gebhart/patrepeval huggingface dataset:
Reciprocal developmental changes in the roles of Bcl-w and Bcl-xL in regulating sensory neuron survival (2001)

We have compared the roles of two anti-apoptotic members of the Bcl2 family, Bcl-w and Bcl-x(L), in regulating the survival of sensory neurons during development. We used microinjection to introduce expression plasmids containing Bcl-w and Bcl-x(L) cDNAs in the sense and antisense orientations into the nuclei of BDNF-dependent nodose neurons and NGF-dependent trigeminal neurons at stages during and after the period of naturally occurring neuronal death. Whilst overexpression of either protein promoted neuronal survival in the absence of neurotrophins and microinjection of antisense constructs reduced neuronal survival in the presence of neurotrophins, the magnitude of these effects changed with age. Whereas Bcl-w overexpression became more effective in promoting neuronal survival with age, Bcl-x(L) overexpression became less effective, and whereas antisense Bcl-w became much more effective in killing neurotrophin-supplemented neurons with age, antisense Bcl-x(L) became much less effective in killing these neurons. There was a marked increased in Bcl-w mRNA and Bcl-w immunoreactive neurons and a decrease in Bcl-x(L) mRNA and Bcl-x(L) immunoreactive neurons in the trigeminal and nodose ganglia over this period of development. Our results demonstrate that both Bcl-w and Bcl-x(L )play an important anti-apoptotic role in regulating the survival of NGF- and BDNF-dependent neurons, and that reciprocal changes occur in the relative importance of these proteins with age. Whereas Bcl-x(L) plays a more important role during the period of naturally occurring neuronal death, Bcl-w plays a more important role at later stages.
Self-configuring Localization Systems: Design and Experimental Evaluation (2004)

Embedded networked sensors promise to revolutionize the way we interact with our physical envi- ronment and require scalable, ad hoc deployable and energy-ecient node localization/positioning. This paper describes the motivation, design, implementation and experimental evaluation (on sharply resource-constrained devices) of a self-conï¿½guring localization system using radio beacons. We identify beacon density as an important parameter in determining localization quality, which saturates at a transition density. We develop algorithms to improve localization quality by (i) automating placement of new beacons at low densities (HEAP) and (ii) rotating functionality among redundant beacons while increasing system lifetime at high densities (STROBE).
Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department* (2010)

Elapsed times from triage and qualification for early goal-directed therapy to administration of appropriate antimicrobials are primary determinants of mortality in patients with severe sepsis and septic shock treated with early goal-directed therapy.
Simultaneous measurement of temperature and strain using dual long-period fiber gratings with controlled temperature and strain sensitivities (2003)

Unambiguous simultaneous measurement of strain and temperature based on dual long-period fiber gratings by controlling their thermal and strain sensitivities is proposed and experimentally demonstrated. The difference in the wavelength peak shift and the separation with the variation of strain and temperature allows discrimination between the strain and temperature effects, respectively.
1124. Correction of Glycogen Storage Disease Type II by an AAV Vector Encoding Highly-Secreted, Chimeric Acid α-glucosidase (2005)

Top of pageAbstract
GSD-II (Pompe disease; MIM 232300) is an autosomal recessive disorder caused by the deficiency in the activity of the lysosomal enzyme acid |[alpha]|-glucosidase (GAA; acid maltase; EC 3.2.1.20). The disease is characterized by the massive accumulation of glycogen in lysosomes and in the cytoplasm of striated muscle, with an accompanying disruption of cellular functions. The efficacy of therapy with lysosomal enzymes, such as GAA, could be markedly improved if secretion of these proteins from producer cells were increased. Secreted proteins are directed extracellularly by the presence of an N-terminal signal peptide. We have investigated the hypothesis that a chimeric lysosomal enzyme containing an alternative signal peptide will achieve much higher secretion of the recombinant lysosomal enzyme from transduced cells. The coding sequence of human GAA was modified by substituting alternative signal peptides from highly secreted proteins for the native GAA signal peptide (denoted chimeric GAA). The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold, compared to the secretion of unmodified GAA. The efficacy of this strategy for gene therapy in Pompe disease was analyzed in GAA-knockout (GAA-KO) mice. An adeno-associated virus (AAV) vector containing a liver-specific promoter to drive the expression of GAA was constructed (AAV-LSPSPhGAApA) and pseudotyped as AAV8. The long-term efficacy of SP-hGAA was evaluated by the quantitation of GAA activity and glycogen content following AAV-LSPSPhGAApA administration. A dose-response analysis revealed sustained, high GAA activity in plasma following administration of at least 3 |[times]| 1010 particles; however, an equivalent number of particles for a vector encoding unmodified GAA did not elevate GAA activity in plasma. Receptor-mediated uptake of secreted GAA can be demonstrated only if plasma levels exceed a therapeutic threshold, and the GAA activity of the heart and diaphragm were significantly elevated 18 weeks following administration of as few as 1 |[times]| 1010 particles of AAV-LSPSPhGAApA. GAA activity in the quadriceps muscle was increased with as few as 3 |[times]| 1010 particles of AAV-LSPSPhGAApA. The lower threshold for significant reduction of heart, diaphragm, and quadriceps glycogen content with AAV-LSPSPhGAApA was 3 |[times]| 1010 particles. Neither fewer particles for that vector, nor an equivalent number of particles of the analogous vector encoding unmodified GAA affected glycogen content in the quadriceps. Thus, an AAV vector encoding chimeric GAA increased the secretion of hGAA from the liver, and reduced the number of vector particles required to achieve a therapeutic effect in GSD-II mice.
Organic Pollution in an Enclosed Bay on the Pacific Coast in Japan Judged from the Macrobenthic Community Structure (1990)

Seasonal fluctuations of macrobenthic community structure were studied in Uranouchi Bay, Japan. In summer, there were no benthic animals in the middle and inner parts of the bay. Benthic animals were recolonized in winter. Dominant animal groups were polychaete worms and bivalves. Most of them were short-lived small animals and are the indicator species for organic pollution. This bay is enclosed, where culturing of yellowtails has been continued for more than 30 years. Therefore, the organic content in sediments is very high. It is also known that the oxygen depletion less than 10 % in saturation in bottom water occurs widely in summer. These facts on benthic community structure and bottom environmental conditions indicate that the organic pollution of this bay is very heavy. The improvement of the organic pollution in this bay will be performed only by the artificial topographic change to facilitate bay water mixing.
Oxidation of Guanine in DNA by Ru(phen)2(dppz)3+ Using the Flash-Quench Technique (1997)

A flash-quench method has been developed to probe oxidative damage to DNA. A photoexcited Ru(II) intercalator is quenched in DNA by a weakly bound, electron-transfer quencher to generate Ru(III), a powerful ground-state oxidant. Once generated, Δ-Ru(phen)2(dppz)3+ bound to poly(dG-dC) rapidly oxidizes guanine within the DNA duplex. Transient absorption spectroscopy indicates rapid formation of the neutral guanine radical within the DNA duplex. Permanent damage resulting from the flash-quench experiment is monitored by gel electrophoresis of synthetic oligonucleotide duplexes. Oxidative damage, visualized by treatment with piperidine, occurs selectively at the 5‘-G of 5‘-GG-3‘ sites and at the 5‘- and central G of 5‘-GGG-3‘ triplets; enzymatic digestion in the absence of piperidine treatment shows formation of 8-oxo-2‘-deoxyguanosine with Ru(NH3)63+ as quencher. The yield of base damage is, furthermore, modulated by the choice of electron-transfer quencher. Quantum yields for damage vary in the order Ru(NH3)63+ < methyl viologen2+ < Co(NH3)5Cl2+ and correlate with the instability of the reduced quencher. The flash-quench method, combining spectroscopy and product analysis, offers a novel and tunable approach to explore electron transfer chemistry on double helical DNA.
Expression and characteristics of a novel human osteosarcoma-associated cell surface antigen. (1988)

The characteristics of a new osteosarcoma-associated cell surface antigen were studied by means of two murine monoclonal antibodies, TP-1 and TP-3, which were found to bind to two different epitopes on the same antigen, a monomeric polypeptide with a molecular weight of approximately 80,000. Immunohistochemical studies showed that the antigen was present in all osteogenic sarcomas tested, in most cases of malignant fibrous histiocytoma, in two malignant hemangiopericytomas and in a few synovial sarcomas, but not in other main groups of sarcomas and nonsarcomatous malignancies. In normal tissues it was detected only in clusters of cells in the adrenal medulla and in proximal kidney tubules. Also endothelial cells in proliferating capillaries in placenta and in most tumors were stained. The antigen was absent in resting but present in actively proliferating osteoblastic cells. The epitopes were resistant to proteolytic and sugar-cleaving enzymes but sensitive to high temperatures and could not be detected in paraffin-embedded specimens. The tissue distribution and properties of the antigen show that it is different from the sarcoma-associated antigens previously studied. In contrast to previous findings with three other anti-sarcoma monoclonal antibodies, no correlation was found between serum alkaline phosphatase activity and the amount of TP-binding substances in the same sera. Nevertheless, an apparently complex association between alkaline phosphatase and the TP-binding antigen seems to exist. Thus, the Mr 80,000 antigen extracted from an osteosarcoma cell line showed enzyme activity, whereas TP-binding molecules precipitated from patient sera contained alkaline phosphatase activity only in a few of the cases studied. Altogether our data suggest that the antigen defined by the TP antibodies may be a marker of osteoblastic differentiation. The pattern of antigen expression in malignant tumors is unique, inasmuch as the antigen is found selectively in sarcomas and in all 31 osteosarcomas tested.
Oligonucleotide N3'-->P5' phosphoramidates as antisense agents (1996)

Uniformly modified oligonucleotide N3'-->P5' phosphoramidates, where every 3'-oxygen is replaced by a 3'-amino group, were synthesized. These compounds have very high affinity to single-stranded RNAs and thus have potential utility as antisense agents. As was shown in this study, the oligonucleotide phosphoramidates are resistant to digestion with snake venom phosphodiesterase, to nuclease activity in a HeLa cell nuclear extract, or to nuclease activity in 50% human plasma, where no significant hydrolysis was observed after 8 h. These compounds were used in various in vitro cellular systems as antisense compounds addressed to different targeted regions of c-myb, c-myc and bcr-abl mRNAs. C-myb antisense phosphoramidates at 5 microM caused sequence and dose-dependent inhibition of HL-60 cell proliferation and a 75% reduction in c-myb protein and RNA levels, as determined by Western blot and RT-PCR analysis. Analogous results were observed for anti-c-myc phosphoramidates, where a complete cytostatic effect for HL-60 cells was observed at 1 microM concentration for fully complementary, but not for mismatched compounds, which were indistinguishable from untreated controls. This was correlated with a 93% reduction in c-myc protein level. Moreover, colony formation by the primary CML cells was also inhibited 75-95% and up to 99% by anti-c-myc and anti-bcr-abl phosphoramidate oligonucleotides, respectively, in a sequence- and dose-dependent manner within a 0.5 nM-5 microM dose range. At these concentrations the colony-forming ability of normal bone marrow cells was not affected. The presented in vitro data indicate that oligonucleotide N3'-->P5' phosphoramidates could be used as specific and efficient antisense agents.
NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains (1998)

Polymers of N-substituted glycines ("peptoids") containing chiral centers at the alpha position of their side chains can form stable structures in solution. We studied a prototypical peptoid, consisting of five para-substituted (S)-N-(1-phenylethyl)glycine residues, by NMR spectroscopy. Multiple configurational isomers were observed, but because of extensive signal overlap, only the major isomer containing all cis-amide bonds was examined in detail. The NMR data for this molecule, in conjunction with previous CD spectroscopic results, indicate that the major species in methanol is a right-handed helix with cis-amide bonds. The periodicity of the helix is three residues per turn, with a pitch of approximately 6 A. This conformation is similar to that anticipated by computational studies of a chiral peptoid octamer. The helical repeat orients the amide bond chromophores in a manner consistent with the intensity of the CD signal exhibited by this molecule. Many other chiral polypeptoids have similar CD spectra, suggesting that a whole family of peptoids containing chiral side chains is capable of adopting this secondary structure motif. Taken together, our experimental and theoretical studies of the structural properties of chiral peptoids lay the groundwork for the rational design of more complex polypeptoid molecules, with a variety of applications, ranging from nanostructures to nonviral gene delivery systems.
Different Immunosuppressive Combinations on T-Cell Regulation in Renal Transplant Recipients (2010)

Overall, immunosuppression lowers CD4+CD25(high)FoxP3+/- Treg levels significantly in the periphery in renal transplant recipients. In addition, different immunosuppressive regimens have different impacts on CD4+CD25(high)FoxP3+ Tregs, a fact that may influence long-term allograft survival.
Solution Structure of an Arabidopsis WRKY DNA Binding Domain (2005)

The WRKY proteins comprise a major family of transcription factors that are essential in pathogen and salicylic acid responses of higher plants as well as a variety of plant-specific reactions. They share a DNA binding domain, designated as the WRKY domain, which contains an invariant WRKYGQK sequence and a CX4-5CX22-23HXH zinc binding motif. Herein, we report the NMR solution structure of the C-terminal WRKY domain of the Arabidopsis thaliana WRKY4 protein. The structure consists of a four-stranded beta-sheet, with a zinc binding pocket formed by the conserved Cys/His residues located at one end of the beta-sheet, revealing a novel zinc and DNA binding structure. The WRKYGQK residues correspond to the most N-terminal beta-strand, kinked in the middle of the sequence by the Gly residue, which enables extensive hydrophobic interactions involving the Trp residue and contributes to the structural stability of the beta-sheet. Based on a profile of NMR chemical shift perturbations, we propose that the same strand enters the DNA groove and forms contacts with the DNA bases.
Anti–Jo‐1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy (2007)

In this large series of patients with idiopathic inflammatory myopathy, anti-Jo-1 antibody levels correlated modestly with muscle and joint disease, an association confirmed by a custom ELISA using recombinant human Jo-1. More striking associations emerged in a smaller longitudinal subset of patients that link anti-Jo-1 antibody levels to muscle, joint, lung, and global disease activity.
Pyruvate Formate-lyase and a Novel Route of Eukaryotic ATP Synthesis in Chlamydomonas Mitochondria (2006)

Pyruvate formate-lyase (PFL) catalyzes the non-oxidative conversion of pyruvate to formate and acetyl-CoA. PFL and its activating enzyme (PFL-AE) are common among strict anaerobic and microaerophilic prokaryotes but are very rare among eukaryotes. In a proteome survey of isolated Chlamydomonas reinhardtii mitochondria, we found several PFL-specific peptides leading to the identification of cDNAs for PFL and PFL-AE, establishing the existence of a PFL system in this photosynthetic algae. Anaerobiosis and darkness led to increased PFL transcripts but had little effect on protein levels, as determined with antiserum raised against C. reinhardtii PFL. Protein blots revealed the occurrence of PFL in both chloroplast and mitochondria purified from aerobically grown cells. Mass spectrometry sequencing of C. reinhardtii mitochondrial proteins, furthermore, identified peptides for phosphotransacetylase and acetate kinase. The phosphotransacetylase-acetate kinase pathway is a common route of ATP synthesis or acetate assimilation among prokaryotes but is novel among eukaryotes. In addition to PFL and pyruvate dehydrogenase, the algae also expresses pyruvate:ferredoxin oxidoreductase and bifunctional aldehyde/alcohol dehydrogenase. Among eukaryotes, the oxygen producer C. reinhardtii has the broadest repertoire of pyruvate-, ethanol-, and acetate-metabolizing enzymes described to date, many of which were previously viewed as specific to anaerobic eukaryotic lineages.
Cell-penetrating-peptide-based delivery of oligonucleotides: an overview (2007)

Cationic CPPs (cell-penetrating peptides) have been used largely for intracellular delivery of low-molecular-mass drugs, biomolecules and particles. Most cationic CPPs bind to cell-associated glycosaminoglycans and are internalized by endocytosis, although the detailed mechanisms involved remain controversial. Sequestration and degradation in endocytic vesicles severely limits the efficiency of cytoplasmic and/or nuclear delivery of CPP-conjugated material. Re-routing the splicing machinery by using steric-block ON (oligonucleotide) analogues, such as PNAs (peptide nucleic acids) or PMOs (phosphorodiamidate morpholino oligomers), has consequently been inefficient when ONs are conjugated with standard CPPs such as Tat (transactivator of transcription), R(9) (nona-arginine), K(8) (octalysine) or penetratin in the absence of endosomolytic agents. New arginine-rich CPPs such as (R-Ahx-R)(4) (6-aminohexanoic acid-spaced oligo-arginine) or R(6) (hexa-arginine)-penetratin conjugated to PMO or PNA resulted in efficient splicing correction at non-cytotoxic doses in the absence of chloroquine. SAR (structure-activity relationship) analyses are underway to optimize these peptide delivery vectors and to understand their mechanisms of cellular internalization.
Clock-deskew buffer using a SAR-controlled delay-locked loop (2000)

A successive approximation register-controlled delay-locked loop (SARDLL) has been fabricated in a 0.25-/spl mu/m standard n-well DPTM CMOS process to realize a fast-lock clock-deskew buffer for long distance clock distribution. This DLL adopts a binary search method to shorten lock time while maintaining tight synchronization between input and output clocks. The measured lock time of the proposed SARDLL is within 30 clock cycles at 100-MWz clock input. The power dissipation is 3.3 mW (not including off-chip driver's) at a 1.1-V supply voltage while the measured rms and peak-to-peak jitter are 11.3 ps and 95 /spl mu/s, respectively.
Catalytic mechanism of fungal glucoamylase as defined by mutagenesis of Asp176, Glu179 and Glu180 in the enzyme from Aspergillus awamori (1990)

Asp176, Glu179 and Glu180 of Aspergillus awamori glucoamylase appeared by differential labeling to be in the active site. To test their functions, they were replaced by mutagenesis with Asn, Gln and Gln respectively, and kinetic parameters and pH dependencies of all enzyme forms were determined. Glu179----Gln glucoamylase was not active on maltose or isomaltose, while the kcat for maltoheptaose hydrolysis decreased almost 2000-fold and the KM was essentially unchanged from wild-type glucoamylase. The The Glu180----Gln mutation drastically increased the KM and moderately decreased the kcat with maltose and maltoheptaose, but affected isomaltose hydrolysis less. Difference in substrate activation energies between Glu180----Gln and wild-type glucoamylases indicate that Glu180 binds D-glucosyl residues in subsite 2. The Asp176----Asn substitution gave moderate increases and decreases in KM and kcat respectively, and therefore similar increases in activation energies for the three substrates. This and the differences in subsite binding energies between Asp176----Asn and wild-type glucoamylases suggest that Asp176 is near subsite 1, where it stabilizes the transition state and interacts with Trp120 at subsite 4. Glu179 and Asp176 are thus proposed as the general catalytic acid and base of pKa 5.9 and 2.7 respectively. The charged Glu180 contributes to the high pKa value of Glu179.
Blocking temperature in magnetic nanoclusters (2005)

A recent study of non-extensive phase transitions in nuclei and nuclear clusters needs a probability model compatible with the appropriate Hamiltonian. For magnetic molecules a representation of the evolution by a Markov process achieves the required probability model that is used to study the probability density function (PDF) of the order parameter, i.e., the magnetization. The existence of one or more modes in this PDF is an indication for the super-paramagnetic transition of the cluster. This allows us to determine the factors that influence the blocking temperature, i.e., the temperature related to the change of the number of modes in the density. It turns out that for our model, rather than the evolution of the system implied by the Hamiltonian, the high temperature density of the magnetization is the important factor for the temperature of the transition. We find that an initial probability density function with a high entropy leads to a magnetic cluster with a high blocking temperature.
Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer's and Parkinson's disease (2007)

Epidemiological studies have identified a negative correlation between smoking and the development of neurodegenerative disorders such as Parkinson's disease, and in some studies, Alzheimer's disease. These findings have been attributed to the ability of nicotine to act as a neuroprotective agent. A large number of studies demonstrate that nicotine can protect against neuronal death in vitro and in vivo, and the mechanisms underlying the ability of nicotine to protect against excitotoxicity and amyloid-? toxicity are beginning to be elucidated. Despite the compelling evidence that nicotine is neuroprotective, it is clear that nicotine can be toxic under some circumstances. The balance between nicotine neuroprotection and toxicity depends on dose, developmental stage and regimen of administration. Therefore, a full understanding of the molecular and cellular effects of nicotine on signaling pathways relevant to neuronal survival is critical for informed drug discovery of nicotinic compounds to combat human neurodegeneration. This review summarizes recent studies related to the mechanisms underlying nicotine-mediated neuroprotection, and addresses issues that are relevant to use of nicotine as a neuroprotective agent in vivo.
A short route for the synthesis of “sweet” macrocycles via a click-dimerization–ring-closing metathesis approach (2005)

A facile and flexible approach for the preparation of macrocyclic molecules containing different carbohydrate moieties is presented, employing the reaction cascade: click-dimerization and ring-closing metathesis.