gebhart/patrepeval huggingface dataset:
Design of “Smart” polymers that can direct intracellular drug delivery (2002)

Abstract One of the important characteristics of biological systems is their ability to change important properties in response to small environmental signals. The molecular mechanisms that biological molecules utilize to sense and respond provide interesting models for the development of “smart” polymeric biomaterials with biomimetic properties. An important example of this is the protein coat of viruses, which contains peptide units that facilitate the trafficking of the virus into the cell via endocytosis, followed by delivery of the genetic material out of the endosome into the cytoplasm, and from there into the nucleus. We have designed several new types of synthetic polymers to facilitate intracellular trafficking of drugs. One of these has been designed to mimic the specific peptides on viral coats that facilitate endosomal escape. Another has been designed to contain pH‐degradable bonds, facilitating endosomal escape of the drug only after the bonds are degraded at the acidic pHs of the endosomes. Both types of polymer are responsive to the lowered pH within endosomes, leading to disruption of the endosomal membrane and release of important biomolecular drugs such as DNA, RNA, peptides and proteins to the cytoplasm before they are trafficked to lysosomes and degraded by lysosomal enzymes. In this article, we review our work on the design, synthesis and action of such smart, pH‐sensitive polymers. Copyright © 2003 John Wiley &amp; Sons, Ltd.
Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion (1999)

Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation and injury from reperfusion. To elucidate components controlling PMNs in vivo, we prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR) for functional characterization. Overexpression of BLTR in leukocytes dramatically increased PMN trafficking to skin microabscesses and lungs after ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and LT biosynthesis are critical for PMN infiltration in reperfusion-initiated second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was produced in ischemic lungs and elevated by reperfusion. Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice. Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation. These results demonstrate a direct role for BLTR with positive feedback, involving BLTR and 5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine.
Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8-deficient mice (1998)

Mice deficient for the homeotic gene Hoxc-8 suffer from a congenital prehension deficiency of the forepaw. During embryogenesis, Hoxc-8 is highly expressed in motoneurons within spinal cord segments C7 to T1. These motoneurons innervate forelimb distal muscles that move the forepaw. In Hoxc-8 mutant embryos, formation of these muscles is normal, but their innervation is perturbed. From E13.5 onwards, distal muscles normally supplied by C(7-8) MNs also receive ectopic projections from C(5-6) and T1 motoneurons. Coordinates of motor pools are altered along the rostrocaudal and also the mediolateral axes. Following this aberrant connectivity pattern and during the time of naturally occurring cell death, apoptosis is specifically enhanced in C7-T1 motoneurons. Loss of Hox-encoded regional specifications subsequently leads to a numerical deficit of motoneurons and an irreversible disorganization of motor pools. In Hoxc-8 null mutants, C(7-8) motoneurons lose their selective advantage in growth cone pathfinding behavior and/or target recognition, two essential steps in the establishment and maintenance of a functional nervous system.
Carfilzomib-Dependent Selective Inhibition of the Chymotrypsin-like Activity of the Proteasome Leads to Antitumor Activity in Waldenstrom's Macroglobulinemia (2011)

These findings suggest that targeting i20S and c20S CT-L activity by carfilzomib represents a valid antitumor strategy in WM and other IgM-secreting lymphomas.
An Intricate Dance: Life Experience, Multisystem Resiliency, and Rate of Telomere Decline Throughout the Lifespan (2012)

Abstract Accumulation of life stressors predicts accelerated development and progression of diseases of aging. Telomere length, the DNA‐based biomarker indicating cellular aging, is a mechanism of disease development, and is shortened in a dose response fashion by duration and severity of life stressor exposures. Telomere length captures the interplay between genetics, life experiences and psychosocial and behavioral factors. Over the past several years, psychological stress resilience, healthy lifestyle factors, and social connections have been associated with longer telomere length and it appears that these factors can protect individuals from stress‐induced telomere shortening. In the current review, we highlight these findings, and illustrate that combining these ‘multisystem resiliency’ factors may strengthen our understanding of aging, as these powerful factors are often neglected in studies of aging. In naturalistic studies, the effects of chronic stress exposure on biological pathways are rarely main effects, but rather a complex interplay between adversity and resiliency factors. We suggest that chronic stress effects can be best understood by directly testing if the deleterious effects of stress on biological aging processes, in this case the cell allostasis measure of telomere shortening, are mitigated in individuals with high levels of multisystem resiliency. Without attending to such interactions, stress effects are often masked and missed. Taking account of the cluster of positive buffering factors that operate across the lifespan will take us a step further in understanding healthy aging. While these ideas are applied to the telomere length literature for illustration, the concept of multisystem resiliency might apply to aging broadly, from cellular to systemic health.
Release, relocate, reorient, resize (2004)

Group work frequently involves transitions between periods of active collaboration and periods of individual activity. We aim to support this typical work practice by introducing four tabletop direct-manipulation interaction techniques that can be used to transition the status of an electronic document from private to group-accessible. After presenting our four techniques - release, relocate, reorient, and resize - we discuss the results of an empirical study that compares and evaluates these mechanisms for sharing documents in a co-located tabletop environment.
Spontaneous decarboxylation of oxalacetic acid (1967)

The kinetic study at different pH values indicates that the monoanion of oxalacetic acid is the major active species which decarboxylates spontaneously. The decarboxylation of the monoanion is favored by nonpolar solvents. Solvent and isotopic effects suggest that the reaction may proceed via an intramolecular hydrogen-bonded intermediate as an activated complex. Infrared spectra which show the formation of an intramolecular hydrogen bond of oxalacetate in solution are obtained. A plausible mechanism consistent with experimental results is proposed for the spontaneous decarboxylation of oxalacetic acid.
DNA-nanotube-induced alignment of membrane proteins for NMR structure determination (2007)

Membrane proteins are encoded by 20-35% of genes but represent <1% of known protein structures to date. Thus, improved methods for membrane-protein structure determination are of critical importance. Residual dipolar couplings (RDCs), commonly measured for biological macromolecules weakly aligned by liquid-crystalline media, are important global angular restraints for NMR structure determination. For alpha-helical membrane proteins >15 kDa in size, Nuclear-Overhauser effect-derived distance restraints are difficult to obtain, and RDCs could serve as the main reliable source of NMR structural information. In many of these cases, RDCs would enable full structure determination that otherwise would be impossible. However, none of the existing liquid-crystalline media used to align water-soluble proteins are compatible with the detergents required to solubilize membrane proteins. We report the design and construction of a detergent-resistant liquid crystal of 0.8-microm-long DNA-nanotubes that can be used to induce weak alignment of membrane proteins. The nanotubes are heterodimers of 0.4-microm-long six-helix bundles each self-assembled from a 7.3-kb scaffold strand and >170 short oligonucleotide staple strands. We show that the DNA-nanotube liquid crystal enables the accurate measurement of backbone N(H) and C(alpha)H(alpha) RDCs for the detergent-reconstituted zeta-zeta transmembrane domain of the T cell receptor. The measured RDCs validate the high-resolution structure of this transmembrane dimer. We anticipate that this medium will extend the advantages of weak alignment to NMR structure determination of a broad range of detergent-solubilized membrane proteins.
Low-threshold synchronously pumped all-fiber ring Raman laser (1987)

Experimental results on a synchronously pumped, all single-mode fiber Raman laser with a low threshold of 740 mW are reported. Suppression of gain fluctuations due to pump phase noise has been achieved by implementing a fiber coupler of high multiplexing effect. Multistokes generation of low-noise optical pulse trains at <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">\lambda = 1.12 \mu</tex> m and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">\lambda = 1.18 \mu</tex> m has also been obtained with a subwatt pump threshold.
Characterization of Osf1, an Osteoblast-specific Transcription Factor Binding to a Critical cis-acting Element in the MouseOsteocalcin Promoters (1999)

To elucidate the mechanisms of osteoblast-specific gene expression we are studying the regulation of osteocalcin, the most osteoblast-specific gene. Previous studies of OG2, one of the two mouse osteocalcin genes, identified two osteoblast-specific cis-acting elements, OSE1 and OSE2, the latter being the binding site of Cbfa1, the only osteoblast-specific transcription factor known to date. Here we show that OSE1 is a cis-acting element as important as OSE2 for the osteoblast-specific expression of OG2 in cell culture and transgenic mice. We also show that OSE1 is present in the promoter of several osteoblast-specific genes including Cbfa1 itself. These biological features demonstrate the importance of OSE1 and led us to further characterize this site and the factor binding to it, provisionally termed Osf1. We first defined the core OSE1 sequence, 5'-TTACATCA-3', which is necessary and sufficient for Osf1 binding to DNA. This sequence has no strong homology to any known transcription factor-binding sites. As a first step in identifying Osf1, we performed an analytical purification of this protein using nuclear extracts from two different osteoblastic cell lines. We purified Osf1 to homogeneity through a five-step procedure including a renaturation experiment and found that its apparent molecular mass is 40 kDa. In conclusion, this study indicates the existence of multiple osteoblast-specific cis-acting elements of equal importance in controlling OG2 promoter activity and provides the first biochemical characterization of Osf1, a novel osteoblast-specific transcription factor.
Proton nuclear magnetic resonance studies of the interaction of the lanthanide ions ytterbium and lutetium with apo- and calcium-saturated porcine intestinal calcium binding protein (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProton nuclear magnetic resonance studies of the interaction of the lanthanide ions ytterbium and lutetium with apo- and calcium-saturated porcine intestinal calcium binding proteinJudith G. Shelling, Theo Hofmann, and Brian D. SykesCite this: Biochemistry 1985, 24, 9, 2332–2338Publication Date (Print):April 1, 1985Publication History Published online1 May 2002Published inissue 1 April 1985https://pubs.acs.org/doi/10.1021/bi00330a031https://doi.org/10.1021/bi00330a031research-articleACS PublicationsRequest reuse permissionsArticle Views40Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Fragment Complementation Studies of Protein Stabilization by Hydrophobic Core Residues (2001)

Interactions that stabilize the native state of a protein have been studied by measuring the affinity between subdomain fragments with and without site-specific residue substitutions. A calbindin D(9k) variant with a single CNBr cleavage site at position 43 between its two EF-hand subdomains was used as a starting point for the study. Into this variant were introduced 11 site-specific substitutions involving hydrophobic core residues at the interface between the two EF-hands. The mutants were cleaved with CNBr to produce wild-type and mutated single-EF-hand fragments: EF1 (residues 1--43) and EF2 (residues 44--75). The interaction between the two EF-hands was studied using surface plasmon resonance (SPR) technology, which follows the rates of association and dissociation of the complex. Wild-type EF1 was immobilized on a dextran matrix, and the wild-type and mutated versions of EF2 were injected at several different concentrations. In another set of experiments, wild-type EF2 was immobilized and wild-type or mutant EF1 was injected. Dissociation rate constants ranged between 1.1 x 10(-5) and 1.0 x 10(-2) s(-1) and the association rate constants between 2 x 10(5) and 4.0 x 10(6) M(-1) s(-1). The affinity between EF1 and EF2 was as high as 3.6 x 10(11) M(-1) when none of them was mutated. For the 11 hydrophobic core mutants, a strong correlation (r = 0.999) was found between the affinity of EF1 for EF2 and the stability toward denaturation of the corresponding intact protein. The observed correlation implies that the factors governing the stability of the intact protein also contribute to the affinity of the bimolecular EF1-EF2 complex. In addition, the data presented here show that interactions among hydrophobic core residues are major contributors both to the affinity between the two EF-hand subdomains and to the stability of the intact domain.
Activated Langerhans Cells Release Tumor Necrosis Factor (1989)

Langerhans cells act as antigen-presenting cells in immune reactions in the skin. What other roles they may play in inflammation is less well defined. We have tested whether these cells can produce TNF-alpha, an important mediator of inflammation. Resting Langerhans cells produce less than 0.1 U TNF-alpha/ml. Langerhans cells stimulated with phorbol myristate acetate (PMA) and lipopolysaccharide (LPS) release 4-5 U TNF-alpha/ml. Specificity of the released TNF-alpha in an L929 cytotoxicity assay was confirmed by using neutralizing anti-TNF-alpha monoclonal antibodies, and the identity of TNF-alpha was further confirmed by Northern blot hybridization with an TNF-alpha oligomer DNA probe. Activated Langerhans cells may contribute to inflammation in the skin by releasing TNF-alpha, which is known to effect fibroblast growth, endothelial cell activation, and lymphocyte function.
Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: Incidence and risk factors* (2003)

ISLs are a common complication during continuous AVP infusion in patients with catecholamine-resistant vasodilatory shock. The presence of septic shock and a history of peripheral arterial occlusive disease are independent risk factors for the development of ISL.
Halophiles (2002)

Abstract Halophiles are salt‐loving organisms that inhabit hypersaline environments. They include mainly prokaryotic and eukaryotic microorganisms with the capacity to balance the osmotic pressure of the environment and resist the denaturing effects of salts.
Human Cytomegalovirus (HCMV) Infection of Endothelial Cells Promotes Naive Monocyte Extravasation and Transfer of Productive Virus To Enhance Hematogenous Dissemination of HCMV (2006)

Human cytomegalovirus (HCMV) pathogenesis is dependent on the hematogenous spread of the virus to host tissue. While data suggest that infected monocytes are required for viral dissemination from the blood to the host organs, infected endothelial cells are also thought to contribute to this key step in viral pathogenesis. We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions. Together, our results provide evidence for an active role of the infected endothelium in HCMV dissemination and pathogenesis.
Abstract 615: PP2A activation as a strategy for treatment of breast cancer (2011)

Abstract Background: Cells respond to stimuli by activating kinase signaling cascades that are counterbalanced by specific phosphatases so that the cell can return to a resting state. PP2A is a critical cellular phosphatase that negatively regulates multiple kinase cascades and displays strong tumor suppressor activity (Westermarck and Hahn, Trends Mol Med, 2008, 14:152-60). Inhibition of PP2A is essential for cell transformation and tumorigenesis (Chen et al., Cancer Cell, 2004, 5:127-36) and several physiological PP2A inhibitory proteins have been described. The oncoprotein SET is a potent inhibitor of PP2A that is overexpressed in cancer. We found that SET is overexpressed in 55-60% of primary breast cancer samples and identified peptides that antagonize SET, activate PP2A, reduce phosphorylation of oncoproteins, and inhibit xenograft tumor growth. Methods: Primary breast cancer samples and matched normal adjacent tissue were evaluated for overexpression of SET using qPCR, immunofluorescence staining, and Western blotting. Cytotoxicity of PP2A activation in breast cancer cell lines was assessed using the MTT assay. PP2A activity was measured using an immunprecipitation assay and cellular correlates of dephosphorylation were measured by Western blotting. Tumors in NOD/SCID mice with human breast cancer cell lines implanted into the mammary fat pad were treated with SET antagonist or a vehicle control by subcutaneous injection. Results: Assessment of SET expression was analyzed by qPCR from breast cancer samples and normal adjacent tissues. We observed greater than 3-fold increased expression of SET in 11 of 19 patients. We also observed SET overexpression in 7 of 13 triple negative breast cancer samples in a commercially available breast cancer cDNA array. SET overexpression was confirmed in breast cancer cell lines by qPCR and Western blotting. Antagonism of SET using COG449 inhibited growth of several cell lines arising from activation of PP2A. Activation of PP2A with COG449 reduced S62 phosphorylation of c-Myc and other known PP2A targets. Finally, subcutaneous treatment with 10 mg/kg COG449 significantly inhibited growth of xenografted tumors in the mammary fat pad of NOD/SCID mice. Importantly, in vivo studies in normal mice using COG449 shows no toxicity even at doses of 100 mg/kg. Conclusions: We demonstrated SET overexpression in breast cancer samples and that SET antagonism with COG449 activated PP2A. This results in cytotoxicity in breast cancer cells in vitro and reduced phosphorylation of c-Myc S62 and other PP2A targets. PP2A activation by SET antagonism inhibited tumor growth in xenograft models at concentrations that are nontoxic in normal mice to demonstrate that PP2A activation is a novel approach to breast cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 615. doi:10.1158/1538-7445.AM2011-615
Naturally Occurring Dicistronic Cricket Paralysis Virus RNA Is Regulated by Two Internal Ribosome Entry Sites (2000)

Cricket paralysis virus is a member of a group of insect picorna-like viruses. Cloning and sequencing of the single plus-strand RNA genome revealed the presence of two nonoverlapping open reading frames, ORF1 and ORF2, that encode the nonstructural and structural proteins, respectively. We show that each ORF is preceded by one internal ribosome entry site (IRES). The intergenic IRES is located 6,024 nucleotides from the 5' end of the viral RNA and is more active than the IRES located at the 5' end of the RNA, providing a mechanistic explanation for the increased abundance of structural proteins relative to nonstructural proteins in infected cells. Mutational analysis of this intergenic-region IRES revealed that ORF2 begins with a noncognate CCU triplet. Complementarity of this CCU triplet with sequences in the IRES is important for IRES function, pointing to an involvement of RNA-RNA interactions in translation initiation. Thus, the cricket paralysis virus genome is an example of a naturally occurring, functionally dicistronic eukaryotic mRNA whose translation is controlled by two IRES elements located at the 5' end and in the middle of the mRNA. This finding argues that eukaryotic mRNAs can express multiple proteins not only by polyprotein processing, reinitiation and frameshifting but also by using multiple IRES elements.