gebhart/patrepeval huggingface dataset:
Synthesis and SAR of 1-Alkyl-2-phenylethylamine Derivatives Designed fromN,N-Dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine To Discover σ1Ligands (1999)

The synthesis and structure-activity relationships (SAR) of 1-alkyl-2-phenylethylamine derivatives 5-8 designed from N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-methoxy-3-(2-phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylam ine hydrochloride ((-)-6d, NE-537) and (-)-N-propyl-1-(3-methybutyl)-2-[4-methoxy-3-(2-phenylethoxy )phenyl]e thylamine hydrochloride ((-)-6i, NE-535), typical compounds in this series, have potent and selective sigma(1) affinity.
Regulation of NMDA receptor trafficking and function by striatal‐enriched tyrosine phosphatase (STEP) (2006)

Regulation of N-methyl-D-aspartate (NMDA) receptors is critical for the normal functioning of the central nervous system. There must be precise mechanisms to allow for changes in receptor function required for learning and normal synaptic transmission, but within tight constraints to prevent pathology. Tyrosine phosphorylation is a major means by which NMDA receptors are regulated through the equilibrium between activity of Src family kinases and tyrosine phosphatases. Identification of NMDA receptor phosphatases has been difficult, the best candidate being striatal-enriched tyrosine phosphatase (STEP). Here we demonstrate that STEP is a critical regulator of NMDA receptors and reveal that the action of this tyrosine phosphatase controls the constitutive trafficking of NMDA receptors and leads to changes in NMDA receptor activity at the neuronal surface. We show that STEP binds directly to NMDA receptors in the absence of other synaptic proteins. The activity of STEP selectively affects the expression of NMDA receptors at the neuronal plasma membrane. The result of STEP's action upon the NMDA receptor affects the functional properties of the receptor and its downstream signaling. These effects are evident when STEP levels are chronically reduced, indicating that there is no redundancy amongst phosphatases to compensate for altered STEP function in the CNS. STEP may have evolved specifically to fill a pivotal role as the NMDA receptor phosphatase, having a distinct and restricted localization and compartmentalization, and unique activity towards the NMDA receptor and its signaling pathway.
Protective Vaccination Against Primary And Recurrent Disease Caused By Herpes Simplex Virus (HSV) Type 2 Using A Genetically Disabled HSV-1 (1994)

The vaccine potential of a mutant herpes simplex virus (HSV) type 1, with a deletion in the glycoprotein H (gH) gene, was evaluated. The virus requires a gH-expressing cell line for multi-cycle growth but can complete a single cycle of infection in noncomplementing cells. Such viruses, termed DISC (disabled infectious single cycle) viruses, should be safe, yet still able to stimulate humoral and cell-mediated responses against a broad range of virus antigens in vaccinated hosts. Prophylactic vaccination of guinea pigs with DISC HSV-1, by ear scarification or direct infection of the vaginal mucosa, afforded a high degree of protection against HSV-2-induced primary genital disease and reduced significantly the frequency of subsequent disease recurrence. There was also a trend toward reduced recurrence following therapeutic vaccination of animals already infected with HSV-2. DISC HSV vaccination, therefore, offers an effective route for control of HSV disease.
Cloning-free CRISPR (2015)

We present self-cloning CRISPR/Cas9 (scCRISPR), a technology that allows for CRISPR/Cas9-mediated genomic mutation and site-specific knockin transgene creation within several hours by circumventing the need to clone a site-specific single-guide RNA (sgRNA) or knockin homology construct for each target locus. We introduce a self-cleaving palindromic sgRNA plasmid and a short double-stranded DNA sequence encoding the desired locus-specific sgRNA into target cells, allowing them to produce a locus-specific sgRNA plasmid through homologous recombination. scCRISPR enables efficient generation of gene knockouts (∼88% mutation rate) at approximately one-sixth the cost of plasmid-based sgRNA construction with only 2 hr of preparation for each targeted site. Additionally, we demonstrate efficient site-specific knockin of GFP transgenes without any plasmid cloning or genome-integrated selection cassette in mouse and human embryonic stem cells (2%-4% knockin rate) through PCR-based addition of short homology arms. scCRISPR substantially lowers the bar on mouse and human transgenesis.
Utility of formaldehyde cross‐linking and mass spectrometry in the study of protein–protein interactions (2008)

For decades, formaldehyde has been routinely used to cross-link proteins in cells, tissue, and in some instances, even entire organisms. Due to its small size, formaldehyde can readily permeate cell walls and membranes, resulting in efficient cross-linking, i.e. the formation of covalent bonds between proteins, DNA, and other reactive molecules. Indeed, formaldehyde cross-linking is an instrumental component of many mainstream analytical/cell biology techniques including chromatin immunoprecipitation (ChIP) of protein-DNA complexes found in nuclei; immunohistological analysis of protein expression and localization within cells, tissues, and organs; and mass spectrometry (MS)-compatible silver-staining methodologies used to visualize low abundance proteins in polyacrylamide gels. However, despite its exquisite suitability for use in the analysis of protein environments within cells, formaldehyde has yet to be commonly employed in the directed analysis of protein-protein interactions and cellular networks. The general purpose of this article is to discuss recent advancements in the use of formaldehyde cross-linking in combination with MS-based methodologies. Key advantages and limitations to the use of formaldehyde over other cross-linkers and technologies currently used to study protein-protein interactions are highlighted, and formaldehyde-based experimental approaches that are proving very promising in their ability to accurately and efficiently identify novel protein-protein and multiprotein interaction complexes are presented.
De novo design of protein homo-oligomers with modular hydrogen-bond network–mediated specificity (2016)

In nature, structural specificity in DNA and proteins is encoded differently: In DNA, specificity arises from modular hydrogen bonds in the core of the double helix, whereas in proteins, specificity arises largely from buried hydrophobic packing complemented by irregular peripheral polar interactions. Here, we describe a general approach for designing a wide range of protein homo-oligomers with specificity determined by modular arrays of central hydrogen-bond networks. We use the approach to design dimers, trimers, and tetramers consisting of two concentric rings of helices, including previously not seen triangular, square, and supercoiled topologies. X-ray crystallography confirms that the structures overall, and the hydrogen-bond networks in particular, are nearly identical to the design models, and the networks confer interaction specificity in vivo. The ability to design extensive hydrogen-bond networks with atomic accuracy enables the programming of protein interaction specificity for a broad range of synthetic biology applications; more generally, our results demonstrate that, even with the tremendous diversity observed in nature, there are fundamentally new modes of interaction to be discovered in proteins.
Pulmonary artery smooth muscle cells from chronically hypoxic neonatal calves retain fetal-like and acquire new growth properties (1997)

Growth properties retained and acquired by immature pulmonary artery (PA) smooth muscle cells (SMC) in vivo after chronic exposure to hypoxia and the mechanisms that regulate hypoxia-induced change in proliferative phenotype are not known. We tested the hypothesis that PA SMC from neonatal calves exposed to hypoxia after birth would both retain fetal-like and acquire new growth characteristics and that these changes would be at least partially dependent on protein kinase C (PKC), a key proproliferative signal transduction pathway. Like fetal cells, PA SMC from hypoxic calves grew faster in the presence and absence of serum and were more responsive to insulin-like growth factor I and platelet-derived growth factor-BB than control neonatal and adult cells. PA SMC from hypoxic calves also acquired other growth properties (i.e., including increased hypoxic growth after PKC activation) that were new compared with those observed for fetal cells. The proliferative response to hypoxia was first detectable in the neonatal period and was further increased in cells from hypoxic calves. SMC from fetuses and hypoxic calves were more susceptible to the growth-inhibiting effects of PKC antagonists (dihydrosphingosine and calphostin C) than control neonatal and adult cells. To test if the Ca(2+)-dependent isozymes of PKC were uniquely important in the developmental and acquired growth changes observed, the antagonistic effect of the specific, but isozyme nonselective, PKC inhibitor Ro-81-8220 was then compared with GF-109203X, a structural analog with relative specificity for the Ca(2+)-dependent isozymes of PKC (alpha and beta in PA SMC). The faster growing PA SMC from bovine fetuses and hypoxia-exposed calves again demonstrated greater growth inhibition in response to both inhibitors. GF-109203X was equipotent to Ro-31-8220, and its antiproliferative effects were shown to not be due to an increase in apoptosis. Phorbol ester-induced PKC downregulation, another inhibitor strategy that selectively depletes bovine PA SMC of PKC-alpha, but not -beta, mimicked the antiproliferative effects of GF-109203X. Whole cellular PKC catalytic activity paralleled the pattern of peptide-induced growth and susceptibility to PKC inhibition. These results suggest that PA SMC from hypoxia-exposed neonatal calves retain enhanced fetal-like proliferative capacity and acquire new growth properties that are at least partially dependent on the Ca(2+)-regulated isozymes of PKC and in particular PKC-alpha.
Progress in HIV vaccine development (2017)

An HIV-1 vaccine is needed to curtail the HIV epidemic. Only one (RV144) out of the 6 HIV-1 vaccine efficacy trials performed showed efficacy. A potential mechanism of protection is the induction of functional antibodies to V1V2 region of HIV envelope. The 2 main current approaches to the generation of protective immunity are through broadly neutralizing antibodies (bnAb) and induction of functional antibodies (non-neutralizing Abs with other potential anti-viral functions). Passive immunization using bnAb has advanced into phase II clinical trials. The induction of bnAb using mimics of the natural Env trimer or B-cell lineage vaccine design is still in pre-clinical phase. An attempt at optimization of protective functional antibodies will be assessed next with the efficacy trial (HVTN702) about to start. With on-going optimization of prime/boost strategies, the development of mosaic immunogens, replication competent vectors, and emergence of new strategies designed to induce bnAb, the prospects for a preventive HIV vaccine have never been more promising.
Assessing agricultural research - towards consensus on a framework for performance and impact assessment (1998)

The study is a comprehensive approach to assessing agricultural research, and identifies the need for it to be based on a clear cause-effect framework, that addresses both the impact, and performance aspects of research monitoring, relating progress, and results to planned targets, based on ex ante projections of program impact. While the complexity of monitoring research performance, is not new, information technology is now available to manage supporting data on agricultural research, and the report builds on the potential agricultural, social, and biophysical data to support research planning, execution, and impact assessment. It offers a review on the well-known difficulties in monitoring performance, and impact of research, summarizing current experiences, and proposals for research performance, and impact monitoring. Monitoring approaches are proposed through the establishment of research-support information systems, while developing consensus on program assessment is recommended for international agricultural research.
콩연구논문 발표요약 ( 1985 년도 ) : 콩나방 저항성검정에 관한 연구 (1985)

大豆의 콩나방에 대한 抵抗性品種育成에 基礎資料를 얻고저 鬼集種을 供試하여 被害率을 調査한 結果, 콩나방의 被害率은 系統間에 현저한 有意差가 있었으며 5月 27日 早植한 group 이 6 月 17日 晩植한 group보다 被害率이 훨씬 높았다. 콩나방의 被害調査方法으로서 被害莢을 基準한 것이나 被害콩粒을 基準한 것이나 被害率에는 큰 差異가 없는 것으로 나타나 抵抗性檢定에서는 被害粒基準의 調査方法이 훨씬 便利할것으로 判斷된다. 콩나방에 저항성인 系統은 罹病性의 것보다 種實重이 낮은 傾向이 있는 것으로 나타났다.
Distribution of Tranexamic Acid to Plasma and Saliva After Oral Administration and Mouth Rinsing: A Pharmacokinetic Study (1987)

The objective of the study was to investigate the content of tranexamic acid in plasma and in mixed, unstimulated whole saliva after oral administration and mouth rinsing. Ten healthy volunteers each received 1 g of tranexamic acid orally, whereas 20 healthy volunteers rinsed their mouths with 10 mL of a 5% aqueous tranexamic acid solution for two minutes. Blood and saliva were collected 30, 60, 120, 240, 360, and 480 minutes after administration of tranexamic acid. Samples of blood and saliva were analyzed for tranexamic acid content by electron capture gas chromatography. After oral administration, the mean plasma concentration of tranexamic acid reached its maximum after 120 minutes at approximately 7 micrograms/mL, whereas none of the saliva samples contained tranexamic acid at detectable levels. After mouth rinse, the plasma concentrations remained below 2 micrograms/mL, whereas the concentrations found in saliva initially were very high (after 30 minutes mean concentration above 200 micrograms/mL) and remained at a therapeutic level for more than two hours. These findings indicate, that fibrinolysis in the oral cavity can be inhibited only by local administration of tranexamic acid. This finding may be of significance when the drug is used for prevention and treatment of bleeding in the oral cavity in patients with coagulation defects.
The G4 Gene of Arabidopsis thaliana Encodes a Chlorophyll Synthase of Etiolated Plants (1997)

Abstract: The gene coding for a putative chlorophyll synthase gene (C4) from Arabidopsis thaliana was amplified by the polymerase chain reaction and cloned into the expression vector pQE‐ 31. Lysates of bacteria ( E.coli ) that had been transformed with this construct were used for in vitro enzymatic assays. The chlorophyll synthase catalyzed esterification of chlorophyllides a and b at the same rate but preferred geranylgeranyl‐PP over phytyl‐PP. This corresponds to the enzyme specificity previously described for etiolated plants and differed from that of green plants.
Three-dimensional holographic head mounted display using holographic optical element (2015)

Recently, head mounted displays based on holographic optical elements have been reported. These head mounted displays can be implemented in a compact form factor but the image delivered to user's each eye is still two-dimensional, which causes accommodation-vergence mismatch. In this paper, we propose a holographic three-dimensional head mounted display which displays holographic three-dimensional images to each eye. The proposed configuration can achieve a compact form factor by using holographic optical elements, and solve the accommodation-vergence mismatch by presenting holographic three-dimensional images to each eye.
In Vitro Selection and Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-378, a Novel Protease Inhibitor (1998)

ABT-378, a new human immunodeficiency virus type 1 (HIV-1) protease inhibitor which is significantly more active than ritonavir in cell culture, is currently under investigation for the treatment of AIDS. Development of viral resistance to ABT-378 in vitro was studied by serial passage of HIV-1 (pNL4-3) in MT-4 cells. Selection of viral variants with increasing concentrations of ABT-378 revealed a sequential appearance of mutations in the protease gene: I84V-L10F-M46I-T91S-V32I-I47V. Further selection at a 3.0 microM inhibitor concentration resulted in an additional change at residue 47 (V47A), as well as reversion at residue 32 back to the wild-type sequence. The 50% effective concentration of ABT-378 against passaged virus containing these additional changes was 338-fold higher than that against wild-type virus. In addition to changes in the protease gene, sequence analysis of passaged virus revealed mutations in the p1/p6 (P1' residue Leu to Phe) and p7/p1 (P2 residue Ala to Val) gag proteolytic processing sites. The p1/p6 mutation appeared in several clones derived from early passages and was present in all clones obtained from passage P11 (0.42 microM ABT-378) onward. The p7/p1 mutation appeared very late during the selection process and was strongly associated with the emergence of the additional change at residue 47 (V47A) and the reversion at residue 32 back to the wild-type sequence. Furthermore, this p7/p1 mutation was present in all clones obtained from passage P17 (3.0 microM ABT-378) onward and always occurred in conjunction with the p1/p6 mutation. Full-length molecular clones containing protease mutations observed very late during the selection process were constructed and found to be viable only in the presence of both the p7/p1 and p1/p6 cleavage-site mutations. This suggests that mutation of these gag proteolytic cleavage sites is required for the growth of highly resistant HIV-1 selected by ABT-378 and supports recent work demonstrating that mutations in the p7/p1/p6 region play an important role in conferring resistance to protease inhibitors (L. Doyon et al., J. Virol. 70:3763-3769, 1996; Y. M. Zhang et al., J. Virol. 71:6662-6670, 1997).
Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells (2008)

The prospective addition of valproic acid to stable antiretroviral therapy reduced the frequency of resting CD4+ T-cell infection in a minority of volunteers. In patients in whom resting CD4+ T-cell infection depletion was observed, viremia was rarely detectable by single copy assay.
Role of Viral Factor E3L in Modified Vaccinia Virus Ankara Infection of Human HeLa Cells: Regulation of the Virus Life Cycle and Identification of Differentially Expressed Host Genes (2005)

Modified vaccinia virus Ankara (MVA) is a highly attenuated virus strain being developed as a vaccine for delivery of viral and recombinant antigens. The MVA genome lacks functional copies of numerous genes interfering with host response to infection. The interferon resistance gene E3L encodes one important viral immune defense factor still made by MVA. Here we demonstrate an essential role of E3L to allow for completion of the MVA molecular life cycle upon infection of human HeLa cells. A deletion mutant virus, MVA-DeltaE3L, was found defective in late protein synthesis, viral late transcription, and viral DNA replication in infected HeLa cells. Moreover, we detected viral early and continuing intermediate transcription associated with degradation of rRNA, indicating rapid activation of 2'-5'-oligoadenylate synthetase/RNase L in the absence of E3L. Further molecular monitoring of E3L function by microarray analysis of host cell transcription in MVA- or MVA-DeltaE3L-infected HeLa cells revealed an overall significant down regulation of more than 50% of cellular transcripts expressed under mock conditions already at 5 h after infection, with a more prominent shutoff following MVA-DeltaE3L infection. Interestingly, a cluster of genes up regulated exclusively in MVA-DeltaE3L-infected cells could be identified, including transcripts for interleukin 6, growth arrest and DNA damage-inducible protein beta, and dual-specificity protein phosphatases. Our data indicate that lack of E3L inhibits MVA antigen production in human HeLa cells at the level of viral late gene expression and suggest that E3L can prevent activation of additional host factors possibly affecting the MVA molecular life cycle.
Selective antibody activation through protease-activated pro-antibodies that mask binding sites with inhibitory domains (2017)

Abstract Systemic injection of therapeutic antibodies may cause serious adverse effects due to on-target toxicity to the antigens expressed in normal tissues. To improve the targeting selectivity to the region of disease sites, we developed protease-activated pro-antibodies by masking the binding sites of antibodies with inhibitory domains that can be removed by proteases that are highly expressed at the disease sites. The latency-associated peptide (LAP), C2b or CBa of complement factor 2/B were linked, through a substrate peptide of matrix metalloproteinase-2 (MMP-2), to an anti-epidermal growth factor receptor (EGFR) antibody and an anti-tumor necrosis factor-α (TNF-α) antibody. Results showed that all the inhibitory domains could be removed by MMP-2 to restore the binding activities of the antibodies. LAP substantially reduced (53.8%) the binding activity of the anti-EGFR antibody on EGFR-expressing cells, whereas C2b and CBa were ineffective (21% and 9.3% reduction, respectively). Similarly, LAP also blocked 53.9% of the binding activity of the anti-TNF-α antibody. Finally, molecular dynamic simulation showed that the masking efficiency of LAP, C2b and CBa was 33.7%, 10.3% and −5.4%, respectively, over the binding sites of the antibodies. This strategy may aid in designing new protease-activated pro-antibodies that attain high therapeutic potency yet reduced systemic on-target toxicity.
Gold nanoparticlebased optical probes for target-responsive DNA structures (2008)

In this work, we report the use of unmodified gold nanoparticles (AuNPs) as an optical probe for the detection of target-responsive structural variations of DNA. By employing two DNA structures, i.e., a pH-responsive i-motif oligonucleotide and a mercury-specific oligonucleotide (MSO), we demonstrated that AuNPs could selectively distinguish target-free and target-bound oligonucleotides via the characteristic surface plasmon resonance-associated red-to-blue color change. Based on these observations, we developed a convenient “mix-and-detect” approach that could selectively detect environmentally toxic mercury ions.
Family Perspectives on Integrated Employment for Adults with Intellectual and Developmental Disabilities (2018)

Families are essential partners in efforts to elevate the employment outcomes of adults with intellectual and developmental disabilities (IDD). We examined the employment-related expectations, preferences, and concerns of 673 parents and other family members of adults with IDD. Participants prioritized paid integrated employment over sheltered options, and such perspectives were strongly associated with the recent employment status of their family member with IDD. In addition, they valued qualitative dimensions of a potential workplace (e.g., personal satisfaction, social interaction opportunities) more highly than prevailing employment metrics (e.g., rate of pay, hours per week, benefits). Multiple factors informed the views of parents and other family members regarding integrated employment and the extent to which their family member with IDD had been employed previously in the community. We offer recommendations for research, practice, and systems change efforts aimed at raising expectations for and access to integrated employment for adults with IDD.