gebhart/patrepeval huggingface dataset:
Oxidation of Guanine in Cellular DNA by Solar UV Radiation: Biological Role† (1999)

The formation of cyclobutane pyrimidine dimers (CPD) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) was investigated in Chinese hamster ovary cells upon exposure to either UVC, UVB, UVA or simulated sunlight (SSL). Two cell lines were used, namely AT3-2 and UVL9, the latter being deficient in nucleotide excision repair and consequently UV sensitive. For all types of radiation, including UVA, CPD were found to be the predominant lesions quantitatively. At the biologically relevant doses used, UVC, UVB and SSL irradiation yielded 8-oxodGuo at a rather low level, whereas UVA radiation produced relatively higher amounts. The formation of CPD was 10(2) and 10(5) more effective upon UVC than UVB and UVA exposure. These yields of formation followed DNA absorption, even in the UVA range. The calculated relative spectral effectiveness in the production of the two lesions showed that efficient induction of 8-oxodGuo upon UVA irradiation was shifted toward longer wavelengths, in comparison with those for CPD formation, in agreement with a photosensitization mechanism. In addition, after exposure to SSL, about 19% and 20% of 8-oxodGuo were produced between 290-320 nm and 320-340 nm, respectively, whereas CPD were essentially (90%) induced in the UVB region. However, the ratio of CPD to 8-oxodGuo greatly differed from one source of light to the other: it was over 100 for UVB but only a few units for UVA source. The extent of 8-oxodGuo and CPD was also compared to the lethality for the different types of radiation. The involvement of 8-oxodGuo in cell killing by solar UV radiation was clearly ruled out. In addition, our previously reported mutation spectra demonstrated that the contribution of 8-oxodGuo in the overall solar UV mutagenic process is very minor.
A hybrid approach to determining cornea mechanical properties using a combination of inverse finite element analysis and experimental techniques (2014)

It is of great clinical importance to predict the behaviour of the cornea in various diseases and post-surgical recovery. Therefore, a numerical model that is able to simulate the corneal behaviour, considering corneal material properties obtained from individuals is highly desirable. In this work a combined numerical-experimental technique has been developed that can characterize the mechanical properties of a cornea properties from two aspects: time-dependency and spatial variation. Initially, an analysis of the material properties of porcine corneas was performed to investigate the time-dependent behaviour of the cornea. A simple stress relaxation test was used to determine the viscoelastic properties of a cornea and a rheological model was built based on the Generalized Maxwell (GM) approach. A validation experiment using nano-indentation showed that an isotropic GM model was insufficient for describing the corneal time-dependent behaviour when exposed to a complex stress state. A technique was proposed that takes into account the microstructural composition of the cornea and is based on a combination of nano-indentation experiment, isotropic and transversely isotropic numerical models, and an inverse finite element method. The good agreement using this method suggests that this is a promising technique for measuring the time-dependent properties of the cornea. The spatial variation of the properties was then investigated. This time, the long term structural response of the cornea was targeted. A full field displacement response of a loaded cornea was evaluated from Optical Coherence Tomography (OCT) volume reconstructions of the cornea using Digital Volume Correlation (DVC). The inverse finite element method was employed with two models sequentially; first, a radially partitioned model and then a circumferentially partitioned model, in order to recover the elastic parameters in radial and circumferential directions. The good agreement using this method suggests that this is a promising and reliable technique for identifying the distribution of the corneal properties. \nIn this research, we have shown that it is possible to determine the local time-dependent properties of the cornea and the in-depth (2D) distribution of the properties using the hybrid technique. This technique has the potential to be implemented in vivo. However, further work should focus on the feasibility of this technique in practice.
PULMONARY ANGIOGRAPHY WITH 64‐MULTIDETECTOR‐ROW COMPUTED TOMOGRAPHY IN NORMAL DOGS (2011)

Pulmonary angiography using 64-multidetector-row computed tomography (MDCT) was used to evaluate pulmonary artery anatomy, and determine the sensitivity of pulmonary artery segment visualization in four Beagle dogs using images reconstructed to 0.625 mm and retro-reconstructed to 1.25 and 2.5 mm slice thickness. Morphologically, characteristic features included a focal narrowing in the right cranial pulmonary artery in all dogs, which should not be mistaken as stenosis. While the right cranial pulmonary artery divided into two equally sized branches that were tracked into the periphery of the lung lobe in all dogs, only a single left cranial (cranial portion) lobar artery was present. Compared with 1.25 and 2.5 mm retro-reconstructions, 0.625 mm reconstructions allowed for detection of significantly (P≤0.05) more pulmonary artery segments and sharper depiction of vessel margins. Clinical applications such as prevalence and significance of diameter changes, and detection of pulmonary arterial thrombembolism on lobar and sublobar level, using pulmonary angiography with 64-MDCT applying 0.625 mm reconstruction slice thickness remain to be established.
Abstract 3650: Discovery of the clinical candidate AZD9496: a potent and orally bioavailable selective estrogen receptor downregulator and antagonist (2015)

Abstract With over 70% of breast cancers expressing the estrogen receptor alpha (ERα), treatment with either anti-hormonal therapies that directly block ER function or therapies that block the production of estrogen itself have proven to be effective treatments of the disease. Following the pioneering discovery of the ERα antagonist tamoxifen in the 1960s, identification of the selective estrogen receptor downregulator (SERD) fulvestrant represented a further step forward in the treatment of advanced ER+ breast cancer especially in the endocrine resistance setting. The pure estrogen downregulator-antagonist fulvestrant offers the advantage of not only antagonising ERα-driven tumor cell growth but also degrading ERα via ubiquitinylation and thus diminishing growth due to reduced ERα content. Given its low level of bioavailability and metabolic profile, fulvestrant has been formulated as an intramuscular monthly injection. We have sought to identify a novel, non-steroidal ERα antagonist and down-regulator that can be administered orally and could yield improved exposure and clinical benefit. This presentation will describe the discovery of AZD9496, a novel, orally bioavailable small molecule that can induce ERα degradation in breast cancer cell lines at picomolar concentrations. Data will be shared for the first time on the medicinal chemistry efforts that led to AZD9496, the good oral pharmacokinetic properties of the compound which led to significant tumor efficacy in both endocrine sensitive model (complete tumor growth inhibition (TGI) in a MCF-7 model at a dose of 10 mpk) and resistant models (tumor regressions in a HCC1428 long term estrogen deprived (LTED) model, with significant down-regulation of ER protein (81%) at 1 mpk QD and tumour growth inhibition in an ESR1 mutant PDX model). These findings strongly supported selection of AZD9496 as a clinical candidate for the treatment of ER+ breast cancer, and on October 2014 the first patient was dosed with AZD9496. ER alpha human binding IC50 (μM)ER downregulation cell IC50 (μM)MCF7 anti-proliferation EC50 (μM)Aqueous solubility, (pH = 7.4, μM)MCF7 tumor xenograft efficacy (% TGI at 10 mpk PO QD for 22 days)AZD94960.00070.000140.0000411084 Citation Format: Chris De Savi, Robert H. Bradbury, Alfred A. Rabow, Richard A. Norman, David Buttar, Gordon S. Currie, Hazel Weir, Craig Donald, David Andrews, Phil MacFaul, Peter Ballard, Jon Curwen, Zena Wilson, Graham Richmond, Celina D'Cruz, Steve Powell, Graeme Walker, Michael Hulse, Michael Tonge. Discovery of the clinical candidate AZD9496: a potent and orally bioavailable selective estrogen receptor downregulator and antagonist. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3650. doi:10.1158/1538-7445.AM2015-3650
Hyperalphalipoproteinemia in human lecithin cholesterol acyltransferase transgenic rabbits. In vivo apolipoprotein A-I catabolism is delayed in a gene dose-dependent manner. (1996)

Lecithin cholesterol acyltransferase (LCAT) is an enzyme involved in the intravascular metabolism of high density lipoproteins (HDLs). Overexpression of human LCAT (hLCAT) in transgenic rabbits leads to gene dose-dependent increases of total and HDL cholesterol concentrations. To elucidate the mechanisms responsible for this effect, 131I-HDL apoA-I kinetics were assessed in age- and sex-matched groups of rabbits (n=3 each) with high, low, or no hLCAT expression. Mean total and HDL cholesterol concentrations (mg/dl), respectively, were 162+/-18 and 121+/-12 for high expressors (HE), 55+/-6 and 55+/-10 for low expressors (LE), and 29+/-2 and 28+/-4 for controls. Fast protein liquid chromatography analysis of plasma revealed that the HDL of both HE and LE were cholesteryl ester and phospholipid enriched, as compared with controls, with the greatest differences noted between HE and controls. These compositional changes resulted in an incremental shift in apparent HDL particle size which correlated directly with the level of hLCAT expression, such that HE had the largest HDL particles and controls the smallest. In vivo kinetic experiments demonstrated that the fractional catabolic rate(FCR, d(-1)) of apoA-I was slowest in HE (0.328+/-0.03) followed by LE (0.408+/-0.01) and, lastly, by controls (0.528+/-0.04). ApoA-I FCR was inversely associated with HDL cholesterol level (r=-0.851,P<0.01) and hLCAT activity (r=-0.816, P<0.01). These data indicate that fractional catabolic rate is the predominant mechanism by which hLCAT overexpression differentially modulates HDL concentrations in this animal model. We hypothesize that LCAT-induced changes in HDL composition and size ultimately reduce apoA-I catabolism by altering apoA-I conformation and/or HDL particle regeneration.
Abundances of transcripts, proteins, and metabolites in the cell cycle of budding yeast reveals coordinate control of lipid metabolism (2019)

ABSTRACT Establishing the pattern of abundance of molecules of interest during cell division has been a long-standing goal of cell cycle studies. In several systems, including the budding yeast Saccharomyces cerevisiae , cell cycle-dependent changes in the transcriptome are well studied. In contrast, few studies queried the proteome during cell division, and they are often plagued by low agreement with each other and with previous transcriptomic datasets. There is also little information about dynamic changes in the levels of metabolites and lipids in the cell cycle. Here, for the first time in any system, we present experiment-matched datasets of the levels of RNAs, proteins, metabolites, and lipids from un-arrested, growing, and synchronously dividing yeast cells. Overall, transcript and protein levels were correlated, but specific processes that appeared to change at the RNA level (e.g., ribosome biogenesis), did not do so at the protein level, and vice versa. We also found no significant changes in codon usage or the ribosome content during the cell cycle. We describe an unexpected mitotic peak in the abundance of ergosterol and thiamine biosynthesis enzymes. Although the levels of several metabolites changed in the cell cycle, by far the most significant changes were in the lipid repertoire, with phospholipids and triglycerides peaking strongly late in the cell cycle. Our findings provide an integrated view of the abundance of biomolecules in the eukaryotic cell cycle and point to a coordinate mitotic control of lipid metabolism.
Auger recombination dynamics of lead salts under picosecond free-electron-laser excitation (1998)

Pump-probe transmission experiments have been performed on PbSe above the fundamental absorption edge near 4 \ensuremath{\mu}m in the temperature range 30 to 300 K, using the Dutch ps free-electron laser. For temperatures below 200 K and carrier densities above the threshold for stimulated emission, stimulated recombination represents the most efficient recombination mechanism with relatively fast kinetics in the 50--100-ps regime, in good agreement with earlier reports of photoluminescent emission. Above this temperature Auger recombination dominates, and the Auger coefficient C is determined from the pump-probe decay curves. In the low-temperature regime the Auger coefficient is determined from the decay curves at times beyond 100 ps. The Auger coefficient is approximately constant (with a value of about $8\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}28} {\mathrm{cm}}^{6}{\mathrm{}\mathrm{s}}^{\mathrm{\ensuremath{-}}1})$ between 300 and 70 K, and then drops a value of about $1\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}28} {\mathrm{cm}}^{6}{\mathrm{}\mathrm{s}}^{\mathrm{\ensuremath{-}}1}$ at 30 K, in good agreement with the theory for nonparabolic near-mirror bands and nondegenerate statistics. It is found that C for PbSe is between one and two orders of magnitude lower than for ${\mathrm{Hg}}_{1\ensuremath{-}x}{\mathrm{Cd}}_{x}\mathrm{Te}$ of comparable band gap.
Anatomical brain connectivity can assess cognitive dysfunction in multiple sclerosis (2013)

ACM opens a new perspective, clarifying the contribution of anatomical brain disconnection to clinical disabilities in MS.
Enhanced fluorescence diffuse optical tomography with indocyanine green-encapsulating liposomes targeted to receptors for vascular endothelial growth factor in tumor vasculature (2013)

To develop an indocyanine green (ICG) tracer with slower clearance kinetics, we explored ICG-encapsulating liposomes (Lip) in three different formulations: untargeted (Lip/ICG), targeted to vascular endothelial growth factor (VEGF) receptors (scVEGF-Lip/ICG) by the receptor-binding moiety single-chain VEGF (scVEGF), or decorated with inactivated scVEGF (inactive-Lip/ICG) that does not bind to VEGF receptors. Experiments were conducted with tumor-bearing mice that were placed in a scattering medium with tumors located at imaging depths of either 1.5 or 2.0 cm. Near-infrared fluorescence diffuse optical tomography that provides depth-resolved spatial distributions of fluorescence in tumor was used for the detection of postinjection fluorescent signals. All liposome-based tracers, as well as free ICG, were injected intravenously into mice in the amounts corresponding to 5 nmol of ICG/mouse, and the kinetics of increase and decrease of fluorescent signals in tumors were monitored. A signal from free ICG reached maximum at 15-min postinjection and then rapidly declined with t1/2 of ~20 min. The signals from untargeted Lip/ICG and inactive-Lip/ICG also reached maximum at 15-min postinjection, however, declined somewhat slower than free ICG with t1/2 of ~30 min. By contrast, a signal from targeted scVEGF-Lip/ICG grew slower than that of all other tracers, reaching maximum at 30-min postinjection and declined much slower than that of other tracers with t1/2 of ~90 min, providing a more extended observation window. Higher scVEGF-Lip/ICG tumor accumulation was further confirmed by the analysis of fluorescence on cryosections of tumors that were harvested from animals at 400 min after injection with different tracers.
Optimal shape design of shoulder fillets for flat and round bars under various loadings (2009)

Fillets are usually the most critical regions in mechanical parts especially under fatigue loading, considering that an increase in the maximum stress level considerably shortens the fatigue life of a part. The aim of this study is to find the best shape for a fillet in a shouldered shaft or plate so that the maximum equivalent stress has the lowest possible value. Optimization is achieved using a stochastic global search algorithm called the direct search simulated annealing. The boundary is defined using spline curves passing through a number of key points. The method is also applicable to shape optimization problems in which geometric constraints are imposed and, for this reason, tangential stress is not uniform along the optimal fillet boundary. Optimal shapes are obtained for flat and round bars subject to axial, bending, torsional, or combined loads. The results show that stress concentration factors close to one can be achieved even for bars with significant variations in cross-section. Besides, the region occupied by the optimum fillets is much smaller in comparison to circular or elliptical ones.
Intestinal heat shock protein 110 regulates expression of CD1d on intestinal epithelial cells (2003)

CD1d is expressed on the surface of professional and nonprofessional APCs, including intestinal epithelial cells (IECs), for a role in the presentation of glycolipid-based antigens to subsets of T cells. The mechanisms that regulate CD1d expression in any cell type are unknown. To investigate the possibility that expression of CD1d is influenced by exogenous factors present within the intestinal lumen, CD1d expression was analyzed in several IEC lines after culturing in the presence of lumenal contents (LC) of the normal human intestine. Exposure of the colon-derived cell lines T84, HT-29, and Caco-2 to soluble LC resulted in a marked induction of CD1d expression as determined by RT-PCR, confocal microscopy, cell surface ELISA, and Western blot analysis. Similarly, exposure of human IECs to LC isolated from mice bred in both specific pathogen-free and germfree conditions also resulted in the induction of CD1d expression, with the maximum CD1d-inducing activity observed in the small intestine. Biochemical and biophysical characterization of the human CD1d-inducing activity identified heat shock protein 110 (Hsp110) as a major functional component of the LC that contributes to CD1d surface regulation, and immunolocalization studies revealed Hsp110 expression in subsets of human IECs in vivo. These data support the presence of a novel autocrine pathway of CD1d regulation by Hsp110.
Immunohistochemical Validation of a Novel Epithelial and a Novel Stromal Marker of Pancreatic Ductal Adenocarcinoma Identified by Global Expression Microarrays (2002)

We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas. Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adenocarcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium. In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma-associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers.
Analog varactor phase shifter (2017)

The paper presents a novel design of analog phase shifter based on varactor-tuned reflective loads. Each device's reflective load comprises two microstrip stubs with varactor diode, where the stubs are connected in a specific way for average losses and transmission ripple minimization. The device is equipped with two independent varactor control channels. It is shown that the phase shifter structure can be optimized for successive independent varactors tuning, leading to a substantial transmission losses improvement.
Distinct Cortical Pathways for Processing Tool versus Animal Sounds (2005)

Human listeners can effortlessly categorize a wide range of environmental sounds. Whereas categorizing visual object classes (e.g., faces, tools, houses, etc.) preferentially activates different regions of visually sensitive cortex, it is not known whether the auditory system exhibits a similar organization for different types or categories of complex sounds outside of human speech. Using functional magnetic resonance imaging, we show that hearing and correctly or incorrectly categorizing animal vocalizations (as opposed to hand-manipulated tool sounds) preferentially activated middle portions of the left and right superior temporal gyri (mSTG). On average, the vocalization sounds had much greater harmonic and phase-coupling content (acoustically similar to human speech sounds), which may represent some of the signal attributes that preferentially activate the mSTG regions. In contrast, correctly categorized tool sounds (and even animal sounds that were miscategorized as being tool-related sounds) preferentially activated a widespread, predominantly left hemisphere cortical "mirror network." This network directly overlapped substantial portions of motor-related cortices that were independently activated when participants pantomimed tool manipulations with their right (dominant) hand. These data suggest that the recognition processing for some sounds involves a causal reasoning mechanism (a high-level auditory "how" pathway), automatically evoked when attending to hand-manipulated tool sounds, that effectively associates the dynamic motor actions likely to have produced the sound(s).
Electronic properties of the nitrone substituent. Stabilization of benzylic carbocations (2001)

The nitrone substituent CHN(O) t-Bu is electron-withdrawing with a Taft σI value of 0.20. It also retards the solvolysis rate of a cumyl chloride when placed in the meta-position (σ+ = 0.20). However, CHN(O) t-Bu becomes weakly cation stabilizing when placed in the para-position of a cumyl cation (σ+ = −0.04). This weak cation stabilization is a result of a conjugative interaction which delocalizes charge and offsets the inductive effect of the nitrone. When the nitrone is placed in the para-position, but then twisted out of conjugation with the aromatic ring by incorporation of flanking 3,5-dimethyl groups, it again retards solvolysis rates. Computational studies (B3LYP/6–31G*) show that the nitrone substituent stabilizes a para-substituted benzyl cation relative to the meta-substituted analog by a conjugative interaction. However, the calculated stabilization greatly overestimates the cation stabilization seen in solvolytic reactions. Copyright © 2001 John Wiley & Sons, Ltd.