gebhart/patrepeval huggingface dataset:
Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells (2008)

Melanin protects the skin and eyes from the harmful effects of UV irradiation, protects neural cells from toxic insults, and is required for sound conduction in the inner ear. Aberrant regulation of melanogenesis underlies skin disorders (melasma and vitiligo), neurologic disorders (Parkinson's disease), auditory disorders (Waardenburg's syndrome), and opthalmologic disorders (age related macular degeneration). Much of the core synthetic machinery driving melanin production has been identified; however, the spectrum of gene products participating in melanogenesis in different physiological niches is poorly understood. Functional genomics based on RNA-mediated interference (RNAi) provides the opportunity to derive unbiased comprehensive collections of pharmaceutically tractable single gene targets supporting melanin production. In this study, we have combined a high-throughput, cell-based, one-well/one-gene screening platform with a genome-wide arrayed synthetic library of chemically synthesized, small interfering RNAs to identify novel biological pathways that govern melanin biogenesis in human melanocytes. Ninety-two novel genes that support pigment production were identified with a low false discovery rate. Secondary validation and preliminary mechanistic studies identified a large panel of targets that converge on tyrosinase expression and stability. Small molecule inhibition of a family of gene products in this class was sufficient to impair chronic tyrosinase expression in pigmented melanoma cells and UV-induced tyrosinase expression in primary melanocytes. Isolation of molecular machinery known to support autophagosome biosynthesis from this screen, together with in vitro and in vivo validation, exposed a close functional relationship between melanogenesis and autophagy. In summary, these studies illustrate the power of RNAi-based functional genomics to identify novel genes, pathways, and pharmacologic agents that impact a biological phenotype and operate outside of preconceived mechanistic relationships.
New syntheses of 19,21-dihydroxypregn-4-ene-3,20-dione, 21-hydroxy-19-norpregn-4-ene-3,20-dione, and 11β,19,21-trihydroxypregn-4-ene-3,20-dione (1983)

19,21-Dihydroxypregn-4-ene-3,20-dione has been synthesized from 3β-acetoxypregn-5-en-20-one via the ‘hypoiodite reaction’[treatment of the 5α-bromo-6β-hydroxy derivative with Pb(OAc)4 and I2, with irradiation], and Henbest acetoxylation at C-21; oxidation of the intermediate 21-monoacetate to the 19-oxo derivative and alkaline cleavage gave 21-hydroxy-19-norpregn-4-ene-3,20-dione. A similar synthesis of 11β,19,21-trihydroxypreg-4-ene-3,20-dione from 3β-acetoxypregn-5-ene-11,20-dione proceeded through intermediates with the 11β-hydroxy function protected as its acetate. Unusual features mainly of conformational origin were observed in the presence of the 11β-acetoxy substituent; some were helpful to the synthesis, while others led to undesirable side reactions.
Peroxide crosslinking of poly(n‐alkyl methacrylates) (1968)

Abstract The action of dicumyl peroxide on poly( n ‐butyl methacrylate) and poly( n ‐nonyl methacrylate) produces degradation and crosslinking reactions in both polymers. Crosslinking and degradation of poly( n ‐alkyl methacrylates) are influenced also by the initial molecular weight of the polymer as well as by the type of alkyl group. The ratio of degradation to crosslinking p / q determined on the basis of the equation of Charlesby and Pinner, S + S 0.5 = ( p / q ) + (1/ qP n ) is for poly( n ‐butyl methacrylate) of viscosity molecular weight 0.923 × 10 6 and 2.16 × 10 6 of 0.78 and 0.60, respectively; for poly( n ‐nonyl methacrylate) of weight average molecular weight 3.83 × 10 5 , p / q is 0.16. Crosslinking efficiencies (moles of crosslinks per mole of decomposed dicumyl peroxide) of the above polymers are relatively very low: 0.014, 0.005, and 0.039, respectively. The critical concentration of dicumyl peroxide necessary for the formation of gel, provided it undergoes complete decomposition, is for the above polymers 1.82, 1.65, and 0.98 wt.‐%, respectively. Under the critical concentration of dicumyl peroxide the limiting viscosity number of poly( n ‐butyl methacrylate) increases with increasing concentration of dicumyl peroxide. An initial decrease of the value of the limiting viscosity number, which is characteristic for polymers undergoing simultaneous degradation and crosslinking, was not observed.
Sensitization of human cancer cells to gemcitabine by the Chk1 inhibitor MK-8776: cell cycle perturbation and impact of administration schedule in vitro and in vivo (2013)

There are two reasons why delayed addition of MK-8776 enhances sensitivity to gemcitabine: first, there is an increased number of cells arrested in S phase; and second, the arrested cells have adequate time to initiate recombination and thereby become Chk1 dependent. These results have important implications for the design of clinical trials using this drug combination.
Cutting Edge: Ectopic Expression of CD40 Ligand on B Cells Induces Lupus-Like Autoimmune Disease (2002)

CD40 ligand (CD40L) is ectopically expressed on B cells in patients with systemic lupus erythematosus (SLE) and lupus-prone BXSB mice. To assess the role of the ectopic CD40L expression in development of SLE, we have established transgenic mice expressing CD40L on B cells. Some of the 12- to 14-mo-old CD40L-transgenic mice spontaneously produced autoantibodies such as antinuclear Abs, anti-DNA Abs, and antihistone Abs. Moreover, approximately half of the transgenic mice developed glomerulonephritis with immune-complex deposition, whereas the kidneys of the normal littermates showed either no pathological findings or only mild histological changes. These results indicate that CD40L on B cells causes lupus-like disease in the presence of yet unknown environmental factors that by themselves do not induce the disease. Thus, ectopic CD40L expression on B cells may play a crucial role in development of SLE.
Correlations between Blood–Brain Barrier Disruption and Neuroinflammation in an Experimental Model of Penetrating Ballistic-Like Brain Injury (2013)

Abstract Blood-brain barrier (BBB) disruption is a pathological hallmark of severe traumatic brain injury (TBI) and is associated with neuroinflammatory events contributing to brain edema and cell death. The goal of this study was to elucidate the profile of BBB disruption after penetrating ballistic-like brain injury (PBBI) in conjunction with changes in neuroinflammatory markers. Brain uptake of biotin-dextran amine (BDA; 3 kDa) and horseradish peroxidase (HRP; 44 kDa) was evaluated in rats at 4 h, 24 h, 48 h, 72 h, and 7 days post-PBBI and compared with the histopathologic and molecular profiles for inflammatory markers. BDA and HRP both displayed a uniphasic profile of extravasation, greatest at 24 h post-injury and which remained evident out to 48 h for HRP and 7 days for BDA. This profile was most closely associated with markers for adhesion (mRNA for intercellular adhesion molecule-1) and infiltration of peripheral granulocytes (mRNA for matrix metalloproteinase-9 [MMP-9] and myeloperoxidase staining). Improvement of BBB dysfunction coincided with increased expression of markers implicated in tissue remodeling and repair. The results of this study reveal a uniphasic and gradient opening of the BBB after PBBI and suggest MMP-9 and resident inflammatory cell activation as candidates for future neurotherapeutic intervention after PBBI.
Large valence-band offset in strained-layerInxGa1−xAs-GaAs quantum wells (1987)

We report a determination of band offsets in strained-layer ${\mathrm{In}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}\mathrm{As}$-GaAs quantum wells lattice-matched to GaAs. Using a light-scattering method, we find a large offset for the averaged valence bands, which extrapolates to $\ensuremath{\Delta}{E}_{v,\mathrm{av}}=0.49$ eV in the InAs-GaAs system. This vlaue contradicts previous experimental determinations but agrees with predictions of theories that consider charge-transfer effects at the interface. It follows from some of these theories that $\ensuremath{\Delta}{E}_{v,\mathrm{av}}$ has a surprisingly strong uniaxial strain dependence, a fact that is consistent with our experimental result. Our light-scattering experiment leads to a new band structure for the ${\mathrm{In}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}\mathrm{As}$-GaAs system lattice-matched to GaAs in which the ground state for light holes is localized in the ${\mathrm{In}}_{x}{\mathrm{Ga}}_{1\ensuremath{-}x}\mathrm{As}$ layers. This conclusion is supported by photoluminescence excitation experiments.
Interaction between valproic acid and aspirin in epileptic children: Serum protein binding and metabolic effects (1982)

In five of six epileptic children who were taking 18 to 49 mg/kg/day valproic acid (VPA), the steady-state serum free fractions of VPA rose from 12% to 43% when antipyretic doses of aspirin were also taken. Mean total VPA half-life (t1/2) rose from 10.4 +/- 2.7 to 12.9 +/- 1.8 hr and mean free VPA t1/2 rose from 6.7 +/- to 2.1 to 8.9 +2- 3.0 hr when salicylate was present in the serum. The in vitro albumin binding association constant (ka) for VPA was decreased by salicylate, but the in vivo ka value was not affected. The 12-hr (trough) concentrations of both free and total VPA were higher in the presence of serum salicylate in five of six patients. Renal excretion of unchanged VPA decreased in five of six patients, but the VPA carboxyl conjugate metabolite-excretion patterns were not consistently affected. Salicylate appeared to displace VPA from serum albumin in vivo, but the increased VPA t1/2 and changes in VPA elimination patterns suggest that serum salicylate also altered VPA metabolism.
Comparative analysis of right element mutant lox sites on recombination efficiency in embryonic stem cells (2010)

The two mutant RE lox sites, loxJTZ17 and loxKR3, are more suitable than lox66 for Cre-mediated integration or inversion in ES cells.
Combined Microautoradiography–16S rRNA Probe Technique for Determination of Radioisotope Uptake by Specific Microbial Cell Types In Situ (1999)

We propose a novel method for studying the function of specific microbial groups in situ. Since natural microbial communities are dynamic both in composition and in activities, we argue that the microbial "black box" should not be regarded as homogeneous. Our technique breaks down this black box with group-specific fluorescent 16S rRNA probes and simultaneously determines 3H-substrate uptake by each of the subgroups present via microautoradiography (MAR). Total direct counting, fluorescent in situ hybridization, and MAR are combined on a single slide to determine (i) the percentages of different subgroups in a community, (ii) the percentage of total cells in a community that take up a radioactively labeled substance, and (iii) the distribution of uptake within each subgroup. The method was verified with pure cultures. In addition, in situ uptake by members of the alpha subdivision of the class Proteobacteria (alpha-Proteobacteria) and of the Cytophaga-Flavobacterium group obtained off the California coast and labeled with fluorescent oligonucleotide probes for these subgroups showed that not only do these organisms account for a large portion of the picoplankton community in the sample examined ( approximately 60% of the universal probe-labeled cells and approximately 50% of the total direct counts), but they also are significant in the uptake of dissolved amino acids in situ. Nearly 90% of the total cells and 80% of the cells belonging to the alpha-Proteobacteria and Cytophaga-Flavobacterium groups were detectable as active organisms in amino acid uptake tests. We suggest a name for our triple-labeling technique, substrate-tracking autoradiographic fluorescent in situ hybridization (STARFISH), which should aid in the "dissection" of microbial communities by type and function.
Small eyes (Sey) : a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse (1986)

Small eyes (Sey) is a semidominant, homozygous lethal mutation in the mouse (Roberts, 1967). It is allelic with SeyH, a radiation-induced homozygous prenatal lethal which has been mapped on chromosome 2. The effect of the Sey mutation is apparently limited to the growth and differentiation of the presumptive lens and nasal placodes. Homozygous Sey/Sey embryos can be distinguished as early as 10.5 days post coitum (p.c.); the optic vesicles grow out, but the ectoderm does not give rise to a lens and nasal pits never form. Immunohistochemical studies show that the distribution of the extracellular matrix glycoprotein laminin is not significantly different in the cephalic region of Sey/Sey versus Sey/+ or +/+ embryos. Sey/Sey embryos develop to term but without eyes or nose, and die soon after birth. Further analysis of Sey/Sey embryos may throw light on the mechanisms underlying morphogenesis of craniofacial structures in mammals.
A comparison of the actions of BIBN4096BS and CGRP8–37 on CGRP and adrenomedullin receptors expressed on SK‐N‐MC, L6, Col 29 and Rat 2 cells (2002)

1. The ability of the CGRP antagonist BIBN4096BS to antagonize CGRP and adrenomedullin has been investigated on cell lines endogenously expressing receptors of known composition. 2. On human SK-N-MC cells (expressing human calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein 1 (RAMP1)), BIBN4096BS had a pA(2) of 9.95 although the slope of the Schild plot (1.37 +/- 0.16) was significantly greater than 1. 3. On rat L6 cells (expressing rat CRLR and RAMP1), BIBN4096BS had a pA(2) of 9.25 and a Schild slope of 0.89 +/- 0.05, significantly less than 1. 4. On human Colony (Col) 29 cells, CGRP(8-37) had a significantly lower pA(2) than on SK-N-MC cells (7.34 +/- 0.19 (n = 7) compared to 8.35 +/- 0.18, (n = 6)). BIBN4096BS had a pA(2) of 9.98 and a Schild plot slope of 0.86 +/- 0.19 that was not significantly different from 1. At concentrations in excess of 3 nM, it was less potent on Col 29 cells than on SK-N-MC cells. 5. On Rat 2 cells, expressing rat CRLR and RAMP2, BIBN4096BS was unable to antagonize adrenomedullin at concentrations up to 10 microM. CGRP(8-37) had a pA(2) of 6.72 against adrenomedullin. 6. BIBN4096BS shows selectivity for the human CRLR/RAMP1 combination compared to the rat counterpart. It can discriminate between the CRLR/RAMP1 receptor expressed on SK-N-MC cells and the CGRP-responsive receptor expressed by the Col 29 cells used in this study. Its slow kinetics may explain its apparent 'non-competitive' behaviour. At concentrations of up to 10 micro M, it has no antagonist actions at the adrenomedullin, CRLR/RAMP2 receptor, unlike CGRP(8-37).
Hierarchical Effector Protein Transport by the Salmonella Typhimurium SPI-1 Type III Secretion System (2008)

This novel mechanism of hierarchical effector protein injection may serve to avoid functional interference between SipA and SptP. An injection hierarchy of this type may be of general importance, allowing bacteria to precisely time the host cell manipulation by type III effectors.
Nomenclature of the Human Immunoglobulin Lambda (IGL) Genes (2001)

'Nomenclature of the Human Immunoglobulin Lambda (IGL) Genes', the 18th report of the 'IMGT Locus in Focus' section, provides the first complete list of all the human IGL genes. The total number of human IGL genes per haploid genome is 87--96 (93--102 if the orphons are included), of which 37--43 genes are functional. IMGT/Human Genome Organization (HUGO) gene names and definitions of the human IGL genes on chromosome 22q11.2 and IGL orphons on chromosomes 8 and 22 are provided with the gene functionality and the number of alleles, according to the rules of the IMGT Scientific chart, with the accession numbers of the IMGT reference sequences and with the accession ID of the Genome Database GDB and NCBI LocusLink databases, in which all the IMGT human IGL genes have been entered. The tables are available at the IMGT Marie-Paule page of IMGT, the international ImMunoGeneTics database (http://imgt.cines.fr) created by Marie-Paule Lefranc, Université Montpellier II, CNRS, France.
The Xenopus homolog of Drosophila Suppressor of Hairless mediates Notch signaling during primary neurogenesis (1997)

The X-Notch-1 receptor, and its putative ligand, X-Delta-1, are thought to mediate an inhibitory cell-cell interaction, called lateral inhibition, that limits the number of primary neurons that form in Xenopus embryos. The expression of Xenopus ESR-1, a gene related to Drosophila Enhancer of split, appears to be induced by Notch signaling during this process. To determine how the activation of X-Notch-1 induces ESR-1 expression and regulates primary neurogenesis, we isolated the Xenopus homolog of Suppressor of Hairless (X-Su(H)), a component of the Notch signaling pathway in Drosophila. Using animal cap assays, we show that X-Su(H) induces ESR-1 expression, perhaps directly, when modified by the addition of ankyrin repeats. Using a DNA binding mutant of X-Su(H), we show that X-Su(H) activity is required for induction of ESR-1. Finally, expression of the DNA binding mutant in embryos leads to a neurogenic phenotype as well as increased expression of both X-Delta-1 and XNGNR1, a proneural gene expressed during primary neurogenesis. These results suggest that activation of X-Su(H) is a key step in the Notch signaling pathway during primary neurogenesis in Xenopus embryos.
Ultrathin full color visor with large field of view based on multilayered metasurface design (2018)

An augmented reality display system based on an ultra-thin see-through stacked metasurface near eye visor is proposed. We use the unique capabilities of plasmonic metasurfaces to control light at the subwavelength scale and design a see-through diffractive element that can project a full color image from a micro-display into the eye. This element is comprised of three metasurface layers, each designed to diffract only a specific wavelength and keep the rest of the visible spectrum unaffected. By implementing this layered design we can harness the advantages of diffractive optics and reduce their chromatic aberrations. We present here the design process of the proposed metasurface near eye visor and validate it by fabricating and testing a proof of concept sample.
Dual Systemic Tumor Targeting with Ligand-Directed Phage and Grp78 Promoter Induces Tumor Regression (2012)

The tumor-specific Grp78 promoter is overexpressed in aggressive tumors. Cancer patients would benefit greatly from application of this promoter in gene therapy and molecular imaging; however, clinical benefit is limited by lack of strategies to target the systemic delivery of Grp78-driven transgenes to tumors. This study aims to assess the systemic efficacy of Grp78-guided expression of therapeutic and imaging transgenes relative to the standard cytomegalovirus (CMV) promoter. Combination of ligand and Grp78 transcriptional targeting into a single vector would facilitate systemic applications of the Grp78 promoter. We generated a dual tumor-targeted phage containing the arginine-glycine-aspartic acid tumor homing ligand and Grp78 promoter. Next, we combined flow cytometry, Western blot analysis, bioluminescence imaging of luciferase, and HSVtk/ganciclovir gene therapy and compared efficacy to conventional phage carrying the CMV promoter in vitro and in vivo in subcutaneous models of rat and human glioblastoma. We show that double-targeted phage provides persistent transgene expression in vitro and in tumors in vivo after systemic administration compared with conventional phage. Next, we showed significant tumor killing in vivo using the HSVtk/ganciclovir gene therapy and found a systemic antitumor effect of Grp78-driven HSVtk against therapy-resistant tumors. Finally, we uncovered a novel mechanism of Grp78 promoter activation whereby HSVtk/ganciclovir therapy upregulates Grp78 and transgene expression via the conserved unfolded protein response signaling cascade. These data validate the potential of Grp78 promoter in systemic cancer gene therapy and report the efficacy of a dual tumor targeting phage that may prove useful for translation into gene therapy and molecular imaging applications.
Preclinical studies on the pharmacokinetic properties of human monoclonal antibodies to colorectal cancer and their use for detection of tumors. (1988)

We studied the pharmacokinetic properties of two human monoclonal antibodies to colon carcinoma cells and their ability to detect tumors in nude mice bearing primary human colon carcinoma xenografts. The 16-88 and 28A32 monoclonal antibodies are immunoglobulin M class human antibodies produced by cell lines derived from peripheral blood lymphocytes from patients with colon carcinoma. The patients received an autologous tumor cell vaccine as part of an active specific immunotherapy protocol. The 125I-labeled antibodies were cleared from the circulation of non-tumor-bearing and tumor-bearing nude mice with a 6-8-h half-life. The half-life of the antibodies in tumor tissue was 48 to 72 h compared to 8 to 12 h for normal tissues. Tumor:normal tissue ratios were highest 4 to 7 days postinjection with tumor:blood ratios of 12:1 for 16-88 and 10:1 for 28A32 antibody. Experiments with a control human immunoglobulin M myeloma protein confirmed the specificity of the human monoclonal antibodies. Radioimmunoscintigraphic studies using nude mice bearing contralateral antibody-reactive and nonreactive colon tumor xenografts further confirmed that the antibodies specifically localized in tumor tissues. The antibody-reactive tumors were clearly visible by radioimmunoscintigraphy within 4 days of injection. These experiments, undertaken as a preliminary step to clinical trials, demonstrated for the first time that i.v. administered human immunoglobulin M monoclonal antibodies could be taken up by human colon tumor tissue and retained to a sufficient extent to easily permit tumor detection by external radioimmunoscintigraphy. These studies also demonstrated that the nude mouse human colon tumor xenograft model is a useful in vivo system for comparison studies of human monoclonal antibodies as part of a selection process for clinical trials and for evaluating immunoconjugates containing these antibodies for relative pharmacokinetic properties and potential diagnostic or therapeutic efficacy.
An immunocompromised BALB/c mouse model for respiratory syncytial virus infection (2005)

These results demonstrate that CYP-treated BALB/c mice provide a better model for studying RSV immunopathology and that decreased production of IL-12 and IFN-gamma are important determinants of susceptibility to RSV infection.