gebhart/patrepeval huggingface dataset:
"Cleavable Trifunctional" Approach to Receptor Affinity Labeling: Regeneration of Binding to A1-Adenosine Receptors (1995)

A general approach for reversible affinity labeling of receptors has been developed. The objective is to carry out a series of chemical modifications resulting in a covalently-modified, yet functionally-regenerated, receptor protein that also may contain a reporter group. The ligand recognition site of A1-adenosine receptors in bovine brain membranes was probed to demonstrated the feasibility of this approach. Use of disulfide or ester linkages, intended for cleavage by exposure of the labeled receptor to either reducing reagents or hydroxylamine, respectively, was considered. Binding of the antagonist radioligand [3H]CPX was preserved following incubation of the native receptor with 3 M hydroxylamine, while binding was inhibited by the reducing reagent dithiothreitol (DTT) with an IC50 of 0.29 M. Hydroxylamine displaced specific agonist ([3H]PIA) binding in a noncovalent manner. Specific affinity labels containing reactive isothiocyanate groups were synthesized from XCC (8-[4-](carboxymethyl)-oxy]phenyl]-1,3-dipropylxanthine) and shown to bind irreversibly to A1-receptors. The ligands were structurally similar to previously reported xanthine inhibitors (e.g., DITC-XAC: (1989) J. Med. Chem. 32, 1043) except that either a disulfide linkage or an ester linkage was incorporated in the chain between the pharmacophore and the isothiocyanate-substituted ring. These groups were intended for chemical cleavage by thiols or hydroxylamine, respectively. Radioligand binding to A1-receptors was inhibited by these reactive xanthines in a manner that was not reversed by repeated washing. Hydroxylamine or DTT restored a significant fraction of the binding of [3H]CPX in A1-receptors inhibited by the appropriate cleavable xanthine isothiocyanate derivative.
Catalyst Repurposing Sequential Catalysis by Harnessing Regenerated Prolinamide Organocatalysts as Transfer Hydrogenation Ligands (2019)

A catalyst repurposing strategy based on a sequential aldol addition and transfer hydrogenation giving access to enantiomerically enriched α-hydroxy-γ-butyrolactones is described. The combination of a stereoselective, organocatalytic step, followed by an efficient catalytic aldehyde reduction induces an ensuing lactonization to provide enantioenriched butyrolactones from readily available starting materials. By capitalizing from the capacity of prolineamides to act as both an organocatalyst and a transfer hydrogenation ligand, catalyst repurposing allowed the development of an operationally simple, economic, and efficient sequential catalysis approach.
Follow-up clinical results in patients undergoing percutaneous transluminal coronary angioplasty. (1985)

Complete follow-up data were obtained from 229 consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) between 1979 and 1982 (mean follow-up 14 months, range 6 to 37). Single-vessel disease was present in 143 and multivessel disease in 86. PTCA was successful in 153 patients (67%). Failure was followed initially by bypass surgery in 59 and by continued medical therapy in 17. After successful PTCA, 90% of patients were improved subjectively and 74% were asymptomatic at follow-up. After unsuccessful PTCA but prompt bypass, 90% were improved subjectively and 85% were asymptomatic. Among the 229 patients, 39 (17%) required an additional intervention because of angina during follow-up; 15 of these had repeat PTCA and 18 had bypass surgery. Among patients with successful PTCA, revascularization was complete in 77% and partial in 23%. The completeness of revascularization with PTCA had a significant impact on follow-up. The follow-up data of patients with successful single-vessel PTCA and of those with multivessel disease with complete revascularization were similar. When the patients with complete revascularization were compared with those with multivessel disease but incomplete revascularization, the follow-up data were characterized by a higher incidence of angina or need for bypass surgery in the latter group (63%) than in the former group (29%); those with incomplete revascularization also had a significantly reduced event-free survival.
Thermoelectric power of aligned and randomly oriented carbon nanotubes (2000)

Thermoelectric power was used to elucidate the electrical transport properties of aligned and randomly oriented carbon nanotube systems in the temperature range 77--450 K. A weakly negative thermoelectric power, comparable with that of a graphite flake, was observed for a macroscopic bundle of multiwall carbon nanotubes with individual axes aligned parallel to the main axis. However, mats of randomly oriented multiwall carbon nanotubes gave a strongly positive thermoelectric power, as did mats of single-wall nanotubes. This is evidence of the importance of intertube contacts in the interpretation of the thermoelectric power data for carbon nanotube systems. Models for thermoelectric power behavior incorporating contact effects are described.
Perilla extract improves frequent urination in spontaneously hypertensive rats with enhancement of the urothelial presence and anti‐inflammatory effects (2017)

The present findings suggest that perilla extract improves frequent urination, and this improvement seems to be mediated, at least in part, by enhancement of the urothelial presence and by the anti-inflammatory effects of perilla.
A Multi-enzyme Cascade of Hemoglobin Proteolysis in the Intestine of Blood-feeding Hookworms (2004)

Blood-feeding pathogens digest hemoglobin (Hb) as a source of nutrition, but little is known about this process in multicellular parasites. The intestinal brush border membrane of the canine hookworm, Ancylostoma caninum, contains aspartic proteases (APR-1), cysteine proteases (CP-2), and metalloproteases (MEP-1), the first of which is known to digest Hb. We now show that Hb is degraded by a multi-enzyme, synergistic cascade of proteolysis. Recombinant APR-1 and CP-2, but not MEP-1, digested native Hb and denatured globin. MEP-1, however, did cleave globin fragments that had undergone prior digestion by APR-1 and CP-2. Proteolytic cleavage sites within the Hb alpha and beta chains were determined for the three enzymes, identifying a total of 131 cleavage sites. By scanning synthetic combinatorial peptide libraries with each enzyme, we compared the preferred residues cleaved in the libraries with the known cleavage sites within Hb. The semi-ordered pathway of Hb digestion described here is surprisingly similar to that used by Plasmodium to digest Hb and provides a potential mechanism by which these hemoglobinases are efficacious vaccines in animal models of hookworm infection.
Detection of a kallikrein in the mouse lactating mammary gland: a possible processing enzyme for the epidermal growth factor precursor. (1994)

Kallikreins are a multigene subfamily of serine proteases that may have a role in processing precursors of polypeptide hormones and growth factors. The epidermal growth factor (EGF) immunoreactivity in mouse milk is derived from the membrane-bound EGF precursor located on the lumenal border of the alveolar cells in the mammary gland. Release of EGF into the milk requires the hydrolysis of the EGF precursor at Arg-X cleavage sites. We report the presence of a candidate EGF precursor-processing enzyme in the lactating mouse mammary gland. Kallikrein transcripts in the mouse lactating mammary gland were detected by primer-directed enzyme amplification of complementary DNA (cDNA). Primers to selected conserved regions of the kallikrein cDNA resulted in an amplified product of the predicted size (573 basepairs). Sequence analysis of the product over three nonconserved regions identified mGK-6 (mouse renal kallikrein) as the primary kallikrein in BALB/c mouse lactating mammary gland. Transcription products for the EGF-binding protein (mGK-9), mGK-1, MGK-3, and mGK-4 were not detected by enzyme amplification with specific primers corresponding to these kallikrein cDNAs. Positive immunohistochemical staining of the apical membrane of mammary alveolar cells was detected with a polyclonal antiserum to mouse kallikrein. Incubation of cell membranes isolated from lactating mammary glands released soluble EGF-immunoreactive material. Aprotinin partially inhibited the release of this material, whereas other protease inhibitors, such as leupeptin, benzamidine, and limabean trypsin inhibitor, had no detectable effect. These results support the hypothesis that the release of EGF-immunoreactive material into the milk is in part dependent upon a kallikrein enzyme (mGK-6) in the BALB/c mouse lactating mammary gland.
Revealing the Atomic Structures of Exposed Lateral Surfaces for Polymorphic Manganese Dioxide Nanowires (2020)

Polymorphic 1D MnO 2 nanostructures are widely applied in fields such as catalysis, sensing, and energy storage with the functionality mainly determined by the atomic patterns of their laterally exposed facets, which largely remain unclear so far. Herein, by high‐resolution transmission electron microscopy (HRTEM) imaging directly along their axial directions, the atomic structures of the outmost lateral facets of polymorphic MnO 2 nanowires are disclosed. To generalize the findings, four most commonly seen phases with characteristic tunnel structures are targeted, i.e., β‐, γ‐, α‐, and todorokite(t)‐MnO 2 , which are synthesized conventionally using a hydrothermal method reported in the literature. Axially imaging these MnO 2 nanowires via HRTEM, the {hkl} facets covering the lateral surfaces are accurately indexed, the atomic pattern of each {hkl} facet is revealed, and it is further coupled with the outmost tunnel configuration that can significantly affect the physicochemical property of MnO 2 materials via tunnel‐driven mass adsorption/transport. This work provides a reliable reference for atomic modeling of MnO 2 to benefit the pursuit of its structure–property relationship; in addition, it can benefit surface engineering strategies to better rationalize the facet growth control with optimized functionality.
Catheter Ablation of Atrial Tachycardia Following Atrial Fibrillation Ablation (2009)

Atrial tachycardias represent the second front of atrial fibrillation (AF) ablation. They are frequently encountered during the index ablation for patients with persistent AF and are common following ablation of persistent AF, occurring in half of all patients who have had AF successfully terminated. An atrial tachycardia is rightly seen as a failure of AF ablation, as these tachycardias are poorly tolerated by patients. This article describes a simple, practical approach to diagnosis and ablation of these atrial tachycardias.
Effects of Modified Atmosphere Packaging with Various Carbon Dioxide Composition on Biogenic Amines Formation in Indian Mackerel (Rastrelliger kanagurta) stored at 5 ± 1°C (2013)

The profile of major biogenic amines was investigated in Indian mackerel packed in modified atmosphere for up to 12 days at 5 ± 1°C. Beheaded and gutted Indian mackerel was packed under different carbon dioxide compositions to study the effects on biogenic amines formation. The treatments were control air (C), vacuum packaging (VP), 30% CO2/65% N2/5% O2 (M30C), 60% CO2/35% N2/5% O2 (M60C), 80% CO2/15% N2/5% O2 (M80C) and 100% CO2 (M100C). Each amine responded differently to different CO2 levels. After 12 days of storage, concentrations of histamine were reduced by 6.4%, 8.5%, 70.3%, 78.8% and 90.2% in fish packed under VP, M30C, M60C, M80C and M100C, respectively as compared with control air. Changes in putrescine and cadaverine showed a similar pattern. Gas mix of M30C and VP stimulated the formation of tyramine reaching 203 and 172 ppm, respectively. Higher composition of CO2 had a significant inhibitory effect on tyramine concentration (p < 0.05). There were parallel increases of putrescine and spermidine in C, VP and M30C. No significant effect of CO2 was observed on spermine (p > 0.05). After 9 days of storage, more than 300 ppm of histamine was detected in mackerel packed in VP and M30C; therefore, these atmospheres pose a histamine intoxication risk. Copyright © 2013 John Wiley & Sons, Ltd.
Squalene Based Nanocomposites: A New Platform for the Design of Multifunctional Pharmaceutical Theragnostics (2011)

This study reports the design of a novel theragnostic nanomedicine which combines (i) the ability to target a prodrug of gemcitabine to an experimental solid tumor under the influence of a magnetic field with (ii) the imaging of the targeted tumoral nodule. This concept is based on the inclusion of magnetite nanocrystals into nanoparticles (NPs) constructed by self-assembling molecules of the squalenoyl gemcitabine (SQgem) bioconjugate. The nanocomposites are characterized by an unusually high drug loading, a significant magnetic susceptibility, and a low burst release. When injected to the L1210 subcutaneous mice tumor model, these magnetite/SQgem NPs were magnetically guided, and they displayed considerably greater anticancer activity than the other anticancer treatments (magnetite/SQgem NPs nonmagnetically guided, SQgem NPs, or gemcitabine free in solution). The histology and immunohistochemistry investigation of the tumor biopsies clearly evidenced the therapeutic superiority of the magnetically guided nanocomposites, while Prussian blue staining confirmed their accumulation at the tumor periphery. The superior therapeutic activity and enhanced tumor accumulation has been successfully visualized using T(2)-weighted imaging in magnetic resonance imaging (MRI). This concept was further enlarged by (i) the design of squalene-based NPs containing the T(1) Gd(3+) contrast agent instead of magnetite and (ii) the application to other anticancer squalenoyls, such as, cisplatin, doxorubicin, and paclitaxel. Thus, by combining different anticancer medicines as well as contrast imaging agents in NPs, we open the door toward generic conceptual framework for cancer treatment and diagnosis. This new theragnostic nanotechnology platform is expected to have important applications in cancer therapy.
P4‐695: E2814: A NOVEL ANTI‐TAU THERAPEUTIC ANTIBODY FOR ALZHEIMER'S DISEASE (2019)

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders that include Alzheimer's disease (AD). As disease progresses, Braak staging of post-mortem tissue suggest that pathological tau, spreads through the brain via synaptically connected pathways. Tau proteins (full length or fragments) containing the microtubule binding region (MTBR) may be essential to form extracellular ‘seeds’ that initiate and propagate pathology. Indeed, the MTBR forms the core of tau filaments observed in AD brain. Tau immunotherapy has emerged as a promising approach to slow or limit AD progression. Therefore, targeting the tau MTBR-containing seeds with a therapeutic antibody may be a useful strategy to provide disease-modifying treatment for AD. E2814 is a novel humanised IgG1 antibody that binds to the tau MTBR. The preclinical characterisation of this antibody and its murine counterpart 7G6, will be presented. Human and murine antibodies were fine epitope mapped using PEPperPRINT technology. Their effect on inhibiting tau aggregation and ability to immunodeplete seeds was assessed in vitro. The in vivo efficacy of 7G6 was evaluated in an intrahippocampal seed injection model. Finally, the ability of E2814 to bind pathological human tau was tested by immunogold labelling of AD fibrils and by immunohistochemical staining of tissue sections. E2814 and 7G6 are high affinity antibodies bi-epitopic for 4R tau isoforms. Both antibodies effectively inhibited tau aggregation in vitro and immunodepleted different MTBR-containing tau seeds. An attenuation of brain sarkosyl-insoluble tau could also be observed in an in vivo model of tau seeding and transmission. In analysis of AD brain, E2814 was also shown to bind both different types of isolated tau filaments and pathological tau structures in tissue sections. Collectively, these data suggest that E2814 should be investigated further in human clinical trials.
(Nobel Laureate Signature Award for Graduate Education in Chemistry sponsored by Avantor Performance Materials) Trapping an iron(VI) water-splitting intermediate in nonaqueous media (2019)

Understanding the mechanisms of highly-active earth-abundant water oxidn. electrocatalysts can guide the development of advanced water-splitting devices that convert renewable electricity to clean fuels and value-added products. Catalytic intermediates are difficult to isolate and characterize because they tend to be extremely transient and present at low concns. One approach to this problem is to slow down turnover by limiting the availability of the substrate. In cases where substrate and solvent are the same-such as in water oxidn.-the problem can be more complex. By dramatically limiting the availability of substrate (water and hydroxide) in nickel-iron catalyzed heterogeneous water oxidn., we have obsd. and characterized a high-valent iron intermediate. Orthogonal spectroscopies indicate that the intermediate contains iron in the rare 6+ oxidn. state. By considering this "ferrate" analog as a reactive intermediate, we can improve catalytic efficiency for water oxidn., and design new reactions to synthesize chems. and materials.
A Survey of Lawsuits for Metoclopramide and Tardive Dyskinesia (2014)

Introduction: Metoclopramide, (Reglan), is used to treat gastroparesis and other gastrointestinal disorders. In 2009, the Food and Drug Administration (FDA) issued a black box warning about the association of metoclopramide and tardive dyskinesia (TD). TD is a permanent neurological disorder characterized by involuntary muscle movements. This study examined lawsuits involving metoclopramide-induced tardive dyskinesia in an effort to inform physicians of the legal risks of prescribing metoclopramide. Methods: The Westlaw database, one of the primary online legal research services for legal professionals, was used for the study. A first search was conducted for all cases containing “metoclopramide” or “reglan” and “tardive dyskinesia” (search: “adv: metoclopramide reglan and tardive dyskinesia”). This search yielded 96 cases where patients filed a claim. All appeals were excluded from the total number of cases. Of these, 10 (11%) were filed against prescribing physicians, 1 (1%) against a pharmacist, and the remaining 85 (88%) were filed against manufacturers. Cases were commonly filed based off the following premises: fail to warn, medical malpractice. Failure to warn is defined as when a manufacturer or distributor does not provide adequate information regarding the dangers associated with the product. Medical malpractice is when a health care provider does not provide a quality level of care that usually results in harm to a patient. Results: Of the 10 cases filed against physicians, 5 were compliant for malpractice and 5 were for failure to warn. The remaining 85 cases were brought against the generic and brand manufacturers of the drug for negligence or failure to warn physicians and patients about the potential side effects of metoclopramide, including tardive dyskinesia. The number of lawsuits has increased dramatically since the black box warning (Figure 1).Figure 1Conclusion: At present, there appears to be only a small legal risk to physicians prescribing metoclopramide. However, the trends related to lawsuits against physicians need careful monitoring, as the number of suits for metoclopramide and tardive dyskinesia has increased since the FDA black box warning.
Predicate Abstraction with Indexed Predicates (2004)

Predicate abstraction provides a powerful tool for verifying properties of infinite-state systems using a combination of a decision procedure for a subset of first-order logic and symbolic methods originally developed for finite-state model checking. We consider models containing first-order state variables, where the system state includes mutable functions and predicates. Such a model can describe systems containing arbitrarily large memories, buffers, and arrays of identical processes. We describe a form of predicate abstraction that constructs a formula over a set of universally quantified variables to describe invariant properties of the first-order state variables. We provide a formal justification of the soundness of our approach and describe how it has been used to verify several hardware and software designs, including a directory-based cache coherence protocol.
Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium (2019)

Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic-acid-based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose-dependent control of encoded protein expression. Inhaled delivery of IVT-mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g<sup>-1</sup> of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE-mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT-mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.
3D perfusion mapping in the intact mouse heart after myocardial infarction using myocardial contrast echocardiography (2006)

Myocardial contrast echocardiography (MCE) was used to map 3D perfusion of the entire left ventricle (LV) extent of an intact mouse model after a surgically-induced myocardial infarction (MI) caused by permanent occlusion of the Left Anterior Descending (LAD) coronary artery. Normal mice with no occlusion were also studied as controls. For each mouse, MCE images of the heart were acquired in short axis views from apex to base at 1mm increments. For accurate 3D reconstruction, ECG gating and a tri-axial adjustable micromanipulator were used for temporal and spatial registration. MCE images were color-coded in each slice according to the relative perfusion level. The size of perfused areas measured in MCE images was then compared to perfusion areas by postmortem staining with Phthalo blue and TTC red dyes. Good correlation (R>0.93, p<0.005) in perfused area size was observed between in vivo MCE measurements and histological staining. 3D multi-slice models and 3D surface models of relative perfusion distribution were created and provided a good match with postmortem results.