gebhart/patrepeval huggingface dataset:
Site-directed Mutagenesis of Cys-15 and Cys-20 of Pulmonary Surfactant Protein D (1996)

Surfactant protein D (SP-D) molecules are preferentially assembled as dodecamers consisting of trimeric subunits associated at their amino termini. The NH2-terminal sequence of each monomer contains two conserved cysteine residues, which participate in interchain disulfide bonds. In order to study the roles of these residues in SP-D assembly and function, we employed site-directed mutagenesis to substitute serine for cysteine 15 and 20 in recombinant rat SP-D (RrSP-D), and have expressed the mutant (RrSP-Dser15/20) in Chinese hamster ovary (CHO-K1) cells. The mutant, which was efficiently secreted, bound to maltosyl-agarose, but unlike RrSP-D, was assembled exclusively as trimers. The constituent monomers showed a decreased mobility on SDS-polyacrylamide gel electrophoresis resulting from an increase in the size and sialylation of the N-linked oligosaccharide at Asn-70. Although RrSP-Dser15/20 contained a pepsin-resistant triple helical domain, it showed a decreased Tm, and acquired susceptibility to proteolytic degradation. Like RrSP-D, RrSP-Dser15/20 bound to the hemagglutinin of influenza A. However, it showed no viral aggregation and did not enhance the binding of influenza A to neutrophils (PMN), augment PMN respiratory burst, or protect PMNs from deactivation. These studies indicate that amino-terminal disulfides are required to stabilize dodecamers, and support our hypothesis that the oligomerization of trimeric subunits contributes to the anti-microbial properties of SP-D.
HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner (2013)

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.
A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism (1994)

A mechanism for the generation of electrophilic alkylating agents from tamoxifen by hepatic alpha-oxidation of its ethyl group is presented which accounts for the formation of covalent DNA adducts associated with its hepatic carcinogenicity. The key process leading to the generation of electrophilic alkylating agents from tamoxifen is postulated to be alpha-hydroxylation in conjunction with 4-hydroxylation or secondary metabolic conjugation. The mechanism explains the lack of DNA adducts observed for the tamoxifen analogues toremifene, droloxifene and idoxifene and accounts for the species variation in hepatic carcinogenicity of tamoxifen.
Fluorescent bio/chemosensors based on silole and tetraphenylethene luminogens with aggregation-induced emission feature (2010)

New fluorescent sensors have been developed, utilizing the aggregation-induced emission (AIE) attribute of silole and tetraphenylethene luminogens. In this feature article, we briefly summarize recent progress in the development of AIE-based bio/chemosensors for assays of nuclease and AChE activities, screening of inhibitors, and detection of various analytes including charged biopolymers, ionic species, volatile and explosive organic compounds.
Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors (2006)

Current models predict that mouse plasmacytoid dendritic cells (PDCs) derive from lymphoid progenitors. However, we show PDCs arise exclusively from common myeloid progenitors (CMPs) characterized by low-level expression of several lymphoid-associated genes, including a RAG2/GFP reporter transgene. This conclusion is supported by both adoptive transfer experiments and an estrogen treatment strategy that led to marked depletion of very early lymphoid progenitors without affecting RAG2/GFP(+) CMPs or the developmental kinetics, RAG-mediated recombinase activity, and cytokine production of PDCs. These data suggest that PDCs arise exclusively from early myeloid progenitors and that promiscuous low-level expression of lymphoid-associated genes is a general feature of PDC progenitors among CMPs.
Efficient Electrochemical Flow System with Improved Anode for the Conversion of CO2to CO (2014)

The electroreduction of CO2 to CO or other products is one approach to curb the rise in atmospheric CO2 levels and/or to store excess energy of renewable intermittent sources like solar and wind. To date most efforts have focused on improving cathode catalysis, despite other components such as the anode (oxygen evolution reaction, OER) also being of key importance. Here, we report that the dihydrate form of IrO2 as the anode catalyst in alkaline media can achieve onset cell potentials as low as −1.55 V with a cathode overpotential of only 0.02 V, partial current densities for CO as high as 250 mA cm−2 (compared to ∼130 mA cm−2 with a Pt anode), and energy efficiencies as high as 70%. The IrO2 non-hydrate proved to be much more durable by maintaining more than 90% of its activity after cycling the anode potential over the 0 to 1.0 V vs. Ag/AgCl range for over 200 times, whereas the dihydrate lost most of its activity after 19 cycles. Possible causes for these differences are discussed. This work shows that improvements to the anode, so to the OER, can drastically improve the prospects of the electrochemical reduction of CO2 to useful chemicals.
High-order medium frequency micromechanical electronic filters (1999)

Third order, high-Q, micromechanical bandpass filters comprised of three ratioed folded-beam resonators coupled by flexural mode springs are demonstrated using an integrated circuit compatible, doped polycrystalline silicon surface-micromachining technology. A complete design procedure for multiresonator micromechanical filters is presented and solidified via an example design. The use of quarter-wavelength coupling beams attached to resonators at velocity-controllable locations is shown to suppress passband distortion due to finite-mass and process mismatch nonidealities, which become increasingly important on this microscale. In addition, low-velocity coupling methods are shown to greatly alleviate the lithographic resolution required to achieve a given percent bandwidth. Ratioed folded-beam micromechanical resonators are introduced as the key impedance transforming components that enable the needed low-velocity coupling. Using these design techniques, balanced three-resonator microscale mechanical filters with passband frequencies centered around 340 kHz are demonstrated with percent bandwidths of 0.1%, associated insertion losses as small as 0.1 dB, 20-dB shape factors as low as 1.5, and stopband rejections greater than 64 dB. Measurement and theory are rigorously compared and important limitations, such as thermal susceptibility, the need for passband tuning, and inadequate electromechanical coupling, are addressed.
Multilocus sequence typing of Cronobacter sakazakii and Cronobacter malonaticus reveals stable clonal structures with clinical significance which do not correlate with biotypes (2009)

In conclusion, MLST is a more robust means of identifying and discriminating between C. sakazakii and C. malonaticus than biotyping. The MLST database for these organisms is available online at http://pubmlst.org/cronobacter/.
Reversible Inhibition by Histidinol of Protein Synthesis in Human Cells at the Activation of Histidine (1972)

Abstract l-Histidinol has been found to be a potent, reversible inhibitor of protein synthesis in cultured human cells. When the culture medium contains 0.005 mm histidine, protein synthesis is inhibited 50% by 0.1 mm histidinol. Histidinol does not significantly affect the transport of histidine into cells or the amount of histidine accumulated in the free amino acid pool. Histidinol probably inhibits protein synthesis by decreasing the activation of histidine since it competitively inhibits the pyrophosphate-ATP exchange reaction promoted by crude histidyl-tRNA synthetase in the presence of histidine, with an apparent Ki of 4 x 10-7 m. Histidinol alone will not support the exchange reaction. The inhibition by histidinol of the over-all histidine charging reaction with tRNA is also competitive. The apparent Ki of histidinol for the charging reaction, under different reaction conditions than the exchange reaction, is 3 x 10-6 m. Histidinol appears to be a useful inhibitor for studying the regulation of macromolecule synthesis in cultured human cells.
Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas (2004)

Ras signaling is important for the intracellular transduction of mitogenic stimuli from activated growth factor receptors. We have investigated 37 sporadic malignant melanomas (15 primary cutaneous melanomas and 22 melanoma metastases) and 6 melanoma cell lines for mutations in the 3 Ras genes NRAS, KRAS and HRAS. All tumors and cell lines were additionally analyzed for mutation and expression of BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties, as well as for expression of RASSF1A, which encodes a Ras-binding protein with tumor suppressor properties. Mutational analyses identified somatic NRAS mutations in 2 primary melanomas, 4 melanoma metastases and 2 cell lines. One melanoma metastasis showed a somatic KRAS mutation whereas HRAS mutations were not detected. Eight primary melanomas, 6 melanoma metastases and 4 melanoma cell lines carried BRAF mutations affecting the known hot-spot codon 599. None of the tumors or cell lines with BRAF mutation demonstrated NRAS or KRAS mutations. Real-time reverse transcription-PCR showed that 8 melanomas (3 primary tumors, 5 melanoma metastases) had reduced RASSF1A transcript levels of < or =50% relative to benign melanocytic nevi and normal skin. Three melanoma cell lines lacked detectable RASSF1A transcripts. The RASSF1A gene promoter was hypermethylated in these 3 cell lines as well as in 6 of 8 melanomas with reduced RASSF1A mRNA levels. Treatment of the cell lines with 5-aza-2'-deoxycytidine and trichostatin A resulted in demethylation of the RASSF1A promoter and re-expression of RASSF1A transcripts. Most tumors and all cell lines with RASSF1A promoter methylation additionally carried BRAF or NRAS mutations, suggesting a synergistic effect of these aberrations on melanoma growth. Taken together, 57% of the investigated melanomas and 100% of the melanoma cell lines carried mutations in either NRAS, KRAS or BRAF. In addition, 22% of the melanomas and 50% of the cell lines showed reduced RASSF1A transcript levels. Thus, alterations of Ras pathway genes are of paramount importance in the pathogenesis of sporadic melanomas.
PTH receptor coupling to phospholipase C is an alternate pathway of signal transduction in bone and kidney (1990)

The parathyroid hormone (PTH) receptor is coupled via a guanine nucleotide-binding regulatory protein (G protein) to phospholipase C (PLC). Binding of PTH to its receptor leads to activation of PLC with the subsequent hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 generation leads to the release of intracellular calcium stores, which produces an increase in the intracellular calcium concentration. DAG activates protein kinase C (PKC). Both IP3 metabolites and PKC may play a role in returning the intracellular calcium concentration back to base line, by stimulating the movement of calcium from the intracellular to the extracellular compartment, as well as by sequestering calcium within intracellular organelles. PKC appears to be important in the development of desensitization and downregulation of the PTH receptor to PTH. Activation of PLC may be important in modulating the well-known effects of PTH on bone and kidney and also may be relevant to recently described actions, such as the possible role of PTH as a growth factor in skeletal tissue. Important issues that need to be addressed in this field include 1) characterization of the PTH receptor, 2) the possible role of low-molecular-weight G proteins in PTH signal transduction, and 3) further description of the role of alternate pathway signal transduction in producing the effects of PTH.
One‐Flask Synthesis of Cyclic Diguanosine Monophosphate (c‐di‐GMP) (2012)

The bacterial signaling molecule, cyclic diguanosine monophosphate (c-di-GMP), plays a key role in controlling biofilm formation and pathogenic virulence, among many other functions. It has widespread consequences for human health, and current research is actively exploring its molecular mechanisms. The convenient one-flask, gram-scale synthesis of c-di-GMP described here will facilitate these efforts.
The role of matrix metalloproteases and their inhibitors in tumour invasion, metastasis and angiogenesis. (1994)

One critical event of tumour invasion that signals the initiation of the metastatic cascade is thought to be interaction of the tumour cell with the basement membrane. Basement membranes may also pose as barriers to tumour cell invasion at multiple points later in the metastatic cascade, including during the processes of vascular infiltration and extravasation. Thus, an important proteolytic event in the metastatic cascade, and also angiogenesis, appears to be degradation of basement membrane components. A specific class of extracellular matrix degrading metalloenzymes, the matrix metalloproteases, and their endogenous inhibitors, the tissue inhibitors of metalloproteases, are thought to have a role in the creation of the proteolytic defect in basement membrane type IV collagen. We will review the evidence which indicates that matrix metalloproteases and tissue inhibitors of metalloproteases are essential for tumour cell invasion and angiogenesis. The regulation of matrix metalloproteases will be discussed, including gene activation and transcription, messenger ribonucleic acid (mRNA) stability, binding of proenzymes to cell membranes and/or matrix components, proenzyme activation, and inactivation by endogenous inhibitors. We will also discuss the mechanism for tissue inhibitor of metalloproteases-mediated inhibition of tumour invasion and angiogenesis. This appears, at least in part, to be through inhibition of protease activity required for cellular invasion, although recent observations suggest that tissue inhibitors of metalloproteases affect other distinct groups of biological activities through mechanisms other than matrix metalloprotease inhibition.
Evidence for altered synthesis of type II collagen in patients with osteoarthritis. (1998)

There is evidence to suggest that the synthesis of type II collagen is increased in osteoarthritis (OA). Using an immunoassay, we show that the content of the C-propeptide of type II procollagen (CPII), released extracellularly from the newly synthesized molecule, is directly related to the synthesis of this molecule in healthy and osteoarthritic articular cartilages. In OA cartilage, CPII content is often markedly elevated (mean 7.6-fold), particularly in the mid and deep zones, reaching 29.6% of the content in newborn. Synthesis is also directly related to total collagen II content in OA, suggesting its importance in maintaining collagen content and cartilage structure. The release of CPII from cartilage is correlated directly with cartilage content. However, the increase in CPII in OA cartilage is not reflected in serum, where a significant reduction is observed. Together these studies provide evidence for alterations in procollagen II synthesis in vivo in patients with OA.
Total Skin Electron Beam and Non-Myeloablative Allogeneic Hematopoietic Stem-Cell Transplantation in Advanced Mycosis Fungoides and Sézary Syndrome (2010)

Total skin electron beam followed by allogeneic stem-cell transplantation merits additional evaluation for a selected group of patients with refractory, advanced, cutaneous T-cell lymphoma with evidence for graft-versus-tumor effect.
Development of a Long-Acting Erythropoietin by Fusing the Carboxyl-Terminal Peptide of Human Chorionic Gonadotropin β-Subunit to the Coding Sequence of Human Erythropoietin (2007)

Human erythropoietin (EPO) is a glycoprotein hormone secreted from the kidney and controls red blood cell production. EPO has a wide clinical use in the treatment of anemia associated with renal disease, certain chronic diseases, and anemia related to chemotherapy and radiotherapy. One major issue regarding the clinical use of EPO is its relatively short half-life due to its clearance by glomerular filtration. Thus, the therapeutic protocol used in the treatment of patient-required frequent injections of EPO. To address this issue, we constructed a chimeric gene that contains the sequence of the carboxyl-terminal peptide (CTP) of human chorionic gonadotropin-beta subunit bearing four O-linked oligosaccharide recognition sites and the coding sequence of human EPO cDNA. Fusing the CTP to the carboxyl-terminal of EPO did not affect secretion, receptor binding affinity, or in vitro bioactivity. However, both in vivo potency and half-life of EPO-CTP were significantly enhanced. A single injection dose (660 IU/kg) of EPO wild-type administered once a week had no significant effect on haematocrit levels. However, EPO-CTP administered as 660 IU/kg once a week was effective as well as the same total dose of EPO wild-type administered as 220 IU/kg three times a week. This may emphasize the importance of sustained blood levels rather than total dose of administration for in vivo bioactivity. These data established the rationale for using this chimera as a long-acting EPO analog. The therapeutic efficacy of EPO-CTP analog needs to be established in higher animals and human clinical trials.
<title>Flow cytofluorometric assay of human whole blood leukocyte DNA degradation in response to <emph type="1">Yersinia pestis</emph> and <emph type="1">Staphylococcus</emph> aureus</title> (2001)

Human leukocytes containing less than 2C DNA per cell (damaged or dead cells) were detected and quantified by flow cytometry and DNA-specific staining with ethidium bromide and mithramycin in whole blood infected with Staphylococcus aureus or Yersinia pestis. Addition of live S. aureus to the blood (100 microbe cells per one leukocyte) resulted in rapid degradation of leukocyte DNA within 3 to 6 hours of incubation at 37 degree(s)C. However, only about 50 percent cells were damaged and the leukocytes with the intact genetic apparatus could be found in the blood for a period up to 24 hours. The leukocyte injury was preceded by an increase of DNA per cell content (as compared to the normal one) that was likely to be connected with the active phagocytosis of S. aureus by granulocytes (2C DNA of diploid phagocytes plus the all bacterial DNA absorbed). In response to the same dose of actively growing (at 37 degree(s)C) virulent Y. pestis cells, no increase in DNA content per cell could be observed in the human blood leukocytes. The process of the leukocyte DNA degradation started after a 6-hour incubation, and between 18 to 24 hours of incubation about 90 percent leukocytes (phagocytes and lymphocytes) lost their specific DNA fluorescence. These results demonstrated a high potential of flow cytometry in comparative analysis in vitro of the leukocyte DNA degradation process in human blood in response to bacteria with various pathogenic properties. They agree with the modern idea of an apoptotic mechanism of immunosuppression in plague.
A Photocurable Poly(dimethylsiloxane) Chemistry Designed for Soft Lithographic Molding and Printing in the Nanometer Regime (2003)

Patterning techniques that rely on high-resolution elastomeric elements such as stamps, molds, and conformable photomasks are operationally simple methods for nanofabrication that may find applications in areas such as molecular and organic electronics. The resolution of these "soft" lithographic procedures is often limited by the mechanical properties of the elastomers. We introduce here a chemically modified poly(dimethylsiloxane) material that is designed and optimized specifically for soft lithography, particularly in the nanometer regime. We demonstrate its use for nanopatterning tasks that are challenging with the commercially available elastomers that have been used in the past.
Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. (2010)

4010 Background: In a randomized phase II trial of F vs G in 88 MPA patients (pts), we reported that F induces a response rate > 30% (Ychou, ASCO 2007). Because the trial met its planned objectives, it has been pursued as a phase III to compare overall survival (OS). Methods: Chemotherapy-naïve pts aged 18-75 years with histologically/cytologically-confirmed measurable MPA were randomized to receive F (O 85 mg/m2 d1 + I 180 mg/m2 d1 + LV 400 mg/m2 d1 followed by 5FU 400 mg/m2 bolus d1 and 2,400 mg/m2 46h continuous infusion biweekly) or G (1g/m2 IV weekly x7, 1 w rest, then weekly × 3q4w). Eligibility included adequate organ function, performance status (PS) 0-1, no prior chemotherapy or radiotherapy. Pts were stratified by centre, PS, and primary tumor location (head vs. other). The primary endpoint was OS. With a planned sample size of 360 pts, the trial was designed to detect an improvement from 7 to 10 months (m) median survival (HR = 0.70) with 80% power and α = 0.05. Results: 342 pts were enrolled between 01/2005 and 10/2009. Pts were well balanced for baseline characteristics: male 63%; median age 60 years; PS 0 38%. At the planned interim analysis, the Independent Data Monitoring Committee recommended to stop the study. Among 250 treated and monitored pts, median relative dose-intensities of 5FU, I, O and G were 0.81, 0.80, 0.78 and 1.01 respectively. Grade 3/4 toxicities per pts (%) in arms F/G were diarrhea 12.3/1.6, nausea 15.6/6.3, vomiting 17.2/6.3, fatigue 24/14.3, neutropenia 47.9/19.2 and febrile neutropenia 5.7/0. No toxic death occurred. Confirmed response rates (F/G) were 27.6% and 10.9% (p = 0.0008). Median follow-up was 19.5 m. Median PFS was 6.4/3.4 m (p < 0.0001). As of 09/2009, median OS was 10.5/6.9 m (HR = 0.61; 95%CI = 0.46-0.81; p < 0.001). Conclusions: F is the first non containing G therapy that has shown a significantly longer OS, PFS and higher response rate than G alone. The toxicities of this regimen are manageable and F may emerge as a new standard for treatment of MPA in pts with good PS. Final analysis on the total population will be presented. No significant financial relationships to disclose.