gebhart/patrepeval huggingface dataset:
TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR (2014)

TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
Benzotriazole-1-carboxamidinium Tosylate: An Alternative Method for the Conversion of Amines to Guanidines (1995)

Abstract A novel, effective and convenient reagent for the conversion of amines to guanidines is presented. Various primary and secondary amines react with benzotriazole-1-carboxamidinium tosylate (1) to give the corresponding guanidines in good yields under mild conditions.
Cangrelor in percutaneous coronary intervention (2009)

Cangrelor is a novel, intravenous P2Y12 receptor antagonist in development for use in percutaneous coronary intervention. Currently in Phase III testing, the reversible platelet inhibitor provides several inherent advantages over other P2Y12 receptor antagonists in this setting for the prevention of adverse cardiac events. Unlike the class of thienopyridines (ticlopidine, clopidogrel and potentially soon to be available, prasugrel), cangrelor has nearly immediate onset after a bolus dose and a short half-life, and achieves maximal inhibition of ADP-mediated platelet function. Cangrelor's distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism. These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention.
How do synonymous mutations affect fitness? (2007)

While it has often been assumed that, in humans, synonymous mutations would have no effect on fitness, let alone cause disease, this position has been questioned over the last decade. There is now considerable evidence that such mutations can, for example, disrupt splicing and interfere with miRNA binding. Two recent publications suggest involvement of additional mechanisms: modification of protein abundance most probably mediated by alteration in mRNA stability and modification of protein structure and activity, probably mediated by induction of translational pausing. These case histories put a further nail into the coffin of the assumption that synonymous mutations must be neutral.
Immunohistochemical localization of insulin-like growth factor binding protein-1, -3 and -4 in human fetal tissues and their analysis in media from fetal tissue explants. (1996)

The actions of insulin-like growth factor (IGF) II that are important in the regulation of fetal growth and development, are modulated by IGF binding proteins (IGFBPs). We have determined the cellular distribution of IGF-II and IGFBP-1, -3 and -4 in 12-week gestation human fetal tissues using immunocytochemistry. IGF-II immunostaining was found in all organs examined, with strongest immunoreactivity in spinal ganglia, tubular cells of the mesonephros and peri- and epidermal layers of the skin. The immunoreactivity distribution of all IGFBPs was similar to that of IGF-II except lung, hepatic parenchyma, fibrocytes of connective tissue and cells of the growth plate in the cartilage. When conditioned media from skin, liver, lung and kidney explants were analyzed, phosphorylated IGFBP-1 was only detected in liver samples whereas IGFBP-3 was found in all media. Weak immunoreactivity of IGFBP-4 was seen in media from lung tissue. To determine whether proteolytic degradation of IGFBPs were responsible for the different IGFBP levels, cell-free conditioned media were incubated with recombinant human IGFBPs. At neutral pH only proteolysis of IGFBP-4 was observed in media from skin and lung tissue. Upon acidification of the medium samples, IGFBP-1 fragments were formed in skin-derived medium and IGFBP-3 was cleaved by medium from lung and kidney tissue. Acid-activated proteolytic activity against IGFBP-4 was found in the media from lung and liver. These findings suggest that IGFBP proteases may be important in locally defining the concentrations of IGFBPs and contribute to tissue-specific growth response to IGFs.
Red-Shifting Azobenzene Photoswitches for in Vivo Use (2015)

ConspectusRecently, there has been a great deal of interest in using the photoisomerization of azobenzene compounds to control specific biological targets in vivo. These azo compounds can be used as research tools or, in principle, could act as optically controlled drugs. Such “photopharmaceuticals” offer the prospect of targeted drug action and an unprecedented degree of temporal control.A key feature of azo compounds designed to photoswitch in vivo is the wavelength of light required to cause the photoisomerization. To pass through tissue such as the human hand, wavelengths in the red, far-red, or ideally near infrared region are required. This Account describes our attempts to produce such azo compounds.Introducing electron-donating or push/pull substituents at the para positions delocalizes the azobenzene chromophore and leads to long wavelength absorption but usually also lowers the thermal barrier to interconversion of the isomers. Fast thermal relaxation means it is difficult to produce a large steady state fraction of the cis isomer. Thus, specifically activating or inhibiting a biological process with the cis isomer would require an impractically bright light source.We have found that introducing substituents at all four ortho positions leads to azo compounds with a number of unusual properties that are useful for in vivo photoswitching. When the para substituents are amide groups, these tetra-ortho substituted azo compounds show unusually slow thermal relaxation rates and enhanced separation of n−π* transitions of cis and trans isomers compared to analogues without ortho substituents. When para positions are substituted with amino groups, ortho methoxy groups greatly stabilize the azonium form of the compounds, in which the azo group is protonated. Azonium ions absorb strongly in the red region of the spectrum and can reach into the near-IR. These azonium ions can exhibit robust cis–trans isomerization in aqueous solutions at neutral pH.By varying the nature of ortho substituents, together with the number and nature of meta and para substituents, long wavelength switching, stability to photobleaching, stability to hydrolysis, and stability to reduction by thiols can all be crafted into a photoswitch. Some of these newly developed photoswitches can be used in whole blood and show promise for effective use in vivo. It is hoped they can be combined with appropriate bioactive targets to realize the potential of photopharmacology.
Pre-mRNA splicing and the nuclear matrix. (1987)

We examined the relationship between pre-mRNA splicing and the nuclear matrix by using an in vivo system that we have developed. Plasmids containing the inducible herpesvirus tk gene promoter linked to an intron-containing segment of the rabbit beta-globin gene were transfected into HeLa cells, and then the promoter was transactivated by infection with a TK- virus. Northern analysis revealed that the globin pre-mRNA and all its splicing intermediates and products are associated with the nuclear matrix prepared from such transfected cells. When the nuclear matrix was incubated with a HeLa cell in vitro splicing extract in the presence of ATP, the amount of matrix-associated precursor progressively decreased without a temporal lag in the reaction, with a corresponding increase in free intron lariat. Thus, most of the events of the splicing process (endonucleolytic cuts and branching) occur in this in vitro complementation reaction. However, ligation of exons cannot be monitored in this system because of the abundance of preexisting mature mRNA. Since the matrix is not a self-splicing entity, whereas the in vitro splicing system cannot process efficiently deproteinized matrix RNA, we conclude from our in vitro complementation results (which can be reproduced by using micrococcal nuclease-treated splicing extract) that the nuclear matrix preparation retains parts of preassembled ribonucleoprotein complexes that have the potential to function when supplemented with soluble factors (presumably other than most of the small nuclear ribonucleoproteins known to participate in splicing) present in the HeLa cell extract.
Atmospheric pressure plasma effects on the adhesive bonding properties of stainless steel and epoxy composites (2012)

An atmospheric pressure helium and oxygen plasma has been used for the surface preparation of 410 stainless steel and carbon-fiber epoxy laminates prior to bonding to themselves or to each other. Lap shear results for stainless steel coupons and carbon-fiber epoxy laminates demonstrated an 80% and a 150% increase in bond strength, respectively, after plasma activation. Following 7 days of aging, wedge crack extension tests revealed a crack extension length of 7.0 mm and 2.5 mm for the untreated and plasma-activated steel. The untreated stainless steel had 30% cohesive failure compared to 97% for steel activated with the plasma. Surface analysis by X-ray photoelectron spectroscopy showed that carbonaceous contamination was removed by plasma treatment, and specific functional groups, e.g. carboxylic acids, were formed on the surface. These functional groups promoted strong chemical bonding to the epoxy film adhesive. Atmospheric pressure plasmas are an attractive alternative to abrasion techniques for surface preparation prior to bonding.
Catalytic Decarboxylative Fluorination for the Synthesis of Tri- and Difluoromethyl Arenes (2013)

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2.
Color Fusion of Magnetic Resonance Images Improves Intracranial Volume Measurement in Studies of Aging (2012)

Background: Comparison of intracranial volume (ICV) measurements in different subpopulations offers insight into age-related atrophic change and pathological loss of neuronal tissue. For such comparisons to be meaningful the accuracy of ICV measurement is paramount. Color magnetic resonance images (MRI) have been utilised in several research applications and are reported to show promise in the clinical arena. Methods: We selected a sample of 150 older community-dwelling individuals (age 71 to 72 years) representing a wide range of ICV, white matter lesions and atrophy. We compared the extraction of ICV by thresholding on T2*-weighted MR images followed by manual editing (reference standard) done by an analyst trained in brain anatomy, with thresholding plus computational morphological operations followed by manual editing on a framework of a color fusion technique (MCMxxxVI) and two automatic brain segmentation methods widely used, these last three done by two image analysts. Results: The range of ICV was 1074 to 1921 cm3 for the reference standard. The mean difference between the reference standard and the ICV measured using the technique that involved the color fusion was 2.7%, while it was 5.4% compared with any fully automatic technique. However, the 95% confidence interval of the difference between the reference standard and each method was similar: it was 7% for the segmentation aided by the color fusion and was 7% and 8.3% for the two fully automatic methods tested. Conclusion: For studies of aging, the use of color fusion MRI in ICV segmentation in a semi-automatic framework delivered best results compared with a reference standard manual method. Fully automated methods, while fast, all require manual editing to avoid significant errors and, in this post-processing step color fusion MRI is recommended.
Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood–brain barrier penetration (1999)

This paper describes the derivation of a simple QSAR model for the prediction of log BB from a set of 55 diverse organic compounds. The model contains two variables: polar surface area (PSA) and calculated logP, both of which can be rapidly computed. It therefore permits the prediction of log BB for large compound sets, such as virtual combinatorial libraries. The performance of this QSAR on two test sets taken from the literature is illustrated and compared with results from other reported computational approaches to log BB prediction.
The power of choice in data-aware cluster scheduling (2014)

Providing timely results in the face of rapid growth in data volumes has become important for analytical frameworks. For this reason, frameworks increasingly operate on only a subset of the input data. A key property of such sampling is that combinatorially many subsets of the input are present. We present KMN, a system that leverages these choices to perform data-aware scheduling, i.e., minimize time taken by tasks to read their inputs, for a DAG of tasks. KMN not only uses choices to co-locate tasks with their data but also percolates such combinatorial choices to downstream tasks in the DAG by launching a few additional tasks at every upstream stage. Evaluations using workloads from Facebook and Conviva on a 100-machine EC2 cluster show that KMN reduces average job duration by 81% using just 5% additional resources.
Ototoxicity of Vancomycin: An Experimental Study in Guinea Pigs (1991)

Vancomycin (V)-a polypeptide antibiotic-is the drug of choice in severe infections with multiresistant staphylococcus spp. Due to the multimorbidity of the patients receiving V, the interactions with known ototoxic agents and the lack of an audiometric documentation, earlier clinical reports of V-associated hearing loss must be carefully interpreted. To elucidate this topic, a controlled animal study considering nonspecific effects was performed. 40 albino guinea pigs with positive Preyer's reflex and normal hearing were used. The hearing function was controlled by means of brainstem auditory evoked potentials before and after intraperitoneal administration of V (75, 150, 300 mg/kg b.w. for 11-17 days), gentamicin (60 mg/kg b.w. for 26 days), neomycin (100 mg/kg b.w. for 17 days) and sodium chloride solution. The cochleas were dissected for hair cell counting by the surface preparation technique. Additionally, the serum concentrations of V were measured. As a result there was no significant difference in hearing loss between the controls and the animals treated with 75 and 150 mg V; toxic doses of 300 mg V led to a certain threshold elevation after click stimuli, but not after trapezoid stimuli of 1, 4 and 8 kHz. On the other hand, the aminoglycosides as a positive control caused an obvious hearing loss after click and trapezoid stimuli, which was correlated to the amount of outer hair cell loss. Renal damage could be excluded by histological examination of the kidneys and estimation of creatinine in serum. Therefore, treatment with moderate doses of V comparable to clinical conditions does not exhibit a specific ototoxicity as compared to the aminoglycosides.(ABSTRACT TRUNCATED AT 250 WORDS)
Analytical aspects of fet-based biosensors (2005)

Field-effect transistor (FET)-based biosensors (BioFETs) have undergone great progress especially in the last decade, since they were first realized in 1980. Recently, BioFETs have become one of the most important branches of biosensors. This paper briefly reviewed the operating principles of BioFETs and summarized the improvement and application of BioFETs, finally, the future prospects of BioFETs were discussed with 126 references.
Sucrose Synthase Activity in Developing Wheat Endosperms Differing in Maximum Weight (1986)

Past research on kernel growth in wheat (Triticum aestivum) has shown that the kernel itself largely regulates the influx of sucrose for consequent starch synthesis in the endosperm of the grain. The first step in the conversion of sucrose to starch is catalyzed by sucrose synthase (EC 2.4.13). Sucrose synthase activity was assayed in developing endosperms from kernels differing in growth rate and in maximum dry weight accumulation. From 10 to 22 days after anthesis, sucrose synthase activity per wheat endosperm remained constant with respect to time in all grains. However, kernels which had higher rates of kernel growth and which achieved greatest maximum weight had consistently and significantly higher sucrose synthase activities at any point in time than did kernels with slower rates of dry matter accumulation and lower maximum weight. In addition, larger kernels had a significantly greater amount of water in which this activity could be expressed. Although the results do not implicate sucrose synthase as the "rate limiting" enzyme in wheat kernel growth, they do emphasize the importance of sucrose synthase activity in larger or more rapidly growing kernels, as compared to smaller slower growing kernels.
Structure-function analysis of the TBP-binding protein Dr1 reveals a mechanism for repression of class II gene transcription. (1994)

Dr1, a repressor of class II genes, regulates transcription by a novel mechanism. Biochemical analyses reveal that Dr1 directly interacts with the multiprotein TFIID complex. By use of the yeast two-hybrid system, we demonstrate that the association of Dr1 with the TATA-binding protein (TBP) subunit of TFIID occurs in vivo. In addition, Dr1 can repress transcription from TATA-containing as well as TATA-less promoters in transient transfection assays. Importantly, Dr1-mediated repression can be reversed by overexpression of TBP in vivo. By use of diverse approaches, we mapped two distinct domains in Dr1 required for repression. One domain is essential for the Dr1-TBP interaction, and the second is rich in alanine residues. The TBP-binding domain of Dr1 cannot be replaced by a heterologous DNA-binding domain in mediating repression. We demonstrate that some, but not all, transcriptional activators can reverse Dr1-mediated repression in vivo.
Optical TIR switches using PLZT thin-film waveguides on sapphire (1984)

Light beam switching in a four-port channel waveguide has been achieved using electrooptic modulation of epitaxially grown PLZT thin film on sapphire. The switches exhibited a low drive voltage of 4.7 V with a switching speed of higher than 1 GHz.
Very-Low-Temperature Silicon Epitaxy by Plasma-CVD Using SiH4-PH3-H2 Reactants for Bipolar Devices (1988)

A novel plasma-CVD process has been developed for growing specular silicon epitaxial layers at very low temperatures of approximately 200°C. The epitaxial layers were deposited from SiH 4 -PH 3 gases diluted with H 2 on single-crystal substrates just after being etched in a HF dip. The highest electron mobility and lowest resistivity of the n + -layers were 30 cm 2 /V ·s and 4×10 -4 Ω·cm, respectively. This technology has been successfully applied to fabricate bipolar transistors with a high current gain of 370.
Cognitive Effects of MIN-101 in Patients With Schizophrenia and Negative Symptoms (2018)

EU Clinical Trials Register identifier: 2014-004878-42​.
Repression of Smoothened by Patched-Dependent (Pro-)Vitamin D3 Secretion (2006)

The developmentally important hedgehog (Hh) pathway is activated by binding of Hh to patched (Ptch1), releasing smoothened (Smo) and the downstream transcription factor glioma associated (Gli) from inhibition. The mechanism behind Ptch1-dependent Smo inhibition remains unresolved. We now show that by mixing Ptch1-transfected and Ptch1 small interfering RNA-transfected cells with Gli reporter cells, Ptch1 is capable of non-cell autonomous repression of Smo. The magnitude of this non-cell autonomous repression of Smo activity was comparable to the fusion of Ptch1-transfected cell lines and Gli reporter cell lines, suggesting that it is the predominant mode of action. CHOD-PAP analysis of medium conditioned by Ptch1-transfected cells showed an elevated 3beta-hydroxysteroid content, which we hypothesized to mediate the Smo inhibition. Indeed, the inhibition of 3beta-hydroxysteroid synthesis impaired Ptch1 action on Smo, whereas adding the 3beta-hydroxysteroid (pro-)vitamin D3 to the medium effectively inhibited Gli activity. Vitamin D3 bound to Smo with high affinity in a cyclopamine-sensitive manner. Treating zebrafish embryos with vitamin D3 mimicked the smo(-/-) phenotype, confirming the inhibitory action in vivo. Hh activates its signalling cascade by inhibiting Ptch1-dependent secretion of the 3beta-hydroxysteroid (pro-)vitamin D3. This action not only explains the seemingly contradictory cause of Smith-Lemli-Opitz syndrome (SLOS), but also establishes Hh as a unique morphogen, because binding of Hh on one cell is capable of activating Hh-dependent signalling cascades on other cells.
Inhibition of Integrin-linked Kinase/Protein Kinase B/Akt Signaling (2001)

Ganglioside GT1b inhibits keratinocyte attachment to and migration on a fibronectin matrix by binding to alpha(5)beta(1) and preventing alpha(5)beta(1) interaction with fibronectin. The role of gangliosides in triggering keratinocyte apoptosis, however, is unknown. Addition of GT1b to keratinocyte-derived SCC12 cells, grown in serum-free medium but exposed to fibronectin, suppressed Bad phosphorylation, activated caspase-9, and inhibited cyclin D and E expression, resulting in cell cycle arrest at G(1) phase and initiation of apoptosis. The mechanism of GT1b activation of caspase-9 involved inhibition of beta(1) integrin serine/threonine phosphorylation and decreased phosphorylation of both integrin-linked kinase and protein kinase B/Akt at its Ser-473 site, leading to cytochrome c release from mitochondria. Consistently, blockade of GT1b function with anti-GT1b antibody specifically activated the Ser-473 site of Akt, markedly suppressing apoptosis. The ganglioside-induced inhibition of Akt phosphorylation was GT1b-specific and was not observed when cells were treated with other keratinocyte gangliosides, including GD3. These studies suggest that the modulation of keratinocyte cell cycle and survival by GT1b is mediated by its direct interaction with alpha(5)beta(1) and resultant inhibition of the integrin/integrin-linked kinase/protein kinase B/Akt signaling pathway.
EFFECT OF α-METHYLATION ON THE PARAMETERS CHARACTERIZING HYDROLYSIS IN WATER FOR A SERIES OF HALIDES AND SULFONATES (1966)

The aim of this work was to explore the effect of α-methylation on the reactivity and detailed mechanism of hydrolysis. Accordingly, rate data and derived parameters are given for the hydrolysis of a series of halides and sulfonates in water. From the differences in kinetic parameters, an attempt is made to infer further information relating structure and mechanism.