gebhart/patrepeval huggingface dataset:
Application of Base Cleavable Safety Catch Linkers to Solid Phase Library Production (2000)

We have used sulfide "Safety Catch" linkers to anchor typical medicinal chemistry functional groups to amine resins. Compounds are loaded as the ester, carbamate, or amine. At the end of the synthesis, the linker is activated by peracid. The sulfone resins are then cleaved by beta-elimination in the gas phase or in solution by secondary amines to produce acids and primary, secondary, or tertiary amines. Comparison of cleavage rates to other sulfone resins including SEM showed significantly faster cleavage for this system with conditions similar to Fmoc deprotection. Application of this strategy to a medicinal chemistry library gives good yields and purities of the resulting compounds.
Rural Africa (2013)

Evidence of the value of African markets has mounted in recent years, with the continent contributing six of the world's ten fastest-growing economies between 2001 and 2010. Unsurprisingly, therefore, companies are now flocking to assess the business opportunities Africa has to offer – with demand for research consultancy soaring.
The COQ7 Gene Encodes a Protein in Saccharomyces cerevisiae Necessary for Ubiquinone Biosynthesis (1996)

Ubiquinone (coenzyme Q) is a lipid that transports electrons in the respiratory chains of both prokaryotes and eukaryotes. Mutants of Saccharomyces cerevisiae deficient in ubiquinone biosynthesis fail to grow on nonfermentable carbon sources and have been classified into eight complementation groups (coq1 coq8; Tzagoloff, A., and Dieckmann, C. L.(1990) Microbiol. Rev. 54, 211-225). In this study we show that although yeast coq7 mutants lack detectable ubiquinone, the coq7 1 mutant does synthesize demethoxyubiquinone (2-hexaprenyl-3-methyl-6-methoxy-1,4-benzoquinone), a ubiquinone biosynthetic intermediate. The corresponding wild-type COQ7 gene was isolated, sequenced, and found to restore growth on nonfermentable carbon sources and the synthesis of ubiquinone. The sequence predicts a polypeptide of 272 amino acids which is 40% identical to a previously reported Caenorhabditis elegans open reading frame. Deletion of the chromosomal COQ7 gene generates respiration defective yeast mutants deficient in ubiquinone. Analysis of several coq7 deletion strains indicates that, unlike the coq7 1 mutant, demethoxyubiquinone is not produced. Both coq7 1 and coq7 deletion mutants, like other coq mutants, accumulate an early intermediate in the ubiquinone biosynthetic pathway, 3-hexaprenyl-4-hydroxybenzoate. The data suggest that the yeast COQ7 gene may encode a protein involved in one or more monoxygenase or hydroxylase steps of ubiquinone biosynthesis.
Targeted drug delivery (1986)

Cancer chemotherapy drugs are neither specific, i.e., they do not act exclusively on the metabolic pathways of cancer cells, nor are they targeted solely toward cancer cells. However, recent research has begun to address, in part, the latter issue. Improved delivery of chemotherapeutic agents to tumor tissue in man appears to be an achievable goal in the next decade. Improved drug delivery includes developing predictive models that allow for laboratory assessment of the best treatment for a patient's cancer without exposing the patient to an empirical trial or to the possible morbidity from exposure to a less useful drug, or to the loss of time in the fight against cancer because of ineffectual therapy. Monoclonal antibodies directed against tumor-associated antigens have the potential to achieve major advances in targeted drug delivery. Monoclonal antibodies may have direct antitumor effects, or they can be used as "homing devices" when attached to a payload and can guide diagnostic or therapeutic agents to the targeted tissues. Carrier systems of all types have become available; these include liposomes and polymeric compounds which can carry drugs, radionuclides, toxins, or other materials in a protected environment. These carriers can also be bound to monoclonal antibodies for possible targeted delivery. Pharmacological sanctuaries have been recognized as a problem in cancer treatment. The best known of these is the central nervous system (CNS). Techniques to temporarily disrupt the blood-brain barrier are now appearing. Mechanisms to administer therapy directly into the CNS are also being reassessed. Implantable pumps and reservoirs have been used to treat selected organs or for regional perfusions. Other treatments that are regional in scope include administration directly into a cavity or into a tumor. Computerized implantable devices should play a major role in cancer therapy in the future, in pain control as well as antibiotic and hormone administration. In recent years, mathematical models have been developed that can more accurately predict drug distribution and metabolism in various tissues of the body. Such models point the way to more logical designs of chemotherapeutic administration. The expanded use of autologous bone marrow transplantation, along with improving techniques of "purging" the marrow of tumor cells before reinfusion can be anticipated. Pro-drugs are substances that must be biotransformed in vivo to exert their pharmacologic effect.(ABSTRACT TRUNCATED AT 400 WORDS)
The Role of the 3-Hydroxy 3-Methylglutaryl Coenzyme A Reductase Cytosolic Domain in Karmellae Biogenesis (1999)

In all cells examined, specific endoplasmic reticulum (ER) membrane arrays are induced in response to increased levels of the ER membrane protein 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase. In yeast, expression of Hmg1p, one of two yeast HMG-CoA reductase isozymes, induces assembly of nuclear-associated ER stacks called karmellae. Understanding the features of HMG-CoA reductase that signal karmellae biogenesis would provide useful insights into the regulation of membrane biogenesis. The HMG-CoA reductase protein consists of two domains, a multitopic membrane domain and a cytosolic catalytic domain. Previous studies had indicated that the HMG-CoA reductase membrane domain was exclusively responsible for generation of ER membrane proliferations. Surprisingly, we discovered that this conclusion was incorrect: sequences at the carboxyl terminus of HMG-CoA reductase can profoundly affect karmellae biogenesis. Specifically, truncations of Hmg1p that removed or shortened the carboxyl terminus were unable to induce karmellae assembly. This result indicated that the membrane domain of Hmg1p was not sufficient to signal for karmellae assembly. Using beta-galactosidase fusions, we demonstrated that the carboxyl terminus was unlikely to simply serve as an oligomerization domain. Our working hypothesis is that a truncated or misfolded cytosolic domain prevents proper signaling for karmellae by interfering with the required tertiary structure of the membrane domain.
Precursor route chemistry and electronic properties of poly(p-phenylenevinylene), poly[(2,5-dimethyl-p-phenylene)vinylene] and poly[(2,5-dimethoxy-p-phenylene)vinylene] (1992)

Several precursor polymer routes to poly(p-phenylenevinylene)4, poly[(2,5-dimethyl-p-phenylene)vinylene]10 and poly[(2,5-dimethoxy-p-phenylene)vinylene]15 are described. Base induced polymerisation of bis-sulfonium salt monomers afforded the polyelectrolytes 3 and 9 which were converted respectively directly into either polymer 4 or 10. Optimised conditions for the complete displacement of sulfonium groups by methanol to produce the corresponding methoxy precursor polymers 5, 11 and 17 are reported. The fully conjugated polymers obtained after heat and acid treatment of these precursors have been characterised and compared with those obtained via different precursor routes. The 1H NMR spectra of the precursor polymers, as well as IR and UV–VIS data of both the precursor polymers and the materials obtained after conversion into the poly(arylenevinylene)s are discussed.
Identification of novel small molecules that inhibit STAT3-dependent transcription and function (2017)

Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti-cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z' = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter-screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3-dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents.
The molecular chaperone Hsp90 is required for signal transduction by wild-type Hck and maintenance of its constitutively active counterpart. (2001)

We have investigated the relationship between the molecular chaperone heat shock protein-90 (Hsp90) and the signal transducing capacity of the Src-family kinase Hck. Inhibition of Hsp90 with geldanamycin suppressed the ability of bacterial lipopolysaccharide to enhance the cell adhesion properties of macrophages, a phenomenon most likely explained by the reduced expression and activity of Hck in macrophages lacking Hsp90 function. The contribution of Hsp90 to signal transduction by Hck was biochemically dissected further by examining its role in the de novo folding and maintenance of wild-type Hck and its constitutively active counterpart, Hck499F. The folding of nascent wild-type Hck and Hck499F into catalytically active conformations, and their accumulation in cells was found to be dependent on Hsp90 function. Notably, mature Hck499F had a greater requirement for on-going support from Hsp90 than did mature wild-type Hck. This particular finding might have important implications for our understanding of the evolution of oncogenic protein kinases.
Preparation and Biological Characterization of Polymeric Micelle Drug Carriers with Intracellular pH-Triggered Drug Release Property:  Tumor Permeability, Controlled Subcellular Drug Distribution, and Enhanced in Vivo Antitumor Efficacy (2004)

A novel intracellular pH-sensitive polymeric micelle drug carrier that controls the systemic, local, and subcellular distributions of pharmacologically active drugs has been developed in this study. The micelles were prepared from self-assembling amphiphilic block copolymers, poly(ethylene glycol)-poly(aspartate hydrazone adriamycin), in which the anticancer drug, adriamycin, was conjugated to the hydrophobic segments through acid-sensitive hydrazone linkers. By this polymer design, the micelles can stably preserve drugs under physiological conditions (pH 7.4) and selectively release them by sensing the intracellular pH decrease in endosomes and lysosomes (pH 5-6). In vitro and in vivo studies show that the micelles have the characteristic properties, such as an intracellular pH-triggered drug release capability, tumor-infiltrating permeability, and effective antitumor activity with extremely low toxicity. The acquired experimental data clearly elucidate that the optimization of both the functional and structural features of polymeric micelles provides a promising formulation not only for the development of intracellular environment-sensitive supramolecular devices for cancer therapeutic applications but also for the future treatment of intractable cancers with limited vasculature.
Myopalladin, a Novel 145-Kilodalton Sarcomeric Protein with Multiple Roles in Z-Disc and I-Band Protein Assemblies (2001)

We describe here a novel sarcomeric 145-kD protein, myopalladin, which tethers together the COOH-terminal Src homology 3 domains of nebulin and nebulette with the EF hand motifs of alpha-actinin in vertebrate Z-lines. Myopalladin's nebulin/nebulette and alpha-actinin-binding sites are contained in two distinct regions within its COOH-terminal 90-kD domain. Both sites are highly homologous with those found in palladin, a protein described recently required for actin cytoskeletal assembly (Parast, M.M., and C.A. Otey. 2000. J. Cell Biol. 150:643-656). This suggests that palladin and myopalladin may have conserved roles in stress fiber and Z-line assembly. The NH(2)-terminal region of myopalladin specifically binds to the cardiac ankyrin repeat protein (CARP), a nuclear protein involved in control of muscle gene expression. Immunofluorescence and immunoelectron microscopy studies revealed that myopalladin also colocalized with CARP in the central I-band of striated muscle sarcomeres. Overexpression of myopalladin's NH(2)-terminal CARP-binding region in live cardiac myocytes resulted in severe disruption of all sarcomeric components studied, suggesting that the myopalladin-CARP complex in the central I-band may have an important regulatory role in maintaining sarcomeric integrity. Our data also suggest that myopalladin may link regulatory mechanisms involved in Z-line structure (via alpha-actinin and nebulin/nebulette) to those involved in muscle gene expression (via CARP).
High recovery of cell-free methylated DNA based on a rapid bisulfite-treatment protocol (2012)

The method presented here allows low levels of DNA to be easily and reliably analysed, a prerequisite for the clinical usefulness of cell-free methylated DNA detection in plasma.
NIRCA: a rapid robust method for screening for unknown point mutations. (1996)

We describe a method for screening for dispersed point mutations, based on the observation that RNase frequently cleaves both strands of base pair mismatches in duplex RNA targets. The mismatched substrates are generated by in vitro transcription of wild-type and mutant templates amplified by the PCR or reverse transcription (RT)-PCR; bacteriophage promoters are incorporated into the PCR primers to permit both strands of the products to be transcribed into RNA. Complementary wild-type and mutant transcripts are hybridized and treated with RNase, and the cleavage products are separated on agarose gels and detected by visualization of the ethidium-stained sample under UV light. The method is thus non-isotopic, and since the cleavage products remain double-stranded during analysis, the labor-intensive RNase inactivation steps required in the original procedure can be eliminated. Also, nonspecific background cleavage is reduced so that longer target regions (1 kb) can be screened in a single step. The Non-Isotopic RNase Cleavage Assay (NIRCA) achieved a detection rate of 88%-90% in blind studies in a Factor IX model system, and it was also used to detect unknown p53 mutations in breast tumor samples. NIRCA provides a rapid method for sensitive, non-isotopic, high-throughput genetic screening.
Integration of Automatic Intrathoracic Fluid Content Measurement into Clinical Decision Making in Patients with Congestive Heart Failure (2008)

Automatic impedance measurement can be integrated into CHF management. BNP measurement restricted to patients with alert but without clinical signs of worsened CHF may prevent premature therapy escalation.
The use of antidepressants to treat depression in children and adolescents (2006)

The dramatic increase over the past 10 years in the amount of available clinical research on the use of antidepressants to treat major depression in children and adolescents has substantially improved our knowledge of the safety and efficacy of these medications in the pediatric population. Many questions remain, however, that highlight the need to continue research in this patient population rather than relying on the extrapolation of data from trials involving adults. In this article, we review the current state of research into antidepressant therapy for major depression in children and adolescents. In addition, we discuss methodologic issues and clinical implications specific to the pediatric population.
Assessment of mechanical properties of isolated bovine intervertebral discs from multi-parametric magnetic resonance imaging (2012)

The compressive moduli and the permeabilities of isolated IVDs can be assessed mostly by MT and diffusion sequences. However, the relationships have to be improved with the inclusion of MRI parameters more sensitive to IVD degeneration. Before the use of this technique to quantify the mechanical properties of IVDs in vivo on patients suffering from various diseases, the relationships have to be defined for each degeneration state of the tissue that mimics the pathology. Our MRI protocol associated to principal component analysis and agglomerative hierarchical clustering are promising tools to classify the degenerated intervertebral discs and further find biomarkers and predictive factors of the evolution of the pathologies.
Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K (2005)

Pathological changes in the microtubule associated protein tau are a major hallmark of many human dementias collectively defined as tauopathies. In familiar frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), several mutations in the tau gene have been identified showing that primary malfunction of tau can lead to neurodegeneration. In addition to mutation at genetic level, a number of post-translational modifications of tau occur in tauopathies, including abnormal phosphorylation and aberrant proteolysis described in Alzheimer's Disease (AD). The presence of cleaved tau in AD neurons is associated with expression of markers for neuronal death. According to our previous work, tau is a substrate for the apoptotic protease caspase-3 that turns tau itself into an effector of apoptosis (tau cleaved at D-421), generating a positive-feedback loop that is self-propagating. Cleavage of tau by caspase-3 was recently confirmed to occur in AD brain as an early event. Here we show the apoptotic properties of tau fragment tau151-421 in primary cultures of rat hippocampal neurons; such cellular model is of special interest considering the selective vulnerability of hippocampal neurones in AD. The apoptotic capacity of tau151-421 is markedly enhanced by both treatment with amyloid peptide Abeta25-35, and the FTDP-17 tau mutation N279K.
Novel cluster of alpha-interferon gene sequences in a placental cosmid DNA library. (1984)

A human cosmid library was constructed and probed with a human alpha interferon (IFN-alpha) cDNA clone. One clone giving a strong hybridizing signal was isolated and characterized. The cosmid DNA insert represents a section of the human genome containing three regions of IFN-alpha-like sequences. The DNA was characterized with restriction endonuclease mapping, thereby allowing comparison to similar linkage groups reported recently and determination of homologous regions on the known physical map. The three IFN-alpha-like sequences were analyzed by a partial sequence analysis. Mapping and sequence data establish this section as a not-yet-described cluster of IFN-alpha sequences in the human genome; however, a part of the section matches to some degree to a previously described genomic region. The region described here could represent genetic polymorphism or a duplicated segment.
Oxysterols Induced Inflammation and Oxidation in Primary Porcine Retinal Pigment Epithelial Cells (2007)

We conclude that in confluent primary porcine RPE cells, 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol are potent inducers of oxidation and inflammation.
Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours (2002)

To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression.
Ultrathin Molybdenum Polyoxometalate−Polyelectrolyte Multilayer Films (1998)

Ultrathin multilayer films of a novel molybdenum(VI) polyoxometalate cluster ((NH4)21[H3Mo57V6(NO)6O183(H2O)18]) (Mo57) and poly(allylamine hydrochloride) (PAH) have been prepared by the consecutive stepwise adsorption of Mo57 and PAH from dilute aqueous solution. The Mo57/PAH multilayer films have been characterized by optical spectroscopy and small-angle X-ray reflectivity (XR) methods. UV−vis measurements reveal regular film growth with each Mo57 adsorption. The average Mo57 surface density was found to be (1.4 ± 0.4) × 1013 clusters per cm2, corresponding to an average surface coverage of 56 ± 12%. XR experiments confirm uniform film growth, with the film thickness increasing with each Mo57 adsorption step. The average thickness for the Mo57/PAH layer pair was determined to be 0.8 ± 0.1 nm. The Mo57 density in the film can be readily controlled by varying the polyelectrolyte interlayer separation between each Mo57 layer, and the total film thickness can be controlled by altering the number of adsorption cycles.
Optimal Surface Segmentation in Volumetric Images-A Graph-Theoretic Approach (2006)

Efficient segmentation of globally optimal surfaces representing object boundaries in volumetric data sets is important and challenging in many medical image analysis applications. We have developed an optimal surface detection method capable of simultaneously detecting multiple interacting surfaces, in which the optimality is controlled by the cost functions designed for individual surfaces and by several geometric constraints defining the surface smoothness and interrelations. The method solves the surface segmentation problem by transforming it into computing a minimum s-t cut in a derived arc-weighted directed graph. The proposed algorithm has a low-order polynomial time complexity and is computationally efficient. It has been extensively validated on more than 300 computer-synthetic volumetric images, 72 CT-scanned data sets of different-sized plexiglas tubes, and tens of medical images spanning various imaging modalities. In all cases, the approach yielded highly accurate results. Our approach can be readily extended to higher-dimensional image segmentation.