gebhart/patrepeval huggingface dataset:
Discovering functional transcription-factor combinations in the human cell cycle (2005)

With the completion of full genome sequences and advancement in high-throughput technologies, in silico methods have been successfully used to integrate diverse data sources toward unraveling the combinatorial nature of transcriptional regulation. So far, almost all of these studies are restricted to lower eukaryotes such as budding yeast. We describe here a computational search for functional transcription-factor (TF) combinations using phylogenetically conserved sequences and microarray-based expression data. Taking into account both orientational and positional constraints, we investigated the overrepresentation of binding sites in the vicinity of one another and whether these combinations result in more coherent expression profiles. Without any prior biological knowledge, the search led to the discovery of several experimentally established TF associations, as well as some novel ones. In particular, we identified a regulatory module controlling cell cycle-dependent transcription of G2-M genes and expanded its functional generality. We also detected many homotypic combinations, supporting the importance of binding-site density in transcriptional regulation of higher eukaryotes.
Ligand Induction of Retinoic Acid Receptors Alters an Acute Infection by Murine Cytomegalovirus (1998)

Here we report that administration of retinoids can alter the outcome of an acute murine cytomegalovirus (MCMV) infection. We show that a crucial viral control element, the major immediate-early enhancer, can be activated by retinoic acid (RA) via multiple RA-responsive elements (DR2) that bind retinoid X receptor-retinoic acid receptor (RAR) heterodimers with apparent dissociation constants ranging from 15 to 33 nM. Viral growth is dramatically increased upon RA treatment of infected tissue culture cells. Using synthetic retinoid receptor-specific agonists and antagonists, we provide evidence that RAR activation in cells is required for mediating the response of MCMV to RA. Oral administration of RA to infected immunocompetent mice selectively exacerbates an infection by MCMV, while cotreatment with an RAR antagonist protects against the adverse effects of RA on MCMV infection. In conclusion, these chemical genetic experiments provide evidence that an RAR-mediated pathway can modulate in vitro and in vivo infections by MCMV.
Improvement in lateral IGBT design for 500 V 3 A one chip inverter ICs (2003)

This paper reports, for the first time, the development of 500 V, 3 A single chip inverter ICs. The chip size of the IC is 7.1/spl times/5.2 mm/sup 2/, which is only 30% larger than that of 500 A, 1 A inverter ICs. The chip size reduction has been realized by 35% improvement in lateral IGBT on-resistance and an optimized layout of LIGBT unit cells and bonding pads.
Site-Specific Conjugation of the Indolinobenzodiazepine DGN549 to Antibodies Affords Antibody–Drug Conjugates with an Improved Therapeutic Index as Compared with Lysine Conjugation (2019)

Antibody-drug conjugates have elicited great interest recently as targeted chemotherapies for cancer. Recent preclinical and clinical data have continued to raise questions about optimizing the design of these complex therapeutics. Biochemical methods for site-specific antibody conjugation have been a design feature of recent clinical ADCs, and preclinical reports suggest that site-specifically conjugated ADCs generically offer improved therapeutic indices (i.e., the fold difference between efficacious and maximum tolerated doses). Here we present the results of a systematic preclinical comparison of ADCs embodying the DNA-alkylating linker-payload DGN549 generated with both heterogeneous lysine-directed and site-specific cysteine-directed conjugation chemistries. Importantly, the catabolites generated by each ADC are the same regardless of the conjugation format. In two different model systems evaluated, the site-specific ADC showed a therapeutic index benefit. However, the therapeutic index benefit is different in each case: both show evidence of improved tolerability, though with different magnitudes, and in one case significant efficacy improvement is also observed. These results support our contention that conjugation chemistry of ADCs is best evaluated in the context of a particular antibody, target, and linker-payload, and ideally across multiple disease models.
Indeterminate colitis: A review of the concept — Whatʼs in a name? (2008)

The precise diagnosis of colitis cannot always be established with the available diagnostic tools. The subgroup of patients with an uncertain diagnosis has been classified as "indeterminate colitis" (IC). The definition of "indeterminate," however, has changed over the years. Originally, IC was proposed by pathologists for colectomy specimens, usually from patients operated on for severe colitis, showing overlapping features of ulcerative colitis (UC) and Crohn's disease (CD). Later, the same terminology was used for patients showing no clear clinical, endoscopic, histologic, and other features allowing a diagnosis of either UC or CD. Therefore, it is difficult to compare different studies. An International Organization of Inflammatory Bowel Diseases (IOIBD) working party confirmed 1) the ambiguous nature of the term, and 2) proposes an updated classification for the category of patients with an unclear diagnosis. According to this, the term IBD unclassified (IBDU) is confirmed, as suggested by the Montreal Working Party 2005 for patients with clinically chronic colitis, that clearly have IBD but when definitive features of CD or UC are absent. In resected specimens the term "colitis of uncertain type or etiology" (CUTE) is preferred. It is accepted that most of the time this may have a prefix, such as severe, chronic. The classification of IBD varies when based only on biopsies rather than on a colectomy specimen. The vast majority of these have severe colitis. For those that cannot bear to abandon the highly ambiguous term IC, if it is used at all, this is where it can be used parenthetically.
PSD-95 Uncouples Dopamine–Glutamate Interaction in the D1/PSD-95/NMDA Receptor Complex (2009)

Classical dopaminergic signaling paradigms and emerging studies on direct physical interactions between the D(1) dopamine (DA) receptor and the NMDA glutamate receptor predict a reciprocally facilitating, positive feedback loop. This loop, if not controlled, may cause concomitant overactivation of both D(1) and NMDA receptors, triggering neurotoxicity. Endogenous protective mechanisms must exist. Here, we report that PSD-95, a prototypical structural and signaling scaffold in the postsynaptic density, inhibits D(1)-NMDA receptor subunit 1 (NR1) NMDA receptor association and uncouples NMDA receptor-dependent enhancement of D(1) signaling. This uncoupling is achieved, at least in part, via a disinhibition mechanism by which PSD-95 abolishes NMDA receptor-dependent inhibition of D(1) internalization. Knockdown of PSD-95 immobilizes D(1) receptors on the cell surface and escalates NMDA receptor-dependent D(1) cAMP signaling in neurons. Thus, in addition to its role in receptor stabilization and synaptic plasticity, PSD-95 acts as a brake on the D(1)-NMDA receptor complex and dampens the interaction between them.
Lenalidomide (CC-5013; Revlimid®) Promotes Erythropoiesis in Myelodysplastic Syndromes (MDS) by CD45 Protein Tyrosine Phosphatase (PTP) Inhibition. (2006)

Abstract Lenalidomide displays erythroid and cytogenetic remitting activity in MDS that is karyotype-dependent, yielding a high response rate in patients with chromosome 5q deletion (del5q; 76%) whereas cytogenetic and pathologic improvement in non-del5q patients is less common despite transfusion response in a significant proportion of patients [NEJM2005;352:549–57]. We postulated that lenalidomide targets regulatory proteins that repress the erythropoietin (EPO) signal in non-del5q MDS while inhibiting a critical del5q-associated target to account for karyotype-specific clonal suppression. To evaluate the mechanism by which lenalidomide enhances erythropoiesis in non-del5q MDS, we investigated its effects in MDS [N=9] and normal [N=7] marrow specimens, and in an EPO-responsive UT7 cell line model. Pre-incubation exposure to lenalidomide augmented EPO-induced BFU-E recovery up to 2.5-fold in non-del5q MDS specimens [N=7] over a concentration range of 0.001–1 mM, whereas change in BFU-E recovery from normals was nominal. In UT7 cells, lenalidomide [1mM] enhanced clonogenic response to EPO in a supra-additive fashion. To characterize effects on receptor signal response, we investigated the interaction between lenalidomide and EPO on STAT5 activation, and corresponding EPO-receptor (R) associated kinases. Lenalidomide enhanced both EPO-induced STAT5 phosphorylation and DNA binding in UT7 and MDS CD71Hi MDS erythroid precursors with corresponding Bcl-XL up-regulation. The magnitude of lenalidomide enhancement of EPO/STAT5 phosphorylation was significantly higher in MDS CD71Hi erythroid precursors compared to normal donors (median log10 geometric MFI pSTAT5 EPO+CC5013:EPO, 0.989 [s.d.,0.25] MDS vs. 0.0195 [0.07] Normal; P=0.0005). Lenalidomide enhancement of the EPO-R/STAT5 signal was associated with increased Janus kinase-2 (Jak-2) and Lyn kinase auto-phosphorylation and was abolished only by dual Jak and Src kinase inhibition, implicating targeted inhibition of a common Jak/Lyn kinase regulatory molecule. Indeed, lenalidomide potentiation of the EPO/STAT5 axis was replicated by inhibition of the dual Jak-2/Lyn PTP, CD45, with the selective antagonist RWJ-60475. In a cell free assay employing rhu-CD45 and a pp60 c-Src reporter substrate, lenalidomide inhibited CD45 PTP activity in a time-dependent fashion with a 50% inhibitory concentration [IC50] of 10nM, whereas thalidomide was largely ineffective. PTP inhibition was CD45 selective, demonstrating no significant inhibition of rhu-SHP-2 PTP activity. Our data suggest that lenalidomide is a PTP inhibitor that enhances EPO receptor signaling in non-del5q erythroid precursors by relieving CD45 repression of ligand-dependent Jak2 and Lyn kinase mediated STAT5 activation. Moreover, these findings suggest that CD45 over-activity may contribute to impaired EPO-R signaling in MDS erythroid precursors.
Influence of protein histidine phosphatase overexpression and down‐regulation on human umbilical‐vein endothelial cell viability (2011)

PHP (protein histidine phosphatase) is expressed by mammalian tissues, particularly in blood vessel walls. We investigated whether PHP plays a significant role in endothelial cells. By Western blot and immunofluorescence analysis PHP was found in HUVEC (human umbilical-vein endothelial cells). Overexpression of PHP by the use of a plasmid vector, pIRES2-AcGFP1-PHP, induced apoptosis in HUVEC. To exclude the possibility that increased cellular protein alone unspecifically caused cell damage, the inactive H53A mutant of PHP was also overexpressed as a control; it did not lead to apoptosis. Down-regulation of PHP by the RNAi (RNA interference) technique did not affect cell viability. In conclusion, HUVEC are damaged by overexpression, but not down-regulation, of PHP, suggesting a pronounced impact of the enzyme on the cells when its activity is increased.
Data from Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer (2023)

&lt;div&gt;Abstract&lt;p&gt;Androgen receptor (AR) mediates the growth of prostate cancer throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced prostate cancer requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARD) that markedly reduce the activity of wild-type and splice variant isoforms of AR at submicromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced prostate cancer. &lt;i&gt;Cancer Res; 77(22); 6282–98. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;
Parameter estimation for integer-valued Gibbs distributions (2019)

A central problem in computational statistics is to convert a procedure for sampling combinatorial from an objects into a procedure for counting those objects, and vice versa. Weconsider sampling problems coming from *Gibbs distributions*, which are probability distributions of the form $μ^Ω_β(ω) \propto e^{βH(ω)}$ for $β$ in an interval $[β_\min, β_\max]$ and $H( ω) \in \{0 \} \cup [1, n]$. The *partition function* is the normalization factor $Z(β)=\sum_{ω\inΩ}e^{βH(ω)}$. Two important parameters are the log partition ratio $q = \log \tfrac{Z(β_\max)}{Z(β_\min)}$ and the vector of counts $c_x = |H^{-1}(x)|$. Our first result is an algorithm to estimate the counts $c_x$ using roughly $\tilde O( \frac{q}{ε^2})$ samples for general Gibbs distributions and $\tilde O( \frac{n^2}{ε^2} )$ samples for integer-valued distributions (ignoring some second-order terms and parameters). We show this is optimal up to logarithmic factors. We illustrate with improved algorithms for counting connected subgraphs and perfect matchings in a graph. We develop a key subroutine for global estimation of the partition function. Specifically, we produce a data structure to estimate $Z(β)$ for \emph{all} values $β$, without further samples. Constructing the data structure requires $O(\frac{q \log n}{ε^2})$ samples for general Gibbs distributions and $O(\frac{n^2 \log n}{ε^2} + n \log q)$ samples for integer-valued distributions. This improves over a prior algorithm of Kolmogorov (2018) which computes the single point estimate $Z(β_\max)$ using $\tilde O(\frac{q}{ε^2})$ samples. We also show that this complexity is optimal as a function of $n$ and $q$ up to logarithmic terms.
Effects of Sodium Butyrate, a Histone Deacetylase Inhibitor, on TRAIL-mediated Apoptosis in Human Bladder Cancer Cells (2016)

Anti-Aging Research Center and Blue-Bio Industry RIC, Dongeui U niversity, Busan 614-71, KoreaReceived October 26, 2015/Revised November 12, 2015/Accepted November 13, 2015The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer agent due to its unique ability to induce cancer cell death having only negligible effects on normal cells. However, many cancer cells tend to be resistant to TRAIL. In this study, we inves-tigated the effects and molecular mechanisms of sodium butyrate (SB), a histone deacetylase inhibitor, in sensitizing TRAIL-induced apoptosis in 5637 human bladder cancer cells. Our results indicated that co-treatment with SB and TRAIL significantly increased the apoptosis induction, compared with treat-ment with either agent alone. Co-treatment with SB and TRAIL effectively increased the cell-surface expression of death receptor (DR) 5, but not DR4, which was associated with the inhibition of cellular Fas-associated death domain (FADD)-like interleukin-1β-converting enzyme (FLICE) inhibitory protein (c-FLIP). Furthermore, the activation of caspases (caspase-3, -8 and -9) and degradation of poly(ADP- ribose) were markedly increased in 5637 cells co-treated with SB and TRAIL; however, the synergistic effect was perfectly attenuated by caspase inhibitors. We also found that combined treatment with SB and TRAIL effectively induced the expression of pro-apoptotic Bax, cytosolic cytochrome c and cleave Bid to truncated Bid (tBid), along with down-regulation of anti-apoptotic Bcl-xL expression. These re-sults collectively suggest that a combined regimen of SB plus TRAIL may offer an effective therapeutic strategy for safely and selectively treating TRAIL-resistant bladder cancer cells.Keywords :
Electrochemical Microbial Sensor for Rapid Detection and Quantification of Total Bacterial Count (2020)

Early and online detection of pathogens in the agricultural sector is vital in terms of crop protection as well as economy. Within this context, an electrochemical microbial sensor with a locally formed electrocatalyst was used for rapid detection of gram-negative and gram-positive bacteria in a suspension of bacteria in water. Initially, the background signals of each bacterial species in water were determined. Following this, the current response from the sensor was used to detect total bacterial concentration of a suspension containing both types of bacteria. Escherichia coli and Staphylococcus aureus were used as the model bacteria for these experiments. These bacteria had the ability to hinder the reduction reaction occurring at the electrode surface, leading to a drop in the current. Concentrations ranging from 10 2 to 10 8 cfu/ml were detected by this sensor. By monitoring the total bacterial concentration of washed water online, this sensor could be of great use anywhere along the food chain, starting from crop production until the marketing of food.
Noninvasive blood tests for fetal development predict gestational age and preterm delivery (2018)

Noninvasive blood tests that provide information about fetal development and gestational age could potentially improve prenatal care. Ultrasound, the current gold standard, is not always affordable in low-resource settings and does not predict spontaneous preterm birth, a leading cause of infant death. In a pilot study of 31 healthy pregnant women, we found that measurement of nine cell-free RNA (cfRNA) transcripts in maternal blood predicted gestational age with comparable accuracy to ultrasound but at substantially lower cost. In a related study of 38 women (23 full-term and 15 preterm deliveries), all at elevated risk of delivering preterm, we identified seven cfRNA transcripts that accurately classified women who delivered preterm up to 2 months in advance of labor. These tests hold promise for prenatal care in both the developed and developing worlds, although they require validation in larger, blinded clinical trials.
Model Semantics and Simulation of Time Scale Abstractions in Collision Models (1998)

E ective design of models requires simpli cation of di erent components of the system. For example, interactions of the system under scrutiny with its environment are modeled as idealized sources and sinks, and system behavior is derived from idealized interactions among constituent components. Some of the more detailed behavior is governed by small parameters, that produce continuous but complex nonlinear behaviors. These nonlinear continuous behaviors are often simpli ed to piecewise continuous forms, which then results in discontinuities at the temporal or spatial scale of interest. The resulting models are of a mixed continuous/discrete, or hybrid, nature. Physical systems theory based on continuity of power and conservation of energy is well understood. However, once discontinuous e ects are included, these laws may be violated at the macroscopic level. The challenge is to endow hybrid models with semantics that do not violate the underlying physical nature of the system. This paper studies the e ects and semantics of time scale abstraction, suchasembodied by Newton&amp;apos;s collision rule. The results show that hybrid modeling of physical systems can be systematic without the need for ad hoc hysteresis e ects. Keywords|hybrid systems, bond graphs, modeling, simulation Pieter J. Mosterman is supported by a grant from the DFG Schwerpunktprogramm KONDISK. y
On suitability of PSD method for opportunity detection in OFDM(A) based cognitive radio systems (2009)

In this study, orthogonal frequency division multiple access (OFDMA) based primary and secondary usage in a cognitive radio system is considered and conventional power spectral density (PSD) based technique is used to detect the opportunities in the spectrum. Primary user employs block-based or scattered subcarrier allocation scheme and the overlay system aims to utilize the spectral gaps. Comparison of the allocation schemes and effect of windowing are presented in terms of true detection and false alarm rates. It is observed that when block-based allocation is employed, the unlicensed user will be able to detect more opportunities in the spectrum compared to the case in which the scattered allocation is employed. Simulation results show that threshold selection is crucial since it is the main factor in determining the false alarm and true detection rates. It has been shown that, for either of the schemes all possible spectral gaps cannot be found when PSD is used. Questioning the suitability of PSD method results in that a new definition of opportunity is needed, forming a basis for the second part of this study.
Distributed Interference Management and Scheduling in LTE-A Femto Networks (2010)

We design novel mechanisms and algorithms for fast, simple, and distributed interference management and scheduling in wireless femto networks via exchange of information over-the-air (OTA). We focus on Long Term Evolution (LTE) of the 3GPP standard and on the downlink; we leverage the existing signalling in LTE and delineate additional signals that are needed. Key aspects of our work include: (1) the design is based on only one round of exchange of very few bits of information in each subframe (of 1 ms), (2) the algorithm is a heuristic derived from the maximum weight scheduling algorithm for a realistic interference model, and (3) the framework allows for easy control of fairness for best effort flows, control of delay tails for delay sensitive QoS flows, and relative prioritization between best effort and QoS flows. The performance of the mechanisms and algorithms is validated using system simulations based on 3GPP evaluation methodology.
Interval-Valued Reduced-Order Statistical Interconnect Modeling (2007)

We show how advances in the handling of correlated interval representations of range uncertainty can be used to approximate the mass of a probability density function as it moves through numerical operations and, in particular, to predict the impact of statistical manufacturing variations on linear interconnect. We represent correlated statistical variations in resistance-inductance-capacitance parameters as sets of correlated intervals and show how classical model-order reduction methods - asymptotic waveform evaluation and passive reduced-order interconnect macromodeling algorithm - can be retargeted to compute interval-valued, rather than scalar-valued, reductions. By applying a simple statistical interpretation and sampling to the resulting compact interval-valued model, we can efficiently estimate the impact of variations on the original circuit. Results show that the technique can predict mean delay and standard deviation with errors between 5% and 10% for correlated parameter variations up to 35%.
A Phase I, open-label, dose escalation study of MGA271 in combination with ipilimumab in patients with B7-H3-expressing melanoma, squamous cell cancer of the head and neck or non-small cell lung cancer (2015)

Meeting abstracts MGA271 is an Fc optimized, humanized IgG1 monoclonal antibody targeting B7-H3 (CD276), a member of the B7 family, and is currently undergoing Phase I testing. The Fc domain is engineered for enhanced binding to the activating FcγR, CD16A, and decreased binding to the inhibitory