gebhart/patrepeval huggingface dataset:
Covalent Plasmodium falciparum-selective proteasome inhibitors exhibit a low propensity for generating resistance in vitro and synergize with multiple antimalarial agents (2019)

Therapeutics with novel modes of action and a low risk of generating resistance are urgently needed to combat drug-resistant Plasmodium falciparum malaria. Here, we report that the peptide vinyl sulfones WLL-vs (WLL) and WLW-vs (WLW), highly selective covalent inhibitors of the P. falciparum proteasome, potently eliminate genetically diverse parasites, including K13-mutant, artemisinin-resistant lines, and are particularly active against ring-stage parasites. Selection studies reveal that parasites do not readily acquire resistance to WLL or WLW and that mutations in the β2, β5 or β6 subunits of the 20S proteasome core particle or in components of the 19S proteasome regulatory particle yield only <five-fold decreases in parasite susceptibility. This result compares favorably against previously published non-covalent inhibitors of the Plasmodium proteasome that can select for resistant parasites with >hundred-fold decreases in susceptibility. We observed no cross-resistance between WLL and WLW. Moreover, most mutations that conferred a modest loss of parasite susceptibility to one inhibitor significantly increased sensitivity to the other. These inhibitors potently synergized multiple chemically diverse classes of antimalarial agents, implicating a shared disruption of proteostasis in their modes of action. These results underscore the potential of targeting the Plasmodium proteasome with covalent small molecule inhibitors as a means of combating multidrug-resistant malaria.
Preface (2009)

Botulinum toxin is an exciting therapy that is applicable to a wide variety of disorders in many fields of medicine. Because botulinum toxins must be injected locally, physicians must possess the appropriate expertise in order to deliver the therapy effectively. Occasionally, unique approaches to muscles are required, which may differ from those used by electromyographers. Additionally, many physicians are not accustomed to giving injection therapy. A simple anatomical atlas or even an atlas for electromyography will not be helpful in all circumstances – hence the need for this book. We have assembled a team of international experts in the use of botulinum toxin to give guidance on exactly how to administer the injections. The emphasis in this book is on technique, and it is profusely illustrated for maximal advantage. The book can be read as a teaching aid, but may also be useful at the bedside for immediate guidance. We are grateful to the contributors of this book and trust that physicians who employ this therapy in their practices will find it valuable.
How Saliva Interferes with Colorimetric Gold Nanoparticle Aptasensors: Understanding and Mitigating Surface Interactions (2023)

Colorimetric gold-nanoparticle-based biosensors are an attractive platform for the detection of small-molecule analytes. Taking advantage of the adsorption of DNA aptamer probes on AuNPs, these sensors can be simple, rapid, sensitive, selective, and cost-effective. These properties are important for rapid detection of drugs like methamphetamine in biological matrices. Saliva is a highly desirable matrix for development of diagnostic tests because saliva sampling is minimally invasive and drug levels relate to recent use rather than accumulation from historical use. However, saliva is a complex fluid that presents a multitude of challenges when applying colorimetric aggregation assays. Here, we show that the contents of saliva interfere with the sensor in two main ways: (i) suppressing color change signals due to proteins nonspecifically adsorbing to nanoparticles and (ii) blocking aggregation and generating false signals due to specific electrolytes that induce aggregation. With this knowledge, we examine strategies to mitigate these effects, including sample collection and pretreatment procedures. These measures ultimately result in a sensor that can detect methamphetamine spiked into saliva samples and suggest immense promise for the feasibility of these platforms for on-site diagnostic applications.
Determination of the major tautomeric form of the covalently modified adenine in the (+)-CC-1065-DNA adduct by proton and nitrogen-15 NMR studies (1990)

(+)-CC-1065 is an extremely potent antitumor antibiotic produced by Streptomyces zelensis. The potent cytotoxic effects of the drug are thought to be due to the formation of a covalent adduct with DNA through N3 of adenine. Although the covalent linkage sites between (+)-CC-1065 and DNA have been determined, the tautomeric form of the covalently modified adenine in the (+)-CC-1065-DNA duplex adduct was not defined. A [6-15N]deoxyadenosine-labeled 12 base pair non-self-complementary oligomer, d(GGCGGAGTT*AGG).d(CCTAACTCCGCC) (asterisk indicates 15N-labeled base), containing the (+)-CC-1065 most preferred binding sequence 5'AGTTA, was synthesized and modified with (+)-CC-1065. This [6-15N]deoxyadenosine-labeled 12-mer duplex adduct was then studied by 1H and 15N NMR. One-dimensional NOE difference and two-dimensional NOESY 1H NMR experiments on the nonisotopically labeled 12-mer duplex adduct demonstrate that the 6-amino protons of the covalently modified adenine exhibit two signals at 9.19 and 9.08 ppm. Proton NMR experiments on the [6-15N]deoxyadenosine-labeled 12-mer duplex adduct show that the two resonance signals for adenine H6 observed on the nonisotopically labeled duplex adduct were split into doublets by the 15N nucleus with coupling constants of 91.3 Hz for non-hydrogen-bonded and 86.8 Hz for hydrogen-bonded amino protons. Parallel 15N NMR experiments on the [6-15N]deoxyadenosine-labeled (+)-CC-1065-12-mer duplex adduct show a triplet-like signal around -276.9 ppm and coupling constants of 91.5 and 85.6 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
Optical properties of nonpolar III-nitrides for intersubband photodetectors (2013)

We compare the theoretical optical properties of intersubband transitions for polar III-nitrides, nonpolar III-nitrides, and conventional GaAs. We calculate and examine the peak transition wavelengths, dipole matrix elements, and absorption spectra as a function of quantum well thickness for single quantum well structures on each platform. We show that the absence of polarization-related electric fields in nonpolar III-nitrides simplifies device design and facilitates clear performance advantages over conventional polar III-nitrides, including access to a wider range of absorption wavelengths, a several-fold increase in the dipole matrix element, and higher absorption probability. Compared to conventional GaAs-based structures, nonpolar III-nitrides exhibit a somewhat lower absorption probability but allow for a significantly wider design space, permitting devices operating at wavelengths that are unattainable using GaAs.
Facile Synthesis of 1,2,3,4-Tetrasubstituted Pyrroles from Baylis-Hillman Adducts (2007)

Suitably fUnctionalized pyrroles are the basic skeleton of many biologically important substances and numerous synthetic methods of pyrroles have been investigated extensively.1,2 However, the synthesis of pyrrole derivatives from Baylis-Hillman adducts was not developed much.2 Recently, we reported the synthesis of 2,3,4-trisubstituted pyrroles starting from the rearranged aza-Baylis-Hillman adducts (Scheme 1).3
Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013–15: a retrospective observational study (2018)

According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.
An integrated system for information security management with the unified framework (2014)

Information security management plays an essential role for drawing the roadmap of information security; thus, many theoretical methodologies and practical standards are brought into this domain. However, many standards and methodologies are too cumbersome to be adopted by an organization. Additionally, there is no unified framework to systematically handle the tedious tasks of information security management. This study’s primary goal is to design an integrated system for information security management (ISISM) that aims to use current methodologies and standards to solve the above-mentioned issues. Because business impact analysis and risk analysis are the most important areas within this domain, we carefully select the related methods and then integrate them into a unified framework, upon which the proposed ISISM depends. To achieve this outcome for this study, security requirement engineering is adopted, which enables the designed system to support system users in generating risk assessment reports with related information security policies.
Enhancing the Bioconversion of Azelaic Acid to Its Derivatives by Response Surface Methodology (2018)

Azelaic acid (AzA) and its derivatives have been known to be effective in the treatment of acne and various cutaneous hyperpigmentary disorders. The esterification of azelaic acid with lauryl alcohol (LA) to produce dilaurylazelate using immobilized lipase B from <i>Candida antarctica</i> (Novozym 435) is reported. Response surface methodology was selected to optimize the reaction conditions. A well-fitting quadratic polynomial regression model for the acid conversion was established with regards to several parameters, including reaction time and temperature, enzyme amount, and substrate molar ratios. The regression equation obtained by the central composite design of RSM predicted that the optimal reaction conditions included a reaction time of 360 min, 0.14 g of enzyme, a reaction temperature of 46 °C, and a molar ratio of substrates of 1:4.1. The results from the model were in good agreement with the experimental data and were within the experimental range (R² of 0.9732).The inhibition zone can be seen at dilaurylazelate ester with diameter 9.0±0.1 mm activities against <i>Staphylococcus epidermidis</i> S273. The normal fibroblasts cell line (3T3) was used to assess the cytotoxicity activity of AzA and AzA derivative, which is dilaurylazelate ester. The comparison of the IC<sub>50</sub> (50% inhibition of cell viability) value for AzA and AzA derivative was demonstrated. The IC<sub>50</sub> value for AzA was 85.28 μg/mL, whereas the IC<sub>50</sub> value for AzA derivative was more than 100 μg/mL. The 3T3 cell was still able to survive without any sign of toxicity from the AzA derivative; thus, it was proven to be non-toxic in this MTT assay when compared with AzA.
Lectin-like cell adhesion molecule 1 mediates leukocyte rolling in mesenteric venules in vivo (1991)

During the inflammatory response, granulocytes and other leukocytes adhere to and emigrate from small venules. Before firm attachment, leukocytes are observed rolling slowly along the endothelium in venules of most tissues accessible to intravital microscopy. The molecular mechanism underlying this early type of leukocyte-endothelial interaction is unknown. Leukocyte rolling was investigated in venules (diameter, 40 microns) of the exposed rat mesentery. Micro-infusion of a recombinant soluble chimera (LEC-IgG) of the murine homing receptor lectin-like cell adhesion molecule 1 (LEC-CAM 1; gp90MEL) into individual venules reduced the number of rolling leukocytes by 89% +/- 2% (mean +/- SEM, n = 20 venules), while a similar CD4 chimera (CD4-IgG) had no effect (inhibition 14% +/- 7%, n = 25). Rolling was also greatly reduced by a polyclonal serum against LEC-CAM 1 (inhibition 84% +/- 3%, n = 35); preimmune serum was ineffective (11% +/- 13% inhibition, n = 28). These findings indicate that LEC-CAM 1 mediates the adhesive interaction underlying leukocyte rolling and thus may play an important role in inflammation and in pathologic conditions involving leukocytes.
A Flexible Platform for Biofeedback-Driven Control and Personalization of Electrical Nerve Stimulation Therapy (2014)

Electrical vagus nerve stimulation is a treatment alternative for many epileptic and depressed patients whose symptoms are not well managed with pharmaceutical therapy. However, the fixed stimulus, open loop dosing mechanism limits its efficacy and precludes major advances in the quality of therapy. A real-time, responsive form of vagus nerve stimulation is needed to control nerve activation according to therapeutic need. This personalized approach to therapy will improve efficacy and reduce the number and severity of side effects. We present autonomous neural control, a responsive, biofeedback-driven approach that uses the degree of measured nerve activation to control stimulus delivery. We demonstrate autonomous neural control in rats, showing that it rapidly learns how to most efficiently activate any desired proportion of vagal A, B, and/or C fibers over time. This system will maximize efficacy by minimizing patient response variability and by minimizing therapeutic failures resulting from longitudinal decreases in nerve activation with increasing durations of treatment. The value of autonomous neural control equally applies to other applications of electrical nerve stimulation.
Graphene and Metals: Interactions and Magnetism (2011)

Abstract not Available.
Determination of frequency and temperature dependent mechanical material properties by means of an Inverse Method (2013)

We present a method to determine the frequency as well as the temperature dependence of mechanical material parameters. In general, we apply a so-called Inverse Method that adapts simulation results to match the best possible measurements. The variable quantities within the simulation are the sought-after material parameters, namely the elasticity modulus, Poisson's ratio, and a damping factor. Measurements are carried out by applying forced mechanical vibrations over a wide frequency range from quasi static up to more than 5 kHz. In particular, an electromechanical shaker harmonically excites tensile or bending vibrations of clamped plates and cylindrically shaped specimens. Two Laser Doppler vibrometers measure the vibration right next to the clamping and at the free end of the specimen, yielding a frequency dependent transfer function by relating the two measurands. Since the experimental setup is built up within an environmental chamber, temperatures from -40 to 150C can be applied. Based on the experiment and the actual measuring points, a finite element (FE) analysis is performed to simulate the transfer function. Finally, the Inverse Method iteratively adapts the sought-after material parameters in such a convenient way that the simulated transfer function matches the measured one. The presented method was utilized to investigate the frequency and temperature dependence of different material classes: silicon rubber, plastics, metals, ceramics, and glass fibre reinforced plastics. In order to quantify and compare the dynamic material behaviour, functional relations of elasticity modulus/damping factor versus temperature are determined.
Violence and Poltical Incivility (2012)

The charge to our panel refers to "the deterioration of the political conversation," to "deep ... divisions in society," and to recent violence- especially the tragic events in Tuscon. It asks us to identify "the virtues required.for our common life as citizens in a democracy and for civil democratic conversation." I shall offer observations and conjectures on each issue, stressing the historical background.\nLet me suggest, first,. that the nonconstructive and increasingly abusive character of our political discourse may be relatively mild manifestations of an even more troubling malaise of our society- commonplace unlawful violence. I wish to draw your attention to a neglected aspect of that problem. When violence is addressed, we usually focus on practices that are condemned and targeted by public officials and fail to consider the illicit role that officials themselves have often played. A central feature of our civilization since the earliest colonial times has been unlawful violence that is tolerated, encouraged, or engaged in by public officials.\nLet us go back in time. Land and labor were the two great needs of early English colonists in mainland North America. Land was needed to accommodate increasing numbers of immigrants. Labor was mainly sought by those colonies, such as Virginia, that developed economies, and ultimately social systems, built upon the production and export of cash crops such as tobacco and cotton. The latter also created a demand for agricultural land.
Human Lactoferrin and Peptides Derived from a Surface-Exposed Helical Region Reduce ExperimentalEscherichia coliUrinary Tract Infection in Mice (2000)

Lactoferrin (LF) is a multifunctional immunoregulatory protein that has been associated with host defense at mucosal surfaces through its antibacterial properties. The antibacterial and anti-inflammatory properties of LF were further explored with an animal model of experimental urinary tract infection. Bovine LF (bLF), human LF (hLF), and synthetic peptide sequences based on the antibacterial region of hLF (amino acid residues 16 to 40 [HLD1] and 18 to 40 [HLD2]) were given orally to female mice 30 min after the instillation of 10(8) Escherichia coli bacteria into the urinary bladder. The control groups received phosphate-buffered saline or water. C3H/Tif mice were treated with hLF or bLF, and C3H/HeN mice were treated with bLF only. The numbers of bacteria in the kidneys and bladder of C3H/Tif and C3H/HeN mice were significantly reduced 24 h later by the LF treatments compared to the findings for the control group. The hLF-treated group showed the strongest reduction compared with the vehicle-treated-group (P values were 0.009 and 0.0001 for the kidneys and bladder, respectively). The urinary leukocyte response was diminished in the hLF-treated group. The hLF treatment also significantly reduced the urinary interleukin-6 (IL-6) levels at 2 h and the systemic IL-6 levels at 24 h after infection (P values were 0.04 and < 0.002, respectively). In the bLF-treated animals, no such strong anti-inflammatory effects were obtained. In another series of experiments, C3H/Tif mice perorally treated with HLD1 or HLD2 also showed reduced numbers of bacteria in the kidneys compared with the vehicle-treated mice, although the results were significantly different only for HLD2 (P < 0.01). Analysis of urine from hLF-fed C3H/Tif mice showed that hLF was excreted into the urinary tract at 2 h after feeding. Testing of the in vitro bactericidal activity of LF (1 mg/ml) or the peptides (0.1 mg/ml) in mouse urine against the E. coli bacteria revealed moderate killing only by HLD2. In conclusion, these results demonstrate for the first time that oral administration of hLF or peptides thereof is effective in reducing infection and inflammation at a remote site, the urinary tract, possibly through transfer of hLF or its peptides to the site of infection via renal secretion. The antibacterial mechanism is suggested to involve bactericidal capacities of LF, fragments thereof, or its peptides.
A bioengineering approach for rational vaccine design towards the Ebola Virus (2010)

Figure 1 (A) The trimeric Ebola Virus glycoprotein (silver) interacts with the light (orange) and heavy (green) chains of human antibody KZ52. Purple boxes indicate sites of interactions, all of which are identical. (B) The EBOV GP epitope (purple) interacts with antibody loops at GP slits. (C) Salt bridges stabilize epitope-antibody binding. Salt-bridge measurements from top to bottom are 3.41 , 2.77 , 3.24 , 3.35 , and 2.90 .
Development of a robotic system for orthodontic archwire bending (2016)

Customized archwires are demanded in the lingual orthodontic treatment for patients suffering from malocclusion. Traditionally, these archwires could only be bent by experienced orthodontists manually. This pattern requires a specialized skills training and occupies long charside time, but still cannot ensure the accuracy of appliances. Therefore, a novel robotic system was developed for automatic and accurate preparation in our study. First, the implementation of hardware system was designed. Second, a modular and ROS-integrated control system was developed to control automatic bending. Third, an adaptive sampling-based bending planner with collision checker in a time-varying environment was established and realized in control system architecture. Preliminary validation of the developed robot system and its control system have been conducted both in simulation and physical robotic system. Experimental results have shown that the developed robotic system with its ROS-integrated control system was able to accomplish automatic and accurate orthodontic archwire preparation.
Faculty Opinions recommendation of Extracellular calcium-sensing receptor mediates human bronchial epithelial wound repair. (2011)

The airway epithelium routinely undergoes damage that requires repair to restore epithelial barrier integrity. Cell migration followed by proliferation are necessary steps to achieve epithelial repair. Calcium-sensing receptor (CaSR) is implicated in cell migration and proliferation processes. Thus we hypothesized that CaSR mediates lung epithelial wound repair. We detected CaSR expression in human lung and in well-differentiated human bronchial epithelial cells (HBEC). To test the CaSR functionality, HBEC loaded with fura-2 were stimulated with extracellular Ca(2+) ([Ca(2+)](out)) which resulted in a concentration-dependent intracellular Ca(2+) ([Ca(2+)](i)) increase (potency approximately 5.6mM [Ca(2+)](out)). Furthermore, increasing [Ca(2+)](out) induced phosphorylation of the extracellular signal-regulated kinase (ERK1/2) which was blocked by siRNA-CaSR and the specific inhibitor of CaSR, NPS2390. Epithelial repair after mechanical injury of differentiated HBEC was a process dependent of [Ca(2+)](out) since it accelerated wound repair and HBEC proliferation being highest at 5mM [Ca(2+)](out). Furthermore, U73122 (an inhibitor of phospholipase C (PLC)) and PD 98059 (an inhibitor of ERK1/2) as well as siRNA-CaSR and NPS2390 partially inhibited wound repair and HBEC proliferation. On the other hand, mechanical injury produced an [Ca(2+)](i) wave propagation that was partially inhibited by siRNA-CaSR, NPS2390 and the extracellular Ca(2+) chelator EGTA, which suggest a link of CaSR between cell-cell communication and wound repair in differentiated HBEC. Our data, for the first time, shows that CaSR plays an important role in airway epithelial repair, which may help to develop novel regenerative therapeutics allowing the rapid repair of lung damaged epithelium.2010 Elsevier Inc. All rights reserved. PMID: 20381461