gebhart/patrepeval huggingface dataset:
Rapid changes in chromatin structure during dedifferentiation of primary hepatocytes in vitro (2022)

Primary hepatocytes are widely used in the pharmaceutical industry to screen drug candidates for hepatotoxicity, but hepatocytes quickly dedifferentiate and lose their mature metabolic function in culture. Attempts have been made to better recapitulate the in vivo liver environment in culture, but the full spectrum of signals required to maintain hepatocyte function ex vivo remains elusive. To elucidate molecular changes that accompany, and may contribute to dedifferentiation of hepatocytes ex vivo, we performed lineage tracing and comprehensive profiling of alterations in their gene expression profiles and chromatin landscape during culture. First, using genetically tagged hepatocytes we demonstrate that expression of the fetal gene alpha-fetoprotein in cultured hepatocytes comes from cells that previously expressed the mature gene albumin, and not from a population of albumin-negative precursor cells, proving mature hepatocytes undergo true dedifferentiation in culture. Next we studied the dedifferentiation process in detail through bulk RNA-sequencing of hepatocytes cultured over an extended period. We identified three distinct phases of dedifferentiation: an early phase, where mature hepatocyte genes are rapidly downregulated in a matter of hours; a middle phase, where fetal genes are activated; and a late phase, where initially rare contaminating non-parenchymal cells proliferate, taking over the culture. Lastly, to better understand the signaling events that result in the rapid downregulation of mature genes in hepatocytes, we examined changes in chromatin accessibility in these cells during the first 24 h of culture using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq). We find that drastic and rapid changes in chromatin accessibility occur immediately upon the start of culture. Using binding motif analysis of the areas of open chromatin sharing similar temporal profiles, we identify several candidate transcription factors potentially involved in the dedifferentiation of primary hepatocytes in culture.
Supplementary Table 1 from Neutralization of KIT Oncogenic Signaling in Leukemia with Antibodies Targeting KIT Membrane Proximal Domain 5 (2023)

&lt;p&gt;Monitoring of phage antibody selection by titration, ELISA and scFv sequencing.&lt;/p&gt;
P4‐018: Blocking Aβ/Chaperone Interactions to Prevent CAA (2010)

The accumulation of amyloid β (Aβ) peptides as toxic oligomers, amyloid plaques and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of Aβ peptides to apolipoprotein (apo) E plays an important role in modulation of both amyloid deposition and clearance. We have shown that blocking the Aβ/apoE chaperone interaction by Aβ12-28P which is a nontoxic blood-brain-barrier permeable, and non-fibrillogenic synthetic peptide, could constitute a novel treatment for AD by reducing Aβ parenchymal deposition. In the present study, we investigate this therapeutic effect on cerebral amyloid deposits in transgenic AD mice model (TgSwDI) which expresses human Swedish (K670N/M671L), Dutch (E693Q)/ Iowa (D694N) APP mutations. These mice develop abundant cerebral microvascular Aβ depositions beginning at the age of 4 months, and have impaired memory. Developing a therapy which is effective against CAA is important as most AD patients have CAA and ˜33% of aged cognitively normal individuals also having CAA. A problem with other potential AD treatments such as immunomodulation has been persistence and/or further accumulation of CAA with an increase in microhemorrhages, as reported in different AD mouse models and in patients. TgSwDI mice received systemic administration of Aβ12-28P for 6 months, whereas age-matched TgSwDI mice received PBS only. TgSwDI mice and age-matched Wild-type (WT) mice were subjected to behavioral testing with the radial arm maze to assess their working memory. Subsequently, mice were sacrificed and their brains were processed for histological and biochemical analysis. Our behavioral results show that Aβ 12-28P treated TgSwDI AD mice performed comparably to wild-type mice, whereas vehicle treated Tg SwDI AD mice showed significantly worse performance than WT or Aβ 12-28P treated mice (p < 0.0001). Treatment resulted in a 90% reduction in the amyloid burden (p = 0.0096), Deposited Aβ40 and 42 were both reduced by 67% (p = 0.0078 and 0.0086, respectively). Aβ oligomer levels were also reduced by 36% in treated TgSwDI mice (p = 0.0006). These findings suggest that compounds such as Aβ12-28P are highly effective therapeutic approach for preventing CAA in a mouse model. It is likely that Aβ12-28P acts through a number of non-mutually exclusive mechanisms.
Physical association and functional relationship between protein kinase Cζ and the actin cytoskeleton (1995)

Protein kinase C (PKC) was initially identified as a serine/threonine protein kinase dependent on calcium and phospholipids and shown to be involved in intracellular signaling pathways. PKC isoforms have been classified into four groups: Ca(2+)-dependent conventional PKC alpha, beta I, beta II, gamma; Ca(2+)-independent, novel PKC delta, epsilon, eta, phi; atypical PKC zeta, lambda, iota which are not activated by Ca2+ or diacylglycerol, and the recently discovered PKCmu. We reported that activation of the zeta PKC isoform is an important step in interleukin-2 (IL-2)-mediated proliferation (Gómez, J., Pitton, C., García, A., Martínez, A., Silva, A. and Rebollo, A., Exp. Cell Res. 1995. 218: 105.). zeta PKC is also required for mitogenic activation of fibroblasts and for the maturation pathway activated by insulin and Ras. Contradictory results have been reported regarding the subcellular redistribution of zeta PKC upon activation. We report here, using confocal microscopy, that IL-2 induces expression, translocation and association of zeta PKC to a structure coincident with the actin cytoskeleton. Furthermore, we show that zeta PKC has a role in maintaining the integrity of the actin cytoskeletal structure in IL-2-stimulated cells. On the contrary, zeta PKC is not involved in the actin cytoskeleton organization when cells are maintained in IL-4, confirming our previous results showing that IL-4-induced signal transduction is PKC independent.
Reduction in the write error rate of voltage-induced dynamic magnetization switching using the reverse bias method (2018)

Using macro-spin modeling, we studied the reduction in the write error rate (WER) of voltage-induced dynamic magnetization switching by enhancing the effective thermal stability of the free layer using a voltage-controlled magnetic anisotropy change. Marked reductions in WER can be achieved by introducing reverse bias voltage pulses both before and after the write pulse. This procedure suppresses the thermal fluctuations of magnetization in the initial and final states. The proposed reverse bias method can offer a new way of improving the writing stability of voltage-driven spintronic devices.
Switching Frequency Limit for Soft-Switching MF Transformer System for AC-fed Traction (2006)

The migration to line side power conversion topologies comprising a medium frequency transformer in AC-fed propulsion systems may reduce size and weight of the conversion system. The switching frequency is a crucial factor affecting the viability of such a conversion system. An increased switching frequency of a mutually commutated conversion system comprising a medium frequency transformer employing soft switching is verified by single pulse measurements. A test bench to characterize standard IGBT modules under soft switching has been build and loss measurements on a 3.3 kV IGBT module are presented for hard and soft switching. A loss model of the investigated topology is developed and the maximum switching frequency for a converter equipped with the investigated module is estimated for hard and soft switching
Abstract 1452: Myocyte Aging Conditions Cell Growth and Contractile Function (2006)

The recognition that the heart can replace old dying myocytes by activation of resident cardiac stem cells raises the possibility that organism, organ and cell age do not coincide and that the myoc...
Efficient Non‐linear Optimization via Multi‐scale Gradient Filtering (2013)

Abstract We present a method for accelerating the convergence of continuous non‐linear shape optimization algorithms. We start with a general method for constructing gradient vector fields on a manifold, and we analyse this method from a signal processing viewpoint. This analysis reveals that we can construct various filters using the Laplace–Beltrami operator of the shape that can effectively separate the components of the gradient at different scales. We use this idea to adaptively change the scale of features being optimized to arrive at a solution that is optimal across multiple scales. This is in contrast to traditional descent‐based methods, for which the rate of convergence often stalls early once the high frequency components have been optimized. We demonstrate how our method can be easily integrated into existing non‐linear optimization frameworks such as gradient descent, Broyden–Fletcher–Goldfarb–Shanno (BFGS) and the non‐linear conjugate gradient method. We show significant performance improvement for shape optimization in variational shape modelling and parameterization, and we also demonstrate the use of our method for efficient physical simulation.
Cerebral FET uptake owing to epilepsy appears to be a rare phenomenon (2019)

A recent study reported (1) on high and reversible cerebral FET uptake in some patients due to epileptic seizures. We examined cerebral FET uptake in two chemical induced rat epilepsy models and in patients with focal epilepsy to further investigate whether this phenomenon represents a major pitfall in brain tumor diagnostics and whether FET PET may be a potential marker to localize epileptogenic foci.
GnRH-II Analogs for Selective Activation and Inhibition of Non-Mammalian and Type-II Mammalian GnRH Receptors (2003)

Recently, we identified three types of non-mammalian gonadotropin-releasing hormone receptors (GnRHR) in the bullfrog (designated bfGnRHR-1-3), and a mammalian type-II GnRHR in green monkey cell lines (denoted gmGnRHR-2). All these receptors responded better to GnRH-II than GnRH-I, while mammalian type-I GnRHR showed greater sensitivity to GnRH-I than GnRH-II. In the present study, we designed new GnRH-II analogs and examined whether they activated or inhibited non-mammalian and mammalian type-II GnRHRs. [D-Ala6]GnRH-II, with D-Ala substituted for Gly6 in GnRH-II, increased inositol phosphate (IP) production in cells stably expressing non-mammalian GnRHRs more effectively than native GnRH-II. However, it exhibited lower activity for mammalian type-I GnRHR than GnRH-I itself. Trptorelix-1, a GnRH-II antagonist, inhibited GnRH-induced IP production in cells expressing non-mammalian GnRHRs more effectively than Cetrorelix, a GnRH-I antagonist. Trptorelix-1, however, had lower potency for mammalian type-I GnRHR than Cetrorelix. Ligand-receptor binding assays revealed that [D-Ala6]GnRH-II and Trptorelix-1 have higher affinities for non-mammalian GnRHRs but lower affinities for mammalian type-I GnRHR than GnRH-II and Cetrorelix, respectively. Moreover, [D-Ala6]GnRH-II and Trptorelix-1 had a higher affinity for gmGnRHR-2 than GnRH-II and Cetrorelix, respectively. These results indicate that [D-Ala6]GnRH-II and Trptorelix-1 are highly effective agonist and antagonist, respectively, for non-mammalian and type-II mammalian GnRHRs.
Control of NFATx1 Nuclear Translocation by a Calcineurin-Regulated Inhibitory Domain (1997)

The nuclear factor of activated T cells (NFAT) regulates cytokine gene expression in T cells through cis-acting elements located in the promoters of several cytokine genes. NFATx1, which is preferentially expressed in the thymus and peripheral blood leukocytes, is one of four members of the NFAT family of transcription factors. We have performed domain analysis of NFATx1 by examining the effects of deletion mutations. We found that NFATx1 DNA binding activity and interaction with AP-1 polypeptides were dependent on its central Rel similarity region and that transcriptional activation was reduced by deletions of either its N-terminal domain or its C-terminal domain, suggesting the presence of intrinsic transcriptional activation motifs in both regions. We also identified a potent inhibitory sequence within its N-terminal domain. We show that the inactivation of the inhibition was dependent on the activity of calcineurin, a calcium-calmodulin-dependent phosphatase. We also show that calcineurin associated with the N-terminal domain of NFATx1 at multiple docking sites and caused a reduction of size, indicative of dephosphorylation, in NFATx1. We have mapped the inhibitory activity to less than 60 residues, containing motifs that are conserved in all NFAT proteins. Finally, we demonstrate that deletion in NFATx1 of the mapped 60 residues leads to its nuclear translocation independent of calcium signaling. Our results support the model proposing that the N-terminal domain confers calcium-signaling dependence on NFATx1 transactivation activity by regulating its intracellular localization through a protein module that associates with calcineurin and is a target of its phosphatase activity.
Motion-based segmentation using a thresholded merging strategy on watershed segments (2002)

We assess the performance of a thresholded merging technique used as part of a procedure to obtain a motion-based segmentation of an image sequence. First an initial estimate for the motion field is obtained by using an improved block matching method. Then, an intensity-based initial segmentation is performed, using watershed segmentation on a non-linearly diffused version of the image. Next, a motion vector based on the initial motion field is calculated for each segment, and, finally, the obtained segments and their motion vectors are fed into the motion-based merging scheme, yielding the final segmentation. Results for a thresholded minimum distance merging technique are given and are compared with a K-means clustering algorithm.
Phosphorylation of androgen receptor at serine 81 by cyclin-dependent kinases (2016)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
Acute Pancreatitis: An Unusual Complication of Double Balloon Enteroscopy (2007)

Purpose: 76 year old male with critical aortic stenosis presented for evaluation of transfusion-requiring iron deficiency anemia. As esophagoduodenoscopy, colonoscopy, capsule endoscopy, and CT enterography were unremarkable, a double-balloon enteroscopy (DBE) was performed and revealed a moderate sized jejunal vascular ectasia that was treated with argon plasma coagulation. There were no immediate procedure-related complications.FigureApproximately 4 hours later he presented with severe abdominal pain. Significant laboratories included a markedly elevated lipase (924 U/L [10–73 U/L]) and amylase (380 U/L [26–102 U/L]). CT abdomen revealed inflammatory changes in the body and tail of the pancreas and significant edema in the peripancreatic fat (Fig. 1) but there was no evidence of necrosis. He improved gradually over the course of the next week with conservative treatment. CT abdomen 2 months (Fig. 2) later demonstrated persistent inflammatory changes in the pancreatic body and tail and ill-defined fluid collections in and around the pancreatic tail. However, the patient was asymptomatic. Repeat CT 6 weeks later noted decrease in size of the fluid collections and pancreatic inflammation. He had an uneventful aortic valve replacement at this point. CT performed 4 months later demonstrated a normally enhancing pancreas with minimal residual fluid collection. Our report adds to previous case reports from Japan and Netherlands of this uncommon complication of DBE. Though there are no prospective series, the estimated prevalence of pancreatitis following DBE is around 1%. The etiology of pancreatitis following DBE is unclear but may be related to duodenal reflux or transient sphincter of Oddi dysfunction, which may occur during a long procedure such as DBE with compression of the ampulla. Prospective evaluation of the complications of DBE is needed.[figure1][figure2]Figure
Serum stimulation of the c-fos enhancer induces reversible changes in c-fos chromatin structure. (1990)

Transcription of the proto-oncogene c-fos is known to be activated by growth factors in serum and subsequently repressed by the Fos protein. We show that generalized DNase I sensitivity of c-fos chromatin correlates closely with enhancer activity during induction, repression, and superinduction of the c-fos gene. Within 90 s of serum stimulation, proximal DNA sequences on both sides of the enhancer exhibit increased DNase I sensitivity. Within 5 min, elevated DNase I sensitivity spreads to chromatin at the distal 3' end of the c-fos gene. These results suggest that an open state of chromatin is propagated in both directions from the enhancer. The induced alterations in chromatin structure precede the increased transcriptional activity of the c-fos gene, suggesting that these changes in chromatin structure potentiate transcription.
Neonatal Colonisation Expands a Specific Intestinal Antigen-Presenting Cell Subset Prior to CD4 T-Cell Expansion, without Altering T-Cell Repertoire (2012)

Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein α-positive (SIRPα(+)) antigen-presenting cell subset, whilst SIRPα(-)CD11R1(+) antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPα(+) antigen-presenting cells as orchestrators of early-life mucosal immune development.
Random bonds and random fields in two-dimensional orientational glasses (1991)

Two-dimensional orientational glasses are studied using Monte Carlo simulation. The glasses are modelled using rigid rotors, with fixed positional distribution, chosen using either a random parking algorithm, or by randomly diluting a triangular lattice. The glass-like behaviour has its origin in the coupling, inherent in all anisotropic intermolecular pair potentials, between the rotational degrees of freedom and the quenched random positions. The authors show how this coupling can be broken down into random bond terms that lead to spin glass-like behaviour and random field terms that favour single-particle freezing. The authors study in detail the quadrupolar interaction and illustrate this behaviour by an ad hoc variation of the relative strength of the two types of term. For small random field a rich ground-state structure is observed, with the existence of many nonsymmetry related equivalent orientational states. At finite temperature they observe two temperature regimes for the spin glass order parameter. There is a field dependent regime giving some spin glass-like order out to high temperatures, while at low temperatures a cross-over to a field independent regime is observed, which the authors interpret as cooperative freezing to a low-temperature disordered phase. Comparison is made between their results and experiment, as well as with theoretical models for spin and orientational glasses. Finally they investigate the time dependence of the cooperative freezing, and find behaviour consistent with dynamical freezing, and loss of ergodicity on a finite observation time.
Development of Laser-Mediated Nanodroplet Real-Time PCR on Circulating Tumor Cells (CTC) by Microfilter Platform (2015)

Abstract : This project concerns analysis of circulating tumor cells (CTCs), which are proving to be important for prognostics and guiding therapy for breast cancer patients. The project is a collaboration between the University of Miami on the use of microfilters for capture of circulating tumor cells and SRI International on the use of nanodroplet real-time polymerase chain reaction (PCR) for molecular analysis of captured cells. To improve the temperature control for droplet PCR on the University of Miami microfilters, we have extended our DNA melting temperature calibration methodology to use DNA hairpins and dyes that are less sensitive to temperature, adapted our melting and fitting model for the hairpins, have switched the laser heating from a wavelength of 1.45 to 1.9 m, performed sensitivity studies on the influence of water and glycerol on the calibration, and developed software for real-time same-droplet temperature calibration as an image across the droplet. Together with the University of Miami we have produced a strategy for spectrally-multiplexed Taqman to analyze for hMAM, CEA, KRT19 and MUC1 gene expression, including multiplexing optics and relevant primers and probes. We have performed simultaneous multiplexed detection of the four genes using laser-heating PCR in nanoliter droplets at SRI from cDNA prepared at the University of Miami from breast cancer cell lines.
Membrane-Assisted Antisolvent Crystallization: Interfacial Mass-Transfer Simulation and Multistage Process Control (2020)

Antisolvent crystallization is an important purification technology for the pharmaceutical and fine chemical industries. Herein, we investigated the mass-transfer mechanism of membrane-assisted antisolvent crystallization (MAAC) and developed a multistage operation to reinforce the manufacturing features of antisolvent crystallization. Computational fluid dynamics simulation results via a developed mathematics model and the experimental images via in situ detection technology jointly illustrated the advantages of MAAC for accurate mass-transfer control. Further, a three-stage MAAC process was investigated to reveal the process control performance. The diverse functional regions of multistage MAAC under different antisolvent addition strategies were then highlighted by manufacturing the crystal products with a narrow size distribution, a uniform aspect ratio, and the desired morphology. Multistage MAAC that intensifies the product capacity under a stable control is a promising direction for new-generation antisolvent crystallization.
Identification of human CD4 + T cell populations with distinct antitumor activity (2020)

Abstract How naturally arising human CD4 + T helper subsets impact tumor immunity is unknown. We reported that human CD4 + CD26 high T cells elicit potent immunity against solid tumor malignancies. As CD26 high T cells secrete type-17 cytokines and have been categorized as Th17 cells, we posited these helper populations would possess similar molecular properties. Herein, we reveal that CD26 high T cells are epigenetically and transcriptionally distinct from Th17 cells. Of clinical significance, CD26 high T cells engineered with a chimeric antigen receptor (CAR) ablated large human tumors to a greater extent than enriched Th17, Th1, or Th2 cells. Moreover, CD26 high T cells mediated curative responses in mice, even when redirected with a suboptimal CAR and without the aid of CD8 + CAR T cells. CD26 high T cells co-secreted effector cytokines at heightened levels and robustly persisted. Collectively, our work reveals the potential of human CD4 + T cell populations to improve durability of solid tumor therapies.