gebhart/patrepeval huggingface dataset:
Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain (2008)

We have characterized the expression of microRNAs and selected microRNA precursors within several synaptic fractions of adult mouse forebrain, including synaptoneurosomes, synaptosomes and isolated post-synaptic densities (PSDs), using methods of microRNA microarray, real time qRT-PCR, Northern blotting and immunopurification using anti-PSD95 antibody. The majority of brain microRNAs (especially microRNAs known to be expressed in pyramidal neurons) are detectably expressed in synaptic fractions, and a subset of microRNAs is significantly enriched in synaptic fractions relative to total forebrain homogenate. MicroRNA precursors are also detectable in synaptic fractions at levels that are comparable to whole tissue. Whereas mature microRNAs are predominantly associated with soluble components of the synaptic fractions, microRNA precursors are predominantly associated with PSDs. For seven microRNAs examined, there was a significant correlation between the relative synaptic enrichment of the precursor and the relative synaptic enrichment of the corresponding mature microRNA. These findings support the proposal that microRNAs are formed, at least in part, via processing of microRNA precursors locally within dendritic spines. Dicer is expressed in PSDs but is enzymatically inactive until conditions that activate calpain cause its liberation; thus, we propose that synaptic stimulation may lead to local processing of microRNA precursors in proximity to the synapse.
Intrinsic Nucleotide Preference of Diversifying Base Editors Guides Antibody Ex Vivo Affinity Maturation (2018)

Base editors (BEs) are emerging tools used for precision correction or diversifying mutation. It provides a potential way to recreate somatic hypermutations (SHM) for generating high-affinity antibody, which is usually screened from antigen-challenged animal models or synthetic combinatorial libraries. By comparing somatic mutations in the same genomic context, we screened engineered deaminases and CRISPR-deaminase coupling approaches and updated diversifying base editors (DBEs) to generate SHM. The deaminase used in DBEs retains its intrinsic nucleotide preference and mutates cytidines at its preferred motifs. DBE with AID targets the same hotspots as physiological AID does in vivo, while DBE with other deaminases generates distinct mutation profiles from the same DNA substrate. Downstream DNA repair pathways further diversified the sequence, while Cas9-nickase restricted mutation spreading. Finally, application of DBE in an antibody display system achieved antibody affinity maturation ex vivo. Our findings provide insight of DBE working mechanism and an alternative antibody engineering approach.
Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand (1999)

A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells.
Quantification of Membrane Protein Inhibition by Optical Ion Flux in a Droplet Interface Bilayer Array (2012)

Optical platforms for assaying membrane protein function offer a promising route to scalable high-throughput screening (see picture). For the first time quantitative measurements of membrane protein inhibition are reported in an optically addressable lipid bilayer array. Wide-field total internal reflection fluorescence (TIRF) imaging of Ca2+ flux enables the quantification of α-hemolysin inhibition by γ-cyclodextrin. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
A mutation in the receiver domain of the Agrobacterium tumefaciens transcriptional regulator VirG increases its affinity for operator DNA (1994)

We fused the wild-type Agrobacterium tumefaciens virG gene and the constitutive virGN54D allele to the malE gene of Escherichia coli, and studied the binding of MBP-VirG fusions to the autoregulated virG promoter. MBP-VirGN54D protein bound this promoter with 10-fold higher affinity than MBP-VirG, and bound to vir box I with eightfold higher affinity than to vir box III. Disruption of vir box III did not alter the affinity for vir box I, suggesting a lack of cooperativity between these sites. We provide evidence that protein bound at a single vir box may have a higher oligomeric state than non-bound protein, and that a DNA distortion adjacent to vir box I may occur during activation.
Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5‐Bromo‐1H‐indole‐3‐acetohydroxamic Acid (2008)

The lead compound 5-bromoindolyl-3-acetohydroxamic acid (10) was recently identified as a potent inhibitor of bacterial peptide deformylases (PDFs). The synthesis and associated activities of new variants were investigated at position 5 to optimize the fit at the S1' subsite and at position 1 to improve both potency and antibacterial activity. A morphomimetic series, termed "reverse-indole" was synthesized. The indole derivatives remain selective in vitro inhibitors of PDF2 over PDF1. Bromide is the best group at position 5 and cannot be replaced by bulkier substituents. In this series, an N-benzyl group at position 1 in 19 e improves the potency relative to 10. In the case of PDF1, and unlike PDF2, potency is increased as the alkyl chain becomes longer and more ramified. These data support the results of NMR footprinting experiments that were performed with (15)N-labeled Ni-PDF and the corresponding 3-acetic acid derivatives. Most of the compounds have antibacterial activities toward B. subtilis, but are inefficient toward E. coli owing to active removal by the major efflux pumps. Among the reverse-indole derivatives, 23 c, which is the exact mirror image of 19 e, shows strong potency in vitro against PDF2, but little against PDF1, although this compound displays significant antibacterial activity toward an efflux-minus mutant of E. coli. All the compounds were assessed with major pathogenic bacteria, but most of them are inefficient antibacterial agents. The reverse-indole compounds 23 a and 23 c have potency against S. pneumoniae that is similar to that of actinonin.
Cutting Edge: Enhancement of Antibody Responses Through Direct Stimulation of B and T Cells by Type I IFN (2006)

Type I IFN (IFN-alphabeta) is induced rapidly by infection and plays a key role in innate antiviral defense. IFN-alphabeta also exerts stimulatory effects on the adaptive immune system and has been shown to enhance Ab and T cell responses. We have investigated the importance of B and T cells as direct targets of IFN-alphabeta during IFN-alpha-mediated augmentation of the Ab response against a soluble protein Ag. Strikingly, the ability of IFN-alpha to stimulate the Ab response and induce isotype switching was markedly reduced in mice in which B cells were selectively deficient for the IFN-alphabetaR. Moreover, IFN-alpha-mediated enhancement of the Ab response was also greatly impaired in mice in which T cells were selectively IFN-alphabetaR-deficient. These results indicate that IFN-alphabetaR signaling in both B and T cells plays an important role in the stimulation of Ab responses by IFN-alphabeta.
Tagging-via-Substrate Strategy for Probing O-GlcNAc Modified Proteins (2005)

Identification of proteins bearing a specific post-translational modification would imply functions of the modification. Proteomic analysis of post-translationally modified proteins is usually challenging due to high complexity and wide dynamic range, as well as unavailability of efficient methods to enrich the proteins of interest. Here, we report a strategy for the detection, isolation, and profiling of O-linked N-acetylglucosamine (O-GlcNAc) modified proteins, which involves three steps: metabolic labeling of cells with an unnatural GlcNAc analogue, peracetylated azido-GlcNAc; chemoselective conjugation of azido-GlcNAc modified proteins via the Staudinger ligation, which is specific between phosphine and azide, using a biotinylated phosphine capture reagent; and detection and affinity purification of the resulting conjugated O-GlcNAc modified proteins. Since the approach relies on a tag (azide) in the substrate, we designated it the tagging-via-substrate (TAS) strategy. A similar strategy was used previously for protein farnesylation, phosphorylation, and sumoylation. Using this approach, we were able to specifically label and subsequently detect azido-GlcNAc modified proteins from the cytosolic lysates of HeLa, 3T3, COS-1, and S2 cell lines, suggesting the azido-substrate could be tolerated by the enzymatic systems among these cells from diverse biological species. We isolated azido-GlcNAc modified proteins from the cytosolic extract of S2 cells and identified 10 previously reported and 41 putative O-GlcNAc modified proteins, by nano-HPLC-MS/MS. Our study demonstrates that the TAS approach is a useful tool for the detection and proteomic analysis of O-GlcNAc modified proteins.
A review of bioinformatic pipeline frameworks (2016)

High-throughput bioinformatic analyses increasingly rely on pipeline frameworks to process sequence and metadata. Modern implementations of these frameworks differ on three key dimensions: using an implicit or explicit syntax, using a configuration, convention or class-based design paradigm and offering a command line or workbench interface. Here I survey and compare the design philosophies of several current pipeline frameworks. I provide practical recommendations based on analysis requirements and the user base.
by hemodialysis membranes (1993)

I2 integrins are required for neutrophil degranulation induced by hemodialysis membranes. An untoward consequence of hemodialysis is degranulation of peripheral blood neutrophils. The mechanisms that mediate this process, however, have not been conclusively identified. In the present study, the participation of complement activation and 132 integrins (CD1 I/CD 18) in hemodialysis-induced neutrophil degranulation was investigated. Incubation of neutrophils with cuprophan membrane stimulated the release of very small amounts of the cytoplasmic granular protein, elastase. This release was markedly enhanced by the addition of plasma. Inactivation of complement reduced degranulation by --60%, but the contribution of anaphylatoxins C3a and C5a to the degranulation process was modest. Treatment of plasma with EDTA completely abolished neutrophil degranulation in the presence of cuprophan membrane. Further, when incubated with plasma and Cuprophan membrane, neutrophils that are deficient in /32 integrins released only 10% as much elastase as normal cells. Together, these observations strongly suggest that one or more members of the /2 integrin family of receptors is essential for cuprophan membraneinduced neutrophil degranulation and that both complement-related and noncomplement-related factors serve as receptor ligands.
Pancreatic and Islet Transplantation for Diabetes — Cures or Curiosities? (1992)

A PRESSING question in diabetes research is whether transplanting a pancreas or pancreatic islet cells can be used as successful therapy. In animals with insulin-dependent diabetes, pancreatic and islet transplantation has repeatedly been successful in establishing euglycemia. In humans with diabetes, successful transplantation of the pancreas maintains euglycemia, but at considerable cost in terms of morbidity and health care funds. Success with the less costly procedure of islet transplantation remains elusive. Resolution of the remaining technical difficulties with both these procedures is all the more urgent because, if pancreatic or islet transplantation or both are completely successful, they could provide . . .
Association between plasma HDL-cholesterol concentration and Taq1B CETP gene polymorphism in non-insulin-dependent diabetes mellitus (1998)

The effects of CETP gene Taq1B polymorphism on plasma lipoproteins were investigated in 176 patients with non-insulin-dependent diabetes mellitus. The distribution of CETP genotypes was similar to that previously described in the general population. A significant association was found between CETP genotype and both CETP and HDL cholesterol (HDL-c) concentrations. B1B1 had the highest CETP and the lowest HDL-c whereas B2B2 had the lowest CETP and the highest HDL-c. However, HDL-c was not correlated with CETP concentration, even when genetic groups were separately considered. By multivariate analysis, the determinants of HDL were body mass index, triglycerides concentration, net mass CE transfer, and CETP genotype. No association was found between CETP genetic groups and HDL or LDL size distribution. In contrast, net mass CET was positively and HDL and LDL sizes were negatively correlated with plasma triglyceride concentration. Overall, our work demonstrates that, in a population of diabetic patients where lipoprotein-related parameters vary over a large range, the association of CETP gene polymorphism with HDL-c is independent of plasma CETP concentration.
Screening Bicyclic Peptide Libraries for Protein–Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-α Antagonist (2013)

Protein-protein interactions represent a new class of exciting but challenging drug targets, because their large, flat binding sites lack well-defined pockets for small molecules to bind. We report here a methodology for chemical synthesis and screening of large combinatorial libraries of bicyclic peptides displayed on rigid small-molecule scaffolds. With planar trimesic acid as the scaffold, the resulting bicyclic peptides are effective for binding to protein surfaces such as the interfaces of protein-protein interactions. Screening of a bicyclic peptide library against tumor necrosis factor-α (TNFα) identified a potent antagonist that inhibits the TNFα-TNFα receptor interaction and protects cells from TNFα-induced cell death. Bicyclic peptides of this type may provide a general solution for inhibition of protein-protein interactions.
CIS-UltraCal: an open-source ultrasound calibration toolkit (2005)

We present an open-source MATLAB toolkit for ultrasound calibration. It has a convenient graphical user interface which sits on top of an extensive API. Calibration using three different phantoms is explicitly supported: the cross-wire phantom, the single-wall phantom, and the Hopkins phantom. Image processing of the Hopkins phantom is automated by making use of techniques from binary morphology, radon transform and RANSAC. Numerous calibration and termination parameters are exposed. It is also modular, allowing one to apply the system to original phantoms by writing a minimum of new code.
The Risk of Seizures after Receipt of Whole-Cell Pertussis or Measles, Mumps, and Rubella Vaccine (2001)

There are significantly elevated risks of febrile seizures on the day of receipt of DTP vaccine and 8 to 14 days after the receipt of MMR vaccine, but these risks do not appear to be associated with any long-term, adverse consequences.
A Convenient One-Pot Conversion of N-Boc-β-Aminoalcohols into N-Boc-Aziridines (1997)

This paper describes an efficient single step transformation of chiral N-protected β-amino alcohols into appropriate aziridines.
A New Mathematical Model for Coandă Effect Velocity Approximation (2012)

This paper addresses the problem of obtaining a set of mathematical equations that can accurately describe the velocity flow field near a cylindrical surface influenced by the Coand effect. The work is relevant since the current state of the art Reynolds Averaged Navier Stokes models with curvature correction do not completely describe the properties of the flow in accordance with the experimental data. Semi-empirical equations are therefore deduced based on experimental and theoretical state of the art. The resulting model is validated over a wider range of geometric layouts than any other existing semi-empirical model of its kind. The applications of this model are numerous, from super circulation wing calculations to fluidic devices such as actuators or fluidic diodes.
Biofeedback as a Treatment for Childhood Hyperactivity: A Critical Review of the Literature (1991)

Hyperactivity is a significant problem for which no causal theories have been unequivocally substantiated and one in which treatment approaches have met with limited success. Recent research in behavioral medicine has brought biofeedback into use as a treatment for disorders that are mediated by physiologic functioning, with hyperactivity as one such disorder. 36 studies are reviewed in which biofeedback was used as a treatment for hyperactivity. This review indicated that biofeedback treatments alone have not been effectively evaluated, and methodological problems with the current studies severely limit generalizations that may be made to hyperactive populations. Biofeedback in conjunction with other techniques appears to have promise for reducing some of the behavioral symptoms of the hyperactivity syndrome. Directions for further research are presented.
DNA Immunization against Herpes Simplex Virus: Enhanced Efficacy Using a Sindbis Virus-Based Vector (1998)

Previously we reported the development of a plasmid DNA expression vector system derived from Sindbis virus (T. W. Dubensky, Jr., et al., J. Virol. 70:508-519, 1996). In vitro, such vectors exhibit high-level heterologous gene expression via self-amplifying cytoplasmic RNA replication. In the present study, we demonstrated the in vivo efficacy of the Sindbis virus-based pSIN vectors as DNA vaccines. A single intramuscular immunization of BALB/c mice with pSIN vectors expressing the glycoprotein B of herpes simplex virus type 1 induced a broad spectrum of immune responses, including virus-specific antibodies, cytotoxic T cells, and protection from lethal virus challenge in two different murine models. In addition, dosing studies demonstrated that the pSIN vectors were superior to a conventional plasmid DNA vector in the induction of all immune parameters tested. In general, 100- to 1,000-fold-lower doses of pSIN were needed to induce the same level of responsiveness as that achieved with the conventional plasmid DNA vector. In some instances, significant immune responses were induced with a single dose of pSIN as low as 10 ng/mouse. These results indicate the potential usefulness of alphavirus-based vectors for DNA immunization in general and more specifically as a herpes simplex virus vaccine.
Mesothelin Immunotherapy for Cancer: Ready for Prime Time? (2016)

Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.
Computing frequent graph patterns from semistructured data (2003)

Whereas data mining in structured data focuses on frequent data values, in semistructured and graph data the emphasis is on frequent labels and common topologies. Here, the structure of the data is just as important as its content. We study the problem of discovering typical patterns of graph data. The discovered patterns can be useful for many applications, including: compact representation of source information and a road-map for browsing and querying information sources. Difficulties arise in the discovery task from the complexity of some of the required sub-tasks, such as sub-graph isomorphism. This paper proposes a new algorithm for mining graph data, based on a novel definition of support. Empirical evidence shows practical, as well as theoretical, advantages of our approach.
Embryonic Stem Cell Therapy of Heart Failure in Genetic Cardiomyopathy (2008)

Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K(+) (K(ATP)) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K(ATP) channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. Disclosure of potential conflicts of interest is found at the end of this article.