gebhart/patrepeval huggingface dataset:
Production of pathogenic antibodies: Cognate interactions between autoimmune T and B cells (1998)

A select population of autoimmune T-helper (T(H)) cells drive the production of pathogenic anti-DNA autoantibodies in SLE. These T(H) cells recognize nucleosomal peptides that are processed and presented by the anti-DNA B cells that they help. The critical peptide epitopes for the T(H) cells reside in the core histones of the nucleosome particle. Remarkably, the nucleosomal peptide epitopes do not obey the rule of MHC-restriction; they can be promiscuously presented and recognized in the context of diverse MHC alleles. Such promiscuous antigens, called pantigens, are also recognized by autoimmune T cells, in a degenerate fashion, and this promiscuous recognition is conferred by the lupus TCR alpha chains. High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcome the requirement for MHC restriction. These studies open up the possibility of developing 'universally' tolerogenic epitopes for therapy of lupus in humans despite their diversity of HLA alleles. The results also have profound implications regarding the selection of autoimmune T cells in the lupus-prone thymus and their expansion in the periphery. Furthermore, the T(H) cells, as well as B cells of lupus, have a regulatory defect causing markedly increased and prolonged expression of CD40 ligand (CD40L), which mediates abnormal co-stimulatory signals to autoimmune B cells, sustaining the production of pathogenic autoantibodies. These observations suggest a new paradigm for B cell hyperactivity in lupus and provide alternative targets for immunotherapy. Indeed, giving only three injections of anti-CD40L antibody in a one-week period to mice with manifest lupus selectively blocks the pathogenic autoimmune response and delays the development of lupus nephritis by one year (equivalent to three decades in humans). Thus, possession of promiscuous, high-affinity receptors and prolonged expression of CD40L by lupus T cells probably lowers activation threshold, leading to an autoimmune response against nucleosomes derived from apoptotic cells that are normally ignored by the immune system.
Predicted effects of pulse width programming in spinal cord stimulation: a mathematical modeling study (2011)

To understand the theoretical effects of pulse width (PW) programming in spinal cord stimulation (SCS), we implemented a mathematical model of electrical fields and neural activation in SCS to gain insight into the effects of PW programming. The computational model was composed of a finite element model for structure and electrical properties, coupled with a nonlinear double-cable axon model to predict nerve excitation for different myelinated fiber sizes. Mathematical modeling suggested that mediolateral lead position may affect chronaxie and rheobase values, as well as predict greater activation of medial dorsal column fibers with increased PW. These modeling results were validated by a companion clinical study. Thus, variable PW programming in SCS appears to have theoretical value, demonstrated by the ability to increase and even 'steer' spatial selectivity of dorsal column fiber recruitment. It is concluded that the computational SCS model is a valuable tool to understand basic mechanisms of nerve fiber excitation modulated by stimulation parameters such as PW and electric fields.
The allosteric site of human liver fructose-1,6-bisphosphatase. Analysis of six AMP site mutants based on the crystal structure. (1994)

The molecular structure of human liver fructose-1,6-bisphosphatase complexed with AMP was determined by x-ray diffraction using molecular replacement, starting from the pig kidney enzyme AMP complex. Of the 34 amino acid residues which differ between these two sequences, only one interacts with AMP; Met30 in pig kidney is Leu30 in human liver. From this analysis, six sites in which side chains of amino acid residues are in contact with AMP, Ala24, Leu30, Thr31, Tyr113, Arg140, and Met177, were mutated by polymerase chain reaction. The wild-type and mutant forms were expressed in Escherichia coli, purified, and their kinetic properties determined. Circular dichroism spectra of the mutants were indistinguishable from that of the wild-type enzyme. Kinetic analyses revealed that all forms had similar turnover numbers, Km values for fructose 2,6-bisphosphate, and inhibition constants for fructose 2,6-bisphosphate. Apparent Ki values for AMP inhibition of the Leu30 --> Phe and Met177 --> Ala mutants were similar to those of the wild-type enzyme, but the apparent Ki values for the Arg140 --> Ala and Ala24 --> Phe mutants were 7-to 20-fold higher, respectively. The Thr31 --> Ser mutant exhibited a 5-fold increase in apparent Ki for AMP, while mutation of Thr31 to Ala increased the apparent Ki 120-fold. AMP inhibition of the Tyr113 --> Phe mutant was undetectable even at millimolar AMP concentrations. Fructose 2,6-bisphosphate potentiated AMP inhibition of the mutants to the same extent as for the wild-type enzyme, except in the case of the Thr31 --> Ala and Tyr113 --> Phe mutants. Thus, the Met177 --> Ala mutant suggests that the side chain beyond C alpha is not needed for AMP binding, and that the Leu30 --> Phe mutant preserves the AMP contacts with these side chains. Thr31, Tyr113, and Arg140 form key hydrogen bonds to AMP consistent with strong side chain interactions in the wild-type enzyme. Finally, the absence of any effect of fructose 2,6-bisphosphate on AMP inhibition observed in the Thr31 --> Ala mutant may be an important clue relating to the mechanism of synergism of these two inhibitors.
Synthesis and Biological Properties of Sequence-Specific DNA-Alkylating Pyrrole−Imidazole Polyamides (2006)

In recent years, many diseases including cancer and hereditary and viral diseases have been understood at the DNA sequence level. Direct control of the expression level of a specific gene would provide a promising approach for knowledge-based therapy. N-Methylpyrrole (Py) and N-methylimidazole (Im) polyamides are a new type of small compound that precisely bind to the minor groove of the DNA duplex in a sequence-specific fashion and recruit alkylating agents to the target sequence. We designed and synthesized a series of sequence-specific alkylating Py-Im polyamide conjugates that selectively alkylate predetermined DNA sequences. We have demonstrated that sequence-specific alkylating agents possess gene-silencing activities and a promising potency against human cancer cell lines as well as against xenografts of human cancer cell lines. In this Account, we focus on recent progress in alkylating Py-Im polyamides with regard to sequence specificity and biological activities and the future direction of rational molecular design of genetic switches in the postgenome era is described.
13C isotopomer analysis of glucose and alanine metabolism reveals cytosolic pyruvate compartmentation as part of energy metabolism in astrocytes (2001)

After incubation of glial cells with both (13)C-labeled and unlabeled glucose and alanine, (13)C isotopomer analysis indicates two cytosolic pyruvate compartments in astrocytes. One pyruvate pool is in an exchange equilibrium with exogenous alanine and preferentially synthesizes releasable lactate. The second pyruvate pool, which is of glycolytic origin, is more closely related to mitochondrial pyruvate, which is oxidized via tri carbonic acid (TCA) cycle activity. In order to provide 2-oxoglutarate as a substrate for cytosolic alanine aminotransferase, glycolytic activity is increased in the presence of exogenous alanine. Furthermore, in the presence of alanine, glutamate is accumulated in astrocytes without subsequent glutamine synthesis. We suggest that the conversion of alanine to releasable lactate proceeds at the expense of flux of glycolytic pyruvate through lactate dehydrogenase, which is used for ammonia fixation by alanine synthesis in the cytosol and for mitochondrial TCA cycle activity. In addition, an intracellular trafficking occurs between cytosol and mitochondria, by which these two cytosolic pyruvate pools are partly connected. Thus, exogenous alanine modifies astrocytic glucose metabolism for the synthesis of releasable lactate disconnected from glycolysis. The data are discussed in terms of astrocytic energy metabolism and the metabolic trafficking via a putative alanine-lactate shuttle between astrocytes and neurons.
Cell-Associated Plasminogen Activation: Regulation and Physiological Functions (1988)

PLASMINOGEN ACTIVATOR INHIBITORS 104 Plasminogen Activator Inhibitor 1 104 Plasminogen Activator Inhibitor 2 106 Protease Nexin I .... .... 108 PHYSIOLOGICAL FUNCTIONS OF PLASMINOGEN ACTIVATION ........ 109 Matrix Breakdown 109 Cell Migration 111 Ovulation 113 CONCLUDING REMARKS 115
Carbohydrate antigen defined by a monoclonal antibody raised against a gastric cancer xenograft. (1985)

A monoclonal antibody, ST-4-39, was obtained by using a human gastric cancer xenograft, St-4, as an immunogen. Immunization was achieved by transferring immunocompetent mouse spleen cells into a nude mouse bearing St-4. Hybridomas were produced with the spleen cells of the mouse after rejection of the tumor and screened for immunohistochemical reactivity with cancers and normal tissues on formalin-fixed paraffin sections. ST-4-39 immunohistochemically reacted with various cancers including gastric, colorectal and pancreatic cancers as well as some normal tissues. ST-4-39 and NS 19-9 differed in immunohistochemical reactivity, although they reacted with some cancers and a few normal tissues in common. PBS extracts of normal and cancer tissues were examined for antigen reactive with ST-4-39 by sandwich enzyme immunoassay. Extractable antigen was detected in adenocarcinomas of colon, stomach and lung, while it was detected only in salivary gland and trachea among normal tissues examined. Gel filtration analysis of the antigen indicated a molecular weight of greater than or equal to 1 X 10(6), and the antigenic determinant was suggested to be a carbohydrate chain with terminal sialic acid by studies using periodic acid, neuraminidase and pronase treatments. Furthermore, the ST-4-39 antigen affinity-purified from two gastric cancer strains was shown to contain multiple carbohydrate determinants including sialyl-Lewisa and sialyl-Lewisx, suggesting the antigen to be a mucin.
HSP27: Mechanisms of Cellular Protection Against Neuronal Injury (2009)

The heat shock protein (HSP) family has long been associated with a generalized cellular stress response, particularly in terms of recognizing and chaperoning misfolded proteins. While HSPs in general appear to be protective, HSP27 has recently emerged as a particularly potent neuroprotectant in a number of diverse neurological disorders, ranging from ALS to stroke. Although its robust protective effect on a number of insults has been recognized, the mechanisms and regulation of HSP27's protective actions are still undergoing intense investigation. On the basis of recent studies, HSP27 appears to have a dynamic and diverse range of function in cellular survival. This review provides a forum to compare and contrast recent literature exploring the protective mechanism and regulation of HSP27, focusing on neurological disorders in particular, as they represent a range from protein aggregate-associated diseases to acute stress.
CRISPR-Cas: an efficient tool for genome engineering of virulent bacteriophages (2014)

Bacteriophages are now widely recognized as major players in a wide variety of ecosystems. Novel genes are often identified in newly isolated phages as well as in environmental metavirome studies. Most of these novel viral genes have unknown functions but appear to be coding for small, non-structural proteins. To understand their biological role, very efficient genetic tools are required to modify them, especially in the genome of virulent phages. We first show that specific point mutations and large deletions can be engineered in the genome of the virulent phage 2972 using the Streptococcus thermophilus CRISPR-Cas Type II-A system as a selective pressure to increase recombination efficiencies. Of significance, all the plaques tested contained recombinant phages with the desired mutation. Furthermore, we show that the CRISPR-Cas engineering system can be used to efficiently introduce a functional methyltransferase gene into a virulent phage genome. Finally, synthetic CRISPR bacteriophage insensitive mutants were constructed by cloning a spacer-repeat unit in a low-copy vector illustrating the possibility to target multiple regions of the phage genome. Taken together, this data shows that the CRISPR-Cas system is an efficient and adaptable tool for editing the otherwise intractable genomes of virulent phages and to better understand phage-host interactions.
Human Hormone Production in vitro (1968)

A new in vitro hormone-synthesizing cell system, line BeWO, derived from human gestational choriocarcinoma, has been permanently established; a high degree of synthesis of functional hormone has been maintained for 18 months in tissue culture. Predominantly glycolytic metabolism, dependent on the level of glucose in the medium, has been observed. Many facets of placental and tumor-cell metabolism, growth, and differentiation are found in this unique multipotential cell.
Preparation and Properties of Resorcinol–Formaldehyde Organic and Carbon Gels (2003)

Abstract A brief overview on the preparation and properties of resorcinol–formaldehyde organic and carbon gels reveals very interesting features about their structural and performance characteristics. The resulting nanostructure was very sensitive to the various synthesis and processing conditions. This leads to a remarkable potential for designing and tailoring these materials to fit specific applications. Based on step‐by‐step comparisons of the published studies, approximate generalizations on the specific roles the synthesis and processing conditions play on the final properties are provided. Overall, resorcinol–formaldehyde organic gels undergo two main stages during synthesis. The first stage is associated with the preparation of the sol mixture, and the subsequent gelation and curing of the gel. The second stage is associated with the drying of the wet gel. The most important factors that affect the properties of the organic gel during the first stage are the catalyst concentration, the initial gel pH, and the concentration of the solids in the sol. The most important factors that affect the properties of the organic gel during the second stage are the drying procedure (e.g., super‐ or subcritical drying), and the difference between the surface tensions of the solvent before and after drying. The corresponding resorcinol–formaldehyde carbon gels are produced from the organic gels during a third stage, which is associated with carbonization or activation. Depending on the conditions, carbonization and activation both impact the structural and performance characteristics significantly.
Perforin‐dependent nuclear targeting of granzymes: A central role in the nuclear events of granule‐exocytosis‐mediated apoptosis? (1999)

Programmed cell death, apoptosis, involves very distinctive changes within the target cell nucleus, including margination of the chromatin, DNA fragmentation and breakdown of the nuclear envelope. Cytolytic granule-mediated target cell apoptosis is effected, in part, through synergistic action of the membrane-acting protein perforin and serine proteases, such as granzymes A or B. Recent work using confocal laser scanning microscopy as well as other techniques supports the idea that perforin-dependent translocation of granzymes to the nucleus of target cells plays a central role in effecting the nuclear changes associated with apoptosis. In vitro experiments indicate that granzyme nuclear import follows a novel pathway, being independent of ATP, not inhibitable by non-hydrolysable GTP analogues and involving binding within the nucleus, unlike conventional signal- dependent nuclear protein import. In intact cells, perforin-dependent nuclear entry of granzymes precedes the nuclear events of apoptosis such as DNA fragmentation and nuclear envelope breakdown; prevention of granzyme nuclear translocation through bcl2 overexpression or treatment of target cells with inhibitors of caspase activation blocks these events. Nuclear localization of granzymes thus appears to be central to induction of the nuclear changes associated with cytolytic granule-mediated apoptosis.
A novel DSF-like signal from Burkholderia cenocepacia interferes with Candida albicans morphological transition (2007)

In addition to producing lethal antibiotics, microorganisms may also use a new form of antagonistic mechanism in which signal molecules are exported to influence the gene expression and hence the ecological competence of their competitors. We report here the isolation and characterization of a novel signaling molecule, cis-2-dodecenoic acid (BDSF), from Burkholderia cenocepacia. BDSF is structurally similar to the diffusible signal factor (DSF) that is produced by the RpfF enzyme of Xanthomonas campestris. Deletion analysis demonstrated that Bcam0581, which encodes an RpfF homologue, was essential for BDSF production. The gene is highly conserved and widespread in the Burkholderia cepacia complex. Exogenous addition of BDSF restored the biofilm and extracellular polysaccharide production phenotypes of Xanthomonas campestris pv. campestris DSF-deficient mutants, highlighting its potential role in inter-species signaling. Further analyses showed that Candida albicans germ tube formation was strongly inhibited by either coculture with B. cenocepacia or by exogenous addition of physiological relevant levels of BDSF, whereas deletion of Bcam0581 abrogated the inhibitory ability of the bacterial pathogen. As B. cenocepacia and C. albicans are frequently encountered human pathogens, identification of the BDSF signal and its activity thus provides a new insight into the molecular grounds of their antagonistic interactions whose importance to microbial ecology and pathogenesis is now becoming evident.
Nanomechanics of Carbon Tubes: Instabilities beyond Linear Response (1996)

Carbon nanotubes subject to large deformations reversibly switch into different morphological patterns. Each shape change corresponds to an abrupt release of energy and a singularity in the stress-strain curve. These transformations, simulated using a realistic many-body potential, are explained by a continuum shell model. With properly chosen parameters, the model provides a remarkably accurate ``roadmap'' of nanotube behavior beyond Hooke's law.
Ultrastaging of colorectal cancer by sentinel lymph node mapping technique--a multicenter trial. (2001)

Sentinel lymph node (SLN) mapping accurately diagnoses the status of nodal basin with >95% accuracy in melanoma and breast cancer. A multicenter trial for SLN mapping was performed on 203 patients with colorectal cancer to determine accuracy, upstaging, skip metastasis, and aberrant drainage. Lymphazurin 1% was injected subserosally around the tumor and 1-4 blue staining nodes were marked as SLNs for detailed histological analysis. SLN mapping was successful in 98% of patients with an average of 1.7 SLNs per patient. SLNs were negative in 63% of the patients and positive in 37% of the patients. Skip metastasis was seen in 8 of the patients. Occult micrometastasis was found in 14% of patients. In 5% of the patients, unusual lymphatic drainage lead to an alteration of the extent of lymphadenectomy. This multicenter trial proved that SLN mapping in patients with colorectal cancer is simple, cost effective, and upstages at least 14% of patients from AJCC stage I/II to stage III. These patients may then benefit from adjuvant chemotherapy.
On the optimal location of sensors for robust fault detection filter (1997)

Fault detection filter is a full order observer that can detect and isolate faults by constraining residual vector due to a particular fault in a certain detection space. It is known that different faults can be perfectly isolated by designing a fault detection filter when mutual isolability condition is satisfied. This paper discusses such property in detail, considering the transmission zero in conjunction with the location and combination of sensors. And the guideline to choose sensor location which enables the stable mutual isolation of different faults is proposed. Numerical results show that the fault detection filter with this sensor location is robust in the sense that it has minimal sensitivity to measurement noise.
AH/PH Domain-Mediated Interaction between Akt Molecules and Its Potential Role in Akt Regulation (1995)

The cytoplasmic serine-threonine protein kinase coded for by the c-akt proto-oncogene features a protein kinase C-like catalytic domain and a unique NH2-terminal domain (AH domain). The AH domain is a member of a domain superfamily whose prototype was observed in pleckstrin (pleckstrin homology, or PH, domain). In this communication, we present evidence that the AH/PH domain is a domain of protein-protein interaction which mediates the formation of Akt protein complexes. The interaction between c-akt AH/PH domains is highly specific, as determined by the failure of this domain to bind AKT2. The AH/PH domain-mediated interactions depend on the integrity of the entire domain. Akt molecules with deletions of the NH2-terminal portion (amino acids 11 to 60) and AH/PH constructs with deletions of the C-terminal portion of this domain (amino acids 107 to 147) fail to interact with c-akt. To determine the significance of these findings, we carried out in vitro kinase assays using Akt immunoprecipitates from serum-starved and serum-starved, platelet-derived growth factor-stimulated NIH 3T3 cells. Addition of maltose-binding protein-AH/PH fusion recombinant protein, which is expected to bind Akt, to the immunoprecipitates from serum-starved cells induced the activation of the Akt kinase.
Brain 5-HT neurotransmission during paroxetine treatment (1998)

SSRI treatment in depressed patients produces a persistent increase in the cortisol response to 5-HTP, a probable measure of neurotransmission at central 5-HT2 receptors. Potentiation of 5-HT2 neurotransmission is unlikely to account for the efficacy of SSRIs in major depression but might underlie their actions in obsessive-compulsive disorder and also perhaps certain of their adverse effects, notably sexual dysfunction.
Absence of cytokine receptor-dependent specificity in red blood cell differentiation in vivo (1998)

Erythropoietin (EPO) is required for red blood cell development, but whether EPO-specific signals directly instruct erythroid differentiation is unknown. We used a dominant system in which constitutively active variants of the EPO receptor were introduced into erythroid progenitors in mice. Chimeric receptors were constructed by replacing the cytoplasmic tail of constitutively active variants of the EPO receptor with tails of diverse cytokine receptors. Receptors linked to granulocyte or platelet production supported complete erythroid development in vitro and in vivo, as did the growth hormone receptor, a nonhematopoietic receptor. Therefore, EPOR-specific signals are not required for terminal differentiation of erythrocytes. Furthermore, we found that cellular context can influence cytokine receptor signaling.