gebhart/patrepeval huggingface dataset:
Identification of a Heregulin Binding Site in HER3 Extracellular Domain (2001)

HER3 (also known as c-Erb-b3) is a type I receptor tyrosine kinase similar in sequence to the epidermal growth factor (EGF) receptor. The extracellular segment of this transmembrane receptor contains four domains. Domains I and II are similar in sequence to domains III and IV, respectively, and domains II and IV are cysteine-rich. We show that the EGF-like domain of heregulin (hrg) binds to domains I and II of HER3, in contrast to the EGF receptor, for which prior studies have shown that a construct consisting of domains III and portions of domain IV binds EGF. Next, we identified a putative hrg binding site by limited proteolysis of the recombinant extracellular domains of HER3 (HER3-ECD(I-IV)) in both the presence and absence of hrg. In the absence of hrg, HER3-ECD(I-IV) is cleaved after position Tyr(50), near the beginning of domain I. Binding of hrg to HER3-ECD(I-IV) fully protects position Tyr(50) from proteolysis. To confirm that domain I contains a hrg binding site, we expressed domains I and II (HER3-ECD(I-II)) and find that it binds hrg with 68 nm affinity. These data suggest that domains I and II of HER3-ECD(I-IV) act as a functional unit in folding and binding of hrg. Thus, our biochemical findings reinforce the structural hypothesis of others that HER3-ECD(I-IV) is similar to the insulin-like growth factor-1 receptor (IGF-1R), as follows: 1) The protected cleavage site in HER3-ECD(I-IV) corresponds to a binding footprint in domain I of IGF-1R; 2) HER3-ECD(I-II) binds hrg with a 68 nm dissociation constant, supporting the hypothesis that domain I is involved in ligand binding; and 3) the large accessible surface area (1749 A) of domain L1 of IGF-1R that is buried by domain S1, as well as the presence of conserved contacts in this interface of type 1 RTKs, suggests that domains L1 and S1 of IGF-1R function as a unit as observed for HER3-ECD(I-II). Our results are consistent with the proposal that HER3 has a structure similar to IGF-1R and binds ligand at a site in corresponding domains.
Enterococcus faecalis phosphomevalonate kinase (2005)

The six enzymes of the mevalonate pathway of isopentenyl diphosphate biosynthesis represent potential for addressing a pressing human health concern, the development of antibiotics against resistant strains of the Gram-positive streptococci. We previously characterized the first four of the mevalonate pathway enzymes of Enterococcus faecalis, and here characterize the fifth, phosphomevalonate kinase (E.C. 2.7.4.2). E. faecalis genomic DNA and the polymerase chain reaction were used to clone DNA thought to encode phosphomevalonate kinase into pET28b(+). Double-stranded DNA sequencing verified the sequence of the recombinant gene. The encoded N-terminal hexahistidine-tagged protein was expressed in Escherichia coli with induction by isopropylthiogalactoside and purified by Ni(++) affinity chromatography, yield 20 mg protein per liter. Analysis of the purified protein by MALDI-TOF mass spectrometry established it as E. faecalis phosphomevalonate kinase. Analytical ultracentrifugation revealed that the kinase exists in solution primarily as a dimer. Assay for phosphomevalonate kinase activity used pyruvate kinase and lactate dehydrogenase to couple the formation of ADP to the oxidation of NADH. Optimal activity occurred at pH 8.0 and at 37 degrees C. The activation energy was approximately 5.6 kcal/mol. Activity with Mn(++), the preferred cation, was optimal at about 4 mM. Relative rates using different phosphoryl donors were 100 (ATP), 3.6 (GTP), 1.6 (TTP), and 0.4 (CTP). K(m) values were 0.17 mM for ATP and 0.19 mM for (R,S)-5-phosphomevalonate. The specific activity of the purified enzyme was 3.9 micromol substrate converted per minute per milligram protein. Applications to an immobilized enzyme bioreactor and to drug screening and design are discussed.
Template-Based Approaches to the Preparation of Amorphous, Nanoporous Silicas (1996)

This review discusses two classes of organic template-derived amorphous silicas distinguished by the nature of template-matrix interactions and the extent to which subsequent processing dictates the final pore morphology. First we discuss surfactant-templated silicas where the template-matrix interaction is via non-covalent bonding mechanisms and the pore structure is established in the solution stage. We then discuss silicas templated by organic ligands covalently bonded to the siloxane network where subsequent processing strongly influences the final pore structure.
Patterning of Poly(acrylic acid) by Ionic Exchange Reactions in Microfluidic Channels (2006)

A thin film of crosslinked poly(acrylic acid) (PAA), patterned within microfluidic channels (see figure) and crosslinked with metal cations, serves as a platform for rapid “on-chip” growth of patterned metallic and semiconductor nanoparticles. The embedded particles serve as catalysts for electroless deposition of metal films.
RPM: a rapid prototyping engine for multiprocessor systems (1995)

RPM enables rapid prototyping of different multiprocessor architectures. It uses hardware emulation for reliable design verification and performance evaluation. The major objective of the RPM project is to develop a common, configurable hardware platform to accurately emulate different MIMD systems with up to eight execution processors. Because emulation is orders of magnitude faster than simulation, an emulator can run problems with large data sets more representative of the workloads for which the target machine is designed. Because an emulation is closer to the target implementation than an abstracted simulation, it can accomplish more reliable performance evaluation and design verification. Finally, an emulator is a real computer with its own I/O; the code running on the emulator is not instrumented. As a result, the emulator looks exactly like the target machine (to the programmer) and can run several different workloads, including code from production compilers, operating systems, databases, and software utilities.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A Somatic Variant in MYD88 (L265P) Revealed by Whole Genome Sequencing Differentiates Lymphoplasmacytic Lymphoma From Marginal Zone Lymphomas (2011)

Abstract Abstract 261 Lymphoplasmacytic (LPL) and marginal zone lymphoma (MZL) are distinct clinicopathological entities under the WHO classification system for B-cell lymphomas. Differentiation of LPL from MZL has been difficult due to overlapping clinical, morphological, histopathological, immunophenotypic, and cytogenetic features. We therefore sought to identify a molecular marker by which LPL could be differentiated from MZL. Using paired normal/tumor tissues from 10 LPL patients, whole genome sequencing was utilized to identify somatic variants. These studies identified a somatic variant at position 38182641 in chromosome 3p22.2 with a single nucleotide change from T→C in the myeloid differentiation primary response (MYD88) gene, and a predicted non-synonymous change at amino acid position 265 from leucine to proline (L265P) in 10 of 10 LPL patients. MYD88 L265P is an oncogenically active mutation in DLBCL ABC cell lines via activation of IRAK1/4/TRAF-6/NF-κβ signaling, and is present in tumors from 29% of patients with ABC subtype of DLBCL, and 6% of patients with MALT lymphomas (Ngo et al, Nature 2011, 470:115–119). Further to these efforts, we performed Sanger sequencing of MYD88 in malignant cells obtained from 51 patients with LPL, 49 of whom had an IgM monoclonal protein and were therefore classified as Waldenstrom's Macroglobulinemia (WM), and 2 with an IgG monoclonal protein, along with 46 patients with MZL, which included 21 Splenic (SMZL), 20 Extranodal (EMZL), and 5 Nodal (NMZL) Subtypes, as well as B-cells from 15 healthy donors. Among LPL patients, the MYD88 L265P variant was found in malignant cells from 46/51 (90.1%) cases, which included 44 patients with WM, and 2 patients with IgG LPL. Expression of the MYD88 L265P variant was heterozygous in 42, and homozygous in 4 LPL patients. By comparison, only 3/46 (6.5%) patients with MZL (1 SMZL; 1 EMZL; 1 NMZL) exhibited the MYD88 L265P variant which was heterozygous (p&lt;0.0001), and included 2 patients (1 SMZL, 1 NMZL) with extensive bone marrow involvement, a monoclonal IgM protein, and whose clinicopathological characteristics overlapped with LPL. By comparison, the MYD88 L265P variant was absent in CD19+ cells from all 15 healthy donors. The results of this study demonstrate that the MYD88 L265P mutation is widely expressed in patients with LPL, and can be used to differentiate LPL from MZL. Disclosures: Treon: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
VI. The phenomena of rupture and flow in solids (1921)

Abstract In the course of an investigation of the effect of surface scratches on the mechanical strength of solids, some general conclusions were reached which appear to have a direct bearing on the problem of rupture, from an engineering standpoint, and also on the larger question of the nature of intermolecular cohesion. The original object of the work, which was carried out at the Royal Aircraft Estab­lishment, was the discovery of the effect of surface treatment—such as, for instance, filing, grinding or polishing—on the strength of metallic machine parts subjected to alternating or repeated loads. In the case of steel, and some other metals in common use, the results of fatigue tests indicated that the range of alternating stress which could be permanently sustained by the material was smaller than the range within which it was sensibly elastic, after being subjected to a great number of reversals. Hence it was inferred that the safe range of loading of a part, having a scratched or grooved surface of a given type, should be capable of estimation with the help of one of the two hypotheses of rupture commonly used for solids which are elastic to fracture. According to these hypotheses rupture may be expected if (a) the maximum tensile stress, (b) the maximum extension, exceeds a certain critical value. Moreover, as the behaviour of the materials under consideration, within the safe range of alternating stress, shows very little departure from Hooke’s law, it was thought that the necessary stress and strain calculations could be performed by means of the mathematical theory of elasticity.
Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk (2012)

Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world's population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R-deficient (Il36r-/-) mice were protected from imiquimod-induced expansion of dermal IL-17-producing γδ T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn-/-) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36-mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r-/- mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1-independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.
GaAs on Si(111)—crystal shape and strain relaxation in nanoscale patterned growth (2005)

Nanoscale patterned growth of GaAs on Si(111) by molecular beam epitaxy is examined. A 355 nm period two-dimensional array of circular holes (diameter ∼200–250nm) is fabricated into a 45-nm-thick SiO2 film on a Si(111) substrate by large-area interferometric lithography and dry etching. For 300 nm deposition, the GaAs epilayer selectively deposited within each hole on the patterned substrate is surrounded by {11¯0}-type sidewalls perpendicular to Si(111), resulting in a hexagon-based prismatic pillar, without significant lateral overgrowth. At the initial stage of growth, twins parallel to Si(111) and an aperiodic mixture of cubic and hexagonal phases are observed but most of the GaAs pillars are terminated with a cubic phase region. Raman scattering reveals that the individual nanoscale GaAs pillars are completely strain relaxed.
Mechanisms of c-erbB2/neu oncogene-induced metastasis and repression of metastatic properties by adenovirus 5 E1A gene products. (1992)

c-erbB2/neu is a transforming oncogene that encodes a 185-kDa transmembrane glycoprotein. In many but not all studies, amplification and/or overexpression of the human c-erbB2/neu oncogene has been correlated with poor prognosis and the number of lymph node metastases in node-positive breast cancer patients. We have shown that expression of the activated rat c-erbB2/neu oncogene in mouse embryo fibroblast 3T3 cells is sufficient to induce experimental metastases in nude mice. Important steps in the metastatic event are tumor cell adhesion to endothelial cells and invasion of basement membranes. Therefore, we further examined the ability of c-erbB2/neu oncogene-transformed 3T3 cells to adhere to microvessel endothelial cells and secrete basement membrane-degradative enzymes. The c-erbB2/neu oncogene-transformed 3T3 cells were shown to be more adherent and have higher gelatinase activities. Since we had previously shown that the adenovirus 5 E1A gene product can suppress c-erbB2/neu-induced transformation of 3T3 cells, we examined the possibility that E1A can abrogate the metastatic properties of c-erbB2/neu-transformed 3T3 cells. We found that introduction of the E1A gene into c-erbB2/neu-transformed 3T3 cells reduced the formation of experimental metastatic tumors and inhibited metastasis-associated properties, such as adhesion to microvessel endothelial cells, migration through a layer of reconstituted basement membrane (Matrigel) and secretion of basement membrane-degradative enzymes. The results indicate that the mechanism by which the c-erbB2/neu gene induces higher metastatic potential is to promote adhesion and invasion steps of the metastatic cascade. The E1A gene, which functions by inhibiting these steps, is thus a suppressor gene for c-erbB2/neu-induced experimental metastasis.
Outcome of Renal Transplantation in Patients with Non–Shiga Toxin–Associated Hemolytic Uremic Syndrome (2005)

More than 50% of patients with non-Shiga toxin-associated hemolytic uremic syndrome (non-Stx-HUS) progress to ESRD. Kidney transplant failure for disease recurrence is common; hence, whether renal transplantation is appropriate in this clinical setting remains a debated issue. The aim of this study was to identify possible prognostic factors for renal transplant outcome by focusing on specific genetic abnormalities associated with the disease. All articles in literature that describe renal transplant outcome in patients with ESRD secondary to non-Stx-HUS, genotyped for CFH, MCP, and IF mutations, were reviewed, and data of patients who were referred to the International Registry of Recurrent and Familial HUS/TTP and data from the Newcastle cohort were examined. This study confirmed that the overall outcome of kidney transplantation in patients with non-Stx-HUS is poor, with disease recurring in 60% of patients, 91.6% of whom developed graft failure. No clinical prognostic factor that could identify patients who were at high risk for graft failure was found. The presence of a factor H (CFH) mutation was associated with a high incidence of graft failure (77.8 versus 54.9% in patients without CFH mutation). Similar results were seen in patients with a factor I (IF) mutation. In contrast, graft outcome was favorable in all patients who carried a membrane co-factor protein (MCP) mutation. Patients with non-Stx-HUS should undergo genotyping before renal transplantation to help predict the risk for graft failure. It is debatable whether a kidney transplant should be recommended for patients with CFH or IF mutation. Reasonably, patients with an MCP mutation can undergo a kidney transplant without risk for recurrence.
Engineered Nanocarriers of Doxorubicin: A Current Update (2008)

Doxorubicin remains the first line of treatment for various cancers ever since its discovery in 1971. Cardiotoxicity and nephrotoxicity associated with unformulated doxorubicin triggered the development of doxorubicin nanocarriers. Although the therapeutic profile of doxorubicin is appreciably improved by entrapping in nanocarriers, they are largely taken up by organs of the reticuloendothelial system. Engineered nanocarriers of doxorubicin refer to carriers modified to escape recognition by reticuloendothelial system and/or functionalized with target specific ligands for selective accumulation at the target site. The first developments in engineered nanocarriers were the stealth carriers. These effectively bypassed the reticuloendothelial system and enhanced the therapeutic profile of doxorubicin by enabling passive accumulation in tumors. Stealth nanocarriers of doxorubicin revealed significant decrease in cardiotoxicity and nephrotoxicity, which led to the approval of liposomal doxorubicin for clinical applications. Success of liposomal doxorubicin was soon dulled by the appearance of newer toxicities like palmar-plantar erythrodysesthesia commonly referred as hand foot syndrome. The search for the magic bullet of doxorubicin has further intensified and resulted in design of engineered nanocarriers with high specificity for cancer cells. This review charts the progress from nanocarriers to engineered nanocarriers of doxorubicin, and highlights the current status of engineered nanocarriers of doxorubicin in clinical trials.
Molecular Modeling: A Search for a Calpain Inhibitor as a New Treatment for Cataractogenesis (2011)

Studies of 17 analoges of 3 (SJA6017) in an in silico calpain model are reconciled to measured IC(50) values against ovine calpain. The studies validate the potential of the "model" and criteria established for inhibition as a tool to select structures for synthesis to test as calpain inhibitors. Using this screening methodology of virtual libraries led us to synthesize several inhibitors including macrocycle 33, which in vitro sheep eye lens culture experiments showed to substantially slow opacification.
Cooperative Prosurvival Activity by ERK and Akt in Human Alveolar Macrophages is Dependent on High Levels of Acid Ceramidase Activity (2004)

Human alveolar macrophages are unique in that they have an extended life span in contrast to precursor monocytes. In evaluating the role of sphingolipids in alveolar macrophage survival, we found high levels of sphingosine, but not sphingosine-1-phosphate. Sphingosine is generated by the action of ceramidase(s) on ceramide, and alveolar macrophages have high constitutive levels of acid ceramidase mRNA, protein, and activity. The high levels of acid ceramidase were specific to alveolar macrophages, because there was little ceramidase protein or activity (or sphingosine) in monocytes from matching donors. In evaluating prolonged survival of alveolar macrophages, we observed a requirement for constitutive activity of ERK MAPK and the PI3K downstream effector Akt. Blocking acid ceramidase but not sphingosine kinase activity in alveolar macrophages led to decreased ERK and Akt activity and induction of cell death. These studies suggest an important role for sphingolipids in prolonging survival of human alveolar macrophages via distinct survival pathways.
Multiple sclerosis immune complexes: An analysis of component antigens and antibodies (1984)

Serum immune complexes were isolated from 21 patients with multiple sclerosis and 23 control subjects, who were normal or had other neurological diseases, and then probed for neurotropic viral and brain-reactive components. Multiple sclerosis complexes contained antibody to herpes simplex (13 cases), measles (8 cases), cytomegalovirus (5 cases), and rubella virus (5 cases). In some complexes, herpes simplex or cytomegalovirus antigen was detected along with antibody. Myelin basic protein or antibody to myelin basic protein was found in the complexes of 7 patients with multiple sclerosis and 2 patients with other neurological diseases. Serum complexes containing antibody reactive with galactocerebroside and ganglioside were present in 12 patients with multiple sclerosis and 3 with other neurological diseases. Over 60% of the multiple sclerosis group had IgM and IgA serum complexes, including 5 patients with very high IgA complex levels. This study suggests that patients with multiple sclerosis have ongoing systemic virus production with resultant immune complex formation. In addition, they often have serum complexes that contain brain-reactive components.
Possibilities of Fe-Pt media for ultra-high density perpendicular magnetic recording (2003)

Perpendicular recording is fundamentally characterized by demagnetizing field free transitions. This principal feature is a great advantage not only for granular type media but also laterally exchange-coupled (LEC) film media with enhanced wall-pinning effects. Recently, it has been first reported that larger M/sub s/ and K/sub u/, high density pinning sites, and thinner recording layer of LEC film media are effective for coexistence of a larger hysteresis loop slope parameter, /spl alpha/, and a smaller domain size. Thus, higher recording and reproducing resolutions and lower media noise are expected to be realized by the media. Since an ordered Fe-Pt alloy of L1/sub 0/ phase satisfies the requirements for the LEC film media, we discuss the potential of thinner Fe-Pt film media for perpendicular magnetic recording.
Photodynamic Fluorescent Metal Ion Sensors with Parts per Billion Sensitivity (1998)

We report herein the synthesis and spectroscopic study of the first spiropyrandinolines that function as sensors for metal ions in the parts per billion range. These systems operate by either photochemically or chemically induced reversible formation of merocyanine metal ion complexes. The application of this novel photodynamic sensing material to sensor technology is discussed.
SLC45A3-ELK4 Chimera in Prostate Cancer: Spotlight on cis-Splicing (2012)

Using a series of detailed experiments, Zhang and colleagues establish that the prostate cancer RNA chimera SLC45A3-ELK4 is generated by cis-splicing between the 2 adjacent genes and does not involve DNA rearrangements or trans-splicing. The chimera expression is induced by androgen treatment likely by overcoming the read-through block imposed by the intergenic CCCTC insulators bound by CCCTC-binding factor repressor protein. The chimeric transcript, but not wild-type ELK4, is shown to augment prostate cancer cell proliferation.
Future Trends in the Design and Application of Surgical Robots (2004)

Beyond current laparoscopic surgery is the emergence of robotic surgery. The power of this type of surgery is converting both vision and hand motions into electronic signals (video and telemanipulation), which completes the transition of surgery from the Industrial Age to the Information Age. Other advances include replacing scrub and circulation nurses with robots, miniaturization, biosurgery, "intelligent" instruments, and energy-directed rather than mechanical surgical tools. These modalities will supplement-but not totally replace-current forms of surgery such as open conventional, minimally invasive, endoluminal, and interventional.