gebhart/patrepeval huggingface dataset:
Confirmation of the Neurophysiologically Predicted Therapeutic Effects of Trazodone on Its Target Symptoms Depression, Anxiety and Insomnia by Postmarketing Clinical Studies with a Controlled-Release Formulation in Depressed Outpatients (2003)

Early human pharmaco-EEG and subsequent sleep laboratory studies identified trazodone, a 5-HT(2) antagonist and 5-HT reuptake inhibitor (SARI), as an antidepressant with therapeutic effects on its target symptoms depressed mood, anxiety and insomnia. On the occasion of the introduction of a controlled-release (CR) formulation (Trittico 150 mg retard, marketed in Austria by CSC Pharmaceuticals Handels GmbH, Vienna, Austria) in Austria in July 2000, a multi-center, open, clinical post-marketing study on the therapeutic effects, safety and target symptoms of trazodone CR in depression was carried out at 80 offices of Austrian neuropsychiatrists. 549 outpatients (63% females) of all age groups suffering from five different subtypes of depression were enrolled in the study. After a 2-week fixed dose-titration regimen up to 150 mg and a 4-week adjustment period to the optimum dose, 66% of the patients remained on 150 mg, 20% increased the dose and 11% decreased it. Only 3.7% discontinued treatment. Rating by the neuropsychiatrists based on the Clinical Global Impression showed very much to much improvement in 78.3% of the patients, and no change or a deterioration in only 3.6%. In the Hamilton Depression Scale (HAMD) a statistically significant improvement from a baseline score of 21 to a score of 14 after 2 weeks was found, and a normalization to a score of 8 after 6 weeks. Therapeutic effects were similar in the five groups suffering from different subtypes of depression and in patients with and without comedication. Self-rating by the patients based on the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS) also showed a significant improvement in the 2nd and 6th week of therapy. Evaluation of the target symptoms of trazodone by ranking the most improved symptoms identified insomnia as the most improved psychopathological item in all three scales. While in the observer ratings also suicidal tendencies and weight loss were found much improved, in the self-rated Zung SDS sadness and loss of drive came second and third in the improvement ranking, in the self-rated Zung SAS anxiety and the feeling of falling apart. Tolerability was very good. In the 2nd week only 16.9% and in the 6th week only 7.6% of the patients reported side effects, mostly characterized by tiredness and rarely by nausea and vertigo. The present clinical study is in agreement with previous studies identifying trazodone as a safe and effective antidepressant, specifically regarding its target symptoms insomnia, depression and anxiety. It also confirms our own early predictions based on neurophysiological investigations concerning the mode of action of the drug.
Murine Immune Response toNeisseria meningitidisGroup C Capsular Polysaccharide: Analysis of Monoclonal Antibodies Generated in Response to a Thymus-Independent Antigen and a Thymus-Dependent Toxoid Conjugate Vaccine (2000)

Antibody (Ab) responses to polysaccharides (PSs) such as Neisseria meningitidis group C PS (MCPS) are characterized as being thymus independent (TI) and are restricted with regard to clonotype and isotype expression. PS conjugated to proteins, e.g., MCPS coupled to tetanus toxoid (MCPS-TT), elicits a thymus-dependent (TD) response. In order to understand the influence of the form of a vaccine (TI versus TD) on the Ab repertoire, we generated monoclonal antibody (MAb) panels from mice immunized and boosted with MCPS or MCPS-TT in different ways. The panels of MAbs were examined for isotype, fine specificity, affinity, and V(H) gene family usage. The use of MCPS-TT resulted in a shift in the isotype from immunoglobulin M (IgM) and IgG3 elicited in response to the MCPS to primarily IgG1. This isotype shift was accompanied by a change in the fine specificity of the response to the conjugate compared to that of PS. New fine specificities and increased affinity were observed in response to the TD antigen (Ag). Dot blot and Northern analyses of MCPS MAbs revealed that V(H) gene family usage is dominated by V(H)J558, used by 23 of 39 MAbs. V(H)3609 was seen in three MAbs of restricted fine specificity. V(H)Q52, V(H)7183, and V(H)VGAM3-8 were seen in more than one MAb across these panels, while V(H)10 and V(H)X24 were detected only once in response to the TI-2 Ag. All MAbs in the panels utilized kappa light chains, and all functional J(kappa) genes were expressed.
The link between cholesterol and Alzheimer's disease (2005)

A leading hypothesis on the pathophysiology of Alzheimer's disease (AD) is the mis-metabolism of amyloid precursor protein. This mis-metabolism causes the 42-amino acid form of A beta(Abeta42) to form oligomers that in turn start a chain of events leading to the accumulation of amyloid plaques. Vascular factors such as hypertension, hypercholesterolemia and diabetes as well as the inheritance of the epsilon4 allele of the ApoE gene are risk factors for AD. These risks are thought to promote the production of beta-amyloid (Abeta). An association between cholesterol and the development of AD was suggested in 1994 and since then, research has confirmed a link between cholesterol and the development of AD. A high cholesterol level in mid-life is a risk for AD and statins i.e. cholesterol-lowering drugs, reduce this risk. Statins inhibit enzymes involved in the endogenous synthesis of cholesterol and evidence is mounting that they also affect enzymes in Abeta metabolism i.e. beta-secretase. This normalises the breakdown of the precursor of Abeta, amyloid precursor protein, thereby promoting the nonamyloidogenic pathway. This review focusses on the link between cholesterol and Alzheimer's disease.
Modulation by recombinant interleukin 1 of synthesis of types I and III collagens and associated procollagen mRNA levels in cultured human cells. (1987)

Interleukin 1 (IL-1), a monocyte product, exerts a range of biological effects on nonimmune cells such as fibroblasts and chondrocytes including stimulation of synthesis and release of prostaglandin E2 (PGE2) and collagenase. We have previously shown that crude mononuclear cell-conditioned medium, which contains IL-1, also stimulates synthesis of types I and III collagens by human synovial and dermal fibroblasts and chondrocytes when the formation of PGE2, which inhibits collagen synthesis, is blocked by indomethacin. To determine whether IL-1 is responsible for the affects observed using crude monocyte-conditioned medium patterns of collagen synthesis in the three types of human cells in response to recombinant preparations of IL-1 were compared. Preincubation of chondrocytes or synovial fibroblasts with either murine (m)IL-1 alpha or human (h)IL-1 beta alone decreased synthesis of type I collagen and fibronectin. In contrast, when endogenous IL-1-stimulated PGE2 synthesis was blocked by indomethacin, an enhancing effect of IL-1 on synthesis of these matrix proteins was unmasked. The synthesis of type III collagen was enhanced by IL-1 to a greater extent than that of type I collagen in the presence of indomethacin. In human foreskin fibroblasts, which produced low levels of PGE2 even in the presence of IL-1, synthesis of types I and III collagens was increased by IL-1 either in the absence or presence of indomethacin. These cells were more responsive to the hIL-1 beta preparation than to the mIL-1 alpha (half-maximal stimulation of PGE2 production was observed at approximately 2.5-5 pM hIL-1 beta and at approximately 2.5 nM mIL-1 alpha). Levels of alpha 1 (I), alpha 2(I), and alpha 1(III) procollagen mRNAs measured by cytoplasmic dot hybridization paralleled the levels of collagens synthesized under the various experimental conditions. IL-1, therefore, is one product of monocytes capable of modulating collagen synthesis by these human mesenchymal cells probably by altering collagen gene expression. These studies suggest that both positive (IL-1) and negative (PGE2) signals may control collagen synthesis at the transcriptional level resulting in modulation of matrix turnover in cartilage, synovium, and skin.
Sites and sizes of fat deposits around the pharynx in obese patients with obstructive sleep apnoea and weight matched controls (1989)

It has been suggested that deposition of fat in the soft tissues surrounding the upper airway may be an important factor in the pathogenesis of obstructive sleep apnoea (OSA) in obese subjects. We have used magnetic resonance imaging to determine the site(s) and size(s) of fat deposits around the upper airway in six obese patients with OSA (116-153% of ideal body weight) and five weight-matched controls without OSA (107-152% of ideal body weight). In all subjects, large deposits of fat were present postero-lateral to the oropharyngeal airspace at the level of the soft palate. Significantly more fat was present in these regions in the patients with OSA (p = 0.03). Fat deposits in the soft palate were observed in 4 of the 6 patients with OSA but none of the controls. Fatty streaks were observed in the tongue in 2 of the 5 controls and 3 of the 6 patients with OSA. Fat deposits were observed anterior to the laryngopharyngeal airspace, in submental regions, in all obese subjects. This study shows that more fat is present in those areas surrounding the collapsable segment of the pharynx in patients with OSA, compared to equally obese control subjects without OSA.
Solution structure of a defensin-like peptide from platypus venom (1999)

Three defensin-like peptides (DLPs) were isolated from platypus venom and sequenced. One of these peptides, DLP-1, was synthesized chemically and its three-dimensional structure was determined using NMR spectroscopy. The main structural elements of this 42-residue peptide were an anti-parallel β-sheet comprising residues 15-18 and 37-40 and a small 310 helix spanning residues 10-12. The overall three-dimensional fold is similar to that of β-defensin-12, and similar to the sodium-channel neurotoxin ShI (Stichodactyla helianthusneurotoxin I). However, the side chains known to be functionally important in β-defensin-12 and ShI are not conserved in DLP-1, suggesting that it has a different biological function. Consistent with this contention, we showed that DLP-1 possesses no anti-microbial properties and has no observable activity on rat dorsal-root-ganglion sodium-channel currents.
Novel type 1 photosensitizers: viability of leukemia cells exposed to reactive intermediates generated in situ by in vitro photofragmentation (2009)

Photodynamic therapy of tumors involving Type 2 photosenstizers has been conspicuously successful, but the Type 1 process, in contrast, has not received much attention despite its considerable potential. Accordingly, several classes of molecules containing fragile bonds such as azido (-N=N=N), azo (-N=N-), sulfenato (-S-O-) and oxaza (-N-O-) functional groups that produce reactive intermediates such as radicals and nitrenes upon photoexcitation were prepared and tested for cell viability using U397 leukemia cell line. The azido photosensitizer was conjugated to leukemia cell binding peptide, SFFWRLS, for targeted cell viability study. The cells were incubated with the photosensitizer at various concentrations, and were illuminated for 5, 10, and 20 minutes. The results show that all the photosensitizers caused cell death compared to the controls when exposed to both the photosensitizers and light. Most importantly, selective cell death was observed with the azido peptide conjugate 6, which clearly demonstrates that these Type 1 sensitizers are useful for phototherapeutic applications.
Photoinduction of Fast, Reversible Translational Motion in a Hydrogen-Bonded Molecular Shuttle (2001)

A rotaxane is described in which a macrocycle moves reversibly between two hydrogen-bonding stations after a nanosecond laser pulse. Observation of transient changes in the optical absorption spectrum after photoexcitation allows direct quantitative monitoring of the submolecular translational process. The rate of shuttling was determined and the influence of the surrounding medium was studied: At room temperature in acetonitrile, the photoinduced movement of the macrocycle to the second station takes about 1 microsecond and, after charge recombination (about 100 microseconds), the macrocycle shuttles back to its original position. The process is reversible and cyclable and has properties characteristic of an energy-driven piston.
Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease (2009)

In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.
Pathways of Water Oxidation Catalyzed by Ruthenium “Blue Dimers” Characterized by 18O-Isotopic Labeling (2009)

Earlier (18)O-H(2)O labeling studies had indicated that two concurrent pathways may exist for water oxidation catalyzed by [Ru(bpy)(2)(OH(2))](2)O(4+), a mu-oxo bridged diruthenium complex known colloquially as the "blue dimer". Specifically, the distribution of O(2) isotopomers obtained following its generation by the catalytically active form, [Ru(bpy)(2)(O)](2)(4+), suggested pathways in which either (1) one O atom was obtained from the terminally coordinated oxo atom and the second from the solvent or (2) both O atoms were obtained from the solvent. Plausible mechanisms have been advanced for the former pathway, but the second is enigmatic. In the present study, experiments are described that eliminate possibilities that the second pathway arises artifactually from rapid water exchange in reactive intermediary oxidation states of the catalyst, by mechanisms involving scrambling of the O(2) that is formed during reaction, or by mechanisms involving participation of the oxidant (Ce(4+) or S(2)O(8)(2-)). Comparative studies of partitioning between the two pathways made using catalysts containing substituted bipyridine ligands are consistent with a previously proposed pathway that involves noninnocent participation of these ligands.
Facile Preparation of Protected Furanoid Glycals from Thymidine (1997)

The synthesis of O-silyl- and O-acyl-protected furanose glycals from free thymidine was investigated. The method of glycal formation reported by Pedersen et al. was successfully expanded to include 5-ester (toluoyl) protected glycals as well as various combinations of 5‘-ester and 3- and 5-tert-butyldimethylsilyl and tert-butyldiphenylsilyl protection. Gram quantities of furanoid glycals can be prepared in a few days in two−four synthetic steps in overall yields ranging from 17 to 80%.
Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity (2012)

Continual and rapid mutation of seasonal influenza viruses by antigenic drift necessitates the almost annual reformulation of flu vaccines, which may offer little protection if the match to the dominant circulating strain is poor. S139/1 is a cross-reactive antibody that neutralizes multiple HA strains and subtypes, including those from H1N1 and H3N2 viruses that currently infect humans. The crystal structure of the S139/1 Fab in complex with the HA from the A/Victoria/3/1975 (H3N2) virus reveals that the antibody targets highly conserved residues in the receptor binding site and contacts antigenic sites A, B, and D. Binding and plaque reduction assays show that the monovalent Fab alone can protect against H3 strains, but the enhanced avidity from binding of bivalent IgG increases the breadth of neutralization to additional strains from the H1, H2, H13, and H16 subtypes. Thus, antibodies making relatively low affinity Fab interactions with the receptor binding site can have significant antiviral activity when enhanced by avidity through bivalent interactions of the IgG, thereby extending the breadth of binding and neutralization to highly divergent influenza virus strains and subtypes.
Mirk/Dyrk1b Mediates Cell Survival in Rhabdomyosarcomas (2006)

Rhabdomyosarcoma is the most common sarcoma in children and is difficult to treat if the primary tumor is nonresectable or if the disease presents with metastases. The function of the serine/threonine kinase Mirk was investigated in this cancer. Mirk has both growth arrest and survival functions in terminally differentiating skeletal myoblasts. Maintenance of Mirk growth arrest properties would cause down-regulation of Mirk in transformed myoblasts. Alternatively, Mirk expression would be retained if rhabdomyosarcoma cells used Mirk survival capability. Mirk expression was significant in 12 of 16 clinical cases of rhabdomyosarcoma. Mirk was detected in each rhabdomyosarcoma cell line examined. Mirk was a functional kinase in each of three rhabdomyosarcoma cell lines, where it proved to be more active than in C2C12 skeletal myoblasts. Mirk mediated survival of the majority of clonogenic rhabdomyosarcoma cells. Knockdown of Mirk by RNA interference reduced the fraction of RD and of Rh30 rhabdomyosarcoma cells capable of colony formation 3- to 4-fold in multiple experiments. Depletion of Mirk induced cell death by apoptosis, as shown by increased numbers of terminal deoxynucleotidyl transferase-mediated nick-end labeling-positive cells and by increased binding of Annexin V. Mirk is a stress-activated kinase that mediates expression of contractile proteins in differentiating myoblasts, but Mirk is not essential for muscle formation in the embryo. It is likely that Mirk also facilitates survival of satellite cell-derived rhabdomyoblasts in regenerating skeletal muscle and aids their differentiation. This survival function is maintained in rhabdomyosarcoma, where Mirk may be a novel therapeutic target.
Thrombopoietin: its biology, purification, and characterization. (1988)

The existence of thrombopoietin, a hormone that controls blood platelet production, was proposed almost 30 years ago, but it has been only during the past 10-15 years that sufficient knowledge was obtained to establish that this humoral factor is a major in vivo controlling factor of thrombocytopoiesis. This concise review attempts to summarize the hormone's history, background, effects on megakaryocytes and platelet production, sources, and purification and characterization, along with the current status of research on this hematopoietic-stimulating factor. New evidence for biological and chemical similarities of thrombopoietin from thrombocytopenic animals and human embryonic kidney cells is also presented.
Macroeconomic Effects of Federal Reserve Forward Guidance (2012)

A large output gap accompanied by stable inflation close to its target calls for further monetary accommodation, but the zero lower bound on interest rates has robbed the Federal Open Market Committee (FOMC) of the usual tool for its provision. We examine how public statements of FOMC intentions—forward guidance—can substitute for lower rates at the zero bound. We distinguish between Odyssean forward guidance, which publicly commits the FOMC to a future action, and Delphic forward guidance, which merely forecasts macroeconomic performance and likely monetary policy actions. Others have shown how forward guidance that commits the central bank to keeping rates at zero for longer than conditions would otherwise warrant can provide monetary easing, if the public trusts it. We empirically characterize the responses of asset prices and private macroeconomic forecasts to FOMC forward guidance, both before and since the recent financial crisis. Our results show that the FOMC has extensive experience successfully telegraphing its intended adjustments to evolving conditions, so communication difficulties do not present an insurmountable barrier to Odyssean forward guidance. Using an estimated dynamic stochastic general equilibrium model, we investigate how pairing such guidance with bright-line rules for launching rate increases can mitigate risks to the Federal Reserve’s price stability mandate.
Prime-Boost Strategies in DNA Vaccines (2006)

Induction of HIV-specific T-cell responses by vaccines may facilitate efficient control of HIV replication. Plasmid DNA vaccines and recombinant fowlpox virus (rFPV) vaccines are promising HIV-1 vaccine candidates, although delivering either vaccine alone may be insufficient to induce sufficient T-cell responses. A consecutive immunization strategy, known as "prime-boost," involving priming with DNA and boosting with rFPV vaccines encoding multiple common HIV antigens, is used to induce broad and high-level T-cell immunity and ameliorate AIDS in macaques. This vaccine strategy is proceeding to clinical trials. This chapter describes the use of prime-boost vaccines to induce T-cell responses against HIV-1 and protective immunity against AIDS in macaques. Methods for the construction of the vaccines, the use of animal models, and the detection of immune responses are described.
Effect of Particle Size on the Reactivity of Quantum Size ZnO Nanoparticles and Charge-Transfer Dynamics with Adsorbed Catechols (2003)

The photophysics and reactivity of quantum size ZnO nanoparticles have been studied using static and time-resolved emission and absorption spectroscopy. Size quantization of ZnO nanoparticles is confirmed by steady-state optical absorption and emission spectroscopy. On band gap excitation, ZnO nanoparticles give both exciton and trap-state emission. The emission from ZnO nanoparticles is readily quenched by hole scavengers such as catechol (cat.) and naphthyl catechol (Ncat.). Quenching of ZnO emission has been attributed to the reactivity of ZnO nanoparticles with adsorbed catechols. Studies on particle size variation revealed that the reactivity of ZnO nanoparticles decreases as their size increases. The maximum reactivity of the excited ZnO nanoparticles with the catechols has been observed for the smallest size particles. Time-resolved emission studies of ZnO particles in the presence of the catechols confirmed that the catechols react in the same rate with both shallow and deeply trapped holes. We have also carried out time-resolved absorption studies of ZnO nanoparticles exciting at 355 nm laser light in the presence of the catechols. On laser excitation of ZnO nanoparticles, electrons and holes are generated. It has been observed that the holes react with the catechols and form oxidized species, which in turn convert to the phenoxyl radical of the catechols. The transient spectra of the phenoxyl radical of the catechols are confirmed by pulse radiolysis technique, which shows a strong absorbance peak in UV region and small shoulder at visible region for both the catechols. It has been observed that on the ZnO nanoparticle surface the spectrum of the phenoxyl radical of the catechols are little broader.