gebhart/patrepeval huggingface dataset:
Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model (2020)

Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological process underlying clinical manifestations in Alzheimer's disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [<sup>11</sup>C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2-3 months of age. In contrast, retentions of (E)-[<sup>11</sup>C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy. Biochemical and immunohistochemical assessment of postmortem brain tissues demonstrated that inhibitory, but not excitatory, synaptic constituents selectively diminished without overt loss of somas of GABAergic interneurons in the neocortex and hippocampus of rTg4510 mice at 2 months of age, which was concurrent with enhanced immunoreactivity of cFos, a well-characterized immediate early gene, suggesting that impaired inhibitory neurotransmission may cause hyperexcitability of cortical circuits. Our findings indicate that tau-induced disruption of the inhibitory synapse may be a critical trigger of progressive neurodegeneration, resulting in massive neuronal loss, and PET assessments of inhibitory versus excitatory synapses potentially offer <i>in vivo</i> indices for hyperexcitability and excitotoxicity early in the etiologic pathway of neurodegenerative tauopathies.<b>SIGNIFICANCE STATEMENT</b> In this study, we examined the in vivo status of excitatory and inhibitory synapses in the brain of the rTg4510 tauopathy mouse model by PET imaging with (E)-[<sup>11</sup>C]ABP688 and [<sup>11</sup>C]flumazenil, respectively. We identified inhibitory synapse as being significantly dysregulated before brain atrophy at 2 months of age, while excitatory synapse stayed relatively intact at this stage. In line with this observation, postmortem assessment of brain tissues demonstrated selective attenuation of inhibitory synaptic constituents accompanied by the upregulation of cFos before the formation of tau pathology in the forebrain at young ages. Our findings indicate that selective degeneration of inhibitory synapse with hyperexcitability in the cortical circuit constitutes the critical early pathophysiology of tauopathy.
Performance of orthogonal frequency division multiplexing system in terrestrial TV channels-a statistical analysis (1995)

In this paper, the performance of orthogonal frequency division multiplexing (OFDM) in terrestrial TV channels is investigated. Using a statistical channel model, the results will be derived semianalytically for OFDM systems. In this study, we give outage probability characteristics for terrestrial digital TV systems. We obtain results for two kinds of equalization methods and additionally for a system without equalization.
Unexpected Transcriptional Signals in Normal and Mitotically Defective Cells Mediated Through Cytokine and Growth Factor Receptors (1995)

Polypeptide growth factors and cytokines mediate their biochemical functions through their responsive receptors. Known cytokine receptors do not possess intrinsic kinase domains whereas several polypeptide growth factor receptors do. Nevertheless, both classes of ligands are capable of activating sets of overlapping genes. In human epidermoid carcinoma cells, for example, both cytokines and epidermal growth factor (EGF) promote a common transcriptional activation signal through the tyrosine phosphorylation of stat91 (signal transducer and activator of transcription) proteins. The stat family of cytoplasmic proteins also appear to have dual functions. Tyrosine phosphorylated 'stats' are employed for signal transduction and, second, for activation of transcription of several genes. The transcription factor-SIE-DNA binding patterns are now known to be different for EGF and interferon-gamma IFN-gamma-treated cells. Nevertheless, in the active DNA-bound complex, the stat91 polypeptide is a component found in either EGF or INF-gamma-treated extracts. Other stat family members of transcription factors may also be present in the complexes. In this case, tyrosine phosphorylated stat91 polypeptides may form into homodimeric or heterodimeric assemblies with other stat-related transcription factors. We describe a novel stat-related factor, p93, that is found in EGF-treated A431 cell extracts but appears to be absent in bovine fibroblast growth factor (bFGF), IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), and untreated cells. p93 appears to be antigenically related to stat91. p185c-neu+, EGFr+ (M1), and p185c-neu- kinase inactive, EGFr+ (NEN757) expressing cells undergo different mitotic responses to EGF. M1 can respond to EGF mitotically while NEN757 cannot. Both cell lines respond to 10 ng/ml of EGF and also to IFN-gamma in transducing transcriptional activation signals to the nucleus, despite the distinct growth response to EGF. Our work has analyzed the stat pathway in these types of cells and found similar patterns of usage despite the distinct EGF-responsive features. Cytoplasmic nonreceptor tyrosine kinases Jak1 and Jak2 may be involved in the activation of stat91 and other transcription factors in EGF and IFN-gamma signaling pathways. Collectively, these studies suggest that the major EGF-stimulated mitotic growth pathways may not be absolutely linked to the stat91 signaling pathways and that such transcription complexes are more complex than previously reported.
Population Pharmacogenomics and Personalized Medicine Research in Hungary: Achievements and Lessons Learned (2010)

There have been a number of notable strides in Hungary in the field of population pharmacogenomics. This paper aims to summarize and share the recent experiences in population genomics and personalized medicine in Hungary with leaders of the Genomic National Technology Platform. The present day Hungary differs from other populations in the region as Hungary was established some 1100 years ago, with founders of the ancestral Hungarian population originating from the east side of the Urals. Additionally, the Roma population of about 700,000 represents the largest ethnic minority living in Hungary. In a series of investigations, we found significant differences between the Hungarian and Roma populations in clinically relevant pharmacogenomics targets such as VKORC1 and CYP2C9 genes. Pharmacogenomics applications are also of interest from the standpoint of biomarker-guided drug discovery in Hungary which we highlight briefly in this paper. Regulatory, ethical and economic aspects of genomics are other dimensions crucial for efficient transition of basic genomics discoveries from laboratory to the clinic. Importantly, Hungary has a Parliamental Act for regulation of genetic diagnostic and research test procedures, and for regulation of biobanks since 2008. Diagnostic molecular pharmacogenomics tests are reimbursed from the same insurance budget as with the other molecular biology based tests in Hungary. Personalized medicine diagnostics require further considerations on how best to integrate and reimburse them in routine healthcare as this new field evolves in Hungary. Keywords: CYP2C9 and VKORC1 variations, Hungarians and Roma, personalized therapy, population pharmacogenomics, warfarin
Transmission of high-data-rate optical signals through a micrometer-scale silicon ring resonator (2006)

The effects of a micrometer-scale silicon ring resonator with a FWHM of 0.078 nm (9.6 GHz) on a nonreturn to zero amplitude-modulated optical signal with a modulation rate of 10 Gbps are experimentally investigated. By transmitting the optical signal through the device, significant spectral distortion and side band attenuation is introduced, as characterized by amplitude Bode plots, and a power penalty of 0.8 dB is observed. Carrier wavelengths within the transmission resonance, but detuned from the center wavelength, are investigated as well. Numerical simulations further support the experimental results.
Zwei neue privilegierte Bausteine und ein unerwarteter Bindungsmodus für HIV‐Protease‐Inhibitoren (2005)

Für das katalytische Zentrum der Familie der Aspartylproteasen wurden zwei privilegierte Inhibitorstrukturen entwickelt. Sie enthalten eine zentrale Hydroxysulfon- oder Pyrrolidin-Einheit und sind mit rational entworfenen Seitenketten dekoriert. Die Hydroxysulfone binden wie erwartet an HIV-Protease, der Bindungsmodus der Pyrrolidine ist dagegen neuartig und überraschend (siehe Bild).
Comparison of open and robotic-assisted prostatectomy: The University of British Columbia experience (2014)

While hospital length of stay, transfusion rates, positive surgical margin rates and postoperative urinary incontinence were similar, OP had a shorter operative time and a lower cost compared to the very early experience of RAP. Future parallel prospective analysis will address the impact of the learning curve on these outcomes.
Developing a cohesive traffic management strategy for ATM networks (1991)

The background and some of the rationale for the development of an asynchronous transfer mode (ATM) traffic management framework to support the wide variety of services to be carried over the B-ISDN are discussed. The advantages of statistical, as opposed to deterministic, multiplexing are examined. Given the anticipated B-ISDN service characteristics, two classes of quality of service are defined based on cell delay and cell loss. The key ATM traffic management tools are reviewed. These tools are broadly classified as either preventive, limiting the total amount of traffic admitted to the network in order to virtually eliminate probability of cell-level congestion, or reactive, assisting the network and individual connections to avoid the onset of congestion and minimize its severity when it does occur. A strategy for the initial introduction and the long-term evolution of an ATM traffic management framework is described.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Rapid MR elastography using selective excitations (2006)

Rapid MR elastography (MRE) techniques using spatially-selective excitations to reduce acquisition times to a few seconds or less were devised and tested. The techniques included reduced field of view (rFOV) MRE and 1D MRE (beam MRE) using 2D spatially selective RF excitations for gradient-echo (GRE) applications and intersecting 90 degrees and 180 degrees slice-selective excitations for spin-echo (SE) applications. It was shown that scan times could be reduced by a factor of 8 using rFOV MRE, and by 64 using beam MRE, while still obtaining stiffness estimates comparable to full-FOV MRE. Results were shown in gel phantom experiments as well as in the case of a preserved postmortem breast tissue specimen with a stiff lesion. These methods can be used to more rapidly interrogate regions of interest (ROIs) in tissue to quickly obtain information about the viscoelastic properties of that tissue.
Gas chromatography/tandem mass spectrometry as an analytical tool for the identification of fatty acids (1995)

Structures of fatty acids present at very low quantities in mycobacteria are difficult to determine. A commonly used strategy is to introduce heteroatoms into functional groups by chemical means before subjecting them to gas chromatography/tandem mass spectrometry (GC/MS/MS) analysis. Routinely used methods give very low abundance diagnostic ions leading to ambiguities in structural conclusions. GC/MS/MS associated with electron capture ionization of pentafluorobenzyl esters was used to study very complex mixtures of fatty acids from Mycobacterium fallax and M. aurum. The charge-remote fragmentation of fatty acid carboxylate anions was used for structure determination at the nanogram level of a large number of unsaturated, branched, and cyclopropane-containing fatty acids. Some of them have not been observed previously in these Mycobacteria. On the basis of these studies, biosynthetic pathways of unsaturated, branched, and cyclopropane-containing fatty acid are proposed.
HIGH THROUGHPUT MELTING CURVE ANALYSIS IN MONOLITHIC SILICON-BASED MICROFLUIDIC DEVICE (2010)

This paper reports the development of a silicon-based microfluidic device that enables ultra fast melting curve analysis (MCA) for genomic studies (DNA) and drug discovery (proteins). The system relies on the flow of nanoliter-sized discrete phase samples through a buried silicon channel. The samples are subjected to a temperature gradient generated by two external heaters along the channel. The channel also simultaneously serves as a light guide to illuminate the droplets and guide the emitted fluorescence to the detector outside the channel. The system provides a simple melting analysis of fluorescent-labeled molecular complexes, with high multiplexing capability and throughput. The chip-based solution is attractive due to nanolitre sized samples handling, resulting in fast heat transfer thus achieving ultra fast MCA for genomic studies and drug discoveries .
InP/InGaAs double-HBT technology for high bit-ratecommunication circuits (1997)

A InP/InGaAs DHBT technology has been developed to meet the high speed requirements of circuits required in 20 Gbit/s optical communication links. High performance devices were achieved with a current gain over 100 and cutoff frequencies of &gt; 50 GHz. The technology showed excellent behaviour in terms of yield and homogeneity. Over 20 Gbit/s digital ICs were realised: among them, a 20 Gbit/s external modulator driver, and a 32 Gbit/s 2:1 multiplexer.
Generative Inverse Design of Aerodynamic Shapes Using Conditional Invertible Neural Networks (2022)

Abstract Conditional invertible neural networks (cINNs) were used for generative inverse design of aerodynamic shapes for a given aerodynamic performance target. The methodology was used to generate two-dimensional (2D) airfoil shapes for a target lift coefficient and three-dimensional (3D) vehicle shapes for a low drag vehicle given an aerodynamic drag coefficient target. Training data for both cases were generated for the forward process i.e., aerodynamic performance as a function of design variables that define the airfoil or vehicle shape, using design of experiments (DOE) and computational fluid dynamics (CFD) simulations. Due to the structure of the cINNs, the inverse process was learned implicitly, i.e., samples from latent space were transformed back to the design variables. The designs generated by the trained cINN model were simulated under identical conditions to check if they met the desired aerodynamic performance target. The distribution of design variables conditioned on a performance target learned by the cINN model was compared to the distribution in the training data. cINNs provide an easy-to-use tool to generate new designs that meet the desired aerodynamic performance, thereby, reducing the iteration time between aerodynamicists and stylists. In case of vehicle shape generation, since all generated vehicle shapes meet the aerodynamic performance target, the designer can select the shapes that do not conflict with other design constraints such as the interior volume, comfort, styling, and various safety requirements.
The Preparation Of Laboratory Specimens As An Aid To The Diagnosis Of Animal Diseases... (2012)

Many problems in connection with animal diseases require for their solution the application of methods which can only be undertaken in properly equipped laboratories. This ordinarily involves the collection, packing, and shipping of samples of specimens. The manner in which this is done is a most important factor and to a very large extent is responsible either for the success or for the failure of the undertaking. The discussion of the subject to which the following pages are devoted is taken in hand in the hope that it may provide guidance to the veterinarians and others who may have occasion to require the assistance of a laboratory in the solution of disease problems.
O2‐13‐04: Early Clinical Results and Preclinical Validation of the O‐Glcnacase (OGA) Inhibitor Mk‐8719 as a Novel Therapeutic for the Treatment of Tauopathies (2016)

MK-8719 is a selective inhibitor of the O-GlcNAcase (OGA) enzyme that is currently in Phase 1 clinical trials for the treatment of Progressive Supranuclear Palsy (PSP). Here we summarize the preclinical validation data for MK-8719 generated in Tg4510 transgenic mice as well as human tolerability and target engagement (PET) data for MK-8719 following single dose administration. Evaluation of the pharmacodynamic activity and efficacy of MK-8719 was conducted in Tg4510 transgenic mice that overexpress human tau with P301L mutation. The effects of MK-8719 on total protein O-GlcNAcylation and the accumulation of pathological species of tau were determined by immunoassay. The influence of MK-8719 on brain atrophy of Tg4510 mice was evaluated by volumetric MRI and the formation of neurofibrillary tangles was assessed using immunohistochemistry. Safety and tolerability of single doses of MK-8719 between 5 and 1200 mg were evaluated in healthy volunteers (n=16) using an alternating-panel single ascending dose design. MK-8719 target engagement in the brain was evaluated in a separate Phase 1 study using PET with [18F]MK-8553, a radiolabeled tracer of a novel small molecule inhibitor of the OGA enzyme. In vitro studies demonstrated that MK-8719 is a competitive reversible inhibitor of the human OGA enzyme with comparable activity in rat, dog, and mouse. Subchronic administration of MK-8719 significantly increased O-protein levels in brain tissue and reduced the formation of pathological tau species in Tg4510 mouse brain. Reduction of pathological tau accumulation in Tg4510 mice was accompanied by reductions in neurodegeneration, including reduced inflammatory marker expression, attenuation of brain weight loss, and attenuation of forebrain volume loss. In a Phase 1 study, single doses up to 1200 mg were generally well tolerated. No laboratory, ECG, or vital sign adverse experiences were observed. PET studies demonstrated that dosing of MK-8719 causes a decrease of [18F]MK-8553 binding compared to baseline, indicating target engagement of the OGA enzyme in the brain. Preclinical data demonstrate that MK-8719 significantly reduced pathological tau and neurodegeneration in Tg4510 mice. Phase 1 clinical findings support further clinical development of MK-8719 and investigation of safety and efficacy in PSP patients.
Data from Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer: Results from the Finnish Maternity Cohort (2023)

&lt;div&gt;Abstract&lt;p&gt;Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case–control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case–control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (&lt;140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94–1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., &lt;5 years, OR&lt;sub&gt;Q4 vs. Q1&lt;/sub&gt;, 1.10; 95% CI, 0.64–1.89; ≥15 years, OR&lt;sub&gt;Q4 vs. Q1&lt;/sub&gt;, 1.36; 95% CI, 0.86–2.13; p&lt;sub&gt;heterogeneity&lt;/sub&gt; = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk. &lt;i&gt;Cancer Res; 77(1); 134–41. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;
Enhancement of human myeloid stem cell growth in vitro (1983)

Human myeloid stem cell growth in agar was enhanced by the addition of human plasma, red-cell lysate, hemin, and beta-mercaptoethanol to the culture system. Using conditioned media from a human T-cell or leukocyte-conditioned media as a source of colony-stimulating activity, the number of colonies was increased due to enhancement by an average of 54%. Analysis of colony types indicated that over 80% of the increase in colony number at eight days was due to granulocytic colony growth. Light density marrow cells cultured with enhancing agents produced colony levels of approximately 12-27 CFU-C/2 x 10(3) cells.
On the ease and efficiency of human-computer interfaces (2008)

Ease and efficiency are two critical qualities of human-computer interfaces. In this address, I will first examine various contributing factors to these two qualities, including recognition and recall, open and closed loop control, controlled and automatic process [Schneider and Shiffrin, 1977; Shiffrin and Schneider, 1977; Schneider and Chein, 2003], mapping directness [Hutchins et al., 1985], unit of operation, and chunking.
The beneficial effect of alpha-blockers for ureteral stent-related discomfort: systematic review and network meta-analysis for alfuzosin versus tamsulosin versus placebo (2015)

The alpha-blockers significantly decreased USS and BPS in comparison with placebo. Tamsulosin might be more effective than alfuzosin.
Prolyl isomerase Pin1 negatively regulates the stability of SUV39H1 to promote tumorigenesis in breast cancer (2013)

Pin1, a conserved eukaryotic peptidyl-prolyl cis/trans isomerase, has profound effects on numerous key-signaling molecules, and its deregulation contributes to disease, particularly cancer. Although Pin1-mediated prolyl isomerization of protein servers as a regulatory switch in signaling pathways, the significance of proline isomerase activity in chromatin modifying complex remains unclear. Here, we identify Pin1 as a key negative regulator for suppressor of variegation 3-9 homologue 1 (SUV39H1) stability, a major methyltransferase responsible for histone H3 trimethylation on Lys9 (H3K9me3). Pin1 interacts with SUV39H1 in a phosphorylation-dependent manner and promotes ubiquitination-mediated degradation of SUV39H1. Consequently, Pin1 reduces SUV39H1 abundance and suppresses SUV39H1 ability to induce H3K9me3. In contrast, depletion of Pin1 in cancer cells leads to elevated SUV39H1 expression, which subsequently increases H3K9me3, inhibiting tumorigenecity of cancer cells. In a xenograft model with 4T1 metastatic mouse breast carcinoma cells, Pin1 overexpression increases tumor growth, whereas SUV39H1 overexpression abrogates it. In human breast cancer patients, immunohistochemical staining shows that Pin1 levels are negatively correlated with SUV39H1 as well as H3K9me3 levels. Thus, Pin1-mediated reduction of SUV39H1 stability contributes to convey oncogenic signals for aggressiveness of human breast cancer, suggesting that Pin1 may be a promising drug target for anticancer therapy.