gebhart/patrepeval huggingface dataset:
Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs (2021)

Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
Achieving wireline random access throughput in wireless networking via user cooperation (2005)

Well appreciated at the physical layer, user cooperation is introduced here as a diversity enabler for wireless random access (RA) at the medium access control sub-layer. This is accomplished through a two-phase protocol in which active users start with a low power transmission attempting to reach nearby users, and follow up with a high power transmission in cooperation with the users recruited in the first phase. We show that such a cooperative protocol yields a significant increase in throughput. Specifically, we prove that for networks with a large number of users, the throughput of a cooperative wireless RA network operating over Rayleigh fading links approaches the throughput of a RA network operating over additive write Gaussian noise (AWGN) links. As a result, user cooperation migrates diversity benefits to the wireless RA regime, thus bridging the gap to wireline RA networks, without incurring a bandwidth or energy penalty.
Neutral pion and η meson production in proton–proton collisions at s=0.9 TeV and s=7 TeV (2012)

The first measurements of the invariant differential cross sections of inclusive π0 and η meson production at mid-rapidity in proton–proton collisions at s=0.9TeV and s=7TeV are reported. The π0 measurement covers the ranges 0.4<pT<7GeV/c and 0.3<pT<25GeV/c for these two energies, respectively. The production of η mesons was measured at s=7TeV in the range 0.4<pT<15 GeV/c. Next-to-Leading Order perturbative QCD calculations, which are consistent with the π0 spectrum at s=0.9TeV, overestimate those of π0 and η mesons at s=7TeV, but agree with the measured η/π0 ratio at s=7TeV.
Aromatics Saturation Over Hydrotreating Catalysts: Reactivity and Susceptibility to Poisons (2020)

Aromatics saturation over hydrotreating catalysts has been investigated by processing a synthetic feedstock to which naphthalene, biphenyl, tetralin, and cyclohexylbenzene have been added as model aromatic compounds. The saturation reactions were successfully correlated with a kinetic model of consecutive first order reactions. The rates of saturation of the di-aromatics, naphthalene and biphenyl, were approximately 5-40 times faster than the rate of saturation of the mono-aromatics, tetralin and cyclohexylbenzene. The nature of the di-aromatic is a significant determinant of its reactivity for saturation. The rate of saturation of naphthalene is 10 - 20 times faster than the rate of saturation of biphenyl. The two mono-aromatics, tetralin and cyclohexylbenzene, exhibited nearly identical reactivities for saturation. An investigation of the effect of organo-nitrogen compounds on saturation activity revealed a very severe poisoning and attenuation of saturation activity. Since activity was recoverable upon the removal of the poisoning agent the chemical effect was conjectured to be due to adsorption of the poison on the active sites of the catalyst. The adsorption constants were determined for three model nitrogen compounds - quinoline, indole, and tert-butylamine. The poisoning action of an organo-nitrogen compound was found to be dependent on both basicity and chemical structure.254
Molecular variant of hairy cell leukemia with poor prognosis (2011)

Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%) with HCLv versus six (10%) with HCLc (p = 0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as >98% homologous to the germline sequence. Clinical features of VH4-34+ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis (p = 0.002) and lower response (p = 0.00001) and progression-free survival (p = 0.007) after first-line cladribine, and shorter overall survival from diagnosis (p < 0.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis. We conclude that VH4-34+ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine. However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog.
PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells (2022)

Expansion and differentiation of antigen-experienced PD-1<sup>+</sup>TCF-1<sup>+</sup> stem-like CD8<sup>+</sup> T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade<sup>1-4</sup>. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8<sup>+</sup> T cells similar to those generated in an acute infection<sup>5</sup>. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed<sup>6-10</sup>. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8<sup>+</sup> T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.
Abstract 14525: Cardiac Magnetic Resonance Elastography as a Quantitative Non-Invasive Metric for Myocardial Stiffness: Initial Pilot Study in Patients With Cardiac Amyloidosis (2016)

Introduction: The biomechanical properties of myocardial tissue play an important role in cardiac function. Specifically in cardiac amyloidosis there is evidence that abnormal protein fibrils build...
The oral glucose minimal model: Estimation of insulin sensitivity from a meal test (2002)

Recently, a new approach has been proposed to estimate insulin sensitivity (S(I)) from an oral glucose tolerance test or a meal using an "integral equation". Here, we improve on the "integral equation" by resorting to a "differential equation" approach. The classic glucose kinetics minimal model was used with the addition of a parametric model for the rate of appearance into plasma of oral glucose (Ra). Three behavioral models of Ra were proposed: piecewise-linear (P), spline (S) and dynamic (D). All three models performed satisfactorily allowing a precise estimation of S(I) and a plausible reconstruction of Ra. Mean S(I) estimates were virtually identical: S(I)P = 6.81 +/- 0.87 (SE); S(I)S = 6.53 +/- 0.80; and S(I)D = 6.62 +/- 0.79. S(I) strongly correlated with the integral-equation index (I) S(I)I: r = 0.99, p < 0.01 for models D and S, and r 0.97, p < 0.01 for P. Also, SI compared well with insulin sensitivity estimated from intravenous glucose tolerance test in the same subjects (r = 0.75, p < 0.01; r = 0.71, p < 0.01; r = 0.73, p < 0.01, respectively, for P, S, and D models versus s(I)IVGTT). Finally, the novel approach allows estimation of SI from a shorter test (120 min): model P yielded S(I)R = 7.16 +/- 1.0 (R for reduced) which correlated very well with S(I)P and S(I)I (respectively, r = 0.94, p < 0.01; r = 0.95, p < 0.01) and still satisfactorily with S(I)IVGTT (r = 0.77, p < 0.01).
Assessment of nitrogen and phosphorus loads present in environments impacted by alternative poultry processing operations utilized in pasture-raised poultry production (2015)

Abstract Pasture-raised poultry (PP) production systems allow chickens, turkeys or other poultry types to be raised entirely on pasture or in small, open-air moveable pens with access to fresh pasture daily. With an increase in consumer demand for poultry products produced using more humane and potentially environmentally sustainable practices, PP production systems are regaining popularity among farmers across the USA. The majority of research on PP is related to meat quality and forage conditions while the environmental effects have remained largely unstudied. The rotation of poultry on pasture is one of the primary best management practices (BMP) used to avoid over grazing and buildup of excess nutrients and pathogens; however, BMPs for handling and processing of the associated wastes (i.e., wastewater, feathers, offal) related to on-farm processing and mobile poultry processing units (MPPU) are not as well established. Therefore, a study with PP growers in the southern USA was initiated to provide important baseline information on the potential environmental impacts of processing methods used by PP production systems. Here, three farms utilizing on-farm processing were sampled over a 9-month period and two farms utilizing a MPPU pilot plant were sampled over a 3-month period. Soil, compost and wastewater samples were collected during each sampling date for on-farm processing while only wastewater was collected at the MPPU pilot plant. Soil samples (24-cm cores) were analyzed for total nitrogen (TN), Mehlich-3 extractable phosphorus (M3-P) and moisture content. Compost derived from processing wastes was analyzed for TN, total phosphorus (TP), water extractable P and moisture content. Wastewaters were analyzed for total Kjeldahl nitrogen (TKN) and TP. Soil TN levels (0.075–0.30%) reported here are comparable with TN levels reported for various soils in the Southeastern USA while M3-P was generally below levels found in agricultural soils subject to conventional poultry litter application based on previously published data. Conversely, TN and TP levels—0.3 to 1.3 and &lt;0.4%, respectively—in compost were well below recommended values (i.e., approximately 2% each of N and P) for compost highlighting an opportunity for PP growers to create a more useful compost for land application. Last, wastewater collected from both, on-farm processing and the MPPU measure TKN and TP levels were much less than conventional processing. Overall, the present study provided baseline data on soil and compost nutrients related to on-farm poultry processing as well as wastewater composition for on-farm processing and MPPUs.
Automated Feedback and Recognition through Data Mining in Code Hunt (2015)

Learning to code has become so popular that it is now almost the default that beginners will encounter coding on a website, along with thousands of others at the same time. Providing feedback and recognition in the face of such increasing numbers is a challenge that can be met by the automated test generation. Through automation and access to massive amounts of data, we show that the frequency, coverage, accuracy and personalization of feedback can be improved over earlier systems. Recognition can also be made automatic by using a gaming model. Based on the Code Hunt programming Game, we have developed and tested a system of test-driven synthesis (TDS) and produced results that show that we can accurately produce sensible feedback. Moreover the feedback increases engagement in continuing with the difficult task of learning to code. We also report on the effect of recognition of progress during the game and during contests.
Enhancement of multiphoton excitation-induced photoacoustic signals by using gold nanoparticles surrounded by fluorescent dyes (2009)

Recently, we have developed multiphoton excitation-induced photoacoustic imaging for thick tissues employing a 1064-nm nanosecond pulsed laser. The combination of multiphoton excitation and photoacoustic imaging improves the depth resolution. To apply the multiphoton-photoacoustic imaging for precise investigation in living tissues, it is important to enhance only the photoacoustic signals induced by multiphoton excitation, because the generation of multiphotonphotoacoustic signals is less efficient than that of one-photon photoacoustic signals. In this study, we investigated the relation between the signal intensity and the thermophysical properties of various solutions of fluorescent dyes in multiphoton-photoacoustic imaging. We found that the signal intensity is proportional to the coefficient of thermal expansion divided by the specific heat of the solvent. Thus thermophysical properties are also important, together with absorption properties, in enhancing the multiphoton-photoacoustic signal. Based on our findings, we propose the use of gold nanoparticles surrounded by fluorescent dyes as contrast agents. Rhodamine B, which is employed in fluorescent dyes, selectively evokes the two-photon absorption. In addition, because gold nanoparticles have a small specific heat, the multiphoton-photoacoustic signal generated is strong due to effective photon-to-heat conversion. We conclude that this combination allows deeper observation in living tissues by multiphoton-photoacoustic imaging.
A Novel Facile Synthesis of 2,5-Di- and 2,3,5-Trisubstituted Pyrroles (2000)

Heterocyclization of ketoximes with propyne or allene in superbase systems MOR/DMSO (M = K, Cs; R = H, t-Bu), which leads to 2-alkyl(aryl, hetaryl)-5-methyl- and 2,3-dialkyl-5-methylpyrroles or 2-methyl-4,5,6,7-tetrahydroindole in yields of up to 63%, has been accomplished for the first time. The reaction is mostly regioselective affording mainly or exclusively 2,5-di- and 2,3,5-trisubstituted pyrroles. The minor isomers in most cases are the corresponding 2,4-di and 2,3,4-trisubstituted pyrroles, only in the case of acetoxime the isomer ratio is ca 1 : 1. For oximes of methyl isopropyl ketone and pinacolone, the 4-methyl-isomers become predominant (78, 83%, respectively).
Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination (2021)

Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.
Nano- und Mikro Strukturierung von Nanokompositen auf Glas durch optische Raster-Nahfeldmikroskopie (2005)

Die Erzeugung von Strukturen im Bereich von Mikro- bzw. Nanometern ist eine wesentliche Voraussetzung für die Funktionalisierung von Glasoberflächen. Bis in den Bereich von 0,10 µm stellt die Lithografie die dominierende Strukturierungstechnik dar. Unterhalb dieser Abmessungen verhindern Beugungsphänomene die Erzeugung von noch kleineren Strukturen. Verbesserungen hinsichtlich der Auflösung konnten durch Verringerung der verwendeten Wellenlänge erzielt werden. Gleichzeitig erfordert dies die Entwicklung von Linsen, die im Bereich von &amp;lambda;~193 nm hinreichend durchlässig sind. Die lithografische Technik wurde zudem durch weiterführende Ansätze verbessert. Exemplarisch sei hier die Röntgenlithografie, extreme Ultraviolettlithografie, Elektronenstrahllithografie oder Rastersondenlithografie genannt. Rastersondenlithografie ist aufgrund ihrer hohen Auflösung von bis zu 20 nm eine der vielversprechendsten Methoden. Die vorliegende Arbeit beschäftigt sich aus diesem Grund mit der lithografischen Mikro- und Nanostrukturierung unter Verwendung der optischen Rasternahfeldmikroskopie (Scanning Near Field Optical Microskopie (SNOM)). SNOM-Lithografie kombiniert die etablierte Rastersondentechnik mit den Vorteilen der Nahfeldoptik und erreicht auf diese Weise Auflösungen im Bereich von Rasterelektronenmikroskopen (REM). Zudem besitzt die SNOM Methode den Vorteil, dass für den Betrieb kein Vakuum erforderlich ist. Eine Großserienproduktion oder großflächige Herstellung von strukturierten Oberflächen durch direktes Schreiben mit SNOM-Sonden auf ein Substrat ist ökonomisch nicht sinnvoll.
SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy (2021)

SARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.
Abstract 2618: DNMT1 as a marker of differential sensitivities to epigenetic therapy of a Kras mutant and Kras wild type human non small cell lung cancer cell line (2011)

Abstract INTRODUCTION: Epigenetic therapy with a demethylating agent and an histone deacetylase inhibitor (HDACi) is now being pursued in hematological as well as solid tumor malignancies. Clinical responses have been varied with complete responses in some patients and no efficacy of the drugs in others. We investigated the effect of this therapy on two targets, DNA methyltransferase1 (DNMT1) and H3K4 modified histones, respectively. METHODS: Two human lung adenocarcinoma cell lines, A549 (Kras mutant) and H838 (Kras wild type) were pre-exposed for 72 hours with daily treatment of 500nM azacitidine alone or 72 hours of daily 500nM azacitidine followed subsequently with 10 nM, 100nM, 1000nM entinostat at 96 hours. DNMT1 and H3K4 protein levels were assayed by Western blot analysis at various time points after treatment. Cells were also re-plated after treatment to assess differential growth characteristics. RESULTS: In vitro growth of H838 cells is sensitive to azacitidine alone and in combination with entinostat whereas growth of the A549 cell line is only sensitive to azacitidine and entinostat in combination. Treatment with azacitidine, severely depleted DNMT1 protein expression in H838 cells both when given alone and in combination with most dose levels of entinostat. This decrease was transient and within 4 days, the protein was fully replenished. Azacitidine alone did not cause an appreciable decrease in DNMT1 protein expression of A549 cells but, when combined with increasing levels of entinostat, DNMT1 levels were significantly depleted and did not replenish for 7 days. Re-plating after treatment showed growth inhibition versus mock of all regimens containing azacitidine in the H838 cell line only whereas growth inhibition in the A549 cells was observed only in the combinatory therapy arms. Furthermore, in the A549 cell line, H3K4 protein levels (a marker of active gene expression) peaked at 7 days after treatment versus a peak in the first 24 hours in the H838 cell line. CONCLUSIONS: Differing sensitivities to epigenetic therapy in lung adenocarcinoma cell lines may reflect underlying differences in molecular phenotypes. Large decreases in DNMT1 expression are associated with sensitivity to azacitidine. In a cell line insensitive to azacidine alone, the addition of entinostat may accentuate DNMT1 protein depletion and delay its reexpression. This effect on DNMT1 may render this latter cancer cell line more sensitive to epigenetic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2618. doi:10.1158/1538-7445.AM2011-2618
Correlates of Protection, Thresholds of Protection, and Immunobridging among Persons with SARS-CoV-2 Infection (2023)

Several studies have shown that neutralizing antibody levels correlate with immune protection from COVID-19 and have estimated the relationship between neutralizing antibodies and protection. However, results of these studies vary in terms of estimates of the level of neutralizing antibodies required for protection. By normalizing antibody titers, we found that study results converge on a consistent relationship between antibody levels and protection from COVID-19. This finding can be useful for planning future vaccine use, determining population immunity, and reducing the global effects of the COVID-19 pandemic.
ChemInform Abstract: trans‐[RuCl2(Phosphane)2(1,2‐diamine)] and Chiral trans‐[RuCl2(Diphosphane)(1,2‐diamine)]: Shelf‐Stable Precatalysts for the Rapid, Productive, and Stereoselective Hydrogenation of Ketones. (1998)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Optical characteristics of GaInP/GaP double-heterostructure core-shell nanowires embedded in polydimethylsiloxane membranes (2010)

The authors report on the optical properties of GaInP/GaP double-heterostructure (DH) core-shell nanowires (NWs) embedded in polydimethylsiloxane (PDMS) membranes. Self-catalyzed NW structures are grown on Si (111) substrates by initiating with the formation of Ga droplets as a catalyst which is followed by the growth of GaP core and GaInP DH shells. Optical characteristics of GaInP/GaP DH core-shell NWs transferred from Si substrates into PDMS membranes show enhanced 77 K light emission at 630 nm. The signal at 775 nm from the surface states of NWs can be mitigated by embedding the NWs in a PDMS membrane that acts as a surface state passivant.