gebhart/patrepeval huggingface dataset:
Mevalonic Aciduria — An Inborn Error of Cholesterol and Nonsterol Isoprene Biosynthesis (1986)

A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 mumol per liter (normal, less than 0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts. In the subsequent pregnancy of the patient's mother, gas chromatography-mass spectrometry demonstrated a marked elevation of mevalonic acid in the mother's urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans.
Telomere Recognition and Assembly Mechanism of Mammalian Shelterin (2017)

Shelterin is a six-subunit protein complex that plays crucial roles in telomere length regulation, protection, and maintenance. Although several shelterin subunits have been studied in vitro, the biochemical properties of the fully assembled shelterin complex are not well defined. Here, we characterize shelterin using ensemble biochemical methods, electron microscopy, and single-molecule imaging to determine how shelterin recognizes and assembles onto telomeric repeats. We show that shelterin complexes can exist in solution and primarily locate telomeric DNA through a three-dimensional diffusive search. Shelterin can diffuse along non-telomeric DNA but is impeded by nucleosomes, arguing against extensive one-dimensional diffusion as a viable assembly mechanism. Our work supports a model in which individual shelterin complexes rapidly bind to telomeric repeats as independent functional units, which do not alter the DNA-binding mode of neighboring complexes but, rather, occupy telomeric DNA in a "beads on a string" configuration.
15N nuclear magnetic resonance relaxation studies on rat beta-parvalbumin and the pentacarboxylate variants, S55D and G98D (2002)

15 N relaxation data for Ca 2+ -bound rat ␤-parvalbumin (a.k.a.oncomodulin) were analyzed using the Lipari-Szabo formalism and compared with existing data for rat ␣-parvalbumin.Although the average S 2 values for the two proteins are very similar (0.85 for ␣, 0.84 for ␤), residue-by-residue inspection reveals systematic differences.␣ tends to have the lower S 2 value in helical regions; ␤ tends to have the lower value in the loop regions.Rat ␤ was also examined in the Ca 2+ -free state.The 59 assigned residues displayed an average order parameter (0.90) significantly greater than the corresponding residues in the Ca 2+ -loaded form.The pentacarboxylate variants of rat ␤-S55D and G98D-also were examined in the Ca 2+ -bound state.Although both mutations significantly heighten Ca 2+ affinity, they utilize distinct energetic strategies.S55D improves the Ca 2+ -binding enthalpy; G98D improves the binding entropy.They also show disparate peptide backbone dynamics.Whereas ␤ G98D displays an average order parameter (0.87) slightly greater than that of the wild-type protein, ␤ S55D displays an average order parameter (0.82) slightly lower than wild-type ␤.Furthermore, whereas just two backbone N-H bonds in ␤ G98D show internal motion on the 20-200-psec timescale, fully 52 of the 93 residues analyzed in ␤ S55D show this behavior.These findings suggest that the increased electrostatic repulsion attendant to introduction of an additional carboxylate into the CD site ligand array impedes backbone vibrational motion throughout the molecule.
Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts (2015)

Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non-cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed.
The Need for Inducing Tolerance in Vascularized Composite Allotransplantation (2012)

Successful hand and face transplantation in the last decade has firmly established the field of vascularized composite allotransplantation (VCA). The experience in VCA has thus far been very similar to solid organ transplantation in terms of the morbidity associated with long-term immunosuppression. The unique immunological features of VCA such as split tolerance and resistance to chronic rejection are being investigated. Simultaneously there has been laboratory work studying tolerogenic protocols in animal VCA models. In order to optimize VCA outcomes, translational studies are needed to develop less toxic immunosuppression and possibly achieve donor-specific tolerance. This article reviews the immunology, animal models, mixed chimerism & tolerance induction in VCA and the direction of future research to enable better understanding and wider application of VCA.
Adenosine analogs with covalently attached lipids have enhanced potency at A1‐adenosine receptors (1987)

Chemically functionalized congeners of N6-phenyladenosine and 1,3-dipropyl-8-phenylxanthine have been covalently coupled to fatty acids, diglycerides, and a phospholipid. The lipid-drug conjugates inhibit R-[3H]-phenylisopropyladenosine binding to A1-adenosine receptors in rat cerebral cortex membranes. A xanthine-phosphatidylethanolamine conjugate bound with a Ki value of 19 nM. Various xanthine esters of low potency are potential prodrugs. Amides of an adenosine amine congener (ADAC) with 18-carbon fatty acids exhibited Ki values at A1-adenosine receptors of 70 pM, representing a 130-fold enhancement over the affinity of the corresponding acetyl amide. The very high affinity of adenosine-lipid conjugates may be due to stabilization of these adducts in the phospholipid microenvironment of the receptor protein.
Cardiovascular effects of thoracic afferent nerve stimulation in conscious dogs (1982)

Afferent stimulation of a severed thoracic autonomic nerve in 18 conscious dogs produced in 13 instances hypertension and in 5 instances hypotension. Reflex hypertension was usually accompanied by augmented atrial and ventricular force of contraction. The hypertension could be maintained for over 5-min duration by constant stimulation. Inotropic changes accompanying this hypertension were accentuated following atropine administration and abolished by propranolol. Blood pressure changes following atropinization were initially augmented. On the other hand reflex hypotension was accompanied by bradycardia and decreased atrial contractility. These changes were essentially abolished by atropine. Afferent nerve stimulation with frequencies as low as 1 Hz initiated reflex changes. Maximal responses were obtained by stimulation frequencies of 10-15 Hz. It is concluded that significant and relatively sustained cardiovascular reflexes can be generated by stimulation of cardiac afferent nerves in conscious dogs.
Meta-Analysis: Apolipoprotein E Genotypes and Risk for Coronary Heart Disease (2004)

Inadequate statistical power, differences in geographic and ethnic background, allele frequency, sex, CHD phenotypes, study design, and potential gene-environment interactions may have contributed to the conflicting results of previous studies. The apoE epsilon4 allele is a significant risk factor for CHD.
Increased Cardiovascular Risk in Hypertriglyceridemic Patients With Statin-Controlled LDL Cholesterol (2018)

CVD risk in high-risk statin-treated patients with atherosclerotic CVD was associated with high TG levels.
Microtubule‐associated STOP protein deletion triggers restricted changes in dopaminergic neurotransmission (2007)

The microtubule-associated stable tubule only polypeptide (STOP) protein plays a key-role in neuron architecture and synaptic plasticity. Recent studies suggest that schizophrenia is associated with alterations in the synaptic connectivity. Mice invalidated for the STOP gene display phenotype reminiscent of some schizophrenic-like symptoms, such as behavioral disturbances, dopamine (DA) hyper-reactivity, and possible hypoglutamatergia, partly improved by antipsychotic treatment. In the present work, we examined potential alterations in some DAergic key proteins and behaviors in STOP knockout mice. Whereas the densities of the DA transporter, the vesicular monoamine transporter and the D(1) receptor were not modified, the densities of the D(2) and D(3) receptors were decreased in some DAergic regions in mutant versus wild-type mice. Endogenous DA levels were selectively decreased in DAergic terminals areas, although the in vivo DA synthesis was diminished both in cell bodies and terminal areas. The DA uptake was decreased in accumbic synaptosomes, but not significantly altered in striatal synaptosomes. Finally, STOP knockout mice were hypersensitive to acute and subchronic locomotor effects of cocaine, although the drug equally inhibited DA uptake in mutant and wild-type mice. Altogether, these data showed that deletion of the ubiquitous STOP protein elicited restricted alterations in DAergic neurotransmission, preferentially in the meso-limbic pathway.
P-Type Conduction in Mg-Doped GaN Treated with Low-Energy Electron Beam Irradiation (LEEBI) (1989)

Distinct p-type conduction is realized with Mg-doped GaN by the low-energy electron-beam irradiation (LEEBI) treatment, and the properties of the GaN p-n junction LED are reported for the first time. It was found that the LEEBI treatment drastically lowers the resistivity and remarkably enhances the PL efficiency of MOVPE-grown Mg-doped GaN. The Hall effect measurement of this Mg-doped GaN treated with LEEBI at room temperature showed that the hole concentration is ∼2·10 16 cm -3 , the hole mobility is ∼8 cm 2 /V·s and the resistivity is ∼35 Ω·cm. The p-n junction LED using Mg-doped GaN treated with LEEBI as the p-type material showed strong near-band-edge emission due to the hole injection from the p-layer to the n-layer at room temperature.
Comparison of adherence of Pseudomonas aeruginosa to respiratory epithelial cells from cystic fibrosis patients and healthy subjects (1992)

The adherence of Pseudomonas aeruginosa PAO1 to primary cultures of cystic fibrosis nasal polyp (CFNP), normal human nasal polyp (NHNP), and immortalized CF and normal cell lines was studied. PAO1 bound significantly more to primary CFNP cells than to NHNP cells as the mean adherence +/- standard deviation of 5 x 10(7) CFU of 35S-labeled bacteria per ml per well was 15.09 x 10(6) +/- 4.25 x 10(6) CFU/ml per well and 7.62 x 10(6) +/- 2.11 x 10(6) CFU/ml per well, respectively (Mann-Whitney U test, P less than 0.0001). There was no significant difference in PAO1 adherence to the immortalized CF and normal cell lines. The primary CFNP cells had more receptors (115 per cell) than did NHNP cells (34 per cell). P. aeruginosa binding to CFNP was blocked by GlcNAc, NeuAc, L-Fuc, and D-Gal, while binding to NHNP was blocked only by GlcNAc, suggesting that receptors on the two cell types were qualitatively different. Pseudomonas supernatants containing protease, phospholipase C, and neuraminidase activity increased adherence to CFNP and NHNP cells. The Pseudomonas exoproducts modified epithelial cell glycoconjugates, as characterized by binding of fluorescein isothiocyanate-labeled lectins and the release of sialic acid. There was minimal release of fibronectin by the bacterial supernatants. The affinity of P. aeruginosa for CF epithelial cells appeared to be due to an increased number of receptors and modification of the epithelial cell surface by P. aeruginosa exoproducts that exposed asialoganglioside binding sites.
Feasibility of a urine-based DNA methylation assay for early detection of bladder cancer (2007)

A62 Introduction: Bladder cancer is the fourth most common cancer in men, often seen in older men with a history of smoking, and the eighth most common cancer in women. In the U.S. and EU, there are >160,000 new cases and >48,000 bladder cancer-related deaths each year. While the five-year survival rate for early-stage bladder cancer is high, there are significant challenges for early detection as well as monitoring for disease recurrence or progression, which can occur in up to 70% of cases. A DNA methylation assay with high sensitivity and specificity could help to identify those patients with bladder cancer, either initially or due to recurrence, while reducing unnecessary invasive cystoscopies.  Materials and Methods: Marker identification: Candidate genes were identified using re-expression profiles of bladder cancerous cell lines. Promoter sequences were linked with gene expression to identify valid epigenetically silenced genes. An established pharmacologic unmasking strategy (5-aza-2’-deoxycytidine (DAC) and trichostatin A (TSA)) for re-expression analysis of epigenetically targeted genes was combined with proprietary advanced bioinformatics tools to identify genes prone to promoter methylation. Marker validation: Differentially methylated genes were validated in tissue using real-time methylation specific PCR (real-time MSP). Best performing tissue markers were selected for testing DNA from urine samples. Urine sample collection, preparation and processing: Prospective randomly collected urine samples from multiple centers in Belgium, UK and The Netherlands are used in the present study. DNA is isolated using a standard DNA isolation method and standard equipment and bisulphite modified using a commercially available kit. Analyte quantitations are done using real-time MSP.  Results: The most differentially methylated genes were validated in tissue using real-time MSP. Of those, a combination of methylation markers reliably detected Bladder cancer in an independent tissue test set. A multicenter trial has been initiated in 2006. In this trial symptomatic patients, attending a urology clinic and ultimately diagnosed with bladder cancer or other non-malignant urological disorders, provided a urine sample for use in real-time MSP analysis. The trial is expected to enroll 600 individuals within 2 years. Best performing tissue markers were assessed on available urine samples from this ongoing trial. Initial data analysis confirmed that a combination of methylation markers has strong performance characteristics to correctly identify patients with bladder cancer.
Scaled Subprofile Model: A Statistical Approach to the Analysis of Functional Patterns in Positron Emission Tomographic Data (1987)

The data obtained from measurements of regional rCMRglu using [18F]fluorodeoxyglucose (FDG)/positron emission tomographic (PET) data contain more structure than can be identified with group mean rCMRglu profiles or regional correlation coefficients. This additional structure is revealed by a novel mathematical-statistical model of regional metabolic interactions that explicitly represents rCMRglu profiles as a combination of region-independent global effects, a group mean pattern and a mosaic of interacting networks. In its application to FDG/PET data, this model removes global subject effects [global scaling factors (GSFs)] and a group mean pattern (profile) so as to maximize statistical power for the detection and simultaneous discovery of all networks of two or more regions that form a significant and consistent linearly covarying pattern. The model approach presented here was applied to the combined rCMRglu data from 12 demented AIDS patients and 18 normal controls: Two significant metabolic covariance pattern descriptors that together accounted for 71 to 96% of the rCMRglu/GSF variation across subjects for 22/28 regions in the AIDS group were extracted. Each descriptor was found to be highly correlated with performance on several neuropsychological tests, providing independent validation of the analysis technique as a means of discovering and describing behaviorally related components of group rCMRglu profiles.
Curcumin (a constituent of turmeric): New treatment option against COVID‐19 (2020)

In late December 2019, the outbreak of respiratory illness emerged in Wuhan, China, and spreads worldwide. World Health Organization (WHO) named this disease severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused by a new member of beta coronaviruses. Several medications are prescribed to patients, and some clinical trials are underway. Scientists are trying to find a specific drug against this virus. In this review, we summarize the pathogenesis, clinical features, and current treatments of coronavirus disease 2019 (COVID-19). Then, we describe the possible therapeutic effects of curcumin and its molecular mechanism against coronavirus-19. Curcumin, as an active constituent of <i>Curcuma longa</i> (turmeric), has been studied in several experimental and clinical trial studies. Curcumin has some useful clinical effects such as antiviral, antinociceptive, anti-inflammatory, antipyretic, and antifatigue effects that could be effective to manage the symptoms of the infected patient with COVID-19. It has several molecular mechanisms including antioxidant, antiapoptotic, and antifibrotic properties with inhibitory effects on Toll-like receptors, NF-κB, inflammatory cytokines and chemokines, and bradykinin. Scientific evidence suggests that curcumin could have a potential role to treat COVID-19. Thus, the use of curcumin in the clinical trial, as a new treatment option, should be considered.
Fast handoff scheme based on mobility prediction in public wireless LAN systems (2004)

Recently, wireless LAN systems have been widely deployed for public mobile Internet services. Public wireless LAN systems can provide high speed Internet connectivity using portable devices such as laptop computers, personal digital assistants (PDAs), etc. In public wireless LAN systems, reliable user authentication and mobility support are essential issues. However, re-authentication during handoff procedures causes long handoff latency and this affects the quality of service in real-time multimedia applications. A fast handoff scheme based on mobility prediction is proposed. In this scheme, a mobile host entering the area covered by an access point (AP) performs authentication procedures for multiple APs, rather than just the current AP. These multiple APs are selected by a prediction method called the frequent handoff region (FHR) selection algorithm, which takes into account users&apos; mobility patterns, service classes, etc. Since a mobile host is registered and authenticated for an FHR in advance, handoff latency resulting from re-authentication can be significantly reduced. Simulation results show that the proposed scheme is more efficient than other schemes in terms of handoff delay and buffer requirements.
Transgenic mouse models in angiogenesis and cardiovascular disease (2000)

Novel gene technologies have allowed us to manipulate the genetic balance of candidate molecules in mice in a controllable manner. Homologous or site-specific recombination in embryonic stem cells allows us to study the consequences of deficiencies, mutations, and conditional or tissue-specific expression of gene products in transgenic mice. These technological breakthroughs have significantly advanced biomedical research and broadened our understanding of the pathophysiological role of candidate disease genes. In addition, gene transfer allows us to test the possible therapeutic use of gene products for gene therapy. A variety of assays have been miniaturized, allowing analysis of cardiovascular physiology in the mouse. With the advent of genome sequencing programmes, these gene technologies provide means of studying gene function in a conclusive manner. Furthermore, disease models can be generated which can be used as test models for (gene) therapy or for the discovery of novel genes using differential gene profiling techniques. The present review will focus on the molecular basis of how blood vessels form (angiogenesis and arteriogenesis) and how they become diseased. A selected number of molecules that have been studied in the authors' laboratory will be reviewed in more detail.
Deconvolution of the Fluorescence Emission Spectrum of Human Antithrombin and Identification of the Tryptophan Residues That Are Responsive to Heparin Binding (1998)

Heparin causes an allosterically transmitted conformational change in the reactive center loop of antithrombin and a 40% enhancement of tryptophan fluorescence. We have expressed four human antithrombins containing single Trp --> Phe mutations and determined that the fluorescence of antithrombin is a linear combination of the four tryptophans. The contributions to the spectrum of native antithrombin at 340 nm were 8% for Trp-49, 10% for Trp-189, 19% for Trp-225, and 63% for Trp-307. Trp-225 and Trp-307 accounted for the majority of the heparin-induced fluorescence enhancement, contributing 37 and 36%, respectively. Trp-49 and Trp-225 underwent spectral shifts of 15 nm to blue and 5 nm to red, respectively, in the antithrombin-heparin complex. The blue shift for Trp-49 is consistent with partial burial by contact with heparin, whereas the red shift for Trp-225 and large enhancement probably result from increased solvent access upon heparin-induced displacement of the contact residue Ser-380. The enhancement for Trp-307 may result from the heparin-induced movement of helix H seen in the crystal structure. The time-resolved fluorescence properties of individual tryptophans of wild-type antithrombin were also determined using the four variants and showed that Trp-225 and Trp-307 experienced the largest change in lifetime upon heparin binding, providing support for the steady-state fluorescence deconvolution.