxicity for pharmaceutical drug development. A homogeneous chemical conjugate was successfully synthesized by using a mutant FGF-2 with Cys96 replaced by Ser ([S96]FGF-2) and a recombinant saporin mutant containing a single Cys at the -1 position (C-SAP). The latter was expressed in Escherichia coli and isolated to 99% purity by expanded-bed adsorption chromatography followed by cation-exchange chromatography. The cysteine in C-SAP was activated by Ellman's reagent and then reacted with the only available cysteine (position 78) in [S96]FGF-2 to produce the homogeneous conjugate, designated as FGF2-C-SAP. The purified FGF2-C-SAP was more than 98% pure as judged by HPLC. In vitro biological assays indicated that FGF2-C-SAP was a potent inhibitor of protein synthesis in a cell-free system and was cytotoxic to FGF-receptor-bearing cells.
Transmembrane Helix M6 in Sarco(endo)plasmic Reticulum Ca2+-ATPase Forms a Functional Interaction Site with Phospholamban (1999)

In an earlier study (Kimura, Y., Kurzydlowski, K., Tada, M., and MacLennan, D. H. (1997) J. Biol. Chem. 272, 15061-15064), mutation of amino acids on one face of the phospholamban (PLN) transmembrane helix led to loss of PLN inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) molecules. This helical face was proposed to form a site of PLN interaction with a transmembrane helix in SERCA molecules. To determine whether predicted transmembrane helices M4, M5, M6, or M8 in SERCA1a interact with PLN, SERCA1a mutants were co-expressed with wild-type PLN and effects on Ca(2+) dependence of Ca(2+) transport were measured. Wild-type inhibitory interactions shifted apparent Ca(2+) affinity of SERCA1a by an average of -0.34 pCa units, but four of the seven mutations in M4 led to a more inhibitory shift in apparent Ca(2+) affinity, averaging -0.53 pCa units. Seven mutations in M5 led to an average shift of -0.32 pCa units and seven mutations in M8 led to an average shift of -0.30 pCa units. Among 11 mutations in M6, 1, Q791A, increased the inhibitory shift (-0.59 pCa units) and 5, V795A (-0.11), L802A (-0.07), L802V (-0.04), T805A (-0.11), and F809A (-0.12), reduced the inhibitory shift, consistent with the view that Val(795), Leu(802), Thr(805), and Phe(809), located on one face of a predicted M6 helix, form a site in SERCA1a for interaction with PLN. Those mutations in M4, M6, or M8 of SERCA1a that enhanced PLN inhibitory function did not enhance PLN physical association with SERCA1a, but mutants V795A and L802A in M6, which decreased PLN inhibitory function, decreased physical association, as measured by co-immunoprecipitation. In related studies, those PLN mutants that gained inhibitory function also increased levels of co-immunoprecipitation of wild-type SERCA1a and those that lost inhibitory function also reduced association, correlating functional interaction sites with physical interaction sites. Thus, both functional and physical data confirm that PLN interacts with M6 SERCA1a.
Long-Lived Qubit Memory Using Atomic Ions (2005)

We demonstrate experimentally a robust quantum memory using a magnetic-field-independent hyperfine transition in 9Be+ atomic ion qubits at a magnetic field B approximately = 0.01194 T. We observe that the single physical qubit memory coherence time is greater than 10 s, an improvement of approximately 5 orders of magnitude from previous experiments with 9Be+. We also observe long coherence times of decoherence-free subspace logical qubits comprising two entangled physical qubits and discuss the merits of each type of qubit.
Cholera (1995)

Despite more than a century of study, cholera still presents challenges and surprises to us. Throughout most of the 20th century, cholera was caused by Vibrio cholerae of the O1 serogroup and the disease was largely confined to Asia and Africa. However, the last decade of the 20th century has witnessed two major developments in the history of this disease. In 1991, a massive outbreak of cholera started in South America, the one continent previously untouched by cholera in this century. In 1992, an apparently new pandemic caused by a previously unknown serogroup of V. cholerae (O139) began in India and Bangladesh. The O139 epidemic has been occurring in populations assumed to be largely immune to V. cholerae O1 and has rapidly spread to many countries including the United States. In this review, we discuss all aspects of cholera, including the clinical microbiology, epidemiology, pathogenesis, and clinical features of the disease. Special attention will be paid to the extraordinary advances that have been made in recent years in unravelling the molecular pathogenesis of this infection and in the development of new generations of vaccines to prevent it.
Vapor phase organic chemistry to deposit conjugated polymer films on arbitrary substrates (2017)

Coating textured, high surface area substrates, such as paper and textiles, with conjugated polymer films is challenging.
An approach to the stereoselective synthesis of Sp-dinucleoside phosphorothioates using phosphotriester chemistry (1987)

An approach to the stereoselective synthesis of Sp- dinucleoside phosphorothioates has been investigated which utilizes phosphotriester chemistry. The stereoselectivity of internucleotide bond formation between N4-benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine-3'-O-(S2-cyano-e thyl) phosphorothioate (3) and 3'-O-acetylthymidine has been studied using either mesitylenesulphonyl-5-(pyridin-2-yl)tetrazole (MSPy) or 1-mesitylenesulphonyl-3-nitro-1,2,4-triazole (MSNT) as the activating agent. The removal of the cyanoethyl group from the protected dinucleoside phosphorothioate has been studied, and conditions are reported which provide rapid deprotection without concomittant desulphurisation.
Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons (1993)

To examine the role of Ca2+ in early neuronal death, we studied the impact of free intracellular calcium concentration ([Ca2+]i) on survivability in populations of cultured mouse spinal neurons. We asked whether early neurotoxicity was triggered by Ca2+ influx, whether elevated [Ca2+]i was a predictive indicator of impending neuronal death, and whether factors other than [Ca2+]i increases influenced Ca2+ neurotoxicity. We found that when neurons were lethally challenged with excitatory amino acids or high K+, they experienced a biphasic [Ca2+]i increase characterized by a primary [Ca2+]i transient that decayed within minutes, followed by a secondary, sustained, and irreversible [Ca2+]i rise that indicated imminent cell death. We showed that in the case of glutamate-triggered neurotoxicity, processes triggering eventual cell death required Ca2+ influx, and that neurotoxicity was a function of the transmembrane Ca2+ gradient. Fura-2 Ca2+ imaging revealed a "ceiling" on measurable changes in [Ca2+]i that contributed to the difficulty in relating [Ca2+]i to neurotoxicity. We found, by evoking Ca2+ influx into neurons through different pathways, that the chief determinants of Ca2+ neurotoxicity were the Ca2+ source and the duration of the Ca2+ challenge. When Ca2+ source and challenge duration were taken into account, a statistically significant relationship between measured [Ca2+]i and cell death was uncovered, although the likelihood of neuronal death depended much more on Ca2+ source than on the magnitude of the measured [Ca2+]i increase. Thus, neurotoxicity evoked by glutamate far exceeded that evoked by membrane depolarization with high K+ when [Ca2+]i was made to increase equally in both groups. The neurotoxicity of glutamate was triggered primarily by Ca2+ influx through NMDA receptor channels, and exceeded that triggered by non-NMDA receptors and Ca2+ channels when [Ca2+]i was made to rise equally through these separate pathways. The greater neurotoxicity triggered by NMDA receptors was related to some attribute other than an ability to trigger greater [Ca2+]i increases as compared with other Ca2+ sources. We hypothesize that this represents a physical colocalization of NMDA receptors with Ca(2+)-dependent rate-limiting processes that trigger early neuronal degeneration.
A new wafer-bonder of ultra-high precision using surface activated bonding (SAB) concept (2002)

A robot-controlled wafer bonding machine was developed for the bonding of different sizes of wafers ranging up to 8 inches diameter. The features of this equipment are such that: (1) After the automatic parallel adjustment for 8-inch wafers to a margin of error within /spl plusmn/1 /spl mu/m, the X, Y, and /spl theta/ axis alignments are performed, allowing a margin of error within /spl plusmn/0.5 /spl mu/m in bonding accuracy; and (2) Room-temperature bonding is enabled using the surface activated (SAB) bonding concept. 8-inch diameter silicon wafers ware successfully bonded by the SAB process at room temperature for the first time. Preliminary investigations across the interface using an Infrared camera show that no bubbles are visibly present in the bonding region.
Extended Life-Span and Stress Resistance in the Drosophila Mutant methuselah (1998)

Toward a genetic dissection of the processes involved in aging, a screen for gene mutations that extend life-span in Drosophila melanogaster was performed. The mutant line methuselah (mth) displayed approximately 35 percent increase in average life-span and enhanced resistance to various forms of stress, including starvation, high temperature, and dietary paraquat, a free-radical generator. The mth gene predicted a protein with homology to several guanosine triphosphate-binding protein-coupled seven-transmembrane domain receptors. Thus, the organism may use signal transduction pathways to modulate stress response and life-span.