gebhart/patrepeval huggingface dataset:
Control of Multidrug Resistance Gene mdr1 and Cancer Resistance to Chemotherapy by the Longevity Gene sirt1 (2005)

Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their ability to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA-mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.
IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease (2009)

Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1R-associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis due to a reduction in infiltrating inflammatory cells into the CNS and reduced Ag-specific CD4(+) T cell-mediated IL-17 production. Adoptive transfer of myelin oligodendrocyte glycoprotein 35-55-specific IRAK4 KI Th17 cells failed to induce experimental autoimmune encephalomyelitis in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease.
P3‐427: Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy (2010)

Targeting hyperphosphorylated tau by immunotherapy is emerging as a promising approach to treat tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia. We have previously reported that active tau immunization clears tau aggregates from the brain and attenuates or prevents functional impairments in two different tangle model mice. Here we assessed the efficacy of passive immunization with the PHF1 antibody, which targets a phospho-epitope within one of our active immunogens. Homozygous JNPL3 P301L mice (2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 μg/125 μl; n = 10 per group) for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue subsequently harvested for analysis of treatment efficacy. The treated mice performed better than controls on the traverse beam task (p < 0.03), and had 58% less tau pathology in the dentate gyrus of the hippocampus (p = 0.02). Plasma levels of PHF1 correlated inversely with tau pathology in the brain stem (p < 0.01) and motor cortex (p = 0.06), indicating that higher dose of antibodies may have a greater therapeutic effect. As assessed by Western blots, the antibody therapy reduced the ratio of pathological- to total tau (PHF1/B19) by 27% (p < 0.0001) but levels of soluble tau were unchanged, compared to controls. Further analysis is underway with other tau antibodies and markers of associated pathologies. These results indicate that passive immunization with tau antibodies can decrease tau pathology and functional impairments in the JNPL3 P301L model. Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models that more closely resemble AD.
A Miniature Robot for Autonomous Single Neuron Recordings (2006)

This paper describes a novel miniature robot that can autonomously position recording electrodes inside cortical tissue to isolate and maintain optimal extracellular action potential recordings. The system consists of a novel motorized miniature recording microdrive and a control algorithm. The microdrive was designed for semi-chronic operation and can independently position four electrodes with micron precision over a 5mm range using small (3mm diameter) piezoelectric linear actuators. The autonomous positioning algorithm is designed to detect, align and cluster action potentials, and then command the microdrive to optimize and maintain the neural signal. This system is shown to be capable of autonomous operation in monkey cortex.
Complex nano-assemblies of polymers and carbon nanotubes (2001)

Since the discovery of carbon nanotubes in 1991 [1], researchers have envisaged potential applications such as nanoscale electronic circuits and the construction of complex carbon-based nano-machines. Thus, the assembly of basic building blocks of complex nano-architectures, such as conjugated polymers and nanotubes, has been a driving goal of much of the nano-science community. A first step towards realizing this goal may be the attachment to, or modification by carbon nanotubes of structures such as polymers. This leads to the possibility of assembling individual polymer molecules onto carbon nanotubes with the net effect being the modification of the polymer's electronic properties and structure in a predictable way. To accomplish this, clearly, a more detailed understanding of the interactions between conjugated polymers and carbon nanotubes must be sought. In this paper, we describe the assembly of the polymer, poly(m-phenylenevinylene-co-2,5-dioctoxy-p-phenylenevinylene) (PmPV), into a coating around single-walled carbon nanotubes. Using scanning tunnelling microscopy, and scanning tunnelling spectroscopy, we demonstrate that the low-energy electronic structure of the assembled material is dominated by the one-dimensional nature of the nanotube as reflected in van Hove singularities. Further, we examine the modifications to electronic structure at higher energies using spectroscopy, which suggests that the polymer's electronic structure is altered by the introduction of nanotubes.
From Human to Mouse and Back: 'Tumorgraft' Models Surge in Popularity (2008)

Mouse xenograft models of cancer, understandably, have a terrible reputation. Although researchers and companies routinely use these human tumors in mice for preclinical drug testing, individual models poorly predict how drugs will act in the clinic. Retrospective re views published by the National Cancer Institute in 2001 and the National Cancer Institute of Canada in 2003 came to the same conclusion: Drugs that work against cancer in xenograft mice rarely work in people with the same tumor, with the exception of lung
ATR-Mediated Checkpoint Pathways Regulate Phosphorylation and Activation of Human Chk1 (2001)

Chk1 is an evolutionarily conserved protein kinase that regulates cell cycle progression in response to checkpoint activation. In this study, we demonstrated that agents that block DNA replication or cause certain forms of DNA damage induce the phosphorylation of human Chk1. The phosphorylated form of Chk1 possessed higher intrinsic protein kinase activity and eluted more quickly on gel filtration columns. Serines 317 and 345 were identified as sites of phosphorylation in vivo, and ATR (the ATM- and Rad3-related protein kinase) phosphorylated both of these sites in vitro. Furthermore, phosphorylation of Chk1 on serines 317 and 345 in vivo was ATR dependent. Mutants of Chk1 containing alanine in place of serines 317 and 345 were poorly activated in response to replication blocks or genotoxic stress in vivo, were poorly phosphorylated by ATR in vitro, and were not found in faster-eluting fractions by gel filtration. These findings demonstrate that the activation of Chk1 in response to replication blocks and certain forms of genotoxic stress involves phosphorylation of serines 317 and 345. In addition, this study implicates ATR as a direct upstream activator of Chk1 in human cells.
Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism (2004)

GnRH plays an essential and central role in neuroendocrine control of reproductive function. The GnRH receptor is located on the plasma membrane of gonadotrophs, pituitary cells that synthesize the gonadotrophins LH and FSH. This receptor belongs to the superfamily of G protein‐coupled receptors, and is preferentially coupled to the Gq/11 protein; its activation by GnRH analogues stimulates the synthesis and release of LH and FSH. Resistance to GnRH by inactivating (loss‐of‐function) mutations of the human GnRH receptor leads to distinct forms of sporadic or inherited hypogonadotrophic hypogonadism. Although in vitro expression of a number of these mutated GnRH receptors in heterologous systems has shown that these mutations appear to alter several functions of the molecule, including ligand binding, receptor activation or interaction with coupled effectors, recent observations from our laboratory have challenged this view and indicated that protein misfolding and resultant misrouting is a mechanism that, by itself, may lead to loss of function of the human GnRH receptor. In this review we describe the experimental data that led us to this conclusion and how these studies revealed previously unsuspected features of the mutant human GnRH receptor.
Open questions in ferredoxin‐NADP+ reductase catalytic mechanism (2003)

Ferredoxin (flavodoxin)-NADP(H) reductases (FNR) are ubiquitous flavoenzymes that deliver NADPH or low potential one-electron donors (ferredoxin, flavodoxin) to redox-based metabolisms in plastids, mitochondria and bacteria. The plant-type reductase is also the basic prototype for one of the major families of flavin-containing electron transferases that display common functional and structural properties. Many aspects of FNR biochemistry have been extensively characterized in recent years using a combination of site-directed mutagenesis, steady-state and transient kinetic experiments, spectroscopy and X-ray crystallography. Despite these considerable advances, various key features in the enzymology of these important reductases remain yet to be explained in molecular terms. This article reviews the current status of these open questions. Measurements of electron transfer rates and binding equilibria indicate that NADP(H) and ferredoxin interactions with FNR result in a reciprocal decrease of affinity, and that this induced-fit step is a mandatory requisite for catalytic turnover. However, the expected conformational movements are not apparent in the reported atomic structures of these flavoenzymes in the free state or in complex with their substrates. The overall reaction catalysed by FNR is freely reversible, but the pathways leading to NADP+ or ferredoxin reduction proceed through entirely different kinetic mechanisms. Also, the reductases isolated from various sources undergo inactivating denaturation on exposure to NADPH and other electron donors that reduce the FAD prosthetic group, a phenomenon that might have profound consequences for FNR function in vivo. The mechanisms underlying this reductive inhibition are so far unknown. Finally, we provide here a rationale to interpret FNR evolution in terms of catalytic efficiency. Using the formalism of the Albery-Knowles theory, we identified which parameter(s) have to be modified to make these reductases even more proficient under a variety of conditions, natural or artificial. Flavoenzymes with FNR activity catalyse a number of reactions with potential importance for biotechnological processes, so that modification of their catalytic competence is relevant on both scientific and technical grounds.
Model-based tracking of self-occluding articulated objects (2002)

Computer sensing of hand and limb motion is an important problem for applications in human computer interaction and computer graphics. We describe a framework for local trading of self occluding motion, in which one part of an object obstructs the visibility of another. Our approach uses a kinematic model to predict occlusions and windowed templates to track partially occluded objects. We present offline 3D tracking results for hand motion with significant self occlusion.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Analysis of α-Synuclein-associated Proteins by Quantitative Proteomics (2004)

To identify the proteins associated with soluble alpha-synuclein (AS) that might promote AS aggregation, a key event leading to neurodegeneration, we quantitatively compared protein profiles of AS-associated protein complexes in MES cells exposed to rotenone, a pesticide that produces parkinsonism in animals and induces Lewy body (LB)-like inclusions in the remaining dopaminergic neurons, and to vehicle. We identified more than 250 proteins associated with Nonidet P-40 soluble AS, and demonstrated that at least 51 of these proteins displayed significant differences in their relative abundance in AS complexes under conditions where rotenone was cytotoxic and induced formation of cytoplasmic inclusions immunoreactive to anti-AS. Overexpressing one of these proteins, heat shock protein (hsp) 70, not only protected cells from rotenone-mediated cytotoxicity but also decreased soluble AS aggregation. Furthermore, the protection afforded by hsp70 transfection appeared to be related to suppression of rotenone-induced oxidative stress as well as mitochondrial and proteasomal dysfunction.
Bioprocess Design Considerations for Cultured Meat Production With a Focus on the Expansion Bioreactor (2019)

Cultured meat, as a cellular agriculture product, utilizes tissue engineering techniques and consequently faces not only cell culture challenges but also scale-up limitations. To ensure cultured meat is financially viable, efficient bioprocess design for scale-up is required. In this mini-review we focus on the design of the expansion bioreactor, and put it in context of the entire bioprocess by providing an overview of the upstream and downstream process considerations. As a full-scale cultured meat bioprocess is still hypothetical we include a review of the key factors and fundamental cell biology parameters required as input data for the design of a process with a product that is not only viable but price competitive. This review highlights the vital aspects of a cultured meat bioreactor design that are often overlooked when parallels are drawn against fermentation processes such as brewing or recombinant protein production in the pharmaceutical industry. Practical application and awareness of the concepts presented here will enable more accurate estimation of the production expenses and raw material requirements. This will form a basis for both further academic research and the design of industrial-scale processes in the field of cultured meat and the wider field of tissue engineering-based cellular agriculture.
Fungal Metabolite Gliotoxin Targets Flavocytochrome b 558 in the Activation of the Human Neutrophil NADPH Oxidase (2004)

Fungal gliotoxin (GT) is a potent inhibitor of the O(2)(-)-generating NADPH oxidase of neutrophils. We reported that GT-treated neutrophils fail to phosphorylate p47(phox), a step essential for the enzyme activation, because GT prevents the colocalization of protein kinase C betaII with p47(phox) on the membrane. However, it remains unanswered whether GT directly affects any of NADPH oxidase components. Here, we examine the effect of GT on the NADPH oxidase components in the cell-free activation assay. The O(2)(-)-generating ability of membranes obtained from GT-treated neutrophils is 40.0 and 30.6% lower, respectively, than the untreated counterparts when assayed with two distinct electron acceptors, suggesting that flavocytochrome b(558) is affected in cells by GT. In contrast, the corresponding cytosol remains competent for activation. Next, GT addition in vitro to the assay consisting of flavocytochrome b(558) and cytosolic components (native cytosol or recombinant p67(phox), p47(phox), and Rac2) causes a striking inhibition (50% inhibitory concentration = 3.3 microM) when done prior to the stimulation with myristic acid. NADPH consumption is also prevented by GT, but the in vitro assembly of p67(phox), p47(phox), and Rac2 with flavocytochrome b(558) is normal. Posterior addition of GT to the activated enzyme is ineffective. The separate treatment of membranes with GT also causes a marked loss of flavocytochrome b(558)'s ability to reconstitute O(2)(-) generation, supporting the conclusion at the cellular level. The flavocytochrome b(558) heme spectrum of the GT-treated membranes stays, however, unchanged, showing that hemes remain intact. These results suggest that GT directly harms site(s) crucial for electron transport in flavocytochrome b(558), which is accessible only before oxidase activation.
Overflow Metabolism in Escherichia coli during Steady-State Growth: Transcriptional Regulation and Effect of the Redox Ratio (2006)

Overflow metabolism in the form of aerobic acetate excretion by Escherichia coli is an important physiological characteristic of this common industrial microorganism. Although acetate formation occurs under conditions of high glucose consumption, the genetic mechanisms that trigger this phenomenon are not clearly understood. We report on the role of the NADH/NAD ratio (redox ratio) in overflow metabolism. We modulated the redox ratio in E. coli through the expression of Streptococcus pneumoniae (water-forming) NADH oxidase. Using steady-state chemostat cultures, we demonstrated a strong correlation between acetate formation and this redox ratio. We furthermore completed genome-wide transcription analyses of a control E. coli strain and an E. coli strain overexpressing NADH oxidase. The transcription results showed that in the control strain, several genes involved in the tricarboxylic acid (TCA) cycle and respiration were repressed as the glucose consumption rate increased. Moreover, the relative repression of these genes was alleviated by expression of NADH oxidase and the resulting reduced redox ratio. Analysis of a promoter binding site upstream of the genes which correlated with redox ratio revealed a degenerate sequence with strong homology with the binding site for ArcA. Deletion of arcA resulted in acetate reduction and increased the biomass yield due to the increased capacities of the TCA cycle and respiration. Acetate formation was completely eliminated by reducing the redox ratio through expression of NADH oxidase in the arcA mutant, even at a very high glucose consumption rate. The results provide a basis for studying new regulatory mechanisms prevalent at reduced NADH/NAD ratios, as well as for designing more efficient bioprocesses.
Combining directional intra prediction and intra block copy with block partition for HEVC (2016)

The directional intra prediction (DIP) modes in HEVC are capable of predicting local continuous image features. Recently, intra block copy (IBC) is proposed for screen content coding, aiming at predicting non-local recurrent image features. For natural video, we observe that recurrent features are often irregular and not aligned with blocks. Thus, we propose a combination of DIP and IBC with block partition for better intra prediction, where one block can be divided into several partitions, each of which may choose between DIP and IBC. We study an intra prediction scheme with the proposed combination, especially the rate-distortion optimization and entropy coding in the scheme. Preliminary experimental results show that the proposed combined intra prediction achieves as high as 5.8% bit-rate saving compared to HEVC anchor.
Molecular Detection of a Novel Human Influenza (H1N1) of Pandemic Potential by Conventional and Real-Time Quantitative RT-PCR Assays (2009)

These assays appear useful for the rapid diagnosis of cases with the novel H1N1 virus, thereby allowing better pandemic preparedness.
Immediate arterial hemostasis after cardiac catheterization: Initial experience with a new puncture closure device (1994)

A novel device for obtaining arterial hemostasis after invasive procedures was tested in 30 patients undergoing diagnostic catheterization (26 patients) or coronary angioplasty (4 patients). The device is deployed through an arterial sheath and forms a positive mechanical seal both inside and outside the defect in the arterial wall. The components are all bioabsorbable. Thirteen patients received a heparin bolus during the catheterization procedure. The activated clotting time recorded in 15 patients just prior to device deployment averaged 264 sec. 29 of 32 attempted device deployments were successful (91%); and the remaining 3 devices pulled completely out as called for by design in the event of incomplete deployment. Twenty-nine patients ultimately achieved successful hemostasis using the device, with the other patient receiving manual hemostasis. Of these 29, hemostasis was immediate and complete in 19 patients. Light digital pressure was required in another 8 patients for less than 5 min. There was minor delayed bleeding requiring supplemental light pressure in several cases. A total of 11 patients required supplemental pressure in addition to the hemostasis device. The use of bolus heparin was significantly (P = 0.05, Fisher's exact test) related to the requirement for supplemental pressure. Three patients developed hematomas, one of which was present prior to device deployment. The other two patients had received bolus heparin. No patient required transfusion or surgical repair. There was no change in the ankle/brachial systolic blood pressure index after device deployment or at late (30-60 day) follow-up. Ultrasound studies revealed no significant pathology relative to the device.(ABSTRACT TRUNCATED AT 250 WORDS)
Real time implementation of subpixel motion estimation for broadcast applications (1990)

Future development in areas such as digital television transmission using data compression techniques, television standards conversion or video noise reduction depends highly on the inclusion of accurate motion vector information in the process. The motion vector field resulting from estimation with a translation model are horizontal and vertical displacement vectors which describe how each pixel has moved between the current and the previous picture. Techniques to generate the motion vector field include pel recursive gradient methods, phase correlation in the transform domain and block correlation techniques. The paper describes an implementation of an extended block correlation method which is robust, gives accurate motion vector estimates and also is suitable for compact implementation for high bandwidth signals.