gebhart/patrepeval huggingface dataset:
Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia (2006)

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little effect on the early disease phase but sharply slowed later disease progression. Onset and progression thus represent distinct disease phases defined by mutant action within different cell types to generate non-cell-autonomous killing of motor neurons; these findings validate therapies, including cell replacement, targeted to the non-neuronal cells.
TLR7 and TLR9 ligands regulate antigen presentation by macrophages (2015)

The toll-like receptors (TLRs) are important innate receptors recognizing potentially pathogenic material. However, they also play a significant role in the development of Alzheimer's disease, cancer, autoimmunity and the susceptibility to viral infections. Macrophages are essential for an effective immune response to foreign material and the resolution of inflammation. In these studies, we examined the impact of different TLR ligands on macrophage cell function. We demonstrate that stimulation of all TLRs tested increases the phagocytosis of apoptotic cells by macrophages. TLR7 and TLR9 ligation decreased the levels of the surface co-expression molecules CD86 and MHCII, which was associated with a concomitant reduction in antigen presentation and proliferation of T cells. This down-regulation in macrophage function was not due to an increase in cell death. In fact, exposure to TLR7 or TLR9 ligands promoted cell viability for up to 9 days, in contrast to TLR3 or TLR4. Additionally, macrophages exposed to TLR7/TLR9 ligands had a significantly lower ratio of Il-12/Il-10 mRNA expression compared with those treated with the TLR4 ligand, LPS. Taken together, these data demonstrate that TLR7/TLR9 ligands push the macrophage into a phagocytic long-lived cell, with a decreased capacity of antigen presentation and reminiscent of the M2 polarized state.
N,N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides (2003)

[reaction: see text] Ullmann-type diaryl ether synthesis can be performed at 90 degrees C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.
Understanding traditional Chinese medicine--a doctor's viewpoint. (2001)

Singapore is a cosmopolitan country and its population comprises the Chinese, Malays, Indians, and others such as the Eurasians. In this heterogeneous, multi-racial, multi-lingual and multi-cultural society, medical treatment is also varied. People can seek modern (mainstream, western) medicine or traditional medicine when they are sick. Usually they first seek modern medicine. Some turn to traditional medicine as complementary treatment or alternative treatment. Traditional medicine is here to stay in this country. In November 2000, the Traditional Chinese Medicine (TCM) Practitioners Bill was passed in the Singapore Parliament. Health care providers, including doctors, would benefit from a good knowledge of both modern and traditional medicine. Practitioners in traditional medicine should also learn modern medicine.
Microfabricated implants for applications in therapeutic delivery, tissue engineering, and biosensing (2008)

By adapting microfabrication techniques originally developed in the microelectronics industry novel devices for drug delivery, tissue engineering and biosensing have been engineered for in vivo use. Implant microfabrication uses a broad range of techniques including photolithography, and micromachining to create devices with features ranging from 0.1 to hundreds of microns with high aspect ratios and precise features. Microfabrication offers device feature scale that is relevant to the tissues and cells to which they are applied, as well as offering ease of en masse fabrication, small device size, and facile incorporation of integrated circuit technology. Utilizing these methods, drug delivery applications have been developed for in vivo use through many delivery routes including intravenous, oral, and transdermal. Additionally, novel microfabricated tissue engineering approaches propose therapies for the cardiovascular, orthopedic, and ocular systems, among others. Biosensing devices have been designed to detect a variety of analytes and conditions in vivo through both enzymatic-electrochemical reactions and sensor displacement through mechanical loading. Overall, the impact of microfabricated devices has had an impact over a broad range of therapies and tissues. This review addresses many of these devices and highlights their fabrication as well as discusses materials relevant to microfabrication techniques.
Disordered water within a hydrophobic protein cavity visualized by x-ray crystallography (1999)

Water in the hydrophobic cavity of human interleukin 1beta, which was detected by NMR spectroscopy but was invisible by high resolution x-ray crystallography, has been mapped quantitatively by measurement and phasing of all of the low resolution x-ray diffraction data from a single crystal. Phases for the low resolution data were refined by iterative density modification of an initial flat solvent model outside the envelope of the atomic model. The refinement was restrained by the condition that the map of the difference between the electron density distribution in the full unit cell and that of the atomic model be flat within the envelope of the well ordered protein structure. Care was taken to avoid overfitting the diffraction data by maintaining phases for the high resolution data from the atomic model and by a resolution-dependent damping of the structure factor differences between data and model. The cavity region in the protein could accommodate up to four water molecules. The refined solvent difference map indicates that there are about two water molecules in the cavity region. This map is compatible with an atomic model of the water distribution refined by using XPLOR. About 70% of the time, there appears to be a water dimer in the central hydrophobic cavity, which is connected to the outside by two constricted channels occupied by single water molecules approximately 40% of the time on one side and approximately 10% on the other.
Differential effects of estrone and estrone-3-O-sulfamate derivatives on mitotic. Arrest, apoptosis, and microtubule assembly in human breast cancer cells. (2000)

There is considerable interest in the potential use of estrogen derivatives for the treatment and prevention of breast cancer. We demonstrated previously that the sulfamoylated estrone derivative 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE) induced G2-M cell cycle arrest and modest levels of apoptosis in breast cancer cells in vitro, whereas the parent estrone derivative, 2-methoxyestrone, did not. 2-MeOEMATE also induced breast tumor regression in vivo in intact rats. To further explore the significance of sulfamoylation on the anticancer activity of estrone derivatives and to elucidate their mechanism of action, we synthesized two additional agents, 2-ethylestrone and 2-ethylestrone-3-O-sulfamate (2EtEMATE). 2-MeOEMATE and 2-EtEMATE inhibited the growth of a panel of estrogen receptor-negative and -positive breast cancer cell lines in vitro, induced mitotic arrest and apoptosis, and suppressed the long-term clonogenic potential of MCF7 and CAL51 breast cancer cells. In each assay, the sulfamoylated estrone derivatives were >10-fold more potent than their parent compounds. The sulfamoylated estrone derivatives were also significantly more potent inhibitors of cell growth than the previously studied endogenous estradiol metabolite 2-methoxyestradiol. 2-MeOEMATE and 2-EtEMATE functioned as antimicrotubule agents and inhibited the ability of paclitaxel to promote tubulin assembly in vitro. Like other antimicrotubule agents, the sulfamoylated estrone derivatives induced BCL-2 and BCL-XL phosphorylation and increased p53 expression. 2-MeOEMATE and 2-EtEMATE are novel antimicrotubule agents that have potent anticancer activity in breast cancer cells in vitro and may be beneficial as anticancer agents in vivo.
Preclinical models of antipsychotic drug action (2013)

One of the main obstacles faced by translational neuroscience is the development of animal models of psychiatric disorders. Behavioural pharmacology studies indicate that psychedelic drugs, such as lysergic acid diethylamide (LSD) and dissociative drugs, such as phencyclidine (PCP), induce in healthy human volunteers psychotic and cognitive symptoms that resemble some of those observed in schizophrenia patients. Serotonin 5-HT2A and metabotropic glutamate 2 receptors have been involved in the mechanism of action of psychedelic and dissociative drugs. Here we review recent advances using LSD-like and PCP-like drugs in rodent models that implicate these receptors in the neurobiology of schizophrenia and its treatment.
In-Cell PCR Method for Specific Genotyping of Genomic DNA from One Individual in a Mixture of Cells from Two Individuals: A Model Study with Specific Relevance to Prenatal Diagnosis Based on Fetal Cells in Maternal Blood (2002)

This approach might be usable on mixed cell populations of fetal and maternal cells obtained after conventional cell-sorting techniques on maternal peripheral vein blood.
Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. (1996)

The focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase implicated in integrin-mediated signal transduction pathways, oncogenic transformation by v-src, and the invasion of human tumors. The overexpression of p125FAK in a variety of human tumors and tumor cell lines in comparison to their nontransformed counterparts suggested that attenuation of p125FAK expression might have an effect on tumor cell proliferation. In this study, we have treated tumor cell lines that expressed high levels of p125FAK with different antisense oligonucleotides to FAK, and have specifically attenuated p125FAK expression. The cells treated with antisense oligonucleotides not only lost their attachment, but also underwent apoptosis. Extensive control oligonucleotide experiments suggested that this attenuation was highly FAK specific. Furthermore, normal human fibroblasts, which did not express high levels of p125FAK, did not lose their attachment or become apoptotic with FAK antisense treatment. These results suggested that FAK is involved in adhesion-mediated growth in tumor cells and that FAK may be a rational gene-directed target for disrupting tumor cell growth.
A CD133-Expressing Murine Liver Oval Cell Population with Bilineage Potential (2007)

Although oval cells are postulated to be adult liver stem cells, a well-defined phenotype of a bipotent liver stem cell remains elusive. The heterogeneity of cells within the oval cell fraction has hindered lineage potential studies. Our goal was to identify an enriched population of bipotent oval cells using a combination of flow cytometry and single cell gene expression in conjunction with lineage-specific liver injury models. Expression of cell surface markers on nonparenchymal, nonhematopoietic (CD45-) cells were characterized. Cell populations were isolated by flow cytometry for gene expression studies. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine toxic injury induced cell cycling and expansion specifically in the subpopulation of oval cells in the periportal zone that express CD133. CD133+CD45- cells expressed hepatoblast and stem cell-associated genes, and single cells coexpressed both hepatocyte and cholangiocyte-associated genes, indicating bilineage potential. CD133+CD45- cells proliferated in response to liver injury. Following toxic hepatocyte damage, CD133+CD45- cells demonstrated upregulated expression of the hepatocyte gene Albumin. In contrast, toxic cholangiocyte injury resulted in upregulation of the cholangiocyte gene Ck19. After 21-28 days in culture, CD133+CD45- cells continued to generate cells of both hepatocyte and cholangiocyte lineages. Thus, CD133 expression identifies a population of oval cells in adult murine liver with the gene expression profile and function of primitive, bipotent liver stem cells. In response to lineage-specific injury, these cells demonstrate a lineage-appropriate genetic response. Disclosure of potential conflicts of interest is found at the end of this article.
Role of the Nonsense-Mediated Decay Factor hUpf3 in the Splicing-Dependent Exon-Exon Junction Complex (2001)

Nonsense-mediated messenger RNA (mRNA) decay, or NMD, is a critical process of selective degradation of mRNAs that contain premature stop codons. NMD depends on both pre-mRNA splicing and translation, and it requires recognition of the position of stop codons relative to exon-exon junctions. A key factor in NMD is hUpf3, a mostly nuclear protein that shuttles between the nucleus and cytoplasm and interacts specifically with spliced mRNAs. We found that hUpf3 interacts with Y14, a component of post-splicing mRNA-protein (mRNP) complexes, and that hUpf3 is enriched in Y14-containing mRNP complexes. The mRNA export factors Aly/REF and TAP are also associated with nuclear hUpf3, indicating that hUpf3 is in mRNP complexes that are poised for nuclear export. Like Y14 and Aly/REF, hUpf3 binds to spliced mRNAs specifically ( approximately 20 nucleotides) upstream of exon-exon junctions. The splicing-dependent binding of hUpf3 to mRNAs before export, as part of the complex that assembles near exon-exon junctions, allows it to serve as a link between splicing and NMD in the cytoplasm.
Application of laser capture microdissection and proteomics in colon cancer (2001)

A method for performing two dimensional gel electrophoresis and mass spectrometry using laser capture microdissected tissue has been developed.
SsrA-mediated trans-translation plays a role in mRNA quality control by facilitating degradation of truncated mRNAs (2003)

An important unsolved question regarding the bacterial SsrA system is the fate of target mRNAs replaced by SsrA RNA during trans -translation. The aim of the present study is to address the potential role of SsrA system in mRNA quality control, focusing on truncated mRNAs that are expected to arise from 3′-to-5′ exonucleolytic attack. We found that significant amounts of truncated mRNAs and polypeptides were produced from genes lacking a ρ-independent terminator in SsrA-deficient cells. These truncated mRNAs, hence truncated polypeptides, were no longer observed in the presence of SsrA RNA. The data indicate that the SsrA system facilitates degradation of “nonstop” mRNAs by presumably removing the stalled ribosomes. Furthermore, analysis of affinity-purified proteins indicated that truncated polypeptides could be produced even from a gene with an intact ρ-independent terminator, although less efficiently, implying that C-terminally truncated proteins and 3′-truncated mRNA may be produced from virtually all protein-coding genes. We conclude that the SsrA system not only promotes the degradation of incomplete polypeptides but also minimizes the synthesis of incomplete polypeptides by facilitating the degradation of truncated mRNAs that are produced in cells.
Isolation and characterisation of a novel extremely thermophilic, anaerobic, chemo-organotrophic eubacterium (1986)

A new, extremely thermophilic, anaerobic, chemo-organotrophic bacterium was isolated from intertidal habitats where seepage of geothermally heated water occurs. The antibiotic sensitivity pattern and the presence of muramic acid strongly suggest an eubacterial nature of the novel isolate. Growth was measured between pH 4.8–8.2 (optimal pH 7.0) and at temperatures up to 90°C with a doubling time of 50 min at optimal temperatures of 80–85°C. This is the highest optimal growth temperature for an eubacterium described so far.
Chaos Out of Order: A Simple, Scalable File Distribution Facility For `Intentionally Heterogeneous' Networks (1997)

In large networks, heterogeneity in hardware, operating systems, user needs, and administrative responsibility often forms boundaries that inhibit sharing of information, expertise, and responsibility. These boundaries can divide networks into `feudal fiefdoms' of administrators, each with a disjoint domain of responsibility. DISTR is an easy-to-use file distribution tool for homogeneous networks that also provides controlled file transfer between disparate architectures and administrative domains. Using DISTR, administrators of unrelated networks can collaborate to reduce duplication of effort while retaining control of their own networks. DISTR's controls allow collaboration, cooperation, and camaraderie to evolve, not from grand and imposed designs, but from informal and serendipitous commonalities of mission and purpose.
Automated Segmentation of MR Images of Brain Tumors (2001)

An automated brain tumor segmentation method was developed and validated against manual segmentation with three-dimensional magnetic resonance images in 20 patients with meningiomas and low-grade gliomas. The automated method (operator time, 5-10 minutes) allowed rapid identification of brain and tumor tissue with an accuracy and reproducibility comparable to those of manual segmentation (operator time, 3-5 hours), making automated segmentation practical for low-grade gliomas and meningiomas.
The Biochemical Pathways of Nitric Oxide Formation from Nitrovasodilators (1991)

Summary: The endogenous formation of nitric oxide (NO) plays a key role in many bioregulatory systems including the control of vascular tone, platelet aggregation, neurotransmission, and macrophage cytotoxicity. Due to the instability and inconvenient handling of aqueous solutions of authentic NO, there is increasing interest in using compounds capable of generating NO in situ. Nitrova-sodilators are prodrugs of NO and thus principally suited to mimic endogenous NO activities. As each class of compound offers distinct biochemical properties, this allows one to choose a compound that best meets the demands of the respective investigations. Several studies in which nitrovasodilator compounds were applied as donors of NO have been performed under experimental conditions that appear to be unsuitable for maintaining a reproducible supply of NO. Potential problems may arise during the preparation of aqueous solutions, their application to biological systems, and during sample processing prior to chemical analysis. The objective of this review is to outline the different pathways and biochemical mechanisms that ultimately lead to the release of NO from organic nitrates and nitrites, S-nitrosothiols, sydnonimines, furoxans, and inorganic compounds such as nitrite and sodium nitroprusside. The influence of changes in pH and oxygen tension on the rate of NO generation as well as the requirement for cofactors to form NO are discussed. In addition, crucial steps in the preparation and use of NO solutions are presented. This overview will help researchers to recognize and avoid experimental traps that can lead to an inappropriate NO supply and/or the misinterpretation of experimental results.
Potential role for monocyte chemotactic protein-4 (MCP-4) in monocyte/macrophage recruitment in acute renal inflammation (2001)

The CC chemokine, monocyte chemoattractant protein-4 (MCP-4), is an important chemoattractant for monocytes and T cells. Recent data indicate a role in renal inflammation. This study has used in situ hybridization and immunohistochemical analysis of cryostat sections of biopsy material taken from patients with acute renal allograft rejection and vasculitic glomerulonephritis to demonstrate renal expression of MCP-4, both at message and protein level. MCP-4 was primarily expressed at peritubular, periglomerular, and perivascular sites, irrespective of the inflammatory condition, and was associated with infiltrating CD3-positive lymphocytes and CD68-positive monocyte/macrophages. In addition, proximal tubular epithelial cells grown in culture from cortical fragments of human kidney showed low levels of constitutive MCP-4 expression, detectable by western blotting; this expression of MCP-4 was up-regulated in response to the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). CCR3-, CCR5- and CCR2-expressing leukocyte populations were identified at sites of MCP-4 expression. Double-staining techniques revealed that CC chemokine receptor-expressing cells were primarily CD68-positive. These studies suggest an important role for MCP-4 in the recruitment and retention of monocytes/macrophages in renal inflammation.
Assembly of filamentous tau aggregates in human neuronal cells (2005)

Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as tauopathies. Formation of such fibril inclusions, consisting of hyperphosphorylated tau in multiple isoforms, correlates with the severity of cognitive decline in AD. How neurofibrillary pathology evolves in tauopathy remains unclear at present, but availability of a cellular model with robust tau aggregation will permit experimental scrutiny of the mechanistic process leading to such neurodegeneration. Through the use of a serial transfection strategy in conjunction with a tau minigene construct, we succeeded in generating conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in isoforms 4R0N, 3R1N and 4R1N via TetOff and ecdysone inducible expression mechanisms. Such transgenic overexpression of tau in multiple isoforms facilitated the assembly of filamentous tau aggregates that exhibit immunoreactivities, physicochemical properties, and ultrastructural attributes reminiscent of those found in human tauopathies. The conditional tau transfectants thus provide us with a useful tool to elucidate the molecular and cellular events leading to neurofibrillary degeneration and a convenient means to test hypothetical mechanisms implicated in the etiopathogenesis of AD and related tauopathies.
The Diploid Genome Sequence of an Individual Human (2007)

Presented here is a genome sequence of an individual human. It was produced from approximately 32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb) of contiguous sequence with approximately 7.5-fold coverage for any given region. We developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel) included 3,213,401 single nucleotide polymorphisms (SNPs), 53,823 block substitutions (2-206 bp), 292,102 heterozygous insertion/deletion events (indels)(1-571 bp), 559,473 homozygous indels (1-82,711 bp), 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggests an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, we were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information.