gebhart/patrepeval huggingface dataset:
In Situ Click Chemistry:  Enzyme Inhibitors Made to Their Own Specifications (2004)

The in situ click chemistry approach to lead discovery employs the biological target itself for assembling inhibitors from complementary building block reagents via irreversible connection chemistry. The present publication discusses the optimization of this target-guided strategy using acetylcholinesterase (AChE) as a test system. The application of liquid chromatography with mass spectroscopic detection in the selected ion mode for product identification greatly enhanced the sensitivity and reliability of this method. It enabled the testing of multicomponent mixtures, which may dramatically increase the in situ screening throughput. In addition to the previously reported in situ product syn-TZ2PA6, we discovered three new inhibitors, syn-TZ2PA5, syn-TA2PZ6, and syn-TA2PZ5, derived from tacrine and phenylphenanthridinium azides and acetylenes, in the reactions with Electrophorus electricus and mouse AChE. All in situ-generated compounds were extremely potent AChE inhibitors, because of the presence of multiple sites of interaction, which include the newly formed triazole nexus as a significant pharmacophore.
A manera de presentación (2013)

DOI: http://dx.doi.org/10.5377/koot.v0i3.1159Revista de Museología "Kóot" No.3; 5-12
Transcutaneous electrical stimulation on the anterior neck region: The impact of pulse duration and frequency on maximum amplitude tolerance and perceived discomfort (2018)

Maximum amplitude tolerance (MAT) has been known as a primary factor determining the depth of electrical current penetration. However, the effect of varying transcutaneous electrical stimulation (TES) parameters on MAT and discomfort level is poorly understood. Furthermore, limited information exists regarding the biopsychological factors that may impact MAT and discomfort. The primary aims of this study were to compare the effects TES protocol with varying levels of pulse duration (300 μs vs 700 μs) and frequency (30 Hz vs 80 Hz) on the MAT and discomfort in healthy older adults. The exploratory aim of this study was to examine relationships between submental adipose tissue thickness, pain sensitivity and gender with MAT and discomfort. Twenty-four healthy older adults participated in this study. Transcutaneous electrical stimulation was delivered to the submental region. Maximum amplitude tolerance and discomfort were measured for each condition. Furthermore, submental adipose tissue thickness and pain sensitivity were measured for each subject. Maximum amplitude tolerance was significantly increased for the TES protocols with short-pulse duration [F (3, 69) = 38.695, P < .0001]. Discomfort was similar across different TES protocols. Submental adipose tissue thickness (r = .30, P < .003) and pain sensitivity (r = -.43, P < .0001) were related to MAT. Pain sensitivity rating was also related to discomfort (r = .45, P < .0001). In conclusion, using TES protocols with short-pulse duration may increase the MAT. Higher amplitude stimulation may increase the impact on deep swallowing muscles. In addition, submental adipose tissue thickness and pain sensitivity are potential biopsychological factors that may affect MAT and discomfort.
Liver Monocytes and Kupffer Cells Remain Transcriptionally Distinct during Chronic Viral Infection (2016)

Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clinical hepatitis, with rise in ALT and serum cytokines, and increased intrahepatic F4/80 expression. Despite ongoing viral replication, whole liver transcriptome showed baseline expression levels of inflammatory cytokines, interferons, and interferon induced genes during the chronic infection phase. Transcriptome analyses of sorted KC and IMs using NanoString technology revealed two unique phenotypes with only minimal overlap. At the chronic viral infection phase, KC showed no increased transcription of activation markers Cd80 and Cd86, but an increased expression of genes related to antigen presentation, whereas monocytes were more activated and expressed higher levels of Tnf transcripts. Although both KCs and intrahepatic IM share the surface markers F4/80 and CD11b, their transcriptomes point towards distinctive roles during virus-induced chronic hepatitis.
UB-165: A Novel Nicotinic Agonist with Subtype Selectivity Implicates the α4β2* Subtype in the Modulation of Dopamine Release from Rat Striatal Synaptosomes (2000)

Presynaptic nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the alpha3beta2-selective alpha-conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this alpha-conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the alpha-conotoxin-MII-insensitive subtype is composed of alpha4 and beta2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at alpha4beta2* and alpha3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over alpha7-type and muscle binding sites. (+/-)-Epibatidine, (+/-)-anatoxin-a, and (+/-)-UB-165 stimulated [(3)H]-dopamine release from striatal synaptosomes with EC(50) values of 2.4, 134, and 88 nM, and relative efficacies of 1:0.4:0.2, respectively. alpha-Conotoxin-MII inhibited release evoked by these agonists by 48, 56, and 88%, respectively, suggesting that (+/-)-UB-165 is a very poor agonist at the alpha-conotoxin-MII-insensitive nAChR subtype. In assays of (86)Rb(+) efflux from thalamic synaptosomes, a model of an alpha4beta2* nAChR response, (+/-)-UB-165 was a very weak partial agonist; the low efficacy of (+/-)-UB-165 at alpha4beta2 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (+/-)-UB-165 and (+/-)-anatoxin-a were similarly efficacious and similarly sensitive to alpha-conotoxin-MII in increasing intracellular Ca(2+) in SH-SY5Y cells, a functional assay for native alpha3-containing nAChR. These data support the involvement of alpha4beta2* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial agonist, together with a selective antagonist, to dissect the functional roles of nAChR subtypes in the brain.
Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING (2018)

Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein-ligand as well as ligand-ligand interactions. Successful implementation of this strategy led to the identification of <b>18</b>, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.
Development of an Azanoradamantane-Type Nitroxyl Radical Catalyst for Class-Selective Oxidation of Alcohols (2014)

The development of 1,5-dimethyl-9-azanoradamantane N-oxyl (DMN-AZADO; 1,5-dimethyl-Nor-AZADO, 2) as an efficient catalyst for the selective oxidation of primary alcohols in the presence of secondary alcohols is described. The compact and rigid structure of the azanoradamantane nucleus confers potent catalytic ability to DMN-AZADO (2). A variety of hindered primary alcohols such as neopentyl primary alcohols were efficiently oxidized by DMN-AZADO (2) to the corresponding aldehydes, whereas secondary alcohols remained intact. DMN-AZADO (2) also has high catalytic efficiency for one-pot oxidation from primary alcohols to the corresponding carboxylic acids in the presence of secondary alcohols and for oxidative lactonization from diols.
Microwave-assisted synthesis of TiO2-reduced graphene oxide composites for the photocatalytic reduction of Cr(vi) (2011)

TiO2-reduced graphene oxide (RGO) composites are successfully synthesized via the microwave-assisted reduction of graphite oxide in a TiO2 suspension using a microwave synthesis system. Their morphology, structure and photocatalytic performance in the reduction of Cr(VI) are characterized by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, X-ray diffraction spectroscopy and UV-vis absorption spectrophotometer. The results show that in the composite the RGO nanosheets are densely decorated by TiO2 nanoparticles, which displays a good combination between RGO and TiO2. TiO2–RGO composites exhibit enhanced photocatalytic performance for the reduction of Cr(VI) with a maximum removal rate of 91% under UV light irradiation as compared with pure TiO2 (83%) and commercial TiO2 P25 (70%) due to the increased light absorption intensity and range as well as the reduction of electron-hole pair recombination in TiO2 with the introduction of RGO.
A Nonopioid Procedure for Outpatient Opioid Detoxification (2010)

The outpatient detoxification of opioid-dependent patients without the use of opioids has traditionally led to such high drop out rates that most clinical programs do not even consider the option. This makes it difficult to induce patients with opioid antagonists such as oral naltrexone or sustained release naltrexone. We describe a protocol here that leads to excellent rates of successful detoxification. This nonopioid detoxification methodology permits induction of naltrexone without the delay experienced in opioid-based titrations, and it thus facilitates the use of opioid antagonists for sustained abstinence, enhanced aftercare treatment outcomes, and opioid-free recovery.
The CIC library: a large insert YAC library for genome mapping in Arabidopsis thaliana (1995)

A new Arabidopsis thaliana (ecotype Columbia) genomic library has been constructed in Yeast Artificial Chromosomes: the CIC library (for CEPH, INRA and CNRS). Optimization of plant culture conditions and protoplast preparation allowed the recovery of large amounts of viable protoplasts. Mechanical shearing of DNA was minimized by isolation of DNA from protoplasts embedded in agarose. Cloning of large inserts was favored by including two successive size fractionation steps (after partial EcoRI digestion and after ligation with the vector arms), which selected DNA fragments larger than 350 kb. The library consists of 1152 clones with an average insert size of 420 kb. Clones carrying chloroplast DNA and various nuclear repeated sequences have been identified. Twenty-one per cent of the clones are found to contain chloroplast DNA. Therefore, the library represents around four nuclear genome equivalents. The clones containing 5S rDNA genes, 18S-25S rDNA sequences and the 180 bp paracentromeric repeated element account for 3.6%, 8.9% and 5.8%, respectively. Only one clone was found to carry the 160 bp paracentromeric repeated element. Given the smaller size of clones carrying Arabidopsis repeated DNA, the average size of remaining clones is around 480 kb. The library was screened by PCR amplification using pairs of primers corresponding to sequences dispersed in the genome. Seventy out of 76 pairs of primers identified from one to seven YAC clones. Thus at least 92% of the genome is represented in the CIC library. The survey of the library for clones containing unlinked DNA sequences indicates that the proportion of chimeric clones is lower than 10%.
Essential and nonessential sequences in malPp, a positively controlled promoter in Escherichia coli (1985)

A plasmid bearing the malPp promoter was digested with Bal31 to obtain a set of deletions with closely spaced endpoints in the upstream region of this promoter. Some of these deletions were sequenced, and their effect on malPQ expression was determined after having transferred them onto the chromosome. We found that a site which binds the cyclic AMP receptor protein in vitro and which is centered at position -93 with respect to the site of transcription initiation could be deleted without affecting malPQ expression. In contrast, the activity of the malPp promoter decreased abruptly when the deletions reached position -72. The downstream region of the promoter was analyzed by using a technique of "sequence replacement" which involved the selection of Mal+ pseudorevertants from strains which carried small deletions in the -25 region. The pseudorevertants, which expressed the malPQ operon in a manner indistinguishable from wild type, had grossly different sequences downstream from position -38, except for a few positions, some of which must be important for promoter function. By combining all presently available information, it is suggested that the malPp promoter contains three binding sites for its activator, the product of gene malT. These sites are defined by three quasi-identical hexanucleotides present in one orientation around position -37 and twice in the other orientation around positions -60 and -73.
Liver Defatting: An Alternative Approach to Enable Steatotic Liver Transplantation (2012)

Macrovesicular steatosis in greater than 30% of hepatocytes is a significant risk factor for primary graft nonfunction due to increased sensitivity to ischemia reperfusion (I/R) injury. The growing prevalence of hepatic steatosis due to the obesity epidemic, in conjunction with an aging population, may negatively impact the availability of suitable deceased liver donors. Some have suggested that metabolic interventions could decrease the fat content of liver grafts prior to transplantation. This concept has been successfully tested through nutritional supplementation in a few living donors. Utilization of deceased donor livers, however, requires defatting of explanted organs. Animal studies suggest that this can be accomplished by ex vivo warm perfusion in a time scale of a few hours. We estimate that this approach could significantly boost the size of the donor pool by increasing the utilization of steatotic livers. Here we review current knowledge on the mechanisms whereby excessive lipid storage and macrosteatosis exacerbate hepatic I/R injury, and possible approaches to address this problem, including ex vivo perfusion methods as well as metabolically induced defatting. We also discuss the challenges ahead that need to be addressed for clinical implementation.
Protein Kinase C Alpha Expression in Breast and Ovarian Cancer (2004)

In recent years research has focused on the development of specific, targeted drugs to treat cancer. One approach has been to block intracellular signaling proteins, such as protein kinase C alpha (PKC-alpha). To help support the rationale for clinical studies of a PKC-alpha-targeted therapy in breast and ovarian cancers, we reviewed publications studying PKC-alpha expression in these tumors. Since these investigations were mostly performed in cell lines, we supplemented this review with some preliminary findings from studies examining PKC-alpha expression in tumor tissue biopsies obtained from patients with breast and ovarian cancer. Based on the reviewed publications using representative cell lines and our preliminary findings on tumor tissue of patients with breast cancer, we infer that PKC-alpha levels may especially be increased in breast cancer patients with low or negative estrogen receptor (ER) levels. Thus, clinical studies determining efficacy of selective or specific inhibitors of PKC-alpha should include determination of ER status in order to help answer whether blocking PKC-alpha in patients with low or absent ER can result in clinical benefit.
Glycosylation of a recombinant protein in the Tn5B1-4 insect cell line: Influence of ammonia, time of harvest, temperature, and dissolved oxygen (1999)

Glycosylation is both cell line and protein dependent. Culture conditions can also influence the profile of glycoforms produced. To examine this possibility in the insect cell/baculovirus system, structures of N-linked oligosaccharides attached to SEAP (human secreted alkaline phosphatase), expressed under various culture conditions in BTI Tn5B1-4 cells, were characterized using FACE (fluorescence-assisted carbohydrate electrophoresis). Parameters varied were time of harvest, ammonia added during infection, dissolved oxygen, and temperature. It was found that glycosylation in the insect cell/baculovirus expression system is a robust, stable system that is less perturbed by variations in culture conditions than the level of protein expression. Addition of ammonia and low oxygen conditions affected SEAP expression, but not the oligosaccharide profile of SEAP. Time of SEAP harvest increased the amount of alpha-mannosidase resistant structures from 4.1% at 34 hours postinfection (h pi), to 5.0% at 100 h pi, and to 7.5% at 120 h pi. These structures were primarily sensitive to N-acetylhexosaminidase digest, although a small amount was insensitive to both mannosidase and N-acetyl-hexosaminidase digests. Lowering the temperature from 28 degrees C to 24 degrees C or even 20 degrees C, resulted in a twofold increase in oligosaccharides containing terminal alpha(1,3)-mannose residues. This condition did not affect the amount of mannosidase-resistant structures. However, this could result in more complete glycosylation of recombinant proteins in the BTI Tn5B1-4 cell line, because more structures with the potential for further processing would be produced.
Iterative Exponential Growth Synthesis and Assembly of Uniform Diblock Copolymers (2016)

Studies on the phase segregation of unimolecular block copolymers (BCPs) are limited by a lack of reliable, versatile methods for the synthesis of such polymers on the preparative scale. Herein, we describe an advancement of Iterative Exponential Growth (IEG) wherein chiral allyl-based IEG oligomers are subjected to thiol-ene reactions and converted into unimolecular BCPs. With this strategy we have synthesized uniform BCPs with molar masses up to 12.1 kDa on ∼1 g scale. BCPs composed of decane-based side chains and either triethyleneglycol- or thioglycerol-based side chains phase-segregate into hexagonal cylinder morphologies. The assembly is not driven by side-chain crystallization, but is instead the result of amorphous BCP assembly.
Parenteral nutrition in marrow transplant recipients after discharge from the hospital. (1983)

The use of parenteral nutrition (PN) following discharge from the hospital and its relation to patient characteristics were evaluated retrospectively in 246 marrow transplant recipients. PN was used in 65% of all patients. Patients with leukemia, regardless of age, sex, type of leukemia, remission status, irradiation schedule, laminar air flow isolation and donor sex match, required more frequent and more prolonged PN than patients with aplastic anemia. Children required PN most often for failure to thrive and adults for stomatitis. There was no significant difference in frequency or duration of PN among 24 patients with acute myelogenous leukemia randomized to receive cyclosporine or methotrexate therapy and among 28 patients with acute lymphoblastic leukemia randomized to interferon or no interferon. We conclude that outpatient PN presents a valuable addition to posttransplant supportive care. It shortens the duration of hospitalization both by earlier discharge of patients still requiring PN and by avoiding readmission to the hospital for the purpose of PN.
Structural and Ionic Requirements for Self-cleavage of Virusoid RNAs and trans Self-cleavage of Viroid RNA (1987)

Certain circular and low-molecular-weight, single-stranded plant pathogenic RNAs can self-cleave at specific sites in vitro in the presence of Mg++ (Buzayan et al. 1986a; Hutchins et al. 1986; Prody et al. 1986; Forster and Symons 1987a). This property is considered to be important in their replication in vivo by a rolling-circle mechanism. All of these self-cleavage reactions generate 5′-OH and 2′,3′-cyclic phosphodiester termini in what is essentially a transphosphorylation reaction involving attack by the free 2′-OH group on the 3′,5′-phosphodiester linkage (Fig. 1A). These self-cleavage reactions are clearly different from the self-splicing reactions involved in the removal of introns from rRNA and mRNA precursors that produce excised fragments with 5′-phosphate and 3′-OH termini (Cech and Bass 1986; Sharp 1987).
Detection of preference shift timing using time-series clustering (2009)

Recommendation methods help online users to purchase products more easily by presenting products that are likely to match their preferences. In these methods, user profiles are constructed according to past activities on the site. When a user accesses an e-commerce site, the user preferences may change during the course of Web shopping. We called this a ldquopreference shiftrdquo in this paper. However, conventional recommendation methods suppose that user profiles are static, and therefore these methods cannot follow the preference shift. Here, a novel product recommendation method is proposed, which responds to the preference shift. With use of this recommendation method, the users remain at the site longer than before. This paper discusses the detection method for finding the preference shift timing using time-series clustering. In the proposed method, the products preferred by a user are clustered and the preference shift timing is detected as the change in the clustering results.
Multiple Sclerosis: Pathogenesis and Treatment (2011)

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.