gebhart/patrepeval huggingface dataset:
Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR‐Targeted Therapy (2016)

Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.
On foreground-background separation in low quality color document images (2005)

This paper proposes an adaptive method for separation of foreground and background in low quality color document images. A connected component labelling is initially implemented to capture the spatially connected similar color pixels. Next, dominant background components are determined to divide the entire image into number of grids each representing local uniformity in illumination, background, etc. Finally foreground parts are located using local information around them. Several color images of old historical documents including manuscripts of high importance are used in the experiment. Apart from a qualitative evaluation, results are quantitatively compared with one popular foreground/background separation technique.
Trans Fatty Acids and Cardiovascular Disease (2006)

The intake of trans fat has been associated with coronary heart disease, sudden death from cardiac causes, and diabetes. This article reviews the evidence for physiological and cellular effects of trans fatty acids, unsaturated fatty acids with at least one double bond in the trans configuration. The authors consider the feasibility and potential implications of reducing or eliminating the consumption of trans fatty acids from partially hydrogenated vegetable oils in the United States.
A comprehensive study of optimal conditions for naked plasmid DNA transfer into skeletal muscle by electroporation (2005)

Efficient gene transfer is a key factor in gene therapy. Reducing the damage caused by gene transfer to muscle by electroporation is very important for its clinical application. Extensive investigation of optimal conditions for gene transfer by electroporation is required. The parameters used for electroporation, including plasmid concentration; injection volume; the plasmid dose of the injection; the concentration of saline media; the size of plasmid DNA; the age of the mice; the lag time between plasmid injection and electroporation; and the effect of repeated gene transfer by electroporation, were systematically investigated in the present study. The efficiencies of gene transfer by electroporation in normal and rodent models of diabetes were also evaluated. We found that electroporation used for non-viral gene transfer could be repeated in the same place in the muscle, but the expression efficiency was closely related to the muscle damage. Increasing pulse times could enhance the efficiency of gene transfer with a lower strength of electric field. It was better to use a higher plasmid concentration than to use a larger dose of plasmid and repeated injection to achieve a high level of transgene expression. Optimal conditions varied in different animal models, being milder for diabetic mice than for normal mice, and it was also shown that the conditions that worked well on these small rodents were not necessarily suitable for larger animals. Our results provide a comprehensive view of the factors that affect the efficiency of gene transfer into skeletal muscle by electroporation.
Influence of Sleep Onset on Upper-Airway Muscle Activity in Apnea Patients Versus Normal Controls (1996)

Current evidence suggests that patients with obstructive sleep apnea (OSA) may have augmented pharyngeal dilator muscle activity during wakefulness, to compensate for deficient anatomy. However, the isolated effect of sleep on the activity of these muscles (comparing OSA patients with controls) has not been studied. We therefore determined waking levels of genioglossus (GG) and tensor palatini (TP) muscle activity (% of maximum electromyographic [EMG] activity) in 10 OSA patients and eight controls, and then assessed the impact of the first two breaths of sleep (theta electroencephalographic [EEG] activity) following a period of stable wakefulness. Apnea patients demonstrated greater genioglossal (27.4 +/- 4.0 versus 10.7 +/- 2.1%) and tensor palatini (31.9 +/- 6.5 versus 10.6 +/- 1.9%) EMG activity than did controls during wakefulness. This augmented muscle activity in apnea patients could be reduced to near control levels during wakefulness with the application of continuous positive airway pressure (CPAP) to the upper airway. At sleep onset, control subjects demonstrated small but consistent decrements in the activity of both the TP and GG muscles. On the other hand, apnea patients demonstrated large, significantly greater decrements in TP EMG at sleep onset than did the control subjects. The effect of sleep on GG EMG in apnea patients was inconsistent, with most (n = 7) demonstrating large (significantly larger than controls) decrements in genioglossal activity. However, three OSA patients demonstrated small increments in GG EMG at sleep onset despite falling TP EMG and obstructive apnea or hypopnea. We conclude that sleep onset is associated with significantly larger decrements in TP muscle EMG activity in OSA patients than in controls, which may represent a loss of neuromuscular compensation that is present during wakefulness. However, our results for the GG muscle were more variable, and did not always support this hypothesis.
rHuEPO and Improved Treatment Outcomes: Potential Modes of Action (2004)

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor 1 (HIF-1), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment. Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.
Inflammatory mechanisms in Alzheimer's disease: implications for therapy (1994)

Clinical trials of anti-inflammatory/immunosuppressive drugs are necessary to determine whether alteration of these inflammatory mechanisms can slow the progression of Alzheimer's disease.
Sequencing the Human Genome (1997)

The human genome project is at the halfway point. The genomes of 11 microbes, Escherichia coli , and yeast are finished, yet the human genome is only 2 percent finished. The scale-up to finish by 2005 presents a significant challenge.
Spectroscopic and lasing characteristics of samarium doped glass fibre (1990)

The fluorescence spectra of trivalent samarium doped glass fibres are described. In silica glass Sm3+ has a narrow fluorescence of 2.2 nm f.w.h.m. at a wavelength of 650 nm. The influence of fluorescence line narrowing and large external electric fields on this line is reported. Visible laser emission is obtained at this wavelength when the fibre is pumped in a Fabry Perot cavity. The performance of the laser in continuous, Q-switched and self mode-locked operation is described. The basic theory of self-mode-locking is presented.
The ShcD signaling adaptor facilitates ligand-independent phosphorylation of the EGF receptor (2014)

Proto-oncogenic Src homology and collagen (Shc) proteins have been considered archetypal adaptors of epidermal growth factor receptor (EGFR)-mediated signaling. We report that in addition to its role as an EGFR-binding partner and Grb2 platform, ShcD acts noncanonically to promote phosphorylation of select EGFR residues. Unexpectedly, Y1068, Y1148, and Y1173 are subject to ShcD-induced, cell-autonomous hyperphosphorylation in the absence of external stimuli. This response is not elicited by other Shc proteins and requires the intrinsic EGFR kinase, as well as the ShcD phosphotyrosine-binding (PTB) domain. Assessments of Erk, Akt, phospholipase C 1γ, and FAK pathways reveal no apparent distal signaling targets of ShcD. Nevertheless, the capacity of cultured cells to repopulate a wounded monolayer is markedly accelerated by ShcD in an EGFR kinase-dependent manner. Furthermore, detection of overexpressed ShcD coincident with EGFR phosphorylation in human gliomas suggests a clinical application for these findings. We thus demonstrate unique and relevant synergy between ShcD and EGFR that is unprecedented among signaling adaptors.
Glioma stem cells: turpis omen in nomen? (the evil in the name?) (2014)

High-grade gliomas remain incurable and lethal. Through the availability of the stem-like cells responsible for glioblastoma (GB) formation, expansion, resilience and recurrence, the discovery of glioma cancer stem cells (GCSCs) is revolutionizing this field. GCSCs provide an unprecedented opportunity to reproduce and study GB pathophysiology more accurately. This critically emphasizes our ability to unambiguously identify, isolate and investigate cells that do qualify as GCSCs, to use them as a potential model that is truly predictive of GBs and of their regulation and response to therapeutic agents. We review this concept against the background of key findings on somatic, neural and solid tumour stem cells (SCs), also taking into account the emerging phenomenon of phenotypic SC plasticity. We suggest that basic approaches in these areas can be imported into the GCSC field, so that the same functional method used to identify normal somatic SCs becomes the most appropriate to define GCSCs. This, combined with knowledge of the cellular and molecular basis of normal adult neurogenesis, promises to improve the identification of GCSCs and of selective markers, as well as the development of innovative, more specific and efficacious antiglioma strategies.
Durable Human Memory T Cells Quantifiable by Cultured Enzyme-Linked Immunospot Assays Are Induced by Heterologous Prime Boost Immunization and Correlate with Protection against Malaria (2005)

Immunological memory is a required component of protective antimalarial responses raised by T cell-inducing vaccines. The magnitude of ex vivo IFN-gamma T cell responses is widely used to identify immunogenic vaccines although this response usually wanes and may disappear within weeks. However, protection in the field is likely to depend on durable central memory T cells that are not detected by this assay. To identify longer-lived memory T cells, PBMC from malaria-naive vaccinated volunteers who had received prime boost vaccinations with a combination of DNA and/or viral vectors encoding the multiepitope string-thrombospondin-related adhesion protein Ag were cultured in vitro with Ag for 10 days before the ELISPOT assay. Ex vivo T cell responses peaked at 7 days after the final immunization and declined substantially over 6 mo, but responses identified after T cell culture increased over the 6-mo period after the final immunization. Moreover, individual cultured ELISPOT responses at the day of challenge time point correlated significantly with degree of protection against malaria sporozoite challenge, whereas ex vivo responses did not, despite a correlation between the peak ex vivo response and magnitude of memory responses 6 mo later. This cultured assay identifies long-lasting protective T cell responses and therefore offers an attractive option for assessments of vaccine immunogenicity.
A comparison of the anabolic effects of rat and bovine parathyroid hormone (1-34) in ovariectomized rats. (2001)

The current study was designed to compare the skeletal effects of comparable doses of rat parathyroid hormone 1-34 (rPTH) and bovine parathyroid hormone 1-34 (bPTH) in ovariectomized (OVX) rats. Female Sprague-Dawley rats were OVX or sham-operated at 6 months of age and maintained untreated for 28 days after surgery. Baseline control and OVX rats were sacrificed at the beginning of treatment. Beginning 28 days post-OVX, the remaining rats were subcutaneously injected daily with rPTH or bPTH at 0, 5, 25, or 50 microg/kg/d for 28 days. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of the distal femoral metaphyses were determined ex vivo using dual energy X-ray absorptiometry. Quantitative bone histomorphometry was performed on undecalcified longitudinal sections of the proximal tibia from each rat. Baseline OVX rats exhibited osteopenia as demonstrated by their significantly reduced femoral BMD and proximal tibia cancellous bone volume compared with those of baseline sham controls. Both rPTH and bPTH restored bone in OVX rats by markedly stimulating bone formation in a dose-dependent manner. However, a difference in potency between the two forms of PTH was evident. The percentage increases of BMC, BMD, cancellous bone volume, trabecular thickness, mineralizing surface, and bone formation rate in the OVX rats treated with bPTH at 5 microg/kg/d were the same as or above those treated with rPTH at the 25 microg/kg/d dose level. A relative potency analysis showed that bPTH was approximately 4- to 6-fold relatively more potent than rPTH in increasing distal femoral BMD as well as cancellous bone volume, mineralizing surface, and bone formation rate of proximal tibial metaphyses at comparable dose levels and a given time. These results may serve as a reference for in vivo study design when rPTH or bPTH are to be the agents for studies on bone anabolism.
Hybrid integration of silicon photonics circuits and InP lasers by photonic wire bonding (2018)

Efficient coupling of III–V light sources to silicon photonic circuits is one of the key challenges of integrated optics. Important requirements are low coupling losses, as well as a small footprint and a high yield of the overall assembly, along with the ability to use automated processes for large-scale production. In this paper, we demonstrate that photonic wire bonding addresses these challenges by exploiting direct-write two-photon lithography for in situ fabrication of three-dimensional freeform waveguides between optical chips. In a series of proof-of-concept experiments, we connect indium phosphide (InP)-based horizontal-cavity surface-emitting lasers to passive silicon photonic circuits with insertion losses down to 0.4 dB. To the best of our knowledge, this is the most efficient interface between an InP light source and a silicon photonic chip that has so far been demonstrated. Our experiments represent a key step in advancing photonic wire bonding to a universal integration platform for hybrid photonic multi-chip assemblies that combine known-good dies of different materials to high-performance hybrid multi-chip modules.
The significance of retention in post and core restorations. (1993)

Endodontically-treated, pulpless teeth tend to become brittle and loose their natural resistance to intraoral functional stress. To retain the core to the root, posts are placed in such teeth. This article presents the rationale for placing the posts, reports past results, and discusses the current materials and implementation procedures. Understanding those principles is the learning objective of this article.
Autoantibodies in insulin-dependent diabetes recognize distinct cytoplasmic domains of the protein tyrosine phosphatase-like IA-2 autoantigen (1996)

Protein tyrosine phosphatase-like IA-2 is a major autoantigen in insulin-dependent diabetes. It has been identified as both a specificity of cytoplasmic islet cell Abs and one of the precursors of the 40- and 37-kDa tryptic fragment islet autoantigens. To characterize autoantibody binding to IA-2 and determine whether humoral autoimmunity extends to other tyrosine phosphatases, we analyzed serum reactivity in 100 patients with insulin-dependent diabetes against different in vitro translated portions of the IA-2 protein as well as the tyrosine phosphatase domains of HPTPbeta and HPTPdelta. All autoantibody reactivity was confined to the cytoplasmic portion of IA-2 (amino acids 601-979). At least four epitopes were found. These were contained within amino acids 605 to 620 and 605 to 682 of the juxtamembrane region and within amino acids 777 to 937 and 687 to 979 in the IA-2 tyrosine phosphatase-like domain. Footprinting studies confirmed the presence of multiple epitopes. Fifty-six percent of sera with IA-2 Abs bound epitopes within the juxtamembrane region, and 83% bound epitopes in the tyrosine phosphatase-like domain; 39% had Abs to both regions. No reactivity against the IA-2 ectodomain or the tyrosine phosphatase domains of HPTPbeta and HPTPdelta was found. These data suggest that the cytoplasmic region, in particular the tyrosine phosphatase-like domain, is the major target of IA-2 Abs in insulin-dependent diabetes, and that autoantibody reactivity is specific for IA-2 or IA-2-like molecules.
Amplifying TLR-MyD88 Signals within Tumor-Specific T Cells Enhances Antitumor Activity to Suboptimal Levels of Weakly Immunogenic Tumor Antigens (2010)

The efficacy of T cell-based immunotherapy to treat cancer patients remains a challenge partly because of the weak activity toward subdominant tumor antigens (TAg) and to tumors expressing suboptimal TAg levels. Recent reports indicate that Toll-like receptor (TLR) stimulation on T cells can lower the activation threshold. In this study, we examined the antitumor activity and survival of TLR2-MyD88-stimulated CD8 T cells derived from melanoma patients and T-cell receptor transgenic pmel mice. TLR2-stimulated pmel CD8 T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, responded to significantly lower TAg levels and resulted in increased production of effector molecules and cytotoxicity. Wild-type or MyD88(-/-) mice treated with TLR2 ligand and pmel T cells, but not TLR2(-/-)pmel or MyD88(-/-)pmel T cells, showed tumor regression of an established melanoma tumor. Overexpressing TLR2 in TAg-specific T cells eradicated tumors; four times fewer cells were needed to generate antitumor responses. The enhanced antitumor activity of TLR2-MyD88-stimulated T cells was associated with increased effector function but perhaps more importantly with improved survival of T cells. Activating TLR-MyD88 signals in patient-derived T cells also reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion, and cytotoxicity. These data highlight a previously unappreciated role for activating TLR-MyD88 signals in tumor-reactive T lymphocytes.
Abnormal Mitochondrial Dynamics in the Pathogenesis of Alzheimer's Disease (2012)

Mitochondrial dysfunction is one of the most early and prominent features in vulnerable neurons in the brain of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondria are highly dynamic organelles characterized by a delicate balance of fission and fusion, a concept that has revolutionized our basic understanding of the regulation of mitochondrial structure and function which has far-reaching significance in studies of health and disease. Tremendous progress has been made in studying changes in mitochondrial dynamics in AD brain and models and the potential underlying mechanisms. This review highlights the recent work demonstrating abnormal mitochondrial dynamics and distribution in AD models and discusses how these abnormalities may contribute to various aspects of mitochondrial dysfunction and the pathogenesis of AD.
On Detecting Adversarial Perturbations (2017)

Machine learning and deep learning in particular has advanced tremendously on perceptual tasks in recent years. However, it remains vulnerable against adversarial perturbations of the input that have been crafted specifically to fool the system while being quasi-imperceptible to a human. In this work, we propose to augment deep neural networks with a small "detector" subnetwork which is trained on the binary classification task of distinguishing genuine data from data containing adversarial perturbations. Our method is orthogonal to prior work on addressing adversarial perturbations, which has mostly focused on making the classification network itself more robust. We show empirically that adversarial perturbations can be detected surprisingly well even though they are quasi-imperceptible to humans. Moreover, while the detectors have been trained to detect only a specific adversary, they generalize to similar and weaker adversaries. In addition, we propose an adversarial attack that fools both the classifier and the detector and a novel training procedure for the detector that counteracts this attack.