gebhart/patrepeval huggingface dataset:
Nerve growth factor binding domain of the nerve growth factor receptor. (1991)

A structural analysis of the rat low-affinity nerve growth factor (NGF) receptor was undertaken to define the NGF binding domain. Mutant NGF receptor DNA constructs were expressed in mouse fibroblasts or COS cells, and the ability of the mutant receptor to bind NGF was assayed. In the first mutant, all but 16 amino acid residues of the intracellular domain of the receptor were removed. This receptor bound NGF with a Kd comparable to that of the wild-type receptor. A second mutant contained only the four cysteine-rich sequences from the extracellular portion of the protein. This mutant was expressed in COS cells and the resultant protein was a secreted soluble form of the receptor that was able to bind NGF. Two N-terminal deletions, in which either the first cysteine-rich sequence of the first and part of the second cysteine-rich sequences were removed, bound NGF. However, a mutant lacking all four cysteine-rich sequences was unable to bind NGF. These results show that the four cysteine-rich sequences of the NGF receptor contain the NGF binding domain.
Microfabricated electrolysis pump system for isolating rare cells in blood (2003)

An integrated system for immunomagnetic separation of rare cells from blood is presented. A micromachined device was fabricated by bonding silicon die with etched structures to a glass cover plate on which electrodes are defined. Electrolytic generation of gas from 0.50 M KNO3 (aqueous) provided pumping actuation for a device that performed the capture and purification of rare cells spiked into a 7.5 ul reconstituted blood sample. The system consisted of two pumps, a sample and a wash buffer meander reservoir, and a main channel for magnetic field trapping of rare cells captured by antibody-coated magnetic beads. A maximum pumping rate of 1.4 +- 0.1 ul min[?]1 was obtained at a current of 180 uA, and the maximum blood sample volume delivered to the capture bed was 6.5-7 ul. The trapped cells could be washed with the buffer from the second pump and then delivered to the exit port of the chip after removing the magnetic field.
Toll-Like Receptor 3 Signaling on Macrophages Is Required for Survival Following Coxsackievirus B4 Infection (2009)

Toll-like receptor 3 (TLR3) has been proposed to play a central role in the early recognition of viruses by sensing double stranded RNA, a common intermediate of viral replication. However, several reports have demonstrated that TLR3 signaling is either dispensable or even harmful following infection with certain viruses. Here, we asked whether TLR3 plays a role in the response to coxsackievirus B4 (CB4), a prevalent human pathogen that has been associated with pancreatitis, myocarditis and diabetes. We demonstrate that TLR3 signaling on macrophages is critical to establish protective immunity to CB4. TLR3 deficient mice produced reduced pro-inflammatory mediators and are unable to control viral replication at the early stages of infection resulting in severe cardiac damage. Intriguingly, the absence of TLR3 did not affect the activation of several key innate and adaptive cellular effectors. This suggests that in the absence of TLR3 signaling on macrophages, viral replication outpaces the developing adaptive immune response. We further demonstrate that the MyD88-dependent signaling pathways are not only unable to compensate for the loss of TLR3, they are also dispensable in the response to this RNA virus. Our results demonstrate that TLR3 is not simply part of a redundant system of viral recognition, but rather TLR3 plays an essential role in recognizing the molecular signatures associated with specific viruses including CB4.
Activation of Ras by receptor tyrosine kinases. (1994)

Ras, a small GTP-binding protein, is an important component of the signal transduction pathway used by growth factors to initiate cell growth and differentiation. Cell activation with growth factors such as epidermal growth factor (EGF) induces Ras to move from an inactive GDP-bound state to an active GTP-bound state. Recently, a combination of genetic and biochemical studies has resulted in the elucidation of a signaling pathway that leads from growth factor receptors to Ras. After binding EGF, the EGF receptor tyrosine kinase is activated, leading to receptor autophosphorylation on multiple tyrosine residues. Signaling proteins with Src homology 2 (SH2) domains then bind to these tyrosine-phosphorylated residues, initiating multiple signaling cascades. One of these SH2 domain proteins, Grb2, exists in the cytoplasm in a preformed complex with a second protein, Son of Sevenless (Sos), which can catalyze Ras GTP/GDP exchange. After growth factor stimulation, the tyrosine phosphorylated EGF receptor binds the Grb2/Sos complex, translocating it to the plasma membrane. This translocation is thought to bring Sos into close proximity with Ras, leading to the activation of Ras. In contrast, the insulin receptor does not bind Grb2 directly but rather induces the tyrosine phosphorylation of two proteins, insulin receptor substrate-1 and Shc, that bind the Grb2/Sos complex. Once Ras is activated, it proceeds to stimulate a cascade of protein kinases that are important in a myriad of growth factor responses.
Carbohydrate–Metal Interactions Shaped by Supramolecular Assembling (2005)

Cyclodextrin ligands: Carbohydrates can be used as framework molecules that provide patterns of metal-binding oxygen atoms. The divalent forms of the biologically important metals iron and manganese can be part of such assemblies (see structure: Fe blue, O red, counterion green, hydrogen bonds between water molecules yellow). The assemblies are stabilized by favorable contributions other than the carbohydrate–metal interaction.
Postprandial control of gallbladder contraction and exocrine pancreatic secretion in man (1992)

To explore the interactions between cholecystokinin (CCK) and the cholinergic system, we compared the effect of cholinergic or peptidergic CCK blockade on gallbladder contraction and pancreatic enzyme secretion using atropine and loxiglumide (a specific CCK antagonist) as pharmacological tools. Gallbladder contraction was measured by sonography and pancreatic secretion by a marker perfusion and aspiration technique. Graded doses of exogenous CCK8 induced dose-dependent contractions of the gallbladder and increasing enzyme outputs. Loxiglumide (10 mg kg-1 h-1) abolished the gallbladder response and prevented an increase in pancreatic enzyme secretion to CCK8. Atropine (5 micrograms kg-1 h-1), however, only reduced gallbladder contraction and enzyme output to CCK8. Gallbladder volumes decreased maximally to 12 +/- 4% after oral food, whereas enzyme output and plasma CCK levels increased 6- to 8-fold. Loxiglumide completely abolished gallbladder contraction and inhibited enzyme secretion by 30%. Atropine caused a small reduction in gallbladder volumes, but essentially blocked postprandial enzyme secretion. The results indicate that CCK is the major regulator of gallbladder contraction with the cholinergic system modulating the response, while the exocrine pancreas is crucially dependent on a cholinergic background with CCK modulating the secretory response.
Kinetic analysis of the folding and unfolding of a mutant form of bovine pancreatic trypsin inhibitor lacking the cysteine-14 and -38 thiols (1988)

The kinetics of the disulfide-coupled unfolding-refolding transition of a mutant form of bovine pancreatic trypsin inhibitor (BPTI) lacking Cys-14 and -38 were measured and compared to previous results for the wild-type protein and other modified forms. The altered cysteines, which were changed to serine in the mutant protein, are normally paired in a disulfide in the native protein but from disulfides with Cys-5 in two-disulfide kinetic intermediates during folding. Although the mutant protein could fold efficiently, the kinetics of both folding and unfolding were altered, reflecting the roles of these cysteines in the two-disulfide intermediates with "wrong" disulfides. The intramolecular rate constant for the formation of the second disulfide of the native mutant protein was more than 10(3)-fold lower than that for the formation of a second disulfide during the refolding of the wild-type protein. The observed rate of unfolding of the mutant protein was also lower than that of the wild-type protein, demonstrating that the altered cysteines are involved in the intramolecular rearrangements that are the rate-determining step in the unfolding of the wild-type protein. These results confirm the previous conclusion [Creighton, T.E. (1977) J. Mol. Biol. 113, 275-293] that the energetically preferred pathway for folding and unfolding of BPTI includes intramolecular rearrangements of intermediates in which Cys-14 and -38 are paired in disulfides not present in the native protein. The present results are also consistent with other, less detailed, studies with similar mutants lacking Cys-14 and -38 [Marks, C.B., Naderi, H., Kosen, P.A., Kuntz, I.D., & Anderson, S. (1987) Science (Washington, D.C.) 235, 1370-1371].
Remarks on space-time codes including a new lower bound and an improved code (2003)

This article presents a new asymptotically exact lower bound on pairwise error probability of a space-time code as well as an example code that outperforms the comparable orthogonal-design-based space-time (ODST) code. Also contained in the article are an exact expression for pairwise error probability (PEP), signal design guidelines, and some observations relating to the reception of ODST codes.
Ligand-Induced Transformation by a Noninternalizing Epidermal Growth Factor Receptor (1990)

Identification of a mutant epidermal growth factor (EGF) receptor that does not undergo downregulation has provided a genetic probe to investigate the role of internalization in ligand-induced mitogenesis. Contact-inhibited cells expressing this internalization-defective receptor exhibited a normal mitogenic response at significantly lower ligand concentrations than did cells expressing wild-type receptors. A transformed phenotype and anchorage-independent growth were observed at ligand concentrations that failed to elicit these responses in cells expressing wild-type receptors. These findings imply that activation of the protein tyrosine kinase activity at the cell membrane is sufficient for the growth-enhancing effects of EGF. Thus, downregulation can serve as an attenuation mechanism, without which transformation ensues.
A novel thiolase–reductase gene fusion promotes the production of polyhydroxybutyrate in Arabidopsis (2005)

The production of polyhydroxybutyrate (PHB) involves a multigene pathway consisting of thiolase, reductase and synthase genes. In order to simplify this pathway for plant-based expression, a library of thiolase and reductase gene fusions was generated by randomly ligating a short core linker DNA sequence to create in-frame fusions between the thiolase and reductase genes. The resulting fusion constructs were screened for PHB formation in Escherichia coli. This screen identified a polymer-producing candidate in which the thiolase and reductase genes were fused via a 26-amino-acid linker. This gene fusion, designated phaA-phaB, represents an active gene fusion of two homotetrameric enzymes. Expression of phaA-phaB in E. coli and Arabidopsis yielded a fusion protein observed to be the expected size by Western blotting techniques. The fusion protein exhibited thiolase and reductase enzyme activities in crude extracts of recombinant E. coli that were three-fold and nine-fold less than those of the individually expressed thiolase and reductase enzymes, respectively. When targeted to the plastid, and coexpressed with a plastid-targeted polyhydroxyalkanoate (PHA) synthase, the fusion protein enabled PHB formation in Arabidopsis, yielding roughly half the PHB formed in plants expressing individual thiolase, reductase and synthase enzymes. This work represents a first step towards simplifying the expression of the PHB biosynthetic pathway in plants.
Gout in 2006: the perfect storm. (2006)

Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.
Kluge Ideen alleine versetzen keine Berge (2011)

Wieso scheitern viele aufwendig erstellte strategische Konzepte während ihrer Umsetzung – oder landen gleich nach der Planung in der Schublade? Unsere Antwort ist eindeutig: Die Konzepterstellung erhält schlicht mehr Aufmerksamkeit. Es ist ein spannendes intellektuelles Abenteuer für innovative Fragestellungen, Antworten zu entwickeln. Aus der Sicht vieler „Überflieger“ ist im Gegensatz dazu die Implementierung eine eher bescheidene Aufgabe, selbst wenn sie erfolgreich abgeschlossen wird. Die reine Umsetzung wirkt wie eine „graue Maus“, und nicht alle nehmen sie deshalb ernst: Immerhin geht es „nur“ darum, Denkmodelle sachkundig zu operationalisieren. In diesem Moment wenden die Strategen ihre Aufmerksamkeit schon der nächsten Strategiefindung zu. Die Allokation von Ressourcen wie Budgets, Mitarbeiter und Zeit folgt häufig dieser Hierarchie der Wahrnehmung. Obwohl das Projekt gerade beginnt, werden die Schritte des Umsetzungsteams nicht immer mit der nötigen Wertschätzung begleitet. Das kann in der betrieblichen Praxis dazu führen, dass hilfreiche Unterstützung fehlt. Die Aufgabe der Umsetzung ist aus unserer Sicht komplex: Ambitionierte Ziele warten darauf, im Unternehmen verankert zu werden. Auch erfahrene Praktiker geraten dabei unter Druck.
Incorporation of 3H-amino acids into proteins in a partially purified fraction of axoplasm: evidence for transfer RNA-mediated, post- translational protein modification in squid giant axons (1983)

Transfer RNA (tRNA) has been demonstrated to be present in axons of both invertebrates and the higher vertebrates, but nothing is known of its role in the metabolism of the axon. The present experiments were performed to determine whether tRNA functions in axons as a participant in post-translational protein modification of endogenous proteins. RNA was extracted from the axoplasm of squid giant axons and incubated with a variety of 3H-amino acids, aminoacyl-tRNA synthetases (obtained from squid optic lobe), and an appropriate reaction mixture. All of the amino acids tested were bound to an RNA fraction, but this reaction did not occur when samples were incubated in the presence of ribonuclease or in the absence of axoplasmic RNA. When radioactive RNA was chromatographed by polyacrylamide gel electrophoresis, the radioactivity comigrated with known tRNA markers, suggesting the presence of 3H-aminoacylated tRNA. Aminoacylation of RNA could also be demonstrated by incubating fresh axoplasm with labeled amino acids and a reaction mixture, minus exogenous aminoacyl-tRNA synthetases. These findings indicate the presence in axoplasm of a variety of species of aminoacyl-tRNAs as well as their corresponding synthetase enzymes. In the latter experiment no radioactivity was found associated with the protein fraction. This was also the finding when 3H-aminoacylated tRNA was either injected directly into the axon or incubated with extruded axoplasm. Thus, under the conditions described above, there is no evidence of transfer of amino acids from tRNA to proteins. In other experiments, axoplasm was pooled to a volume of 50 to 100 microliters, homogenized gently, and centrifuged at 150,000 X g for 1 hr. Some of the high speed supernatant was incubated with labeled amino acids and an appropriate reaction mixture, and the remainder was passed through an S-200 Sephacryl column before incubation with the same reaction mixture. There was no incorporation of amino acids into protein in the high speed supernatant fraction. However, in the S-200 purified fraction 3H-labeled Arg, Lys, Tyr, Leu, and Asp were all incorporated into proteins in amounts of 44, 30, 7, 5 and 3.5 times heat-inactivated controls. The reaction is not inhibited by Ca2+ or Ca2+-activated proteases, but appears to be dependent on the presence of tRNA. The addition of amino acids to protein is not protein synthesis since the reactions occurred in a partially purified fraction of the 150,000 X g supernatant, a fraction devoid of ribosomes and free amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
1277 (2012)

Case Reports: Hypertension occurs in approximately 25% of the adult population and is a major cause of stroke, cardiovascular disease and renal failure, and a significant comorbidity in the ICU. Hypertension control is achieved in approximately 20-50% of treated hypertensive patients, suggesting current antihypertensive therapy could be improved. Although BP level is used to define hypertension, BP is determined by the product of CO and SVR; BP = CO x SVR. Therefore hypertension may be a consequence of high CO, high SVR, or both. Further, CO and SVR are the direct targets of anti-hypertensive therapy, with BP an indirect outcome. Transcutaneous Doppler (USCOM, Uscom Ltd, Australia) provides simple, noninvasive and accurate measurements of CO (validated from 0.12l/min to 18.7l/min), with SVR calculated from CO and BP. USCOM may be useful in determining the pathophysiology of hypertension and guiding therapy.Case History: A 74yo female was ICU hospitalized for 8 weeks with severe uncontrolled hypertension (BP=187/85, MAP=115mmHg, HR=104) and hypertensive encephalopathy. The patient was treated with fluid control using CRRT, and the vasodilator glyceryl trinitrate 1.5ug/min/kg.USCOM baseline: CO=12.3L/min, SVR=697Dyne.s.cm-5, CPo=3.2W and SW=1886mJ. The GTN was reducing the SVR by dilating the vessels, and thereby increasing the CO. Effectively the GTN treatment was increasing the BP.Intervention: The GTN and CRRT were ceased and USCOM’s performed 30minutes and 16hrs later to monitor the circulation.At 30 minutes BP=154/76mmHg, MAP=102mmHg, CO=9.3L/min, SVR=866Dyne.s.cm-5, CPo=2.1W and SW=1107mJ.At 16 hours BP=145/68mmHg, MAP=94mmHg, CO=7.2L/min, SVR=1007Dyne.s.cm-5, CPo=1.5W and SW=965mJ.The total percentage decreases after withdrawal of therapy were HR 11%, MAP 18%, CO 44%, CPo 53%, SW 48%, while SVR was increased by 44%. Conclusion: In this case of cardiogenic hypertension, GTN was an inappropriate therapy. Objective measures of CO and SVR may guide more accurate and cost-effective delivery of individualised anti-hypertensive therapy and improve our understanding of the disease.
Base transitions are the most frequent genetic changes at P53 in gastric cancer. (1993)

We searched for P53 mutations in gastric carcinoma by analyzing tumor DNAs from 29 patients. We detected 13 different somatic mutations in 15 patients (52%) and a biallelic polymorphism in exon 6 (5 heterozygous subjects). The somatic mutations were mainly localized in the sequences corresponding to the highly conserved domains of the protein. Twelve samples showed a single base change: 11 missense and 1 nonsense mutations. Three samples showed deletions leading to a frame shift, to the in-frame loss of 2 amino acids, and to the deletion of a splicing site. All point mutations, except one, were transitions, and 91% of them were G:C-->A:T changes. We previously analyzed this panel of tumors for allelic loss at the 17p13 chromosomal region, where the P53 gene had previously been located: the results showed an increasing incidence of allelic loss in late-stage tumors. On the contrary, in the present study no trend between P53 mutations and tumor stages was found. This observation indicates that mutation events precede allelic loss in gastric cancer. Half (54%) of the mutations occurred in samples without allelic loss, suggesting that specific mutated alleles, acting in a dominant negative fashion, can alter in vivo the P53 protein function.
Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion (2007)

These findings suggest that hypothermic neuroprotection might be achieved by blocking AIF and cytochrome c-mediated apoptosis.
Hydroxyl group of insulin A19Tyr is essential for receptor binding: Studies on (A19Phe) insulin (1998)

One mutant proinsulin gene was constructed through PCR with the code of A19Tyr changed into that of Phe. The mutant proinsulin, (A19Phe)-lysproinsulin (F19KPI) was expressed in E. coli and purified. After trypsin and carboxypeptidase B cleavage and Resource Q separation, (A19Phe)-human insulin (F19HI) was obtained. With native insulin as standard, activity assay and structural analysis were carried out. It was found that the conformation of F19HI is very similar to that of native insulin according to the data from native PAGE, reverse-phase FPLC and circular dichroism spectrum, which are also in agreement with the result of radioimmune assay. F19HI retains almost full immune activity, but displays only 13.3% of receptor binding activity. These results suggest that the hydroxyl group of insulin A19Tyr is essential for receptor binding.
Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors (2011)

The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.
Implant Resist Approaches for 193nm Second Generation Radiation Sensitive Developable Bottom Anti Reflective Coatings (2007)

Our approach towards a second generation radiation sensitive developable bottom antireflective coating (DBARC's) for 193 nm and its use with different implant resist resin types will be discussed. Ion beam implant resistance (As implantation 15 KeV at 5X1015 dose with 20X10-4 amp) and imaging results (1:1 L/S features down to 140 nm) will be shown comparing implant resist materials based upon a fluorinated resins or alicyclic/acrylate resins. Surprisingly, we found that the non-fluorinated materials gave better implant resistance (∼2-3 X1011 atoms/cm2) despite the higher atomic number of fluorine compared to hydrogen in the fluorinated implant materials (∼2-5X1012 atoms/cm2). Finally, an update on the current lithographic performance of the acrylate/alicylic implant resist on second generation DBARC will be discussed.