gebhart/patrepeval huggingface dataset:
The Granulocyte Colony-Stimulating Factor Receptor Is Required for the Mobilization of Murine Hematopoietic Progenitors Into Peripheral Blood by Cyclophosphamide or Interleukin-8 But Not Flt-3 Ligand (1997)

Hematopoietic progenitor cells (HPC) can be mobilized from the bone marrow into the peripheral circulation in response to a number of stimuli including hematopoietic growth factors, cytotoxic agents, and certain chemokines. Despite significant differences in their biological activities, these stimuli result in the mobilization of HPC with a similar phenotype, suggesting that a common mechanism for mobilization may exist. In this study, the role of granulocyte colony-stimulating factor (G-CSF) in progenitor mobilization was examined using G-CSF receptor (G-CSFR)–deficient mice. In contrast to wild-type mice, no increase in circulating colony-forming cells (CFU-C), CD34+ lineage− progenitors, or day 12 colony-forming unit-spleen progenitors (CFU-S) was detected in G-CSFR–deficient mice after cyclophosphamide administration. This defect was not due to a failure to regenerate HPC following cyclophosphamide administration as the number of CFU-C in the bone marrow of G-CSFR–deficient mice was increased relative to wild-type mice. Likewise, no increase in circulating CFU-C was detected in G-CSFR–deficient mice following interleukin-8 (IL-8) administration. In contrast, mobilization of HPC in response to flt-3 ligand was nearly normal. These results show that the G-CSFR is required for mobilization in response to cyclophosphamide or IL-8 but not flt-3 ligand and suggest that the G-CSFR may play an important and previously unexpected role in HPC migration.
Focus Issue: Fine-Tuning Hedgehog Signaling in Development and Disease (2011)

Hedgehog (Hh) signaling plays varied and critical roles in animal development, homeostasis, and disease. The core components of the canonical pathway and many key modulators of signaling have been identified, as have mechanisms by which the quantity and quality of signaling through the pathway are modulated. New research reveals details about generation and interpretation of Hh gradients, noncanonical Hh signaling, and fine-tuning the biological response to Hh signaling, particularly in the context of human diseases such as cancer.
The cellular basis of immune induction at mucosal surfaces by DNA vaccination. (2000)

The nasal mucosa provides a simple, non-invasive route to deliver DNA encoding the gene of interest to stimulate mucosal and systemic immune responses. However, unlike the intradermal or intramuscular routes for plasmid DNA (pDNA) delivery, immune responsiveness to antigen exposure at the respiratory mucosa is tightly regulated, consistent with the balance between active immunity and non-responsiveness to pathogenic or inert environmental antigens. We have characterised the antigen presenting cell types, their distribution and activation status following nasal vaccination with pDNA-cytofectin complexes encoding model antigens. We demonstrate that nasal immunisation is associated with expression of the encoded protein in a small population of dendritic cells and macrophages at the site of pDNA delivery, in the draining lymph nodes (LN) and in the spleen. Antigen expression by nasal dendritic cells was associated with up-regulation of surface MHC class II and CD86 expression and functional activation of T-lymphocytes. The results highlight the potential of intranasal vaccination with pDNA, provided the activation / costimulatory requirements for an active immune response are achieved.
Hot Spots in Tcf4 for the Interaction with β-Catenin (2003)

The interaction of beta-catenin with T-cell factor (Tcf) 4 plays a central role in the Wnt signaling pathway and has been discussed as a possible site of intervention for the development of anti-cancer drugs. In this study, we performed Ala-scanning mutagenesis of all Tcf4 residues in the Tcf-beta-catenin interface and studied the binding energetics of these mutants using isothermal titration calorimetry. Binding of Tcf4 was found to be highly cooperative. Single site mutations of most Tcf4 residues resulted in a significant reduction in binding enthalpies but in similar binding constants as compared with wild type Tcf4. Interestingly, this was also true for residues that are disordered in the reported crystal structures. The mutation D16A caused the largest reduction in binding constant (50-fold) accompanied by a large unfavorable enthalpy change (DeltaDeltaHobs) of +8 kcal/mol at 25 degrees C. In contrast, the mutation of the Tcf residues Glu24 and Glu28, which have been proposed as an interaction hot spot due to their location in a field of strong positive electrostatic potential on the beta-catenin surface (charge button), resulted only in a significant reduction of binding enthalpies, which were largely compensated for by unfavorable entropic contributions to the binding. Other mutations that significantly reduced Tcf binding constants were D11A and alanine mutations of the hydrophobic residues Leu41, Val44, and Leu48. The measured thermodynamic data are discussed with the available structural information of Tcf-beta-catenin crystal structures and allow us to propose possible sites for development of Tcf antagonists.
Regulation of TNF-alpha and IL-1 gene expression during TPA-induced differentiation of "Malignant histiocytosis" DEL cell line t(5;6) (q35:p21). (1996)

The production of TNF-alpha and IL-1 alpha and beta molecules has been shown to be associated with the proliferation and activation of cells of the monocyte/macrophage series, the intermediate steps in the synthesis of these molecules have been less investigated. Unstimulated and TPA stimulated DEL cells (a CD30-positive, t(5;6)(q35;p21) malignant histiocytosis cell line) were used to study the expression of TNF-alpha and IL-1 genes and to evaluate, by nuclear run-on assay and biological measurements, the control of their transcription and the level of protein production. To refine this analysis, the effects of cycloheximide and actinomycin D were also evaluated in this investigation. Following TPA stimulation, transcription of TNF-alpha (constitutively present) increased threefold as early as 30 mins and started decreasing by 24h. Cycloheximide superinduced the expression of TNF-alpha mRNA and, accordingly, the release of its protein. By contrast, transcription of IL-1 molecules appeared de novo and did not result in a biologically detectable protein. Measurements of RNA half line after actinomycin D indicated that TNF-a and IL-1 alpha mRNAs are not as stable as that of IL-1 beta. These results indicate that, despite their common synergistic activity, the transcriptional and post-transcriptional mechanisms regulating the synthesis of TNF-alpha and IL-1 alpha and IL-1 beta involve different pathways.
Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. (2003)

We evaluated the effects of diet on intestinal tumorigenesis in male Apc(Min) mice by comparing AIN-76A diet fed ad libitum (CON); calorie intake restricted by 40% of the CON (CR); diet high in olive oil and supplemented with freeze-dried fruit and vegetable extracts (OFV); and diet high in total fat (HF). Compared with CON, the frequency of intestinal polyps was reduced by 57% by CR (P < 0.001) and by 33% OFV diet (P = 0.04). Both effective interventions reduced total body weight, lean mass, and fat mass and increased daily urinary corticosterone output, but only CR reduced serum insulin-like growth factor I and leptin. We conclude that dietary interventions can partially offset genetic susceptibility to intestinal carcinogenesis.
Defining the Differences Between Episodic Migraine and Chronic Migraine (2011)

Chronic migraine (CM) and episodic migraine (EM) are part of the spectrum of migraine disorders, but they are distinct clinical entities. Population-based studies have shown that those with CM demonstrate higher individual and societal burden because they are significantly more disabled than those with EM and have greater impaired quality of life both inside and outside the home. Proper diagnosis of both conditions requires clearly defined clinical criteria. Diagnosis enables the initiation of appropriate treatments and risk-factor modification, which ultimately improve functional status and quality of life for persons with migraine. Recognizing that both disorders are on the spectrum of migraine, this review serves as a guide to define the disease state of CM as distinct from EM in terms of clinical, epidemiological, sociodemographic, and comorbidity profiles.
A reconfigurable design-for-debug infrastructure for SoCs (2006)

In this paper we present a Design-for-Debug (DFD) reconfigurable infrastructure for SoCs to support at-speed in-system functional debug. A distributed reconfigurable fabric inserted at RTL provides a debug platform that can be configured and operated post-silicon via the JTAG port. The platform can be repeatedly reused to configure many debug structures such as assertions checkers, transaction identifiers, triggers, and event counters.
HLA Haplotyping from RNA-seq Data Using Hierarchical Read Weighting (2013)

Correctly matching the HLA haplotypes of donor and recipient is essential to the success of allogenic hematopoietic stem cell transplantation. Current HLA typing methods rely on targeted testing of recognized antigens or sequences. Despite advances in Next Generation Sequencing, general high throughput transcriptome sequencing is currently underutilized for HLA haplotyping due to the central difficulty in aligning sequences within this highly variable region. Here we present the method, HLAforest, that can accurately predict HLA haplotype by hierarchically weighting reads and using an iterative, greedy, top down pruning technique. HLAforest correctly predicts >99% of allele group level (2 digit) haplotypes and 93% of peptide-level (4 digit) haplotypes of the most diverse HLA genes in simulations with read lengths and error rates modeling currently available sequencing technology. The method is very robust to sequencing error and can predict 99% of allele-group level haplotypes with substitution rates as high as 8.8%. When applied to data generated from a trio of cell lines, HLAforest corroborated PCR-based HLA haplotyping methods and accurately predicted 16/18 (89%) major class I genes for a daughter-father-mother trio at the peptide level. Major class II genes were predicted with 100% concordance between the daughter-father-mother trio. In fifty HapMap samples with paired end reads just 37 nucleotides long, HLAforest predicted 96.5% of allele group level HLA haplotypes correctly and 83% of peptide level haplotypes correctly. In sixteen RNAseq samples with limited coverage across HLA genes, HLAforest predicted 97.7% of allele group level haplotypes and 85% of peptide level haplotypes correctly.
Retina or visual cortex? The site of phosphene induction by transcranial alternating current stimulation (2009)

GENERAL COMMENTARY article Front. Integr. Neurosci., 18 May 2009 https://doi.org/10.3389/neuro.07.006.2009
The influence of monolithic series connection on the efficiency of GaAs photovoltaic converters for monochromatic illumination (2001)

This paper presents a theoretical study of the performance and optimization of monolithically series connected GaAs photovoltaic converters under homogeneous monochromatic illumination. The effects of base resistance, perimeter recombination, and isolation trench optical losses on device efficiency are especially highlighted. All the calculations are made for values of the number of individual photovoltaic converters connected in series, n, of 1 (such is the case of a conventional GaAs photovoltaic converter without monolithic connection) 2, 3, and 6. The results show that the losses in monolithic connection can be minimized by means of an increase in device area together with the inclusion of a highly doped lateral conduction layer, and that monolithic connection does not lead to a greater immunity from high series resistance relative to a conventional photovoltaic converter (as stated in literature). The maximum efficiencies predicted are 60.2, 58.9, 58.5, and 57.5% for n=1, 2, 3, and 6, respectively, for an illumination power density of between 10 and 20 W/cm/sup 2/ and a wavelength of 830 nm. Nevertheless, if a dc-dc converter is considered to boost the voltage of an n=1 GaAs photovoltaic converter (with losses associated to this circuit usually of 20%), its maximum efficiency drops to 48.2%.
Protein stability promotes evolvability (2006)

The biophysical properties that enable proteins to so readily evolve to perform diverse biochemical tasks are largely unknown. Here, we show that a protein's capacity to evolve is enhanced by the mutational robustness conferred by extra stability. We use simulations with model lattice proteins to demonstrate how extra stability increases evolvability by allowing a protein to accept a wider range of beneficial mutations while still folding to its native structure. We confirm this view experimentally by mutating marginally stable and thermostable variants of cytochrome P450 BM3. Mutants of the stabilized parent were more likely to exhibit new or improved functions. Only the stabilized P450 parent could tolerate the highly destabilizing mutations needed to confer novel activities such as hydroxylating the antiinflammatory drug naproxen. Our work establishes a crucial link between protein stability and evolution. We show that we can exploit this link to discover protein functions, and we suggest how natural evolution might do the same.
CLEAVAGE OF XANTHENE ETHERS: A NEW ROUTE TO 9-SUBSTITUTED XANTHENES (1964)

9,9-(Tetrachloro-o-phenylenedioxy) xanthene (IIa) and its thio-analogue (IIb) are cleaved by hydrazines to give the corresponding hydrazones of xanthone and thiaxanthone, respectively, together with tetrachlorocatechol. The unsaturated nitriles (Va), (Vb), and (Vc) are produced similarly by the action of malononitrile and cyanoacetic ester. Dixanthenyl ether itself reacts in a similar manner with active hydrogen compounds to give the corresponding 9-xanthyl derivatives. (IIb) is prepared by the action of 9-diazothiaxanthene on tetrachloro-o-benzoquinone and is readily cleaved by lithium aluminum hydride to give thiaxanthene and tetrachlorocatechol. The reaction mechanisms are discussed.
NCBI GEO: archive for functional genomics data sets--10 years on (2010)

A decade ago, the Gene Expression Omnibus (GEO) database was established at the National Center for Biotechnology Information (NCBI). The original objective of GEO was to serve as a public repository for high-throughput gene expression data generated mostly by microarray technology. However, the research community quickly applied microarrays to non-gene-expression studies, including examination of genome copy number variation and genome-wide profiling of DNA-binding proteins. Because the GEO database was designed with a flexible structure, it was possible to quickly adapt the repository to store these data types. More recently, as the microarray community switches to next-generation sequencing technologies, GEO has again adapted to host these data sets. Today, GEO stores over 20,000 microarray- and sequence-based functional genomics studies, and continues to handle the majority of direct high-throughput data submissions from the research community. Multiple mechanisms are provided to help users effectively search, browse, download and visualize the data at the level of individual genes or entire studies. This paper describes recent database enhancements, including new search and data representation tools, as well as a brief review of how the community uses GEO data. GEO is freely accessible at http://www.ncbi.nlm.nih.gov/geo/.
Retracted: ‘Clinical trials in Alzheimer’s disease’: immunotherapy approaches (2011)

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β (Aβ) peptide represents an important molecular target for intervention in Alzheimer's disease. Several types of Aβ peptide immunotherapy for Alzheimer's disease are under investigation, direct immunization with synthetic intact Aβ(42) , active immunization involving the administration of synthetic fragments of Aβ peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aβ peptide. Pre-clinical studies showed that immunization against Aβ peptide can provide protection and reversal of the pathology of Alzheimer's disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aβ peptide immunotherapy approaches are under investigation but also against tau pathology.
<title>Compact multi-functional skin spectrometry set-up</title> (2006)

A portable fibre-optic spectrometry set-up has been assembled and tested for applications in skin diffuse reflectance spectrometry, laser fluorescence spectrometry and multi-wavelength reflection photoplethysmography (multi-PPG) studies. The spectrometry set was tested by diffuse reflectance and fluorescence measurements for diagnostics of skin vascular malformations and pigmented diseases such as <i>nevi</i> and <i>melanoma</i>. In addition, studies of microcirculation in blood vessels located at different depths from the skin surface were performed by the multi-PPG method. The results of skin diffuse reflectance and autofluorescence showed differences in spectra of healthy and pathologic skin. The parameter ratio "pathologic/healthy" has been calculated in order to check the possibility of quantifying the specific pathology. The autofluorescence fading effect was observed. Our studies of the blood volume pulsations confirmed the possibility to separate the time-variable PPG component from the total skin diffuse reflectance signal.
SLINK: Simple, Effective Filesystem Maintenance Abstractions for Community-Based Administration (1996)

We manage several large UNIX program repositories through a community effort of volunteerism and advocacy. Our effort requires a carefully crafted interplay between administrative policy and tools that operate within the limits of that policy. Rather than restricting administrators' actions, our tools reinforce their own use by making it easier and more effective to comply with policy than to dissent. Our tool SLINK provides a small number of commands that aid in synthesizing user environments from sets of disjoint software package trees. SLINK's commands, while more powerful than typical UNIX commands, refuse to violate predefined policy restrictions, thus protecting the user environment even from mistakes of root users. Our administrative policy and SLINK allow us to employ an arbitrarily large number of volunteer administrators without degrading system behavior or utilizing large amounts of staff time.
Antitumor Agents. 166. Synthesis and Biological Evaluation of 5,6,7,8-Substituted-2-phenylthiochromen-4-ones (1996)

As a continuation of our structure--activity relationship study of substituted 2-phenyl-4-quinolones and flavonoids as antitumor and antiviral agents, a series of 5,6,7,8-substituted-2-phenylthiochromen-4-ones has been synthesized by condensation of substituted thiophenols and ethyl benzoylacetates. Target compounds were evaluated for biological activity. Among them, compounds 7, 10, 12, and 13 displayed significant growth inhibitory action against a panel of tumor cell lines including human ileocecal carcinoma (HCT-8), murine leukemia (P-388), human melanoma (RPMI), and human central nervous system tumor (TE671) cells. Compounds 10, 12, and 19 displayed DNA topoisomerase I inhibitory activity in vitro and compound 11 was an in vitro, inhibitor of DNA topoisomerase II. Compound 11 was most active (ED50 value, 0.65 microM) against HIV in acutely infected H9 lymphocytes and had a therapeutic index of about 5.
Capacity of intrinsic cardiac neurons to modify the acutely autotransplanted mammalian heart. (1995)

The capacity of the intrinsic cardiac nervous system to modify the acutely autotransplanted heart was investigated in eight anesthetized open-chest canine preparations in which the adrenal glands had been removed from the circulation. Cardiac effects elicited by isoproterenol and nicotine were also examined before and after heart-lung transplantation. Cardiac augmentation induced by isoproterenol was similar before and immediately after cardiopulmonary transplantation, indicating that the surgery did not obtund cardiac myocyte function significantly. The initial bradycardia induced by nicotine was greater before transplantation. The subsequent augmentation in left atrial systolic pressure, as well as right and left ventricular intramyocardial systolic pressures, induced by nicotine were similar before and after transplantation. When nicotine was administered to transplanted preparations after atropine administration, cardiac augmentation was induced. Cardiac augmentation was not induced by nicotine after subsequent beta-adrenergic blockade. These data indicate that nicotine-sensitive adrenergic neurons which accompany the transplanted heart are capable of inducing considerable cardiac augmentation. Power spectral analysis of heart rate and left ventricular chamber rate of pressure rise variability indicated an almost complete lack of power in these indexes after, as opposed to before, transplantation. Together with intrinsic cardiac cholinergic neurons, intrinsic cardiac adrenergic neurons may be responsible for physiologically and pharmacologically induced alterations in cardiac variables that occur in acutely transplanted hearts.
ABL Oncogenes and Phosphoinositide 3-Kinase: Mechanism of Activation and Downstream Effectors (2005)

The BCR-ABL oncogene is responsible for most cases of chronic myelogenous leukemia and some acute lymphoblastic leukemias. The fusion protein encoded by BCR-ABL possesses an aberrantly regulated tyrosine kinase activity. Imatinib mesylate (Gleevec, STI-571) is an inhibitor of ABL tyrosine kinase activity that has been remarkably effective in slowing disease progression in patients with chronic phase chronic myelogenous leukemia, but the emergence of imatinib resistance underscores the need for additional therapies. Targeting signaling pathways activated by BCR-ABL is a promising approach for drug development. The study of signaling components downstream of BCR-ABL and the related murine oncogene v-Abl has revealed a complex web of signals that promote cell division and survival. Of these, activation of phosphoinositide 3-kinase (PI3K) has emerged as one of the essential signaling mechanisms in ABL leukemogenesis. This review describes molecular mechanisms by which PI3K is activated and the downstream PI3K effectors that propagate the signal to promote myeloid and lymphoid transformation. Of particular recent interest is the mammalian target of rapamycin, a PI3K-regulated kinase that regulates protein synthesis and contributes to leukemogenesis.