gebhart/patrepeval huggingface dataset:
ZD9331 (1999)

Thymidylate synthase (TS) has been the target enzyme for intensive antifolate drug development for several years and specific inhibition of TS, and hence DNA synthesis, has been achieved with a range of quinazoline analogs of folic acid, including CB3717 (1–3) and its non-nephrotoxic successor, TomudexTM (ZD1694, raltitrexed) (4–6). The latter compound has recently been introduced in a number of counties for the treatment of advanced colorectal cancer and is reviewed by Hughes et al. and Beale et al. (see Chapters 6 and 7). ZD1694 is a polyglutamatable drug that depends on cellular uptake via a carrier-mediated, saturable mechanism (the reduced-folate carrier; RFC) (7–13). ZD1694 polyglutamates are significantly more potent TS inhibitors than the parent drug and retention of high-chain-length forms inside cells results in prolonged inhibition of TS in tumor cells grown in vitro and in vivo. Of more recent interest has been the development of water-soluble acidic, quinazoline-based TS inhibitors that lack FPGS substrate activity but retain high affmity for the RFC. Work from the group of F. Sirotnak (14) has provided evidence that compounds with favorable kinetic parameters for the RFC may offer a tumor-selective advantage, at least in murine models. Additionally, our own research demonstrated a clear potency advantage of compounds that use the RFC. Such compounds would be expected to be active against tumors expressing low FPGS or high folylpolyglutamyl hydrolase (FPGH) activity, both documented mechanisms of resistance in cell lines with acquired resistance to polyglutamatable antifolates (7–13); and give a different, and possibly more controllable, toxicity profile than ZD1694. Whereas examples of antifolates with these biochemical attributes already existed when we started the program, e.g., the water-soluble, nonpolyglutamatable inhibitors of DHFR, none have reached the stage of clinical evaluation (15–17). KeywordsDBA2 MouseTotal White Cell CountKidney HistologyFolylpolyglutamate SynthetaseGrowth Inhibitory PotencyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Tuning the bandgap of Cs2AgBiBr6 through dilute tin alloying (2019)

The promise of lead halide hybrid perovskites for optoelectronic applications makes finding less-toxic alternatives a priority. The double perovskite Cs<sub>2</sub>AgBiBr<sub>6</sub> (<b>1</b>) represents one such alternative, offering long carrier lifetimes and greater stability under ambient conditions. However, the large and indirect 1.95 eV bandgap hinders its potential as a solar absorber. Here we report that alloying crystals of <b>1</b> with up to 1 atom% Sn results in a bandgap reduction of up to <i>ca.</i> 0.5 eV while maintaining low toxicity. Crystals can be alloyed with up to 1 atom% Sn and the predominant substitution pathway appears to be a ∼2 : 1 substitution of Sn<sup>2+</sup> and Sn<sup>4+</sup> for Ag<sup>+</sup> and Bi<sup>3+</sup>, respectively, with Ag<sup>+</sup> vacancies providing charge compensation. Spincoated films of <b>1</b> accommodate a higher Sn loading, up to 4 atom% Sn, where we see mostly Sn<sup>2+</sup> substitution for both Ag<sup>+</sup> and Bi<sup>3+</sup>. Density functional theory (DFT) calculations ascribe the bandgap redshift to the introduction of Sn impurity bands below the conduction band minimum of the host lattice. Using optical absorption spectroscopy, photothermal deflection spectroscopy, X-ray absorption spectroscopy, <sup>119</sup>Sn NMR, redox titration, single-crystal and powder X-ray diffraction, multiple elemental analysis and imaging techniques, and DFT calculations, we provide a detailed analysis of the Sn content and oxidation state, dominant substitution sites, and charge-compensating defects in Sn-alloyed Cs<sub>2</sub>AgBiBr<sub>6</sub> (<b>1:Sn</b>) crystals and films. An understanding of heterovalent alloying in halide double perovskites opens the door to a wider breadth of potential alloying agents for manipulating their band structures in a predictable manner.
A Chemoselective Peptide Bond Formation by Amino Thioacid Coupling (2019)

Enzymes and ribosomes accurately form peptide bonds without protecting groups in vivo. Inspired by biological chemistries, we have been exploring a chemoselective reaction for peptide bond formation. In this manuscript, we describe amino thioacid coupling (ATC) that enables peptide bond formation between a peptide-aryl thioester and an amino thioacid. The results suggest that ATC proceeds through the formation of a thioanhydride intermediate afforded by a chemoselective thioacid-thioester exchange reaction. A new amino thioacid coupling (ATC) for the formation of peptide bond is described. ATC efficiently attaches one amino acid to a peptide C-terminus using an amino thioacid and a peptide-arylthioester as starting materials. Results supported a proposed reaction mechanism that includes the formation of the thioanhydride intermediate via a thioacid-thioester exchanging reaction between a peptide-arylthioester and an amino thioacid.
Blood pressure variability and plasma Alzheimer’s disease biomarkers in older adults (2022)

Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aβ<sub>1-42</sub> (standardized ß = - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R<sup>2</sup> = 0.28) and Aβ<sub>1-42</sub>: Aβ<sub>1-40</sub> ratio (ß = - 0.49 [95% CI - 0.71, - 0.22]; p < 0.001; adjusted R<sup>2</sup> = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R<sup>2</sup> = 0.19) and Ptau<sub>181</sub>:Aβ<sub>1-42</sub> ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R<sup>2</sup> = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.
OP30 Lyophilised orally administered faecal microbiota transplantation for Active Ulcerative Colitis (LOTUS study) (2021)

Abstract Background Faecal microbiota transplantation (FMT) administered via the lower GI tract effectively induces remission in ulcerative colitis (UC). Orally administered FMT capsules may improve patient tolerability and facilitate maintenance therapy while it is unclear if pre-FMT antibiotics enhance therapeutic efficacy. Methods We performed a dual-centre randomised, double blind, placebo-controlled trial of oral lyophilised FMT in adults with mild-moderately active UC (total Mayo 4–10). All subjects received 2-weeks of pre-FMT antibiotics (amoxycillin, metronidazole and doxycycline) before 1:1 randomisation to either oral FMT (0.35g stool content per capsule from 1 of 2 healthy donors) or identical placebo for 8 weeks. Enforced tapering and cessation of corticosteroids was mandated. The primary endpoint was week 8 steroid-free clinical remission with endoscopic remission or response (total Mayo score ≤2 with subscores ≤ 1 for rectal bleeding, stool frequency and endoscopic appearance, and ≥1-point reduction from baseline in endoscopy subscore). Responders to FMT induction were re-randomised to either continue maintenance FMT or withdrawal of FMT with final outcomes assessed at week 56. Results Recruitment was paused due to the COVID-19 pandemic. 37 patients were randomised. Baseline patient and disease characteristics were balanced between the randomised groups. The primary outcome was achieved in 8/16 (50%) receiving FMT versus 3/19 (16%) receiving placebo (OR: 4.63; 95%CI: 1.74–12.30; P=0.002). Steroid-free clinical remission rates and endoscopic remission rates were 69% vs 26% (P=0.012) and 44% vs 16% (P=0.074) in the FMT and placebo arms, respectively. Reported SAE were worsening colitis (2 FMT, 1 placebo) and PR bleeding relating to previous anal surgery (placebo). Ten patients entered the maintenance withdrawal study. Steroid-free clinical, endoscopic and histologic remission was achieved in 4/4 patients who continued daily oral FMT, with all 6 patients randomised to FMT withdrawal having a flare of disease with a median time to relapse of 6 months. Conclusion Oral lyophilised FMT following antibiotic pre-treatment for mild-moderately active ulcerative colitis was associated with a significant increased rate of clinical remission with endoscopic remission or response versus antibiotic treatment alone at week 8. Pre-treatment antibiotics had an additive impact upon treatment efficacy compared with previous studies utilising FMT. Maintenance FMT therapy was associated with sustained clinical, endoscopic and histologic remission at week 56. Treatment was well tolerated and there were no new safety signals related to FMT therapy.
Hierarchical Coupling of First-Principles Molecular Dynamics with Advanced Sampling Methods (2018)

We present a seamless coupling of a suite of codes designed to perform advanced sampling simulations, with a first-principles molecular dynamics (MD) engine. As an illustrative example, we discuss results for the free energy and potential surfaces of the alanine dipeptide obtained using both local and hybrid density functionals (DFT), and we compare them with those of a widely used classical force field, Amber99sb. In our calculations, the efficiency of first-principles MD using hybrid functionals is augmented by hierarchical sampling, where hybrid free energy calculations are initiated using estimates obtained with local functionals. We find that the free energy surfaces obtained from classical and first-principles calculations differ. Compared to DFT results, the classical force field overestimates the internal energy contribution of high free energy states, and it underestimates the entropic contribution along the entire free energy profile. Using the string method, we illustrate how these differences lead to different transition pathways connecting the metastable minima of the alanine dipeptide. In larger peptides, those differences would lead to qualitatively different results for the equilibrium structure and conformation of these molecules.
Labeling Carboxyl Groups of Surface-Exposed Proteins Provides an Orthogonal Approach for Cell Surface Isolation (2018)

Quantitative profiling of cell surface proteins is critically important for the understanding of cell-cell communication, signaling, tissue development, and homeostasis. Traditional proteomics methods are challenging for cell surface proteins due to their hydrophobic nature and low abundance, necessitating alternative methods to efficiently identify and quantify this protein group. Here we established carboxyl-reactive biotinylation for selective and efficient biotinylation and isolation of surface-exposed proteins of living cells. We assessed the efficiency of carboxyl-reactive biotinylation for plasma membrane proteins by comparing it with a well-established protocol, amine-reactive biotinylation, using SILAC (stable isotope labeling in cell culture). Our results show that carboxyl-reactive biotinylation of cell surface proteins is both more selective and more efficient than amine-reactive biotinylation. We conclude that it is a useful approach, which is partially orthogonal to amine-reactive biotinylation, allowing us to cast a wider net for a comprehensive profiling of cell surface proteins.
Spatiotemporal Tuning of Motor Cortical Neurons for Hand Position and Velocity (2004)

A pursuit-tracking task (PTT) and multielectrode recordings were used to investigate the spatiotemporal encoding of hand position and velocity in primate primary motor cortex (MI). Continuous tracking of a randomly moving visual stimulus provided a broad sample of velocity and position space, reduced statistical dependencies between kinematic variables, and minimized the nonstationarities that are found in typical "step-tracking" tasks. These statistical features permitted the application of signal-processing and information-theoretic tools for the analysis of neural encoding. The multielectrode method allowed for the comparison of tuning functions among simultaneously recorded cells. During tracking, MI neurons showed heterogeneity of position and velocity coding, with markedly different temporal dynamics for each. Velocity-tuned neurons were approximately sinusoidally tuned for direction, with linear speed scaling; other cells showed sinusoidal tuning for position, with linear scaling by distance. Velocity encoding led behavior by about 100 ms for most cells, whereas position tuning was more broadly distributed, with leads and lags suggestive of both feedforward and feedback coding. Individual cells encoded velocity and position weakly, with comparable amounts of information about each. Linear regression methods confirmed that random, 2-D hand trajectories can be reconstructed from the firing of small ensembles of randomly selected neurons (3-19 cells) within the MI arm area. These findings demonstrate that MI carries information about evolving hand trajectory during visually guided pursuit tracking, including information about arm position both during and after its specification. However, the reconstruction methods used here capture only the low-frequency components of movement during the PTT. Hand motion signals appear to be represented as a distributed code in which diverse information about position and velocity is available within small regions of MI.
Human lung adenocarcinoma cell cultures derived from malignant pleural effusions as model system to predict patients chemosensitivity (2016)

Results obtained using primary cultured cells from MPEs underscore the heterogeneity of NSCLC in advanced stage as indicated by drug response and mutation profile. Comparison of data obtained from in vitro assays with patients' responses to therapy leads to the conclusion that this strategy may provide a potentially useful approach for evaluating individual chemosensitivity profile and tailor the therapy accordingly. Furthermore, combining MPE-derived primary cultures with their genomic testing allows to identify patients eligible to trials with novel targeted agents.
Probing the Organic−Mineral Interface at the Molecular Level in Model Biominerals (2008)

It is widely known that macromolecules, such as proteins, can control the nucleation and growth of inorganic solids in biomineralizing organisms. However, what is not known are the complementary molecular interactions, organization, and rearrangements that occur when proteins interact with inorganic solids during the formation of biominerals. The organic-mineral interface (OMI) is expected to be the site for these phenomena, and is therefore extraordinarily interesting to investigate. In this report, we employ X-ray absorption near edge (XANES) spectromicroscopy to investigate the electronic structure of both calcium carbonate mineral crystals and polypeptides, and detect changing bonds at the OMI during crystal growth in the presence of polypeptides. We acquired XANES spectra from calcium carbonate crystals grown in the presence of three mollusk nacre-associated polypeptides (AP7N, AP24N, n16N) and in the presence of a sea urchin spicule matrix protein, LSM34. All these model biominerals gave similar results, including the disruption of CO bonds in calcite and enhancement of the peaks associated with C-H bonds and C-O bonds in peptides, indicating ordering of the amino acid side chains in the mineral-associated polypeptides and carboxylate binding. This is the first evidence of the mutual effect of calcite on peptide chain and peptide chain on calcite during biomineralization. We also show that these changes do not occur when Asp and Glu are replaced in the n16N sequence with Asn and Gln, respectively, demonstrating that carboxyl groups in Asp and Glu do participate in polypeptide-mineral molecular associations.
Resolution of Reprogramming Transition States by Single Cell RNA-Sequencing (2017)

Abstract The Yamanaka factors convert mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs) through a highly heterogeneous process. Here we profile single cells undergoing an optimized 7-day reprogramming process and show that cells start reprogramming relatively in sync, but diverge into two branches around day 2. The first branch of cells expressing Cd34/Fxyd5/Psca become nonpluripotent. The second one contains cells that are first Oct4 +, then Dppa5a + and pluripotent. We show that IFN-γ blocks this late transition. Our results reveal the heterogeneous nature of somatic cell reprogramming, identify Dppa5a as a marker for pluripotent and innate immunity as a potential barrier for reprogramming. One Sentence Summary Single cell RNA sequencing reveals a continuum of cell fates from somatic to pluripotent and Dppa5a as a marker for chimera-competent iPSCs.
Origin of colour stability in blue/orange/blue stacked phosphorescent white organic light-emitting diodes (2008)

The origin of colour stability in phosphorescent white organic light-emitting diodes (PHWOLEDs) with a blue/orange/blue stacked emitting structure was studied by monitoring the change in a recombination zone. A balanced recombination zone shift between the blue and the orange light-emitting layers was found to be responsible for the colour stability in the blue/orange/blue stacked PHWOLEDs.
The Use of High Rate Li-ion Cells in Hybrid Fuel-Cell/Battery Power Systems for Application in Large Robotic Vehicles (2007)

The utilization of high-rate LiFePO 4 -based batteries in hybrid power system environments is described. Two 250 Wh (24V & 10 Ah) large- format battery packs based on A123 Systems “M1” cells were designed and implemented in a hydrogen-air fuel cell/battery hybrid power system for a large robotic platform, the ATHELTE rover developed at JPL. Analyses of the performance of these batteries (at both the system and cell levels) under variety of test conditions will be discussed and the advantages of these batteries over other alternatives will be shown. Data from full testing as well as bench top qualification will be discussed. Charge/discharge currents exceeding 100A were tolerated safely and repeatedly. The performance of this pack will be compared to that of other battery chemistries and the promise of this new class of batteries will be discussed.
42 ELECTRICAL STIMULATION OF THE VENTRAL LATERAL PERIAQUEDUCTAL GRET (VIPAG) PRODUCES SUSTAINED REDUCTIONS IN BLOOD PRESSURE IN SPONTANEOUSLY HYPERTENSIVE (SH) BUT NOT NORMOTENSIVE RATS (2012)

Background and Objectives: Deep brain stimulation of the vlPAG is used for the clinical treatment of chronic neuropathic pain in man. It has also been shown to produce sustained reductions in arterial pressure (AP) in hypertensive patients1. We have developed an implantable electrical stimulation system and applied it to the vlPAG of conscious, freely moving rats. Methods and Results: AP and heart rate (HR) responses to stimulation were measured via telemetry. When resting quietly, rats were stimulated for 60 min at a series of frequency steps (15, 20, 30, 40 Hz) with >30 min recovery between steps. SH rats (mean baseline AP 139 ± 10 mmHg; n = 5) showed frequency-dependent AP reductions (12 ± 4 vs 28 ± 6 mmHg; 15 vs 40 Hz; p<0.05), which persisted throughout the stimulation period. In contrast, in Wistar rats (mean baseline AP 101 ± 9mmHg; n = 4) a smaller depressor response was evoked (1 ± 2 mmHg vs 4 ± 2 mmHg; 15 vs 40 Hz), which tended to return to baseline after 20-30mins. In SH rats the depressor response was maintained throughout 3 days of continuous 10 Hz vlPAG stimulation (135 mmHg to 121 mmHg; baseline vs day 3) and associated with a reduction in the low frequency power of systolic blood pressure (1.75 to 1.51 mmHg2), suggesting sympathoinhibition. Conclusions: In conclusion, our results show that the vlPAG of the SH rat is a more effective depressor site than it is in Wistar rats. Our current studies are now determining the underlying mechanisms for this response. Reference N.K. Patel, S. Javed, S. Khan, M. Papouchado, A.L. Malizia, A.E. Pickering, and J.F.R. Paton. Deep brain stimulation relieves refractory hypertension. Neurology, 2011 76:405–407.
Diode-pumped ytterbium-based chirped-pulse amplifier (2008)

This paper will describe a comparative study on four different Yb-doped laser materials in a diode-pumped femtosecond chirped-pulse amplifier. Broadband multi-pass amplification using single crystalline Yb:CaF2, Yb:KGW, and Yb:YAG as well as Yb-doped fluoride phosphate glass was demonstrated. The seed pulses as short as 85 fs were generated in a Ti:Sapphire oscillator tuned to a center-wavelength of 1030nm and then boosted to the 100 &#956;J-level in a diode-pumped Yb:glass regenerative amplifier. Furthermore, the amplifier performance at nanosecond and microsecond time-scales was analyzed. With regard to the 10-nm line-width of the emission cross section the gain narrowing in Yb:YAG was investigated in particular. The pulse spectrum was narrowed to 1.9nm at a total gain of 103 in an Yb:YAG multi-pass amplifier. This corresponds to a compressed pulse duration of 0.85 ps. When seeding with nanosecond pulses of a Q-switched oscillator a maximum pulse energy of 220mJ at a repetition rate of 10Hz has been achieved.
Direct Decomposition of NO over Ba–Y2O3 Catalyst Prepared by Coprecipitation (2011)

Abstract The catalytic performance of Ba–Y2O3 prepared by a coprecipitation method for the direct decomposition of NO was investigated. Although Y2O3 catalyzed NO decomposition, its activity was increased by addition of Ba. The maximum NO decomposition activity was achieved on Ba–Y2O3 with 5 wt % Ba loading. XRD measurements revealed the formation of a solid solution of Ba and Y2O3 as well as BaCO3 small particles, when Ba loading was increased up to 5 wt %. From the comparison between the amount of CO2 desorption measured by temperature-programmed desorption of CO2 (CO2-TPD) and the NO decomposition activity of Ba–Y2O3, highly dispersed Ba species, which is initially present as BaCO3 small particles, on the catalyst surface act as catalytically active sites for NO decomposition. On the basis of in situ observation of surface species formed during NO decomposition by Fourier transform infrared (FT-IR) spectroscopy, we proposed that highly dispersed Ba species plays a role for the formation and adsorption of nitrite (NO2−) as reactive species for NO decomposition over Ba–Y2O3 catalyst.
Efficient Hydrogen Production from Methanol by Combining Micro Channel with Carbon Membrane Catalyst Loaded with Cu/Zn (2009)

An assemble-type multi-stage microreactor with thin film catalyst has been developed. A new thin membrane carbon catalyst loaded with Cu/Zn is prepared through the carbonization of polyamic acid membrane loading Cu and Zn by ion exchange method. Using the microreactor with the catalyst developed, we perform steam reforming of methanol in order to selectively produce hydrogen for fuel cell usage. The methanol conversion and yield of H2 reached 0.74 and 2.2 mol mol-methanol–1, respectively, at the low temperature of 220°C when using a 15-stage microreactor. As compared with the yields by a conventional tubular reactor, the methanol conversion is high and the CO yield is significantly suppressed in the microreactor. The advantage of the microreactor is presumably due to the concentration profile under a gaseous laminar flow in the micro space. Finally, the compact reactor system, which consists of a micro-reformer, micro-combustor and tubular-combustor, has been developed, and high yield of hydrogen and less than 5 ppm of CO has been successfully achieved.