gebhart/patrepeval huggingface dataset:
A Complex Adenovirus Vector That Delivers FASL–GFP with Combined Prostate-Specific and Tetracycline-Regulated Expression (2001)

Cell-type-restricted transgene expression delivered by adenovirus vectors is highly desirable for gene therapy of cancer, as it can limit cytotoxic gene expression to tumor cells. However, many tumor- and tissue-specific promoters are weaker than the constitutively active promoters and are thus less effective. To combine cell-type specificity with high-level regulated transgene expression, we have developed a complex adenoviral vector. We have placed the tetracycline transactivator gene under the control of a prostate-specific ARR2PB promoter, and a mouse Tnfsf6 (encoding FASL)-GFP fusion gene under the control of the tetracycline responsive promoter. We have incorporated both expression cassettes into a single construct. We show that FASL-GFP expression from this vector is essentially restricted to prostate cancer cells, in which it can be regulated by doxycycline. Higher levels of prostate-specific FASL-GFP expression were generated by this approach than by driving the FASL-GFP expression directly with ARR2PB. More FASL-GFP expression correlated with greater induction of apoptosis in prostate cancer LNCaP cells. Mouse studies confirmed that systemic delivery of both the prostate-specific and the prostate-specific/tet-regulated vectors was well tolerated at doses that were lethal for FASL-GFP vector with CMV promoter. This strategy should be able to improve the safety and efficacy of cancer gene therapy using other cytotoxic genes as well.
Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin (2001)

In skin, multipotent stem cells generate the keratinocytes of the epidermis, sebaceous gland, and hair follicles. In this paper, we show that Tcf3 and Lef1 control these differentiation lineages. In contrast to Lef1, which requires Wnt signaling and stabilized beta-catenin to express the hair-specific keratin genes and control hair differentiation, Tcf3 can act independently of its beta-catenin interacting domain to suppress features of epidermal terminal differentiation, in which Tcf3 is normally shut off, and promote features of the follicle outer root sheath (ORS) and multipotent stem cells (bulge), the compartments which naturally express Tcf3. These aspects of Tcf3's action are dependent on its DNA binding and Groucho repressor-binding domains. In the absence of its beta-catenin interacting domain, Lef1's behavior (Delta NLef1) seems to be markedly distinct from that of Delta NTcf3. Delta NLef1 does not suppress epidermal differentiation and promote ORS/bulge differentiation, but rather suppresses hair differentiation and gives rise to sebocyte differentiation. Taken together, these findings provide powerful evidence that the status of Tcf3/Lef complexes has a key role in controlling cell fate lineages in multipotent skin stem cells.
Engineering metal coordination sites into the antibody light chain (1993)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEngineering metal coordination sites into the antibody light chainWarren S. Wade, Jong S. Koh, Nianhe Han, Denise M. Hoekstra, and Richard A. LernerCite this: J. Am. Chem. Soc. 1993, 115, 11, 4449–4456Publication Date (Print):June 1, 1993Publication History Published online1 May 2002Published inissue 1 June 1993https://pubs.acs.org/doi/10.1021/ja00064a005https://doi.org/10.1021/ja00064a005research-articleACS PublicationsRequest reuse permissionsArticle Views201Altmetric-Citations34LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Nondestructive analysis of threading dislocations in GaN by electron channeling contrast imaging (2007)

Threading dislocations in metal-organic chemical-vapor grown GaN films were imaged nondestructively by the electron channeling contrast imaging (ECCI) technique. Comparisons between ECCI and cross-sectional transmission electron microscopy indicated that pure edge dislocations can be imaged in GaN by ECCI. Total threading dislocation densities were measured by ECCI for various GaN films on engineered 4H-SiC surfaces and ranged from 107to109cm−2. A comparison between the ultraviolet electroluminescent output measured at 380nm and the total dislocation density as measured by ECCI revealed an inverse logarithmic dependence.
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012)

Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.
Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains (2016)

Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can improve binding affinity and other peptide properties, but determining the best stapled peptide variant often requires laborious trial and error. Here, we describe the rapid discovery and optimization of a stapled-helix peptide that binds to Mcl-1, an antiapoptotic protein that is overexpressed in many chemoresistant cancers. To accelerate discovery, we developed a peptide library synthesis and screening scheme capable of identifying subtle affinity differences among Mcl-1-binding stapled peptides. We used our method to sample combinations of non-natural amino-acid substitutions that we introduced into Mcl-1 inhibitors in the context of a fixed helix-stabilizing hydrocarbon staple that increased peptide helical content and reduced proteolysis. Peptides discovered in our screen contained surprising substitutions at sites that are conserved in natural binding partners. Library-identified peptide M3d is the most potent molecule yet tested for selectively triggering mitochondrial permeabilization in Mcl-1 dependent cell lines. Our library approach for optimizing helical peptide inhibitors can be readily applied to the study of other biomedically important targets.
PET Radioimmunoscintigraphy of Renal Cell Cancer Using 89 Zr-Labeled cG250 Monoclonal Antibody in Nude Rats (2004)

The cG250 antibody can be stably labeled with the positron-emitter 89Zr, while preserving the immunoreactivity of the moAb. In this rat model, the in vivo biodistribution of 89Zr-Df-cG250 was identical to that of 111In-DTPA-cG250. Immuno-PET of RCC is feasible with 89Zr-cG250, and relatively small tumors could be visualized, even without a dedicated PET camera for small animals.
Photonic vector signal generation at microwave/millimeter-wave bands employing an optical frequency quadrupling scheme (2009)

To the best of our knowledge, a novel photonic architecture to generate vector signals at microwave/millimeter-wave bands employing an optical frequency quadrupling technique based on an external dual-parallel modulator is proposed for the first time. A 312.5 MSym/s quadruple phase-shift keying signal at 25 GHz is experimentally demonstrated using properly precoding driving signal at 6.25 GHz, and optical power penalty is negligible following 50 km single-mode fiber transmission.
Carbonic anhydrase inhibitors: Inhibition of the tumor-associated isozymes IX and XII with polyfluorinated aromatic/heterocyclic sulfonamides (2005)

The tumor-associated transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isozymes IX (CA IX) and XII (CA XII) are involved in acidification of hypoxic tumors, a process correlated with poor prognosis and clinical outcome of patients harboring such tumors. This process may be reversed by inhibiting these enzymes with potent sulfonamide/sulfamate inhibitors. A series of such aromatic/heterocyclic sulfonamides incorporating 2,3,5,6-tetrafluorobenzoyl-, 2,3,5,6-tetrafluorophenylsulfonyl- and pentafluorophenylureido moieties has been investigated for its interaction with the catalytic domain of the human isozymes hCA IX and hCA XII. Some of these compounds showed excellent inhibitory properties against both isozymes IX and XII, with several subnanomolar inhibitors detected for the first time. These sulfonamides may constitute valuable candidates for the development of novel antitumor therapies based on the inhibition of such tumor-associated CA isozymes.
A universal scaling law between gray matter and white matter of cerebral cortex (2000)

Neocortex, a new and rapidly evolving brain structure in mammals, has a similar layered architecture in species over a wide range of brain sizes. Larger brains require longer fibers to communicate between distant cortical areas; the volume of the white matter that contains long axons increases disproportionally faster than the volume of the gray matter that contains cell bodies, dendrites, and axons for local information processing, according to a power law. The theoretical analysis presented here shows how this remarkable anatomical regularity might arise naturally as a consequence of the local uniformity of the cortex and the requirement for compact arrangement of long axonal fibers. The predicted power law with an exponent of 4/3 minus a small correction for the thickness of the cortex accurately accounts for empirical data spanning several orders of magnitude in brain sizes for various mammalian species, including human and nonhuman primates.
Targeting Receptor-Mediated Transport for Delivery of Biologics Across the Blood-Brain Barrier (2014)

Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo.
Analysis and observation of coupling ratio dependence of Rayleigh backscattering noise in a fiber optic gyroscope (1989)

Noise due to Rayleigh backscattering in a fiber-optic gyroscope is observed in quadrature with the Sagnac signal. This noise can be nulled by adjustment of the coupling ratio of the loop coupler and the state of polarization in the gyro loop. A rigorous analysis of the phases of, and the modulations applied to, the primary and scattered beams shows that no coherent Rayleigh backscatter noise should be detected on the Sagnac signal even with relatively coherent semiconductor laser sources.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Localized thermal analysis using a miniaturized resistive probe (1996)

We describe a novel thermal characterization technique based on a differential arrangement, which achieves spatially localized calorimetric analysis. It involves the use of an active probe which acts both as a highly localized heat source and a thermometer. This ability opens the way for the implementation of scanning calorimetric microscopy where image contrast will be created from thermal analysis data. For a number of polymers we have recorded events such as glass transitions, meltings, recrystallizations and thermal decomposition within volumes of material estimated at a few μm3. The data obtained are compared with those obtained from conventional calorimetry and the events registered in both cases are found to match. For a full quantitative analysis of the results obtained, mathematical modelling of the operation of the technique, taking account of physical and other changes in materials, is required.
Antidepressant Drug Interactions and the Cytochrome P450 System: A Critical Appraisal (1995)

Evaluation of the inhibitory effects of antidepressant drugs on hepatic cytochrome P450 isoenzymes can allow clinicians to predict drug interactions occurring via this mechanism a priori. The magnitude and clinical relevance of these drug interactions are dependent on many factors including concentration of the isoenzyme inhibitor, contribution of active metabolites with isoenzyme inhibitory activity, and toxicity of the concomitant medication. This review summarizes information to date regarding the inhibitory potency of fluoxetine, fluvoxamine, paroxetine, sertraline, nefazodone, and venlafaxine on five isoenzyme systems: CYP2D6, CYP3A3/4, CYP1A2, CYP2C9, and CYP2C19. Both in vitro and in vivo isoenzyme inhibition data are presented and correlated to drug interactions of clinical relevance.
Transannular additions of selectfluor and xenon difluoride: regioselectivity and mechanism (2010)

Abstract The addition of 1‐chloromethyl‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis‐tetrafluoroborate (F‐TEDA) to unsaturated systems was modelled computationally at the ab initio levels and studied experimentally. The reaction of olefins with F‐TEDA is driven exclusively by charge transfer and displays the antibonding orbital picture in the transition structure for F‐transfer, similarly to that for the reactions of olefins with F‐radical. In contrast, the electrophilic and concerted fluorinations, respectively with H 2 O•••F + complex and with F 2 , show strong bonding interactions between the fluorine and olefin moieties in the transition structures. The reaction with F‐TEDA involves an initial formation of highly delocalized charge‐transfer complexes in the first step with further low‐barrier (ca 4 kcal) migration of fluorine and is best described as an inner‐sphere electron transfer. This nonelectrophilic mechanism is operative for the transannular addition of F‐TEDA to 3‐methylene‐7‐ethylidenebicyclo[3.3.1]nonane studied experimentally. The addition mode is determined by the formation of a more stable complex via the ethylidene fragment and demonstrates selectivities that differ from conventional electrophilic additions. This mechanistic scenario may be extended to the fluorination with xenon difluoride where similar products are formed in high yields. Copyright © 2010 John Wiley &amp; Sons, Ltd.
Structural Determinants of Lateral Gate Opening in the Protein Translocon (2007)

The heterotrimeric SecY/Sec61 complex is a protein-conducting channel that provides a passage for proteins across the membrane as well as a means to integrate nascent proteins into the membrane. While the first function is common among membrane protein channels and transporters, the latter is unique. Insertion of nascent membrane proteins, one transmembrane segment at a time, by SecY likely occurs through a lateral gate in the channel. Molecular dynamics simulations have been used to investigate the mechanism of gate opening. Opening and closing the gate under different conditions allowed us to identify structural elements that resist opening as well as those that aid closure. SecE, considered to act as a clamp keeping the lateral gate closed, was found to play no such role. Loosening of the plug by lateral gate opening, a potential step in channel gating, was also observed. The simulations revealed that lipids on time scales of up to 1 micros do not flood channels with an open lateral gate.
Surface slice generation and interpretation: A review (1996)

This paper provides a review of surface slice generation and a comparison to standard interpretation procedures.
Medications Reduce Incidence of Substance Abuse Among ADHD Patients (1999)

Attention-deficit/hyperactivity disorder (ADHD) causes difficulties in paying attention, keeping still, and suppressing impulsive behaviors. It can lead to problems in school and on the job and create tensions with family members and other people. In addition, research has shown that children with ADHD have an elevated risk of becoming abusers of drugs and alcohol. Studies that have tracked children to adulthood have found higher rates of transition to abuse among those with ADHD compared to those without the disorder.
Routing multipoint connections using virtual paths in an ATM network (2002)

The point-to-multipoint routing problem is studied for an asynchronous transfer mode (ATM) network that uses virtual paths (VPs). ATM networks with asymmetric and symmetric VPs are considered, and the performance factors studied are bandwidth and establishment and switching costs. A VP with intermediate exit, where a node that performs VP switching can copy the switched packets for the local destination, is proposed and studied. Mathematical formulations of multicast routing problems are presented, and heuristics for finding a low cost multicast routing tree, based on the transshipment simplex algorithm, are developed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Microseismic hydraulic fracture imaging: The path toward optimizing shale gas production (2011)

Economic shale gas production involves hydraulic fracture stimulation in order to create permeable flow paths within these low-permeability reservoirs. Microseismic monitoring has shown that often these “fracs” consist of complex fracture networks, with large surface contact areas with the reservoir. Optimized production is therefore dependent on the ability of the stimulation to activate an extensive fracture network. Much of the current attention around hydraulic fractures focuses on microseismic imaging of the activated network; however, the path toward optimized shale gas production also requires methods to both predict and model the fracture networks. Along the path, engineers will be able to close the loop for an optimally designed stimulation: being able to predict, monitor, and assess the stimulated fracture network. As an industry, we are just starting down this path, and this paper describes a few case studies that highlight recent advancements. Before we can ultimately predict the fracture network that will result from a specific injection, we first need to understand the factors that control the variability in hydraulic fracture networks that are routinely observed. To this end, two case studies are described integrating microseismic imaging with seismic reservoir characterization, both of which show that the hydraulic fracture geometries are controlled by pre-existing fractures and stresses. Many engineering tools exist to model the performance of a fracture network, and one of the case studies describes a reservoir simulation investigation of the production sensitivity to various ways of characterizing the stimulated hydraulic fracture network. To begin, however, because microseismic is the basis of these case studies and will likely remain the primary hydraulic fracture monitoring technique, some general comments are first made regarding microseismic specific to shale gas.
Modulation of eicosanoid formation by lesional skin of psoriasis: an ex vivo skin model. (1993)

The purpose of the present study was to develop an ex vivo skin model to determine the capacity of lesional skin of psoriasis to form leukotriene B4 and other eicosanoids. Keratomed skin samples were incubated in the presence of the calcium ionophore A23187 and arachidonic acid for 45 min at 37 degrees C. After extraction of lipids, eicosanoids were determined by quantitative reversed-phase high-performance liquid chromatography in combination with specific radioimmunoassays. We found that stimulation of skin samples with A23187 and arachidonic acid increased the amount of leukotriene B4 4.0-fold. The 12-lipoxygenase product, 12-hydroxy-eicosatetraenoic acid, and the 15-lipoxygenase product, 15-hydroxy-eicosatetraenoic acid, were both increased 2.7-fold. The cyclooxygenase product, prostaglandin E2, was increased 8.0-fold. Similar incubations using psoriatic scales did not result in formation of eicosanoids. Incubations with the 5-lipoxygenase inhibitor RS43179 inhibited the formation of leukotriene B4 and prostaglandin E2 without significantly affecting the formation of 12-hydroxy-eicosatetraenoic acid and 15-hydroxy-eicosatetraenoic acid. These results reveal that lesional psoriatic skin ex vivo has the enzymatic capacity to increase the levels of eicosanoids. This provides an ex vivo skin model to determine whether putative lipoxygenase inhibitors are able to modulate the formation of eicosanoids in psoriatic skin.
Cefoperazone: A Review of Its Antimicrobial Spectrum, β-Lactamase Stability, Enzyme Inhibition, and Other in Vitro Characteristics (1983)

The in vitro qualities of cefoperazone were reviewed on the basis of international medical literature and some new observations. Cefoperazone is highly active against the Enterobacteriaceae. Its activity against Staphylococcus aureus is comparable to that of the other newer cephem antibiotics. Cefoperazone is also active against all beta-hemolytic streptococci and Streptococcus pneumoniae and is relatively inactive against methicillin-resistant S. aureus and enterococci. Against Pseudomonas aeruginosa cefoperazone is at least fourfold more active than cefotaxime or moxalactam and is approximately as active as azlocillin or piperacillin. Haemophilus and Neisseria species, regardless of beta-lactamase production, are highly susceptible to cefoperazone. Against the Bacteroides fragilis group, cefoperazone is either very active or quite inactive because of endemic variations. The drug is slightly less stable to some beta-lactamases than are cefotaxime-like or 7-methoxy cephem drugs. Cefoperazone is a bactericidal beta-lactam, and its minimal inhibitory concentrations are influenced only by high inoculum concentrations of beta-lactamase-producing strains. Its ability to permeate bacterial cell membranes appears similar to that of cefotaxime. Synergy studies with cefoperazone plus beta-lactamase inhibitors or aminoglycosides against Enterobacteriaceae and P. aeruginosa show enhanced killing. Cefoperazone is 70%-94% protein bound and has high affinities for bacterial penicillin-binding proteins 3, 1a, 2, and 1 bs.