gebhart/patrepeval huggingface dataset:
Intra- and Intermonomer Interactions Are Required to Synergistically Facilitate ATP Hydrolysis in Hsp90 (2008)

Nucleotide-dependent conformational changes of the constitutively dimeric molecular chaperone Hsp90 are integral to its molecular mechanism. Recent full-length crystal structures (Protein Data Bank codes 2IOQ, 2CG9, AND 2IOP) of Hsp90 homologs reveal large scale quaternary domain rearrangements upon the addition of nucleotides. Although previous work has shown the importance of C-terminal domain dimerization for efficient ATP hydrolysis, which should imply cooperativity, other studies suggest that the two ATPases function independently. Using the crystal structures as a guide, we examined the role of intra- and intermonomer interactions in stabilizing the ATPase activity of a single active site within an intact dimer. This was accomplished by creating heterodimers that allow us to differentially mutate each monomer, probing the context in which particular residues are important for ATP hydrolysis. Although the ATPase activity of each monomer can function independently, we found that the activity of one monomer could be inhibited by the mutation of hydrophobic residues on the trans N-terminal domain (opposite monomer). Furthermore, these trans interactions are synergistically mediated by a loop on the cis middle domain. This loop contains hydrophobic residues as well as a critical arginine that provides a direct linkage to the gamma-phosphate of bound ATP. Small angle x-ray scattering demonstrates that deleterious mutations block domain closure in the presence of AMPPNP (5'-adenylyl-beta,gamma-imidodiphosphate), providing a direct linkage between structural changes and functional consequences. Together, these data indicate that both the cis monomer and the trans monomer and the intradomain and interdomain interactions cooperatively stabilize the active conformation of each active site and help explain the importance of dimer formation.
Diabetic kidney disease: Act now or pay later (2010)

The 21st century has the most diabetogenic environment in human history with the number of people with diabetes worldwide increasing to 380 million by 2025. The fastest rate of increase will be in developing countries. Diabetes is now the major cause of end-stage kidney disease globally; 20%-40% of people on dialysis are diabetic. In Australia, the number of people with type 2 diabetes starting dialysis increased fivefold between 1993 and 2007. We must act now at local, national and international levels to prevent type 2 diabetes; screen for early diabetic kidney disease; increase public awareness of kidney disease; treat with medications proven to reduce kidney disease progression; and promote research into and trialling of new therapies. The problem is global yet requires local action. World Kidney Day on 11 March 2010 is a time to intensify action on diabetic kidney disease and to continue to do so until this huge but largely preventable health burden is controlled.
Pressure-Transient Analysis of Dual Packer-Probe Wireline Formation Testers in Slanted Wells (2004)

Abstract This paper examines the use of spatial pressure transient measurements acquired by packer-probe wireline formation testers (WFT) in slanted (deviated) wells for estimating formation parameters; e.g., horizontal and vertical permeabilities, skin, tool storage coefficient as well as initial formation pressures. The well&apos;s inclination angle ranges from 0 to 90°, covering vertical and horizontal wells as limiting cases. New approximate analytical equations for spherical flow, which is often exhibited by dual-packer interval and observation probe(s), are presented. These analytical equations are valid for all inclination angles and provide a technique for determining formation parameters from spherical and/or radial flow exhibited by packer and probe(s) pressure transient measurements in slanted wells for single layer systems. These equations also provide a useful set of good initial parameter estimates when nonlinear regression analysis is employed for parameter estimation. It is shown that nonlinear regression provides a useful analysis procedure to identify the formation parameters that can be uniquely determined from different sets of spatial pressures measurements of packer/probe WFTs. A field dual-packer/probe test example is provided to illustrate the methodology and procedures developed in this work.
Microglial expression of CD83 governs cellular activation and restrains autoimmune neuroinflammation (2022)

Abstract Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue and the initial response of microglia determines the severity of neuroinflammatory diseases. CD83 has been associated with early activation of microglia in various disease settings albeit its functional relevance for microglial biology was still elusive. Thus, we conducted a thorough assessment of CD83 regulation in microglia as well as its impact on microglial mediated neuroinflammation. Here, we describe for the first time that CD83 expression in microglia is not only associated with cellular activation but also with pro-resolving functions. Conditional deletion of CD83 causes malfunctioning responses to myelin debris, which results in an over-activated state during autoimmune neuroinflammation. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system and deteriorate resolving mechanism, which exacerbates the disease. Thus, CD83 in microglia orchestrates cellular activation and consequently, also resolution of neuroinflammation.
Abstract 227: Inhibition of Histone Deacetylase Catalytic Activity Improves Cardiac and Pulmonary Function in a Feline Model of Heart Failure with Preserved Ejection Fraction (2018)

Rationale: Heart Failure with preserved Ejection Fraction (HFpEF) accounts for about 50% of all heart failure cases but has no effective therapies. Hypothesis: Inhibition of histone deacetylase (HDAC) catalytic activity exerts beneficial effects on the cardiopulmonary system in a feline model of HFpEF. Methods and Results: Male domestic short hair cats (n=21, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=16) using a customized pre-shaped band, resulting in slow progressive pressure overload during growth. 2 months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid ( b+SAHA ) (n=8), a pan-HDAC inhibitor, or vehicle ( b+veh ) (n=8) for 2 months. At 4 months post-banding, b+SAHA cats showed significantly reduced LV wall thickness and LA size (LA/Ao) compared to b+veh cats (Fig). Invasively measured left ventricular end-diastolic pressure (Fig. LVEDP) at 4 months was significantly elevated in b+veh cats compared to b+SAHA and sham cats (Fig). After dobutamine infusion, the increase in dp/dt max was significantly attenuated in b+veh , but not in b+SAHA cats (Fig). In vivo measurements of pulmonary function at 4 months post-banding demonstrated marked improvement in b+SAHA cats, reflected by an increase in lung compliance and a decrease in alveolar-arterial oxygen gradient (A-aDO 2 ) and intrapulmonary shunt (Fig). Efficacy of SAHA in vivo correlated with enhanced ex vivo myofibril relaxation. Conclusion: HDAC inhibition rescues the established HFpEF phenotype by reducing LV hypertrophy, LVEDP, LA size, and enhancing myofibril relaxation, which ultimately results in improved pulmonary function.
Cytokine/Chemokine Release Patterns and Transcriptomic Profiles of LPS/IFNγ-Activated Human Macrophages Differentiated with Heat-Killed Mycobacterium obuense, M-CSF, or GM-CSF (2021)

Macrophages (Mφs) are instrumental regulators of the immune response whereby they acquire diverse functional phenotypes following their exposure to microenvironmental cues that govern their differentiation from monocytes and their activation. The complexity and diversity of the mycobacterial cell wall have empowered mycobacteria with potent immunomodulatory capacities. A heat-killed (HK) whole-cell preparation of <i>Mycobacterium obuense</i> (<i>M. obuense</i>) has shown promise as an adjunctive immunotherapeutic agent for the treatment of cancer. Moreover, HK <i>M. obuense</i> has been shown to trigger the differentiation of human monocytes into a monocyte-derived macrophage (MDM) type named Mob-MDM. However, the transcriptomic profile and functional properties of Mob-MDMs remain undefined during an activation state. Here, we characterized cytokine/chemokine release patterns and transcriptomic profiles of lipopolysaccharide (LPS)/interferon γ (IFNγ)-activated human MDMs that were differentiated with HK <i>M. obuense</i> (Mob-MDM(LPS/IFNγ)), macrophage colony-stimulating factor M-MDM(LPS/IFNγ)), or granulocyte/macrophage colony-stimulating factor (GM-MDM(LPS/IFNγ)). Mob-MDM(LPS/IFNγ) demonstrated a unique cytokine/chemokine release pattern (interleukin (IL)-10<sup>low</sup>, IL-12/23p40<sup>low</sup>, IL-23p19/p40<sup>low</sup>, chemokine (C-x-C) motif ligand (CXCL)9<sup>low</sup>) that was distinct from those of M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ). Furthermore, M-MDM(LPS/IFNγ) maintained IL-10 production at significantly higher levels compared to GM-MDM(LPS/IFNγ) and Mob-MDM(LPS/IFNγ) despite being activated with M1-Mφ-activating stimuli. Comparative RNA sequencing analysis pointed to a distinct transcriptome profile for Mob-MDM(LPS/IFNγ) relative to both M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ) that comprised 417 transcripts. Functional gene-set enrichment analysis revealed significant overrepresentation of signaling pathways and biological processes that were uniquely related to Mob-MDM(LPS/IFNγ). Our findings lay a foundation for the potential integration of HK <i>M. obuense</i> in specific cell-based immunotherapeutic modalities such as adoptive transfer of Mφs (Mob-MDM(LPS/IFNγ)) for cancer treatment.
Targeting Platelet–Leukocyte Interactions (2003)

The firm adhesion and transplatelet migration of leukocytes on vascular thrombus are dependent on the interaction of the leukocyte integrin Mac-1 (alphaMbeta2, CD11b/CD18) and the platelet counter receptor glycoprotein (GP) Ibalpha. Previous studies have established a central role for the I domain, a stretch of approximately 200 amino acids within the alphaM subunit, in the binding of GP Ibalpha. This study was undertaken to establish the molecular basis of GP Ibalpha recognition by alphaMbeta2. The P201-K217 sequence, which spans an exposed loop and amphipathic alpha4 helix in the three-dimensional structure of the alphaMI domain, was identified as the binding site for GP Ibalpha. Mutant cell lines in which the alphaMI domain segments P201-G207 and R208-K217 were switched to the homologous, but non-GP Ibalpha binding, alphaL domain segments failed to support adhesion to GP Ibalpha. Mutation of amino acid residues within P201-K217, H210-A212, T213-I215, and R216-K217 resulted in the loss of the binding function of the recombinant alphaMI domains to GP Ibalpha. Synthetic peptides duplicating the P201-K217, but not scrambled versions, directly bound GP Ibalpha and inhibited alphaMbeta2-dependent adhesion to GP Ibalpha and adherent platelets. Finally, grafting critical amino acids within the P201-K217 sequence onto alphaL, converted alphaLbeta2 into a GP Ibalpha binding integrin. Thus, the P201-K217 sequence within the alphaMI domain is necessary and sufficient for GP Ibalpha binding. These observations provide a molecular target for disrupting leukocyte-platelet complexes that promote vascular inflammation in thrombosis, atherosclerosis, and angioplasty-related restenosis.
GH Knockout Mice Have Increased Subcutaneous Adipose Tissue With Decreased Fibrosis and Enhanced Insulin Sensitivity (2019)

In 1997, our laboratory used targeted gene disruption of the GH receptor (GHR) to generate GHR knockout (GHR-/-) mice, which have been used in >127 published studies to help elucidate GH's numerous activities. However, because GH replacement studies cannot be performed using this line, a GH knockout mouse line via targeted disruption of the GH gene is needed. Therefore, we created and characterized GH gene-disrupted (GH-/-) mice. GH-/- mice have severely decreased IGF-1 levels, small body size, and altered body composition with increased adiposity. GH-/- mice are extremely insulin sensitive but glucose intolerant, with a dramatic reduction in pancreatic islet size. Importantly, disruption of the GH gene had profound and depot-specific effects on white adipose tissue (WAT). Subcutaneous WAT from male and female GH-/- mice have significantly larger adipocytes and reduced fibrosis, neither of which occurred in perigonadal WAT, suggesting that GH has a more pronounced effect on subcutaneous WAT. Comparisons of GH-/- mice to previously published data on GHR-/- mice show a remarkably similar phenotype. Finally, we demonstrate that GH-/- mice are responsive to GH treatment, as shown by changes to serum IGF-1 levels; body length, weight, and composition; and insulin sensitivity. This study not only provides characterization of the first mouse line with targeted mutation of the GH gene but also indicates that GH gene disruption dramatically influences fibrosis of subcutaneous WAT.
Influence of Anion Delocalization on Electron Transfer in a Covalent Porphyrin Donor–Perylenediimide Dimer Acceptor System (2016)

Photodriven electron transfer from a donor excited state to an assembly of electronically coupled acceptors has been proposed to enhance charge transfer efficiency in functional organic electronic materials. However, the circumstances under which this may occur are difficult to investigate in a controlled manner in disordered donor-acceptor materials. Here we investigate the effects of anion delocalization on electron transfer using zinc meso-tetraphenylporphyrin (ZnTPP) as a donor and a perylene-3,4:9,10-bis(dicarboximide) dimer as the acceptor (PDI<sub>2</sub>). The PDI units of the dimer are positioned in a cofacial orientation relative to one another by attachment of the imide group of each PDI to the 4- and 5-positions of a xanthene spacer. Furthermore, the distal imide group of one PDI is linked to the para-position of one ZnTPP phenyl group to yield ZnTPP-PDI<sub>2</sub>. The data for the dimer are compared to two different ZnTPP-PDI monomer reference systems designed to probe electron transfer to each of the individual PDI molecules comprising PDI<sub>2</sub>. The electron transfer rate from the ZnTPP lowest excited singlet state to PDI<sub>2</sub> is increased by 50% relative to that in ZnTPP-PDI, when the data are corrected for the statistics of having two electron acceptors. Femtosecond transient IR absorption spectroscopy provides evidence that the observed enhancement in charge separation results from electron transfer producing a delocalized PDI<sub>2</sub> anion.
64Cu Labeled TNT-3 antibody for PET imaging of U87MG tumors in mice. (2016)

1374 Objectives Necrosis is a major part of solid tumors up to 80%, but is devoid in normal tissues. Antibody TNT-3 targets stable intracellular antigens exposed in dead and/or dying cells. As a proof of principle study, we report for the first time the quantitative positron emission tomography (PET) imaging of necrosis expression in U87MG tumor bearing mice using 64Cu-labeled TNT-3. Methods We used two macrocyclic chelating agents, 1,4,7,10-tetraazadodecane-N,N9,N99,N999-tetraacetic acid (DOTA) and Sarcophagine cage (Sar) to make DOTA-TNT-3 and Sar-TNT-3 respectively. 64Cu Labeling was achieved in sodium acetate buffer (pH 5.5). The resulted 64Cu-DOTA-TNT-3 and 64Cu-Sar-TNT-3 were tested in U87MG tumor xenografts in nude mice. 64Cu Labeled IgG was synthesized for negative control. Results The radiotracer was synthesized with a specific activity of 0.5-1.0 MBq/mg antibody and 50-60% radiochemical yield. In U87MG xenografts, 64Cu-DOTA-TNT-3 demonstrated prominent tumor accumulation 5.3 ± 1.4, 12.4 ± 4.6, and 16.3 ± 1.8, at 1, 22, and 48 h post injection, respectively. Similarly 64Cu-Sar-TNT-3 had 4.8 ± 0.5, 13.5 ± 0.9, and 17.6 ± 2.8, at 1, 22, and 48 h post injection in U87MG tumor bearing mice, respectively. Due to the stronger chelation of 64Cu-Sar, 64Cu-Sar-TNT-3 demonstrated higher tumor to liver and tumor to muscle uptake. The U87MG tumor uptake was significantly lower after 48 h injection of 64Cu-IgG and this confirmed the specific tumor uptake of TNT-3 antibody. Conclusions We have demonstrated that necrosis could serve as a valid target for glioblastoma tumor imaging. The success of this approach would be valuable to evaluate disease course and therapeutic efficacy at the earliest stages of anti-necrosis treatment in many types of cancers.
Beyond conventional cellular frameworks (2013)

So far we have studied the system design principles of OFDMA-based mobile broadband under a conventional cellular network framework. The basic premises of the framework are:
Characterization of Deoxyribonucleic Acid Synthesis and the Transition from Maternal to Embryonic Control in the 4-Cell Porcine Embryo1 (1992)

These studies were conducted to identify the point during the 4-cell stage at which the porcine embryo begins to control development. Reproductive tracts of gilts were flushed 48 h after the onset of estrus to obtain 1- and 2-cell embryos. To determine the duration of the 4-cell stage in vitro, development of 29 embryos was timed from cleavage to the 4-cell stage and from cleavage to the 8-cell stage. The average duration of the 4-cell stage was 50.5 h. The duration of the 4-cell stage was positively correlated (p < 0.01) with culture time in vitro before cleavage to the 4-cell stage. DNA content was determined by using the Feulgen's reaction and quantified with micro-densitometry. Staining units (SU; density x area) were calculated at 0, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, and 36 h post-cleavage to the 4-cell stage (P4C). Results revealed a possible G1 phase (< 2 h) with DNA synthesis starting within 2 h P4C. DNA synthesis was completed by 16 h P4C, and was followed by an extended G2 phase. Embryos were evaluated for uptake and incorporation of [35S]methionine and for qualitative changes in protein profiles specific to time points during the 4-cell stage (2, 10, 14, 16, 18, 24, 30, and 40 h P4C). Methionine uptake and incorporation into protein followed similar patterns, both decreasing until 16-18 h P4C, followed by a steady increase through the 4-cell stage. Protein profiles revealed qualitative changes beginning at 14 and 16 h P4C.(ABSTRACT TRUNCATED AT 250 WORDS)
Modulation of spontaneous B-cell differentiation in macroglobulinemia by retinoic acid (1994)

We previously showed that clonal blood B cells from patients with macroglobulinemia spontaneously differentiate in vitro to plasma cells. This process is dependent on an interleukin (IL)-6 autocrine pathway. We investigate here whether all-trans-retinoic acid (RA) interferes with B-cell differentiation either in patients with IgM gammapathy of undetermined significance (MGUS) or Waldenström's macroglobulinemia (WM). RA at a concentration of 10(-5) to 10(-8) mol/L inhibited by 50% to 80% the in vitro differentiation of purified B cells from four of five patients with MGUS and from one of five patients with WM as assessed by the IgM content of day 7 culture supernatants. We next determined whether this effect could be related to an inhibition of IL-6 secretion by cultured B cells and/or a downregulation of the IL-6 receptor (IL-6R), which was constitutively expressed on patients' blood B cells. A 50% to 100% (mean, 80%) inhibition of IL-6 production was found in seven of 10 patients (five with MGUS and two with WM). The IL-6R was no more detectable on cells from patients with MGUS after 2 days of treatment with RA and slightly downregulated in patients with WM. It was of interest that B cells susceptible to the action of RA belonged mostly to patients with IgM MGUS, which reinforces our previous data showing distinct requirements for IL-6-dependent differentiation of blood B cells from patients with VM or IgM MGUS.
Probing Dynamic Generation of Hot-Spots in Self-Assembled Chains of Gold Nanorods by Surface-Enhanced Raman Scattering (2011)

Further progress in the applications of self-assembled nanostructures critically depends on developing a fundamental understanding of the relation between the properties of nanoparticle ensembles and their time-dependent structural characteristics. Following dynamic generation of hot-spots in the self-assembled chains of gold nanorods, we established a direct correlation between ensemble-averaged surface-enhanced Raman scattering and extinction properties of the chains. Experimental results were supported with comprehensive finite-difference time-domain simulations. The established relationship between the structure of nanorod ensembles and their optical properties provides the basis for creating dynamic, solution-based, plasmonic platforms that can be utilized in applications ranging from sensing to nanoelectronics.
Synthesis of esters of the potent anti-bacterial trinems and analogues (1996)

Coupling the silyl enol ether 5 and the β-lactam 9(R = Me3Si) affords the ketones 13a–d. Compounds 13a, 13c and 13d are converted into the tricyclic lactams 16–20, 23–25. (Chemoenzymatic synthesis of optically pure silyl enol ether 5 gave access to homochiral lactams 23–25.) In addition the ketoazetidinones 13 are protected as the 1,3-oxazanes 30. A hydroxyethyl moiety is introduced into these oxazanes at C-11 with the desired stereochemistry using the Bouffard methodology, to afford the alcohols 32. Formation of the corresponding nitrobenzyl carbonate, deprotection and oxidation furnishes the ketones 35a and 35b, which are subsequently converted into the trinems 41a and 41b, respectively.
Atomic resolution imaging of electrode surfaces in solutions containing reversible redox species (1989)

Procedures are described for insulating metal scanning tunneling microscope (STM) tips with either glass or polymer coatings. In solutions containing 0.10 M of a reversible redox couple, Fe(CN)−3/−46, the faradaic limiting current to polymer coated tips was 200–500 pA and that for glass coated tips was &amp;lt;10 pA. For polymer insulated tips, steady-state currents of 10–100 pA were observed at tip-sample displacements less than 0.3 μm. The suppression of faradaic current achieved by these coating procedures enabled the collection of the first atomic resolution STM images of highly ordered pyrolytic graphite electrodes in contact with redox-active electrolytes. Preliminary data for the in situ electrochemical characterization of these tips are also discussed.
Coordinated carrier aggregation for campus of home base stations (2015)

This paper present resource optimization for improving the performance of coordinated multi- point transmission (CoMP) with carrier aggregation. The resulting coordinated carrier aggregation system CCA can improve the throughput performance of the CoMP systems by using different carriers for the multi- point transmission and so reducing the overall interference. However, this performance improvement comes at the expense of using more spectrum, especially for uncoordinated deployment of clusters of HeNBs. The paper propose to use graph coloring technique for optimizing the component carriers usage in the campus and evaluate the performance for a test scenario of 25 open HeNBs deployed outdoor in a square coverage region of 800m long. It is shown that performance improvement of 8 % is possible for such deployment with an average of 2 component carriers over CoMP without carrier aggregation.
Use of the Intramolecular Heck Reaction for Forming Congested Quaternary Carbon Stereocenters. Stereocontrolled Total Synthesis of (.+‐.)‐Gelsemine. (2006)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.