gebhart/patrepeval huggingface dataset:
Peptide environment specifies conformation. Helicity of hydrophobic segments compared in aqueous, organic, and membrane environments. (1993)

Transmembrane segments in integral membrane proteins exist characteristically as helices in lipid bilayers, yet are often rich in residues considered helix-destabilizing (Val, Ile, Gly) in soluble proteins. We propose that helicity of a transmembrane segment is likely to be affected by factors other than the "intrinsic" helical propensities of its component amino acids. This hypothesis is tested by comparing the conformation(s) in aqueous, organic, membrane-mimetic (micellar), and membrane (bilayer) environments of designed model peptides with systematically altered helical propensity and/or segmental hydrophobicity. Peptides of prototypic sequence NH2-(Ser-Lys)2-Ala5-Leu6-Ala7-Ala8-Leu9-Ala10-++ +Trp11-Ala12-Leu13-Ala14- (Lys-Ser)3-OH were synthesized, which incorporate a hydrophobic core "guest" segment (residues 5-14) into a water-soluble hydrophilic host matrix. Related peptides featured substitution of Leu6,9,13-->Gly, Leu6,9,13-->Ala, and Ala7,10,14-->Gly. Circular dichroism spectra revealed that algorithms for soluble proteins correctly predicted peptide helical proclivities in aqueous solutions, but peptide helicity in organic (trifluoroethanol) solvents, membrane-mimetic SDS micelles, and negatively charged lipid bilayer vesicles, was found to be governed almost exclusively by the segmental hydrophobicity of the peptide mid-hydrophobic core segment. In related Trp fluorescence studies, peptide-membrane association was similarly correlated with extent of hydrophobic interaction.
Efficient Virus-Induced Gene Silencing in Roots Using a Modified Tobacco Rattle Virus Vector (2004)

Due to their capability of eliciting a form of posttranscriptional gene silencing (termed virus-induced gene silencing or VIGS), plant viruses are increasingly used as reverse-genetics tools for functional characterization of plant genes. RNA viruses have been shown to trigger silencing in a variety of host plants, including members of Solanacae and Arabidopsis (Arabidopsis thaliana). Several factors affect the silencing response, including host range and viral tropism within the plant. The work presented here demonstrates that a modified tobacco rattle virus (TRV) vector retaining the helper protein 2b, required for transmission by a specific vector nematode, not only invades and replicates extensively in whole plants, including meristems, but also triggers a pervasive systemic VIGS response in the roots of Nicotiana benthamiana, Arabidopsis, and tomato (Lycopersicon esculentum). This sustained VIGS response was exemplified by the silencing of genes involved in root development (IRT1, TTG1 [transparent testa glabra], RHL1 [root hairless1], and beta-tubulin), lateral root-meristem function (RML1 [root meristemless1]), and nematode resistance (Mi). Roots of silenced plants exhibit reduced levels of target mRNA and phenocopy previously described mutant alleles. The TRV-2b vector displays increased infectivity and meristem invasion, both key requirements for efficient VIGS-based functional characterization of genes in root tissues. Our data suggest that the TRV helper protein 2b may have an essential role in the host regulatory mechanisms that control TRV invasion.
Rescuing AAV gene transfer from neutralizing antibodies with an IgG-degrading enzyme (2020)

Preexisting humoral immunity to recombinant adeno-associated virus (AAV) vectors restricts the treatable patient population and efficacy of human gene therapies. Approaches to clear neutralizing antibodies (NAbs), such as plasmapheresis and immunosuppression, are either ineffective or cause undesirable side effects. Here, we describe a clinically relevant strategy to rapidly and transiently degrade NAbs before AAV administration using an IgG-degrading enzyme (IdeZ). We demonstrate that recombinant IdeZ efficiently cleaved IgG in dog, monkey, and human antisera. Prophylactically administered IdeZ cleaved circulating human IgG in mice and prevented AAV neutralization in vivo. In macaques, a single intravenous dose of IdeZ rescued AAV transduction by transiently reversing seropositivity. Importantly, IdeZ efficiently cleaved NAbs and rescued AAV transduction in mice passively immunized with individual human donor sera representing a diverse population. Our antibody clearance approach presents a potentially new paradigm for expanding the prospective patient cohort and improving efficacy of AAV gene therapy.
Pharmacological effects of nicergoline and its metabolites, decomposition products and impurities in animals. (1987)

The main pharmacological effects and acute toxicity of nicergoline (NCG, ester type), its 5 metabolites [1-DN (ester type), 1-MMDL, 1-OHMMDL, MDL (ergoline-alcohol type) and 5-BNA (bromonicotinic acid)], 2 decomposition products (1-MMDL and 5-BNA) and 2 impurities [1-DN and 5-CN (ester type)] were studied in animals. In mice, the acute intraperitoneal toxicity of 1-MMDL, 1-OHMMDL and 5-CN was similar to that of NCG (LD50 197.6 mg/kg). The toxicity of 1-DN, MDL and 5-BNA was approximately 2-fold, 2- fold and one half of NCG, respectively. These substances caused no delayed death. In protective effects against KCN- and adrenaline-induced death in mice when given i.p., 1-DN and 1-MMDL were less potent than NCG, and 1-CN was similar in potency to NCG. In competitive inhibitory effects on phenylephrine-induced contraction of isolated guinea pig vas deferens, 1-DN was less potent, 1-MMDL was much less potent and 5-CN was more potent than NCG. In an inhibitory effect on collagen-induced platelet aggregation in vitro using rat platelet-rich plasma, 1-DN and 5-CN were similar in activity to NCG and 1-MMDL was less active than NCG. On the other hand, 1-OHMMDL, MDL and 5-BNA were inactive in these experiments. In experiments on gross behavior, motor function and barbital anesthesia using mice, when given i.p., 5-CN as well as NCG moderately induced depressive effects on the central nervous systems. 1-DN and 1-MMDL were less potent in the effects than NCG. In anesthetized rats, when given i.v., 1-DN and 5-CN dose-dependently caused lowering effects on blood pressure similar to NCG. 1-MMDL and 1-OHMMDL were less potent than NCG in the lowering effect. 1-DN and 5-CN moderately decreased the contractile force in the isolated guinea pig heart when given i.a. 5-CN alone decreased urine volume in rats when given i.p. and all the substances had no effect on the intestinal transit ability in mice when given i.p. These results suggest that the pharmacological effects of NCG are due to NCG per se and in part to its metabolites. As regards structure-activity relationships, NCG, 1-DN and 5-CN with an ester linkage were found to be more potent in pharmacological activities than ergoline-alcohol compounds.(ABSTRACT TRUNCATED AT 400 WORDS)
Restoration of the Unfolded Protein Response in Pancreatic β Cells Protects Mice Against Type 1 Diabetes (2013)

Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA's actions were dependent on ATF6 and were lost in mice with β cell-specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.
c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases (2020)

Alzheimer's Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.
Skin Color Correction for Tissue Spectroscopy: Demonstration of a Novel Approach with Tissue-Mimicking Phantoms (2005)

The application of partial least squares (PLS) regression to visible-near-infrared (VIS-NIR) spectroscopy for modeling important blood and tissue parameters is generally complicated by the variation in skin pigmentation (melanin) across the human population. An orthogonal correction method for removing the influence of skin pigmentation has been demonstrated in diffuse reflectance spectra from two-layer tissue-mimicking phantoms. The absorption properties of the phantoms were defined by lyophilized human hemoglobin (bottom layer) and synthetic melanin (top layer). Tissue-like scattering was simulated in both layers with intralipid. The approach uses principal components analysis (PCA) loading vectors from a separate set of phantom spectra that encode the unwanted melanin variation to remove the effect of melanin from the test phantoms. The preprocessing of phantom spectra using this orthogonal correction method resulted in PLS models with reduced complexity and enhanced prediction performance. Preliminary results from a separate study that evaluates the feasibility of defining skin color variation in an experiment with a single human subject are also presented.
A randomised controlled trial comparing GnRH antagonist Cetrorelix with GnRH agonist Leuprorelin for endometrial thinning prior to transcervical resection of endometrium (2008)

In dosages used, leuprorelin produced more consistent thinning of the endometrium as compared with cetrorelix, although this did not make any significant difference to operative or menstrual outcomes. The endometrial thinning effect with cetrorelix does appear to be more favourable than that seen at postmenstrual phase in other studies. The optimum (possibly higher) dosage of cetrorelix for this purpose has not yet been established.
Sequential Quadratic Method for GPS NLOS Positioning in Urban Canyon Environments (2013)

In this paper, the problem of GPS non-line-of-sight (NLOS) positioning in urban canyon environments is considered. We propose a new position-determination estimator based on sequential quadratic programming (SQP) that is able to estimate and eliminate the path-delay error caused by the indirect transmission of the GPS signal. The estimator takes into account the measurement bias resulting from NLOS transmission and also improves the location accuracy of the satellite positioning system. The present method can effectively eliminate NLOS delay errors and improves the location accuracy of a satellite navigation receiver in an urban canyon environment. A Wilcoxon-norm-based regressor is further derived to improve the probability of detection of NLOS biases. The Wilcoxon regressor is a robust estimator that is well-suited to identifying outliers (in our case, NLOS biases) during the regression process. Experimental results demonstrate that the proposed estimator can accurately compute a user’s location after identifying and removing the measurement biases.
Internalization of the TXA2 Receptor α and β Isoforms (1999)

Thromboxane A2 (TXA2) potently stimulates platelet aggregation and smooth muscle constriction and is thought to play a role in myocardial infarction, atherosclerosis, and bronchial asthma. The TXA2 receptor (TXA2R) is a member of the G protein-coupled receptor family and is found as two alternatively spliced isoforms, alpha (343 residues) and beta (407 residues), which share the first 328 residues. In the present report, we demonstrate by enzyme-linked immunosorbent assay and immunofluorescence microscopy that the TXA2Rbeta, but not the TXA2Ralpha, undergoes agonist-induced internalization when expressed in HEK293 cells as well as several other cell types. Various dominant negative mutants were used to demonstrate that the internalization of the TXA2Rbeta is dynamin-, GRK-, and arrestin-dependent in HEK293 cells, suggesting the involvement of receptor phosphorylation and clathrin-coated pits in this process. Interestingly, the agonist-stimulated internalization of both the alpha and beta isoforms, but not of a mutant truncated after residue 328, can be promoted by overexpression of arrestin-3, identifying the C-tails of both receptors as necessary in arrestin-3 interaction. Simultaneous mutation of two dileucine motifs in the C-tail of TXA2Rbeta did not affect agonist-promoted internalization. Analysis of various C-tail deletion mutants revealed that a region between residues 355 and 366 of the TXA2Rbeta is essential for agonist-promoted internalization. These data demonstrate that alternative splicing of the TXA2R plays a critical role in regulating arrestin binding and subsequent receptor internalization.
Spooky action achieved at record distance (2017)

Entangled photons from Chinese satellite foreshadow space-based quantum network.
SpaceTokens (2018)

Map users often need to interact repetitively with multiple important locations. For example, a traveler may frequently check her hotel or a train station on a map, use them to localize an unknown location, or investigate routes involving them. Ironically, these location-centric tasks cannot be performed using locations directly; users must instead pan and zoom the map or use a menu to access locations. We propose SpaceTokens, interactive widgets that act as clones of locations, and which users can create and place on map edges like virtual whiteboard magnets. SpaceTokens make location a first-class citizen of map interaction. They empower users to rapidly perform location-centric tasks directly using locations: users can select combinations of on-screen locations and SpaceTokens to control the map window, or connect them to create routes. Participants in a study overwhelmingly preferred a SpaceTokens prototype over Google Maps on identical smartphones for the majority of tasks.
Nucleophilic Substitution on (Pentafluorophenyl)dipyrromethane: A New Route to Building Blocks for Functionalized BODIPYs and Tetrapyrroles (2015)

The reaction of alcohols with (pentafluorophenyl)dipyrromethane (PFP-DPM) under basic conditions has been studied, giving access to the corresponding alkoxy-substituted DPMs. This method represents the first high-yielding substitution of PFP-DPM carried out with oxygen nucleophiles. Condensation of these prefunctionalized DPMs with aldehydes led to the respective trans-A2B2 porphyrins. This pathway allows a simple synthesis of multifunctionalized tetrapyrroles. Oxidation and boron complexation of these DPMs, on the other hand, led to meso-functionalized difluoroboraindacenes (BODIPYs). In addition, nucleophilic substitution of PFP-BODIPY with sodium azide led to a 4-azidophenyl derivative, thus further enhancing the scope of reactive sites suitable for subsequent transformations.
Human herpesvirus 6 and multiple sclerosis: A study of t cell cross‐reactivity to viral and myelin basic protein antigens (2002)

Several reports have suggested an association of human herpesvirus 6 (HHV-6) with multiple sclerosis. Autoreactive T lymphocytes directed against myelin components seem to contribute to the pathogenesis of the disease. It has been suggested that molecular mimicry between viral and self-antigens might be one of the mechanisms that determine the onset of several autoimmune diseases. Following this hypothesis, the purpose of the present study was to evaluate if HHV-6 could play a role in activating T cells capable of cross-reaction with an important myelin component, the myelin basic protein. T cell lines were established from 22 multiple sclerosis patients and from 16 healthy controls, and their capability to react to both virus and myelin basic protein antigens was compared. The analysis of T cell cross-reactivity in patients and controls did not show significant differences in the HHV-6 ability to activate myelin basic protein-reactive T cells. Similarly, the evaluation of the humoral immune response to HHV-6 in patients and controls did not mirror any abnormality in the HHV-6 status in multiple sclerosis patients. Therefore, although the findings of activity in vitro of T cell lines with dual specificity are consistent with the hypothesis of molecular mimicry, the lack of differences in cross-reactivity between patients and controls do not support molecular mimicry as an important mechanism in the physiopathology of this disease.
Fabrication Process of Microsurgical Tools for Single-Cell Trapping and Intracytoplasmic Injection (2004)

We introduce chemical etching-based processes for fabricating micromanipulators from fused silica microcapillary tubing. The resulting devices are capable of manipulating individual cells and can be used for intracytoplasmic injection. Two types of micromanipulating tools: single-cell trappers and micro-injectors, were fabricated with two single-step etching processes. These etching mechanisms, which are either surface tension controlled or diffusion rate limited, are discussed in detail with experimental verifications. The fabrication processes are reproducible and amenable to mass production due to their simplicity and low fabrication cost. Single cell capture and intracytoplasmic injection have been successfully demonstrated on brassica oleracea protoplasts.
Experiences with using Data Cleaning Technology for Bing Services. (2012)

Over the past few years, our Data Management, Exploration and Mining (DMX) group at Microsoft Research has worked closely with the Bing team to address challenging data cleaning and approximate matching problems. In this article we describe some of the key Big Data challenges in the context of these Bing services primarily focusing on two key services: Bing Maps and Bing Shopping. We describe ideas that proved crucial in helping meet the quality, performance and scalability goals demanded by these services. We also briefly reflect on the lessons learned and comment on opportunities for future work in data cleaning technology for Big Data.
The Total Synthesis of Herbimycin A (1992)

Abstract The first total synthesis of herbimycin A (1), the benzoquinonoid ansamycin antibiotic, is described. (2E,4S,5R,6S,8S)-5,6-Dimethoxy-9-(4-methoxybenzyl)oxy-2,4,8-trimethyl-2-nonenal (40), corresponding to the C7–C15 portion of the ansa-chain of 1, was prepared from methyl 3,4-anhydro-2-deoxy-2-C-methyl-6-O-(triphenylmethyl)-α-d-altropyranoside (16), which had been previously prepared from methyl α-d-mannopyranoside according to our developed procedure, by using a regioselective epoxide opening [bis(1,2-dimethylpropyl)borane–NaBH4] and a stereoselective hydroboration (BH3·SMe2) as the key steps. This aldehyde 40 was subjected to the Brown’s diastereo- and enantioselective allylation conditions [[(Z)-3-methoxyallyl]diisopinocampheylborane] to afford the desired syn 3-methoxy-1,5-dodecadien-4-ol derivative. Subsequent three-step conversion of this alcohol furnished the synthesis of the C5–C15 ansa-chain aldehyde, (2S,4S,5R,6S,7E,9S,10S)-9-[(t-butyldimethylsilyl)oxy]-4,5,10-trimethoxy-2,6,8-trimethyl-7,11-dodecadienal (7). Union of 7 and the lithiated aromatic chromophore, prepared from N-(triphenylmethyl)-3-bromo-2,5-dimethoxyaniline and butyllithium, provided the coupling product, which was transformed to herbimycin A (1) through elongation of the C1–C4 carbon unit and macrolactamization. This fully enantiospecific synthesis elucidates the absolute stereochemistry of 1.
Perspectives on Bioenergy and Biotechnology in Brazil (2005)

Brazil is one of the world’s largest producers of alcohol from biomass at low cost and is responsible for more than 1 million direct jobs. In 1973, the Brazilian Program of Alcohol (Proalcool) stimulated the creation of a bioethanol industry that has led to large economic, social, and scientific improvements. In the year 1984, 94.5% of Brazil’s cars used bioethanol as fuel. In 2003/2004, 350.3 million of sugarcane produced 24.2 million t of sugar and 14.4 billion L of ethanol for an average 4.3 million cars using ethanol. Since its inception, cumulative investment in Proalcool totals US$11 billion, and Brazil has saved US$27 billion in oil imports. The ethanol production industry from sugarcane generates 152 times more jobs than would have been the case if the same amount of fuel was produced from petroleum, and the use of ethanol as a fuel is advantageous for environmental reasons. In 2003, one of the biggest Brazilian ethanol industries started consuming 50% of the residual sugarcane bagasse to produce electrical energy (60 MW), a new alternative use of bioenergy for the Brazilian market. Other technologies for commercial uses of bagasse are in development, such as in the production of natural fibers, sweeteners (glucose and xylitol), single-cell proteins, lactic acid, microbial enzymes, and many other products based on fermentations (submerged and semisolid). Furthermore, studies aimed at the increase in the biosynthesis of sucrose and, consequently, ethanol productivity are being conducted to understand the genetics of sugarcane. Although, at present, there remain technical obstacles to the economic use of some ethanol industry residues, several research projects have been carried out and useful data generated. Efficient utilization of ethanol industry residues has created new opportunities for new value-added products, especially in Brazil, where they are produced in high quantities.
Subspace-Based Learning for Automatic Dysarthric Speech Detection (2020)

To assist the clinical diagnosis and treatment of speech dysarthria, automatic dysarthric speech detection techniques providing reliable and cost-effective assessment are indispensable. Based on clinical evidence on spectro-temporal distortions associated with dysarthric speech, we propose to automatically discriminate between healthy and dysarthric speakers exploiting spectro-temporal subspaces of speech. Spectro-temporal subspaces are extracted using singular value decomposition, and dysarthric speech detection is achieved by applying a subspace-based discriminant analysis. Experimental results on databases of healthy and dysarthric speakers for different languages and pathologies show that the proposed subspace-based approach using temporal subspaces is more advantageous than using spectral subspaces, also outperforming several state-of-the-art automatic dysarthric speech detection techniques.