gebhart/patrepeval huggingface dataset:
Predominance ofEhrlichia ewingiiin Missouri Dogs (2003)

To investigate the species distribution of Ehrlichia present in Missouri dogs, we tested 78 dogs suspected of having acute ehrlichiosis and 10 healthy dogs. Blood from each dog was screened with a broad-range 16S rRNA gene PCR assay that detects known pathogenic species of Ehrlichia and ANAPLASMA: The species was determined by using species-specific PCR assays and nucleotide sequencing. Ehrlichia antibody testing was performed by using an indirect immunofluorescence assay with Ehrlichia chaffeensis as the antigenic substrate. The broad-range assay detected Ehrlichia or Anaplasma DNA in 20 (26%) of the symptomatic dogs and 2 (20%) of the asymptomatic dogs. E. ewingii accounted for 20 (91%), and E. chaffeensis accounted for 1 (5%) of the positives. Anaplasma phagocytophilum DNA was detected in one dog, and the sequences of regions of the 16S rRNA gene and the groESL operon amplified from the blood of this dog matched the published sequences of this organism. Antibodies reactive with E. chaffeensis were detected in 14 (67%) of the 21 PCR-positive dogs and in 12 (19%) of the 64 PCR-negative dogs. Combining the results of PCR and serology indicated that 33 (39%) of 85 evaluable dogs had evidence of past or current Ehrlichia infection. We conclude that E. ewingii is the predominant etiologic agent of canine ehrlichiosis in the areas of Missouri included in this survey. E. canis, a widely recognized agent of canine ehrlichiosis, was not detected in any animal. The finding of E. ewingii in asymptomatic dogs suggests that dogs could be a reservoir for this Ehrlichia species.
Class IB-Phosphatidylinositol 3-Kinase (PI3K) Deficiency Ameliorates IA-PI3K-Induced Systemic Lupus but Not T Cell Invasion (2006)

Class I PI3K catalyzes formation of 3-poly-phosphoinositides. The family is divided into IA isoforms, activated by Tyr kinases and the IB isoform (PI3Kgamma), activated by G protein-coupled receptors. Mutations that affect PI3K are implicated in chronic inflammation, although the differential contribution of each isoform to pathology has not been elucidated. Enhanced activation of class IA-PI3K in T cells extends CD4+ memory cell survival, triggering an invasive lymphoproliferative disorder and systemic lupus. As both IA- and IB-PI3K isoforms regulate T cell activation, and activated pathogenic CD4+ memory cells are involved in triggering systemic lupus, we examined whether deletion of IB could reduce the pathological consequences of increased IA-PI3K activity. IB-PI3Kgamma deficiency did not abolish invasion or lymphoproliferation, but reduced CD4+ memory cell survival, autoantibody production, glomerulonephritis, and systemic lupus. Deletion of the IB-PI3Kgamma isoform thus decreased survival of pathogenic CD4+ memory cells, selectively inhibiting systemic lupus development. These results validate the PI3Kgamma isoform as a target for systemic lupus erythematosus treatment.
N-[(N-nitrosoarylamino)methyl]succinimide as a new agent generating aromatic diazotate. (1977)

We have newly synthesized a series of N-[(N-nitrosoarylamino) methyl] succinimides, disclosing their syn and anti equilibria in a state of solution. It has been found that these nitrosoamines are capable of furnishing aromatic diazotates in basic media. By allowing the generating aromatic diazotates to react in situ, azo-couplings and triazene formations have been provided. The nitrosoamines behaved in acidic media to suffer a migration of the nitroso group similarly to the Fischer-Hepp migration.
Detecting ssDNA at single-nucleotide resolution by sub-2-nanometer pore in monoatomic graphene: A molecular dynamics study (2012)

Obtaining a sequence-based signal at a resolution of single nucleotide during the passage of a DNA strand through nanopores remains a challenging problem. Here, we demonstrate by molecular dynamics simulations that the single-base resolution detection can be realized by pulling a single-stranded DNA through graphene nanopores with diameters down to ∼1 nm. By simply monitoring and analyzing the peak values of the pulling force profile, each nucleotide in the DNA strand can be identified and characterized, except for cytosine and thymine which remain indistinguishable. This intriguing character through narrow nanopores should help realize the low-cost and time-efficient DNA sequencing.
Identification of denatured double‐stranded DNA by matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (1995)

We created double-stranded DNA (dsDNA) by annealing synthetic oligonucleotides and used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to measure the difference in molecular weight of the complementary strands after denaturation. Refined sample preparation and deliberate rectilinear construction at a linear mass spectrometer produced a mass resolution exceeding 1000 for single-stranded DNA. We present methodologies and demonstrate the potential for analysing dsDNA by determining the mass of the complementary strands.
Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy (2014)

Owing to their integral involvement in cell cycle regulation, the Polo-like kinase (Plk) family, particularly Plk1, has emerged as an attractive therapeutic target in oncology. In recent years, several Plk1 inhibitors have been developed, with some agents showing encouraging results in early-phase clinical trials. This review focuses on volasertib (BI 6727; an investigational agent), a potent and selective Plk inhibitor. Volasertib has shown promising activity in various cancer cell lines and xenograft models of human cancer. Trials performed to date suggest that volasertib has clinical efficacy in a range of malignancies, with the most promising results seen in patients with acute myeloid leukemia (AML). Encouragingly, recent phase II data have demonstrated that volasertib combined with low-dose cytarabine (LDAC) was associated with higher response rates and improved event-free survival than LDAC alone in patients with previously untreated AML. Based on these observations, and its presumably manageable safety profile, volasertib is currently in phase III development as a potential treatment for patients with AML who are ineligible for intensive remission induction therapy. Given that many patients with AML are of an older age and frail, this constitutes an area of major unmet need. In this review, we discuss the biologic rationale for Plk1 inhibitors in cancer, the clinical development of volasertib to date in solid tumors and AML, and the future identification of biomarkers that might predict response to volasertib and help determine the role of this agent in the clinic.
Improving genetic diagnosis in Mendelian disease with transcriptome sequencing (2017)

Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in <i>COL6A1</i> that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.
A rule to predict which enantiomer of a secondary alcohol reacts faster in reactions catalyzed by cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosa (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA rule to predict which enantiomer of a secondary alcohol reacts faster in reactions catalyzed by cholesterol esterase, lipase from Pseudomonas cepacia, and lipase from Candida rugosaRomas J. Kazlauskas, Alexandra N. E. Weissfloch, Aviva T. Rappaport, and Louis A. CucciaCite this: J. Org. Chem. 1991, 56, 8, 2656–2665Publication Date (Print):April 1, 1991Publication History Published online1 May 2002Published inissue 1 April 1991https://pubs.acs.org/doi/10.1021/jo00008a016https://doi.org/10.1021/jo00008a016research-articleACS PublicationsRequest reuse permissionsArticle Views5401Altmetric-Citations839LEARN 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
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. (1994)

beta-Amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, we created (i) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (ii) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. These results indicate that beta A neurotoxicity requires fibril formation. These findings and our previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses.
Chemical imaging of artificial fingerprints by desorption electro-flow focusing ionization mass spectrometry (2014)

Desorption electro-flow focusing ionization (DEFFI) mass spectrometry was used to image chemical distributions of endogenous, e.g., fatty acids, and trace exogenous compounds, e.g., explosives, narcotics and lotions, in deposited and lifted artificial fingerprints, directly from forensic lift tape. An artificial fingerprint mold and synthetic fingerprint material were incorporated for the controlled deposition of material for technique demonstration and evaluation.
A human peripheral blood monocyte-derived subset acts as pluripotent stem cells (2003)

We have identified, cultured, characterized, and propagated adult pluripotent stem cells (PSC) from a subset of human peripheral blood monocytes. These cells, which in appearance resemble fibroblasts, expand in the presence of macrophage colony-stimulating factor and display monocytic and hematopoietic stem cell markers including CD14, CD34, and CD45. We have induced these cells to differentiate into mature macrophages by lipopolysaccharide, T lymphocytes by IL-2, epithelial cells by epidermal growth factor, endothelial cells by vascular endothelial cell growth factor, neuronal cells by nerve growth factor, and liver cells by hepatocyte growth factor. The pluripotent nature of individual PSC was further confirmed by a clonal analysis. The ability to store, expand, and differentiate these PSC from autologous peripheral blood should make them valuable candidates for transplantation therapy.
The Utility and Limitations of Current Web-Available Algorithms To Predict Peptides Recognized by CD4 T Cells in Response to Pathogen Infection (2012)

The ability to track CD4 T cells elicited in response to pathogen infection or vaccination is critical because of the role these cells play in protective immunity. Coupled with advances in genome sequencing of pathogenic organisms, there is considerable appeal for implementation of computer-based algorithms to predict peptides that bind to the class II molecules, forming the complex recognized by CD4 T cells. Despite recent progress in this area, there is a paucity of data regarding the success of these algorithms in identifying actual pathogen-derived epitopes. In this study, we sought to rigorously evaluate the performance of multiple Web-available algorithms by comparing their predictions with our results--obtained by purely empirical methods for epitope discovery in influenza that used overlapping peptides and cytokine ELISPOTs--for three independent class II molecules. We analyzed the data in different ways, trying to anticipate how an investigator might use these computational tools for epitope discovery. We come to the conclusion that currently available algorithms can indeed facilitate epitope discovery, but all shared a high degree of false-positive and false-negative predictions. Therefore, efficiencies were low. We also found dramatic disparities among algorithms and between predicted IC(50) values and true dissociation rates of peptide-MHC class II complexes. We suggest that improved success of predictive algorithms will depend less on changes in computational methods or increased data sets and more on changes in parameters used to "train" the algorithms that factor in elements of T cell repertoire and peptide acquisition by class II molecules.
Current clinical overview of cutaneous melanoma (2008)

This article reviews current evidence on epidemiology, diagnosis and management of cutaneous melanoma. Incidence of cutaneous melanoma is rising in all Caucasian populations across the world; thus, melanoma represents a significant public health burden. Although, incidence of melanoma is in continuous increase, a decrease of mortality and improved survival has been observed in most western European populations. Clinical characteristics of four major types of melanoma (superficial spreading, nodular, lentigo maligna melanoma and acral lentiginous melanoma) have been described. Surgical removal of melanoma remains the standard care in all primary melanomas. Current evidence suggests use of 1 to 2 cm excision margins. Wider margins may be necessary in patients with thicker melanomas with higher risk for local recurrence. In the treatment of regional lymph nodes elective lymphadenectomy has been surpassed by the sentinel lymph node biopsy (SLNB). However, although prognostic value of SLNB has been confirmed, its therapeutical benefit still needs to be evaluated. Currently there is no standard adjuvant therapy for melanoma although interferon-alpha has been the most widely used treatment in the adjuvant setting. The role of metastasectomy (removal of distant metastases) is still controversial. Chemotherapeutic agents have a limited activity in patients with metastatic melanoma with response rates up to 25%. Although different vaccines have been tested in melanoma patients their role still remain to be established in phase III trials. Progresses in molecular biology and genetics of melanoma may lead to the development of novel melanoma therapies.
Vicilin with carboxy‐terminal KDEL is retained in the endoplasmic reticulum and accumulates to high levels in the leaves of transgenic plants (1992)

Gene constructs were designed to test the effect of the endoplasmic reticulum (ER)-targeting signal, KDEL, on the level of accumulation of a foreign protein in transgenic plants. The gene for the pea seed protein vicilin was modified by the addition of a sequence coding for this tetrapeptide at its carboxyl terminus. The altered gene was placed under the control of a CaMV 35S promoter and its expression in the leaves of both tobacco and lucerne (alfalfa) was compared with that of an equivalent vicilin construct lacking the KDEL-coding sequence. The presence of the ER-targeting signal led to a greatly enhanced accumulation of the heterologous protein. In lucerne and tobacco leaves, the level of vicilin-KDEL protein was 20 and 100 times greater than that of the unmodified vicilin, respectively. These differences in expression level could not be explained by corresponding differences in the steady-state levels or the translatability of the mRNAs. However, when the stability of vicilin and vicilin-KDEL proteins was compared in their respective transgenic hosts, unmodified vicilin was found to be degraded with a half-life of 4.5 h while vicilin-KDEL was much more stable with a half-life of more than 48 h. Immunogold labelling of leaf tissues from transgenic lucerne and tobacco showed the presence of vicilin associated with large aggregates within the ER lumen of vicilin-KDEL plants. No such aggregates were detected in transgenic plants expressing wild-type vicilin. It is concluded that the carboxy-terminal KDEL caused the retention of the modified vicilin in the ER, and that this retention led to the increased stability and higher level of accumulation of vicilin-KDEL in leaves of transgenic plants.
Establishment of tumor‐specific copy number alterations from plasma DNA of patients with cancer (2013)

With the increasing number of available predictive biomarkers, clinical management of cancer is becoming increasingly reliant on the accurate serial monitoring of tumor genotypes. We tested whether tumor-specific copy number changes can be inferred from the peripheral blood of patients with cancer. To this end, we determined the plasma DNA size distribution and the fraction of mutated plasma DNA fragments with deep sequencing and an ultrasensitive mutation-detection method, i.e., the Beads, Emulsion, Amplification, and Magnetics (BEAMing) assay. When analyzing the plasma DNA of 32 patients with Stage IV colorectal carcinoma, we found that a subset of the patients (34.4%) had a biphasic size distribution of plasma DNA fragments that was associated with increased circulating tumor cell numbers and elevated concentration of mutated plasma DNA fragments. In these cases, we were able to establish genome-wide tumor-specific copy number alterations directly from plasma DNA. Thus, we could analyze the current copy number status of the tumor genome, which was in some cases many years after diagnosis of the primary tumor. An unexpected finding was that not all patients with progressive metastatic disease appear to release tumor DNA into the circulation in measurable quantities. When we analyzed plasma DNA from 35 patients with metastatic breast cancer, we made similar observations suggesting that our approach may be applicable to a variety of tumor entities. This is the first description of such a biphasic distribution in a surprisingly high proportion of cancer patients which may have important implications for tumor diagnosis and monitoring.
Cotargeting signaling pathways driving survival and cell cycle circumvents resistance to Kit inhibitors in leukemia (2012)

Oncogenic mutations leading to persistent kinase activities are associated with malignancies. Therefore, deciphering the signaling networks downstream of these oncogenic stimuli remains a challenge to gather insights into targeted therapy. To elucidate the biochemical networks connecting the Kit mutant to leukemogenesis, in the present study, we performed a global profiling of tyrosine-phosphorylated proteins from mutant Kit-driven murine leukemia proerythroblasts and identified Shp2 and Stat5 as proximal effectors of Kit. Shp2 or Stat5 gene depletion by sh-RNA, combined with pharmacologic inhibition of PI3kinase or Mek/Erk activities, revealed 2 distinct and independent signaling pathways contributing to malignancy. We demonstrate that cell survival is driven by the Kit/Shp2/Ras/Mek/Erk1/2 pathway, whereas the G(1)/S transition during the cell cycle is accelerated by both the Kit/Stat5 and Kit/PI3K/Akt pathways. The combined use of the clinically relevant drugs NVP-BEZ235, which targets the cell cycle, and Obatoclax, which targets survival, demonstrated synergistic effects to inhibit leukemia cell growth. This synergy was confirmed with a human mast leukemia cell line (HMC-1.2) that expresses mutant Kit. The results of the present study using liquid chromatography/tandem mass spectrometry analysis have elucidated signaling networks downstream of an oncogenic kinase, providing a molecular rationale for pathway-targeted therapy to treat cancer cells refractory to tyrosine kinase inhibitors.
All-optical micromechanical chemical sensors (2006)

The authors describe experimental results from micromechanical resonators coated with a chemoselective polymer that detect chemical vapors from volatile organic compounds using all-optical interrogation. The shift in the resonant frequency of the gold microbeam is read out using photothermal actuation and microcavity interferometry. Response times of less than 5s are achieved for vapor concentrations as low as 60ppm using optical powers of a few megawatts.
Cholesterol-dependent Pore Formation of Clostridium difficile Toxin A (2006)

The large clostridial cytotoxins toxin A and toxin B from Clostridium difficile are major virulence factors known to cause antibiotic-associated diarrhea and pseudomembranous colitis. Both toxins mono-glucosylate and thereby inactivate small GTPases of the Rho family. Recently, it was reported that toxin B, but not toxin A, induces pore formation in membranes of target cells under acidic conditions. Here, we reassessed data on pore formation of toxin A in cells derived from human colon carcinoma. Treatment of 86Rb+-loaded cells with native or recombinant toxin A resulted in an increased efflux of radioactive cations induced by an acidic pulse. The efficacy of pore formation was dependent on membrane cholesterol, since cholesterol depletion of membranes with methyl-beta-cyclodextrin inhibited 86Rb+ efflux, and cholesterol repletion reconstituted pore-forming activity of toxin A. Similar results were obtained with toxin B. Consistently, methyl-beta-cyclodextrin treatment delayed intoxication of cells in a concentration-dependent manner. In black lipid membranes, toxin A induced ion-permeable pores only in cholesterol containing bilayers and at low pH. In contrast, release of glycosylphosphatidylinositol-anchored structures by phosphatidylinositol specific phospholipase C treatment did not reduce cell sensitivity toward toxins A and B. These data indicate that in colonic cells toxin A induces pore formation in an acidic environment (e.g. endosomes) similar to that reported for toxin B and suggest that pore formation by clostridial glucosylating toxins depends on the presence of cholesterol.