gebhart/patrepeval huggingface dataset:
Understanding HIV protease: Can it be translated into effective therapy against AIDS? (1992)

The protease of human immunodeficiency virus (HIV) has been extensively studied. The structure and function relationships of this protease and its role in HIV life cycle is well known. We have use recombinant HIV protease and mutagenesis technology to study HIV protease and compare it to the eukaryotic aspartic proteases. When putative active-site hydrogen bonds are placed in the HIV protease, the pKa values of two active-site groups are only slightly downshifted. Corresponding removal of these H-bonds from the active sites of pepsin and rhizopuspepsin do not appreciably alter the active-site pKa values. The Kcat values are strongly decreased by these mutations. These observations suggest that the active-site H-bonds in HIV protease and other aspartic proteases control the rigidity of the catalytic apparatus but not the ionization of the active-site groups. A mechanism of catalysis by the HIV protease has been suggested based on kinetic and mutagenesis studies. The strategies involved in the development of HIV protease inhibitors are discussed. In spite of the pitfalls in each approach, it appears probable that a battery of inhibitors can be developed for the treatment of AIDS.
Optimization of Droplet Generation by Controlling PDMS Surface Hydrophobicity (2004)

This paper presents an optimized method for droplet generation in PDMS microchannels. With controllable PDMS surface hydrophobicity and hydrophobicity recovery, alternative component droplets can be generated as anticipated. Different surface hydrophobicity results in different droplet generation patterns. Monodispersed water-in-oil and oil-in-water droplets are generated from hydrophilic and hydrophobic surface respectively. Nearly hydrophilic surface (30°&amp;lt;θ&amp;lt;50°) results in long-tailed droplets and less hydrophilic surface (70°&amp;lt;θ&amp;lt;80°) results in stream mixing. Discussion of methods to loss and recovery hydrophobicity of PDMS also included.
Synthesis of Near-Infrared-Emitting, Water-Soluble CdTeSe/CdZnS Core/Shell Quantum Dots (2009)

Applications of near-infrared (NIR) emitting CdTe-based QDs have been hampered by their sensitivity to oxidation. Here, we describe a synthetic method for the growth of CdTeSe/CdZnS core/shell QDs emitting in the NIR range (700−800 nm). We first synthesize high-quantum-yield zinc-blende CdTeSe cores with gradient composition and tunable emission up to 800 nm. The CdZnS shell growth is performed with cadmium and zinc carboxylate and trioctylphosphine sulfur precursors in trioctylamine solvent, and yields thick shell with controlled zinc blende crystalline structure. The presence of a high-band-gap, oxidation-resistant shell considerably improves the quantum yield and stability of these QDs when solubilized in saline buffers, making them promising fluorescence probes for NIR biological imaging.
Design, Synthesis, and Estrogenic Activity of a Novel Estrogen Receptor ModulatorA Hybrid Structure of 17β-Estradiol and Vitamin E in Hippocampal Neurons (2007)

We recently discovered that ICI 182,780 (1), an antagonist of estrogen receptor (ER)-dependent proliferation in reproductive tissues, functions as an estrogenic agonist in primary neurons. The present study investigated whether the agonist properties of 1 in neurons could be translated into structural analogs. 7alpha-[(4R,8R)-4,8,12-trimethyltridecyl]estra-1,3,5-trien-3,17beta-diol (2), a hybrid structure of 17beta-estradiol and vitamin E, was synthesized and found to bind to both ERalpha and ERbeta. In vitro analyses demonstrated that 2 was neuroprotective and effective in activating molecular mechanisms associated with estrogenic agonist activity in rat primary hippocampal neurons. Collectively, the data support an estrogenic agonist profile of 2 action comparable to 1 in primary neurons, confirming that estrogenic activity of 1 in neurons is not a unique phenomenon. These results provide support for the development of a brain-selective ER modulator, with potential as an efficacious and safe estrogen alternative to prevent Alzheimer's disease and cognitive decline in postmenopausal women.
Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment. (1995)

The major histocompatibility complex class I-restricted cytotoxic T lymphocyte (CTL) response is important in the clearance of viral infections in humans. After influenza A infection, a peptide from the matrix protein, M58-66, is presented in the context of the MHC allele HLA-A0201 and the resulting CTL response is detectable in most HLA-A0201 subjects. An initial study suggested that M58-66-specific CTL clones show conserved T cell receptor (TCR) alpha and beta gene segments. We have addressed the significance of this observation by determining the expression of V beta 17 during the development of M58-66-specific CTL lines in 21 unrelated HLA-A0201 subjects, and analyzing TCR usage by M58-66-specific CTL clones. TCR V beta 17 was the dominant V beta segment used and CD8 V beta 17 expansion correlated with M58-66-specific lysis. Limiting dilution analysis from five subjects showed the M58-66 CTL precursor frequency to vary between 1/54,000 and less than 1/250,000, and that up to 85% of the matrix peptide (M58-66)-specific CTL used the V beta 17 gene segment. The M58-66 specific CTL response was dependent on previous viral exposure and specific V beta 17 expansion, as it was not found in cord blood, despite a readily expandable V beta 17+ CD8+ T cell subpopulation. Sequence analysis of 38 M58-66-specific V beta 17 transcripts from 13 subjects revealed extensive conservation in the CDR3 region including conservation of an arginine-serine motif. To test the dependence of this CTL response on the V beta 17 gene segment, peripheral blood lymphocytes were depleted of CD8+ TCR V beta 17+ cells, before the generation of M58-66-specific CTL. In most cases such depletion blocked or severely reduced the generation of the M58-66-specific response, and under limiting dilution conditions could abolish M58-66-specific CTL precursors. These studies reveal the dependence of this natural human immune response on a particular TCR gene segment.
Optimization of CIGS-Based PV Device through Antimony Doping (2009)

This communication discusses grain size enhancement in CIGS thin films induced by Sb-doping and demonstrates consequent photovoltaic (PV) device performance improvement in CIGS-based solar cells. The chemical-doping approach also shows promise in enabling low-temperature (≤ 400°C) processing of CIGS-based PV technology.
Demonstration of cross-protection between Pasteurella multocida type A and Pasteurella haemolytica, serotype 1 (1977)

Mice immunized with the potassium thiocyanate extract of Pasteurella haemolytica, serotype 1, were found to resist a challenge infection of P. multocida type A, thus demonstrating cross-protection. This finding was further supported by the finding that an antiserum directed against the potassium thiocyanate extract of P. haemolytica was bactericidal to P. multocida and vice versa.
CD20-Directed Small Modular Immunopharmaceutical, TRU-015, Depletes Normal and Malignant B Cells (2009)

These results indicate that TRU-015 may improve CD20-directed therapy by effectively depleting embedded malignant B cells and nonmalignant pathogenic B cells and do so with reduced complement activation.
Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669 (1991)

A growth factor-stimulated protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669 has been described (Countaway, J. L., Northwood, I. C., and Davis, R. J. (1989) J. Biol. Chem. 264, 10828-10835). Anion-exchange chromatography demonstrated that this protein kinase activity was accounted for by two enzymes. The first peak of activity eluted from the column corresponded to the microtubule-associated protein 2 (MAP2) kinase. However, the second peak of activity was found to be a distinct enzyme. We present here the purification of this enzyme from human tumor KB cells by sequential ion-exchange chromatography. The isolated protein kinase was identified as a 46-kDa protein by polyacrylamide gel electrophoresis and silver staining. Gel filtration chromatography demonstrated that the enzyme was functional in a monomeric state. A kinetic analysis of the purified enzyme was performed at 22 degrees C using a synthetic peptide substrate based on the primary sequence of the EGF receptor (KREL VEPLT669PSGEAPNQALLR). The Km(app) for ATP was 40 +/- 5 microM (mean +/- S.D., n = 3). GTP was not found to be a substrate for the purified enzyme. The Km(app) for the synthetic peptide substrate was 260 +/- 40 microM (mean +/- S.D., n = 3). The Vmax(app) for the isolated protein kinase was determined to be 400-900 nmol/mg/min. The purified enzyme was designated EGF receptor Thr669 (ERT) kinase. It is likely that the MAP2 and ERT kinases account for the phosphorylation of the EGF receptor at Thr669 observed in cultured cells. The marked stimulation of protein kinase activity caused by growth factors indicates that these enzymes may have an important function during signal transduction.
Laser capture microdissection, microarrays and the precise definition of a cancer cell (2004)

Most expression profiling studies of solid tumors have used biopsy samples containing large numbers of contaminating stromal and other cell types, thereby complicating any precise delineation of gene expression in nontumor versus tumor cell types. Combining laser capture microdissection, RNA amplification protocols, microarray technologies and our knowledge of the human genome sequence, it is possible to isolate pure populations of cells or even a single cell and interrogate the expression of thousands of sequences for the purpose of more precisely defining the biology of the tumor cell. Although many of the studies that currently allow for characterization of small sample preparations and single cells were performed utilizing noncancer cell types, and in some cases isolation protocols other than laser capture microdissection, a list of protocols are described that could be used for the expression analysis of individual tumor cells. Application of these experimental approaches to cancer studies may permit a more accurate definition of the biology of the cancer cell, so that ultimately, more specific targeted therapies can be developed.
Two novel GALNT3 mutations in familial tumoral calcinosis (2007)

Familial tumoral calcinosis (TC) is characterized by elevated serum phosphate concentrations, normal or elevated 1,25(OH)2 vitamin D, as well as periarticular and vascular calcifications. Recessive mutations in the mucin-like glycosyltransferase GalNAc transferase-3 (GALNT3) and the phosphaturic hormone fibroblast growth factor-23 (FGF23) have been shown to result in TC. In the present study, mutational analyses were performed on two patients with TC to determine the molecular basis of their diseases. Analysis of the first patient revealed a novel, homozygous base insertion (1102_1103insT) in GALNT3 exon 5 that results in a frameshift and premature stop codon (E375X). The second patient had a novel homozygous transition (1460 g>a) in GALNT3 exon 7, which caused a nonsense mutation (W487X). Both mutations are predicted to markedly truncate the mature GALNT3 protein product. Although the patients carry GALNT3 mutations, these individuals presented with low-normal serum concentrations of intact biologically active FGF23 and high levels of C-terminal FGF23. In order to discern a possible relationship between GALNT3 and FGF23 in TC, a comprehensive assessment of the reported TC mutations was also performed. In summary, we have detected novel GALNT3 mutations that result in familial TC, and show that disturbed serum FGF23 concentrations are present in our TC cases as well as in previously reported cases. These studies expand our current genetic understanding of familial TC, and support a pathophysiological association between GALNT3 and FGF23.
Diabetes Treatment, Part 3: Insulin and Incretins (2008)

I nsulin is the oldest and the most effective treatment to control glucose levels in diabetic patients. It was first used in the treatment of diabetes by Frederick Banting and Charles Best in 1922. Although originally thought to be a cure for diabetes, it soon became evident that insulin was a method of controlling the disorder. Insulin has been the most versatile of diabetes treatments because it may be used to control any degree of hyperglycemia of type 1 or type 2 diabetes. Although it was initially prepared by isolation from animal pancreatic tissue, insulin is now prepared through recombinant DNA techniques using microorganisms. Use of recombinant insulin has decreased the immunogenicity of commercially available insulin.

Type 1 diabetes is characterized by a loss of s-cells and therefore an absolute insulin deficiency. The mainstay of therapy, therefore, is insulin treatment. Because the disease does not affect insulin sensitivity, patients typically require small doses of insulin to maintain control of glucose levels. Type 2 diabetes, however, is characterized by preexisting insulin resistance followed by a relative insulin deficiency. As a result of insulin resistance and progressive insulin deficiency, patients with type 2 diabetes typically require higher doses of insulin and gradual upward titration of insulin doses.

Since the discovery of insulin and its use to treat diabetes, insulin has been combined with additives and modified at the molecular level to change its pharmacokinetic properties. Some insulin preparations accelerate insulin's effects in the bloodstream, whereas others prolong the pharmacokinetic profile. These insulin preparations may be used alone or in combination with other insulins in formulating an insulin regimen.

Regular insulin. Regular insulin was the first available insulin preparation and therefore the first short-acting insulin. At the time of injection, regular insulin self-associates to form hexamers, which are poorly absorbed into the circulation. …
Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors (2011)

Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NF-κB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O(2)•- and •NO and can be excluded for fast reacting radicals such as •OH, •OR, or Cl•; (ii) oxidant signals are H(2)O(2), enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)- and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-κB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed.
Biosynthesis of FVIII in megakaryocytic cells: improved production and biochemical characterization (2004)

Haemophilia A is an attractive target for gene therapy. We designed a haemophilia A gene therapy strategy involving the genetic modification of haematopoietic stem cells to achieve tissue-specific expression of a factor VIII (FVIII) transgene in the megakaryocytic lineage. Platelets would then serve as vehicles to store the expressed FVIII and deliver the coagulation factor at the site of vascular injury. A local correction of the haemostasis defect could, therefore, be expected following platelet activation and secretion. In this study, we demonstrated that a model of haematopoietic cell lines (Dami cells) could produce a correctly processed FVIII. FVIII transgenes were placed under the control of the human platelet glycoprotein IIb (GPIIb) promoter and used for stable transfection of the Dami megakaryocytic cell line. The highest FVIII production was obtained when the FVIII transgene contained a factor IX intron 1 gene sequence inserted in the FVIII intron 1 and 13 sites. Reverse transcription polymerase chain reaction demonstrated that the splicing of these introns was complete. Recombinant FVIII (rFVIII) produced in Dami cells was a biologically active molecule (specific activity: 5664 IU/mg) that was correctly glycosylated and sulphated. This recombinant FVIII protein exhibited biochemical characteristics after deglycosylation or thrombin activation that were comparable to a commercially available B-domainless rFVIII. These results demonstrate the advantages of a modified FVIII transgene and represent the first biochemical characterization of megakaryocyte-produced FVIII.
Defining the Role of Wnt/β‐Catenin Signaling in the Survival, Proliferation, and Self‐Renewal of Human Embryonic Stem Cells (2005)

We used a panel of human and mouse fibroblasts with various abilities for supporting the prolonged growth of human embryonic stem cells (hESCs) to elucidate growth factors required for hESC survival, proliferation, and maintenance of the undifferentiated and pluripotent state (self-renewal). We found that supportive feeder cells secrete growth factors required for both hESC survival/proliferation and blocking hESC spontaneous differentiation to achieve self-renewal. The antidifferentiation soluble factor is neither leukemia inhibitory factor nor Wnt, based on blocking experiments using their antagonists. Because Wnt/beta-catenin signaling has been implicated in cell-fate determination and stem cell expansion, we further examined the effects of blocking or adding recombinant Wnt proteins on undifferentiated hESCs. In the absence of feeder cell-derived factors, hESCs cultured under a feeder-free condition survived/proliferated poorly and gradually differentiated. Adding recombinant Wnt3a stimulated hESC proliferation but also differentiation. After 4-5 days of Wnt3a treatment, hESCs that survived maintained the undifferentiated phenotype but few could form undifferentiated hESC colonies subsequently. Using a functional reporter assay, we found that the beta-catenin-mediated transcriptional activation in the canonical Wnt pathway was minimal in undifferentiated hESCs, but greatly upregulated during differentiation induced by the Wnt treatment and several other methods. Thus, Wnt/beta-catenin activation does not suffice to maintain the undifferentiated and pluripotent state of hESCs. We propose a new model for the role of Wnt/beta-catenin signaling in undifferentiated hESCs.
Bone grafts and biomaterials substitutes for bone defect repair: A review (2017)

Bone grafts have been predominated used to treat bone defects, delayed union or non-union, and spinal fusion in orthopaedic clinically for a period of time, despite the emergency of synthetic bone graft substitutes. Nevertheless, the integration of allogeneic grafts and synthetic substitutes with host bone was found jeopardized in long-term follow-up studies. Hence, the enhancement of osteointegration of these grafts and substitutes with host bone is considerably important. To address this problem, addition of various growth factors, such as bone morphogenetic proteins (BMPs), parathyroid hormone (PTH) and platelet rich plasma (PRP), into structural allografts and synthetic substitutes have been considered. Although clinical applications of these factors have exhibited good bone formation, their further application was limited due to high cost and potential adverse side effects. Alternatively, bioinorganic ions such as magnesium, strontium and zinc are considered as alternative of osteogenic biological factors. Hence, this paper aims to review the currently available bone grafts and bone substitutes as well as the biological and bio-inorganic factors for the treatments of bone defect.
Distributed dynamic feedback control for smart power networks with tree topology (2014)

In this paper, we design a distributed dynamic feedback controller that implements real-time economic optimization in power networks with tree topology. We consider the coupling between the dynamics of the power network and the appropriately formulated optimization problem in the real-time market, i.e., when the time-scale separation between markets and network dynamics fades. The design methodology is motivated by optimization decomposition methods in that the controller is derived from a primal-dual decomposition approach. We then prove the asymptotic stability of the overall (closed-loop) system in a scalable fashion. The performance of the controller is illustrated by numerical investigations.
Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor [see comments] (1995)

Peripheral blood stem cells (PBSCs) are widely used in autologous transplantation because of ease of collection and rapid hematopoietic reconstitution. However, PBSCs have rarely been used for allogeneic transplantation because of concerns about donor toxicities from cytokine administration and the theoretical increased risk of graft-versus-host-disease (GVHD) from the large number of T cells infused. Eight patients with advanced malignancies received allogeneic PBSC transplants from genotypically HLA-identical sibling donors. All donors received 5 days of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 16 micrograms/kg/day) subcutaneously and were leukapheresed for 2 days. After treatment of the patient with total body irradiation and cyclophosphamide (n = 7) or etoposide, thiotepa, and cyclophosphamide (n = 1), PBSCs were infused immediately after collection and without modification. All patients received cyclosporine and either methotrexate (n = 6) or prednisone (n = 2) for GVHD prophylaxis, rhG-CSF was well tolerated with mild bone pain requiring acetaminophen occurring in two donors. All patients engrafted and in seven hematopoietic recovery was rapid, with 500 neutrophils/microL achieved by day 18 and 20,000 platelets/microL by day 12. Complete donor engraftment was documented by Y chromosome analysis in all four sex-mismatched donor-recipient pairs tested and by DNA analysis in two sex-matched pairs. One patient died on day 18 of veno-occlusive disease of the liver with engraftment but before chromosome analysis could be performed (results are pending in 1 patient). A second patient died of fungal infection 78 days after transplant. Grade 2 acute GVHD occurred in two patients and grade 3 GVHD occurred in one patient. One patient is 301 days from transplant in remission with chronic GVHD; the remaining five patients are alive and disease free 67 to 112 days after transplantation. Preliminary results indicate that allogeneic PBSCs mobilized by rhG-CSF can provide rapid hematologic recovery without an appreciably greater incidence of acute GVHD than would be expected with marrow. Further follow-up is required to determine the incidence of chronic GVHD and any potential beneficial effects on relapse after transplant.