gebhart/patrepeval huggingface dataset:
Characterization of the copper(II) and nickel(II) transport site of human serum albumin. Studies of copper(II) and nickel(II) binding to peptide 1-24 of human serum albumin by carbon-13 and proton NMR spectroscopy (1984)

As a basis for understanding the role of albumin in the transport of metal ions, detailed investigations have been carried out to elucidate the structure of Ni(II)- and Cu(II)-binding site of the peptide residue corresponding to the NH2-terminal peptide fragment 1-24 of human serum albumin by 1H and 13C NMR spectroscopy. These studies have been conducted in aqueous medium at different pH values and at different ligand/metal ratios. The results show the following: (i) Diamagnetic Ni(II) complex and paramagnetic Cu(II) complex are in slow exchange NMR time scale. (ii) Titration results of Ni(II)-bound form of peptide 1-24 show the presence of a 1:1 complex in the wide pH range (6.0-11.0), and the same stoichiometry is proposed for Cu(II) as well. (iii) Analysis of the spectra suggests that both Ni(II) and Cu(II) have one specific binding site at the NH2-terminal tripeptide segment (Asp-Ala-His...) involving the Asp alpha-NH2, His N(1) imidazole, two deprotonated peptide nitrogens (Ala NH and His NH), and the Asp COO- group. (iv) Complexation of Ni(II) and Cu(II) causes conformational change near the metal-binding site of the polypeptide chain, but there is no other binding group involved besides those in the first three residues.
Distinct Machinery Is Required in Saccharomyces cerevisiae for the Endoplasmic Reticulum-associated Degradation of a Multispanning Membrane Protein and a Soluble Luminal Protein (2004)

The folding and assembly of proteins in the endoplasmic reticulum (ER) lumen and membrane are monitored by ER quality control. Misfolded or unassembled proteins are retained in the ER and, if they cannot fold or assemble correctly, ultimately undergo ER-associated degradation (ERAD) mediated by the ubiquitin-proteasome system. Whereas luminal and integral membrane ERAD substrates both require the proteasome for their degradation, the ER quality control machinery for these two classes of proteins likely differs because of their distinct topologies. Here we establish the requirements for the ERAD of Ste6p*, a multispanning membrane protein with a cytosolic mutation, and compare them with those for mutant form of carboxypeptidase Y (CPY*), a soluble luminal protein. We show that turnover of Ste6p* is dependent on the ubiquitin-protein isopeptide ligase Doa10p and is largely independent of the ubiquitin-protein isopeptide ligase Hrd1p/Der3p, whereas the opposite is true for CPY*. Furthermore, the cytosolic Hsp70 chaperone Ssa1p and the Hsp40 co-chaperones Ydj1p and Hlj1p are important in ERAD of Ste6p*, whereas the ER luminal chaperone Kar2p is dispensable, again opposite their roles in CPY* turnover. Finally, degradation of Ste6p*, unlike CPY*, does not appear to require the Sec61p translocon pore but, like CPY*, could depend on the Sec61p homologue Ssh1p. The ERAD pathways for Ste6p* and CPY* converge at a post-ubiquitination, pre-proteasome step, as both require the ATPase Cdc48p. Our results demonstrate that ERAD of Ste6p* employs distinct machinery from that of the soluble luminal substrate CPY* and that Ste6p* is a valuable model substrate to dissect the cellular machinery required for the ERAD of multispanning membrane proteins with a cytosolic mutation.
Control of Fingertip Forces in Multidigit Manipulation (1999)

Previous studies of control of fingertip forces in skilled manipulation have focused on tasks involving two digits, typically the thumb and index finger. Here we examine control of fingertip actions in a multidigit task in which subjects lifted an object using unimanual and bimanual grasps engaging the tips of the thumb and two fingers. The grasps resembled those used when lifting a cylindrical object from above; the two fingers were some 4.25 cm apart and the thumb was approximately 5.54 cm from either finger. The three-dimensional forces and torques applied by each digit and the digit contact positions were measured along with the position and orientation of the object. The vertical forces applied tangential to the grasp surfaces to lift the object were synchronized across the digits, and the contribution by each digit to the total vertical force reflected intrinsic object properties (geometric relationship between the object's center of mass and the grasped surfaces). Subjects often applied small torques tangential to the grasped surfaces even though the object could have been lifted without such torques. The normal forces generated by each digit increased in parallel with the local tangential load (force and torque), providing an adequate safety margin against slips at each digit. In the present task, the orientations of the force vectors applied by the separate digits were not fully constrained and therefore the motor controller had to choose from a number of possible solutions. Our findings suggest that subjects attempt to minimize (or at least reduce) fingertip forces while at the same time ensure that grasp stability is preserved. Subjects also avoid horizontal tangential forces, even at a small cost in total force. Moreover, there were subtle actions exerted by the digits that included changes in the distribution of vertical forces across digits and slight object tilt. It is not clear to what extent the brain explicitly controlled these actions, but they could serve, for instance, to keep tangential torques small and to compensate for variations in digit contact positions. In conclusion, we have shown that when lifting an object with a three-digit grip, the coordination of fingertip forces, in many respects, matches what has been documented previously for two-digit grasping. At the same time, our study reveals novel aspects of force control that emerge only in multidigit manipulative tasks.
Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases (2010)

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 A resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 A resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.
MorphNet: Fast & Simple Resource-Constrained Structure Learning of Deep Networks (2018)

We present MorphNet, an approach to automate the design of neural network structures. MorphNet iteratively shrinks and expands a network, shrinking via a resource-weighted sparsifying regularizer on activations and expanding via a uniform multiplicative factor on all layers. In contrast to previous approaches, our method is scalable to large networks, adaptable to specific resource constraints (e.g. the number of floating-point operations per inference), and capable of increasing the network's performance. When applied to standard network architectures on a wide variety of datasets, our approach discovers novel structures in each domain, obtaining higher performance while respecting the resource constraint.
A Real-Time PCR-Based Semi-Quantitative Breakpoint to Aid in Molecular Identification of Urinary Tract Infections (2013)

This study presents a novel approach to aid in diagnosis of urinary tract infections (UTIs). A real-time PCR assay was used to screen for culture-positive urinary specimens and to identify the causative uropathogen. Semi-quantitative breakpoints were used to screen for significant bacteriuria (presence of ≥ 10(5) CFU/ml of uropathogens) or low-level bacteriuria (containing between 10(3) and 10(4) CFU/ml of uropathogens). The 16S rDNA-based assay could identify the most prevalent uropathogens using probes for Escherichia coli, Pseudomonas species, Pseudomonas aeruginosa, Staphylococcus species, Staphylococcus aureus, Enterococcus species and Streptococcus species. 330 urinary specimens were analysed and results were compared with conventional urine culture. Using a PCR Ct value of 25 as semi-quantitative breakpoint for significant bacteriuria resulted in a sensitivity and specificity of 97% and 80%, respectively. In 78% of the samples with monomicrobial infections the assay contained probes to detect the bacteria present in the urine specimens and 99% of these uropathogens was correctly identified. Concluding, this proof-of-concept approach demonstrates that the assay can distinguish bacteriuria from no bacteriuria as well as detect the involved uropathogen within 4 hours after sampling, allowing adequate therapy decisions within the same day as well as drastically reduce consequent urine culturing.
Validated stability-indicating spectrofluorimetric methods for the determination of ebastine in pharmaceutical preparations (2011)

Two sensitive, selective, economic, and validated spectrofluorimetric methods were developed for the determination of ebastine (EBS) in pharmaceutical preparations depending on reaction with its tertiary amino group. Method I involves condensation of the drug with mixed anhydrides (citric and acetic anhydrides) producing a product with intense fluorescence, which was measured at 496 nm after excitation at 388 nm.Method (IIA) describes quantitative fluorescence quenching of eosin upon addition of the studied drug where the decrease in the fluorescence intensity was directly proportional to the concentration of ebastine; the fluorescence quenching was measured at 553 nm after excitation at 457 nm. This method was extended to (Method IIB) to apply first and second derivative synchronous spectrofluorimetric method (FDSFS & SDSFS) for the simultaneous analysis of EBS in presence of its alkaline, acidic, and UV degradation products.The proposed methods were successfully applied for the determination of the studied compound in its dosage forms. The results obtained were in good agreement with those obtained by a comparison method. Both methods were utilized to investigate the kinetics of the degradation of the drug.
Internal Modification of U2 Small Nuclear (Snrna) Occurs in Nucleoli of Xenopus Oocytes (2001)

U2 small nuclear (sn)RNA contains a large number of posttranscriptionally modified nucleotides, including a 5' trimethylated guanosine cap, 13 pseudouridines, and 10 2'-O-methylated residues. Using Xenopus oocytes, we demonstrated previously that at least some of these modified nucleotides are essential for biogenesis of a functional snRNP. Here we address the subcellular site of U2 internal modification. Upon injection into the cytoplasm of oocytes, G-capped U2 that is transported to the nucleus becomes modified, whereas A-capped U2 that remains in the cytoplasm is not modified. Furthermore, by injecting U2 RNA into isolated nuclei or enucleated oocytes, we observe that U2 internal modifications occur exclusively in the nucleus. Analysis of the intranuclear localization of fluorescently labeled RNAs shows that injected wild-type U2 becomes localized to nucleoli and Cajal bodies. Both internal modification and nucleolar localization of U2 are dependent on the Sm binding site. An Sm-mutant U2 is targeted only to Cajal bodies. The Sm binding site can be replaced by a nucleolar localization signal derived from small nucleolar RNAs (the box C/D motif), resulting in rescue of internal modification as well as nucleolar localization. Analysis of additional chimeric U2 RNAs reveals a correlation between internal modification and nucleolar localization. Together, our results suggest that U2 internal modification occurs within the nucleolus.
Changes in Inflammatory Cytokines Are Related to Impaired Glucose Tolerance in Offspring of Type 2 Diabetic Subjects (2006)

Nondiabetic offspring of type 2 diabetic subjects have changes in the levels of inflammatory cytokines. The level of IL-1Ra seems to be the most sensitive marker of cytokine response in the pre-diabetic state.
Multicistronic Lentiviral Vector-Mediated Striatal Gene Transfer of Aromatic l-Amino Acid Decarboxylase, Tyrosine Hydroxylase, and GTP Cyclohydrolase I Induces Sustained Transgene Expression, Dopamine Production, and Functional Improvement in a Rat Model of Parkinson's Disease. (2002)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients.
XULRunner: A New Approach for Developing Rich Internet Applications (2007)

The Web 2.0 world abounds with solutions for developing Web-based rich Internet applications (RIAs). Desktop application developers have seen a similar maturation of full-featured frameworks to help simplify development. Mozilla's XULRunner application runtime engine offers a compromise between Web-based RIAs and a desktop application's power
A hierarchical transactive control architecture for renewables integration in Smart Grids (2012)

In this paper, we propose a hierarchical transactive control architecture that combines market transactions at the higher levels with inter-area and unit-level control at the lower levels. A model of the overall grid is introduced, with dynamics at primary, secondary, and tertiary levels. With a goal of ensuring frequency regulation using optimal allocation of resources in the presence of uncertainties in renewables and load, a hierarchical control methodology is presented.
Calling Cards enable multiplexed identification of the genomic targets of DNA-binding proteins (2011)

Transcription factors direct gene expression, so there is much interest in mapping their genome-wide binding locations. Current methods do not allow for the multiplexed analysis of TF binding, and this limits their throughput. We describe a novel method for determining the genomic target genes of multiple transcription factors simultaneously. DNA-binding proteins are endowed with the ability to direct transposon insertions into the genome near to where they bind. The transposon becomes a "Calling Card" marking the visit of the DNA-binding protein to that location. A unique sequence "barcode" in the transposon matches it to the DNA-binding protein that directed its insertion. The sequences of the DNA flanking the transposon (which reveal where in the genome the transposon landed) and the barcode within the transposon (which identifies the TF that put it there) are determined by massively parallel DNA sequencing. To demonstrate the method's feasibility, we determined the genomic targets of eight transcription factors in a single experiment. The Calling Card method promises to significantly reduce the cost and labor needed to determine the genomic targets of many transcription factors in different environmental conditions and genetic backgrounds.
Efficient mode conversion in telecommunication fibre using externally written gratings (1990)

A novel approach to grating writing in optical fibres is described. This method involves writing the grating point by point through the side of the fibre using a UV laser source. Efficient mode conversion between forward propagating modes is demonstrated. The wavelength at which conversion occurs is determined by the periodicity of the grating. The grating can be designed to couple light at any wavelength of interest.
Convenient Preparation of 2-Deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl Chloride (1997)

Abstract By using acetyl chloride as HCl generator, the procedure for the Hoffer preparation of the α-chloro sugar 4a was significantly improved. The α-configuration of the chloro atom was confirmed by using NOE measurement. Sequential transformation of 4a to the β-anomer and to the furfuryl derivative 6 was studied.
Enzymes Harboring Unnatural Amino Acids:  Mechanistic and Structural Analysis of the Enhanced Catalytic Activity of a Glutathione Transferase Containing 5-Fluorotryptophan, (1998)

The catalytic characteristics and structure of the M1-1 isoenzyme of rat glutathione (GSH) transferase in which all four tryptophan residues in each monomer are replaced with 5-fluorotryptophan are described. The fluorine-for-hydrogen substitution does not change the interaction of the enzyme with GSH even though two tryptophan residues (Trp7 and Trp45) are involved in direct hydrogen-bonding interactions with the substrate. The rate constants for association and dissociation of the peptide, measured by stopped-flow spectrometry, remain unchanged by the unnatural amino acid. The 5-FTrp-substituted enzyme exhibits a kcat of 73 s-1 as compared to 18 s-1 for the native enzyme toward 1-chloro-2,4-dinitrobenzene. That the increase in the turnover number is due to an enhanced rate of product release in the mutant is confirmed by the kinetics of the approach to equilibrium for binding of the product. The crystal structure of the 5-FTrp-containing enzyme was solved at a resolution of 2.0 A by difference Fourier techniques. The structure reveals local conformational changes in the structural elements that define the approach to the active site which are attributed to steric interactions of the fluorine atoms associated with 5-FTrp146 and 5-FTrp214 in domain II. These changes appear to result in the enhanced rate of product release. This structure represents the first of a protein substituted with 5-fluorotryptophan.
Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells (2002)

PCTAIRE-1 is a CDK-related protein kinase found in terminally differentiated cells in brain and testis, and in many immortalised and transformed cell lines. Bacterially expressed PCTAIRE is completely inactive as a protein kinase, but is a very good substrate for protein kinase A (PKA), which phosphorylates a total of four sites in the N-terminus of PCTAIRE-1. Phosphorylation of one of these sites, Ser119, generates a 14-3-3 binding site, which is functional in vitro as well as in vivo. Mutation of another PKA site, Ser153, to an alanine residue generated an activated kinase in transfected mammalian cells. This activity was comparable to that of CDK5 activated by a bacterially expressed, truncated version of p35(nck), p21. Gel filtration analysis of a brain extract suggested that monomeric PCTAIRE-1 was the active species, implying that PCTAIRE-1 may not be a true CDK, in that it does not require a partner (cyclin-like) subunit for kinase activity. Finally, we found that various forms of PCTAIRE-1 transfected into neuroblastoma cell lines could either promote or inhibit neurite outgrowth, suggesting a potential role for the PCTAIRE-1 gene product in the control of neurite outgrowth.
A novel telomerase template antagonist (GRN163) as a potential anticancer agent. (2003)

Telomerase, the enzyme responsible for proliferative immortality, is expressed in essentially all cancer cells, but not in most normal human cells. Thus, specific telomerase inhibition is potentially a universal anticancer therapy with few side effects. We designed N3'-->P5' thio-phosphoramidate (NPS) oligonucleotides as telomerase template antagonists and found that their ability to form stable duplexes with the telomerase RNA subunit was the key factor for antitelomerase activity. In biochemical assays 11-13-mer NPS oligonucleotides demonstrated sequence- and dose-dependent inhibition of telomerase with IC(50) values <1 nM. Optimization of the sequence, length, and bioavailability resulted in the selection of a 13-mer NPS oligonucleotide, GRN163, as a drug development candidate. GRN163 inhibited telomerase in a cell-free assay at 45 +/- 7 pM, and in various tumor cell lines at approximately 1 nM and approximately 0.3-1.0 micro M in the presence and absence of carriers, respectively. GRN163 was competitive with telomeric primer binding, primarily because of hybridization to human telomerase RNA (hTR) component. Tumor cells treated with GRN163 in culture underwent telomere shortening, followed by cellular senescence or apoptosis after a period of time that generally correlated with initial telomere length. In a flank DU145 (prostate cancer) xenograft model, parenterally administered GRN163 caused suppression of tumor growth in the absence of gross toxicity. These data demonstrate that GRN163 has significant potential for additional development as an anticancer agent.
Selective cache ways: on-demand cache resource allocation (1999)

Increasing levels of microprocessor power dissipation call for new approaches at the architectural level that save energy by better matching of on-chip resources to application requirements. Selective cache ways provides the ability to disable a subset of the ways in a set associative cache during periods of modest cache activity, while the full cache may remain operational for more cache-intensive periods. Because this approach leverages the subarray partitioning that is already present for performance reasons, only minor changes to a conventional cache are required, and therefore, full-speed cache operation can be maintained. Furthermore, the tradeoff between performance and energy is flexible, and can be dynamically tailored to meet changing application and machine environmental conditions. We show that trading off a small performance degradation for energy savings can produce a significant reduction in cache energy dissipation using this approach.