gebhart/patrepeval huggingface dataset:
Biological and systematic implications of phylogenetic analysis of ~ 2,800 full length small subunit ribosomal DNA sequences (2014)

As compared to other ancient and basal Ecdysozoan phyla such as the Nematomorpha (~ 350 known species), the Priapulida (~16 species) and the Kinorhyncha (~180 species), the phylum Nematoda stands out for being speciose (~ 27,000 described species), highly abundant, and widespread in nearly all terrestrial, freshwater and marine habitats. We will present results of phylogenetic analyses of approximately 10% of the described nematode biodiversity (~ 2,800 taxa; with underrepresentation of marine and tropical terrestrial species). We have tried multiple genes for phylogenetic reconstruction but so far the small subunit of the ribosomal DNA (~ 1,700 bp) is the only gene that could easily be amplified and aligned for a wide range of nematode species. The resulting alignment including secondary structure information was analysed on the CIPRES Science Gateway (San Diego, USA), using RAxML, a maximum likelihood-based inference for large phylogenetic trees, and Bayesian inference, and the outcome of both analyses will be presented. Some relevant features of the resulting phylogenetic trees will be discussed, and attention will be paid as to whether or not such a single gene tree does provide us with useful information about organismal relationships. This talk will also be used to describe the positioning and the relationships between the nematode taxa that will be discussed in more detail in Theme 2: Morphology, taxonomy, phylogeny and classification.
Targeted Mutagenesis in Arabidopsis Using Zinc-Finger Nucleases (2010)

We report here an efficient method for making targeted mutations in Arabidopsis thaliana genes. The approach uses zinc-finger nucleases (ZFNs) - enzymes engineered to create DNA double-strand breaks at specific target loci. Imprecise repair of double-strand breaks by nonhomologous end-joining generates small insertions or deletions at the cleavage site. In this protocol, constructs encoding ZFNs for specific loci are transformed into Arabidopsis by Agrobacterium-mediated transformation. ZFN expression is induced during germination to initiate mutagenesis of the target locus. Typically, more than 20% of the primary transgenics segregate loss-of-function mutations in the next generation. ZFNs make it possible to expand the range of Arabidopsis mutants available for study and to create mutations in genes missed by random mutagenesis approaches, such as those using T-DNA, transposons, or chemical mutagens.
Two-dimensional proton nuclear magnetic resonance investigation of the synthetic deoxyribonucleic acid decamer d(ATATCGATAT) (1983)

In this study two-dimensional NMR techniques (COSY and NOESY) have been used in conjunction with one-dimensional NMR results to complete the assignment of the proton NMR spectrum of the double-stranded DNA decamer, d(ATATCGATAT)2, and to obtain qualitative information about numerous interproton distances in this molecule and some limited information about conformational dynamics. COSY and NOESY measurements have been combined to systematically assign many of the resonances from the H1' and H2',2" sugar protons to specific nucleotides in the double helix. This method relies on the fact that sugar protons within a specific nucleotide are scalar coupled and that base protons (AH8, GH8, TH6, and CH6) in right-handed helices can interact simultaneously with their own H2',2" sugar protons and those of the adjacent (5'-3') nucleotide attached to its 5' side (i.e., XpA not ApX). A COSY experiment is used to identify sugar resonances within a residue whereas the NOESY experiment allows the neighboring sugar to be connected (linked). The CH5 and CH6 resonances in the spectrum can immediately be identified by the COSY experiment. The methyl protons of thymine residues exhibit strong through-space interbase interactions both with their own TH6 proton and with AH8 proton on the adjacent (5'-3') adenine residue. These interactions are used both to make assignments of the spectra and to establish that the thymine methyl groups are in close proximity to the AH8 protons of adjacent adenine residues [Feigon, J., Wright, J. M., Leupin, W., Denny, W. A., & Kearns, D. R. (1982) J. Am. Chem. Soc. 104, 5540].(ABSTRACT TRUNCATED AT 250 WORDS)
Polymorphism of the beta 3-adrenergic receptor gene in morbid obesity. (1996)

Our data do not support a significant role for the codon 64 polymorphism of the beta 3-adrenergic receptor as a genetic marker of morbid obesity. Although there was an association between the Arg64 allele and an earlier onset of obesity in individuals subsequently developing morbid obesity, this allele was not associated with the actual BMI gained or response to weight-loss therapy on a hypocaloric diet.
Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression (2004)

The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl--coupled betaine/gamma-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function.
MAPDP: A Cloud-Based Computational Platform for Immunopeptidomics Analyses (2020)

The immunopeptidome corresponds to the repertoire of peptides presented at the cell surface by the major histocompatibility complex (MHC) molecules. Cytotoxic T cells scan this repertoire to identify nonself antigens that can arise from tumors or infected cells. The identification of actionable antigenic targets is key to the development of therapeutic cancer vaccines, T-cell therapy, and other T-cell receptor-based biologics. The growing clinical interest for immunopeptidomics has accelerated the development of high throughput proteogenomic platforms that provide a system-level analysis of MHC-associated peptides. Improvement in sensitivity and throughput of mass spectrometers now allows the detection of a few thousands of peptides from less than 100 million cells. To manage the amount of data generated by these instruments, we have developed the MHC-associated peptide discovery platform (MAPDP), a novel open-source cloud-based computational platform for immunopeptidomic analyses. It provides convenient access from a web portal to immunopeptidomes stored in the database, filtering tools, various visualizations, annotations (e.g., IEDB, dbSNP, gnomAD), peptide-binding affinity prediction (mhcflurry, NetMHC), HLA genotyping, and the generation of personalized proteome databases. MAPDP functionalities are demonstrated here by the discovery of MHC peptides featuring new genetic variants identified in two previously published ovarian carcinoma data sets.
Figure S3 from Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs (2023)

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And then there were none (2012)

Programmers are turning to radical architectures such as reconfigurable hardware (FPGAs) to achieve performance. But such systems, programmed at a very low level in languages with impoverished abstractions, are orders of magnitude more complex to use than conventional CPUs. The continued exponential increase in transistors, combined with the desire to implement ever more sophisticated algorithms, makes it imperative that such systems be programmed at much higher levels of abstraction. One of the fundamental high-level language features is automatic memory management in the form of garbage collection.
Buckling and layering transitions in confined colloids (2009)

We report layering transitions within a charged silica colloidal dispersion confined by two opposite like-charged dielectric walls. The ensemble-averaged concentration profiles of the colloids (radius 60±2 nm) along the confinement direction have been determined using synchrotron X-ray diffraction from microfluidic arrays of channels of different widths. For small channel widths up to a critical value of 300 nm, the channel can accommodate just one layer of colloids which is stabilized against buckling by the confining charged walls. For channel widths larger than this critical value, a buckling of the single layer is observed. These phenomena are explained using a theoretical analysis of buckling instabilities due to Chou and Nelson, and a value for the charge density on the stabilizing charged walls is derived. At still larger channel widths a sequence of complex layering transitions is observed which involve the splitting and merging of individual layers.
Oligopeptide patterns produced from Theobroma cacao L of various genetic origins (2002)

Abstract Acetone dry powder (AcDP) was prepared for six cocoa genotypes, namely Forastero (Amelonado type), Criollo, Trinitario, SCA 12, UIT1 and PBC 140. Hydrophobic oligopeptides were produced when autolysis of AcDP was carried out at pH 3.5. Comparative HPLC analysis showed that autolysis of AcDP from various genotypes revealed a similar pattern of oligopeptides. Most of the hydrophobic oligopeptides were not generated during autolysis of AcDP in the presence of protease inhibitor (Pepstatin A), indicating that the generation of these oligopeptides was due to the action of cocoa cotyledon aspartic endoprotease. This finding implies that the splitting action of aspartic endoprotease on vicilin (7S)‐class globulin (VCG) from various genotypes was the same. The information from the study provides additional evidence that there are no obvious differences in VCG composition between various genotypes. © 2002 Society of Chemical Industry
Cytokines alter target cell susceptibility to lysis: I. Evaluation of non-major histocompatibility complex-restricted effectors reveals differential effects on natural and lymphokine-activated killing. (1990)

Interferon-gamma (IFN) and tumor necrosis factor-alpha (TNF) were examined for their ability to enhance major histocompatibility complex (MHC) expression on a variety of human tumor and normal tissue targets. Enhanced expression of MHC correlated with decreased target susceptibility to lysis by fresh peripheral blood mononuclear cells (PBMCs) and IL-2-augmented PBMCs (aPBL) but not as clearly with cells with lymphokine-activated killer (LAK) activity. These studies revealed maximal MHC enhancement after 48-72 h of incubation in IFN. Resistance to lysis by natural killer (NK) cells was best demonstrated after 72 h. Further, IFN and TNF were synergistic in their effects on MHC expression and induction of resistance of the cultured leukemias K562 and Molt-4 to aPBL effectors. Conversely, LAK susceptibility was usually unaltered after target IFN and TNF treatment. Incubation of fibroblasts and vascular endothelial cells with IFN also consistently resulted in MHC class I enhancement and resistance to NK lysis, whereas LAK susceptibility was variably affected. The brief incubation of fresh PBL in IL-2 (4-6 h) resulted in effectors highly lytic toward cultured cells, but with no activity against fresh tumor. Cultured cell lines treated with IFN and TNF were rendered relatively resistant to lysis by these activated cells. Fresh tumor MHC expression and LAK susceptibility was unchanged after IFN incubation. Additionally, there was no correlation between the level of MHC class I or class II expression and LAK susceptibility to any fresh, uncultured melanoma studied. These data suggest that LAK effectors possess different mechanisms of tumor recognition or lysis than cells with NK activity or cells briefly incubated (4-6 h) in IL-2. The ability of tumor-infiltrating lymphocytes to lyse the cultured autologous tumor target was markedly increased by preincubation of the targets with IFN and TNF. Finally, it appears that IL-2 treatment and the resultant endogenous production of IFN by T-lymphocytes should not adversely affect tumor susceptibility to current immunotherapy using IL-2.
Engineering the substrate specificity of rhizopuspepsin: The role of Asp 77 of fungal aspartic proteinases in facilitating the cleavage of oligopeptide substrates with lysine in P1 (1995)

Rhizopuspepsin and other fungal aspartic proteinases are distinct from the mammalian enzymes in that they are able to cleave substrates with lysine in the P1 position. Sequence and structural comparisons suggest that two aspartic acid residues, Asp 30 and Asp 77 (pig pepsin numbering), may be responsible for generating this unique specificity. Asp 30 and Asp 77 were changed to the corresponding residues in porcine pepsin, Ile 30 and Thr 77, to create single and double mutants. The zymogen forms of the wild-type and mutant enzymes were overexpressed in Escherichia coli as inclusion bodies. Following solubilization, denaturation, refolding, activation, and purification to homogeneity, structural and kinetic comparisons were made. The mutant enzymes exhibited a high degree of structural similarity to the wild-type recombinant protein and a native isozyme. The catalytic activities of the recombinant proteins were analyzed with chromogenic substrates containing lysine in the P1, P2, or P3 positions. Mutation of Asp 77 resulted in a loss of 7 kcal mol-1 of transition-state stabilization energy in the hydrolysis of the substrate containing lysine in P1. An inhibitor containing the positively charged P1-lysine side chain inhibited only the enzymes containing Asp 77. Inhibition of the Asp 77 mutants of rhizopuspepsin and several mammalian enzymes was restored upon acetylation of the lysine side chain. These results suggest that an exploitation of the specific electrostatic interaction of Asp 77 in the active site of fungal enzymes may lead to the design of compounds that preferentially inhibit a variety of related Candida proteinases in immunocompromised patients.
Secure lightweight ECC-based protocol for multi-agent IoT systems (2017)

The rapid increase of connected devices and the major advances in information and communication technologies have led to great emergence in the Internet of Things (IoT). IoT devices require software adaptation as they are in continuous transition. Multi-agent based solutions offer adaptable composition for IoT systems. Mobile agents can also be used to enable interoperability and global intelligence with smart objects in the Internet of Things. The use of agents carrying personal data and the rapid increasing number of connected IoT devices require the use of security protocols to secure the user data. Elliptic Curve Cryptography (ECC) Algorithm has emerged as an attractive and efficient public-key cryptosystem. We recommend the use of ECC in the proposed Broadcast based Secure Mobile Agent Protocol (BROSMAP) which is one of the most secure protocols that provides confidentiality, authentication, authorization, accountability, integrity and non-repudiation. We provide a methodology to improve BROSMAP to fulfill the needs of Multi-agent based IoT Systems in general. The new BROSMAP performs better than its predecessor and provides the same security requirements. We have formally verified ECC-BROSMAP using Scyther and compared it with BROSMAP in terms of execution time and computational cost. The effect of varying the key size on BROSMAP is also presented. A new ECC-based BROSMAP takes half the time of Rivest-Shamir-Adleman (RSA) 2048 BROSMAP and 4 times better than its equivalent RSA 3072 version. The computational cost was found in favor of ECC-BROSMAP which is more efficient by a factor of 561 as compared to the RSA-BROSMAP.
Selective mGlu 1 Potentiation Reverses Cortical Disinhibition and Schizophrenia‐like Social and Cognitive Deficits (2022)

There is a critical need to develop novel therapeutic strategies for addressing the negative and cognitive symptom domains in schizophrenia (SCZ). Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive and social behavioral deficits in SCZ patients. Recently, we demonstrated that activation of the mGlu 1 subtype of metabotropic glutamate receptor increases inhibitory transmission in the PFC by selective excitation of somatostatin‐expressing GABA interneurons. Genetic studies in humans reveal an association between deleterious non‐synonymous single nucleotide polymorphisms (nsSNPS) in of the human gene encoding mGlu 1 ( GRM1) and SCZ, raising the possibility that mGlu 1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder. Here, we examine whether novel positive allosteric modulators (PAMs) selective for mGlu 1 reverse electrophysiological effects and behavioral deficits in an MK‐801‐induced animal model of SCZ. We used ex vivo whole‐cell patch‐clamp electrophysiology to show that MK‐801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC, and this cortical disinhibition was reversed by mGlu 1 activation. Furthermore, acute MK‐801 treatment induces inhibitory deficits onto PFC‐basolateral amygdala (BLA), but not PFC‐nucleus accumbens, projecting layer V pyramidal cells that can be reversed by selective mGlu 1 activation. PFC‐BLA projections are known to contribute functionally to social‐approach behavior, while the BLA plays a critical role in object recognition and cognition broadly. We found that the mGlu 1 PAM VU6004909 effectively reversed MK801‐induced deficits in social interaction and social novelty preference in a three‐chamber assay. Additionally, VU6004909 restored novel object recognition following MK‐801 treatment. In combination with our previous reports that mGlu 1 PAMs reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence for mGlu 1 PAMs as a promising novel approach for the treatment of social and cognitive deficits in SCZ patients.
Heat Transfer Coefficients on the Squealer Tip and Near-Tip Regions of a Gas Turbine Blade With Single or Double Squealer (2003)

Detailed heat transfer coefficient distributions on a gas turbine squealer tip blade were measured using a hue detection based transient liquid-crystals technique. The heat transfer coefficients on the shroud and near tip regions of the pressure and suction sides of a blade were also measured. Squealer rims were located along (a) the camber line, (b) the pressure side, (c) the suction side, (d) the pressure and suction sides, (e) the camber line and the pressure side, and (f) the camber line and the suction side, respectively. Tests were performed on a five-bladed linear cascade with a blow down facility. The Reynolds number based on the cascade exit velocity and the axial chord length of a blade was 1.1×106 and the overall pressure ratio was 1.2. Heat transfer measurements were taken at the three tip gap clearances of 1.0%, 1.5%, and 2.5% of blade span. Results show that the heat transfer coefficients on the blade tip and the shroud were significantly reduced by using a squealer tip blade. Results also showed that a different squealer geometry arrangement changed the leakage flow path and resulted in different heat transfer coefficient distributions. The suction side squealer tip provided the lowest heat transfer coefficient on the blade tip and near tip regions compared to the other squealer geometry arrangements.
Collaborative assessment of molecular geometries and energies from the Open Force Field (2022)

Force fields form the basis for classical molecular simulations and their accuracy is crucial for the quality of, for instance, protein-ligand binding simulations in drug discovery. The huge diversity of small molecule chemistry makes it a challenge to build and parameterize a suitable force field. The Open Force Field Initiative is a combined industry and academic consortium developing a state-of-the-art small molecule force field. In this report industry members of the consortium worked together to objectively evaluate the performance of the force fields (referred to here as OpenFF) produced by the initiative on a combined public and proprietary dataset of 19,653 relevant molecules selected from their internal research and compound collections. This evaluation was important because it was completely blind; at most partners, none of the molecules or data were used in force field development or testing prior to this work. We compare the Open Force Field "Sage" version 2.0.0 and "Parsley" version 1.3.0 with GAFF-2.11-AM1BCC, OPLS4 and SMIRNOFF99Frosst. We analyzed force field-optimized geometries and conformer energies compared to reference quantum mechanical data. We show that OPLS4 performs best, and the latest Open Force Field release shows a clear improvement compared to its predecessors. The performance of established force fields such as GAFF-2.11 was generally worse. While OpenFF researchers were involved in building the benchmarking infrastructure used in this work, benchmarking was done entirely in-house within industrial organizations and the resulting assessment is reported here. This work assesses the force field performance using separate benchmarking steps, external datasets, and involving external research groups. This effort may also be unique in terms of the number of different industrial partners involved, with 10 different companies participating in the benchmark efforts.
Workers Whose Employment Is Not Confined to England and Wales (2022)

Abstract This chapter considers whistleblowing claims with an extraterritorial element. It first addresses the forum (the jurisdiction of the tribunal in terms of international rules of jurisdiction), including the provision introduced in section 15C Civil Jurisdiction and Judgments Act 1982 (as amended to take account of Brexit). It then considers the applicable law, before turning to the territorial scope of the relevant legislation in sections 47B and 103A ERA. There is distinct consideration of the position as against the employer, and the principles applicable to claims against a co-worker or agent in the light of the leading guidance in FCO v Bamieh [2019] EWCA Civ 803, [2020] ICR 465.
Achieving precision in high density batch mode micro-electro-discharge machining (2007)

This paper reports a parametric study of batch mode micro-electro-discharge machining (EDM) of high density features in stainless steel. Lithographically fabricated copper tools with single cross, parallel line and 8 8 circle/square array features of 5-100 m width and 5-75 m spacing were used to quantify trends in machining tolerance and the impact of debris accumulation. As the tool feature density is increased, debris accumulation effects begin to dominate, eventually degrading both tool and workpiece. Two independent techniques for mitigating this debris buildup are separately investigated. The first is a passivation coating which suppresses spurious discharges triggered from the sidewalls of the machining tool. By this method, the mean tool wear rate decreases from a typical of about 34% to 1.7% and machining non-uniformity reduces from 4.9 m to 1.1 m across the workpiece. The second technique involves a two-step machining process that enhances the hydrodynamic removal of machining debris compared to standard methods. This improves surface and edge finish, machining time and tool wear.