gebhart/patrepeval huggingface dataset:
Stable Mutated tau441 Transfected SH-SY5Y Cells as Screening Tool for Alzheimer’s Disease Drug Candidates (2012)

The role of hyperphosphorylation of the microtubule-associated protein tau in the pathological processes of several neurodegenerative diseases is becoming better understood. Consequently, development of new compounds capable of preventing tau hyperphosphorylation is an increasingly hot topic. For this reason, dependable in vitro and in vivo models that reflect tau hyperphosphorylation in human diseases are needed. In this study, we generated and validated an in vitro model appropriate to test potential curative and preventive compound effects on tau phosphorylation. For this purpose, a stably transfected SH-SY5Y cell line was constructed over-expressing mutant human tau441 (SH-SY5Y-TMHT441). Analyses of expression levels and tau phosphorylation status in untreated cells confirmed relevance to human diseases. Subsequently, the effect of different established kinase inhibitors on tau phosphorylation (e.g., residues Thr231, Thr181, and Ser396) was examined. It was shown with several methods including immunosorbent assays and mass spectrometry that the phosphorylation pattern of tau in SH-SY5Y-TMHT441 cells can be reliably modulated by these compounds, specifically targeting JNK, GSK-3, CDK1/5, and CK1. These four protein kinases are known to be involved in in vivo tau phosphorylation and are therefore authentic indicators for the suitability of this new cell culture model for tauopathies.
Camping in the digital wilderness (2002)

A projection screen in the shape of a tent provides children with a shared immersive experience of a virtual world based on the metaphor of camping. RFID aerials at its entrances sense tagged children and objects as they enter and leave. Video tracking allows multiple flashlights to be used as pointing devices. The tent is an example of a traversable interface, designed for deployment in public spaces such as museums, galleries and classrooms.
Los carnavales de El Callao, patrimonio de la cultura venezolana (2016)

El presente trabajo es el resultado de una investigacion realizada en el acervo de la cultura popular tradicional del municipio El Callao del estado Bolivar en Venezuela. A traves del estudio de la historia local, la vida cotidiana del callaoense y el quehacer artistico-cultural de la region ha sido posible profundizar en la memoria cultural, y las expresiones propias del municipio al abundarse sobre elementos propios de su identidad cultural, unica en Venezuela.  Con  estas indagaciones hemos  querido contribuir al mayor conocimiento de las raices identitarias del Callao asi como a la preservacion de un patrimonio insuficientemente conocido y divulgado.
Fabrication of microfluidic mixers and artificial vasculatures using a high-brightness diode-pumped Nd:YAG laser direct write method (2003)

This paper describes a direct write laser technology, which is fast and flexible, for fabricating multiple-level microfluidic channels. A high brightness diode-pumped Nd-YAG laser with slab geometry was used for its excellent beam quality. Channels with flat walls and staggered herringbone ridges on the floor have been successfully fabricated and their ability to perform passive mixing of liquid is discussed. Also, a multi-width multi-depth microchannel has been fabricated to generate biomimetic vasculatures whose channel diameters change according to Murray's law, which states that the cube of the radius of a parent vessel equals the sum of the cubes of the radii of the daughters. The multi-depth architecture allows for flow patterns to resemble physiological vascular systems with lower overall resistance and more uniform flow velocities throughout the network compared to planar patterning techniques which generate uniformly thin channels. The ability to directly fabricate multiple level structures using relatively straightforward laser technology enhances our ability to rapidly prototype complex lab-on-a-chip systems and to develop physiological microfluidic structures for tissue engineering and investigations in biomedical fluidics problems.
NGF/BDNF chimeric proteins: analysis of neurotrophin specificity by homolog-scanning mutagenesis (1992)

Despite their extensive sequence identities at the amino acid level (approximately 55%), NGF and brain-derived neurotrophic factor (BDNF) display distinct neuronal specificity toward neurons of both the PNS and CNS. To explore which region(s) within these neurotrophic factors might determine their differential actions on various subpopulations of peripheral neurons, a systematic series (homolog-scanning mutagenesis) of chimeric NGF/BDNF molecules was prepared using PCR overlap-extension techniques. After expression in COS-7 cells, the chimeric proteins were tested for their biological activities in neurite outgrowth and neuronal survival assays. This approach led to the functional expression of 12 NGF/BDNF chimeras. Surprisingly, despite replacing successive amino acid segments throughout the entire length of NGF with the corresponding parts of BDNF, all chimeras displayed full NGF-like activity in bioassays carried out with PC12 cells, embryonic chick dorsal root ganglion explants, sympathetic ganglion explants, and dissociated cultures of dorsal root ganglion neurons. Most of the chimeras additionally showed BDNF-like activity as defined by neurite outgrowth on chick nodose ganglion explants. However, none of the chimeras supported the survival of dissociated nodose ganglion neurons. Our results suggest that NGF and BDNF must share very similar higher-order protein structures, and we propose that the overall structure or conformation of NGF, in contrast to short amino acid "active-site" segments, may determine its exact neuronal specificity.
Differences between Asn-Xaa-Thr-containing peptides: a comparison of solution conformation and substrate behavior with oligosaccharyltransferase (1991)

A series of tripeptides that satisfy the -Asn-Xaa-Thr/Ser- primary sequence requirement [Marshall, R. D. (1972) Annu. Rev. Biochem. 41, 673-702] for N-glycosylation have been synthesized and examined as potential acceptors in an oligosaccharyltransferase assay. Of these, six (Ac-Asn-Ala-Thr-NH2, Ac-Asn-Leu-Thr-NH2, Ac-Asn-Asp-Thr-NH2, Ac-Asn-D-Ala-Thr-NH2, Ac-Asn-Pro-Thr-NH2, and Ac-Asn-AIB-Thr-NH2) were examined for solution conformational properties in dimethyl sulfoxide with use of amide proton temperature coefficients, 3JHN alpha analysis [Pardi, A., et al. (1984) J. Mol. Biol. 180, 741-751], and 2-D ROESY experiments [Bothner-By, A. A., et al. (1984) J. Am. Chem. Soc. 106, 811-813]. The analysis reveals that the peptides that serve as acceptors in the transferase assay demonstrate similar conformational properties in solution. These are highlighted by a secondary structural motif that involves the interaction between the asparagine side-chain carboxamide and the backbone amide of the threonine. The peptides that show very poor acceptor, or even nonacceptor, properties in the oligosaccharyltransferase assay demonstrate different conformational features in solution. These observations may explain the distinct biological activity observed for these peptides.
Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold (2013)

Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8(+) dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.
Synthesis and Triplex Forming Properties of Pyrimidine Derivative Containing Extended Functionality (1999)

Two pyrimidine nucleosides have been synthesized containing extended hydrogen bonding functionality. In one case the side chain is based upon semicarbazide and in the second monoacetylated carbohydrazide was employed. DNA sequences could be prepared using both analogue nucleosides in a reverse coupling protocol, and provided that the normal capping step was eliminated and that the iodine-based oxidizing solution was replaced with one based upon 10-camphorsulfonyl oxaziridine. Both derivatives exhibited moderate effects in targeting selectively C-G base pairs embedded within a polypurine target sequence.
Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial (2018)

IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.
Anatomy, physiology and pathophysiology of the meibomian gland (2012)

Abstract Purpose The sebaceous meibomian glands (MG) in the eyelids, that secrete lipids for the superficial tear film layer, are of increased scientific and clinical interest. The recent MGD report of the non‐profit organization Tear Film and Ocular Surface Society (TFOS, www.tearfilm.org) revealed that MG Dysfunction (MGD) with lack of tear film lipids and the resultant evaporative type of dry eye is the main underlying reason for the wide‐spread dry eye disease that affects millions of patients world wide Methods A literature review based on the TFOS MGD Report together with own findings is discussed in order to explain the anatomy, physiology, pathophysiology and clinics of MGD. Results MGD is a multifactorial disease based on endogeneous and exogeneous factors that interact in self propagating vicious circles. Advancing age, female sex, environmental factors such as topical medication, bacterial influences and probably subclinical inflammatory pathways as well as contact lens wear are some main factors lead to the onset and propagation of MGD. These result in hyperkeratinization of the gland epithelium as well as increased viscosity of the secretum. Together this results in the obstructive type of MGD. Two effector arms of obstruction lead to a primary lack of oil on the tear film with downstream evaporative dry eye but also to a secondary hidden degeneration of the glandular tissue inside the lids that results in gland atrophy. Conclusion Obstructive MGD with downstream lipid deficiency is now recognized as the main cause for dry eye disease and this achievement of the TFOS MGD Workshop has already changed/revolutionized our view on dry eye disease as well as lead to several new developments for diagnosis and treatment that specifically address MGD. Support DFG KN 317‐11
Action of the vinca alkaloids vincristine, vinblastine, and desacetyl vinblastine amide on microtubules in vitro. (1976)

The Vinca alkaloids differ in their chemotherapeutic effectiveness and their toxicities. To determine whether differences are due to a differential effect on the assembly of tubulin into microtubules, we examined the effects of vincristine, vinblastine, and a newer alkaloid, desacetyl vinblastine amide, on the assembly of bovine brain tubulin in vitro. The three compounds block bovine tubulin polymerization in vitro and almost equally effectively at a 1 muM concentration (tubulin, 6.5 muM). At 10 muM, the three alkaloids also interact with preformed microtubules in vitro, causing spiral-like distortions of the microtubules. No effect of the alkaloids on polymerization of another fibrous protein, actin, was observed. Thus the differential actions of vinblastine, vincristine, and desacetyl vinblastine amide in vivo seems to be based on some biological process other than the reaction with tubulin or the microtubules per se.
The role of collagen antibodies in mediating arthritis (2008)

This review examines evidence that rheumatoid arthritis (RA) depends on autoimmunity to articular collagen, and mechanisms whereby autoantibodies to type II collagen contribute to disease development. Three major autoantigenic reactants have been identified in RA; the corresponding autoantibodies are rheumatoid factor (RF), antibodies to citrullinated peptide antigens (ACPA), citrullinated peptides (anti-CCP), and anti-type II collagen (anti-CII). Both RF and ACPA are well-validated and predictive markers of severe erosive RA, but cannot be linked to pathogenesis. By contrast, in various animal species immunized with CII there occurs an erosive inflammatory arthritis resembling that seen in human RA, together with antibodies to CII with an epitope specificity similar to that in RA. We discuss the well-known role of immune complexes in the induction of inflammation within the joint, and present recent data showing, additionally, that antibodies to CII cause direct damage to cartilage in vitro. The close resemblances between human RA and collagen-induced arthritis in animals suggest that autoimmunity, and particularly autoantibodies to CII, are important for both the initiation and perpetuation of RA in a dual manner: as contributors to the inflammation associated with immune complex deposition, and as agents with direct degradative effects on cartilage integrity and its repair.
Ecophysiological Interaction between Nitrifying Bacteria and Heterotrophic Bacteria in Autotrophic Nitrifying Biofilms as Determined by Microautoradiography-Fluorescence In Situ Hybridization (2004)

Ecophysiological interactions between the community members (i.e., nitrifiers and heterotrophic bacteria) in a carbon-limited autotrophic nitrifying biofilm fed only NH(4)(+) as an energy source were investigated by using a full-cycle 16S rRNA approach followed by microautoradiography (MAR)-fluorescence in situ hybridization (FISH). Phylogenetic differentiation (identification) of heterotrophic bacteria was performed by 16S rRNA gene sequence analysis, and FISH probes were designed to determine the community structure and the spatial organization (i.e., niche differentiation) in the biofilm. FISH analysis showed that this autotrophic nitrifying biofilm was composed of 50% nitrifying bacteria (ammonia-oxidizing bacteria [AOB] and nitrite-oxidizing bacteria [NOB]) and 50% heterotrophic bacteria, and the distribution was as follows: members of the alpha subclass of the class Proteobacteria (alpha-Proteobacteria), 23%; gamma-Proteobacteria, 13%; green nonsulfur bacteria (GNSB), 9%; Cytophaga-Flavobacterium-Bacteroides (CFB) division, 2%; and unidentified (organisms that could not be hybridized with any probe except EUB338), 3%. These results indicated that a pair of nitrifiers (AOB and NOB) supported a heterotrophic bacterium via production of soluble microbial products (SMP). MAR-FISH revealed that the heterotrophic bacterial community was composed of bacteria that were phylogenetically and metabolically diverse and to some extent metabolically redundant, which ensured the stability of the ecosystem as a biofilm. alpha- and gamma-Proteobacteria dominated the utilization of [(14)C]acetic acid and (14)C-amino acids in this biofilm. Despite their low abundance (ca. 2%) in the biofilm community, members of the CFB cluster accounted for the largest fraction (ca. 64%) of the bacterial community consuming N-acetyl-D-[1-(14)C]glucosamine (NAG). The GNSB accounted for 9% of the (14)C-amino acid-consuming bacteria and 27% of the [(14)C]NAG-consuming bacteria but did not utilize [(14)C]acetic acid. Bacteria classified in the unidentified group accounted for 6% of the total heterotrophic bacteria and could utilize all organic substrates, including NAG. This showed that there was an efficient food web (carbon metabolism) in the autotrophic nitrifying biofilm community, which ensured maximum utilization of SMP produced by nitrifiers and prevented buildup of metabolites or waste materials of nitrifiers to significant levels.
Recent developments in intestinal magnesium absorption (2008)

The recent developments in intestinal magnesium absorption and cellular magnesium homeostasis provide a basis for understanding magnesium deficiency disorders and provide a platform for future investigations.
Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target (2008)

Cyclin D1 (CyD1) is a pivotal cell cycle-regulatory molecule and a well-studied therapeutic target for cancer. Although CyD1 is also strongly up-regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles (tsNPs) were loaded with CyD1-small interfering RNA (siRNA). Antibodies to beta(7) integrin (beta(7) I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of beta(7) I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.
Different temperature sensitivity of cardiac Na+ channels in cell-attached and cell-free conditions (1990)

At 19 degrees C and after cooling to 9 degrees C, elementary Na+ currents were recorded in cell-attached and inside-out patches from cultured neonatal rat myocytes. The study aimed to define the temperature sensitivity of single cardiac Na+ channels and to detect a possible modulating influence arising from the recording conditions. Cooling prolonged the open state by reducing the exit rate into a nonconducting configuration [tau open; temperature coefficient (Q10) = 1.90 +/- 0.02] and reduced the unitary current size (i(unit); Q10 = 1.26 +/- 0.03). Reopening proved to be only slightly temperature dependent; the mean number of sequential openings decreased to 91 +/- 2.1% of the value at 19 degrees C. Cooled Na+ channels are still capable of switching to ultralong sequential activity. Cooling reduced reconstructed peak Na+ current (INa) strongly, with Q10 values between 1.85 and 3.11 (mean, 2.36 +/- 0.29), if Na+ channels remained in their natural environment as was the case in cell-attached recording conditions. However, after disrupting the cellular contact, in inside-out patches, the same 10 degrees C drop in temperature diminished peak INa only slightly to 91 +/- 8.1% of the initial control value at 19 degrees C. This suggests a modulating influence on the open probability of cardiac Na+ channels arising from the cytosol of cooled myocytes.
Mismatch Negativity and N100 in Comatose Patients (2000)

Mismatch negativity (MMN) and N100 auditory evoked potential were recorded in 52 healthy subjects and in 128 severely comatose patients. The MMN was present in 33/128 patients and N100 in 84/128. A ratio of 30/33 patients with MMN and 70/84 with N100 regained consciousness in a mean time of 6.3 +/- 4 days after the recording session. Thus, in terms of predicting return to consciousness, the MMN was more specific (90.9%) than the N100 (57.6%), but its sensitivity was lower (31.6% for MMN and 73.7% for N100, respectively). The amplitudes of MMN and N100 in comatose patients were smaller than those of healthy subjects. It is concluded that MMN and N100 can be very useful in predicting whether or not a comatose patient will regain consciousness.
Update on Alzheimer's disease (1999)

In the past decade, significant progress has been made in the understanding and treatment of Alzheimer's disease. Modest success has been achieved using new drugs in treatment of mild symptoms of the disease. Vitamin E, estrogen, and NSAIDs may slow the progression of Alzheimer's disease, but their routine use is not without risk, and there is no evidence that these agents are effective in preventing the disease in asymptomatic people. With our increased understanding of the pathogenesis of Alzheimer's disease, it is likely that the next decade will see further refinement and development of treatment strategies to halt progression and possibly reduce the incidence of disease.
Chirped-pulse-amplification circuits for fiber amplifiers, based on chirped-period quasi-phase-matching gratings (1998)

A new type of compact chirped-pulse-amplification circuit for high-power amplification of femtosecond pulses in an optical fiber is demonstrated. This circuit is based on a novel pulse compressor, chirped-period quasi-phase-matching gratings in electric-field-poled lithium niobate. The main advantages of this circuit are simplicity, the small number of components, compactness, and wavelength conversion of Er-doped fiber output to the technologically important 780-nm wavelength region.
IgM and its receptors: Structural and functional aspects (2011)

This review combines the data obtained before the beginning of the 1990s with results published during the last two decades. The predominant form of the IgM molecule is a closed ring composed of five 7S subunits and a J chain. The new model of spatial structure of the pentamer postulates nonplanar mushroom-shaped form of the molecule with the plane formed by a radially-directed Fab regions and central protruding portion consisting of Cµ4 domains. Up to the year 2000 the only known Fc-receptor for IgM was pIgR. Interaction of IgM with pIgR results in secretory IgM formation, whose functions are poorly studied. The receptor designated as Fcα/µR is able to bind IgM and IgA. It is expressed on lymphocytes, follicular dendritic cells, and macrophages. A receptor binding IgM only named FcµR has also been described. It is expressed on T- and B-lymphocytes. The discovery of new Fc-receptors for IgM requires revision of notions that interactions between humoral reactions involving IgM and the cells of the immune system are mediated exclusively by complement receptors. In the whole organism, apart from IgM induced by immunization, natural antibodies (NA) are present and comprise in adults a considerable part of the circulating IgM. NA are polyreactive, germ-line-encoded, and emerge during embryogenesis without apparent antigenic stimuli. They demonstrate a broad spectrum of antibacterial activity and serve as first line of defense against microbial and viral infections. NA may be regarded as a transitional molecular form from invariable receptors of innate immunity to highly diverse receptors of adaptive immunity. By means of interaction with autoantigens, NA participate in maintenance of immunological tolerance and in clearance of dying cells. At the same time, NA may act as a pathogenic factor in atherosclerotic lesion formation and in development of tissue damage due to ischemia/reperfusion.