gebhart/patrepeval huggingface dataset:
Machine learning and AI-based approaches for bioactive ligand discovery and GPCR-ligand recognition (2020)

In the last decade, machine learning and artificial intelligence applications have received a significant boost in performance and attention in both academic research and industry. The success behind most of the recent state-of-the-art methods can be attributed to the latest developments in deep learning. When applied to various scientific domains that are concerned with the processing of non-tabular data, for example, image or text, deep learning has been shown to outperform not only conventional machine learning but also highly specialized tools developed by domain experts. This review aims to summarize AI-based research for GPCR bioactive ligand discovery with a particular focus on the most recent achievements and research trends. To make this article accessible to a broad audience of computational scientists, we provide instructive explanations of the underlying methodology, including overviews of the most commonly used deep learning architectures and feature representations of molecular data. We highlight the latest AI-based research that has led to the successful discovery of GPCR bioactive ligands. However, an equal focus of this review is on the discussion of machine learning-based technology that has been applied to ligand discovery in general and has the potential to pave the way for successful GPCR bioactive ligand discovery in the future. This review concludes with a brief outlook highlighting the recent research trends in deep learning, such as active learning and semi-supervised learning, which have great potential for advancing bioactive ligand discovery.
Vaccinia DNA topoisomerase I: Single-turnover and steady-state kinetic analysis of the DNA strand cleavage and ligation reactions (1994)

Vaccinia DNA topoisomerase I catalyzes a reversible, site-specific strand cleavage and resealing reaction with duplex DNA involving a transient 3'-phosphotyrosyl linkage between the DNA and Tyr-274 of the enzyme. Single-turnover and steady-state kinetic measurements, as well as DNA binding studies with DNA duplexes containing the preferred cleavage sequence (5'-CCCTT decreases -3') in 50 mM Tris-HCl, pH 7.5, at 20 degrees C, have permitted the evaluation of the individual rate constants for strand cleavage (kcl) and religation (kr) and for duplex DNA binding and dissociation. The values of kcl = 0.07 s-1 and kr = 0.66 s-1 indicate that the internal cleavage equilibrium (Kcl = kcl/kr = 0.1) favors the uncleaved E.DNA complex. The apparent second-order rate constant kcl/KmDNA + = 8 x 10(5) M-1 s-1 for the single-turnover cleavage reaction is 10(2)-10(3)-fold less than the rate of diffusional encounter and provides an estimate of k(on) (DNA). Single-turnover cleavage experiments using a duplex substrate with a nonbridging racemic phosphorothioate nucleotide substitution at the cleavage site showed biphasic cleavage kinetics with equal amplitudes for each phase, which was fit to a double exponential: kfast = 0.01 s-1 and kslow = 0.0004 s-1. These "thio effects" (= kclphos/kclthiol) of 4.6- and 115-fold indicate that cleavage is at least partially rate-limiting in the single-turnover reaction; the two kinetic phases indicate a strong preference for cleavage of one thio isomer. Multiple-turnover cleavage-religation reactions showed an initial pre-steady-state burst proportional to enzyme, followed by a slower steady-state rate with a value of kcat = 0.006 s-1. The phosphorothioate substrate showed a smaller burst and no significant thio effect on kcat. These results indicate fast chemical steps and largely rate-limiting dissociation of the religated product (KD = 54 nM) in the steady-state, a conclusion confirmed by direct measurement of the rate constant for product dissociation as 0.01 s-1. MgCl2 (5 mM) increases this rate constant by an order of magnitude, thus explaining the divalent cation induced acceleration of DNA supercoil relaxation by this enzyme. No divalent cation binding by the enzyme was detected indicating this effect to result from metal binding to DNA. The rate constants kcl and kr for the nucleophilic attack of Tyr-274 and deoxyribose 5'-OH at phosphorus represent approximately 10(9)- and 10(12)-fold enhancements over the analogous attack of phenolate and alcoholate anions at the phosphorus backbone of DNA in solution at pH 7.5. Consistent with this estimate, the Y274F mutant is at least 10(6)-fold less active in cleavage than the wild-type enzyme.
Wine's globalization: the next phase (2012)

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yong yuan de hu die (1998)

对于五年前那个美丽而荒凉的夏天，我的记忆单纯而又清晰，有足够的空间让一只只色彩斑斓的蝴蝶翩然飞舞。那是很抽象的飞舞。那个夏天，蝴蝶以她纤弱身躯的某种颤动完成了对我灵魂的长久占据。以蝴蝶为背景的青春岁月，是我一生永远笙歌四起的剧场。因为，蝴蝶的生命是一...
The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis (1999)

B- and T-cell recirculation is crucial for the function of the immune system, with the control of cell migration being mainly mediated by several chemokines and their receptors. In this study, we investigated the expression and function of CXCR3 on normal and malignant B cells from 65 patients with chronic lymphoproliferative disorders (CLDs). Although CXCR3 is lacking on CD5(+) and CD5(-) B cells from healthy subjects, it is expressed on leukemic B lymphocytes from all (31/31) patients with chronic lymphocytic leukemia (CLL). The presence of CXCR3 was heterogeneous in other B-cell disorders, being expressed in 2 of 7 patients with mantle cell lymphoma (MCL), 4 of 12 patients with hairy cell leukemia (HCL), and 11 of 15 patients with other subtypes of non-Hodgkin's lymphomas (NHLs). Chemotaxis assay shows that normal B cells from healthy subjects do not migrate in response to IFN-inducible protein 10 (IP-10) and IFN-gamma-induced monokine (Mig). In contrast, a definite migration in response to IP-10 and Mig has been observed in all malignant B cells from patients with CLL, but not in patients with HCL or MCL (1/7 cases tested). Neoplastic B cells from other NHLs showed a heterogenous pattern. The migration elicited by IP-10 and Mig was inhibited by blocking CXCR3. No effect of IP-10 and Mig chemokines was observed on the cytosolic calcium concentration in malignant B cells. The data reported here demonstrate that CXCR3 is expressed on malignant B cells from CLDs, particularly in patients with CLL, and represents a fully functional receptor involved in chemotaxis of malignant B lymphocytes.
Characterization of Dicarboxylic Acids for Cellulose Hydrolysis (2001)

In this paper, we show that dilute maleic acid, a dicarboxylic acid, hydrolyzes cellobiose, the repeat unit of cellulose, and the microcrystalline cellulose Avicel as effectively as dilute sulfuric acid but with minimal glucose degradation. Maleic acid, superior to other carboxylic acids reported in this paper, gives higher yields of glucose that is more easily fermented as a result of lower concentrations of degradation products. These results are especially significant because maleic acid, in the form of maleic anhydride, is widely available and produced in large quantities annually.
The essential tyrosine‐containing loop conformation and the role of the C‐terminal multi‐helix region in eukaryotic phenylalanine ammonia‐lyases (2006)

Besides the post-translationally cyclizing catalytic Ala-Ser-Gly triad, Tyr110 and its equivalents are of the most conserved residues in the active site of phenylalanine ammonia-lyase (PAL, EC 4.3.1.5), histidine ammonia-lyase (HAL, EC 4.3.1.3) and other related enzymes. The Tyr110Phe mutation results in the most pronounced inactivation of PAL indicating the importance of this residue. The recently published X-ray structures of PAL revealed that the Tyr110-loop was either missing (for Rhodospridium toruloides) or far from the active site (for Petroselinum crispum). In bacterial HAL ( approximately 500 amino acids) and plant and fungal PALs ( approximately 710 amino acids), a core PAL/HAL domain ( approximately 480 amino acids) with >or= 30% sequence identity along the different species is common. In plant and fungal PAL a approximately 100-residue long C-terminal multi-helix domain is present. The ancestor bacterial HAL is thermostable and, in all of its known X-ray structures, a Tyr83-loop-in arrangement has been found. Based on the HAL structures, a Tyr110-loop-in conformation of the P. crispum PAL structure was constructed by partial homology modeling, and the static and dynamic behavior of the loop-in/loop-out structures were compared. To study the role of the C-terminal multi-helix domain, Tyr-loop-in/loop-out model structures of two bacterial PALs (Streptomyces maritimus, 523 amino acids and Photorhabdus luminescens, 532 amino acids) lacking this C-terminal domain were also built. Molecular dynamics studies indicated that the Tyr-loop-in conformation was more rigid without the C-terminal multi-helix domain. On this basis it is hypothesized that a role of this C-terminal extension is to decrease the lifetime of eukaryotic PAL by destabilization, which might be important for the rapid responses in the regulation of phenylpropanoid biosynthesis.
Electron temperature, density, and metastable-atom density of argon electron–cyclotron-resonance plasma discharged by 7.0, 8.0, and 9.4 GHz microwaves (2000)

The characteristics of argon plasma discharged by electron–cyclotron resonance (ECR) with the microwave frequencies of 7.0, 8.0, and 9.4 GHz are investigated in the pressure range of 0.013–0.13 Pa, where the magnetic field was adjusted to keep the ECR point at the same position. The input power of the microwave was set at 10 and 50 W. Plasma densities and the electron temperatures were found to be almost independent of the microwave frequency at low pressure. The dependence of the electron density on the microwave frequencies becomes apparent in the higher-pressure range above 0.080 Pa. In the case that the discharge power is 50 W, the plasma operated using 9.4 GHz microwave showed the highest electron density and the plasma operated using 7.0 GHz had the lowest electron density. Metastable-atom densities were estimated by using a collisional radiative model. The mestable-atom densities, ∼1017 m−3, are lower than the electron density ∼1018 m−3 at the discharge power of 50 W, whereas these densities were comparable at the discharge power of 10 W.
Psychiatric treatment outcome following traumatic brain injury (2000)

The relationship between self-reported history of traumatic brain injury (TBI) and psychiatric treatment outcome was investigated. TBI was hypothesized to be frequent, associated with cognitive deficits on neuropsychological testing, and less amenable to standard psychiatric treatment. Subjects were 42 psychiatric patients with a self-reported history of TBI and 25 psychiatric patients with no TBI history. Subjects received approximately 2 weeks of inpatient psychiatric treatment. Subjects received neuropsychological testing and completed the Brief Symptom Inventory weekly. TBI was frequent (66% of subjects); multiple injuries were common. Neuropsychological performance was generally average in both groups with few group differences. Subjects, on average, reported significantly decreased psychiatric symptoms on discharge. However, the TBI group appeared to improve less than the control group; group status was a significant predictor of treatment outcome. Implications of results for assessment and treatment of psychiatric disorders in patients with a history of TBI are discussed.
Reduction of lysine intake while avoiding malnutrition—Major goals and major problems in dietary treatment of glutaryl‐CoA dehydrogenase deficiency (2004)

Treatment in glutaryl-CoA dehydrogenase deficiency, an inborn error of metabolism of lysine and tryptophan, is mainly based on restriction of lysine intake, supplementation of carnitine, and an intensification of therapy during intercurrent illnesses. The major principle of dietary treatment is to reduce the production of glutaric acid and 3-hydroxyglutaric acid by restriction of natural protein in general and of lysine in particular. In parallel to development, the growing child learns to utilize different protein sources, shifting the primarily milk-based diet to a mixed diet. The changes in nutritional demands and food composition during the first years of life greatly influence nutritional support for affected patients at different ages. This article highlights frequent pitfalls of dietary treatment for this disease and focuses on particular risks of malnutrition in terms of essential amino acids and micronutrients and/or excess intake of lysine between age 3 months and age 6 years. We conclude from the examples given that restriction of natural protein intake plus application of lysine-free amino acid mixtures minimizes the risk of malnutrition and allows a reliable control of protein and lysine intake and, thus, seems particularly recommendable during the vulnerable period for acute encephalopathic crises. The efficacy of these theoretical and experience-based approaches to dietary treatment of glutaryl-CoA dehydrogenase deficiency should be investigated in detail in prospective clinical studies.
JAK-STAT3 and somatic cell reprogramming (2013)

Reprogramming somatic cells to pluripotency, especially by the induced pluripotent stem cell (iPSC) technology, has become widely used today to generate various types of stem cells for research and for regenerative medicine. However the mechanism(s) of reprogramming still need detailed elucidation, including the roles played by the leukemia inhibitory factor (LIF) signaling pathway. LIF is central in maintaining the ground state pluripotency of mouse embryonic stem cells (ESCs) and iPSCs by activating the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway. Characterizing and understanding this pathway holds the key to generate naïve pluripotent human iPSCs which will facilitate the development of patient-specific stem cell therapy. Here we review the historical and recent developments on how LIF signaling pathway regulates ESC pluripotency maintenance and somatic cell reprogramming, with a focus on JAK-STAT3.
A survey of top- k query processing techniques in relational database systems (2008)

Efficient processing of top- k queries is a crucial requirement in many interactive environments that involve massive amounts of data. In particular, efficient top- k processing in domains such as the Web, multimedia search, and distributed systems has shown a great impact on performance. In this survey, we describe and classify top- k processing techniques in relational databases. We discuss different design dimensions in the current techniques including query models, data access methods, implementation levels, data and query certainty, and supported scoring functions. We show the implications of each dimension on the design of the underlying techniques. We also discuss top- k queries in XML domain, and show their connections to relational approaches.
Positron Emission Tomography Using [18F]-Fluorodeoxy-d-Glucose to Predict the Pathologic Response of Breast Cancer to Primary Chemotherapy (2000)

PURPOSE: To determine whether [ 18 F]-fluorodeoxy-d-glucose ([ 18 F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS: Thirty patients with noninflammatory, large (&gt; 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [ 18 F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS: Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P = .037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P = .013), complete macroscopic (P = .003), or complete microscopic (P = .001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P = .076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P = .037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P = .038; K, P = .012). CONCLUSION: [ 18 F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.
Computational Design of a PDZ Domain Peptide Inhibitor that Rescues CFTR Activity (2012)

The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial chloride channel mutated in patients with cystic fibrosis (CF). The most prevalent CFTR mutation, ΔF508, blocks folding in the endoplasmic reticulum. Recent work has shown that some ΔF508-CFTR channel activity can be recovered by pharmaceutical modulators ("potentiators" and "correctors"), but ΔF508-CFTR can still be rapidly degraded via a lysosomal pathway involving the CFTR-associated ligand (CAL), which binds CFTR via a PDZ interaction domain. We present a study that goes from theory, to new structure-based computational design algorithms, to computational predictions, to biochemical testing and ultimately to epithelial-cell validation of novel, effective CAL PDZ inhibitors (called "stabilizers") that rescue ΔF508-CFTR activity. To design the "stabilizers", we extended our structural ensemble-based computational protein redesign algorithm K* to encompass protein-protein and protein-peptide interactions. The computational predictions achieved high accuracy: all of the top-predicted peptide inhibitors bound well to CAL. Furthermore, when compared to state-of-the-art CAL inhibitors, our design methodology achieved higher affinity and increased binding efficiency. The designed inhibitor with the highest affinity for CAL (kCAL01) binds six-fold more tightly than the previous best hexamer (iCAL35), and 170-fold more tightly than the CFTR C-terminus. We show that kCAL01 has physiological activity and can rescue chloride efflux in CF patient-derived airway epithelial cells. Since stabilizers address a different cellular CF defect from potentiators and correctors, our inhibitors provide an additional therapeutic pathway that can be used in conjunction with current methods.
Commentary: HIV Infection and Family Processes: Toward the Next Generation of Research (2001)

psychosocial adjustment (or psychoeducational performance) and have attempted to identify mechanisms that may explain these associations (e.g., predominant coping strategies, caregiver attitudes and practices, caregiver emotional distress). In an attempt to encourage further research on these mechanisms, this commentary will focus on factors identified by the four investigations that may hold promise for future intervention research. The findings of Coscia et al. are particularly noteworthy in that they identify both a mediating and a moderating mechanism in the relationship between HIV infection and cognitive functioning in children. As highlighted by the authors, the literature has identified a variety of central nervous system (CNS) outcomes associated with pediatric HIV infection. These outcomes include both changes in the structural integrity of the infected CNS (Campbell, 1997), as well as changes in neurochemical processes within the CNS of infected individuals (Kraiselburd, 1995). Yet, despite these biological differences, reports in the literature on the cognitive functioning of children with HIV/AIDS are varied (e.g., Bisiacchi, Suppiej, & Laverda, 2000; Fishkin et al., 2000; Loveland et al., 2000). Perhaps contributing to the explanation of the varied findings, Coscia et al. have identified home environment as a mediator between HIV infection and neurocognitive outcomes. These results suggest a need for prevention efforts (i.e., prior to significant disease progression), as well as specialized intervention for families once the child’s illness has progressed. A number of issues resulting from this finding will require further investigation, including whether, how, and when Journal of Pediatric Psychology, Vol. 26, No. 6, 2001, pp. 363–366
Control of Human Embryonic Stem Cell Colony and Aggregate Size Heterogeneity Influences Differentiation Trajectories (2008)

To better understand endogenous parameters that influence pluripotent cell differentiation we used human embryonic stem cells (hESCs) as a model system. We demonstrate that differentiation trajectories in aggregate (embryoid body [EB])-induced differentiation, a common approach to mimic some of the spatial and temporal aspects of in vivo development, are affected by three factors: input hESC composition, input hESC colony size, and EB size. Using a microcontact printing approach, size-specified hESC colonies were formed by plating single-cell suspensions onto micropatterned (MP) extracellular matrix islands. Subsequently, size-controlled EBs were formed by transferring entire colonies into suspension culture enabling the independent investigation of colony and aggregate size effects on differentiation induction. Gene and protein expression analysis of MP-hESC populations revealed that the ratio of Gata6 (endoderm-associated marker) to Pax6 (neural-associated marker) expression increased with decreasing colony size. Moreover, upon forming EBs from these MP-hESCs, we observed that differentiation trajectories were affected by both colony and EB size-influenced parameters. In MP-EBs generated from endoderm-biased (high Gata6/Pax6) input hESCs, higher mesoderm and cardiac induction was observed at larger EB sizes. Conversely, neural-biased (low Gata6/Pax6) input hESCs generated MP-EBs that exhibited higher cardiac induction in smaller EBs. Our analysis demonstrates that heterogeneity in hESC colony and aggregate size, typical in most differentiation strategies, produces subsets of appropriate conditions for differentiation into specific cell types. Moreover, our findings suggest that the local microenvironment modulates endogenous parameters that can be used to influence pluripotent cell differentiation trajectories.
The CAVE-WP4 generic speaker verification system (1998)

This papers describes the generic speaker veri#cation system that was developed within Work Package 4, which was responsible for Research and Technology improvements for Speaker Veri#cation in the CAVE project. With this perspective, di#erent SV algorithms were implemented in a common HMM framework and compared on several databases. This paper is concerned with the design of this generic system and not with the experiments we performed using the system. It shows the importance of having a common and generic package for cooperative research. We intend to make the Generic System available to the research community. 1. CONTEXT The CAVE project #CAller VEri#cation in Banking and Telecommunications# was a 2 year project supported by 1 ENST - D#ept Signal, CNRS - URA 820, 46 Rue Barrault, 75634 Paris cedex 13, FRANCE-EU 2 IDIAP, Rue du Simplon 4, Case Postale 592, CH-1920 Martigny, SWITZERLAND 3 KTH, Department of Speech, Music and Hearing, Drottning Kristinas V#ag 31, S-100 44 Stockh...