gebhart/patrepeval huggingface dataset:
On conformation analysis, molecular graphics, fentanyl and its derivatives (1986)

In 1680, Thomas Sydenham noted that ‘Among the remedies which it has pleased Almighty God to give man to relieve his sufferings, none is so universal and so efficacious as opium’. After Friedrich Sertürner in the beginning of the 19th century isolated an opium alkaloid which he called morphine after the Greek god Morpheus, and following the invention of the syringe and the hollow needle in the fifties of the 19th century, the controlled administration of morphine became possible. Imagine the terror of a patient in the first half of the 19th century subjected conscious to the saw and the knife! In fact, during the Lister Lecture in memory of the first Baron Lister, pioneer of antiseptic surgery, Spinks [1] recalled the reputation for quick surgery of James Syme, who allegedly performed a mid-thigh amputation in nine sec-onds, including the patient’s left testicle and the forefinger of the chief assistant! Ever since the introduction of morphine in clinical practice it has been recognized that morphine has a number of side-effects such as addiction potential, tolerance and respiratory depression, which prompted the quest for new opiates lacking these side-effects. This quest went over heroine which was introduced in 1890 as a non-addictive morphine derivative, to meperidine and methadone, the latter two being purely synthetic compounds.
The Emerging Significance of O-GlcNAc in Cellular Regulation (2002)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Emerging Significance of O-GlcNAc in Cellular RegulationNatasha E. Zachara and Gerald W. HartView Author Information The Department of Biological Chemistry, The Johns Hopkins University Medical School, Baltimore, Maryland 21205-2185 Cite this: Chem. Rev. 2002, 102, 2, 431–438Publication Date (Web):January 18, 2002Publication History Received18 July 2001Published online18 January 2002Published inissue 1 February 2002https://pubs.acs.org/doi/10.1021/cr000406uhttps://doi.org/10.1021/cr000406uresearch-articleACS PublicationsCopyright © 2002 American Chemical SocietyRequest reuse permissionsArticle Views1941Altmetric-Citations249LEARN 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 SUBJECTS:Cell and molecular biology,Genetics,Modification,Peptides and proteins,Post-translational modification Get e-Alerts
Haplotype Structure, LD Blocks, and Uneven Recombination Within the LRP5 Gene (2003)

Patterns of linkage disequilibrium (LD) in the human genome are beginning to be characterized, with a paucity of haplotype diversity in "LD blocks," interspersed by apparent "hot spots" of recombination. Previously, we cloned and physically characterized the low-density lipoprotein-receptor-related protein 5 (LRP5) gene. Here, we have extensively analysed both LRP5 and its flanking three genes, spanning 269 kb, for single nucleotide polymorphisms (SNPs), and we present a comprehensive SNP map comprising 95 polymorphisms. Analysis revealed high levels of recombination across LRP5, including a hot-spot region from intron 1 to intron 7 of LRP5, where there are 109 recombinants/Mb (4882 meioses), in contrast to flanking regions of 14.6 recombinants/Mb. This region of high recombination could be delineated into three to four hot spots, one within a 601-bp interval. For LRP5, three haplotype blocks were identified, flanked by the hot spots. Each LD block comprised over 80% common haplotypes, concurring with a previous study of 14 genes that showed that common haplotypes account for at least 80% of all haplotypes. The identification of hot spots in between these LD blocks provides additional evidence that LD blocks are separated by areas of higher recombination.
Identification and treatment of postmenopausal women at risk for the development of osteoporosis. (1992)

One in the three women develops osteoporosis--low bone mass and structural deterioration leading to fractures. Pre- and postmenopausal deficiency states are main causes. Estrogens prevent bone loss: Oral doses of 2 mg estradiol or 0.625 conjugated estrogens/day or 50-100 micrograms transdermal estradiol/day substantially reduce vertebral, forearm, and hip fractures. Certain progestins may enhance this effect. Calcium as a prerequisite for attainment of peak bone mass will not substitute for estrogen replacement. Selection of patients actually being at risk for postmenopausal osteoporosis needs to be improved substantially; there is no sensitive single test or testing system for osteoporosis. As individual history and physical exam or biochemical markers of bone resorption and formation rarely provide the early diagnosis of osteoporosis, prophylactic estrogen replacement therapy has to be considered in the majority of postmenopausal women to achieve prevention of postmenopausal osteoporosis. Compliance of replacement therapy in the European countries is poor, only 5-25% of postmenopausal women use estrogen replacement therapy for more than one year. Major compliance problems are alleged weight gain, resumption of withdrawal bleeding and fear to develop breast or endometrial cancer.
Fractionation of Spatial Memory in GRM2/3 (mGlu2/mGlu3) Double Knockout Mice Reveals a Role for Group II Metabotropic Glutamate Receptors at the Interface Between Arousal and Cognition (2011)

Group II metabotropic glutamate receptors (mGluR2 and mGluR3, encoded by GRM2 and GRM3) are implicated in hippocampal function and cognition, and in the pathophysiology and treatment of schizophrenia and other psychiatric disorders. However, pharmacological and behavioral studies with group II mGluR agonists and antagonists have produced complex results. Here, we studied hippocampus-dependent memory in GRM2/3 double knockout (GRM2/3(-/-)) mice in an iterative sequence of experiments. We found that they were impaired on appetitively motivated spatial reference and working memory tasks, and on a spatial novelty preference task that relies on animals' exploratory drive, but were unimpaired on aversively motivated spatial memory paradigms. GRM2/3(-/-) mice also performed normally on an appetitively motivated, non-spatial, visual discrimination task. These results likely reflect an interaction between GRM2/3 genotype and the arousal-inducing properties of the experimental paradigm. The deficit seen on appetitive and exploratory spatial memory tasks may be absent in aversive tasks because the latter induce higher levels of arousal, which rescue spatial learning. Consistent with an altered arousal-cognition relationship in GRM2/3(-/-) mice, injection stress worsened appetitively motivated, spatial working memory in wild-types, but enhanced performance in GRM2/3(-/-) mice. GRM2/3(-/-) mice were also hypoactive in response to amphetamine. This fractionation of hippocampus-dependent memory depending on the appetitive-aversive context is to our knowledge unique, and suggests a role for group II mGluRs at the interface of arousal and cognition. These arousal-dependent effects may explain apparently conflicting data from previous studies, and have translational relevance for the involvement of these receptors in schizophrenia and other disorders.
Inversion of the IDS gene resulting from recombination with IDS-related sequences in a common cause of the Hunter syndrome (1995)

We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.
Microfabricated arrays of cylindrical wells facilitate single‐molecule enzymology of α‐chymotrypsin (2009)

Single-molecule enzymology allows scientists to examine the distributions of kinetic rates among members of a population. We describe a simple method for the analysis of single-molecule enzymatic kinetics and provide comparisons to ensemble-averaged kinetics. To isolate our model enzyme, alpha-chymotrypsin, into single molecules, we use an array of cylindrical poly(dimethylsiloxane) wells 2 microm in diameter and 1.35 microm in height. Inside the wells, a protease assay with a profluorescent substrate detects alpha-chymotrypsin activity. We hold the concentration of alpha-chymotrypsin at 0.39 nM in a given well with an enzyme-to-substrate ratio of 1:6,666 molecules. Fluorescence emitted by the substrate is proportional to enzyme activity and detectable by a charge-coupled device. This method allows for the simultaneous real-time characterization of hundreds of individual enzymes. We analyze single-molecule kinetics by recording and observing their intensity trajectories over time. By testing our method with our current instruments, we confirm that our methodology is useful for the analysis of single enzymes for extracting static inhomogeneity.
Reactive Tumor-Like Lesions of the Peritoneum (1995)

Reactive Tumor-Like Lesions of the Peritoneum Get access Philip B. Clement, MD Philip B. Clement, MD Department of Pathology Vancouver Hospital and Health Sciences Centre Vancouver, Canada Search for other works by this author on: Oxford Academic Google Scholar American Journal of Clinical Pathology, Volume 103, Issue 6, 1 June 1995, Pages 673–676, https://doi.org/10.1093/ajcp/103.6.673 Published: 01 June 1995
Identification of an EF-Tu protein that is periplasm-associated and processed in Neisseria gonorrhoeae (1996)

A 44 kDa protein is a dominant component of periplasmic extracts of Neisseria gonorrhoeae. Peptide sequence generated from a cyanogen-bromide-cleaved fragment of this protein indicated sequence homology with elongation factor-Tu (EF-Tu). Polyclonal antiserum was made against the 44 kDa protein purified from periplasm extracts of N. gonorrhoeae. The preabsorbed antiserum was immunoblotted against whole-cell lysates on two-dimensional gels. A 44 kDa protein and a smaller 37 kDa protein were recognized by this antiserum. A N. gonorrhoeae gamma phage DNA library was screened and a clone expressing a 44 kDa protein was identified. The DNA insert in this clone contained several genes homologous to genes contained in the str operon of Escherichia coli. One ORF product with a calculated molecular mass of 43 kDa was highly homologous to the EF-TuA of E. coli. A synthetic peptide antiserum specific for a portion of the C terminus of EF-Tu confirmed that the 37 kDa protein in whole-cell lysates of N. gonorrhoeae was a processed form of EF-Tu. Deletion of the tufA gene homologue in N. gonorrhoeae was attempted but was unsuccessful.
Gene-Modified Tumor Vaccine with Therapeutic Potential Shifts Tumor-Specific T Cell Response from a Type 2 to a Type 1 Cytokine Profile (1998)

Vaccination with a poorly immunogenic/nonimmunogenic tumor fails to protect the host from a subsequent challenge with the same tumor. The mechanisms underlying the failure of these tumors to sensitize therapeutic T cells are not clearly understood, but the inability of host T cells to recognize tumor has been implicated. In this study, vaccination with the poorly immunogenic B16BL6-D5 (D5 H-2b) tumor fails to generate therapeutic T cells from the tumor vaccine-draining lymph nodes (TVDLN) in our adoptive immunotherapy model. However, if vaccination is performed with an allogeneic MHC class I gene (H-2 Kd)-modified tumor, the T cells obtained from the TVDLN are therapeutic after activation with anti-CD3 and IL-2. Lymph nodes (LN) draining both D5 and D5-Kd tumor vaccines contained increased numbers of cells with reduced expression of L-selectin (L-selectin(low/-)) compared with naive LN. This implies that vaccination led to sensitization of T cells even in LN draining the unmodified D5 tumor. L-selectin(low/-) cells from D5-Kd, but not D5, TVDLN were therapeutic in our animal model. No antitumor activity was seen in the high level L-selectin T cells. L-selectin(low/-) T cells exhibited tumor-specific cytokine release that was type 2 (IL-4, IL-10) following vaccination with native D5 and type 1 (IFN-gamma) following vaccination with gene-modified D5-Kd. Our data suggest that the failure of unmodified D5 to generate therapeutic T cells is not due to an inability to recognize tumor Ags, but, rather, to the induction of an immune response that is ineffective in mediating tumor regression, i.e., immune deviation.
Interleukin-1–Receptor Antagonist in Type 2 Diabetes Mellitus (2007)

The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].).
Cultured Human Corneal Endothelial Cell Transplantation with a Collagen Sheet in a Rabbit Model (2004)

The findings indicate that cultured HCECs transplanted from adult human donor cornea by means of a collagen sheet can retain their function of corneal dehydration in a rabbit model and suggest the feasibility of transplantation for CEC dysfunction using cultured HCECs with a collagen sheet.
Time course of recovery of health status following an infective exacerbation of chronic bronchitis (2003)

A single infective AECB has a sustained effect on health status. The recovery period is long even in patients who have no further exacerbations. A second episode within 6 months limits recovery markedly. Treatments that reduce exacerbation frequency could have a significant impact on health status.
Sparsity and incoherence in compressive sampling (2007)

We consider the problem of reconstructing a sparse signal x^0\\in{\\bb R}^n from a limited number of linear measurements. Given m randomly selected samples of Ux0, where U is an orthonormal matrix, we show that ell1 minimization recovers x0 exactly when the number of measurements exceeds&#13;\n&#13;\nm\\geq \\mathrm{const}^{\\vphantom{\\frac12}}_{\\vphantom{\\frac12}} \\cdot\\mu^2(U)\\cdot S\\cdot\\log n,&#13;\n&#13;\nwhere S is the number of nonzero components in x0 and μ is the largest entry in U properly normalized: \\mu(U) = \\sqrt{n} \\cdot \\max_{k,j} |U_{k,j}| . The smaller μ is, the fewer samples needed. The result holds for 'most' sparse signals x0 supported on a fixed (but arbitrary) set T. Given T, if the sign of x0 for each nonzero entry on T and the observed values of Ux0 are drawn at random, the signal is recovered with overwhelming probability. Moreover, there is a sense in which this is nearly optimal since any method succeeding with the same probability would require just about as many samples.
Immunohistochemical localization of subtype 4a metabotropic glutamate receptors in the rat and mouse basal ganglia (1999)

Recent studies suggest that metabotropic glutamate receptors (mGluRs) may play a significant role in regulating basal ganglia functions. In this study, we investigated the localization of mGluR4a protein in the mouse and rat basal ganglia. Polyclonal antibodies that specifically react with the metabotropic glutamate receptor subtype mGluR4a were produced and characterized by Western blot analysis. These antibodies recognized a native protein in wild-type mouse brain with a molecular weight similar to the molecular weight of the band from a mGluR4a-transfected cell line. The immunoreactivity was absent in brains of knockout mice deficient in mGluR4. mGluR4a immunoreactivity was most intense in the molecular layer of the cerebellum. We also found a striking mGluR4a immunoreactivity in globus pallidus, and moderate staining in substantia nigra pars reticulata and entopeduncular nucleus. Moderate to low mGluR4a immunoreactivity was present in striatum and other brain regions, including hippocampus, neocortex, and thalamus. Double labeling with mGluR4a antibodies and antibodies to either a dendritic marker or a marker of presynaptic terminals suggest a localization of mGluR4a on presynaptic terminals. Immunocytochemistry at electron microscopy level confirmed these results, revealing that in the globus pallidus, mGluR4a is mainly localized in presynaptic sites in axonal elements. Finally, quinolinic acid lesion of striatal projection neurons decreased mGluR4a immunoreactivity in globus pallidus, suggesting a localization of mGluR4a on striatopallidal terminals. These data support the hypothesis that mGluR4a serves as a presynaptic heteroreceptor in the globus pallidus, where it may play an important role in regulating g-amino-n-butyric acid (GABA) release from striatopallidal terminals.
Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase (2010)

Multiple mechanisms for feedback control of cholesterol synthesis converge on the rate-limiting enzyme in the pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase. This complex feedback regulatory system is mediated by sterol and nonsterol metabolites of mevalonate, the immediate product of reductase activity. One mechanism for feedback control of reductase involves rapid degradation of the enzyme from membranes of the endoplasmic reticulum (ER). This degradation results from the accumulation of sterols in ER membranes, which triggers binding of reductase to ER membrane proteins called Insig-1 and Insig-2. Insig binding leads to the recruitment of a membrane-associated ubiquitin ligase called gp78 that initiates ubiquitination of reductase. Ubiquitinated reductase then becomes extracted from ER membranes and is delivered to cytosolic 26S proteasomes through an unknown mechanism that is mediated by the gp78-associated ATPase Valosin-containing protein/p97 and appears to be augmented by nonsterol isoprenoids. Here, we will highlight several advances that have led to the current view of mechanisms for sterol-accelerated, ER-associated degradation of reductase. In addition, we will discuss potential mechanisms for other aspects of the pathway such as selection of reductase for gp78-mediated ubiquitination, extraction of the ubiquitinated enzyme from ER membranes, and the contribution of Insig-mediated degradation to overall regulation of reductase in whole animals.
Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma (2011)

DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently identified mTOR-interacting protein, is a novel candidate oncogene. Previous studies reveal that high DEPTOR expression is required to maintain PI3K and Akt activation and to inhibit apoptosis. However, its significance in differentiated thyroid carcinoma (DTC) is not yet known. The present study verifies the mRNA and protein expression of DEPTOR in five cell lines, DTC tissues and normal adjacent tissues. Tissue microarrays of 114 DTC patients were used to detect DEPTOR protein expression. The assessment of DEPTOR levels demonstrated that DEPTOR in DTC cells and tissues was significantly increased compared with normal cells and adjacent normal tissues. DEPTOR protein expression was significantly associated with lymph node status, extrathyroid extension and distant metastasis. Patients exhibiting high DEPTOR expression were statistically susceptible to earlier recurrence and poorer survival than those with low expression. Univariate and multivariate analyses showed that DEPTOR expression was an independent prognostic factor for DTC recurrence. In conclusion, our data indicate DEPTOR as a novel prognostic marker for DTC.
Prevention of Spontaneous Autoimmune Diabetes in NOD Mice by Transferring in Vitro Antigen-Pulsed Syngeneic Dendritic Cells (2000)

To evaluate the effect of antigen-pulsed dendritic cell (DC) transfer on the development of diabetes, 5-week-old female NOD mice received a single iv injection of splenic syngeneic DC from euglycemic NOD mice pulsed in vitro with human globulin (HGG). Eleven of 12 mice were protected from the development of diabetes up to the age of 25 weeks, and the insulitis score was significantly reduced. In contrast, NOD mice receiving unpulsed splenic DCs showed histological signs of insulitis and course of type 1 diabetes similar to untreated NOD mice. Treatment with HGG-pulsed DC was associated with profound modifications of cytokine secretory capacities within the islets. Thus, supernatants of islets from these mice contained increased levels of interleukin (IL)-4, IL-10, and, to a lesser extent, interferon- and diminished levels of tumor necrosis factor- compared with controls. Because exogenous IL-4 and IL-10 exert antidiabetogenic effect in NOD mice and early blockade of endogenous tumor necrosis factor- prevents NOD mouse diabetes, these phenomena may be causally related to the antidiabetogenic effect of HGG-pulsed DC treatment.
The Hydrophobic Barrier Properties of Gastrointestinal Mucus (1995)

Impressive evidence has accumulated over the past 12 years indicating that one of the potentially important biophysical characteristics of mucus relates to its hydrophobic character. This surface property is region specific and reaches high values in the stomach and colon, where barrier properties against noxious agents in the lumen are most important. The hydrophobic properties of mucus appear to be related to its lipidic constituents and specifically to the presence of phospholipid surfactants that are synthesized, stored, and secreted by GI mucus cells in a regulated fashion.