gebhart/patrepeval huggingface dataset:
Recent progress in the discovery and development of cyclin-dependent kinase inhibitors (2005)

Cyclin-dependent kinases (CDKs) have long been known to be the main facilitators of the cell proliferation cycle. However, they also play important roles in the regulation of the RNA polymerase II transcription cycle. Cancer cells display aberrant cell cycle regulation to gain proliferative advantages and they also appear to have an exaggerated dependence on RNA polymerase II transcriptional activity to sustain pro-survival and antiapoptotic signalling. A picture is now starting to emerge that both the cell-cycle and transcriptional functions of CDKs can be exploited pharmacologically with CDK inhibitors that possess appropriate selectivity profiles. In this article, recent advances into these mechanistic insights and how they can guide clinical development in terms of choice of indication are reviewed, as well as combinations with existing chemotherapies. An overview is also given of recent clinical trial results with the lead CDK inhibitor drug candidates seliciclib (CYC202, (R)-roscovitine; Cyclacel) and alvocidib (flavopiridol; Aventis-NCI), as well as the development of other clinical entries and advanced preclinical compounds. The discussion focuses on oncology, but we point out recent results with CDK inhibitors in virology and nephrology.
Clostridium difficile infection: The scope of the problem (2012)

Clostridium difficile infection (CDI) is increasingly common, and it is associated with significant morbidity, mortality, and cost burden for patients and the healthcare system. The severity and rates of recurrent CDI and associated mortality are also increasing. This article is an overview of the changes in CDI epidemiology that have occurred since the turn of the century and the current scope of the problem. The 3 articles that follow in this supplement address the diagnosis and treatment of initial and recurrent CDI, and current practice guidelines for the prevention and control of CDI in the hospital setting.
Shuttling Gold Nanoparticles into Tumoral Cells with an Amphipathic Proline‐Rich Peptide (2009)

Cell-penetrating peptides (CPPs) are a potential tool for intracellular delivery of different kinds of cargoes. Because of their growing use in nanobiomedicine, both for diagnostics and for treatment, metal nanoparticles are an interesting cargo for CPPs. Here, gold nanoparticles (AuNps) and the amphipathic proline-rich peptide SAP have been used. Conjugation of the peptide onto the AuNps was achieved by addition of a cysteine to the SAP sequence for thiol chemisorption on gold, and the attachment was confirmed by visible spectroscopy, dynamic light scattering (DLS), zeta-potential (ZP), stability towards ionic strength (as high as 1 M NaCl), X-ray photoelectron spectroscopy (XPS) and high-resolution transmission electron microscopy (HR-TEM) coupled to electron energy loss spectroscopy (EELS). AuNp-C-SAP internalization in HeLa cells was observed by three different microscopy techniques-TEM, confocal laser scanning microscopy (CLSM) and transmission X-ray microscopy (TXM)-and all of them have confirmed the effective intracellular delivery of AuNps by SAP.
Evolutionary Protein Design (2001)

This is the first high-quality, comprehensive overview of the field of evolutionary protein design. Topics include new protein design strategies, the structures of laboratory-evolved proteins, the evolution of non-natural enzyme functions, and the theory of laboratory evolution.
Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus -Derived Proteinases (2004)

Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus, a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.
Kinetic Control of Histidine-Tagged Protein Surface Density on Supported Lipid Bilayers (2008)

Nickel-chelating lipids are general tools for anchoring polyhistidine-tagged proteins to supported lipid bilayers (SLBs), but controversy exists over the stability of the protein-lipid attachment. Here, we show that chelator lipids are suitable anchors for building stable, biologically active surfaces but that a simple Langmuirian model is insufficient to describe their behavior. Desorption kinetics from chelator lipids are governed by the valency of surface binding: monovalently bound proteins desorb within minutes (t1/2 approximately 6 min), whereas polyvalently bound species remain bound for hours (t1/2 approximately 12 h). Evolution between surface states is slow, so equilibrium is unlikely to be reached on experimental timescales. However, by tuning incubation conditions, the populations of each species can be kinetically controlled, providing a wide range of protein densities on SLBs with a single concentration of chelator lipid. We propose guidelines for the assembly of SLB surfaces functionalized with specific protein densities and demonstrate their utility in the formation of hybrid immunological synapses.
Refractory and metastatic infantile fibrosarcoma harboring LMNA–NTRK1 fusion shows complete and durable response to crizotinib (2019)

Infantile fibrosarcoma (IFS) is a rare soft-tissue sarcoma, which classically presents as an aggressive and rapidly enlarging tumor over the distal extremities of children in their first year of life. The presence of ETV6 and NTRK3 gene rearrangement is characteristic of IFS, which can be detected on routine fluorescence in situ hybridization (FISH) testing. Patients with IFS typically respond well to surgical resection and chemotherapy and have an overall survival of ∼90%. In this report, we outline the use of integrative clinical sequencing (ICS) including RNA-seq in a patient with refractory, metastatic IFS to reveal an unusual fusion ( LMNA–NTRK1 ), not detected by routine FISH testing, which was treated with oral crizotinib and resulted in a complete and durable long-term response. This study highlights the utility of ICS in identifying cryptic gene fusions, especially in refractory malignancies, and demonstrates how such information can be used to select targeted therapies in patients with actionable molecular alterations.
Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways (2011)

Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27⁻IgG⁺ and CD27⁺IgM⁺ B cells are derived from primary germinal center reactions, and CD27⁺IgA⁺ and CD27⁺IgG⁺ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27⁻IgA⁺ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27⁻IgA⁺ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.
Monitoring during cardiac arrest: are we there yet? (2003)

Advancements in electronic data acquisition have translated into improved monitoring of victims of cardiac arrest, but initial techniques remain direct observation of pulses and respirations. The most essential monitor continues to be the electrocardiogram. However, monitoring diastolic blood pressure, myocardial perfusion pressure, and end-tidal carbon dioxide are extremely useful. Most of the current research on monitoring during cardiopulmonary resuscitation focuses on methods for analyzing ventricular fibrillation waveforms. By analyzing the waveform, defibrillation shocks may be delivered at the time when the chance of success is optimal. Low-amplitude and low-frequency fibrillation waveforms are associated with increased rates of asystole and pulseless electrical activity after defibrillation. Methods of analyzing the ventricular fibrillation waveform include measuring the amplitude and frequency and combining the contributions of amplitude and frequency by various methods to improve discrimination. Other types of monitoring being studied for their usefulness during cardiac arrests include sonography, Bispectral Index monitoring, tissue carbon dioxide monitors, and pupil observation. The test of these monitoring techniques is ultimately their ability to improve patient survival to hospital discharge, which is a major challenge for resuscitation researchers.
Designed to be stable: Crystal structure of a consensus ankyrin repeat protein (2003)

Ankyrin repeat (AR) proteins mediate innumerable protein-protein interactions in virtually all phyla. This finding suggested the use of AR proteins as designed binding molecules. Based on sequence and structural analyses, we designed a consensus AR with fixed framework and randomized interacting residues. We generated several combinatorial libraries of AR proteins consisting of defined numbers of this repeat. Randomly chosen library members are expressed in soluble form in the cytoplasm of Escherichia coli constituting up to 30% of total cellular protein and show high thermodynamic stability. We determined the crystal structure of one of those library members to 2.0-A resolution, providing insight into the consensus AR fold. Besides the highly complementary hydrophobic repeat-repeat interfaces and the absence of structural irregularities in the consensus AR protein, the regular and extended hydrogen bond networks in the beta-turn and loop regions are noteworthy. Furthermore, all residues found in the turn region of the Ramachandran plot are glycines. Many of these features also occur in natural AR proteins, but not in this rigorous and standardized fashion. We conclude that the AR domain fold is an intrinsically very stable and well-expressed scaffold, able to display randomized interacting residues. This scaffold represents an excellent basis for the design of novel binding molecules.
A single amino acid substitution in the A subunit of Escherichia coli enterotoxin results in a loss of its toxic activity. (1990)

A plasmid encoding a mutant gene of heat-labile enterotoxin (LT), produced by enterotoxigenic Escherichia coli, was induced by treatment of plasmid EWD 299 with hydroxylamine. A mutant strain of E. coli HB 101 carrying the mutant plasmid pTUH 6A produced a low toxic LT analogue (mutant LT), which was cross-reactive with anti-LT antibody. The mutant LT activity was less than 0.15 and 0.006% of the normal LT in the rabbit ileal loop test and in the rabbit skin permeability test, respectively. The amino acid composition of the mutant LT-B subunit was the same as that of the normal B subunit. Though the A2 fragment of the mutant LT was identical to normal LT by DNA analysis, the A1 fragment of the mutant LT differed from the normal A1 fragment in one amino acid at position 112; namely it had lysine instead of glutamic acid from the N terminus. These data suggest that glutamic acid at position 112 from the N terminus of the A1 fragment is important for the A subunit to express its biological activity.
Differences in the immune responses of mice and sheep to an aromatic-dependent mutant of Salmonella typhimurium (1994)

A live mutant aroA Salmonella serotype Typhimurium ovine strain (S25/1) could be cultured from tissues of mice for up to 90 days after oral infection. Following vaccination, high levels of Salmonella-specific serum IgM, IgG and IgA were produced in addition to high levels of specific intestinal IgA. Moreover, there was also evidence of Salmonella-specific cell-mediated immunity in vaccinated mice in the form of strong delayed-type hypersensitivity and the production of interferon-gamma (IFN-tau) by spleen cells stimulated with Salmonella antigen. The aroA strain was also recovered from the mesenteric lymph nodes and most tissues examined from sheep vaccinated by the oral route. Salmonella-specific IgM was detected in the serum; however, specific IgG responses were very low and there was an absence of specific copro-antibody. Although strong Salmonella-specific lymphocyte proliferative responses were detected, they did not result in the production of IFN-tau and flow cytometric analysis revealed that the proliferating cells were predominantly B lymphocytes. Despite the absence of strong vaccine-specific immune responses in vaccinated sheep compared with those seen in mice, both mice and sheep were protected against challenge with virulent wild-type strain S25/1.
Large electrical currents traverse developing Ceropia follicles (1979)

An intense (up to 20 muA/cm(2)) steady electrical current enters the anterior or nurse cell end of the growing follicle (or oocyte-nurse cell complex) of the Cecropia moth and is balanced by a more diffuse current leaving elsewhere. In late growth stages, the total transfollicular current is about 100 nA. Moreover, a separate small current, of about 1 nA, seems to leave the furrow between the oocyte and the nurse cells. After the nurse cells collapse, but before shell formation, the transfollicular current is redistributed so that a second relatively localized inward current appears at the posterior pole of the follicle. Thus, at this later stage currents enter both poles of the follicle and leave its sides. Previous measurements, with intracellular microelectrodes, seem to imply a very large (order of 1000 nA) back current across the cytoplasmic bridge between the oocyte and nurse cells. A simple model is presented that attributes the apparent bridge current, and the more directly measured transfollicular and furrow currents, to the action of an ion pump lying within the nurse cell face of the furrow membrane.
A new rate control scheme using quadratic rate distortion model (1997)

A new rate control scheme is used to calculate the target bit rate for each frame based on a quadratic formulation of the rate distortion function. The distortion measure is assumed to be the average quantization scale of a frame. The rate distortion function is modeled as a second-order function of the inverse of the distortion measure. We present a closed form solution for the target bit allocation which includes the MPEG-2 TM5 rate control scheme as a special case. The model parameters are estimated using statistical linear regression analysis. Since the estimation uses the past encoded frames of the same picture prediction type (I, P, B pictures), the proposed approach is a single pass rate control technique. Because of the improved accuracy of the rate distortion function, the fluctuations of the bit counts are significantly reduced by 20-65% in the standard deviation of the bit count while the picture quality remains the same. Thus, the buffer requirement is reduced at a small increase in complexity. This technique has been adopted by the MPEG committee as part of VM5.0 in November 1996.
Characterization of exoplanets from their formation II. The planetary mass-radius relationship (2012)

The research of exoplanets has entered an era in which we characterize extrasolar planets. This has become possible with measurements of radii and luminosities. Meanwhile, radial velocity surveys discover also very low-mass planets. Uniting all this observational data into one coherent picture to better understand planet formation is an important, but difficult undertaking. Our approach is to develop a model which can make testable predictions for all these observational methods. We continue to describe how we have extended our formation model into a self-consistently coupled formation and evolution model. We show how we calculate the internal structure of the solid core and radiogenic heating. We also improve the protoplanetary disk model. Finally, we conduct population synthesis calculations. We present how the planetary mass-radius relationship of planets with primordial H/He envelopes forms and evolves in time. The basic shape of the M-R relation can be understood from the core accretion model. Low-mass planets cannot bind massive envelopes, while super-critical cores necessarily trigger runway gas accretion, leading to "forbidden" zones in the M-R plane. For a given mass, there is a considerable diversity of radii. We compare the synthetic M-R relation with the observed one, finding good agreement for a&gt;0.1 AU. The synthetic radius distribution is characterized by a strong increase towards small R, and a second, lower local maximum at ~1 Jovian radius. The increase towards small radii reflects the increase of the mass function towards low M. The second local maximum is due to the fact that radii are nearly independent of mass for giant planets. A comparison of the synthetic radius distribution with Kepler data shows agreement for R&gt;2 Earth radii, but divergence for smaller radii. We predict that in the next few years, Kepler should find the second, local maximum at ~1 Jovian radius.
Proximity-induced activation of human Cdc34 through heterologous dimerization (2005)

Cdc34 is an E2-conjugating enzyme required for catalyzing the polyubiquitination reaction mediated by the Skp1.CUL1.F-box (SCF) protein E3 ubiquitin (Ub) ligase. Here, we show that the activity of human Cdc34 in the Ub-Ub ligation reaction was enhanced dramatically by SCF's core Ub ligase module, composed of a heterodimeric complex formed by the ROC1 RING finger protein and the CUL1 C terminus that contains a Nedd8 moiety covalently conjugated at K720. Unexpectedly, we found that N-terminal fusion of a GST moiety to human Cdc34 generated dimeric GST-Cdc34 that was constitutively active in supporting the assembly of K48-linked polyUb chains independently of SCF. Furthermore, fusion of a FK506-binding protein (FKBP) to the N terminus of human Cdc34 yielded FKBP-Cdc34 that was induced to form a dimer upon treatment with the chemical inducer AP20187. The AP20187-induced dimeric form of FKBP-Cdc34 was substantially more active than the monomer in catalyzing Ub-Ub ligation. Thus, juxtaposition of human Cdc34 activates its catalytic capability, suggesting that the SCF-mediated polyubiquitination reaction may require the conversion of Cdc34 from an inactive monomer to a highly active dimeric form.
Cloning, sequencing, and expression of the fadD gene of Escherichia coli encoding acyl coenzyme A synthetase. (1992)

In the enteric bacterium, Escherichia coli, acyl coenzyme A synthetase (fatty acid:CoA ligase (AMP-forming) EC 6.2.1.3) activates exogenous long-chain fatty acids concomitant with their transport across the inner membrane into metabolically active CoA thioesters. These compounds serve as substrates for acyl-CoA dehydrogenase in the first step in the process of beta-oxidation. The acyl-CoA synthetase structural gene, fadD, has been identified on clone 6D1 of the Kohara E. coli gene library and by a process of subcloning and complementation analyses shown to be contained on a 2.2-kilobase NcoI-ClaI fragment of genomic DNA. The polypeptide encoded within this DNA fragment was identified following T7 RNA polymerase-dependent induction and estimated to be M(r) = 62,000 using SDS-polyacrylamide gel electrophoresis. The N-terminal amino acid sequence of acyl-CoA synthetase was determined by automated sequencing to be Met-Lys-Lys-Val-Trp-Leu-Asn-Arg-Tyr-Pro. Sequence analysis of the 2.2-kilobase NcoI-ClaI fragment revealed a single open reading frame encoding these amino acids as the first 10 residues of a protein with a molecular weight of 62,028. The initiation codon for methionine was TTG. Primer extension of total in vivo mRNA from two fadD-specific oligonucleotides defined the transcriptional start at an adenine residue 60 base pairs upstream from the predicted translational start site. Two FadR operator sites of the fadD gene were identified at positions -13 to -29 (OD1) and positions -99 to -115 (OD2) by DNase I footprinting. Comparisons of the predicted amino acid sequence of the E. coli acyl-CoA synthetase to the deduced amino acid sequences of the rat and yeast acyl-CoA synthetases and the firefly luciferase demonstrated that these enzymes shared a significant degree of similarity. Based on the similar reaction mechanisms of these four enzymes, this similarity may define a region required for the same function.
Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia (2007)

The IL-12 family of cytokines, which include IL-12, IL-23, and IL-27, play critical roles in the differentiation of Th1 cells and are believed to contribute to the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Relatively little is known concerning the expression of IL-12 family cytokines by cells of the CNS, the affected tissue in MS. Previously, we and others demonstrated that peroxisome proliferator-activated receptor (PPAR)-gamma agonists suppress the development of EAE, alter T cell proliferation and phenotype, and suppress the activation of APCs. The present studies demonstrated that PPAR-gamma agonists, including the naturally occurring 15-deoxy-Delta(12,14)-PGJ(2) and the synthetic thiazoladinedione rosiglitazone, inhibited the induction of IL-12p40, IL-12p70 (p35/p40), IL-23 (p19/p40), and IL-27p28 proteins by LPS-stimulated primary microglia. In primary astrocytes, LPS induced the production of IL-12p40, IL-23, and IL-27p28 proteins. However, IL-12p70 production was not detected in these cells. The 15-deoxy-Delta(12,14)-PGJ(2) potently suppressed IL-12p40, IL-23, and IL-27p28 production by primary astrocytes, whereas rosiglitazone suppressed IL-23 and IL-27p28, but not IL-12p40 in these cells. These novel observations suggest that PPAR-gamma agonists modulate the development of EAE, at least in part, by inhibiting the production of IL-12 family cytokines by CNS glia. In addition, we demonstrate that PPAR-gamma agonists inhibit TLR2, MyD88, and CD14 expression in glia, suggesting a possible mechanism by which these agonists modulate IL-12 family cytokine expression. Collectively, these studies suggest that PPAR-gamma agonists may be beneficial in the treatment of MS.