gebhart/patrepeval huggingface dataset:
Activation of nuclear factor-kappaB via T cell receptor requires a Raf kinase and Ca2+ influx. Functional synergy between Raf and calcineurin (1996)

Signals transduced via the TCR activate the transcription factor nuclear factor-kappaB (NF-kappaB), which, in turn, is critical to the transcriptional induction of many genes important for the proliferation and expression of a differentiated phenotype. Treatment of T cells with the protein kinase C activator PMA in combination with Ca2+ ionophores mimics this process, and the two agents are often substituted for TCR stimulation, bypassing the TCR. Here we identify intracellular signaling components involved in activation of NF-kappaB following TCR stimulation. TCR signaling was triggered by treating Jurkat T cells with PHA or anti-CD3 Abs, and NF-kappaB activation was monitored by electrophoretic mobility shift assays and/or by kappaB-dependent reporter assays. Contrary to the idea that protein kinase C is involved in TCR-mediated activation of NF-kappaB, high doses of staurosporine did not interfere with activation of NF-kappaB by PHA, while the same dose of staurosporine completely blocked activation by PMA. PHA-induced kappaB-dependent reporter activity was, however, effectively blocked by a dominant negative form of Raf-1, suggesting a critical role for a Raf kinase. The TCR-mediated activation of NF-kappaB was also dependent on a Ca2+ influx, because the Ca2+ channel blocker, SK&F 96365, as well as other agents that prevented the Ca2+ influx, inhibited NF-kappaB activation. Cotransfection of a constitutively active form of calcineurin largely substituted for the Ca2+ requirement and reversed the blockade by SK&F 96365. Consistent with these observations, coexpression of constitutively active forms of Raf-1 and calcineurin synergistically induced kappaB-dependent reporter activity, suggesting a physiologically relevant functional interaction between the kinase and the phosphatase.
De novo production of the flavonoid naringenin in engineered Saccharomyces cerevisiae (2012)

The results reported in this study demonstrate that S. cerevisiae is capable of de novo production of naringenin by coexpressing the naringenin production genes from A. thaliana and optimization of the flux towards the naringenin pathway. The engineered yeast naringenin production host provides a metabolic chassis for production of a wide range of flavonoids and exploration of their biological functions.
Wireless Proximity Communications for 3D System Integration (2007)

Capacitive and inductive coupling I/Os are emerging non-contact parallel links for chips that are stacked in a package. The capacitive coupling utilizes a pair of electrodes that are formed by top layer of IC interconnections. The inductive coupling uses coils, just like a transformer, that are rolled by the IC interconnections. They are implemented by digital circuits in a standard CMOS. No new wafer process or mechanical process is required, and hence inexpensive. Since there is no pad exposed for contact, ESD protection structure can be removed. Chips under difference supply voltages can be directly connected, since they provide with an AC-coupling interface. This paper presents fundamental differences between the inductive coupling and the capacitive coupling. Secondly, advantages of the inductive coupling over Through-Silicon-Vias and micro-bumps are discussed. Circuit techniques to raise aggregated data rate to 1 Th/s, and lower energy dissipation to 0.14 pJ/h are presented. Future challenges and opportunities such as a 3D scaling scenario are described.
R-Spondin Family Members Regulate the Wnt Pathway by a Common Mechanism (2008)

The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo.
Role of Glutamate 91 in Information Transfer during Substrate Activation of Yeast Pyruvate Decarboxylase (1999)

Oligonucleotide-directed site-specific mutagenesis was carried out on pyruvate decarboxylase (EC 4.1.1.1) from Saccharomyces cerevisiae at E91, located on the putative substrate activation pathway and linking the alpha and gamma domains of the enzyme. While C221 on the beta domain is the residue at which substrate activation is triggered [Baburina, I., et al. (1994) Biochemistry 33, 5630-5635; Baburina, I., et al. (1996) Biochemistry 35, 10249-10255], that information, via the substrate bound at C221, is transmitted to H92 on the alpha domain, across the domain divide from C221 [Baburina, I. , et al. (1998) Biochemistry 37, 1235-1244], thence to E91 on the alpha domain, and then on to W412 on the gamma domain [Li, H., and Jordan, F. (1999) Biochemistry 38, 10004-10012] and to the active site thiamin diphosphate located at the interface of the alpha and gamma domains [Arjunan, D., et al. (1996) J. Mol. Biol. 256, 590-600]. Substitution at E91 with Q, D, or A led to modest reductions in the specific activity (4-, 5-, and 30-fold), as well as in both the turnover number and the catalytic efficiency, in that order. Interestingly, the Hill coefficient was only slightly reduced for the E91D variant, but cooperativity was virtually abolished for the E91Q and E91A variants. The thermal stability of the variants was reduced in the following order: wild type > E91Q > E91D > E91A; circular dichroism and fluorescence experiments also demonstrated that the tertiary structure of the enzyme was affected by these substitutions. The variants could be purified as apoenzymes, demonstrating their impaired ability to bind thiamin diphosphate. Apparently, the charge at residue 91 is quite important for maintaining optimal cooperativity. To maintain strong domain-domain interactions, the length of the side chain at position 91 with hydrogen bonding potential to W412 is sufficient.
Development of an intein-mediated split–Cas9 system for gene therapy (2015)

Using CRISPR/Cas9, it is possible to target virtually any gene in any organism. A major limitation to its application in gene therapy is the size of Cas9 (>4 kb), impeding its efficient delivery via recombinant adeno-associated virus (rAAV). Therefore, we developed a split-Cas9 system, bypassing the packaging limit using split-inteins. Each Cas9 half was fused to the corresponding split-intein moiety and, only upon co-expression, the intein-mediated trans-splicing occurs and the full Cas9 protein is reconstituted. We demonstrated that the nuclease activity of our split-intein system is comparable to wild-type Cas9, shown by a genome-integrated surrogate reporter and by targeting three different endogenous genes. An analogously designed split-Cas9D10A nickase version showed similar activity as Cas9D10A. Moreover, we showed that the double nick strategy increased the homologous directed recombination (HDR). In addition, we explored the possibility of delivering the repair template accommodated on the same dual-plasmid system, by transient transfection, showing an efficient HDR. Most importantly, we revealed for the first time that intein-mediated split-Cas9 can be packaged, delivered and its nuclease activity reconstituted efficiently, in cells via rAAV.
Ligand-Directed Reduction-Sensitive Shell-Sheddable Biodegradable Micelles Actively Deliver Doxorubicin into the Nuclei of Target Cancer Cells (2013)

The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that about 81.1 and 75.0% DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under nonreducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced antitumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 μg DOX equiv/mL, which was comparable to free DOX and approximately six times lower than that for nontargeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and nontargeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.
Toll‐like receptors, RIG‐I‐like RNA helicases and the antiviral innate immune response (2007)

The antiviral innate immune response follows the detection of viral components by host pattern recognition receptors (PRRs). Two families of PRRs have emerged as key sensors of viral infection: Toll-like receptors (TLRs) and retinoic acid inducible gene-I like RNA helicases (RLHs). TLRs patrol the extracellular and endosomal compartments; signalling results in a type-1 interferon response and/or the production of pro-inflammatory cytokines. In contrast, RLHs survey the cytoplasm for the presence of viral double-stranded RNA. In the face of such host defence, viruses have developed strategies to evade TLR/RLH signalling. Such host-virus interactions provide the opportunity for manipulation of PRR signalling as a novel therapeutic approach.
cIBR Effectively Targets Nanoparticles to LFA-1 on Acute Lymphoblastic T Cells (2009)

Leukocyte function associated antigen-1 (LFA-1) is a primary cell adhesion molecule of leukocytes required for mediating cellular transmigration into sites of inflammation via the vascular endothelium. A cyclic peptide, cIBR, possesses high affinity for LFA-1, and conjugation to the surface of poly(DL-lactic-co-glycolic acid) nanoparticles can specifically target and deliver the encapsulated agents to T cells expressing LFA-1. The kinetics of targeted nanoparticle uptake by acute lymphoblastic leukemia T cells was investigated by flow cytometry and microscopy and compared to untargeted nanoparticles. The specificity of targeted nanoparticles binding to the LFA-1 integrin was demonstrated by competitive inhibition using free cIBR peptide or using the I domain of LFA-1 to inhibit the binding of targeted nanoparticles. The uptake of targeted nanoparticles was concentration and energy dependent. The cIBR-conjugated nanoparticles did not appear to localize with lysosomes whereas untargeted nanoparticles were detected in lysosomes in 6 h and steadily accumulated in lysosomes for 24 h. Finally, T-cell adhesion to epithelial cells was inhibited by cIBR nanoparticles. Thus, nanoparticles displaying the cIBR ligand may offer a useful targeted drug delivery system as an alternative treatment of inflammatory diseases involving transmigration of leukocytes.
Neutron capture cross sections ofGd148and the decay ofGd149 (2006)

The thermal cross section and resonance integral were measured for radiative neutron capture by radioactive $^{148}\mathrm{Gd}$. The deduced values are $\ensuremath{\sigma}=9600\ifmmode\pm\else\textpm\fi{}900$ b and $I=28,200\ifmmode\pm\else\textpm\fi{}2300$. We also deduced upper limits for the n,p and n, \ensuremath{\alpha} cross sections, respectively, 0.25 b and 13 b. The \ensuremath{\gamma}-ray spectrum from the decay of $^{149}\mathrm{Gd}$ was studied in singles mode at high resolution to verify the previously determined energies and intensities. From the latter measurements, new transitions are proposed and upper limits are deduced for previously reported transitions.
Chlamydia-induced septic polyarthritis in a dog : case report (1999)

A systemic disease associated with pyrexia, lymphadenopathy, and arthropathy of several joints of the appendicular skeleton in a dog is described. Chlamydia-like organisms were detected on light-microscopic examination of a smear made from joint fluid aspirated from one of the affected joints. A group-specific lipopolysaccharide antigen shared by all Chlamydia spp. was demonstrated by direct fluorescent antibody staining of joint fluid, which also proved positive for chlamydia by means of the relevant polymerase chain reaction test. An indirect fluorescent antibody test on serumwas also positive, although the complement fixation test was negative. Attempts to grow the organism from joint aspirates in the yolk sac of embryonating hens' eggs and on appropriate tissue cultures, however, failed. Chlamydia spp. are considered to have played an aetiological role in this case, making it the first substantiated case of naturally-occurring arthropathy in a dog due to chlamydiosis. The origin of the infection could not be traced.
25th Anniversary Dinner: 2 September 2010 (2010)

Dr. Bruce Kaye delivered a speech at the 25th Anniversary Dinner of the Christian Research Association (CRA) on 2 September 2010. He spoke about how the CRA came about and all it has achieved so far.
Nuvion. Protein Design Labs. (2002)

Protein Design Labs Inc (PDL) is developing SMART anti-CD3 (Nuvion) as a potential therapeutic for autoimmune diseases such as inflammatory bowel disease (IBD), and as a prophylactic for transplant rejection. The therapy had been in phase II trials for the prevention of kidney rejection, but in December 2000 PDL decided not to continue the development of Nuvion in kidney transplantation to allow the company to focus on the rapid development of Nuvion for the treatment of acute GvHD, as well as on the larger autoimmune indications 13921621. In April 1999, Nuvion was in phase I/II trials for the treatment of psoriasis and phase I trials for GvHD, with phase II/III trials planned for 2001 for this indication. Following the release of disappointing trial results in June 2001, however, the development of Nuvion for the psoriasis indication was dropped. As of December 2000, PDL planned to initiate a phase I trial in IBD in the near future. In March 1999, Protein Design Labs was issued US-05834597. The patent relates generally to certain modifications of the constant (Fc) region of IgG2 antibodies and more specifically to anti-CD3 antibodies incorporating these modifications, including the company's SMART anti-CD3 antibody. In January 2002, analysts at Salomon Smith Barney predicted that the product would make sales of US $3.13 million in 2005, rising to US $7.20 million in 2006.
Inverse Targeting of Peritoneal Tumors: Selective Alteration of the Disposition of Methotrexate Through the Use of Anti-Methotrexate Antibodies and Antibody Fragments (1996)

We have hypothesized that antidrug antibodies (ADAb) may be employed to impart site-specific alterations in the disposition of drug molecules, potentially allowing for targeted drug therapy. We are specifically interested in minimizing systemic exposure to free drug and systemic toxicities resultant from regional chemotherapy through the intravenous administration of ADAb. In this report, we present the production and purification of anti-methotrexate Fab fragments, and we present investigations of the effects of anti-methotrexate Fab and anti-methotrexate immunoglobulin G on the disposition of methotrexate in the rat. Pharmacokinetic studies revealed that intravenous anti-methotrexate immunoglobulin G (anti-MTX IgG) and anti-methotrexate Fab (anti-MTX Fab) administration produced dramatic alterations in the plasma pharmacokinetics of methotrexate (MTX), following intraperitoneal MTX administration (area under the total MTX concentration vs time curve for anti-MTX IgG relative to control, 420 +/- 90 (p < 0.05); for anti-MTX Fab relative to control, 46 +/- 6.1 (p < 0.05); area under the free MTX concentration vs time curve for anti-MTX IgG relative to control, 0.64 +/- 0.16; for anti-MTX Fab relative to control, 0.45 +/- 0.20 (p < 0.05)). Additional studies conducted in anesthetized rats revealed no significant alterations in the area under the total peritoneal MTX concentration vs time curves, free MTX peritoneal concentration vs time curves, or peritoneal exit rate of MTX in anti-MTX Fab treated animals relative to controls. Therefore, our pharmacokinetic studies demonstrate that ADAb may produce site-specific alterations in drug pharmacokinetics, potentially enhancing the site specificity of drug distribution and drug action following regional chemotherapy.
Systemic and Central Nervous System Correction of Lysosomal Storage in Mucopolysaccharidosis Type VII Mice (1999)

Mucopolysaccharidosis (MPS) type VII patients lack functional beta-glucuronidase, leading to systemic and central nervous system dysfunction. In this study we tested whether recombinant adenovirus that encodes beta-glucuronidase (Adbetagluc), delivered intravenously and into the brain parenchyma of MPS type VII mice, could provide long-term transgene expression and correction of lysosomal distension. We also tested whether systemic treatment with the immunosuppressive anti-CD40 ligand antibody, MR-1, affected transgene expression. We found substantial plasma beta-glucuronidase activity for over 9 weeks after gene transfer in the MR-1- treated group, with subsequent decline in activity corresponding to a delayed anti-beta-glucuronidase antibody response. At 16 weeks, near wild-type amounts of beta-glucuronidase activity and striking reduction of lysosomal pathology were detected in livers from mice that had received either MR-1 cotreatment or control antibody. In the lung and kidney, beta-glucuronidase activity was markedly higher for the MR-1-treated group. beta-Glucuronidase activity in the brain persisted independently of MR-1 treatment. Activity was intense in the injected hemisphere and was also evident in the noninjected cortex and striatum, with dramatic improvements in storage deposits in areas of both hemispheres. These results indicate that prolonged enzyme expression from transgenes delivered to deficient liver and brain can mediate pervasive correction and illustrate the potential for gene therapy of MPS and other lysosomal storage diseases.
Principles of interleukin (IL)-6-type cytokine signalling and its regulation (2003)

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Optimum Graft Density for Dispersing Particles in Polymer Melts (1996)

We investigate the dispersion of polymer-grafted particles suspended in a polymer matrix by viscoelastic measurements and electron microscopy. We find that, when the graft density is low, the particle dispersion improves with an increase of the graft density, while the particle dispersion becomes worse when the graft density is too high; i.e., there is an optimum graft density for dispersing the particles. We explain the phenomena by showing that the grafted polymers cause attraction for high graft density.
Locality-aware predictive scheduling of network processors (2005)

Demands for flexible processing have moved generalpurpose processing into the data path of networks. Processor schedulers have a great impact on the pegormance of these real-time systems. We present measurements that show that the workload of a network processor is highly regular and predictable. Processing time predictions, based on these measurements, can be used in scheduling together with information about locality in the instruction stream to signijicantly improve throughput performance. We propose two scheduling schemes, Locality-Aware and Locality-Aware Predictive, that try to avoid cold caches when scheduling packets for processors. Simulations of the schedulers using packet processing times obtained from an operational network processor show the tradeoffs between the algorithms and their pe@ormance improvements over First-Come-FirstServe scheduling.