gebhart/patrepeval huggingface dataset:
RANK-L and RANK: T Cells, Bone Loss, and Mammalian Evolution (2002)

TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.
Inhibitors of glycolic acid oxidase. 4-Substituted-2,4-dioxobutanoic acid derivatives (1983)

Fourteen new 4-substituted 2,4-dioxobutanoic acids have been synthesized. These compounds, all of which contain lipophilic 4-substituents, are potent inhibitors in vitro of porcine liver glycolic acid oxidase. The I50 value of the two most potent representatives, 4-(4'-bromo[1,1'-biphenyl]-4-yl)-2, 4-dioxobutanoic acid (8) and 4-[4'-[[(3,4-dihydro-3-hydroxy-2H-1, 5-benzodioxepin-3-yl)methyl]thio][1,1'-biphenyl]-4-yl]-2, 4-dioxobutanoic acid (13) is 6 X 10(-8)M.
Regulation of tyrosinase in human melanocytes grown in culture. (1983)

Tyrosinase, the enzyme that controls the synthesis of melanin, is a unique product of melanocytes. Normal and malignant human melanocytes grown in culture were used to study the factors that regulate the expression of tyrosinase. Immunoprecipitation experiments showed that newly synthesized tyrosinase appeared as a protein with an apparent molecular weight of 70,000 that was processed to a protein with an apparent molecular weight of 80,000. Neither tunicamycin nor 2-deoxy-D-glucose inhibited this conversion, suggesting that O-glycosylation is the major biochemical event in the posttranslational modification of tyrosinase. Agents that stimulated the proliferation of normal melanocytes also stimulated tyrosinase activity. Melanocytes with low levels of tyrosinase activity synthesized less tyrosinase, processed the enzyme more slowly, and degraded it more rapidly than melanocytes with high levels of tyrosinase activity. We conclude that tyrosinase activity in cultures of human melanocytes derived from different donors is determined predominantly by its abundance.
mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants (2021)

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines <sup>1,2</sup> . These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known <sup>3-6</sup> . Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers <sup>3,5,6</sup> . Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection <sup>7,8</sup> . However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.
Science behind total androgen blockade: from gene to combination therapy. (1993)

Probably the most important finding in the endocrine therapy of prostate cancer is that the testicles and adrenals contribute approximately equal amounts of dihydrotestosterone (DHT), the active androgen that stimulates normal and cancerous prostatic cell growth and function. Structure of the cDNAs and genes encoding most of the enzymes responsible for the transformation of the adrenal precursor dehydroepiandrosterone (DHEA) into DHT have recently been elucidated, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, and 5 alpha-reductase. With the action of these enzymes, DHT is then made locally in the prostate from circulating DHEA of adrenal origin. Given such an important role of the adrenals, it is essential to use a pure antiandrogen for maximal blockade of the interaction of DHT with the androgen receptor while the testicles are blocked by orchiectomy or treatment with a luteinizing hormone-releasing hormone (LHRH) super-agonist. This combination therapy was first developed to treat advanced prostate cancer. The multicenter clinical data recently obtained confirm our original data and demonstrate the major importance of the intracrine or in situ formation of androgens in the human prostate from the inactive adrenal steroid precursors. Combination therapy thus permits, for the first time, to prolong life in advanced prostate cancer and, most importantly, offers the possibility of a major improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.
THE CATALYTIC MECHANISM AND STRUCTURE OF THYMIDYLATE SYNTHASE (1995)

Thymidylate synthase (TS, EC 2.1.1.45) catalyzes the reductive methylation of dUMP by CH2H4folate to produce dTMP and H2folate. Knowledge of the catalytic mechanism and structure of TS has increased substantially over recent years. Major advances were derived from crystal structures of TS bound to various ligands, the ability to overexpress TS in heterologous hosts, and the numerous mutants that have been prepared and analyzed. These advances, coupled with previous knowledge, have culminated in an in-depth understanding of many important molecular details of the reaction. We review aspects of TS catalysis that are most pertinent to understanding the current status of the structure and catalytic mechanism of the enzyme. Included is a discussion of available sources and assays for TS, a description of the enzyme's chemical mechanism and crystal structure, and a summary of data obtained from mutagenesis experiments.
Production of Green Fluorescent Protein Transgenic Embryonic Stem Cells Using the GENSAT Bacterial Artificial Chromosome Library (2006)

Transgenic green fluorescent protein (GFP) reporter embryonic stem (ES) cells are powerful tools for studying gene regulation and lineage choice during development. Here we present a rapid method for the generation of ES cells expressing GFP under the control of selected genes. Bacterial artificial chromosomes (BACs) from a previously constructed GFP transcriptional fusion library (Gene Expression Nervous System Atlas [GENSAT]) were modified for use in ES cells, and multiple BAC transgenic ES cell lines were generated. Specific GFP expression in transgenic cell lines was confirmed during neural differentiation marking neural stem cells, neuronal precursors, and glial progeny by Hes5, Dll1, and GFAP, respectively. GFP was dynamically regulated in ES cell progeny in response to soluble factors that inhibit Notch signaling and a factor that directs astroglial fate choice. Our protocols provide a simple and efficient strategy to utilize the whole GENSAT BAC library to create hundreds of novel fluorescent cell lines for use in ES cell biology.
Apoptosis modulators as cancer therapeutics. (2001)

In the past ten years a wealth of fundamental knowledge delineating the molecular mechanism(s) of apoptosis has emerged, and can now be exploited to identify novel apoptotic modulators for the treatment of cancer. Two distinct yet complimentary classes of non-genotoxic agonists that can selectively kill tumor cells are discussed; agents that target 'classical' and 'atypical' apoptotic signaling pathways. The goal of agents targeting classical apoptosis and survival pathways is to directly modulate key apoptotic regulators such as Bcl-2, Akt/PKB, and p53. The aim of agents targeting atypical apoptotic pathways is to target signaling cascades whose inhibition remains non-lethal in normal cells, yet is suicidal in tumor cells. Such compounds presently under development include inhibitors of heat shock protein 90, histone deacetylases and HMG-CoA reductase. Both classes of apoptotic modulators have merit and identification of additional agonists of this nature will provide the many diverse cytotoxic agents that are required to combat the many diseases we call cancer.
MALDI-TOF mass spectrometric typing of single nucleotide polymorphisms with mass-tagged ddNTPs (1998)

A matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based method has recently been reported for the typing of single nucleotide polymorphisms using single nucleotide primer extension. This method is limited in some cases by the resolution of the mass determination, as the mass difference between nucleotides can be as little as 9 Da (the difference between A and T). A variation of this method is described here in which a mass-tagged dideoxynucleotide is employed in the primer extension reactions in place of the unmodified dideoxynucleotide. The increased mass difference due to the presence of the mass-tags substantially improves the accuracy and versatility of the procedure.
Cutting Edge: Differential Fine-Tuning of IL-2– and IL-15–Dependent Functions by Targeting Their Common IL-2/15Rβ/γc Receptor (2017)

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/γ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15- and IL-2-dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2-dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.
Stab injury and device implantation within the brain results in inversely multiphasic neuroinflammatory and neurodegenerative responses (2012)

An estimated 25 million people in the US alone rely on implanted medical devices, ∼2.5 million implanted within the nervous system. Even though many devices perform adequately for years, the host response to medical devices often severely limits tissue integration and long-term performance. This host response is believed to be particularly limiting in the case of intracortical microelectrodes, where it has been shown that glial cell encapsulation and localized neuronal cell loss accompany intracortical microelectrode implantation. Since neuronal ensembles must be within ∼50 µm of the electrode to obtain neuronal spikes and local field potentials, developing a better understanding of the molecular and cellular environment at the device-tissue interface has been the subject of significant research. Unfortunately, immunohistochemical studies of scar maturation in correlation to device function have been inconclusive. Therefore, here we present a detailed quantitative study of the cellular events and the stability of the blood-brain barrier (BBB) following intracortical microelectrode implantation and cortical stab injury in a chronic survival model. We found two distinctly inverse multiphasic profiles for neuronal survival in device-implanted tissue compared to stab-injured animals. For chronically implanted animals, we observed a biphasic paradigm between blood-derived/trauma-induced and CNS-derived inflammatory markers driving neurodegeneration at the interface. In contrast, stab injured animals demonstrated a CNS-mediated neurodegenerative environment. Collectively these data provide valuable insight to the possibility of multiple roles of chronic neuroinflammatory events on BBB disruption and localized neurodegeneration, while also suggesting the importance to consider multiphasic neuroinflammatory kinetics in the design of therapeutic strategies for stabilizing neural interfaces.
Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region. (1987)

A human genomic phage library was screened using a human factor XII cDNA as a hybridization probe. Two overlapping phage clones were isolated which contain the entire human factor XII gene. DNA sequence and restriction enzyme analysis of the clones indicate that the gene is approximately 12 kilobase pairs in size and is comprised of 13 introns and 14 exons. Exons 3-14 are contained in a genomic region of only 4.2 kilobase pairs with introns ranging in size from 80 to 554 base pairs. The coding sequence of factor XII consists of multiple putative domains that are homologous to putative domains found in fibronectin and tissue-type plasminogen activator. These regions were found as separate exons in the gene. The intron/exon gene organization is similar to the serine protease gene family of plasminogen activators and not to the clotting factor family. Analysis of the 5' end of the gene shows that it does not contain the typical TATA and CAAT sequences found in other genes. This is consistent with the finding that transcription of the gene is initiated at multiple sites.
Breast Cancer (2001)

To identify genes involved in breast cancer, polymerase chain reaction-selected cDNA subtraction was utilized to construct a breast cancer-subtracted library. Differential screening of the library isolated the growth factor-inducible immediate-early gene Cyr61, a secreted, cysteine-rich, heparin binding protein that promotes endothelial cell adhesion, migration, and neovascularization. Northern analysis revealed that Cyr61 was expressed highly in the invasive breast cancer cell lines MDA-MB-231, T47D, and MDA-MB-157; very low levels were found in the less tumorigenic MCF-7 and BT-20 breast cancer cells and barely detectable amounts were expressed in the normal breast cells, MCF-12A. Univariate analysis showed a significant or borderline significant association between Cyr61 expression and stage, tumor size, lymph node positivity, age, and estrogen receptor levels. Interestingly, expression of Cyr61 mRNA increased 8- to 12-fold in MCF-12A and 3- to 5-fold in MCF-7 cells after 24- and 48-h exposure to estrogen, respectively. Induction of Cyr61 mRNA was blocked by tamoxifen and ICI182,780, inhibitors of the estrogen receptor. Stable expression of Cyr61 cDNA under the regulation of a constitutive promoter in MCF-7 cells enhanced anchorage-independent cell growth in soft agar and significantly increased tumorigenicity and vascularization of these tumors in nude mice. Moreover, overexpression of Cyr61 in MCF-12A normal breast cells induced their tumor formation and vascularization in nude mice. In summary, these results suggest that Cyr61 may play a role in the progression of breast cancer and may be involved in estrogen-mediated tumor development.
Process and content in semantic memory (2007)

Semantic content knowledge and ability to process that knowledge are both necessary. Theories of semantic memory have tended to focus on knowledge content. Semantic memory impairments in patients with neurodegenerative diseases, manifested in difficulties naming, recognizing, or describing objects, are well documented. Neurologically healthy individuals, including the elderly, are able to appropriately use similarity-or rule-based categorization, both in daily functioning and in controlled studies. This chapter details some work investigating semantic knowledge and semantic categorization processes. The novel animal categorization task was designed to separate content from process and to relate the findings to semantic memory. Processing matters and it may be that category-specific deficits arise because different categories are more or less conducive to particular categorization processes, which can be selectively compromised. Additionally, knowledge of the diagnostic status of features, as well as executive resources, appears to be a necessary component of rule-based processing.
Smart versus dumb antennas-capacities and FEC performance (2002)

We compare two approaches to use multiple transmit antennas in an FEC coded wireless system: smart antennas use an antenna array to direct a beam in the direction of the dominant transmission path in order to obtain an antenna gain. Another approach is to use multiple transmit antennas for diversity using space-time block codes. Since no knowledge of the channel is required at the transmitter we denote this approach as dumb antennas. Using equivalent single-input channel models we compare smart and dumb antennas in terms of the BER performance and channel capacity and discuss under which conditions it is preferable to use multiple transmit antennas for transmit diversity or for beamforming.
Similarities and differences in the currents activated by capsaicin, piperine, and zingerone in rat trigeminal ganglion cells (1996)

1. Capsaicin, piperine, and zingerone are natural pungent-tasting compounds found in chili pepper, black pepper, and ginger, respectively. These structurally related compounds evoke many of the same physiological responses, but at comparable concentrations capsaicin produces complete tachyphylaxis, piperine produces partial tachyphylaxis, and zingerone can either induce or not induce tachyphylaxis. Whole cell patch-clamp studies were performed on rat trigeminal ganglion cells to determine the similarities and differences between these three pungent compounds. 2. Capsaicin (1 microM) activated a variety of inward currents having peak times ranging from 2 to 46 s that desensitized to various extents ranging from 0 to 100%. The inward currents activated by zingerone (30 mM) had peak times of approximately 2 s and all currents exhibited marked desensitization. The inward currents activated by piperine (100 microM) had peak times of approximately 25 s and all exhibited a small desensitization. 3. Piperine- and zingerone-induced currents were found only in cells that could be activated by capsaicin. 4. Capsazepine (10 microM), an established antagonist of capsaicin-induced currents, inhibited the currents evoked by piperine and zingerone, suggesting that all three compounds activate vanilloid receptors. 5. Dose-response relationships for capsaicin, piperine, and zingerone obtained at a holding potential of -60 mV had threshold and apparent dissociation constants of 0.1 and 0.68 microM, 3 and 35 microM, and 1 and 15 mM, respectively. These values were consistent with those previously obtained in behavioral studies. 6. After seven 30-s applications of 1 microM capsaicin or 100 microM piperine (in a buffer with 2 mM Ca2+), each interspersed with 2-min, 50-s washes, the peak currents were inhibited by approximately 60 and 40%, respectively. In contrast, 30 mM zingerone failed to evoke a current after six applications. After complete tachyphylaxis produced by 30 mM zingerone, 1 microM capsaicin failed to evoke a current, suggesting that these two compounds cross desensitize. 7. The similar physiological responses produced by these three compounds can be rationalized by their binding to receptors and activating currents that can all be inhibited by capsazepine. Their different physiological responses evoked by these compounds can be rationalized, in part, by their very different activation and desensitization kinetics, and perhaps by the existence of different subtypes of vanilloid receptors.
Evidence for the presence of tissue factor activity on subendothelium (1989)

By a variety of methods, tissue factor activity was demonstrated in the subendothelium of rabbit aorta and human umbilical artery. In one method, everted segments of de-endothelialized vessels were mounted in an annular perfusion chamber and the subendothelial surface was exposed to nonanticoagulated human blood under controlled flow. Procoagulant activity was assessed by measuring fibrin deposition on subendothelium and fibrinopeptide A (FPA) levels in post chamber blood. Both fibrin deposition and FPA were decreased with rabbit vessel segments exposed (at a shear rate of 650 seconds-1) to blood from patients with factor VII deficiency and with umbilical artery segments (at shear rates of 90 to 180 seconds-1) that had been pretreated with a monoclonal antibody to human tissue factor. In a second method, everted umbilical artery segments were mounted on a stir bar and the subendothelial surface was exposed, with stirring, to plasma or purified coagulation factors. The capacity of the surface to clot plasma on addition of calcium was inhibited by the antibody to tissue factor. The surface also activated purified 3H-factor X in the presence of factor VIIa, but not in its absence, and this surface property was almost entirely eliminated by pretreating the vessel segments with antitissue factor. Tissue factor activity in subendothelium could play a role in both the arrest of bleeding and in promoting the formation of thrombi at sites of vascular injury.
Bringing Ideas to Life (2017)

This story originally appeared in IWU Magazine, Summer 2017.