gebhart/patrepeval huggingface dataset:
Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts (2001)

Osteoblast development is a complex process involving the expression of specific growth factors and regulatory proteins that control cell proliferation, differentiation, and maturation. In this study, we used the rat mutation, osteopetrosis (op), to examine differences in skeletal gene expression between mutant op and normal littermates. Total RNA isolated from long bone and calvaria was used as a template for mRNA differential display. One of many cDNAs that were selectively expressed in either normal or mutant bone was cloned and sequenced and found to share some homology to the human nmb and Pmel 17 genes. This novel cDNA was named osteoactivin. Osteoactivin has an open reading frame of 1716 bp that encodes a protein of 572 amino acids with a predicted molecular weight of 63.8 kD. Protein sequence analysis revealed the presence of a signal peptide and a cleavage site at position 23. The protein also has thirteen predicted N-linked glycosylation sites and a potential RGD integrin recognition site at position 556. Northern blot analysis confirmed that osteoactivin was 3- to 4-fold overexpressed in op versus normal bone. RT-PCR analysis showed that osteoactivin is most highly expressed in bone compared with any of the other non-osseous tissues examined. In situ hybridization analysis of osteoactivin in normal bone revealed that it is primarily expressed in osteoblasts actively engaged in bone matrix production and mineralization. In primary rat osteoblast cultures, osteoactivin showed a temporal pattern of expression being expressed at highest levels during the later stages of matrix maturation and mineralization and correlated with the expression of alkaline phosphatase and osteocalcin. Our findings show that osteoactivin expression in bone is osteoblast-specific and suggest that it may play an important role in osteoblast differentiation and matrix mineralization. Furthermore, osteoactivin overexpression in op mutant bone may be secondary to the uncoupling of bone resorption and formation resulting in abnormalities in osteoblast gene expression and function.
Abstract 618: Role of multidrug resistance transporters in the biological response to trastuzumab-cytotoxic drug conjugates (2010)

Abstract Trastuzumab-DM1 (T-DM1, TMAb-mcc-DM1, trastuzumab emtansine) is an antibody-cytotoxic drug conjugate that is composed of the maytansine derivative DM1 directly coupled, via a thioether SMCC linker, to trastuzumab. T-DM1 is currently undergoing clinical evaluation in metastatic HER2-positive breast cancer patients. T-DM1 has been shown to retain all of the mechanisms of action of trastuzumab and to deliver DM1 to HER2-overexpressing tumor cells. In the present study, we investigated potential mechanisms of resistance to T-DM1 and other trastuzumab conjugates, including a different class of anti-microtubule drugs, the auristatins (MMAE and MMAF). Expression of selected multi-drug resistance (MDR) transporters MDR1, MRP1, MRP3 and BCRP was determined by qRT-PCR (Taqman). MDR1 was expressed at moderate levels by only one line, while expression of MRP3 occurred in several HER2-overexpressing cell lines. Cell viability assays with either free drugs (DM1 or MMAE) or the respective trastuzumab conjugates showed that all lines were sensitive to treatment with these agents. The NCI-AdrRes line, which expresses high levels of MDR1, was transfected to overexpress HER2 and used as a positive control. This line was resistant to treatment with DM1 or MMAE, consistent with previous reports that these drugs are substrates for MDR1. Additional studies were performed with the clinical conjugate, T-DM1, on the HER2-amplified breast cancer line SK-BR-3 transfected to express either MDR1, MRP1, MRP3 or BCRP, focusing on the clinical conjugate, T-DM1. In cell proliferation assays, both NCI-AdrRes/HER2 and SK-BR-3/MDR1 were resistant to free DM1, and the addition of XR9051 (a specific MDR1 inhibitor) reversed this resistance. Although the sensitivity to T-DM1 for both cell lines was restored by the addition of XR9051, NCI-AdrRes/HER2 showed more resistance to T-DM1 in the absence of XR9051. SK-BR-3 cells expressing MRP1 or BCRP maintained sensitivity to free and conjugated drugs, while cells expressing MRP3 showed a very modest induction of resistance only at high drug concentrations. The effects of linker stability were also investigated by comparing trastuzumab conjugates comprised of stable vs. cleavable (reducible or protease-sensitive) linkers. MDR1 expressing cells showed relatively more resistance to conjugates with cleavable linkers, presumably due to efflux of free drug upon release after linker cleavage. Together, these data show that, of the MDR transporters studied, only MDR1 confers high level resistance to trastuzumab-cytotoxic drug conjugates comprised of DM1 or auristatins, and that linking the drug through a stable linker may allow evasion of drug efflux through MDR-mediated mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 618.
High neutralizing antibody titer in intensive care unit patients with COVID-19 (2020)

Coronavirus disease 2019 (COVID-19) has a wide spectrum of disease severity from mild upper respiratory symptoms to respiratory failure. The role of neutralizing antibody (NAb) response in disease progression remains elusive. This study determined the seroprevalence of 733 non-COVID-19 individuals from April 2018 to February 2020 in the Hong Kong Special Administrative Region and compared the neutralizing antibody (NAb) responses of eight COVID-19 patients admitted to the intensive care unit (ICU) with those of 42 patients not admitted to the ICU. We found that NAb against SARS-CoV-2 was not detectable in any of the anonymous serum specimens from the 733 non-COVID-19 individuals. The peak serum geometric mean NAb titer was significantly higher among the eight ICU patients than the 42 non-ICU patients (7280 [95% confidence interval (CI) 1468-36099]) vs (671 [95% CI, 368-1223]). Furthermore, NAb titer increased significantly at earlier infection stages among ICU patients than among non-ICU patients. The median number of days to reach the peak Nab titers after symptoms onset was shorter among the ICU patients (17.6) than that of the non-ICU patients (20.1). Multivariate analysis showed that oxygen requirement and fever during admission were the only clinical factors independently associated with higher NAb titers. Our data suggested that SARS-CoV-2 was unlikely to have silently spread before the COVID-19 emergence in Hong Kong. ICU patients had an accelerated and augmented NAb response compared to non-ICU patients, which was associated with disease severity. Further studies are required to understand the relationship between high NAb response and disease severity.
Hydrodynamic properties of rigid macromolecules composed of ellipsoidal and cylindrical subunits (2002)

A procedure is devised for the calculation of hydrodynamic properties of rigid macromolecules composed subunits that are modeled as ellipsoids of revolution and cylinders. Owing to the axial symmetry of these shapes, smooth shell models can be constructured for the subunit structure. The bead shell model so constructed is employed for the calculation of the properties. A computer program, HYDROSUB, has been written implementing both the model building and the hydrodynamic calculation. A detailed example of the use of this methodology is presented for the case of the solution properties of the human antibody molecule immunoglobulin G3 (IgG3). Finally, hints are given on other uses and applications of the procedure.
Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury (2003)

Estradiol accelerates reendothelialization and attenuates medial thickening after carotid injury in part by augmenting mobilization and proliferation of bone marrow-derived EPCs and their incorporation into the recovering endothelium at the site of injury.
Identification of Transcriptional Activation Domain of TREB5, a CREB/ATF Family Protein That Binds to HTLV-1 Enhancer (1995)

TREB5 (hXBP-1) protein is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and activates their transcription. TREB5 is a member of the CREB/ATF family, containing a basic amino acid region and leucine zipper structure (b-Zip structure). To characterize the key domain of TREB5 for transcriptional activation, mutational analysis was carried out. The C-terminal region of 148-221 amino acids was identified as an activation domain and was also active when fused to Gal4 DNA binding domain. This domain contains three unique regions rich in glutamic acid, glutamine, or serine/threonine and is active in both osteosarcoma (HOS) and T (Jurkat) cell lines. All of these three regions are essential; however, a part of the serine/threonine region was dispensable in Jurkat, but not in HOS cells. In addition to the activation domain, the N-terminal region showed activity in conjunction with the b-Zip structure, but not with the Gal4 DNA binding domain. Furthermore, this region showed activity in Jurkat cells, but not in HOS cells. These results suggest that TREB5 has two activational functions in transcription and may provide diversity in cell-type-specific transcriptional activation, possibly through dimerization with other b-Zip proteins and phosphorylation.
Immunotherapy for advanced prostate cancer. (2007)

The absence of curative therapies for advanced or recurrent forms of prostate cancer mandates continued development of novel, more effective treatment regimens. Due to recent advances in basic and translational research, therapeutic vaccines and monoclonal antibody-based therapies are steadily gaining ground as promising treatment modalities against prostate cancer. Several immunotherapeutic products have recently been investigated in later-phase trials and have reported evidence for clinical benefit while maintaining an excellent quality of life for participants. The cumulative clinical results available to date indicate that immune-based therapies will likely play a role in the treatment of patients with prostate and other malignancies. The objective of this article is to increase awareness of contemporary immunologic therapies and clinical trials of new biologic reagents against prostate cancer. We also seek to encourage urologists to actively participate in clinical trials and evaluate the potential of immunotherapeutic drugs for impacting standards of care.
How Would Surround Vehicles Move? A Unified Framework for Maneuver Classification and Motion Prediction (2018)

Reliable prediction of surround vehicle motion is a critical requirement for path planning for autonomous vehicles. In this paper, we propose a unified framework for surround vehicle maneuver classification and motion prediction that exploits multiple cues, namely, the estimated motion of vehicles, an understanding of typical motion patterns of freeway traffic and intervehicle interaction. We report our results in terms of maneuver classification accuracy and mean and median absolute error of predicted trajectories against the ground truth for real traffic data collected using vehicle mounted sensors on freeways. An ablative analysis is performed to analyze the relative importance of each cue for trajectory prediction. Additionally, an analysis of execution time for the components of the framework is presented. Finally, we present multiple case studies analyzing the outputs of our model for complex traffic scenarios.
Biochemical Pathways of Caspase Activation During Apoptosis (1999)

Caspase activation plays a central role in the execution of apoptosis. The key components of the biochemical pathways of caspase activation have been recently elucidated. In this review, we focus on the two most well-studied pathways of caspase activation: the cell surface death receptor pathway and the mitochondria-initiated pathway. In the cell surface death receptor pathway, activation of caspase-8 following its recruitment to the death-inducing signaling complex (DISC) is the critical event that transmits the death signal. This event is regulated at several different levels by various viral and mammalian proteins. Activated caspase-8 can activate downstream caspases by direct cleavage or indirectly by cleaving Bid and inducing cytochrome c release from the mitochondria. In the mitochondrial-initiated pathway, caspase activation is triggered by the formation of a multimeric Apaf-1/cytochrome c complex that is fully functional in recruiting and activating procaspase-9. Activated caspase-9 will then cleave and activate downstream caspases such as caspase-3, -6, and -7. This pathway is regulated at several steps, including the release of cytochrome c from the mitochondria, the binding and hydrolysis of dATP/ATP by Apaf-1, and the inhibition of caspase activation by the proteins that belong to the inhibitors of apoptosis (IAP).
Effect of Temperature on In Vivo Protein Synthetic Capacity in Escherichia coli (1998)

In this report, we examine the effect of temperature on protein synthesis. The rate of protein accumulation is determined by three factors: the number of working ribosomes, the rate at which ribosomes are working, and the rate of protein degradation. Measurements of RNA/protein ratios and the levels of individual ribosomal proteins and rRNA show that the cellular amount of ribosomal machinery in Escherichia coli is constant between 25 and 37 degreesC. Within this range, in a given medium, temperature affects ribosomal function the same as it affects overall growth. Two independent methodologies show that the peptide chain elongation rate increases as a function of temperature identically to growth rate up to 37 degreesC. Unlike the growth rate, however, the elongation rate continues to increase up to 44 degreesC at the same rate as between 25 and 37 degreesC. Our results show that the peptide elongation rate is not rate limiting for growth at high temperature. Taking into consideration the number of ribosomes per unit of cell mass, there is an apparent excess of protein synthetic capacity in these cells, indicating a dramatic increase in protein degradation at high temperature. Temperature shift experiments show that peptide chain elongation rate increases immediately, which supports a mechanism of heat shock response induction in which an increase in unfolded, newly translated protein induces this response. In addition, we find that at low temperature (15 degreesC), cells contain a pool of nontranslating ribosomes which do not contribute to cell growth, supporting the idea that there is a defect in initiation at low temperature.
Changes in corneal wavefront aberrations with aging. (1999)

Comalike aberrations of the cornea correlate with age, implying that the corneas become less symmetrical along with aging. Spherical-like aberrations do not vary significantly with aging. Pupillary dilation markedly increases wavefront aberrations, and those effects are more prominent in older subjects than in younger subjects.
Molecular Electronics (2003)

Improvements in our understanding of how molecules transport charge, and how they interface to the macroscopic world, are fueling new devices and applications.
Biodistribution, Kinetics, and Efficacy of Highly Phosphorylated and Non-phosphorylated β-Glucuronidase in the Murine Model of Mucopolysaccharidosis VII (2001)

Enzyme replacement therapy (ERT) has been shown to be effective at reducing the accumulation of undegraded substrates in lysosomal storage diseases. Most ERT studies have been performed with recombinant proteins that are mixtures of phosphorylated and non-phosphorylated enzyme. Because different cell types use different receptors to take up phosphorylated or non-phosphorylated enzyme, it is difficult to determine which form of enzyme contributed to the clinical response. Here we compare the uptake, distribution, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase (GUSB) in the MPS VII mouse. Highly phosphorylated murine GUSB was efficiently taken up by a wide range of tissues. In contrast, non-phosphorylated murine GUSB was taken up primarily by tissues of the reticuloendothelial (RE) system. Although the tissue distribution was different, the half-lives of both enzymes in any particular tissue were similar. Both preparations of enzyme were capable of preventing the accumulation of lysosomal storage in cell types they targeted. An important difference in clinical efficacy emerged in that phosphorylated GUSB was more efficient than non-phosphorylated enzyme at preventing the hearing loss associated with this disease. These data suggest that both forms of enzyme contribute to the clinical responses of ERT in MPS VII mice but that enzyme preparations containing phosphorylated GUSB are more broadly effective than non-phosphorylated enzyme.
Evaluation of spectral imaging for plant cell analysis (2004)

Fluorescence imaging at high spectral resolution is now a practical reality and has great promise in plant cell biology. Emission spectral curve data can be used computationally to distinguish spectrally similar fluorophores, or to remove autofluorescence, and to spectrally analyse autofluorescent molecules, which are especially abundant in plant tissues. Examples of these applications in plant cells are given, and a comparison is made between the current offerings in spectral imaging laser scanning confocal microscopes.
Crumbling Walls: A Class of High Availability Quorum Systems (1994)

A quorum system is a collection of sets (quorums) every two of which have a nonempty intersection. Quorum systems have been used for a number of applications in the area of distributed systems. The most available quorum systems are the non-dominated coteries (NDC). In this paper we introduce a general class of quorum systems called Crumbling Walls and study its properties. The elements of a wall are logically arranged in rows of varying widths. A quorum in a wall is the union of one full row and a representative from every row below the full row. This class considerably generalizes a number of known NDC classes. We prove that a wall is ND iff its first row is of width 1 and that all other rows are wider, and that the monotone increasing walls have the best availability among all the row permutations. We also show that the ND crumbling walls are an exponential family of quorum systems. We then turn to studying the availability of the wall family. In order to quantify the availability of...
Comparative Analysis of Pharmacophore Features and Quantitative Structure–Activity Relationships for CD38 Covalent and Non‐covalent Inhibitors (2015)

In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non-covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure-based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure-activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non-covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/non-bonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross-validated correlation coefficient values (q(2)) of 0.564 and 0.571, and non-cross-validated values (r(2)) of 0.967 and 0.971, respectively. The CD38 non-covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non-covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross-validated correlation coefficient values (q(2)) of 0.469 and 0.454, and non-cross-validated values (r(2)) of 0.814 and 0.819, respectively.
Molecular beam epitaxy-grown PbSnTe-PbEuSeTe buried heterostructure diode lasers (1990)

Buried heterostructure (BH) PbSnTe-PbEuSeTe lasers with a PbSnTe active layer were fabricated for the first time using a two-stage molecular beam epitaxy (MBE) growth procedure. Lasers with 4- mu m-wide and 0.65- mu m-thick buried Pb/sub 0.961/Sn/sub Sn0.039/Te active layer and Pb/sub 0.985/Eu/sub 0.015/Se/sub 0.02/Te/sub 0.98/ cladding layers were grown. Continuous wave (CW) operating temperature of 175 K was measured with CW threshold currents of 1.6 mA (20 K), 13.6 mA (80 K), and 195 mA (160 K). Single-mode operation with 3.0-cm/sup -1/-mode tuning was measured at 1639.8 cm/sup -1/ emission.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
CuI‐Catalyzed Alkyne–Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective (2005)

Abstract Cu I ‐catalyzed alkyne–azide cycloaddition provides 1,4‐disubstituted 1,2,3‐triazoles with such efficiency and scope that the transformation has been described as “click” chemistry. An overview of the mechanism of this remarkable reaction is presented as a means to explain the myriad of experimental results, particularly the various methods of catalyst generation, solvent and substrate effects, and choice of base or ligand. Both solution‐phase and solid‐phase results are comprehensively examined. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2006)
Eighty‐six cases of Addison's disease (1994)

The calculated prevalence was 110 per million population. The cause was attributed to autoimmune destruction of the adrenal cortex in 81 (93%). There were two cases of metastatic malignancy and three unrelated cases of late onset adrenoleukodystrophy, but none were attributable to tuberculosis. Twenty-one new cases were diagnosed between 1987 and 1993. The calculated incidence was 5.6 per million per annum. The biochemical basis of the diagnosis was reviewed in these 21 patients and as a result firm criteria are suggested for the interpretation of the short Synacthen test; criteria for normality being baseline cortisol >250 and 30 minute peak >600 nmol/l, taking into account clinical circumstances.
On the Pharmacology of Farnesoid X Receptor Agonists: Give me an “A”, Like in “Acid” (2016)

The Farnesoid X Receptor (FXR) has recently moved into the spotlight through the release of clinical data using Obeticholic Acid, an FXR agonist, that demonstrated effectiveness of this bile acid-like drug in patients with Primary Biliary Cirrhosis and Non-alcoholic Steatohepatitis (NASH). FXR holds the promise to become an attractive drug target for various conditions, from Non-alcoholic Fatty Liver Disease (NAFLD), NASH, liver cirrhosis, portal hypertension and a variety of cholestatic disorders to intestinal diseases including inflammatory bowel disease and bile acid diarrhea. Despite the wide therapeutic potential, surprisingly little is known about the pharmacology, pharmacokinetics and tissue distribution properties of drugs targeting FXR. Are tissue specific FXR agonists preferable for different indications, or might one type of ligand fit all purposes? This review aims to summarize the sparse data which are available on this clinically and pharmacologically relevant topic and provides a mechanistic model for understanding tissue-specific effects in vivo.