gebhart/patrepeval huggingface dataset:
Interpretable, Probability-Based Confidence Metric for Continuous Quantitative Structure–Activity Relationship Models (2013)

A great deal of research has gone into the development of robust confidence in prediction and applicability domain (AD) measures for quantitative structure-activity relationship (QSAR) models in recent years. Much of the attention has historically focused on structural similarity, which can be defined in many forms and flavors. A concept that is frequently overlooked in the realm of the QSAR applicability domain is how the local activity landscape plays a role in how accurate a prediction is or is not. In this work, we describe an approach that pairs information about both the chemical similarity and activity landscape of a test compound's neighborhood into a single calculated confidence value. We also present an approach for converting this value into an interpretable confidence metric that has a simple and informative meaning across data sets. The approach will be introduced to the reader in the context of models built upon four diverse literature data sets. The steps we will outline include the definition of similarity used to determine nearest neighbors (NN), how we incorporate the NN activity landscape with a similarity-weighted root-mean-square distance (wRMSD) value, and how that value is then calibrated to generate an intuitive confidence metric for prospective application. Finally, we will illustrate the prospective performance of the approach on five proprietary models whose predictions and confidence metrics have been tracked for more than a year.
Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect (2021)

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, <b>12c</b> exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC<sub>50</sub> ranging from 0.010 to 0.042 µM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that <b>12c</b> can inhibit tubulin polymerisation and cell migration, leading to G<sub>2</sub>/M phase arrest. Besides, <b>12c</b> induces apoptosis <i>via</i> a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer.HighlightsA novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised.Compound <b>12c</b> showed significant antiproliferative activities against different cancer cell lines.Compound <b>12c</b> effectively inhibited tubulin polymerisation and competed with [<sup>3</sup>H] colchicine in binding to tubulin.Compound <b>12c</b> arrested the cell cycle at G<sub>2</sub>/M phase, effectively inducing apoptosis and inhibition of cell migration.
Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1 (2003)

Glucagon-like peptide-1(7-36)amide (GLP-1) is an incretin hormone with therapeutic potential for type 2 diabetes. Rapid removal of the N-terminal dipeptide, His7-Ala8, by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) curtails the biological activity of GLP-1. Chemical modifications or substitutions of GLP-1 at His7 or Ala8 improve resistance to DPP-IV action, but this often reduces potency. Little attention has focused on the metabolic stability and functional activity of GLP-1 analogues with amino acid substitution at Glu9, adjacent to the DPP IV cleavage site. We generated three novel Glu9-substituted GLP-1 analogues, (Pro9)GLP-1, (Phe9)GLP-1 and (Tyr9)GLP-1 and show for the first time that Glu9 of GLP-1 is important in DPP IV degradation, since replacing this amino acid, particularly with proline, substantially reduced susceptibility to degradation. All three novel GLP-1 analogues showed similar or slightly enhanced insulinotropic activity compared with native GLP-1 despite a moderate 4-10-fold reduction in receptor binding and cAMP generation. In addition, (Pro9)GLP-1 showed significant ability to moderate the plasma glucose excursion and increase circulating insulin concentrations in severely insulin resistant obese diabetic (ob/ob) mice. These observations indicate the importance of Glu9 for the biological activity of GLP-1 and susceptibility to DPP IV-mediated degradation.
Differential monocyte adhesion and adhesion molecule expression in venous and arterial endothelial cells (1999)

We compared U-937 cell adhesion and adhesion molecule expression in human umbilical venous (HUVECs) and arterial (HUAECs) endothelial cells exposed to tumor necrosis factor (TNF), interleukin-1, and lipopolysaccharide (LPS). TNF and LPS stimulated vascular cell adhesion molecule (VCAM)-1 surface expression and adhesion of U-937 monocyte-like cells to HUVECs but not to HUAECs. Antibody studies demonstrated that in HUVECs at least 75% of the adhesion response is VCAM-1 mediated. Interleukin-1 stimulated U-937 cell adhesion to and VCAM-1 surface expression in both HUVECs and HUAECs. Pyrrolidinedithiocarbamate and the proteasome inhibitor MG-132 blocked TNF- and LPS-stimulated U-937 cell adhesion to HUVECs. These agents also significantly decreased TNF- and LPS-stimulated increases in HUVEC surface VCAM-1. TNF increased VCAM-1 protein and mRNA in HUVECs that was blocked by pyrrolidinedithiocarbamate. However, neither TNF or LPS stimulated VCAM-1 expression in HUAECs. TNF stimulated expression of both intercellular adhesion molecule-1 and E-selectin in HUVECs, but in HUAECs, only intercellular adhesion molecule-1 was increased. Electrophoretic mobility shift assays demonstrated no difference in the pattern of TNF-stimulated nuclear factor-kappaB activation between HUVECs and HUAECs. These studies demonstrate a novel and striking insensitivity of arterial endothelium to the effects of TNF and LPS and indicate a dissociation between the ability of HUAECs to upregulate nuclear factor-kappaB and VCAM-1.
A Temporary Pause in the Replication Licensing Restriction Leads to Rereplication during Early Human Cell Differentiation (2022)

Gene amplifications in amphibians and flies are known to occur during development and have been well characterized, unlike in mammalian cells, where they are predominantly investigated as an attribute of tumors. Recently, we first described gene amplifications in human and mouse neural stem cells, myoblasts, and mesenchymal stem cells during differentiation. The mechanism leading to gene amplifications in amphibians and flies depends on endocycles and multiple origin-firings. So far, there is no knowledge about a comparable mechanism in normal human cells. Here, we describe rereplication during the early myotube differentiation of human skeletal myoblast cells, using fiber combing and pulse-treatment with EdU (5'-Ethynyl-2'-deoxyuridine)/CldU (5-Chlor-2'-deoxyuridine) and IdU (5-Iodo-2'-deoxyuridine)/CldU. We found rereplication during a restricted time window between 2 h and 8 h after differentiation induction. Rereplication was detected in cells simultaneously with the amplification of the <i>MDM2</i> gene. Our findings support rereplication as a mechanism enabling gene amplification in normal human cells.
Hydrogel‐Actuated Integrated Responsive Systems (HAIRS): Creating Cilia‐like ‘Hairy’ Surfaces (2013)

Cilia bend and swirl in tune with their environment, continuously adjusting their motions in response to an onslaught of chemical and physical signals. In this chapter we present a strategy for designing surfaces of chemo‐mechanically driven nanohairs that, like their natural counterparts, can sense and autonomously adapt to a changing environment. We describe how elastic hairs are fabricated to reversibly bend, twist and assemble into bundles with diverse shapes, sizes, chirality and hierarchical complexity, and how these motions are driven by a muscle‐like responsive hydrogel layer that translates temperature, pH, light and other stimuli into directional mechanical forces. By tailoring the geometry, material and surface chemistry of the hairs, as well as the composition, surface contour, and configuration of the hydrogel muscle, we demonstrate how these hybrid architectures can be designed to integrate complex spatio‐temporal signals and respond with an endless variety of multi‐scale patterned motions. The reconfigurations lead to a wide range of adaptive multifunctional outputs, from catch and release, anti‐fouling, propulsion, and chemical reaction switching to responsive wettability, optical, structural color, and electrical properties. At the same time, the hybrid system provides an experimental model for addressing the fundamental question of how chemistry and motion are interconverted over multiple scales.
A Deep Learning Model System for Diagnosis and Management of Adnexal Masses (2022)

Appropriate clinical management of adnexal masses requires a detailed diagnosis. We retrospectively collected ultrasound images of 1559 cases from the first Center of Chinese PLA General Hospital and developed a fully automatic deep learning (DL) model system to diagnose adnexal masses. The DL system contained five models: a detector, a mass segmentor, a papillary segmentor, a type classifier, and a pathological subtype classifier. To test the DL system, 462 cases from another two hospitals were recruited. The DL system identified benign, borderline, and malignant tumors with macro-F1 scores that varied from 0.684 to 0.791, a benefit to preventing both delayed and overextensive treatment. The macro-F1 scores of the pathological subtype classifier to categorize the benign masses varied from 0.714 to 0.831. The detailed classification can inform clinicians of the corresponding complications of each pathological subtype of benign tumors. The distinguishment between borderline and malignant tumors and inflammation from other subtypes of benign tumors need further study. The accuracy and sensitivity of the DL system were comparable to that of the expert and intermediate sonographers and exceeded that of the junior sonographer.
Overproduction of the acyl carrier protein component of a type II polyketide synthase stimulates production of tetracenomycin biosynthetic intermediates in Stteptomyces glaucescens. (1994)

The development of microorganisms with improved antibiotic production is an important goal in the commercialization of new pharmaceuticals or in lowering the cost of established drugs. We report a way to achieve this for biosynthetic intermediates of an antibiotic made by the polyketide pathway whose earliest steps involve a Type II multienzyme complex. Introduction of the tcmKLM beta-ketoacyl: ACP synthase and acyl carrier protein (ACP) genes or just the tcmM ACP gene into the tetracenomycin (Tcm) C-producing Streptomyces glaucescens wild-type strain, or its tcmN or tcmO blocked mutants, on high copy vectors under the control of strong promoters caused a 2 to 30-fold overproduction of Tcm D3 and some other biosynthetic intermediates (or shunt products) and a 25 to 30% increase in Tcm C production relative to the control strains carrying the plasmid vector only. However, Tcm C production was not greater than that obtained with the vector-free wild-type strain. The unexpected effect of increased ACP on Tcm D3 production suggests that the level of this protein can influence either the activity or level of the three other components of the Tcm polyketide synthase.
Nitric oxide suppresses inducible nitric oxide synthase expression by inhibiting post-translational modification of IκB (2004)

The expression of inducible nitric oxide synthase (iNOS) is a critical factor in both normal physiological functions and the pathogenesis of disease. This study was undertaken to determine the molecular mechanism by which nitric oxide (NO) exerts negative feedback regulation on iNOS gene expression. Isolated rat hepatocytes stimulated with cytokines exhibited a marked increase in NO production as well as iNOS mRNA and protein levels, which were significantly reduced by pretreatment of the NO donors S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and V-PYRRO/NO. This effect of SNAP was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO2-, or NO3- did not suppress the cytokine-induced NO production. Moreover, LPS/ IFN-gamma-stimulated RAW264.7 cells, which produce endogenous NO, expressed lower levels of iNOS, IL-1beta, IL-6 and TNF-alpha mRNAs, without changes in their mRNA half-lives, than those in the presence of the iNOS inhibitor NG-monomethyl-L-arginine. The iNOS gene transcription rate exhibited an 18-fold increase after cytokine stimulation, which was significantly inhibited by SNAP pretreatment. SNAP also blocked cytokine- induced increase in NF-kappaB activation, iNOS promoter activity, nuclear translocation of cytosolic NF-kappaB p65 subunit, and IkappaBalpha degradation, which correlated with its inhibitory effect on phosphorylation and ubiquitination of IkappaB. These data indicate that NO down-regulates iNOS gene expression and NO production by inhibiting the post-translational processes of IkappaBalpha thereby preventing NF-kappaB activation. These results identify a novel negative feedback mechanism whereby NO down-regulates iNOS gene expression.
Activin E–ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice (2023)

Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (<i>INHBE</i>, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes <i>INHBE</i> expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing β-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.
Versatile Organometallic Initiators for the Living Polymerization of Isocyanates (1994)

Shashoua and Sweeney first demonstrated that isocyanates could by polymerized via an anionic mechanism to form high molecular weight materials. We have sought to eliminate the problems associated with the anionic procedure by developing transition metal complexes which are capable of catalyzing the living polymerization of isocyanates. Recently, we reported the living polymerization of alkyl isocyanates using TiCl3OCH2CF3, I. Using I, polyisocyanates with controlled molecular weights and narrow polydispersities can be obtained at room temperature. ε5-CpTiCl2N(CH3)2 (Cp = cyclopentadienyl), III, is also an excellent catalyst for the polymerization of isocyanates, and in terms of ease of handling and purification and tolerance toward monomer functionality, superior to I. In order to prepare triblock copolymers containing amorphous segments sandwiched between two isocyanate segments, we have prepared bimetallic initiators comprised of titanium alkoxides con- nected by flexible linkers. These linkers may be a small molecule (1,4- dihydroxycyclohexane, V) or a polymer (polydimethylsiloxane, PDMS, VI). Complexes V and VI can be used to initiate the living polymerization of isocyanates to yield polymers possessing central cyclohexyl bends (ldquo;broken worms rdquo;) or PDMS segments (triblock copolymers), respectively. Finally, cyclopolymerizations of 1,2-diisocyanates using these or- ganometallic initiators are reported.
Phase-optical time domain reflectometry ([theta]-OTDR) with enhanced performance (2020)

In this paper, the phase-sensitive optical time-domain reflectometry (Φ-OTDR) system is experimentally demonstrated using a Rayleigh enhanced AcoustiSens optical fiber to improve the acoustic sensing performance. The AcoustiSens optical fiber made of continuous gratings over the fiber, which significantly enhances the backscattered signal by 15 dB compared to the standard single-mode silica fiber. In addition, a simple and cost-effective self-mixing demodulation technique has been employed in coherent Φ-OTDR system to eliminate the frequency offset between the electrical local oscillator and the beat signal. The acoustic sensing performance with various acoustic frequencies are experimentally demonstrated in the proposed system using a 2 km sensing fiber with 1 m spatial resolution.
Intelligence for Human-Assistant Planetary Surface Robots (2006)

Robots will require intelligence to succeed in the uncertain and changing environment on lunar and planetary surfaces. Even with humans directly involved in controlling such robots, individual robotic intelligence is still needed. In fact, robotic intelligence may be even more necessary in human-robot collaborative work than for robots operating alone. In addition to knowledge of
Interstrain variation in the deoxynucleotide composition of Cryptococcus neoformans: nucleotide composition of Cryptococcus neoformans. (1998)

The deoxynucleotide (dNMP) composition of ten strains of C. neoformans was analysed by 32P-labelling and two-dimensional thin-layer chromatography. This technique is very sensitive for detecting rare deoxynucleotide adducts and analogues (minor bases) in DNA. The results indicate considerable variation among strains in DNA nucleotide composition.
short-pass edge filter (2011)

We demonstrate pulsewidth-stretchable Er3+-doped femtosecond mode-locked fiber lasers by incorporating a tunable short-pass edge filter into the ring cavity. Pulsewidth stretch ratio of 3.53 (882/250) can be efficiently achieved under a temperature variation of 4°C
On the Locality of Codeword Symbols in Non-Linear Codes (2013)

Consider a possibly non-linear (n,K,d)_q code. Coordinate i has locality r if its value is determined by some r other coordinates. A recent line of work obtained an optimal trade-off between information locality of codes and their redundancy. Further, for linear codes meeting this trade-off, structure theorems were derived. In this work we give a new proof of the locality / redundancy trade-off and generalize structure theorems to non-linear codes.
Sensing system for detection and control of deposition on pendant tubes in recovery and power boilers (2023)

A system for detection and control of deposition on pendant tubes in recovery and power boilers includes one or more deposit monitoring sensors operating in infrared regions and about 4 or 8.7 microns and directly producing images of the interior of the boiler. An image pre-processing circuit (95) in which a 2-D image formed by the video data input is captured, and includes a low pass filter for performing noise filtering of said video input. An image segmentation module (105) for separating the image of the recovery boiler interior into background, pendant tubes, and deposition. An image-understanding unit (115) matches derived regions to a 3-D model of said boiler. It derives a 3-D structure the deposition on pendant tubes in the boiler and provides the information about deposits to the plant distributed control system (130) for more efficient operation of the plant pendant tube cleaning and operating systems.
Novel ASIC architecture and synthesis methodologies for future multiplexed datapath designs (2002)

An overview is presented of the main objectives and current achievements of the architecture synthesis work within part of the Basic Research Action ASCIS (architecture synthesis for complex integrated systems) project. The main goal of this work is to contribute to the solution of one of the major bottlenecks restricting the use of ASICs in industrial systems, namely, the lack of efficient design methodologies and corresponding CAD techniques which support the development of cost-effective application-specific architectures for given throughput or latency. The following areas of the project are emphasized: novel design methodologies and CAD techniques for partitioning, memory management, allocation, binding and scheduling; generic global optimization techniques to support those synthesis approaches; and performance-driven controller synthesis.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Exhaled breath olfactory signature of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) (2020)

<b>Background:</b> PH is diagnosed by right heart catheterization, an invasive procedure not suitable for large-scale screening. In a small proof-of-concept study we have shown that a bio-inspired intelligent artificial olfactory system (e-nose based on cross-reactive nanoarray and pattern recognition) could distinguish PAH from controls <i>(Cohen-Kaminsky, AJRCCM 2013)</i>. <b>Aims:</b> The SNOOPY2 study (NCT02782026) main objective was to evaluate the performance of a novel e-nose for the detection of PAH. We also tested whether the e-nose could detect CTEPH, BMPR2 mutation carriers and high-risk PAH. <b>Methods:</b> In 273 subjects, e-nose signals were analyzed with discriminant factor analysis and a K-fold cross-validation method, to test the accuracy of the models. A subset of samples was also analyzed through GC-MS, to identify discriminant volatile organic compounds (VOCs). <b>Results:</b> E-nose discriminated between breaths from PAH (n=73) and controls (n=121) with an accuracy of 72.1 %, a specificity of 81.8 % and a NPV of 75.6 %. CTEPH (n=41) were distinguished from controls (accuracy 80.3 %, sensitivity 89.4%, NPV 86.9%). PH patients (CTEPH and PAH) were discriminated from controls (NPV 73.4%). E-nose was able to classify patients with and without BMPR2 mutation (accuracy 75.6%). It was also possible to distinguish ESC/ERS guidelines “low-risk” and “high-risk” PAH (sensitivity 92%, NPV 88%). GC-MS revealed 10 discriminant VOCs between PAH and controls and 1 discriminant VOC between CTEPH and controls, that might contribute to the e-nose signature. <b>Conclusions:</b> E-nose is a promising tool for the diagnosis and management of PH. *equal contribution first 3 and last 3 authors