gebhart/patrepeval huggingface dataset:
Large shifts in pK a values of lysine residues buried inside a protein (2011)

Internal ionizable groups in proteins are relatively rare but they are essential for catalysis and energy transduction. To examine molecular determinants of their unusual and functionally important properties, we engineered 25 variants of staphylococcal nuclease with lysine residues at internal positions. Nineteen of the Lys residues have depressed pK(a) values, some as low as 5.3, and 20 titrate without triggering any detectable conformational reorganization. Apparently, simply by being buried in the protein interior, these Lys residues acquired pK(a) values comparable to those of naturally occurring internal ionizable groups involved in catalysis and biological H(+) transport. The pK(a) values of some of the internal Lys residues were affected by interactions with surface carboxylic groups. The apparent polarizability reported by the pK(a) values varied significantly from location to location inside the protein. These data will enable an unprecedented examination of the positional dependence of the dielectric response of a protein. This study also shows that the ability of proteins to withstand the presence of charges in their hydrophobic interior is a fundamental property inherent to all stable proteins, not a specialized adaptation unique to proteins that evolved to depend on internal charges for function.
IL-18 Induces Emphysema and Airway and Vascular Remodeling via IFN-γ, IL-17A, and IL-13 (2012)

These studies define the spectrum of inflammatory, parenchymal, airway, and vascular alterations that are induced by pulmonary IL-18; highlight the similarities between these responses and the lesions in COPD; and define the selective roles that type 1, type 2, and type 17 responses play in the generation of IL-18-induced pathologies.
Measuring thrombin generation as a tool for predicting hemostatic potential and transfusion requirements following trauma (2014)

Prognostic/epidemiologic study, level III.
Effects of Antihypertensive Therapy on Serum Lipids (1995)

With the exception of calcium antagonists, nearly all antihypertensive agents affect serum lipids. These effects differ among patient populations.
Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer (2006)

Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).
Glial gene expression during aging in rat striatum and in long-term responses to 6-OHDA lesions (1999)

The male rat striatum was examined for age-related changes in mRNAs expressed in astrocytes and microglia in two rat genotypes that differ by 35% in mean and maximum life spans: F344 and the longer-lived F1 (BN x F344) hybrid. The findings extend the established age-related increases in GFAP (glial fibrillary acidic protein) to other glial mRNAs: two lipoprotein mRNAs that are predominantly expressed in striatal astrocytes, apoE (apolipoprotein E) and apoJ (apolipoprotein J, clusterin, CLI, or SGP-2), and two mRNAs expressed in striatal microglia, TGF-beta1 and complement C1qB. By Northern blot hybridization, both genotypes showed progressive increases of GFAP mRNA to > 2.5-fold by the lifespan. Although the rat strains differed 35% in life span, the slope of the GFAP mRNA regression on age did not differ. Relative to GFAP, the increases of apoE, apoJ, C1q, and TGF-beta1 mRNAs were smaller, < or = 1.5-fold. Because prior studies showed that acute damage to striatal afferents induced astrocyte gene expression increases resembling those that also occur during aging, we examined long-term effects of damage to substantia nigra neurons on striatal astrocyte changes during aging. Young F344 rats were given 6-OHDA lesions that cause striatal dopamine deficits and induce GFAP. When examined 15 months later at age 18 months, there was no effect during prior lesions on the age-related elevation of GFAP mRNA. We conclude that aging changes in striatal GFAP mRNAs do not interact with loss of dopaminergic output to the striatum from 6-OHDA lesions and may be independent of the relatively modest dopaminergic losses during normal aging.
Episodic Memory Retrieval, Parietal Cortex, and the Default Mode Network: Functional and Topographic Analyses (2011)

The default mode network (DMN) is often considered a functionally homogeneous system that is broadly associated with internally directed cognition (e.g., episodic memory, theory of mind, self-evaluation). However, few studies have examined how this network interacts with other networks during putative "default" processes such as episodic memory retrieval. Using functional magnetic resonance imaging, we investigated the topography and response profile of human parietal regions inside and outside the DMN, independently defined using task-evoked deactivations and resting-state functional connectivity, during episodic memory retrieval. Memory retrieval activated posterior nodes of the DMN, particularly the angular gyrus, but also more anterior and dorsal parietal regions that were anatomically separate from the DMN. The two sets of parietal regions showed different resting-state functional connectivity and response profiles. During memory retrieval, responses in DMN regions peaked sooner than non-DMN regions, which in turn showed responses that were sustained until a final memory judgment was reached. Moreover, a parahippocampal region that showed strong resting-state connectivity with parietal DMN regions also exhibited a pattern of task-evoked activity similar to that exhibited by DMN regions. These results suggest that DMN parietal regions directly supported memory retrieval, whereas non-DMN parietal regions were more involved in postretrieval processes such as memory-based decision making. Finally, a robust functional dissociation within the DMN was observed. Whereas angular gyrus and posterior cingulate/precuneus were significantly activated during memory retrieval, an anterior DMN node in medial prefrontal cortex was strongly deactivated. This latter finding demonstrates functional heterogeneity rather than homogeneity within the DMN during episodic memory retrieval.
Increasing the speed of solid-state nanopores (2011)

In this work, the authors studied the time response of solid-state nanopores to the applied potentials and the corresponding capacitances. They primarily examined the effect of the doping of the silicon substrates as well as the addition of dielectrics above and below the device membrane. For simple silicon nitride membranes on a moderately doped Si, the measured RC time constants in 1M KCl are on the order of hundreds of microseconds or larger. The authors found that the silicon substrate’s doping level has a significant effect on the equivalent circuit of the device and the use of a more lightly doped Si significantly speeds up the device response. They attributed this effect to the reduction of depletion layer capacitance at the Si-electrolyte interfaces. In the best device structure tested, time constants of ∼425 ns were observed in 1M KCl, which is much faster than most DNA translocation times and on the same order of magnitude as the transit time of each base through typical nanopores.
The ring test: a quantitative method for assessing the ‘cataleptic’ effect of cannabis in mice (1972)

1. A bioassay for cannabis, called the ring test, has been developed in which the percentage of the total time spent on a horizontal wire ring during which a mouse remains completely immobile is recorded.2. The effect of cannabis on mobility is a dose-related, graded response.3. Threshold doses of cannabis extract are 12.5 mg/kg when injected intravenously, and 100 mg/kg when injected intraperitoneally or subcutaneously.4. The method provides a measure of the ;cataleptic' effect of cannabis. Chlorpromazine in doses of 1 mg/kg upwards also produces the effect but barbitone does not.5. It is concluded that Delta(1)-tetrahydrocannabinol (Delta(1)-THC) is largely responsible for the effect of cannabis extract on mobility; the potency ratio of Delta(1)-THC to cannabis extract is between 10 and 20. Delta(1)-Tetrahydrocannabidivarol (Delta(1)-THD) also affects mobility but is less active than Delta(1)-THC. Cannabidiol has no effect when injected intraperitoneally in doses up to 100 mg/kg.
Novel Potent σ1 Ligands:  N-[ω-(Tetralin-1-yl)alkyl]piperidine Derivatives (1996)

A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl-[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective sigma 1 affinity. They were tested in radioligand binding assays on sigma 1, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma 1 affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [3H]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl] piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n- butyl]piperidine (26) reached the lowest Ki values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (Ki = 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, Ki = 3.9 nM on sigma 1 sites) caused an increase in 5-HT1A affinity (Ki < 0.14 nM).
Abnormal intrastore calcium signaling in chronic heart failure (2005)

Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca]SR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].
Highly Luminescent Tridentate N∧C*N Platinum(II) Complexes Featured in Fused Five–Six-Membered Metallacycle and Diminishing Concentration Quenching (2011)

A series of cyclometalating ligands, N-phenyl-N-(3-(pyridin-2-yl)phenyl)pyridin-2-amine (L1), N-(3-(1H-pyrazol-1-yl)phenyl)-N-phenylpyridin-2-amine (L2), N-phenyl-N-(3-(quinolin-2-yl)phenyl)pyridin-2-amine (L3), N-phenyl-N-(3-(pyridin-2-yl)phenyl)quinolin-2-amine (L4), N-(3-(isoquinolin-1-yl)phenyl)-N-phenylpyridin-2-amine (L5), and N-phenyl-N-(3-(pyridin-2-yl)phenyl)isoquinolin-1-amine (L6), were synthesized, which reacted with K2PtCl4 in glacial acetic acid to produce N∧C*N-coordinated platinum(II) complexes featured in a fused five–six-membered metallacycle, 1–6, respectively. The structures of 1, 3, 4, and 6 were determined by single crystal X-ray crystallography. The square geometries of the complexes are improved when compared with those of the N∧C∧N-coordinated complexes as the bite angles for the platinum in N∧C*N-coordinated complexes 1, 3, and 4 are increased. The Pt–C bonds (1.94–1.95 Å) are shorter than those of C∧N∧N-coordinated platinum complexes but longer than those found for N∧C∧N-coordinated platinum complexes. With the increase of the steric interaction, the distortion of the molecules from a planar coordination geometry becomes more and more severe from 1 to 3 to 4 and 6, and in 6, the N-phenyl ring has to stand up on the coordination sphere to minimize the steric interaction with the N-isoquinolyl ring. The photophysical properties of the complexes were studied, and their absorption and emission spectra were interpreted by relating to the structural features revealed by the X-ray crystal structures and the orbital characters predicted by DFT calculations. All complexes are emissive in fluid at room temperature, and the quantum yields (up to 0.65) are comparable to those of highly emissive N∧C∧N-coordinated platinum complexes. Self-quenching was not observed in the concentration range of 10–6 to 10–4 M. Large rigidochromic shifts for the emissions of 2, 4, and 6 upon cooling from room temperature to rigid glass (77 K) were observed. Two different triplet states that control the emissions were proposed to account for the photophysical properties of 6.
Hairpin loop and second kringle domain are essential sites for heparin binding and biological activity of hepatocyte growth factor. (1994)

Hepatocyte growth factor (HGF) has a strong affinity for heparin. About one fourth of HGF secreted from MRC-5 human embryonic lung fibroblast cells was found to be associated with heparin and heparan sulfate proteoglycan on the cell surface and extracellular matrix. To identify heparin-binding sites within the HGF molecule, we constructed variously deleted mutant HGFs and examined their binding ability to an immobilized heparin column. Native HGF and mutant HGFs, including d-K1 (deletion of the first kringle domain), d-K3 (deletion of the third kringle domain), d-K4 (deletion of the fourth kringle domain), d-beta (deletion of beta-chain), and HK1K2 (consisting of the N-terminal hairpin loop and the first two kringle domains), tightly bound to a heparin column, but d-H (deletion of the N-terminal hairpin loop) and d-K2 (deletion of the second kringle domain) markedly decreased binding ability to the column. These observations suggest that the N-terminal hairpin loop and the second kringle domain are essential for the heparin-binding of HGF. The finding that HK1K2 competed the binding of 125I-HGF to immobilized heparin provided additional evidence that the N-terminal half of HGF alpha-chain is the principal heparin-binding site. The hairpin loop in HGF possesses a cluster of basic amino acid residues and a highly positive net charge, when compared with hairpin loop structures in the other proteins, plasminogen and HGF-like protein. The second kringle domain in HGF has the basic amino acid cluster in the central region. Thus, it is likely that the basic clusters in these domains cooperatively contribute to the binding of HGF to the anionic heparin or heparan sulfate molecule.
Vertically aligned ZnO nanostructures grown on graphene layers (2009)

We report the vertical growth of ZnO nanostructures on graphene layers and their photoluminescence (PL) characteristics. ZnO nanostructures were grown vertically on the graphene layers using catalyst-free metal-organic vapor-phase epitaxy. The surface morphology of the ZnO nanostructures on the graphene layers depended strongly on the growth temperature. Further, interesting growth behavior leading to the formation of aligned ZnO nanoneedles in a row and vertically aligned nanowalls was also observed and explained in terms of enhanced nucleation on graphene step edges and kinks. Additionally, the optical characteristics and carbon incorporation into ZnO were investigated using variable-temperature PL spectroscopy.
Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer (2006)

Addition of LMWH to GEM plus CDDP combination significantly improved the response and survival in patients with APC and the current schedule deserves to be tested in phase III trials.
Cytotoxicity testing of poly(anhydride‐co‐imides) for orthopedic applications (1995)

The cytotoxicity of a series of poly(anhydride-co-imides) with osteoblast-like cells (MC3T3-E1) was evaluated. The imide component of the copolymers was based on trimellitylimidoglycine (TMA-gly), and the anhydride component was based on either sebacic acid (SA) or 1,6-bis(carboxyphenoxy)hexane (CPH). Cell adhesion and proliferation on surfaces of the polymer discs were observed by environmental scanning electron microscopy (ESEM). During the first 24 h of attachment, cells showed normal morphology when cultured on the various copolymers of CPH. Concurrently, the effects of polymer breakdown products on osteoblast-like cells were evaluated by studying their proliferation (cell numbers), viability (dye exclusion), and morphology (light microscopy). Cell cultures in the presence of these breakdown products resulted in normal morphologies and reached confluency after 7 days. This initial in vitro evaluation with osteoblast-like cells suggests that the poly(anhydride-co-imides) may be viable carriers for osteoblasts.
High-frequency characterization of thin-film Y-Ba-Cu oxide superconducting transmission lines (1988)

We report the first measurements of picosecond pulse propagation on transmission lines patterned from YBa2Cu3O7−x films. Distortion-free propagation of high current density transients is demonstrated. The high-frequency properties were analyzed by careful study of the relative phase delays of the electrical transients as the temperature of the sample was varied from 1.8 K to Tc. Simulations using Mattis–Bardeen complex conductivities showed good agreement with the measured results. High-frequency critical current densities in excess of 105 A/cm2 were measured.
Radiometal labeling of recombinant proteins by a genetically engineered minimal chelation site: technetium-99m coordination by single-chain Fv antibody fusion proteins through a C-terminal cysteinyl peptide. (1995)

We describe a method to facilitate radioimaging with technetium-99m (99mTc) by genetic incorporation of a 99mTc chelation site in recombinant single-chain Fv (sFv) antibody proteins. This method relies on fusion of the sFv C terminus with a Gly4Cys peptide that specifically coordinates 99mTc. By using analogues of the 26-10 anti-digoxin sFv as our primary model, we find that addition of the chelate peptide, to form 26-10-1 sFv', does not alter the antigen-binding affinity of sFv. We have demonstrated nearly quantitative chelation of 0.5-50 mCi of 99mTc per mg of 26-10-1 sFv' (1 Ci = 37 GBq). These 99mTc-labeled sFv' complexes are highly stable to challenge with saline buffers, plasma, or diethylenetriaminepentaacetic acid. We find that the 99mTc-labeled 741F8-1 sFv', specific for the c-erbB-2 tumor-associated antigen, is effective in imaging human ovarian carcinoma in a scid mouse tumor xenograft model. This fusion chelate methodology should be applicable to diagnostic imaging with 99mTc and radioimmunotherapy with 186Re or 188Re, and its use could extend beyond the sFv' to other engineered antibodies, recombinant proteins, and synthetic peptides.
QuickScorer (2015)

Learning-to-Rank models based on additive ensembles of regression trees have proven to be very effective for ranking query results returned by Web search engines, a scenario where quality and efficiency requirements are very demanding. Unfortunately, the computational cost of these ranking models is high. Thus, several works already proposed solutions aiming at improving the efficiency of the scoring process by dealing with features and peculiarities of modern CPUs and memory hierarchies. In this paper, we present QuickScorer, a new algorithm that adopts a novel bitvector representation of the tree-based ranking model, and performs an interleaved traversal of the ensemble by means of simple logical bitwise operations. The performance of the proposed algorithm are unprecedented, due to its cache-aware approach, both in terms of data layout and access patterns, and to a control flow that entails very low branch mis-prediction rates. The experiments on real Learning-to-Rank datasets show that QuickScorer is able to achieve speedups over the best state-of-the-art baseline ranging from 2x to 6.5x.
From Blood Monocytes to Adipose Tissue-Resident Macrophages (2004)

Obesity has been suggested to be a low-grade systemic inflammatory state, therefore we studied the interaction between human adipocytes and monocytes via adipose tissue (AT)-derived capillary endothelium. Cells composing the stroma-vascular fraction (SVF) of human ATs were characterized by fluorescence-activated cell sorter (FACS) analysis and two cell subsets (resident macrophages and endothelial cells [ECs]) were isolated using antibody-coupled microbeads. Media conditioned by mature adipocytes maintained in fibrin gels were applied to AT-derived ECs. Thereafter, the expression of endothelial adhesion molecules was analyzed as well as the adhesion and transmigration of human monocytes. FACS analysis showed that 11% of the SVF is composed of CD14(+)/CD31(+) cells, characterized as resident macrophages. A positive correlation was found between the BMI and the percentage of resident macrophages, suggesting that fat tissue growth is associated with a recruitment of blood monocytes. Incubation of AT-derived ECs with adipocyte-conditioned medium resulted in the upregulation of EC adhesion molecules and the increased chemotaxis of blood monocytes, an effect mimicked by recombinant human leptin. These results indicate that adipokines, such as leptin, activate ECs, leading to an enhanced diapedesis of blood monocytes, and suggesting that fat mass growth might be linked to inflammatory processes.
Human muscle cultured in monolayer and cocultured with fetal rat spinal cord: importance of dorsal root ganglia for achieving successful functional innervation (1987)

Adult human muscle cultured in monolayer was cocultured with explants of 13-14-d-old rat embryo using (a) ventral spinal cord (VSC), (b) transverse section of whole spinal cord (WSC), and (c) WSC with dorsal root ganglia (DRG) attached (WSC + DRG). AChR clusters and AChE-positive patches, both at the nerve-muscle contacts, were studied at 5, 12, and 21 d of coculture with each of the 3 spinal cord preparations. In addition, AChE-positive patches were studied after 31-64 d of coculture with WSC + DRG to evaluate further organization of those patches. Compared to VSC and WSC cocultures, WSC + DRG induced significantly more AChR clusters per muscle fiber at the nerve-muscle contacts at 5 d of coculture, and the percentage of muscle fibers containing AChR clusters was higher at all 3 time points quantitated. The number of AChE-positive sites was the same with all 3 spinal cord preparations in early (day 5) cocultures. Between 12 and 21 d of coculture, the number of muscle fibers containing AChE patches increased significantly only with WSC + DRG, correlating with the increased number of contracting muscle fibers in that coculture system. Only in human muscle cocultured with WSC + DRG was successful innervation of the cultured muscle fibers achieved, as manifested by (1) contractions in a continuous rhythm of large groups of muscle fibers that were reversibly blocked by 1 mM d-tubocurarine (aneurally cultured human muscle does not spontaneously contract); (2) well-developed cross-striations throughout the fiber; (3) well-organized AChE-positive sites; and (4) a trend from multifocal toward unifocal innervation of those muscle fibers. Our studies demonstrate that adult human muscle cultured in monolayer can be innervated by fetal rat spinal cord and that, in our system, DRG are essential for achieving functional innervation.