gebhart/patrepeval huggingface dataset:
Separation Of Stochastic Processes (2005)

Assume we observe an unknown linear combination of p stochastic processes. The problem we are addressing here is to recover original source processes by applying an inverse transform, F, based solely upon their statistical independence. The conditions under which this problem is solvable are first pointed out. Then, by imposing the cancellation of output crosscumulants, we obtain a polynomial system of equations that the entries of the linear transform F must cancel. In the ring of polynomials with real or complex coefficients, obtaining a greatest common divisor is not easy; for instance Euclid's algorithm is unstable. Our approach is rather based on a detailed analysis of properties of input cumulants, and provides when p=2 a direct solution, which can be also implemented in an adaptive fashion. The extension to p>2 sources raises several specific problems; the solution we propose in this more general case becomes iterative.
Protected P-element termini suggest a role for inverted-repeat-binding protein in transposase-induced gap repair in Drosophila melanogaster. (1995)

P-element transposition is thought to occur by a cut-and paste mechanism that generates a double-strand break at the donor site, the repair of which can lead to internally deleted elements. We have generated a series of both phenotypically stronger and weaker allelic derivatives of vg21, a vestigial mutant caused by a P-element insertion in the 5' region of the gene. Virtually all of the new alleles arose by internal deletion of the parental element in vg21, and we have characterized a number of these internally deleted P elements. Depending upon the selection scheme used, we see a very different spectrum of amount and source of P-element sequences in the resultant derivatives. Strikingly, most of the breakpoints occur within the inverted-repeats such that the last 15-17 bp of the termini are retained. This sequence is known to bind the inverted-repeat-binding protein (IRBP). We propose that the IRBP may act to preserve the P-element ends when transposition produces a double-strand gap. This allows the terminus to serve as a template upon which DNA synthesis can act to repair the gap. Filler sequences found at the breakpoints of the internally deleted P elements resemble short stretches, often in tandem arrays, of these terminal sequences. The structure of the filler sequences suggests replication slippage may occur during the process of gap repair.
Ruxolitinib Prevents Cytokine Release Syndrome after Car T-Cell Therapy Without Impairing the Anti-Tumor Effect in a Xenograft Model (2017)

Chimeric antigen receptor T (CART) cell therapy results in impressively high remission rates in B cell neoplasms but is limited by the development of cytokine release syndrome (CRS). While the use of the anti-IL6 receptor antibody tocilizumab with or without steroids can reverse this syndrome, there is concern that early immunosuppression could impair the anti-tumor activity and therefore is reserved for severe CRS. Ruxolitinib is a JAK/STAT pathway inhibitor that has resulted in a significant reduction of inflammatory cytokines in preclinical and clinical studies. Therefore, there is a compelling rationale to develop ruxolitinib as a modality to prevent CRS after CART cell therapy. In this study, we established a novel acute myeloid leukemia (AML) xenograft model to study the development of CRS. Here, NSG-S (Non Obese Diabetic, SCID ɣ -/- mice that are additionally transgenic for human stem cell factor, IL-3 and GM-CSF) are engrafted with blasts from AML patients and treated with 1 × 106 CD123-directed CART cells (CART123), ten-fold higher than we previously used in our primary AML xenograft models. These animals develop an illness characterized by progressive weight loss, generalized weakness, emaciation, hunched bodies, withdrawal and poor motor response. This illness starts within one week of CART cell injection, correlates with T cell expansion and rapidly evolves and results in the death of the animals in 7-14 days. Serum from these mice seven days after CART123 shows an extreme elevation of human IL-6, Interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines, resembling human CRS after CART cell therapy. NSG-S mice bearing primary AML were treated with CART123 and randomized to receive different doses of ruxolitinib (30, 60, or 90 mg/kg) or vehicle by oral gavage twice a day. Treatment started on the day of CART123 injection and continued for a week. Mice treated with ruxolitinib 60 or 90 mg/kg exhibited less severe clinical illness as manifested by attenuated weight loss when compared with mice treated with CART123 alone (Figure 1A). With the exception of ruxolitinib-only treated mice, all other groups exhibited an equivalent anti-leukemic effect (Figure 1B). We therefore established ruxolitinib 60 mg/kg for further experimental use. Most importantly, ruxolitinib treatment attenuated inflammatory cytokines (Figure 1C) and led to long-term survival (Figure 1D). Here we have described a clinically relevant animal model of human CRS and demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent the development of severe CRS without impairing the anti-tumor effect of CART cells. These findings provide a useful platform for the future study of CRS prevention and treatment modalities. These experiments indicate that ruxolitinib could also be combined with CART cell therapy for the prevention of CRS in patients identified to be at high risk for the development of CRS.
The Human Sef-a Isoform Utilizes Different Mechanisms to Regulate Receptor Tyrosine Kinase Signaling Pathways and Subsequent Cell Fate (2006)

Negative feedback is among the key mechanisms for regulating receptor tyrosine kinase (RTK) signaling. Human Sef, a recently identified inhibitor of RTK signaling, encodes different isoforms, including a membrane spanning (hSef-a) and a cytosolic (hSef-b) isoform. Previously, we reported that hSef-b inhibited fibroblast proliferation and prevented the activation of mitogen-activated protein kinase (MAPK), without affecting protein kinase B/Akt or p38 MAPK. Conflicting results were reported concerning hSef-a inhibition of MAPK activation, and the effect of hSef-a on other RTK-induced signaling pathways is unknown. Here we show that, in fibroblasts, similar to hSef-b, ectopic expression of hSef-a inhibited fibroblast growth factor-induced cell proliferation. Unlike hSef-b, however, the growth arrest was mediated via a MAPK-independent mechanism, and was accompanied by elevated p38 MAPK phosphorylation and inhibition of protein kinase B/Akt. In addition, hSef-a, but not hSef-b, mediated apoptosis in fibroblast growth factor-stimulated cells. Chemical inhibitor of p38 MAPK abrogated the effect of hSef-a on apoptosis. In epithelial cells, ectopic expression of hSef-a inhibited the activation of MAPK, whereas down-regulation of endogenous hSef-a significantly increased MAPK activation and accelerated growth factor-dependent cell proliferation. These results indicate that hSef-a is a multifunctional negative modulator of RTK signaling and clearly demonstrate that hSef-a can inhibit the activation of MAPK, although in a cell type-specific manner. Moreover, the differences between the activities of hSef-a and hSef-b suggest that hSef isoforms can control signal specificity and subsequent cell fate by utilizing different mechanisms to modulate RTK signaling.
Inhibition of Moloney murine leukemia virus-induced leukemia in transgenic mice expressing antisense RNA complementary to the retroviral packaging sequences. (1991)

Recombinant plasmids pLP psi as and pCP psi as were constructed by positioning the Moloney murine leukemia virus (M-MuLV) proviral packaging (psi) sequences in reverse orientation under the transcriptional regulation of lymphotropic promoter/regulatory elements from the M-MuLV long terminal repeat or the cytomegalovirus immediate-early region. Linear fragments containing the antisense psi and the appropriate transcriptional regulatory sequences from these plasmids were introduced into the mouse germ line by zygote microinjection. The chromosomal integration, germ-line transmission, and lymphocyte-directed expression of the antisense psi RNA were confirmed. Control (nontransgenic) and transgenic mice containing either the pLP psi as or the pCP psi as sequences were infected with M-MuLV on the day of birth and assayed for signs of leukemia between 12 and 14 weeks of age with standard assay procedures. While 31% (11 of 36) of the control, nontransgenic, mice developed leukemia, none of the antisense psi transgenic mice developed any symptoms of leukemia. The pCP psi as sequences were also introduced into mouse NIH 3T3 cells and stably transformed cell lines were isolated. When infected with M-MuLV these cells were shown to produce virus devoid of packaged viral RNA.
Electrophilic Aromatic Substitutions of Amine and Sulfonate onto Fine-Grained Activated Carbon for Aqueous-Phase Metal Ion Removal (2004)

Two new materials for adsorption of metal ions from aqueous media have been developed. The organic functional groups amine (−NH2) and sulfonate (−SO3H) were successfully attached to a commercially available fine-grained activated carbon (AC) via electrophilic aromatic substitutions. The surface properties of the materials were investigated using FTIR spectroscopy, XPS, BET surface area analysis, gravimetric methods, and elemental analysis. The NH2-AC and SO3H-AC each had a functional group density of 3 mmol/g. Batch metal ion adsorption experiments were conducted to determine metal binding properties of the adsorbent materials. Based on the distribution coefficients (Kd) of metal ions tested, the unmodified AC and sulfonated-AC both had an affinity for metal ions in decreasing order of Nd > Lu ≈ La > Pb > Cu > Ni ≈ Cd > Mn ≈ Ca, while the amine-AC had an affinity for metal ions in the order of Cu ≫ Nd ≈ Lu ≈ La > Pb > Ni > Cd > Mn ≈ Ca. With maximum Kd values of 130,000 for amine-AC and 25,000 for sulfonated-AC, compared to a Kd of 2,000 for unmodified AC, the modified activated carbons have a strong potential for use in removing heavy metal ions and lanthanide ions from aqueous wastes.
The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis (2006)

Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.
Fermentation of sugar mixtures using Escherichia coli catabolite repression mutants engineered for production of L -lactic acid (2002)

Conversion of lignocellulose to lactic acid requires strains capable of fermenting sugar mixtures of glucose and xylose. Recombinant Escherichia coli strains were engineered to selectively produce L-lactic acid and then used to ferment sugar mixtures. Three of these strains were catabolite repression mutants (ptsG(-)) that have the ability to simultaneously ferment glucose and xylose. The best results were obtained for ptsG(-) strain FBR19. FBR19 cultures had a yield of 0.77 (g lactic acid/g added sugar) when used to ferment a 100 g/l total equal mixture of glucose and xylose. The strain also consumed 75% of the xylose. In comparison, the ptsG(+) strains had yields of 0.47-0.48 g/g and consumed 18-22% of the xylose. FBR19 was subsequently used to ferment a variety of glucose (0-40 g/l) and xylose (40 g/l) mixtures. The lactic acid yields ranged from 0.74 to 1.00 g/g. Further experiments were conducted to discover the mechanism leading to the poor yields for ptsG(+) strains. Xylose isomerase (XI) activity, a marker for induction of xylose metabolism, was monitored for FBR19 and a ptsG(+) control during fermentations of a sugar mixture. Crude protein extracts prepared from FBR19 had 10-12 times the specific XI activity of comparable samples from ptsG(+) strains. Therefore, higher expression of xylose metabolic genes in the ptsG(-) strain may be responsible for superior conversion of xylose to product compared to the ptsG(+) fermentations.
Enhanced Targeting Specificity to Tumor Cells by Simultaneous Recognition of Two Antigens (2000)

Radioimmunotherapy recently afforded convincing results for B-cell non-Hodgkin's lymphoma treatment with antibody specific for B-cell differentiation antigens. High doses of unlabeled or labeled antibodies are necessary to saturate specific sites on normal B-cells. We thus developed a new targeting strategy, taking advantage of dual binding cooperativity, to enhance the specificity of the radioactive uptake by tumor cells. This approach was evaluated using human Burkitt lymphoma cells (Ramos) which express both CD10 and CD20 antigens. Most normal cells express at most one of these two differentiation antigens but many hematological tumors, including most human B type acute lymphoblastic leukemia cells, express both. Cells pretargeted with two bispecific antibodies, one recognizing CD10 and a histamine derivative (HSG), the other recognizing CD20 and the DTPA-indium complex, bind cooperatively radiolabeled mixed-haptens (DTPA-HSG). Increased binding (about 5-fold compared to binding to only one of CD10 or CD20 antigens) is observed at 37 degrees C, demonstrating the feasibility of the technique. This binding enhancement is a slow process, not observed at 4 degrees C. Such a binding enhancement will increase specificity for targeting isotopes to double antigen positive tumor cells compared to nontumor tissue cells bearing only one of them. This approach might be used to increase tumor irradiation with minimal irradiation of normal cells.
Protection againstPseudomonas aeruginosaChronic Lung Infection in Mice by Genetic Immunization against Outer Membrane Protein F (OprF) ofP. aeruginosa (2001)

The Pseudomonas aeruginosa major constitutive outer membrane porin protein OprF, which has previously been shown to be a protective antigen, was targeted as a DNA vaccine candidate. The oprF gene was cloned into plasmid vector pVR1020, and the plasmid vaccines were delivered to mice by biolistic (gene gun) intradermal inoculation. Antibody titers in antisera from immunized mice were determined by enzyme-linked immunosorbent assay, and the elicited antibodies were shown to be specifically reactive to OprF by immunoblotting. The immunoglobulin G (IgG) immune response was predominantly of the IgG1 isotype. Sera from DNA vaccine-immunized mice had significantly greater opsonic activity in opsonophagocytic assays than did sera from control mice. Following the initial immunization and two consecutive boosts, each at 2-week intervals, protection was demonstrated in a mouse model of chronic pulmonary infection by P. aeruginosa. Eight days postchallenge, both lungs were removed and examined. A significant reduction in the presence of severe macroscopic lesions, as well as in the number of bacteria present in the lungs, was seen. Based on these findings, genetic immunization with oprF has potential for development as a vaccine to protect humans against infection by P. aeruginosa.
Optimizing parameters for clinical-scale production of high IL-12 secreting dendritic cells pulsed with oxidized whole tumor cell lysate (2011)

This study examined criteria including DC phenotype, viability, IL-12p70 production and the ability to stimulate MLR as metrics of whole oxidized tumor lysate-pulsed DC immunogenicity and functionality. Development and optimization of this unique method is now being tested in a clinical trial of autologous oxidized tumor lysate-pulsed DC in clinical-scale in recurrent ovarian, primary peritoneal or fallopian tube cancer (NCT01132014).
The metabolism of δ-aminolaevulic acid. 1. Normal pathways, studied with the aid of 15N (1956)

On the basis of results obtained with in vitro systems, 6-aminolaevulic acid (ALA) has been found by several groups ofworkers to be a biological precursor of porphyrins and haem. The following reactions are believed to occur (Shemin & Russell, 1953; Neuberger & Scott, 1953):
Application of Tissue-Engineering Principles toward the Development of a Semilunar Heart Valve Substitute (2004)

Heart valve disease is a significant medical problem worldwide. Current treatment for heart valve disease is heart valve replacement. State of the art replacement heart valves are less than ideal and are associated with significant complications. Using the basic principles of tissue engineering, promising alternatives to current replacement heart valves are being developed. Significant progress has been made in the development of a tissue-engineered semilunar heart valve substitute. Advancements include the development of different potential cell sources and cell-seeding techniques; advancements in matrix and scaffold development and in polymer chemistry fabrication; and the development of a variety of bioreactors, which are biomimetic devices used to modulate the development of tissue-engineered neotissue in vitro through the application of biochemical and biomechanical stimuli. This review addresses the need for a tissue-engineered alternative to the current heart valve replacement options. The basics of heart valve structure and function, heart valve disease, and currently available heart valve replacements are discussed. The last 10 years of investigation into a tissue-engineered heart valve as well as current developments are reviewed. Finally, the early clinical applications of cardiovascular tissue engineering are presented.
Antioxidants are necessary for myelination of dorsal root ganglion neurons, in vitro (2003)

We have demonstrated that myelination of dorsal root ganglion (DRG) axons occurs in a fully defined, serum-free medium (B27). This implies that there may be components in B27 medium that support myelination. To determine which of the components in B27 were essential for myelination, we systematically removed components from B27 until myelination was lost. We added these components to a fully defined minimal medium (N2) that supports neuron survival but not myelination. When antioxidants were removed from B27, myelination was lost. However, the individual antioxidants did not induce myelination when added to N2 medium. Addition of ascorbic acid along with the B27 antioxidants was sufficient to induce myelination in N2 medium, which was enhanced by retinyl acetate. Removal of vitamin E from B27 caused a partial loss of myelination, and addition of vitamin E to N2 medium containing ascorbic acid induced partial myelination. Addition of serum to the B27 myelinating medium inhibited myelination completely. These results indicate that antioxidants are important for myelination, in vitro. Vitamin E may play an important role. Use of a serum-free medium may be beneficial for in vitro myelination studies because serum has unknown inhibitory effects.
EFFECT OF ANTI-LFA1 (CD11a) MONOCLONAL ANTIBODIES IN ACUTE REJECTION IN HUMAN KIDNEY TRANSPLANTATION (1991)

A murine IgG1 monoclonal antibody, 25-3 (Immunotech, France), directed against the alpha chain (CD11a) of the human LFA1 molecule was used in the treatment of 7 histologically documented first acute rejection in first kidney transplantations under cyclosporine. Four patients (group I) received 20 mg/day for 2 days and 10 mg/day for 8 days of 25-3 MoAb. One developed Quincke's edema after the first injection of 25-3 and was immediately withdrawn from the study. In 2 patients, whose serum creatinine continued to increase, 25-3 MoAb was replaced by steroids, followed by ALG after 3 and 4 days of treatment, respectively. In the last case, rejection was reversed by 25-3 MoAb alone. As the clinical response of rejection to 25-3 was poor, another group of 3 patients (group II) was treated with 25-3 at a dose of 40 mg/day for 2 days, 20 mg/day for 2 days, and 10 mg/day for 6 days, but 25-3 was still unsuccessful in reversing acute rejection, and rescue treatment was initiated between days 5 and 8 in all cases. MoAb tolerance was excellent in 3 patients. With the exception of the one case of Quincke's edema, only minor side effects were noted in the last 3 recipients. 25-3 MoAb serum trough levels peaked between 1.5-3.5 micrograms/ml at day 3 in group I and between 2-9 micrograms/L at day 2 in group II. Surprisingly, only one patient, in group I, exhibited a borderline IgG immune response against 25-3. These findings suggest that the 25-3 anti-CD11a MoAb is ineffective in controlling the course of acute rejection in kidney transplantation. However as already reported for another anti-LFA1 or with an anti-CD4 MoAb in mouse, 25-3 would be the first example in humans of a MoAb that does not elicit a strong immune response against its own determinants. This property might have important applications if 25-3 can prevent rejection in a prophylactic protocol or block the immune response against other MoAbs.
Pharmacophores Incorporating Numerous Excluded Volumes Defined by X-ray Crystallographic Structure in Three-Dimensional Database Searching:  Application to the Thyroid Hormone Receptor (1998)

In the present study we investigate whether augmentation of pharmacophores with excluded (ligand-inaccessible) volumes can condense the lengthy unspecific hit lists often obtained in 3D-database searching. Our pharmacophores contained hydrophobic features defined by the hormone, hydrogen bond donor and acceptor features of the liganded rat THR-alpha X-ray structure, and excluded volumes located at the positions and scaled according to the sizes of atoms delineating the binding cavity. We now show, for the first time, that it is perfectly feasible with the Catalyst software to search, in 1-2 h, medium-sized databases such as Maybridge (with 5 x 10(5) compounds registered as multiple conformers) with pharmacophores containing numerous (approximately 10(2)) excluded volumes. The excluded volumes did not slow the search significantly; for pharmacophores containing more features they also reduced the size of the hit list the most. For example, with a 7-feature pharmacophore, the Maybridge hit list shrank from 4 to 1. The single remaining compound was subsequently shown to bind to THR-alpha with an IC50 of 69 microM. Thus, we conclude that structure-based pharmacophores augmented with numerous excluded volumes can effectively prune and focus hit lists. The performance of multiple excluded volume-supplemented structure-based pharmacophores in 3D-database mining as implemented with the Catalyst software compares very favorably with other published procedures, with respect to speed, specificity, and ease of use.