gebhart/patrepeval huggingface dataset:
Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models (2001)

The induction and maintenance of allograft tolerance is a daunting challenge. Although combined blockade of CD28 and CD40 ligand (CD40L)-costimulatory pathways prevents allograft rejection in some murine models, this strategy is unable to sustain engraftment in the most immunogenic allograft and strain combinations. By targeting T cell activation signals 1 and 2 with the novel combination of anti-CD45RB and anti-CD40L, we now demonstrate potent enhancement of engraftment in C57BL/6 recipients that are relatively resistant to costimulatory blockade. This combination significantly augments the induction of tolerance to islet allografts and dramatically prolongs primary skin allograft survival. Compared with either agent alone, anti-CD45RB plus anti-CD40L inhibits periislet infiltration by CD8 cells, B cells, and monocytes; inhibits Th1 cytokines; and increases Th2 cytokine expression within the graft. These data indicate that interference with activation signals one and two may provide synergy essential for prolonged engraftment in situations where costimulatory blockade is only partially effective.
Suppression of Adenylate Kinase Catalyzed Phosphotransfer Precedes and Is Associated with Glucose-induced Insulin Secretion in Intact HIT-T15 Cells (1996)

Adenine nucleotide metabolism was characterized in intact insulin secreting HIT-T15 cells during the transition from non-stimulated (i. e. 0.2 mM glucose) to the glucose-stimulated secretory state. Metabolic dynamics were monitored by assessing rates of appearance of 18O-labeled phosphoryls of endogenous nucleotides in cells incubated in medium enriched in [18O]water. Most prominent of the metabolic alterations associated with stimulated insulin secretion was the suppression in the rate of adenylate kinase (AK)-catalyzed phosphorylation of AMP by ATP. This was manifest as a graded decrease of up to 50% in the rate of appearance of beta-18O-labeled species of ADP and ATP and corresponded to the magnitude of the secretory response elicited over a range of stimulatory glucose concentrations. The only nucleotide exhibiting a significant concentration change associated with suppression of AK activity was AMP, which decreased by about 50%, irrespective of the glucose concentration. Leucine-stimulated secretion also decreased the rate of AK-catalyzed phosphotransfer. This secretory stimulus-related suppression of AK-catalyzed phosphotransfer occurs within 45 s of glucose addition, precedes insulin secretion, depends on the internalization and metabolism of glucose, and is independent of membrane depolarization and the influx of extracellular calcium. The secretory stimulus-induced decrease in AK-catalyzed phosphotransfer, therefore occurs prior to or at the time of KATP+ channel closure but it is not associated with or a consequence of events occurring subsequent to KATP+ channel closure. These results indicate that AK-catalyzed phosphotransfer may be a determinant of ATP to ADP conversion rates in the KATP+ channel microenvironment; secretory stimuli-linked decreased rates of AK-catalyzed ADP generation from ATP (and AMP) would translate into an increased probability of ATP-liganded and, therefore, closed state of the channel.
Coordinate linkage of HIV evolution reveals regions of immunological vulnerability (2011)

Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.
Growth of Well-Aligned Carbon Nanotube Structures in Successive Layers (2005)

Layered structures of well-aligned carbon nanotubes were grown using three variations of vapor-phase chemical vapor deposition growth processes. The reactants (typically ferrocene and benzene) were introduced either directly to a heated furnace or carried into the furnace by evaporation or spray pyrolysis in an argon flow. Thick mats of densely packed, well-aligned nanotubes were produced when the reactants were continuously introduced to the reaction; however, when the reactant flow was interrupted, the pauses allowed growth to stop and then restart as a new layer. These pauses were achieved by either completely stopping the reactant flow for a given time or by modifying the dispensing system to introduce the reactants in discrete drops. Time intervals between drops were varied between 20 s and 120 s, with distinct layers observed for pauses of 30 s or greater. The best results were achieved when drops of a catalyst-rich solution were alternated with drops of pure benzene. Layers were grown with thicknesses ranging from several microns to several hundred microns, and structures were grown with well over 100 layers.
Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation (2013)

Background: A growing body of evidence is demonstrating that the nitrogen-containing bisphosphonate zoledronic acid (zol) improves clinical outcomes in various cancer settings, including multiple myeloma. Those findings provided the rationale for conducting an open-label randomized controlled phase iii trial to evaluate the effect of zol on overall survival (os) and progression-free survival (pfs) in patients with previously untreated high-risk multiple myeloma. Methods: The trial randomly assigned 308 adult patients less than 65 years of age with previously untreated symptomatic multiple myeloma (1:1) to receive zol 4 mg intravenously once every 28 days for 24 months (n = 151) or no zol (n = 157). Before autologous stem-cell transplantation (asct), all patients received a high-dose noncytotoxic induction regimen of dexamethasone, all-trans-retinoic acid, and interferon alpha 2b. Results: After a median follow-up of 69.8 months (range: 36.5–96 months), the 10-year pfs (66% vs. 52%, p &lt; 0.001) and os (67% vs. 48%, p &lt; 0.001) rates were significantly higher in treated patients than in control patients. Overall response (77% zol vs. 75% control), complete response (52% vs. 46%), and very good partial response (25% vs. 29%) rates were similar between the groups. Treatment was generally well tolerated, with no reports of renal impairment or osteonecrosis of the jaw. Conclusions: In symptomatic previously untreated multiple myeloma patients, zol combined with high-dose therapy followed by asct improved os and pfs without appreciable toxicity. These findings provide additional evidence of the meaningful anticancer activity of zol in this patient population.
Structure of the lambda att sites generated by int-dependent deletions. (1978)

Bacteriophage lambda integrates into the chromosome of its Escherichia coli host by means of a site-specific recombination between a locus on the phage chromosome (phage att site) and a locus on the bacterial chromosome (bacterial att site). The nucleotide sequence of four lambda att sites altered in site-specific recombination has been determined. The int-dependent deletions that generated these att sites have one end point within the phage att site and extend either to the left or to the right. As a result of the new internucleotide bond created by deletion formation, these phage have alterations in the 15-base-pair common core region. The new DNA sequences brought to the att sites by the deletions, designated delta for regions to the left and delta' for regions to the right, do not share any discernible homology with their analogous counterparts in the phage att site arms, P and P', respectively, or with the bacterial att site arms, B and B', respectively. The finding of alterations in the 15-base-pair common core region necessitates a reinterpretation of the genetic properties of these att sites in site-specific recombination. The structure of these sites in relation to their genetic properties can be viewed as being consistent with a model in which the only specificity elements in int-dependent site-specific recombination are the common core region, O, and the phage arms, P and P'.
Differentiation and integrity of cardiac muscle cells are impaired in the absence of βi integrin (1996)

Cellular interactions with substrata of the microenvironment are one of the major mechanisms for differentiation and morphogenesis. Many of these interactions are mediated via the beta 1 integrin subfamily of cell surface receptors, which are believed to transduce signals upon cell adhesion. We have used beta 1 integrin-deficient embryonic stem cells to test their ability to differentiate into cardiac muscle cells. We show here by several approaches that beta 1 integrin is important for normal cardiogenesis. First, the in vitro differentiation of beta 1 integrin-deficient embryonic stem cells into cardiac muscle cells is retarded. This is demonstrated by the delayed expression of cardiac muscle-specific genes and action potentials. Second, the specification of cardiac precursor cells into pacemaker-, atrial- and ventricular-like cells is significantly impaired in beta 1 integrin-deficient cells. The occurrence of atrial- and ventricular-like cells is reduced and transient. Only cells exhibiting peacemaker-like action potentials of high frequency and arrhythmias survive. Third, the sarcomeric architecture is incomplete and disarranged in the absence of beta 1 integrin. Fourth, beta 1-deficient embryonic stem cells can contribute to the developing heart in chimaeric mice but many areas with beta 1-null cells contain cell debris. The number of beta 1-null cells decrease from prenatal to postnatal stages and is lost completely in 6-month-old hearts. Thus, we conclude that interactions with the extracellular matrix via beta 1 integrin is necessary for differentiation and the maintenance of a specialized phenotype of cardiac muscle cells.
Mouse CD1 is mainly expressed on hemopoietic-derived cells (1997)

The mouse CD1 (mCD1) is a class I-like molecule that is encoded outside the MHC. Recent studies demonstrate that mCD1 presents hydrophobic peptides to CD8+ T cells and also that it is recognized by a population of NK1.1+ T cells that are thought to play an immunoregulatory role because of their ability to secrete IL-4. It has previously been reported that mCD1 is expressed predominantly by intestinal epithelial cells, although most NK1.1+ T cells are located elsewhere. We, therefore, have generated new mAbs to mCD1 to investigate its tissue distribution. The principal site of mCD1 expression in normal mice is on cells in the hemopoietic series, including constitutive expression on nearly all T and B cells, on macrophages, and on dendritic cells. Other than bone marrow-derived cells, mCD1 is not widely expressed and is not detectable on great majority of intestinal epithelial cells. The B cells, but not the T cells, from beta2m-deficient mice can be recognized by two mCD1 autoreactive T hybridomas. Therefore, although we could not detect a beta2m-independent form of mCD1 using these mAbs, mCD1 in a different conformation or a mCD1-related molecule is likely to be expressed in the absence of beta2m on some cell types. The pattern of expression of mCD1 correlates with the distribution of NK1 T cells and is consistent with an important Ag-presenting function for this molecule.
First-in-Human Study of AMG 820, a Monoclonal Anti-Colony-Stimulating Factor 1 Receptor Antibody, in Patients with Advanced Solid Tumors (2017)

<b>Purpose:</b> Binding of colony-stimulating factor 1 (CSF1) ligand to the CSF1 receptor (CSF1R) regulates survival of tumor-associated macrophages, which generally promote an immunosuppressive tumor microenvironment. AMG 820 is an investigational, fully human CSF1R antibody that inhibits binding of the ligands CSF1 and IL34 and subsequent ligand-mediated receptor activation. This first-in-human phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AMG 820.<b>Experimental Design:</b> Adult patients with relapsed or refractory advanced solid tumors received intravenous AMG 820 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks until disease progression, adverse event (AE), or consent withdrawal.<b>Results:</b> Twenty-five patients received ≥1 dose of AMG 820. AMG 820 was tolerated up to 20 mg/kg; the MTD was not reached. One dose-limiting toxicity was observed (20 mg/kg; nonreversible grade 3 deafness). Most patients (76%) had treatment-related AEs; the most common were periorbital edema (44%), increased aspartate aminotransferase (AST; 28%), fatigue (24%), nausea (16%), increased blood alkaline phosphatase (12%), and blurred vision (12%). No patients had serious or fatal treatment-related AEs; 28% had grade ≥3 treatment-related AEs. Grade 3 AST elevations resolved when treatment was withheld. AMG 820 showed linear pharmacokinetics, with minimal accumulation (<2-fold) after repeated dosing. Pharmacodynamic increases in serum CSF1 concentrations and reduced numbers of skin macrophages were observed. Best response was stable disease in 8 patients (32%).<b>Conclusions:</b> AMG 820 was tolerated with manageable toxicities up to 20 mg/kg every 2 weeks. Pharmacodynamic response was demonstrated, and limited antitumor activity was observed. <i>Clin Cancer Res; 23(19); 5703-10. ©2017 AACR</i>.
[1H, 15N] Heteronuclear Single Quantum Coherence NMR Study of the Mechanism of Aquation of Platinum(IV) Ammine Complexes (2008)

The aquation and hydrolysis of a series of platinum(IV) complexes of the general form cis, trans, cis-[PtCl 2(X) 2( (15)NH 3) 2] (X = Cl (-), O 2CCH 3 (-), OH (-)) have been followed by [ (1)H, (15)N] Heteronuclear Single Quantum Coherence NMR spectroscopy. Negligible aquation (<5%) is observed for the complexes where X = O 2CCH 3 (-) or OH (-) over 3-4 weeks. Aquation of cis-[PtCl 4( (15)NH 3) 2] ( 1) is observed, and the rate of aquation increases with increasing pH and upon the addition of 0.01 mol equiv of the platinum(II) complex cis-[PtCl 2( (15)NH 3) 2] (cisplatin). The first aquated species formed from cis-[PtCl 4(NH 3) 2] has one of the axial chloro groups (relative to the equatorial NH 3 ligands) replaced by an aqua/hydroxo ligand. The second observed substitution occurs in an equatorial position. Peaks that are consistent with five of the eight possible aquation species were observed in the NMR spectra.
MRI-based finite-element analysis of left ventricular aneurysm (2005)

Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling.
Adenine transport inEscherichia coli (1994)

The purP gene for energized high-affinity adenine uptake in Escherichia coli is localized to a restriction fragment between tnaB and bglR. Comparison with DNA sequence data (Burland et al. 1993) indicates the involvement of the open-reading frame f445 (86003 < 84666). A non-energized transport route of lower affinity also occurs. The purP system is known to require metabolic removal of transported adenine which would diminish futile cycling by the two transport systems and toxicity by external adenine. Analysis of a conventional kinetic model for permeases suggests that internal adenine might inhibit transport sufficiently to account for the lack of accumulation.
Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity (2004)

Plasmacytoid dendritic cells (pDCs) are one of two principal subsets of human dendritic cells (DCs). pDCs were initially identified in pathological specimens of reactive or neoplastic lymph nodes (LNs), in close association with high endothelial venules (HEVs) ([44][1]). Their plasma cell-like
LYSOSTAPHIN: A NEW BACTERIOLYTIC AGENT FOR THE STAPHYLOCOCCUS (1964)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Reactions of Model Compounds of Biomass-Pyrolysis Oils over ZSM—5 Zeolite Catalysts (1988)

The catalytic conversion of model compounds (e.g. cyclopentanone, cyclopentenone, furfural, glycerol, glucose, fructose and their derivatives usually found in the pyrolysis oils of biomass materials) to hydrocarbon products over H-ZSM-5, Zn-ZSM-5 and Mn-ZSM-5 zeolite catalysts have been studied in a fixed bed microreactor at temperatures ranging from 350°C to 500°C. Although the deoxygenation of cyclopentanone was completed at 400°C, low yields of hydrocarbons were obtained for furfural, glycerol and carbohydrate derivatives. This is due possibly to thermal polymerization at reaction temperatures of 400°C and higher. Increasing the (H/C)eff ratio of the feed with methanol increased significantly the hydrocarbon yield of furfural but not that of carbohydrates. Reaction mechanisms for deoxygenation and tar formation are proposed.
Retinoid X Receptor (RXR) Ligands Activate the Human 25-Hydroxyvitamin D3-24-hydroxylase Promoter via RXR Heterodimer Binding to Two Vitamin D-responsive Elements and Elicit Additive Effects with 1,25-Dihydroxyvitamin D3 (1997)

We have previously shown that RNA levels of kidney 25-hydroxyvitamin D3-24-hydroxylase (24(OH)ase), a key metabolic enzyme for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is up-regulated by retinoids in mice within hours. Deletion analysis of approximately 5500 base pairs of the human 24(OH)ase promoter showed that the sequence between -316 and -142 contained the information necessary and sufficient for retinoid-induced activation of the promoter. This region contains two previously defined vitamin D-responsive elements (VDREs) at -294 to -274 and -174 to -151. Mutation of either VDRE diminished responsiveness of the -316 to -22 promoter sequence to retinoids or 1,25(OH)2D3, while mutation of both VDREs essentially abolished the activity of the ligands via the promoter. Heterologous promoter vectors driven by the VDREs were responsive to a retinoid X receptor (RXR)-selective ligand (LG100268), a retinoic acid receptor (RAR)-selective ligand (TTNPB), or 1,25(OH)2D3, while combinations of LG100268 with either TTNPB or 1,25(OH)2D3 resulted in additive increases in activity. Band shift analyses showed that vitamin D receptor, RAR, or RXR alone did not bind to the VDREs; however, the combination of either vitamin D receptor or RAR with RXR led to retardation of each of the labeled probes. Treatment of nontransfected CV-1 cells with retinoids or 1,25(OH)2D3 resulted in induction of 24(OH)ase RNA, and ligand combinations led to increased RNA levels. These data imply that either or both of the heterodimer partners can be occupied with ligand to induce this enzyme, with dual receptor occupation leading to increased activation.
Longitudinal assessment of feline immunodeficiency virus kinetics in plasma by use of a quantitative competitive reverse transcriptase PCR (1995)

Cats infected with feline immunodeficiency virus (FIV) develop a disease syndrome similar to that caused by human immunodeficiency virus type 1 (HIV-1) infection in humans. HIV-1 replication has been shown to correlate with the disease stage and progression. To assess replication kinetics and disease progression in early FIV infection, we developed a quantitative competitive reverse transcriptase PCR to measure the plasma virus load at serial time points after virus exposure. We found that an early peak viremia immediately preceded the onset of acute-phase symptoms in infected cats. Plasma virus levels remained high throughout the symptomatic phase of infection, which lasted for 8 to 10 weeks, and then declined as clinical symptoms resolved; however, all cats maintained significant plasma virus titers through 36 weeks postinfection. Early peak viral replication coincided with the initial precipitous decline in circulating CD4+ T lymphocytes. These results indicate that FIV kinetics are similar to those of HIV-1 during the acute and secondary phase of infection and that the plasma FIV load correlates with the disease stage. These results serve to further develop the FIV model and to enhance its usefulness for pathogenesis, vaccine development, and therapeutic studies related to HIV.
Sequential Copper(I)‐Catalyzed Reaction of Amines with o‐Acetylenyl‐Substituted Phenyldiazoacetates (2008)

Abstract A highly efficient, tetrakis(acetonitrile)copper(I) hexafluorophosphate [Cu(MeCN) 4 PF 6 ]‐catalyzed tandem Cu(I)‐carbene NH insertion/Cu(I)‐catalyzed hydroamination of alkynes, which leads to sequential formation of two CN bonds to yield isoindole derivatives, has been developed.