gebhart/patrepeval huggingface dataset:
A web site for the computational analysis of yeast regulatory sequences (2000)

A series of computer programs were developed for the analysis of regulatory sequences, with a special focus on yeast. These tools are publicly available on the web (http://copan.cifn.unam.mx/Computational_Biology/yeast-tools or http://www.ucmb.ulb.ac.be/bioinformatics/rsa-tools/). Basically, three classical problems can be addressed: (a) search for known regulatory patterns in the upstream regions of known genes; (b) discovery of unknown regulatory patterns within a set of upstream regions known to be co-regulated; (c) search for unknown genes potentially regulated by a known transcription factor. Each of these tasks can be performed on basis of a simple (string) or more refined (matrix) description of the regulatory patterns. A feature-map program automatically generates visual representations of the positions at which patterns were found. The site also provides a series of general utilities, such as generation of random sequence, automatic drawing of XY graphs, interconversions between sequence formats, etc. Several tools are linked together to allow their sequential utilization (piping), but each one can also be used independently by filling the web form with external data. This widens the scope of the site to the analysis of non-regulatory and/or non-yeast sequences. Copyright © 2000 John Wiley & Sons, Ltd.
Rational engineering of a miniprotein that reproduces the core of the CD4 site interacting with HIV-1 envelope glycoprotein (1999)

Protein-protein interacting surfaces are usually large and intricate, making the rational design of small mimetics of these interfaces a daunting problem. On the basis of a structural similarity between the CDR2-like loop of CD4 and the beta-hairpin region of a short scorpion toxin, scyllatoxin, we transferred the side chains of nine residues of CD4, central in the binding to HIV-1 envelope glycoprotein (gp120), to a structurally homologous region of the scorpion toxin scaffold. In competition experiments, the resulting 27-amino acid miniprotein inhibited binding of CD4 to gp120 with a 40 microM IC(50). Structural analysis by NMR showed that both the backbone of the chimeric beta-hairpin and the introduced side chains adopted conformations similar to those of the parent CD4. Systematic single mutations suggested that most CD4 residues from the CDR2-like loop were reproduced in the miniprotein, including the critical Phe-43. The structural and functional analysis performed suggested five additional mutations that, once incorporated in the miniprotein, increased its affinity for gp120 by 100-fold to an IC(50) of 0.1-1.0 microM, depending on viral strains. The resulting mini-CD4 inhibited infection of CD4(+) cells by different virus isolates. Thus, core regions of large protein-protein interfaces can be reproduced in miniprotein scaffolds, offering possibilities for the development of inhibitors of protein-protein interactions that may represent useful tools in biology and in drug discovery.
Multiple Inhibitor Analysis of the Brequinar and Leflunomide Binding Sites on Human Dihydroorotate Dehydrogenase (2001)

Brequinar and the active metabolite of leflunomide, A77 1726, have been clearly shown to inhibit human dihydroorotate dehydrogenase (DHODH), but conflicting mechanisms for their inhibition have been reported. DHODH catalyses the conversion of dihydroorotate (DHO) to orotate concurrent with the reduction of ubiquinone. This study presents data that indicates brequinar is a competitive inhibitor versus ubiquinone; A77 1726 is noncompetitive versus ubiquinone and both are uncompetitive versus DHO. 2-Phenyl 5-quinolinecarboxylic acid (PQC), the core moiety of brequinar also shows competitive inhibition versus ubiquinone. Multiple inhibition experiments indicate that PQC (and thus brequinar) and A77 1726 have overlapping binding sites. Both PQC and A77 1726 are also mutually exclusive with barbituric acid (a competitive inhibitor versus DHO). In addition, we failed to observe brequinar binding to E.orotate by isothermal titration calorimetry (ITC). These results indicate that the E.DHO.inhibitor and E.orotate.inhibitor ternary complexes do not form. The absence of these complexes is consistent with the two-site ping-pong mechanism reported for DHODH. This kinetic data suggests that recent crystal structures of human DHODH complexed with orotate and A77 1726 or brequinar may not represent the relevant physiological binding sites for these inhibitors [Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T., and Clardy J. (2000) Structure 8, 25-33].
Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome (2017)

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. <i>miR-223<sup>-/y</sup></i> mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2<sup>+</sup> inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3' untranslated region, phenocopied the characteristics of <i>miR-223<sup>-/y</sup></i> mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation.
Synergistic interaction between insulin-like growth factors-I and -II in central regulation of pulsatile growth hormone secretion. (1992)

Insulin-like growth factor (IGF)-I and -II peptides, receptors, mRNAs, and binding proteins are widely distributed in the central nervous system (CNS), yet their physiological role in the brain remains largely unknown. While earlier in vivo studies in the rat suggested that IGF-I may participate in feedback regulation of GH secretion at a CNS level, the preparations used were only partially pure. The recent availability of purified recombinant IGF-I and -II peptides prompted us to reexamine the involvement of the IGFs in vivo in central regulation of pulsatile GH secretion. Five groups of free-moving adult male rats bearing chronic intracerebroventricular (icv) and intracardiac venous cannulae were icv administered IGF-I (in doses of 0.5, 2, 3, and 10 micrograms) or the acid-saline vehicle; an additional group received 1 microgram of the potent IGF-I analog, long R3 IGF-I. Spontaneous 6-h plasma GH secretory profiles were obtained from all groups. Vehicle-injected control animals exhibited the typical pulsatile pattern of GH secretion, with most peak GH values above 150 ng/ml and trough levels below 1.2 ng/ml. Central administration of IGF-I alone or long R3 IGF-I at all doses tested failed to alter the pulsatile pattern of GH release; there were no significant differences in GH peak amplitude, GH trough level, GH interpeak interval, or mean 6-h plasma GH level compared to those in vehicle-injected controls. In a second study, designed to determine the effects of central administration of IGF-I and IGF-II, in combination, icv injection of 1 microgram IGF-I and 1 microgram IGF-II resulted in a marked suppression in the amplitude of spontaneous GH secretory bursts approximately 3 h after injection; both GH pulse amplitude (43.5 +/- 5.6 vs. 130.6 +/- 14.6 ng/ml; P less than 0.001) and mean plasma GH level (16.3 +/- 1.9 vs. 35.2 +/- 1.8 ng/ml; P less than 0.001) were severely reduced 3-6 h after injection compared to those in vehicle-injected controls. These results demonstrate that IGF-I alone does not play a physiologically important role in feedback regulation of GH secretion at the level of the CNS. Our findings suggest a synergistic interaction between IGF-I and -II in the brain for central control of pulsatile GH secretion.
Recruitment of different subsets of antigen‐presenting cells selectively modulates DNA vaccine‐elicited CD4+ and CD8+ T lymphocyte responses (2004)

The immunogenicity of plasmid DNA vaccines may be limited by the availability of professional antigen-presenting cells (APC) at the site of inoculation. Here we demonstrate that the types of APC recruited to the injection site can selectively modulate CD4(+) or CD8(+) T lymphocyte responses elicited by an HIV-1 Env DNA vaccine in mice. Coadministration of plasmid GM-CSF with the DNA vaccine resulted in the recruitment of macrophages to the site of inoculation and specifically augmented vaccine-elicited CD4(+) T lymphocyte responses. In contrast, coadministration of plasmid MIP-1 alpha with the DNA vaccine resulted in the recruitment of dendritic cells to the injection site and enhanced vaccine-elicited CD8(+) T lymphocyte responses. Interestingly, coadministration of both plasmid GM-CSF and plasmid MIP-1 alpha with the DNA vaccine recruited both macrophages and dendritic cells and led to a synergistic and sustained augmentation of CD4(+)and CD8(+) T lymphocyte responses. These data demonstrate the critical importance of locally recruited professional APC in determining the magnitude and nature of immune responses elicited by plasmid DNA vaccines. Moreover, these studies show that different subsets of professional APC can selectively modulate DNA vaccine-elicited T lymphocyte responses.
Matrix Metalloproteinase-9 Is Necessary for the Regulation of Smooth Muscle Cell Replication and Migration After Arterial Injury (2002)

Matrix metalloproteinases (MMPs) and, in particular, MMP-9 are important for smooth muscle cell (SMC) migration into the intima. In this study, we sought to determine whether MMP-9 is critical for SMC migration and for the formation of a neointima by using mice in which the gene was deleted (MMP-9(-/-) mice). A denuding injury to the arteries of wild-type mice promoted the migration of medial SMCs into the neointima at 6 days, and a large neointimal lesion was observed after 28 days. In wild-type arteries, medial SMC replication was approximately 8% at day 4, 6% at day 6, and 4% at day 8 and had further decreased to 1% at day 14. Intimal cell replication was 65% at 8 days and had decreased to approximately 10% at 14 days after injury. In MMP-9(-/-) arteries, SMC replication was significantly lower at day 8. In addition, SMC migration and arterial lesion growth were significantly impaired in MMP-9(-/-) arteries. SMCs, isolated from MMP-9(-/-) mouse arteries, showed an impairment of migration and replication in vitro. Thus, our present data indicate that MMP-9 is critical for the development of arterial lesions by regulating both SMC migration and proliferation.
Mutations and polymorphisms of the gene of the major human blood protein, serum albumin (2008)

We have tabulated the 77 currently known mutations of the familiar human blood protein, serum albumin (ALB). A total of 65 mutations result in bisalbuminemia. Physiological and structural effects of these mutations are included where observed. Most of the changes are benign. The majority of them were detected upon clinical electrophoretic studies, as a result of a point mutation of a charged amino acid residue. Three were discovered by their strong binding of thyroxine or triiodothyronine. A total of 12 of the tabulated mutations result in analbuminemia, defined as a serum albumin concentration of <1 g/L. These were generally detected upon finding a low albumin concentration in patients with mild edema, and involve either splicing errors negating translation or premature stop codons producing truncated albumin molecules. A total of nine mutations, five of those with analbuminemia and four resulting in variants modified near the C-terminal end, cause frameshifts. Allotypes from three of the point mutations become N-glycosylated and one C-terminal frameshift mutation shows O-glycosylation.
High-volume production of laser-polarized 129Xe (1996)

A method is described for producing several liters of nuclear spin polarized 129Xe gas via spin exchange with an optically pumped Rb vapor. We use a 140 W AlGaAs laser diode array whose broad spectral output is efficiently absorbed by employing ∼10 atm of 4He to pressure broaden the Rb D1 absorption profile. 129Xe is polarized in a continuous gas flow and is then cryogenically accumulated and stored. Extensions of this technique should enable the production of tens of liters of 129Xe with a nuclear spin polarization of order 50%. Production of laser-polarized 129Xe in liter quantities is important for the continued development of magnetic resonance imaging using spin-polarized 129Xe.
An Arabidopsis porB porC double mutant lacking light‐dependent NADPH:protochlorophyllide oxidoreductases B and C is highly chlorophyll‐deficient and developmentally arrested (2003)

A key reaction in the biosynthesis of chlorophylls (Chls) a and b from cyanobacteria through higher plants is the strictly light-dependent reduction of protochlorophyllide (Pchlide) a to chlorophyllide (Chlide) a. Angiosperms, unlike other photosynthetic organisms, rely exclusively upon this mechanism to reduce Pchlide and hence require light to green. In Arabidopsis, light-dependent Pchlide reduction is mediated by three structurally related but differentially regulated NADPH:Pchlide oxidoreductases, denoted as PORA, PORB, and PORC. The PORA and PORB genes, but not PORC, are strongly expressed early in seedling development. In contrast, expression of PORB and PORC, but not PORA, is observed in older seedlings and adult plants. We have tested the hypothesis that PORB and PORC govern light-dependent Chl biosynthesis throughout most of the plant development by identifying porB and porC mutants of Arabidopsis, the first higher plant por mutants characterized. The porB-1 and porC-1 mutants lack the respective POR transcripts and specific POR isoforms because of the interruption of the corresponding genes by a derivative of the maize Dissociation (Ds) transposable element. Single por mutants, grown photoperiodically, display no obvious phenotypes at the whole plant or chloroplast ultrastructural levels, although the porB-1 mutant has less extensive etioplast inner membranes. However, a light-grown porB-1 porC-1 double mutant develops a seedling-lethal xantha phenotype at the cotyledon stage, contains only small amounts of Chl a, and possesses chloroplasts with mostly unstacked thylakoid membranes. PORB and PORC thus seem to play redundant roles in maintaining light-dependent Chl biosynthesis in green plants, and are together essential for growth and development.
Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion (2021)

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.
A Viral Platform for Chemical Modification and Multivalent Display (2003)

The ability to chemically modify the surfaces of viruses and virus-like particles makes it possible to confer properties that make them potentially useful in biotechnology, nanotechnology and molecular electronics applications. RNA phages (e.g. MS2) have characteristics that make them suitable scaffolds to which a variety of substances could be chemically attached in definite geometric patterns. To provide for specific chemical modification of MS2's outer surface, cysteine residues were substituted for several amino acids present on the surface of the wild-type virus particle. Some substitutions resulted in coat protein folding or stability defects, but one allowed the production of an otherwise normal virus-like particle with an accessible sulfhydryl on its surface.
Cytochrome P450 Nomenclature (2003)

With genome projects spewing forth DNA sequence at tens of Megabases per year, the problem of genetic nomenclature becomes daunting. In the field of cytochrome P450 (P450), there are more than 750 sequences and they are accumulating rapidly. At the current rate, there will be more than 1000 P450 sequences by late 1998 or early 1999. For these data to be accessible and useful they must be sorted and categorized in some meaningful way. To that end, a cytochrome P450 nomenclature system was devised (1). This system relied on evolutionary relationships as depicted in phylogenetic trees or dendrograms derived from the P450 protein sequences. The whole collection of sequences represents the P450 superfamily, with families and subfamilies being arbitrarily defined as distinct clusters on the tree. Orrgmally, 40% identity was used as a cutoff for family membership and 55% was used for subfamily membership. Since the inception of the system, both numbers have crept downward. The actual decision to mclude a sequence in an existing group largely depends on how it clusters on a tree and not so much on the absolute percent identity, which is more or less a rule of thumb. The most recent published compilation of the nomenclature is given in Nelson et al. (1996) (2). More up-to-date information is available at .
Assembly and Antigenicity of Hepatitis B Virus Core Particles (1995)

Recent studies in Xenopus oocytes and other systems have led to an understanding of the HBV capsid, or core particle, assembly process. Nascent HBV core polypeptides rapidly dimerize. Accumulation of free dimers to a signature concentration (approximately 0.8 microM) then triggers a highly cooperative capsid assembly reaction. This dimer-to-capsid transition is accompanied by a switch from HBe to HBc antigenicity and appears to be nucleated by interaction between core protein and RNA: deletion of a protamine-like RNA binding domain at the C-terminus of the core protein markedly increases the concentration of dimers needed to drive capsid assembly. The simple assembly pathway seen for HBV capsids mirrors that of R17 bacteriophage.
Adenoviral Delivery of Recombinant DNA into Transgenic Mice Bearing Hepatocellular Carcinomas (1996)

To evaluate the applicability of recombinant adenoviral vectors in gene transfer to liver cancers, we infused the recombinant adenoviruses AD5CMV-LacZ and Ad5CMV-p53 through the portal veins into two lines of transgenic mice, one bearing the SV40 T antigen and the other the human hepatitis B viral envelope protein. These transgenic animals develop hepatocellular carcinomas (HCC) with predictable pathological manifestations. The levels of expression of the transgenes were dependent upon the viral doses. In all cases, high levels of expression were detected within 2 or 3 days after infusion, but were drastically reduced 7 days after infusion. Significant toxicities were found in the infused animals: > 80% of them died within 7 days after infusion with 10(10) pfu, and transgenic animals bearing HCC apparently were more sensitive to viral toxicity. Although a lower dose (10(9) pfu/animal) produced less toxicity, the levels of expression were substantially reduced (only about 10% of that in animals infused with 10(10) pfu). When Ad5CMV-p53 was infused into animals with nodular hyperplastic stage, the expression of the reporter gene seemed to distribute preferentially at the peripheries of the tumor nodules, and low levels of transgene expression were seen inside the nodules. In tumors in which necrotic lesions were evident, p53 was also expressed at the perpheries of the lesions. These distribution patterns were seen in both tumor models. There was no apparent suppression of tumor growth in the Ad5CMV-p53-infused animals. Our results suggest that alternative methods for gene therapy for HCC need to be explored.
The Total Synthesis of Corallopyronin A and Myxopyronin B (2012)

Leading the way: the synthesis of natural products with new biological targets is one of the driving forces for the development of new antibiotics. The synthesis of the two secondary metabolites corallopyronin and myxopyronin have been achieved, which are prominent leads for the inhibition of bacterial RNA polymerase.
Relaxation and frequency shifts induced by quasiparticles in superconducting qubits (2011)

As low-loss nonlinear elements, Josephson junctions are the building blocks of superconducting qubits. The interaction of the qubit degree of freedom with the quasiparticles tunneling through the junction represents an intrinsic relaxation mechanism. We develop a general theory for the qubit decay rate induced by quasiparticles, and we study its dependence on the magnetic flux used to tune the qubit properties in devices such as the phase and flux qubits, the split transmon, and the fluxonium. Our estimates for the decay rate apply to both thermal equilibrium and nonequilibrium quasiparticles. We propose measuring the rate in a split transmon to obtain information on the possible nonequilibrium quasiparticle distribution. We also derive expressions for the shift in qubit frequency in the presence of quasiparticles.
Expression of neuronal markers in oligodendrogliomas: an immunohistochemical study (1998)

The oligodendroglioma has been considered to be a tumour showing oligodendrocyte differentiation, but studies of the expression of oligodendrocyte markers have not conclusively demonstrated this and the pattern of differentiation of this tumour remains uncertain. Recent studies have suggested that some oligodendrogliomas may show neuronal differentiation. The aim of this study was to determine whether there was evidence of neuronal differentiation in a series of oligodendrogliomas, and, if so, to determine whether this identified a biologically or clinically distinct group. Immunohistochemistry was carried out on paraffin sections using antibodies to synaptophysin, phosphorylated and non-phosphorylated neurofilament proteins. An archival series of 32 oligodendrogliomas had been previously characterized for histological features, histological grade, Ki-67 labelling index, apoptosis index and prognosis. Six per cent of tumours showed expression of synaptophysin. Thirty-one per cent of cases showed expression of neurofilament proteins with an antibody to non-phosphorylated epitopes, but no cases were positive with antibodies to phosphorylated neurofilament epitopes. Tumours showing expression of neuronal markers did not show a difference in the distribution of histological grade or GFAP expression from those which did not express these markers, and there was no difference in labelling indices or prognosis between the two groups. In conclusion, a subset of oligodendrogliomas showed expression of neuronal lineage markers; this is discussed in relation to histogenesis and differential diagnosis. The expression of such markers did not identify a biologically or clinically distinct subgroup.