gebhart/patrepeval huggingface dataset:
Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups (2012)

The two major mammalian sialic acids are N-acetylneuraminic acid and N-glycolylneuraminic acid (Neu5Gc). The only known biosynthetic pathway generating Neu5Gc is the conversion of CMP-N-acetylneuraminic acid into CMP-Neu5Gc, which is catalyzed by the CMP-Neu5Ac hydroxylase enzyme. Given the irreversible nature of this reaction, there must be pathways for elimination or degradation of Neu5Gc, which would allow animal cells to adjust Neu5Gc levels to their needs. Although humans are incapable of synthesizing Neu5Gc due to an inactivated CMAH gene, exogenous Neu5Gc from dietary sources can be metabolically incorporated into tissues in the face of an anti-Neu5Gc antibody response. However, the metabolic turnover of Neu5Gc, which apparently prevents human cells from continued accumulation of this immunoreactive sialic acid, has not yet been elucidated. In this study, we show that pre-loaded Neu5Gc is eliminated from human cells over time, and we propose a conceivable Neu5Gc-degrading pathway based on the well studied metabolism of N-acetylhexosamines. We demonstrate that murine tissue cytosolic extracts harbor the enzymatic machinery to sequentially convert Neu5Gc into N-glycolylmannosamine, N-glycolylglucosamine, and N-glycolylglucosamine 6-phosphate, whereupon irreversible de-N-glycolylation of the latter results in the ubiquitous metabolites glycolate and glucosamine 6-phosphate. We substantiate this finding by demonstrating activity of recombinant human enzymes in vitro and by studying the fate of radiolabeled pathway intermediates in cultured human cells, suggesting that this pathway likely occurs in vivo. Finally, we demonstrate that the proposed degradative pathway is partially reversible, showing that N-glycolylmannosamine and N-glycolylglucosamine (but not glycolate) can serve as precursors for biosynthesis of endogenous Neu5Gc.
Evaluation of Single-Drug and Combination Antifungal Therapy in an Experimental Model of Candidiasis in Rabbits with Prolonged Neutropenia (1988)

We developed an experimental model of candidiasis in rabbits with prolonged neutropenia. Rabbits were made neutropenic with cytosine arabinoside (Ara-C) administered through an indwelling silastic catheter that had been surgically implanted in the external jugular vein. Neutropenia was sustained with intravenous Ara-C, and bacterial complications were prevented with parenteral ceftazidime plus ampicillin. Candidiasis was established by intravenously administering Candida albicans or Candida tropicalis (1-2 x 10(5) colony-forming units) and resulted in hepatic and splenic lesions that mimicked those associated with hepatosplenic candidiasis in humans. The kidney proved to be the site most refractory to eradication of Candida spp. and offered a target organ for assessing antifungal therapy. We evaluated amphotericin B, 5-flucytosine, ketoconazole, and rifampin, alone and in combination. Although each agent reduced the colony counts of Candida in the liver, spleen, and lung, the combination of amphotericin B and 5-flucytosine was the only regimen effective in eradicating renal candidiasis.
Synthesis of cyclophanes derived from 1-amino-3,7-dialkyl-4-methylnaphthalenes (1979)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of cyclophanes derived from 1-amino-3,7-dialkyl-4-methylnaphthalenesD. S. Kemp, M. E. Garst, R. W. Harper, D. D. Cox, D. Carlson, and S. DenmarkCite this: J. Org. Chem. 1979, 44, 25, 4469–4473Publication Date (Print):December 1, 1979Publication History Published online1 May 2002Published inissue 1 December 1979https://pubs.acs.org/doi/10.1021/jo00393a001https://doi.org/10.1021/jo00393a001research-articleACS PublicationsRequest reuse permissionsArticle Views237Altmetric-Citations6LEARN 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
Comparison of the effects of vinblastine, vincristine, vindesine, and vinepidine on microtubule dynamics and cell proliferation in vitro. (1985)

Vinepidine, a new derivative of vincristine, and three clinically used Catharanthus derivatives, vinblastine, vincristine, and vindesine, were examined for their abilities to inhibit net tubulin addition at the assembly ends of bovine brain microtubules at steady state. Although all four derivatives were generally similar in potency, their relative abilities to inhibit tubulin addition were distinguishable. Vinepidine and vincristine were the most potent derivatives (Ki, 0.079 +/- 0.018 (SD) microM and 0.085 +/- 0.013 microM, respectively), followed by vindesine (Ki, 0.110 +/- 0.007 microM) and vinblastine (Ki, 0.178 +/- 0.025 microM). In contrast to their relative abilities to inhibit microtubule assembly in vitro, vinblastine and its derivative, vindesine, were generally more potent than vincristine and vinepidine in inhibiting cell proliferation in culture. Vinblastine was nine times more potent than the weakest derivative, vinepidine, in B16 melanoma cells. In L-cells, vinblastine completely inhibited growth at 40 nM, whereas vincristine and vindesine caused about 25% inhibition, and vinepidine was inactive. When B16 melanoma cells were treated with drug before being injected into mice, retardation of tumor growth was best achieved with vindesine, one of the weaker of the four derivatives in vitro. The results demonstrate that chemical differences among the Catharanthus derivatives, which affect to small extents the abilities of the derivatives to inhibit microtubule assembly in vitro, result in significant differences in the order and the magnitude of the abilities of the drugs to inhibit cell growth.
An Efficient Implementation of Distance-Based Diversity Measures Based on k−d Trees (1998)

The problem of quantifying molecular diversity continues to attract significant interest among computational chemists. Most algorithms reported to date are distance-based and scale to the square of the size of the data set. This paper reports an alternative algorithm based on k-dimensional (or k−d) trees. k−d trees are combinatorial data structures that allow expedient location of nearest neighbors in multivariate spaces. Nearest neighbor detection forms the basis of many popular diversity measures, such as maximin, minimum spanning trees, and many others. In this report, we demonstrate that k−d trees exhibit excellent scaling characteristics and can be used to accelerate diversity estimation without compromising the quality of the design. The advantages of this approach are contrasted with an alternative algorithm that was recently proposed by Turner et al. based on the cosine similarity coefficient.
Stabilization of Aerosol Emulsions and Foams (1970)

Synopsis--It is proposed that the INTERFACIAL REGION around PROPELLANT droplets in AEROSOL EMULSIONS stabilized with MOLECULAR COMPLEXES is polymo~ lecular and consists of alternating layers of oriented water molecules and bimolecular layers of the molecular complex. The molecular complex has a LIQUID CRYSTAL STRUCTURE and, since it is almost insoluble in either the propellant or aqueous phase, concentrates at the interface and stabilizes the emulsion by forming essentially a solid interfacial fihn in somewhat the same way as finely divided iuorgauic solids. This hypothesis is based upon the evidence that molecular complexes have liquid crystal structures in aqueous systems and that almost all aerosol emulsions and FOAMS are stabilized by substances which are practically insoluble in both the aqueous and propellant phases.
DAISY (1997)

Although VLIW architectures offer the advantages of simplicity of design and high issue rates, a major impediment to their use is that they are not compatible with the existing software base. We describe new simple hardware features for a VLIW machine we call DAISY ( D ynamically A rchitected I nstruction S et from Y orktown ). DAISY is specifically intended to emulate existing architectures, so that all existing software for an old architecture (including operating system kernel code) runs without changes on the VLIW. Each time a new fragment of code is executed for the first time, the code is translated to VLIW primitives, parallelized and saved in a portion of main memory not visible to the old architecture, by a Virtual Machine Monitor (software) residing in read only memory. Subsequent executions of the same fragment do not require a translation (unless cast out). We discuss the architectural requirements for such a VLIW, to deal with issues including self-modifying code, precise exceptions, and aggressive reordering of memory references in the presence of strong MP consistency and memory mapped I/O. We have implemented the dynamic parallelization algorithms for the PowerPC architecture. The initial results show high degrees of instruction level parallelism with reasonable translation overhead and memory usage.
Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease (2003)

These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.
Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice (2007)

The anti-granulocyte receptor-1 (Gr-1) mAb, RB6-8C5, has been used extensively to deplete neutrophils in mice and to investigate the role of these cells in host defense. RB6-8C5 binds to Ly6G, which is present on neutrophils, and to Ly6C, which is expressed on neutrophils, dendritic cells, and subpopulations of lymphocytes and monocytes. It is thus likely that in vivo administration of RB6-8C5 may deplete not only neutrophils but also other Gr-l+ (Ly6C+) cells. This study describes the use of an Ly6G-specific mAb, 1A8, as an alternative means to deplete neutrophils. In vivo administration of RB6-8C5 reduced blood neutrophils and Gr-1+ monocytes, whereas administration of 1A8 reduced blood neutrophils but not Gr-1+ monocytes. Plasma TNF-alpha in endotoxemia was increased 20-fold by RB6-8C5 pretreatment and fourfold by 1A8 pretreatment. In a wound model, pretreatment with either antibody decreased wound neutrophils and macrophages. TNF-alpha staining in brefeldin-treated wound leukocytes was increased by pretreatment with RB6-8C5, but not 1A8. Neutrophil depletion with 1A8 offers advantages over the use of RB6-8C5, as it preserves non-neutrophil Gr-1+ cells depleted by the anti-Gr-1 antibody. The loss of non-neutrophil Gr-1+ populations in RB6-8C5-treated animals is associated with increased TNF-alpha responses, suggesting these cells may function to suppress TNF-alpha production.
Acute kidney injury (2008)

Diagnosis and classification of acute pathology in the kidney are major clinical problems. Azotemia and oliguria represent not only disease but normal responses of the kidney to extracellular volume depletion or decreased renal blood flow. Changes in urine output and glomerular filtration rate are therefore neither necessary nor sufficient for the diagnosis of renal pathology. However, no simple alternative for the diagnosis currently exists. By examining both glomerular and tubular function, clinicians routinely make inferences not only on the presence of renal dysfunction but also on its cause. However, pure prerenal physiology is unusual in hospitalized patients, and its effects are not necessary benign. Sepsis, the most common condition associated with acute renal failure in the intensive care unit, may alter renal function without any characteristic changes in urine indices, and classification of these abnormalities as prerenal will undoubtedly lead to incorrect management decisions. The clinical syndrome known as acute tubular necrosis does not actually manifest the morphologic changes that the name implies. A precise biochemical definition of acute renal failure has never been proposed, and until recently, there has been no consensus on the diagnostic criteria or clinical definition. Depending on the definition used, acute renal failure has been reported to affect from 1% to 25% of intensive care unit patients and has led to mortality rates ranging from 15% to 60%. From this chaos, two principles emerged: first, the need for a standard definition and, second, the need to classify the severity of the syndrome rather than only consider its most severe form. The RIFLE criteria were developed to achieve these goals, and the term acute kidney injury has been proposed to encompass the entire spectrum of the syndrome, from minor changes in renal function to requirement for renal replacement therapy. Thus, acute kidney injury is not acute tubular necrosis, nor is it renal failure. Small changes in kidney function in hospitalized patients are important and are associated with significant changes in short-term and possibly long-term outcomes. The RIFLE criteria provide a uniform definition of acute kidney injury and have now been validated in numerous studies.
Combination Phase I/II Study of Irinotecan Hydrochloride (CPT-11) and Carboplatin in Relapsed or Refractory Non-Hodgkin's Lymphoma (1996)

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecin which inhibits topoisomerase I. Phase II studies have demonstrated that CPT-11 is active against a broad spectrum of neoplasms including intractable non-Hodgkin's lymphoma. An early phase II study in lymphoma suggested that a schedule of daily infusions of 40 mg/m2/day for three or five consecutive days is more effective than a single infusion of 200 mg/m2 every three to four weeks. Carboplatin is also an active agent against lymphoma, and preclinical studies have shown that CPT-11 and its active metabolite have a synergistic effect with platinum compounds. To evaluate the maximal tolerated dose (MTD) and the therapeutic efficacy of CPT-11 in combination with carboplatin in relapsed or refractory non-Hodgkin's lymphoma, we conducted a combination phase I/II study. The starting dose of CPT-11 was 20 mg/m2/day (days 1 through 3 and 8 through 10), and dose escalations of 5 mg/m2/day increments were planned, with a fixed dose of carboplatin (300 mg/m2, day 1). Six of the eight patients receiving both agents at the starting dose level developed critical toxicities such as grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8) and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminase elevation 1/8). Further dose escalation of CPT-11 was halted, and the starting doses were judged to be the MTDs. The response rate (25%, 2/8) to the combination of the MTDs was not superior to that of CPT-11 alone in a previous phase II study (38%, 26/69), and the MTD of CPT-11 in combination with carboplatin was less than half the single-agent dose. We conclude that carboplatin is not recommendable for combination with CPT-11 in lymphoma patients. Other suitable agents for such a combination should be sought.
Parallel nanoliter detection of cancer markers using polymer microchips (2005)

A general multipurpose microchip technology platform for point-of-care diagnostics has been developed. Real-time nucleic acid sequence-based amplification (NASBA) for detection of artificial human papilloma virus (HPV) 16 sequences and SiHa cell line samples was successfully performed in cyclic olefin copolymer (COC) microchips, incorporating supply channels and parallel reaction channels. Samples were distributed into 10 parallel reaction channels, and signals were simultaneously detected in 80 nl volumes. With a custom-made optical detection unit, the system reached a sensitivity limit of 10(-6) microM for artificial HPV 16 sequences, and 20 cells microl(-1) for the SiHa cell line. This is comparable to the detection limit of conventional readers, and clinical testing of biological samples in polymer microchips using NASBA is therefore possible.
Geographical models of crises: Evidence from ICEWS (2012)

Developing political forecasting models is not only relevant for scientific advancement, but also increases the ability of political scientists to inform public policy decisions. Taking this perspective seriously, the International Crisis Early Warning System (ICEWS) was developed under a DARPA initiative to provide predictions of international crisis, domestic crisis, rebellion, insurgency, and ethnic violence in about two-dozen countries in the US PACOM Area of Responsibility. As part of a larger project coordinated by Lockheed Martin Advanced Technology Labs, a team at Duke University created a series of geographically informed statistical models for these events. The generated predictions have been highly accurate, with few false negative and false positive categorizations. Predictions are made at the monthly level for three months periods into the future.
Faecalibacterium prausnitziisupernatant improves intestinal barrier function in mice DSS colitis (2013)

OBJECTIVE. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. MATERIAL AND METHODS. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with (51)Cr-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. RESULTS. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in (51)Cr-EDTA-passage compared to controls. (51)Cr-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. CONCLUSIONS. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.
The JAK/STAT pathway in obesity and diabetes (2016)

Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes.
Focused Evolution of HIV-1 Neutralizing Antibodies Revealed by Structures and Deep Sequencing (2011)

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.
Synthesis and Biological Evaluation of 2',3'-Dideoxy-L-pyrimidine Nucleosides as Potential Antiviral Agents against Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV) (1994)

Various 2',3'-dideoxy-L-cytidine,2',3'-dideoxy-L-uridine, and 3'-deoxy-L-thymidine analogues have been synthesized and evaluated in vitro as potential anti-HIV and anti-HBV agents. Coupling of 1-O-acetyl-5-O-(tert-butyldimethylsilyl)-2,3-dideoxy-L-ribofuranose (1) with silylated derivatives of 5-fluorocytosine, cytosine, 5-fluorouracil, uracil, and thymine in the presence of ethylaluminum dichloride gave the corresponding nucleosides 2, 3, 4, 5, 10, 11, 12, 16, 17, and 18 as a mixture of alpha- and beta-anomers, which were then deblocked to yield the corresponding 2',3'-dideoxy-L-5-fluorocytidine derivatives, 6 and 7, 2',3'-dideoxy-L-cytidine derivatives, 8 and 9, 2',3'-dideoxy-beta-L-fluorouridine (13), 2',3'-dideoxy-beta-L-uridine (14), and 3'-deoxy-L-thymidine derivatives, 15 and 19. Among these 2',3'-dideoxy-L-nucleoside analogues, 2',3'-dideoxy-beta-L-5-fluorocytidine (6, beta-L-FddC) was found to be the most active against HIV-1, which is approximately 3 and 4 times more active against HIV-1 in vitro than 2',3'-dideoxy-beta-D-cytidine (ddC) and 2',3'-dideoxy-beta-D-5-fluorocytidine (beta-D-FddC) with ED50 values of 0.5, 1.5, and 2 microM, respectively. The dose-limiting toxicity of ddC is severe neuropathy which may be caused by the inhibition of the synthesis of mitochondrial DNA. ddC has an IC50 value of 0.022 microM against host mitochondrial DNA synthesis. Conversely, the IC50 values for beta-L-FddC and beta-L-ddC are > 100 microM; therefore, neuropathy may not present itself to be a problem with beta-L-FddC and beta-L-ddC as chemotherapeutic agents. In addition, beta-L-FddC and 2',3'-dideoxy-beta-L-cytidine (8, beta-L-ddC) demonstrated equally potent activity against HBV in vitro by having the same ED50 value of 0.01 microM. Both beta-L-FddC and beta-L-ddC, which have an "unnatural" L-configuration in the sugar moiety, are approximately 1000 and 280 times more potent, respectively, against HBV than the D-configuration beta-D-FddC and ddC which have an ED50 values of 10 and 2.8 microM. In view of the potent antiviral activity of beta-L-FddC against both HIV-1 and HBV and potent antiviral activity of beta-L-ddC against HBV in vitro, their low cytotoxicity, and especially the negligible inhibitory effect on host mitochondrial DNA synthesis, beta-L-FddC and beta-L-ddC merit further development as potential anti-HIV and anti-HBV agents.
Phase 1b Study of Pegylated Interferon Lambda 1 With or Without Ribavirin in Patients with Chronic Genotype 1 Hepatitis C Virus Infection† (2010)

Weekly PEG-IFN-lambda with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.