gebhart/patrepeval huggingface dataset:
Combination Therapy of Mithramycin A and Immune Checkpoint Inhibitor for the Treatment of Colorectal Cancer in an Orthotopic Murine Model (2021)

The axis of Programmed cell death-1 receptor (PD-1) with its ligand (PD-L1) plays a critical role in colorectal cancer (CRC) in escaping immune surveillance, and blocking this axis has been found to be effective in a subset of patients. Although blocking PD-L1 has been shown to be effective in 5-10% of patients, the majority of the cohorts show resistance to this checkpoint blockade (CB) therapy. Multiple factors assist in the growth of resistance to CB, among which T cell exhaustion and immunosuppressive effects of immune cells in the tumor microenvironment (TME) play a critical role along with other tumor intrinsic factors. We have previously shown the polyketide antibiotic, Mithramycin-A (Mit-A), an effective agent in killing cancer stem cells (CSCs) <i>in vitro</i> and <i>in vivo</i> in a subcutaneous murine model. Since TME plays a pivotal role in CB therapy, we tested the immunomodulatory efficacy of Mit-A with anti-PD-L1 mAb (αPD-L1) combination therapy in an immunocompetent MC38 syngeneic orthotopic CRC mouse model. Tumors and spleens were analyzed by flow cytometry for the distinct immune cell populations affected by the treatment, in addition to RT-PCR for tumor samples. We demonstrated the combination treatment decreases tumor growth, thus increasing the effectiveness of the CB. Mit-A in the presence of αPD-L1 significantly increased CD8<sup>+</sup> T cell infiltration and decreased immunosuppressive granulocytic myeloid-derived suppressor cells and anti-inflammatory macrophages in the TME. Our results revealed Mit-A in combination with αPD-L1 has the potential for augmented CB therapy by turning an immunologically "cold" into "hot" TME in CRC.
ChemInform Abstract: Synthesis of Heterocycles via Pd‐Ligand Controlled Cyclization of 2‐Chloro‐N‐(2‐vinyl)aniline: Preparation of Carbazoles, Indoles, Dibenzazepines, and Acridines. (2011)

Abstract The palladium‐catalyzed condensation of 2‐bromostyrene and 2‐chloroaniline derivatives provides stable diphenylamine intermediates (VI), which are selectively converted to the entitled five‐, six‐, or seven‐membered heteroaromatics.
Correction for Mechanical Inaccuracies in a Scanning Talbot-Lau Interferometer (2023)

Grating-based X-ray phase-contrast and in particular dark-field radiography are promising new imaging modalities for medical applications. Currently, the potential advantage of dark-field imaging in early-stage diagnosis of pulmonary diseases in humans is being investigated. These studies make use of a comparatively large scanning interferometer at short acquisition times, which comes at the expense of a significantly reduced mechanical stability as compared to tabletop laboratory setups. Vibrations create random fluctuations of the grating alignment, causing artifacts in the resulting images. Here, we describe a novel maximum likelihood method for estimating this motion, thereby preventing these artifacts. It is tailored to scanning setups and does not require any sample-free areas. Unlike any previously described method, it accounts for motion in between as well as during exposures.
The mid-term outcomes of the Oxford Domed Lateral unicompartmental knee replacement (2014)

Mobile-bearing unicompartmental knee replacements (UKRs) with a flat tibial plateau have not performed well in the lateral compartment, owing to a high dislocation rate. This led to the development of the Domed Lateral Oxford UKR (Domed OUKR) with a biconcave bearing. The aim of this study was to assess the survival and clinical outcomes of the Domed OUKR in a large patient cohort in the medium term. We prospectively evaluated 265 consecutive knees with isolated disease of the lateral compartment and a mean age at surgery of 64 years (32 to 90). At a mean follow-up of four years (sd 2.2, (0.5 to 8.3)) the mean Oxford knee score was 40 out of 48 (sd 7.4). A total of 12 knees (4.5%) [corrected] had re-operations, of which four (1.5%) were for dislocation. All dislocations occurred in the first two years. Two (0.8%) were secondary to significant trauma that resulted in ruptured ligaments, and two (0.8%) were spontaneous. In four patients (1.5%) the UKR was converted to a primary TKR. Survival at eight years, with failure defined as any revision, was 92.1% (95% confidence interval 81.3 to 100). The Domed Lateral OUKR gives good clinical outcomes, low re-operation and revision rates and a low dislocation rate in patients with isolated lateral compartmental disease, in the hands of the designer surgeons.
Enzymatic Breakage and Joining of Deoxyribonucleic Acid (1968)

Radioactive labeling of the 5′-termini of DNA with polynucleotide kinase has been used in conjunction with treatment by alkaline phosphatase from Escherichia coli to study single strand breaks (phosphodiester bond interruptions) produced in duplex DNA molecules by the action of pancreatic deoxyribonuclease. At 37° alkaline phosphatase will quantitatively hydrolyze external phosphomonoesters (those located at either end of the duplex molecule), but it will not hydrolyze internal phosphomonoesters (those located at single strand breaks). However, at elevated temperatures or following denaturation of the DNA, both external and internal phosphomonoesters are hydrolyzed by phosphatase. These methods permit (a) the identification, measurement, and characterization of single strand breaks in DNA molecules and (b) the preparation of specifically labeled DNAs used for studies on enzymes acting at internal and external termini.
A Density Ratio Approach to Language Model Fusion in End-To-End\n Automatic Speech Recognition (2020)

This article describes a density ratio approach to integrating external\nLanguage Models (LMs) into end-to-end models for Automatic Speech Recognition\n(ASR). Applied to a Recurrent Neural Network Transducer (RNN-T) ASR model\ntrained on a given domain, a matched in-domain RNN-LM, and a target domain\nRNN-LM, the proposed method uses Bayes' Rule to define RNN-T posteriors for the\ntarget domain, in a manner directly analogous to the classic hybrid model for\nASR based on Deep Neural Networks (DNNs) or LSTMs in the Hidden Markov Model\n(HMM) framework (Bourlard &amp; Morgan, 1994). The proposed approach is evaluated\nin cross-domain and limited-data scenarios, for which a significant amount of\ntarget domain text data is used for LM training, but only limited (or no)\n{audio, transcript} training data pairs are used to train the RNN-T.\nSpecifically, an RNN-T model trained on paired audio &amp; transcript data from\nYouTube is evaluated for its ability to generalize to Voice Search data. The\nDensity Ratio method was found to consistently outperform the dominant approach\nto LM and end-to-end ASR integration, Shallow Fusion.\n
The current status of nano-imprint lithography and its future outlook toward carbon neutrality by 2050 (2022)

Nano-imprint lithography (NIL) has unique features, including the ability to design at a resolution of 1x nm and three dimensional patterning. Although productivity was a concern for NIL, improvement has been made with recent technologies such as multi-field imprint and spin-coating resist. However, the environment surrounding the semiconductor industry is changing. One of the biggest waves is “carbon neutrality,” and it is believed that energy-saving technologies will be important for the future of the semiconductor industry. In this study, we evaluate the current performance of NIL and its future prospects as an energy-saving technology that will help the world achieve carbon neutrality by 2050.
High-efficiency mid-infrared ZnGeP_2 optical parametric oscillator in a multimode-pumped tandem optical parametric oscillator (1999)

We demonstrate a high-efficiency ZnGeP(2) optical parametric oscillator (OPO) pumped by another KTP OPO in a multimode-pumped tandem OPO configuration. The maximum optical-to-optical and slope efficiencies were 32% and 42.5%, respectively. Our setup also provides tunable multiband radiation in the 2.03-2.32-microm range and the 2.9-6.2-microm range simultaneously.
Development of a potent and selective GPR7 (NPBW1) agonist: a systematic structure–activity study of neuropeptide B (2007)

Neuropeptide B (NPB) has been recently identified as an endogenous ligand for GPR7 (NPBW1) and GPR8 (NPBW2) and has been shown to possess a relatively high selectivity for GPR7. In order to identify useful experimental tools to address physiological roles of GPR7, we synthesized a series of NPB analogs based on modification of an unbrominated form of 23 amino acids with amidated C-terminal, Br(-)NPB-23-NH(2). We confirmed that truncation of the N-terminal Trp residue resulted in almost complete loss of the binding affinity of NPB for GPR7 and GPR8, supporting the special importance of this residue for binding. Br(-)NPB-23-NH2 analogs in which each amino acid in positions 4, 5, 7, 8, 9, 10, 12 and 21 was replaced with alanine or glycine exhibited potent binding affinity comparable to the parent peptide. In contrast, replacement of Tyr(11) with alanine reduced the binding affinity for both GPR7 and GPR8 four fold. Of particular interest, several NPB analogs in which the consecutive amino acids from Pro4 to Val(13) were replaced with several units of 5-aminovaleric acid (Ava) linkers retained their potent affinity for GPR7. Furthermore, these Ava-substituted NPB analogs exhibited potent agonistic activities for GPR7 expressed in HEK293 cells. Among the Ava-substituted NPB analogs, analog 15 (Ava-5) and 17 (Ava-3) exhibited potency comparable to the parent peptide for GPR7 with significantly reduced activity for GPR8, resulting in high selectivity for GPR7. These highly potent and selective NPB analogs may be useful pharmacological tools to investigate the physiological and pharmacological roles of GPR7.
Temporally and Spatially Heterogeneous Distribution of mTHPC in a Murine Tumor Observed by Two‐color Confocal Fluorescence Imaging and Spectroscopy in a Whole‐mount Model (2005)

Efficient intratumor delivery of anticancer drugs and photosensitizers is an important factor in the success of chemotherapy and photodynamic therapy, respectively. Unfortunately, their adequate and uniform intratumor distribution is impeded by several physiological barriers and by binding to tissue components. Measurement of gross tumor drug accumulation is a routine method of investigating the uptake and clearance of chemotherapy agents and photosensitizers but tells little about their extravascular spatial distribution. We use whole-mount two-color confocal fluorescence imaging and imaging spectroscopy of unprocessed excised murine tumor fragments to investigate the intratumor distribution of the photosensitizer meso-tetrahydroxyphenyl chlorin (mTHPC) as a function of distance from blood vessels perfused with 0.2 mum diameter fluorescent microspheres. Significant mismatches between drug and perfused vasculature are caused by heterogeneities in tumor blood supply. We describe complex microscopic mTHPC gradients that reverse dramatically relative to the perfused vasculature with time after injection. This imaging technique can be applied to screen the dynamic intratumor distribution of other fluorescent photosensitizers and anticancer drugs.
Analysis of Transient and Catalytic Desosamine-binding Pockets in Cytochrome P-450 PikC from Streptomyces venezuelae (2009)

The cytochrome P-450 PikC from Streptomyces venezuelae exhibits significant substrate tolerance and performs multiple hydroxylation reactions on structurally variant macrolides bearing the deoxyamino sugar desosamine. In previously determined co-crystal structures (Sherman, D. H., Li, S., Yermalitskaya, L. V., Kim, Y., Smith, J. A., Waterman, M. R., and Podust, L. M. (2006) J. Biol. Chem. 281, 26289-26297), the desosamine moiety of the native substrates YC-17 and narbomycin is bound in two distinct buried and surface-exposed binding pockets, mediated by specific interactions between the protonated dimethylamino group and the acidic amino acid residues Asp(50), Glu(85), and Glu(94). Although the Glu(85) and Glu(94) negative charges are essential for maximal catalytic activity of native enzyme, elimination of the surface-exposed negative charge at Asp(50) results in significantly enhanced catalytic activity. Nevertheless, the D50N substitution could not rescue catalytic activity of PikC(E94Q) based on lack of activity in the corresponding double mutant PikC(D50N/E94Q). To address the specific role for each desosamine-binding pocket, we analyzed the x-ray structures of the PikC(D50N) mutant co-crystallized with narbomycin (1.85A resolution) and YC-17 (3.2A resolution). In PikC(D50N), the desosamine moiety of both YC-17 and narbomycin was bound in a catalytically productive "buried site." This finding suggested a two-step substrate binding mechanism, whereby desosamine is recognized in the two subsites to allow the macrolide substrate to sequentially progress toward a catalytically favorable orientation. Collectively, the binding, mutagenesis, kinetic, and x-ray structural data suggest that enhancement of the catalytic activity of PikC(D50N) is due to the facilitated relocation of substrate to the buried site, which has higher binding affinity, as opposed to dissociation in solution from the transient "surface-exposed site."
Erratum: “Carrier leakage via interface-roughness scattering bridges gap between theoretical and experimental internal efficiencies of quantum cascade lasers” [Appl. Phys. Lett. 117, 051101 (2020)] (2020)

Highly efficient 8 m
COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A (2014)

COMMD1 deficiency results in defective copper homeostasis, but the mechanism for this has remained elusive. Here we report that COMMD1 is directly linked to early endosomes through its interaction with a protein complex containing CCDC22, CCDC93, and C16orf62. This COMMD/CCDC22/CCDC93 (CCC) complex interacts with the multisubunit WASH complex, an evolutionarily conserved system, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer. Interactions between the WASH complex subunit FAM21, and the carboxyl-terminal ends of CCDC22 and CCDC93 are responsible for CCC complex recruitment to endosomes. We show that depletion of CCC complex components leads to lack of copper-dependent movement of the copper transporter ATP7A from endosomes, resulting in intracellular copper accumulation and modest alterations in copper homeostasis in humans with CCDC22 mutations. This work provides a mechanistic explanation for the role of COMMD1 in copper homeostasis and uncovers additional genes involved in the regulation of copper transporter recycling.
A NATURALLY OCCURRING BONE-MARROW-CHIMERIC PRIMATE (1985)

The New World primate species Saguinus oedipus, the cotton-top tamarin, has a high incidence of spontaneously occurring adenocarcinoma of the colon and develops a fatal lymphoproliferative syndrome following infection with various herpes viruses. Some investigators have linked such disease susceptibilities to abnormalities in the immune function of the cotton-top tamarin that may result from the natural bone marrow chimerism that occurs in this species. The present studies were initiated to establish conditions for studying the immune system of these primates and to assess the integrity of this system. First, we document the state of bone marrow chimerism of S oedipus. We then show that standard in vitro assays of lymphocyte function can be done with cells from this animal. Proliferative T cell assays, cytotoxic T lymphocyte (CTL) assays, and measurements of CTL precursor frequency all indicate that the immune system of this animal functions normally. Finally, we demonstrate in vitro the tolerance of lymphocytes from one S oedipus for the cells of its twin. The ability to manipulate tamarin blood cells in vitro will allow future investigation into mechanisms of immune tolerance and major histocompatibility complex restrictions on cell cooperation in this species.
Influence of Parallel Paths on Current-Regulated Sine-Wave Interior-Permanent-Magnet Machines With Rotor Eccentricity (2012)

The behavior of rotor eccentricities in current-regulated interior-permanent-magnet machines is investigated. The study focuses on two typical topologies of significant industrial relevance: machines with distributed windings with two slots per pole and phase and motors with concentrated coils and three slots per pole pair. The effect of stator-winding parallel paths is examined for both cases. Coil and terminal electrical quantities and radial forces were simulated using finite-element analysis. Unbalanced operation, where the currents are not equal in parallel phase connections due to eccentricity, is also investigated. Experimental measurements of electrical quantities and forces on motors with static eccentricity are carried out using two special test setups. The experimental measurements validated the simulation results.
Fully Integrated Selectivity at High Frequency Using Gyrators (1973)

An electronic gyrator is a two-port capable of transforming a capacitor into an inductance and therefore allows one to construct a tuned circuit using only transistors, resistors and capacitors. At frequencies below say 1 MHz it is possible to simulate inductance of high purity, but the value of capacitance required demands the use of discrete capacitors. The cost advantage of monolithic circuitry is therefore denied, but very high performance tuned circuits are possible.
ChemInform Abstract: A ONE‐STEP SYNTHESIS OF OPTICALLY PURE 1,2‐ETHANO BIS SULFOXIDES AND PHOSPHINE OXIDES VIA THE COPPER‐PROMOTED OXIDATIVE DIMERIZATION OF CHIRAL SULFINYL AND PHOSPHINYL CARBANIONS (1973)

Abstract Verfasser beschreiben eine anderen bekannten Synthesewegen überlegene Methode zur Darstellung der Titelverbindungen in hoher enantiomerer Reinheit.
Embolization of small vessels with a double-lumen microballoon catheter. Part II: Laboratory, animal, and histological studies. Work in progress. (1984)

A double-lumen microballoon catheter system measuring 0.5-0.85 mm in outer diameter (1.3-2.8 F) was fabricated for passage through standard 4.1 and 5 F catheters. By arresting circulation with the balloon, embolization with low-viscosity silicone rubber, ethanol, or isobutyl-2-cyanoacrylate can proceed in a methodical, unhurried manner, permitting precise control of tissue penetration and preventing paradoxical embolization of other vessels. Problems such as gluing the catheter in situ with cyanoacrylate did not occur. The catheter may also be inserted during surgery to control embolization at a remote site, which did result in the catheter being glued in situ in one case.
Improving Accuracy and Transferability of Machine Learning Chemical Activation Energies by Adding Electronic Structure Information (2023)

Predicting chemical activation energies is one of the longstanding and important challenges in computational chemistry. Recent advances have shown that machine learning can be used to create tools to predict them. Such tools can significantly decrease the computational cost for these predictions compared to traditional methods, which require an optimal path search along a high-dimensional potential energy surface. To enable this new route, we need both large and accurate datasets and a compact yet complete description of the reactions. Although data for chemical reactions is becoming increasingly available, the key step of encoding the reaction as an efficient descriptor remains a big challenge. In this paper, we demonstrate that including electronic energy levels in the description of the reaction significantly improves the prediction accuracy and transferability. Feature importance analysis further demonstrates that electronic energy levels have a higher importance than some structural information and typically require less space in the reaction encoding vector. In general, we observe that the results of the feature importance analysis relate well to the domain knowledge of fundamental chemical principles. This work can help to build better chemical reaction encodings for machine learning and thus improve the predictions of machine learning models for reaction activation energies. These models could ultimately be used to recognize reaction limiting steps in large reaction systems, allowing to account for bottlenecks at the design stage.
Crucial role of prostaglandin D 2 and adenosine in sleep regulation: experimental evidence from pharmacological approaches to gene-knockout mice (2010)

Prostaglandin (PG) D2 is the most potent endogenous sleep-promoting substance reported thus far. Its mechanism of action has been extensively studied at the molecular level. PGD2 is produced by lipocalin-type PGD synthase, which is predominantly localized in the leptomeninges, choroid plexus and oligodendrocytes in the brain; it is secreted into the cerebrospinal fluid and stimulates DP1 receptors localized in the arachnoid membrane of the ventral surface from the basal forebrain to the hypothalamus, increasing the extracellular concentration of adenosine as a paracrine sleep-promoting molecule. Adenosine diffuses into the brain parenchyma, suppresses cholinergic arousal neurons in the basal forebrain via adenosine A1 receptors, activates sleep-active neurons in the ventrolateral preoptic area via adenosine A2A receptors and concomitantly suppresses the histaminergic arousal center in the tuberomammillary nucleus through GABAergic and galaninergic inhibitory projections. Administration of an inhibitor of lipocalin-type PGD synthase (SeCl4), an antagonist of DP1 receptors (ONO-4127Na) or an antagonist of adenosine A2A receptors (caffeine) results in sleep inhibition in rats and mice. These results indicate that the PGD2–adenosine system is crucial for the maintenance of physiological sleep.
Can C-ITS lead to the emergence of Traffic Management 2.0? (2014)

Advances in Information and Communication Technologies (ICT) allow the transportation community to foresee relevant improvements for the incoming years in terms of a more efficient, environmental friendly and safe traffic management and operations. In that context, new ITS paradigms like Cooperative Systems (C-ITS) enable an efficient traffic state estimation and traffic control. C-ITS refers to three levels of cooperation between vehicles and infrastructure: (i) equipped vehicles with Advanced Driver Assistance Systems (ADAS) adjusting their motion to surrounding traffic conditions; (ii) information exchange with the infrastructure; (iii) vehicle-to-vehicle communication. Therefore, C-ITS make it possible to go a step further in providing real time information and tailored control strategies to specific drivers. As a response to an expected increasing penetration rate of these systems, traffic managers and researchers have to come up with new methodologies that override the classical methods of traffic modelling and traffic control. We focus in this paper on the potentialities of C-ITS for traffic management with the methodological issues following the expansion of such systems. The methods for introducing a cooperative modelling framework within existing traffic models are discussed. The paper also provides a building block for Cooperative Traffic Management (CTM). Finally, the potential applications of such blocks are presented from a technical as well as an operational standpoint.