gebhart/patrepeval huggingface dataset:
Scandium(III) Triflate Catalyzed Friedel-Crafts Alkylation with Benzyl and Allyl Alcohols (1996)

Scandium(III) triflate [Sc(OTf)3] was found to be an efficient Friedel-Crafts catalyst for benzylation and allylation reactions of various aromatics with the corresponding alcohols as the alkylating agents.
NMDA/NR2B Selective Antagonists in the Treatment of Ischemic Brain Injury (2005)

Glutamate is the main excitatory neurotransmitter in the central nervous system and it plays a significant role not only in synaptic transmission but also in acute and chronic neuropathologies including stroke. Presently, four receptors for glutamate have been identified and the NMDA receptor family is the most intensively studied. A number of NMDA receptor antagonists have been developed and used for treatment of neurological diseases in patients. However, all of these drugs have been failed in clinical trials either because of intolerable side effects or lack of medical efficacy. Recently, the understanding of molecular structure of NMDA receptors has been advanced and this finding thus provides information for designing subtype-selective antagonists. Using NR2B subunit selective antagonists, ifenprodil and eliprodil, as basic structure models, second and third generation congeners have been developed. Several NR2B-selective compounds showed neuroprotective actions at doses that did not produce measurable side effects in preclinical studies. Some of NR2B subunit selective antagonists have also been tested for the treatment of ischemic brain injury. The present review describes the role of glutamate in ischemic brain injury with an emphasis on the NR2B containing NMDA receptors.
Analog Space–Time Coding for Multiantenna Ultra-Wideband Transmissions (2004)

Ultra-wideband (UWB) transmissions have well-documented advantages for low-power, peer-to-peer, and multiple-access communications. Space-time coding (STC), on the other hand, has gained popularity as an effective means of boosting rates and performance. Existing UWB transmitters rely on a single antenna, while ST coders have mostly focused on digital linearly modulated transmissions. In this paper, we develop ST codes for analog (and possibly nonlinearly) modulated multiantenna UWB systems. We show that the resulting analog system is able to collect not only the spatial diversity, but also the multipath diversity inherited by the dense multipath channel, with either coherent or noncoherent reception. Simulations confirm a considerable increase in both bit-error rate performance and immunity against timing jitter, when wedding STC with UWB transmissions.
Using adiabatic inversion pulses for long‐T2 suppression in ultrashort echo time (UTE) imaging (2007)

Ultrashort echo time (UTE) imaging is a technique that can visualize tissues with sub-millisecond T(2) values that have little or no signal in conventional MRI techniques. The short-T(2) tissues, which include tendons, menisci, calcifications, and cortical bone, are often obscured by long-T(2) tissues. This paper introduces a new method of long-T(2) component suppression based on adiabatic inversion pulses that significantly improves the contrast of short-T(2) tissues. Narrow bandwidth inversion pulses are used to selectively invert only long-T(2) components. These components are then suppressed by combining images prepared with and without inversion pulses. Fat suppression can be incorporated by combining images with the pulses applied on the fat and water resonances. Scaling factors must be used in the combination to compensate for relaxation during the preparation pulses. The suppression is insensitive to RF inhomogeneities because it uses adiabatic inversion pulses. Simulations and phantom experiments demonstrate the adiabatic pulse contrast and how the scaling factors are chosen. In vivo 2D UTE images in the ankle and lower leg show excellent, robust long-T(2) suppression for visualization of cortical bone and tendons.
Bioconversion of hybrid poplar to ethanol and co‐products using an organosolv fractionation process: Optimization of process yields (2006)

An organosolv process involving extraction with hot aqueous ethanol has been evaluated for bioconversion of hybrid poplar to ethanol. The process resulted in fractionation of poplar chips into a cellulose-rich solids fraction, an ethanol organosolv lignin (EOL) fraction, and a water-soluble fraction containing hemicellulosic sugars, sugar breakdown products, degraded lignin, and other components. The influence of four independent process variables (temperature, time, catalyst dose, and ethanol concentration) on product yields was analyzed over a broad range using a small composite design and response surface methodology. Center point conditions for the composite design (180 degrees C, 60 min, 1.25% H(2)SO(4), and 60% ethanol), yielded a solids fraction containing approximately 88% of the cellulose present in the untreated poplar. Approximately 82% of the total cellulose in the untreated poplar was recovered as monomeric glucose after hydrolysis of the solids fraction for 24 h using a low enzyme loading (20 filter paper units of cellulase/g cellulose); approximately 85% was recovered after 48 h hydrolysis. Total recovery of xylose (soluble and insoluble) was equivalent to approximately 72% of the xylose present in untreated wood. Approximately 74% of the lignin in untreated wood was recovered as EOL. Other cooking conditions resulted in either similar or inferior product yields although the distribution of components between the various fractions differed markedly. Data analysis generated regression models that describe process responses for any combination of the four variables.
Nitro-oleic Acid, a Novel and Irreversible Inhibitor of Xanthine Oxidoreductase (2008)

Xanthine oxidoreductase (XOR) generates proinflammatory oxidants and secondary nitrating species, with inhibition of XOR proving beneficial in a variety of disorders. Electrophilic nitrated fatty acid derivatives, such as nitro-oleic acid (OA-NO2), display anti-inflammatory effects with pleiotropic properties. Nitro-oleic acid inhibits XOR activity in a concentration-dependent manner with an IC50 of 0.6 microM, limiting both purine oxidation and formation of superoxide (O2.). Enzyme inhibition by OA-NO2 is not reversed by thiol reagents, including glutathione, beta-mercaptoethanol, and dithiothreitol. Structure-function studies indicate that the carboxylic acid moiety, nitration at the 9 or 10 olefinic carbon, and unsaturation is required for XOR inhibition. Enzyme turnover and competitive reactivation studies reveal inhibition of electron transfer reactions at the molybdenum cofactor accounts for OA-NO2-induced inhibition. Importantly, OA-NO2 more potently inhibits cell-associated XOR-dependent O2. production than does allopurinol. Combined, these data establish a novel role for OA-NO2 in the inhibition of XOR-derived oxidant formation.
Donepezil mediated memory improvement in traumatic brain injury during post acute rehabilitation (1998)

Memory dysfunction is a recognized and difficult to treat complication of traumatic brain injury (TBI). Since medial-temporal lobe injury is a frequent contributor to memory dysfunction in TBI, it is likely that an acetylcholine deficit contributes to memory dysfunction in this population. Recently, Donepezil, an acetylcholine-esterase inhibitor which has demonstrated a high selectivity for neural Ach-esterase (with minimal side effects), was approved for use in dementia in Alzheimer's patients. Due to its promising results in Alzheimer's patients, and reports in the literature describing the use of physostigmine (an anti-cholinesterase with significant cardiovascular and autonomic side effects) to treat memory deficits in closed head injury, we decided to begin a trial of Donepezil in two patients with TBI who were experiencing long term static memory dysfunction refractory to conventional treatment. Both patients were admitted to our facility for physical and cognitive rehabilitation, and were started on a trial of Donepezil. Modified memory tests and subjective observations by both family and staff pointed to an improvement in memory within three weeks of starting Donepezil. Should these initial results be supported in larger trials, Donepezil may prove to be a valuable tool for the treatment of memory dysfunction in TBI.
Identification of 22 candidate structured RNAs in bacteria using the CMfinder comparative genomics pipeline (2007)

We applied a computational pipeline based on comparative genomics to bacteria, and identified 22 novel candidate RNA motifs. We predicted six to be riboswitches, which are mRNA elements that regulate gene expression on binding a specific metabolite. In separate studies, we confirmed that two of these are novel riboswitches. Three other riboswitch candidates are upstream of either a putative transporter gene in the order Lactobacillales, citric acid cycle genes in Burkholderiales or molybdenum cofactor biosynthesis genes in several phyla. The remaining riboswitch candidate, the widespread Genes for the Environment, for Membranes and for Motility (GEMM) motif, is associated with genes important for natural competence in Vibrio cholerae and the use of metal ions as electron acceptors in Geobacter sulfurreducens. Among the other motifs, one has a genetic distribution similar to a previously published candidate riboswitch, ykkC/yxkD, but has a different structure. We identified possible non-coding RNAs in five phyla, and several additional cis-regulatory RNAs, including one in epsilon-proteobacteria (upstream of purD, involved in purine biosynthesis), and one in Cyanobacteria (within an ATP synthase operon). These candidate RNAs add to the growing list of RNA motifs involved in multiple cellular processes, and suggest that many additional RNAs remain to be discovered.
From interleukin‐9 to T helper 9 cells (2012)

Interleukin-9 (IL-9), cloned more than 20 years ago, was initially thought to be a Th2-specific cytokine. This assumption was initially confirmed by functional analyses showing that both IL-9 and Th2 cells play an important role in the pathogenesis of asthma, IgE class switch recombination, and resolution of parasitic infections. However, recently it was shown that IL-9-producing CD4(+) T cells represent the discrete T helper subset Th9 cells. Herein, we will review the cytokines and transcription factors known to promote the development of Th9 cells and their potential functional properties in relation to the biological activities of IL-9. In addition, we will discuss how Th9 cells are related to Th2, Th17, and T(reg) cells, as both an alternative source of IL-9 and in view of the fact that plasticity of CD4(+) T cell differentiation is currently a strong matter of debate in immunologic research.
Characterizing and circumventing sequence restrictions for synthesis of circular RNA in vitro (2020)

Just as eukaryotic circular RNA (circRNA) is a product of intracellular backsplicing, custom circRNA can be synthesized in vitro using a transcription template in which transposed halves of a split group I intron flank the sequence of the RNA to be circularized. Such permuted intron-exon (PIE) constructs have been used to produce circRNA versions of ribozymes, mimics of viral RNA motifs, a streptavidin aptamer, and protein expression vectors for genetic engineering and vaccine development. One limitation of this approach is the obligatory incorporation of small RNA segments (E1 and E2) into nascent circRNA at the site of end-joining. This restriction may preclude synthesis of small circRNA therapeutics and RNA nanoparticles that are sensitive to extraneous sequence, as well as larger circRNA mimics whose sequences must precisely match those of the native species on which they are modelled. In this work, we used serial mutagenesis and in vitro selection to determine how varying E1 and E2 sequences in a thymidylate synthase (td) group I intron PIE transcription template construct affects circRNA synthesis yield. Based on our collective findings, we present guidelines for the design of custom-tailored PIE transcription templates from which synthetic circRNAs of almost any sequence may be efficiently synthesized.
Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. (1995)

Sporadic and familial malignant melanoma susceptibility has been linked to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2) or p16 gene, has been shown to be deleted, mutated, or rearranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a M(r) 16,000 protein (p16) that plays a key role in cell cycle control by binding to the cyclin-dependent kinase 4 enzyme and inhibiting its ability to phosphorylate critical substrates necessary for transition past the G1 phase of the cell cycle. Thus, mutations or deletions of the CDKN2 gene could result in abnormal proliferation via defective cell cycle control. The correlation of 9p21 cytogenetic and molecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whether this gene is the CDKN2 gene. If so, then loss of p16 is potentially an initiating or early event in melanoma progression. To address the issues of what is the potential involvement of the CDKN2 gene in sporadic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2 occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our results suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in situ and the majority of primary invasive melanomas retain expression of this protein; and (b) potentially more related to invasiveness or the ability to metastasize, because 52% of primary invasive tumors and 72% of metastatic lesions show partial or complete loss of expression of p16.
Data clone detection and visualization in spreadsheets (2013)

Spreadsheets are widely used in industry: it is estimated that end-user programmers outnumber programmers by a factor 5. However, spreadsheets are error-prone, numerous companies have lost money because of spreadsheet errors. One of the causes for spreadsheet problems is the prevalence of copy-pasting. In this paper, we study this cloning in spreadsheets. Based on existing text-based clone detection algorithms, we have developed an algorithm to detect data clones in spreadsheets: formulas whose values are copied as plain text in a different location. To evaluate the usefulness of the proposed approach, we conducted two evaluations. A quantitative evaluation in which we analyzed the EUSES corpus and a qualitative evaluation consisting of two case studies. The results of the evaluation clearly indicate that 1) data clones are common, 2) data clones pose threats to spreadsheet quality and 3) our approach supports users in finding and resolving data clones.
Alteration of B-cell Antigen Receptor Signaling by CD19 Co-ligation. (1996)

The activation of B-cell antigen receptor-associated protein tyrosine kinases is an early and crucial event in B-cell signaling. Apart from the B-cell antigen receptor (BCR), the B-cell-specific transmembrane glycoprotein CD19 has also been shown to directly activate intracellular signaling cascades. In addition, because CD19 and the BCR are associated on the surface of activated B-cells, it has been proposed that close approximation between these two entities is crucial for optimal B-cell triggering. To test this hypothesis, bispecific antibodies were generated that bind membrane IgM and CD19 simultaneously. Although CD19 bispecific antibodies strongly induced tyrosine phosphorylation, they were, in contrast to muF(ab)2 fragments, unable to induce a proliferative response. Detailed analysis of the early signaling events showed that compared with muF(ab)2 fragments CD19 bispecific antibodies potently raised the intracellular [Ca2+], which was correlated with an efficient tyrosine phosphorylation of syk. Strikingly, the assembly of Grb2 complexes that may couple the BCR to p21(ras) was clearly altered by the CD19 bispecific antibody. In addition to the reported Shc and 145-kDa phosphoproteins, a prominent 90-95-kDa phosphoprotein resembling CD19 was detected in the Grb2 complexes. Thus, studies with CD19 bispecific antibodies show that CD19 co-ligation both quantitatively and qualitatively alters BCR signaling.
Differentiation‐associated expression of prostaglandin G/H synthase in monocytic cells (1993)

Significant progress in the investigation of the regulation of prostanoid formation has recently been made by cloning a second gene coding for prostaglandin G/H synthase (PGHS; EC 1.14.99.1). In this study we examined the expression of the two PGHS isoforms during phorbol ester induced monocytic differentiation of human myeloid leukemia cells (U937). Murine and ovine PGHS‐1 probes hybridized to 2.8‐ and 5.5‐kb mRNA species, whereas the murine PGHS‐2 probe hybridized to a 5.3‐kb species. Western blot analysis using antisera to mouse PGHS‐1 and to a synthetic peptide derived from a mouse PGHS‐2‐specific region revealed a band of 70 kDa for PGHS‐1 and a doublet of about 85 kDa for PGHS‐2. Unlike PGHS‐2, which was not expressed in U937 control cells, both PGHS‐1 protein and mRNA were detected in untreated U937 cells. TPA strongly induced PGHS‐2 protein and also increased the amount of PGHS‐1 protein. Correspondingly, a marked induction of PGHS‐2 mRNA was found, but virtually no change in the expression of the PGHS‐1 2.8‐kb mRNA occurred. The induction of both PGHS isoforms turned out to be dexamethasone‐sensitive. The suppression of PGHS‐2 induction was more pronounced. These results suggest that both PGHS‐1 and to a larger extent PGHS‐2 contribute to the upregulation of prostanoid synthesis during monocytic differentiation.
Targeting CD137 enhances the efficacy of cetuximab (2014)

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.
ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete- response rate and durable disease control. (2014)

7015 Background: Overexpression of Bcl-2 in relapsed CLL/SLL is associated with dysregulated apoptosis and chemoresistance. ABT-199 is an orally bioavailable, selective Bcl-2 inhibitor that triggers apoptosis of CLL cells in vitro and in vivo, making it a promising agent for the treatment of patients (pts) with CLL/SLL. Methods: The primary objectives of this phase I study were to evaluate the safety and pharmacokinetics (PK) and to determine the maximum tolerated dose and a recommended phase 2 dose (RPTD) of ABT-199. A secondary objective was to assess preliminary efficacy. Following early events of tumor lysis syndrome (TLS), a weekly ramp-up period to the final cohort dose (150 – 1200 mg) was implemented. Pts are now being enrolled in the safety expansion (SE) cohort. A ramp-up period with weekly dose increases occurred from 20, 50, 100, 200 mg to the final RPTD of 400 mg. Results: As of 12/04/2013, 84 pts (11 in SE) were enrolled with a median time on study of 14.7 (range, 0.5-29.3) months. 23 (27%) pts had del(17p) and 48 (57%) had fludarabine (F)-refractory CLL. Most common AEs were diarrhea (37%), nausea (36%), neutropenia (35%), upper respiratory tract infection (29%), and fatigue (27%). Grade 3/4 AEs (≥3 pts) were neutropenia (32%), anemia (8%), TLS (8% including 1 G5), and febrile neutropenia, thrombocytopenia, hyperglycemia, and hypokalemia (6% each). 28 have discontinued: 18 for progressive disease, 8 for AEs, and 2 for other reasons. The objective response rate (ORR) was 79% (CR/CRi 22%) with a median duration of response (DOR) of 20.5 months [95% CI; 13.8, 20.5] for the 63 pts evaluable for efficacy. At 12 months, 91% of CR and 65% of PR pts remain progression free. The ORR was 78% for del(17p) and 79% for F-refractory CLL. Of the 14 CR/CRi pts, 9 were evaluated in local labs for minimal residual disease (MRD); 5 were negative and 4 of these were F-refractory. Conclusions: ABT-199 induces a high rate of response in pts with R/R CLL, including those with del(17p) and F-refractory disease. Responses are durable, especially in the 22% achieving CR/CRi, with several of these high risk pts achieving MRD negativity. Enrollment in the SE cohort is continuing. Clinical trial information: NCT01328626.
Fc gamma receptor III on human neutrophils. Allelic variants have functionally distinct capacities. (1990)

As a model system to explore the functional consequences of structural variants of human Fcy receptors (FcyR), we have investigated Fc-yR-mediated phagocytosis in relation to the NA1-NA2 polymorphism of FcyRIII (CD16) on neutrophils (Fc'yRIIIpMN). The neutrophil-specific NA antigen system is a biallelic polymorphism with codominant expression demon- strating a gene dose effect with the anti-NAl MAb CLB-gran 11 in a large donor population. To explore the impact of this allelic variation of FcyRIIIPMN on phagocytosis, we used two FcyRIII-dependent probes, IgG-sensitized erythrocytes (EA) and concanavalin A-treated erythrocytes (E-ConA). Compari- son of FcyR-mediated phagocytosis by PMN from NA1 sub- jects and from NA2 subjects showed lower levels of phagocytosis of both probes by the NA2 individuals. The difference was most pronounced with lightly opsonized EA: at the lowest level of sensitization the phagocytic index was 72% lower for NA2 donors, whereas at the highest level of sensitization it was 21% lower (P < 0.003). Blockade of FcyRII with MAb IV.3 Fab amplified by threefold the difference between NAI and NA2 donors.
Mouse genetics and transgenics : a practical approach (2000)

Hetherington, Doe and Hay, mouse care and husbandry Glenister and Rall, cryopreservation and rederivation of embryos and gametes Nonchev and Maconochie, spatial analysis of gene expression Maine, mapping phenotypic trait loci Denny and Brown, mapping genomes Akeson et al, mouse cytogenetics and FISH Eppig, electronic tools for accessing the mouse genome Justice, mutagenesis of the mouse germline Hammes and Schedl, generation of transgenic mice from plasmids, BACs and YACS Plagge, Kelsey and Allen, directed mutagenesis in embryonic stem cells.