gebhart/patrepeval huggingface dataset:
Mechanism of TNF‐α‐induced lipolysis in human adipocytes uncovered (2016)

Increased lipolysis is linked to obesity, insulin resistance, and type 2 diabetes (1). The complex mechanistic interactions between lipid droplet-associated proteins, lipases, and stimuli that promote lipolysis play a critical role in maintaining a balance between the healthy state versus pathogenic metabolic disease. Tumor necrosis factor (TNF)-α increases lipolysis in adipocytes by regulating lipid droplet-associated proteins and lipases in adipocytes (1, 2). TNF-α reduces the expression of cell death-inducing DFF45-like effector C (CIDEC), also known as fat-specific protein 27, which plays an important role in regulating lipid droplet dynamics, triglyceride accumulation, and lipolysis in adipocytes (1, 2). Recent studies have showed that CIDEC regulates lipolysis in human adipocytes by regulating catalytic capacity (3), as well as transcription of adipose triglyceride lipase (4). The study by Tan et al. published in this issue of Obesity provides a detailed mechanism for TNF-α-mediated downregulation of CIDEC that ultimately leads to increased basal lipolysis in human adipocytes (5). TNF-α represses CIDEC expression in adipocytes, and this downregulation is critical to enhance lipolysis, as adenoviral maintenance of CIDEC expression blocks TNF-α-mediated lipolysis (6). Previous studies have demonstrated that TNF-α represses peroxisome proliferator-activated receptor (PPAR)-γ expression and activity (1). Since CIDEC is transcriptionally regulated by PPAR-γ (7), does TNF-α downregulate CIDEC expression by affecting PPAR-γ expression and/or activity? Utilizing a commercially available SW872-cultured human adipocyte model system, Tan et al. systematically studied the mechanism of action of TNF-α on lipolysis and found that indeed TNF-α decreases PPAR-γ's transcriptional activity to reduce CIDEC expression, which increases lipolysis (5). Although TNF-α treatment did not affect PPAR-γ expression, mitogen-activated ERK kinase (MEK) and extracellular signal-regulated kinase (ERK)-dependent PPAR-γ phosphorylation were robustly increased. MEK-mediated PPARγ redistribution from nucleus to cytoplasm results in downregulation of PPARγ target genes (8). Furthermore, ERK-dependent inhibitory phosphorylation of PPAR-γ in the nucleus cripples its transcriptional activity (9). The study by Tan et al. highlights MEK/ERK as a central signaling pathway and demonstrates that activation of these signaling cascades is essential for TNF-α-induced CIDEC downregulation, as well as an increase in TNF-α-induced lipolysis (5). Using a systematic approach of siRNA-mediated knockdown and pharmacological inhibitors of MEK/ERK signaling, Tan et al. have shown that repression of these signaling pathways can inhibit TNF-α-induced lipolysis and restore CIDEC expression, thus confirming the direct role of MEK/ERK cascade in TNF-α-induced lipolysis in adipocytes. We are grateful to Dr. Kevin Lee for a helpful discussion on this commentary.
Semi-Supervised Verified Feedback Generation (2016)

Students have enthusiastically taken to online programming lessons and contests. Unfortunately, they tend to struggle due to lack of personalized feedback when they make mistakes. The overwhelming number of submissions precludes manual evaluation. There is an urgent need of program analysis and repair techniques capable of handling both the scale and variations in student submissions, while ensuring quality of feedback. Towards this goal, we present a novel methodology called semi-supervised verified feedback generation. We cluster submissions by solution strategy and ask the instructor to identify or add a correct submission in each cluster. We then verify every submission in a cluster against the instructor-validated submission in the same cluster. If faults are detected in the submission then feedback suggesting fixes to them is generated. Clustering reduces the burden on the instructor and also the variations that have to be handled during feedback generation. The verified feedback generation ensures that only correct feedback is generated. We have applied this methodology to iterative dynamic programming (DP) assignments. Our clustering technique uses features of DP solutions. We have designed a novel counter-example guided feedback generation algorithm capable of suggesting fixes to all faults in a submission. In an evaluation on 2226 submissions to 4 problems, we could generate verified feedback for 1911 (85%) submissions in 1.6s each on an average. Our technique does a good job of reducing the burden on the instructor. Only one submission had to be manually validated or added for every 16 submissions.
Chemogenomics with Protein Secondary-Structure Mimetics (2009)

During molecular recognition of proteins in biological systems, helices, reverse turns, and beta-sheets are dominant motifs. Often there are therapeutic reasons for blocking such recognition sites, and significant progress has been made by medicinal chemists in the design and synthesis of semirigid molecular scaffolds on which to display amino acid side chains. The basic premise is that preorganization of the competing ligand enhances the binding affinity and potential selectivity of the inhibitor. In this chapter, current progress in these efforts is reviewed.
Supplementary Video 3 from p38γ Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase, Cytoskeletal Architecture, and a Novel Leading Edge Behavior (2023)

&lt;p&gt;AVI file - 623K&lt;/p&gt;
Nanocomposite Architecture for Rapid, Spectrally-Selective Electrochromic Modulation of Solar Transmittance (2015)

Two active electrochromic materials, vacancy-doped tungsten oxide (WO(3-x)) nanocrystals and amorphous niobium oxide (NbOx) glass are arranged into a mesostructured architecture. In a strategy applicable across electrochemical applications, the critical dimensions and interfacial connections in the nanocomposite are designed to optimize pathways for electrochemical charging and discharging. The result is an unprecedented optical range for modulation of visible and near-infrared solar radiation with rapid switching kinetics that indicate the WO(3-x) nanocrystal framework effectively pumps charge out of the normally sluggish NbOx glass. The material is durable for at least 2000 electrochemical cycles.
Photocatalyzed [2 + 2 + 2]-Cycloaddition of Nitriles with Acetylene:  An Effective Method for the Synthesis of 2-Pyridines under Mild Conditions (2002)

The photocatalyzed [2 + 2 + 2]-cycloaddition of nitriles with 2 equiv of acetylene to 2-pyridines can be carried out under mild conditions and represents a valuable extension to common synthetical methods. For the ideal wavelength range (350-500 nm), lamps as well as sunlight can be used. Working at room temperature and in organic solvents such as toluene or hexane as well as in water gives satisfying results in many cases. However, it is also possible to vary the solvent and the reaction temperature of the photocatalyzed synthesis and to choose, with respect to the specific substrate, specific requirements for this particular reaction and general requirements of the method. This simple and selective method derives its potential mainly from the large variety of applicable nitriles. Suitable substrates include (functionalized) aliphatic and aromatic nitriles as well as cyanamides derived from secondary amines.
Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome (2022)

Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.
A study on cross-talk nerve stimulation: electrode placement and current leakage lid (2016)

Cross-talk phenomena should be avoided when stimulating nerves. One option to limit the current spread is to use tripolar electrodes, but at the cost of increasing the number of wires connection. This should be avoided since cables must be thin and compliant. We investigated the impact of the central electrode position and of current spread due to a gap between book and lid on cross-talk, in a set of tripolar or quasi-tripolar configurations..
Application of GaN-based heterojunction FETs for advanced wireless communication (2001)

We review the features of GaN-based FETs and describe their expected development direction, GaN has a high breakdown field, but this does not necessarily mean it is suitable for high-voltage and high-power applications. The main advantage is that it enables scaling down beyond the silicon MOSFET miniaturization limitation from the Maxwell-Boltzmann distribution. Thus, fine gate patterns together with a high carrier velocity make GaN-based FETs be suited for millimeter and near millimeter wavelength high-power applications. In addition, by using large-area sapphire substrates, high-performance and low-cost MMICs can be produced on GaN. We expect that such devices will be the key to future advanced wireless communication systems.
Sensitivity of mottled sculpins (Cottus bairdi) and rainbow trout (Onchorhynchus mykiss) to acute and chronic toxicity of cadmium, copper, and zinc (2007)

Studies of fish communities of streams draining mining areas suggest that sculpins (Cottus spp.) may be more sensitive than salmonids to adverse effects of metals. We compared the toxicity of zinc, copper, and cadmium to mottled sculpin (C. bairdi) and rainbow trout (Onchorhynchus mykiss) in laboratory toxicity tests. Acute (96-h) and early life-stage chronic (21- or 28-d) toxicity tests were conducted with rainbow trout and with mottled sculpins from populations in Minnesota and Missouri, USA, in diluted well water (hardness = 100 mg/L as CaCO3). Acute and chronic toxicity of metals to newly hatched and swim-up stages of mottled sculpins differed between the two source populations. Differences between populations were greatest for copper, with chronic toxicity values (ChV = geometric mean of lowest-observed-effect concentration and no-observed-effect concentration) of 4.4 microg/L for Missouri sculpins and 37 microg/L for Minnesota sculpins. Cadmium toxicity followed a similar trend, but differences between sculpin populations were less marked, with ChVs of 1.1 microg/L (Missouri) and 1.9 microg/L (Minnesota). Conversely, zinc was more toxic to Minnesota sculpins (ChV = 75 microg/L) than Missouri sculpins (chronic ChV = 219 microg/L). Species-average acute and chronic toxicity values for mottled sculpins were similar to or lower than those for rainbow trout and indicated that mottled sculpins were among the most sensitive aquatic species to toxicity of all three metals. Our results indicate that current acute and chronic water quality criteria for cadmium, copper, and zinc adequately protect rainbow trout but may not adequately protect some populations of mottled sculpins. Proposed water quality criteria for copper based on the biotic ligand model would be protective of both sculpin populations tested.
Cloning, Mapping, Expression, Function, and Mutation Analyses of the Human Ortholog of the Hamster Putative Tumor Suppressor Gene doc-1 (1998)

doc-1 is a putative tumor suppressor gene isolated and identified from the hamster oral cancer model. Here, we report the molecular cloning and the functional characterization of the human ortholog of the hamster doc-1 gene. Human doc-1 cDNA is 1.6 kilobase pairs in length and encodes for a 115-amino acid polypeptide (12.4 kDa, pI 9. 53). Sequence analysis showed 98% identity between human and hamster doc-1 protein sequences. DOC-1 is expressed in all normal human tissues examined. In oral keratinocytes, expression of DOC-1 is restricted to normal oral keratinocytes. By immunostaining of normal human mucosa, DOC-1 is detected in both the cytoplasm and nuclei of basal oral keratinocytes; while in suprabasilar cells, it is primarily found in the nuclei. Human oral cancers in vivo did not exhibit immunostaining for DOC-1. Like murine DOC-1, human DOC-1 associates with DNA polymerase alpha/primase and mediates the phosphorylation of the large p180 catalytic subunit, suggesting it may be a potential regulator of DNA replication in the S phase of the cell cycle. Using a human doc-1 cosmid as a probe, human doc-1 is mapped to chromosome 12q24. We identified four exons in the entire human doc-1 gene and determined the intron-exon boundaries. By polymerase chain reaction and direct sequencing, we examined premalignant oral lesion and oral cancer cell lines and found no intragenic mutations.
Prototype Test of an All-Electric Intelligent-Completion System for Extreme-Reservoir-Contact Wells (2014)

Summary One of the core focus areas in Saudi Aramco's effort to increase hydrocarbon recovery is in the application of extreme-reservoir-contact (ERC) wells. These wells, with more than 20 km of reservoir contact, are needed to ensure fluid off-take points are distributed throughout the reservoir efficiently. Accurate sensing and control are crucial to the efficient sweep of heterogeneous formations. This paper describes a recent multilateral (ML)-well trial that validated a number of core technologies and methods required to make ERC a reality, including Well construction and deployment practices to allow electrical umbilicals to be reliably deployed in openhole laterals Deployment and testing of revolutionary low-power, infinitely positioned electric flow-control valves (FCVs) designed to be deployed in each compartment in an openhole segmented lateral completion Validation of the fully integrated onboard-production-monitoring system providing direct downhole measurements of pressures, temperatures, flow rates, and water cut for each controlled compartment Integration of the surface acquisition and monitoring system to the production supervisory-control-and-data-acquisition (SCADA) system to provide real-time downhole production information, as well as valuable system-health-status data that can ensure operational integrity during the life cycle of the well An ML well close to the oil/water-contact point was allocated to validate the functionality of two prototype systems installed and has provided valuable reservoir data for more than 1 year of production. The well trial successfully demonstrated the ability to install and retrieve an umbilical completion from a 10,000-ft horizontal lateral. The ability to control downhole flow to within a few barrels per day measured at the reservoir face is proving revolutionary to the way the operator will approach future reservoir management. The sensing system will be capable of delivering continuous compartment productivity. The SCADA integration allows for a real-time management function such that the compartment can be controlled to a target off-take rate directly, without resorting to the use of traditional well-system models for estimating control settings. This paper highlights the objectives, installation, validation, and functional aspects of this new ERC well system, as well as identifying some of the immediate production effects emerging from this level of visibility and control at the formation face.
Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties (2018)

We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.
Gradient-index beam shapers: fabricated devices and 3D design (2018)

Advances in 3D fabrication have afforded new freedoms in the design of custom optical elements. We explore a design space where the refractive index may vary freely with position in a material by considering applications in coherent beam shaping. First, we will describe experimental results where we have used femtosecond laser writing to fabricate custom GRIN waveguides in a planar geometry. We show a 2D device that converts a Gaussian beam to a flat top in one transverse direction, and is a single-mode waveguide in the other. Second, we describe a numerical method for designing 3D refractive index profiles. As an example, we will use the 3D method to design a device that transforms a circular beam with a Gaussian intensity profile into a square beam with a flat top.
Solid Freeform Fabrication of Polycaprolactone∕Hydroxyapatite Tissue Scaffolds (2008)

Bone tissue engineering is an emerging field providing viable substitutes for bone regeneration. Freeform fabrication provides an effective process tool to manufacture scaffolds with complex shapes and designed properties. We developed a novel precision extruding deposition (PED) technique to fabricate composite polycaprolactone∕hydroxyapatite (PCL∕HA) scaffolds. 25% concentration by weight of HA was used to reinforce 3D scaffolds. Two groups of scaffolds having 60% and 70% porosities and with pore sizes of 450μm and 750μm respectively, were evaluated for their morphology and compressive properties using scanning electron microscopy and the mechanical testing. In vitro cell-scaffold interaction study was carried out using primary fetal bovine osteoblasts. The cell proliferation and differentiation were evaluated by Alamar Blue assay and alkaline phosphatase activity. Our results suggested that compressive modulus of PCL∕HA scaffold was 84MPa for 60% porous scaffolds and was 76MPa for 70% porous scaffolds. The osteoblasts were able to migrate and proliferate for the cultured time over the scaffolds. Our study demonstrated the viability of the PED process to fabricate PCL scaffolds having necessary mechanical property, structural integrity, controlled pore size, and pore interconnectivity desired for bone tissue engineering.
Inulin-type fructans and bone health: state of the art and perspectives in the management of osteoporosis (2005)

If the primary role of diet is to provide sufficient nutrients to meet the metabolic requirements of an individual, there is an emerging rationale to support the hypothesis that, by modulating specific target functions in the body, it can help achieve optimal health. Regarding osteoporosis prevention, since Ca is most likely to be inadequate in terms of dietary intake, every strategy targeting an improvement in Ca absorption is very interesting. Actually, this process may be susceptible to manipulation by fermentable substrates. In this light, inulin-type fructans are very interesting, even if we need to gather more data targeting bone metabolism before health professionals can actively advocate their consumption to prevent senile osteoporosis. Besides targeting the prevention of postmenopausal osteoporosis, inulin-type fructans still remain a source for putative innovative dietary health intervention. Indeed, given in combination with isoflavones, they may have a potential for maintaining or improving the bone mass of human subjects, by modulating the bioavailability of phyto-oestrogens.
Conjugated Oligoelectrolytes for Long‐Term Tumor Tracking with Incremental NIR‐II Emission (2022)

The design and synthesis of the near-infrared (NIR)-II emissive conjugated oligoelectrolyte COE-BBT are reported. COE-BBT has a solubility in aqueous media greater than 50 mg mL<sup>-1</sup> , low toxicity, and a propensity to intercalate lipid bilayers, wherein it exhibits a higher emission quantum yield relative to aqueous media. Addition of COE-BBT to cells provides two emission channels, at ≈500 and ≈1020 nm, depending on the excitation wavelength, which facilitates in vitro confocal microscopy and in vivo animal imaging. The NIR-II emission of COE-BBT is used to track intracranial and subcutaneous tumor progression in mice. Of relevance is that the total NIR-II intensity increases over time. This phenomenon is attributed to a progressive attenuation of a COE-BBT self-quenching effect within the cells due to the expected dye dilution per cell as the tumor proliferates.