gebhart/patrepeval huggingface dataset:
p35 and Rac1 underlie the neuroprotection and cognitive improvement induced by CDK5 silencing (2015)

CDK5 plays an important role in neurotransmission and synaptic plasticity in the normal function of the adult brain, and dysregulation can lead to Tau hyperphosphorylation and cognitive impairment. In a previous study, we demonstrated that RNAi knock down of CDK5 reduced the formation of neurofibrillary tangles (NFT) and prevented neuronal loss in triple transgenic Alzheimer's mice. Here, we report that CDK5 RNAi protected against glutamate-mediated excitotoxicity using primary hippocampal neurons transduced with adeno-associated virus 2.5 viral vector eGFP-tagged scrambled or CDK5 shRNA-miR during 12 days. Protection was dependent on a concomitant increase in p35 and was reversed using p35 RNAi, which affected the down-stream Rho GTPase activity. Furthermore, p35 over-expression and constitutively active Rac1 mimicked CDK5 silencing-induced neuroprotection. In addition, 3xTg-Alzheimer's disease mice (24 months old) were injected in the hippocampus with scrambled or CDK5 shRNA-miR, and spatial learning and memory were performed 3 weeks post-injection using 'Morris' water maze test. Our data showed that CDK5 knock down induced an increase in p35 protein levels and Rac activity in triple transgenic Alzheimer's mice, which correlated with the recovery of cognitive function; these findings confirm that increased p35 and active Rac are involved in neuroprotection. In summary, our data suggest that p35 acts as a mediator of Rho GTPase activity and contributes to the neuroprotection induced by CDK5 RNAi.
[Cytokeratins as markers of differentiation. Expression profiles in epithelia and epithelial tumors]. (1993)

Intermediate filaments (IFs; diameter, about 10 nm) are cytoplasmic cytoskeletal structures found in most vertebrate cells. Their protein subunits comprise a large multi-gene family of related proteins, which make it possible to divide IFs into seven separate classes whose expression is cell-type-dependent. The most important IF classes are cytokeratin (CK) filaments (epithelial cells), vimentin filaments (mesenchymal cells), desmin filaments (muscle cells), glial filaments (astrocytes), and neurofilaments (nerve cells). As the specificity of expression of IF proteins is retained in malignant tumors, they are suitable as histological markers of differentiation (tumor markers). The protein subunits of the epithelial CK filaments are unusually diverse, and within the various types of epithelia, their expression is differentiation specific. Until recently, the catalog of human CKs comprised 19 related, yet distinct polypeptides (CKs 1-19; Moll et al., 1982a); CK 20 can now be added to this list. On the basis of sequence relationships, two CK subfamilies can be delineated (CKs 9-20 = type I; CKs 1-8 = type II). Any given epithelial cell exhibits a characteristic, differentiation-dependent combination of two or more CK polypeptides, with type-I and -II polypeptides always occurring in stoichiometric amounts (i.e., as "pairs"), because the basic structural unit of the CK filaments is a heterotypical tetramer complex. On the basis of their main tissue distribution patterns, it is possible further to subdivide these polypeptides into CKs typical of stratified squamous epithelia (CKs 1-6, 9-17) and those typical of simple columnar epithelia (CKs 7, 8, 18-20); these CKs exhibit differential expression patterns in the various types of squamous and columnar epithelia. The actual characterization of the novel CK 20 as a CK initially proved to be rather difficult, as this cytoskeletal protein, which can be biochemically isolated from cells of the intestinal epithelium (M(r) 46,000; previously called "IT protein"), exhibits no reaction with numerous well-known CK antibodies in Western blots. However, a series of other characteristics typical of CKs could be demonstrated. Thus, IT protein was found, in vitro (nitrocellulose-blot binding test, native gel electrophoresis), to for heterotypical complexes with the type-II CK 8, and these complexes were able to reconstitute themselves into typical IFs in vitro. Chymotrypsin-cleaving experiments revealed the presence of a resistant core fragment (M(r) 38,000), indicating a alpha-helical "coiled-coil" conformation typical of IFs.(ABSTRACT TRUNCATED AT 400 WORDS)
Tissue non-specific alkaline phosphatase is expressed in both embryonic and extraembryonic lineages during mouse embryogenesis but is not required for migration of primordial germ cells (1995)

Mouse primordial germ cells express tissue non-specific alkaline phosphatase (TNAP) during development, but the widespread expression of another alkaline phosphatase gene in the early embryo limits the potential use of this marker to trace germ cells. To attempt to identify germ cells at all stages during embryonic development and to understand the role of TNAP in germ cell ontogeny, mice carrying a beta geo (lacZ/neor) disrupted allele of the TNAP gene were generated by homologous recombination in embryonic stem cells. Using beta-galactosidase activity, the embryonic pattern of TNAP expression was examined from the blastocyst stage to embryonic day 14. Results indicate that primordial germ cell progenitors do not express TNAP prior to gastrulation although at earlier times TNAP expression is found in an extraembryonic lineage destined to form the chorion. In homozygous mutants, primordial germ cells appear unaffected indicating that TNAP is not essential for their development or migration.
Ectodermal commitment of insulin‐producing cells derived from mouse embryonic stem cells (2005)

Embryonic stem cells possess the ability to differentiate in vitro into a variety of cell lineages, including insulin-producing cells. Pancreatic beta-cells derive from foregut endoderm during embryonic development. However, previous reports using transgenic mice strongly indicate that insulin-positive cells may be generated also through the neuroectoderm pathway. To analyze this point, a culture system was performed in which only ectoderm committed cells were present. Based on published work, we achieved this by maintaining transfected clonal R1 mouse embryonic stem cells in monolayer in the absence of LIF. Contrary to differentiation protocols via embryoid body formation, monolayer cultured cells displayed ectodermal fates according to the marker gene expression pattern. Under these particular conditions, neomycin was added in order to select insulin-expressing cells. The cell lineage obtained expressed Pdx1, Pax6, Isl1, AChE, MBP, TH, and GS genes, confirming ectodermal commitment, even though some of these factors are also expressed in endoderm. In addition these cells displayed excitatory properties similar to astrocytes. Co-expression of insulin II and nestin was observed in monolayer culture and in the presence of specific conditioned media. No expression of early endodermal markers was detected along monolayer cultures. Altogether, these observations suggest that cells with ectoderm fates could participate in vitro in the derivation of insulin-producing cells. These results have implications for insulin gene regulation and hormone secretion in order to generate insulin-producing cells for replacement protocols in the treatment of diabetes.
A Modular Synthetic Approach toward Exhaustively Stereodiversified Ligand Libraries (2000)

[structure] This report describes a modular approach to the synthesis of stereodiversified natural product-like libraries. Monomers 2 and 3 were coupled in parallel by silyl-tethered olefin metathesis to generate all 16 stereoisomers of cis-enediols 1. All 16 stereoisomers were incorporated into chimerae having flanking peptidic segments. These chimerae exhibited a broad range of hydrophobicities, raising the possibility that stereochemical variation might be used to tune the pharmacologic properties of small molecules.
Autophagy and Crohn's Disease (2013)

Advances in genetics have shed light on the molecular basis of Crohn's disease (CD) predisposition and pathogenesis, via linkage disequilibrium analysis to genome-wide association studies. The discovery of genetic variants of NOD2, an intracellular pathogen molecular sensor, as risk factors for CD has paved the way for further research on innate immunity in this disease. Remarkably, polymorphisms in autophagy genes, such as ATG16L1 and IRGM, have been identified, allowing the pivotal role of autophagy in innate immunity to be uncovered. In this review, we summarize recent studies on the CD-associated NOD2, ATG16L1 and IRGM risk variants and their contribution to the autophagy functions that have most influenced our understanding of CD pathophysiology.
Codon Optimization OnLine (COOL): a web-based multi-objective optimization platform for synthetic gene design (2014)

Supplementary data are available at Bioinformatics online.
PCR random mutagenesis into Escherichia coli serine acetyltransferase: isolation of the mutant enzymes that cause overproduction of L‐cysteine and L‐cystine due to the desensitization to feedback inhibition (1999)

PCR random mutagenesis in the cysE gene encoding Escherichia coli serine acetyltransferase was employed to isolate the mutant enzymes that, due to a much less feedback inhibition by L-cysteine, cause overproduction of L-cysteine and L-cystine in the recombinant strains. The L-cysteine auxotrophic and non-utilizing E. coli strain was transformed with plasmids having the altered cysE genes. Then, several transformants overproducing L-cysteine were selected by detecting the halo formation of the L-cysteine auxotroph. The production test of amino acids and analysis of the catalytic property on the mutant enzymes suggest that the carboxy-terminal region of serine acetyltransferase plays an important role in the desensitization to feedback inhibition and the high level production of L-cysteine and L-cystine.
Neural Architecture Optimization (2018)

Automatic neural architecture design has shown its potential in discovering powerful neural network architectures. Existing methods, no matter based on reinforcement learning or evolutionary algorithms (EA), conduct architecture search in a discrete space, which is highly inefficient. In this paper, we propose a simple and efficient method to automatic neural architecture design based on continuous optimization. We call this new approach neural architecture optimization (NAO). There are three key components in our proposed approach: (1) An encoder embeds/maps neural network architectures into a continuous space. (2) A predictor takes the continuous representation of a network as input and predicts its accuracy. (3) A decoder maps a continuous representation of a network back to its architecture. The performance predictor and the encoder enable us to perform gradient based optimization in the continuous space to find the embedding of a new architecture with potentially better accuracy. Such a better embedding is then decoded to a network by the decoder. Experiments show that the architecture discovered by our method is very competitive for image classification task on CIFAR-10 and language modeling task on PTB, outperforming or on par with the best results of previous architecture search methods with a significantly reduction of computational resources. Specifically we obtain 1.93% test set error rate for CIFAR-10 image classification task and 56.0 test set perplexity of PTB language modeling task. Furthermore, combined with the recent proposed weight sharing mechanism, we discover powerful architecture on CIFAR-10 (with error rate 2.93%) and on PTB (with test set perplexity 56.6), with very limited computational resources (less than 10 GPU hours) for both tasks.
Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung (2009)

Adenocarcinomas of the lung commonly show an increase in the activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, yet many are resistant to apoptosis induced by the inhibition of PI3K. We hypothesized that Bcl-xL would have a synergistic effect on the apoptotic response induced by inhibition of the PI3K/Akt pathway in lung adenocarcinoma. To test this, we examined the effect of the PI3K inhibitor (LY294002) on lung adenocarcinoma cell lines expressing varying levels of Bcl-xL. We found that cells that overexpress Bcl-xL are resistant to LY294002-induced apoptosis, whereas cells that express little Bcl-xL readily are not. Restoring Bcl-xL expression in cells that express low level of Bcl-xL conferred resistance to apoptosis in response to LY294002. The simultaneous inhibition of the PI3K/Akt pathway by LY294002 or Akt1 small interfering RNA and Bcl-xL function by ABT-737 or Bcl-xL small interfering RNA greatly enhanced the apoptotic response. Moreover, this response was associated with the induction of proapoptotic BH3-only Bcl-2 family member Bim. Our data suggest that PI3K/Akt and Bcl-xL pathways control cell death in lung adenocarcinoma cells in a synergistic manner. Modulation of Bcl-xL expression may represent one important strategy to optimize the efficacy of therapeutic agents targeting the PI3K/Akt pathway in adenocarcinoma of the lung.
The Simple Virtual Environment Library: An Extensible Framework for Building VE Applications (2000)

As virtual environment (VE) technology becomes accessible to (and affordable for) an ever-widening audience of users, the demand for VE applications will increase. Tools that assist and facilitate the development of these applications, therefore, will also be in demand. To support our efforts in quickly designing and implementing VE applications, we have developed the Simple Virtual Environment (SVE) library. In this article, we describe the characteristics of the library that support the development of both simple and complex VE applications. Simple applications are created by novice programmers or for rapid prototyping. More-complex applications incorporate new user input and output devices, as well as new techniques for user interaction, rendering, or animation. The SVE library provides more-comprehensive support for developing new VE applications and better supports the various device configurations of VE applications than current systems for 3-D graphical applications. The development of simple VE applications is supported through provided default interaction, rendering, and user input and output device handling. The library's framework includes an execution framework that provides structure for incrementally adding complexity to selected tasks of an application, and an environment model that provides a layer of abstraction between the application and the device configuration actually used at runtime. This design supports rapid development of VE applications through incremental development, code reuse, and independence from hardware resources during the development.
Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone (2001)

The structures of the ligand-binding domains (LBD) of the wild-type androgen receptor (AR) and the T877A mutant corresponding to that in LNCaP cells, both bound to dihydrotestosterone, have been refined at 2.0 A resolution. In contrast to the homodimer seen in the retinoid-X receptor and estrogen receptor LBD structures, the AR LBD is monomeric, possibly because of the extended C terminus of AR, which lies in a groove at the dimerization interface. Binding of the natural ligand dihydrotestosterone by the mutant LBD involves interactions with the same residues as in the wild-type receptor, with the exception of the side chain of threonine 877, which is an alanine residue in the mutant. This structural difference in the binding pocket can explain the ability of the mutant AR found in LNCaP cells (T877A) to accommodate progesterone and other ligands that the wild-type receptor cannot.
Broadband calibration of E-field probes in lossy media [mobile telephone safety application] (1996)

A broadband calibration procedure for E-field probes that minimizes the overall uncertainties inherent in E-field measurements in lossy dielectric liquids has been developed. The analysis of the calibration requirements shows that probes that are symmetrical with respect to their axis greatly facilitate accurate calibration, since the calibration procedure can be divided into several discrete steps. Such a procedure is presented and analyzed with respect to its uncertainties. Absolute calibration is performed at three frequency bands utilized in Europe for mobile communications (450 MHz, 900 MHz, and 1.8 GHz) and in different tissue-simulating liquids. The parameters obtained are verified by numerical simulations of the probe in the surrounding media. Such simulations allow the assessment of some of the calibration parameters with sufficient accuracy in cases where the experimental determination would be too tedious and time consuming.
Identification of an estrogen response element in the 3'-flanking region of the murine c-fos protooncogene. (1992)

We have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyltransferase, linked to regions of mouse c-fos, to identify a specific estrogen response element (ERE) in this protooncogene. This element is located in the untranslated 3'-flanking region of the c-fos gene, 5 kilobases (kb) downstream from the c-fos promoter and 1.5 kb downstream of the poly(A) signal. This element confers estrogen responsiveness to chloramphenicol acetyltransferase reporters linked to both the herpes simplex virus thymidine kinase promoter and the homologous c-fos promoter. Deletion analysis localized the response element to a 200-base pair fragment which contains the element GGTCACCACAGCC that resembles the consensus ERE sequence GGTCACAGTGACC originally identified in Xenopus vitellogenin A2 gene. A synthetic 36-base pair oligodeoxynucleotide containing this c-fos sequence conferred estrogen inducibility to the thymidine kinase promoter. The corresponding sequence also induced reporter activity when present in the c-fos gene fragment 3 kb from the thymidine kinase promoter. Gel-shift experiments demonstrated that synthetic oligonucleotides containing either the consensus ERE or the c-fos element bind human estrogen receptor obtained from a yeast expression system. However, the mobility of the shifted band is faster for the fos-ERE-complex than the consensus ERE complex suggesting that the three-dimensional structure of the protein-DNA complexes is different or that other factors are differentially involved in the two reactions. When the 5'-GGTCA sequence present in the c-fos ERE is mutated to 5'-TTTCA, transcriptional activation and receptor binding activities are both lost. Mutation of the CAGCC-3' element corresponding to the second half-site of the c-fos sequence also led to the loss of receptor binding activity, suggesting that both half-sites of this element are involved in this function. The estrogen induction mediated by either the c-fos or the consensus ERE was blunted by the antiestrogen tamoxifen. Based on these studies, we believe the 3'-fos ERE sequence we have identified may be a major cis-acting element involved in the physiological regulation of the gene by estrogens in vivo.
Polyelectrolyte Multilayers Containing a Weak Polyacid:  Construction and Deconstruction (2001)

The growth of multilayers made from a combination of a weak polyacid and a strongly dissociated polycation is studied as a function of salt concentration and molecular weight. Film thickness reaches a maximum at around 0.3 M salt and then decreases quickly. Preformed multilayers are shown to decompose rapidly and, for high molecular weights, completely when exposed to aqueous solutions of NaCl of concentration >0.6 M. The apparent dissociation of multilayer polyelectrolyte complexes is due to competition for polymer/polymer ion pairs by external salt ions. Similar experiments aimed at decomposing multilayers by protonating the weak acid, thus decreasing polymer/polymer interactions, lead to incomplete loss of polymer, probably due to additional hydrogen bonding from the protonated weak acid. A model based on ion exchange/swelling of multilayers is used to explain their stability and permeability as well as the dependence of film thickness on salt concentration and type.
PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice (2012)

Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.
Direct identification of bacterial isolates in blood cultures by using a DNA probe (1991)

This study involved the rapid, direct identification of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Enterococcus sp., and Streptococcus agalactiae from positive blood culture bottles (BACTEC, Johnston Laboratories, Inc.) by using the AccuProbe (Gen-Probe, San Diego, Calif.) culture confirmation test. This method uses a chemiluminescent DNA probe that detects the rRNA of the target organisms. The manufacturer's instructions were modified to use a pellet of bacteria made directly from positive blood culture broth rather than a colony from an agar plate. Two separate procedures of selective centrifugation were employed in order to obtain the pellet. The first utilized a routine clinical centrifuge and a large volume of broth (10 to 12 ml) from the blood culture bottle. The second method used a microcentrifuge and less volume (1 to 1.5 ml). A total of 196 clinical specimens taken directly from positive blood culture broths were correctly identified by AccuProbe from pellets made by using the clinical centrifuge technique, while 166 clinical specimens used as negative controls failed to show hybridization. The microcentrifuge technique for obtaining pellets was performed on 105 patient specimens, and all were correctly identified. When combined with the microcentrifuge technique for pellet preparation, the AccuProbe test has several advantages: (i) direct identification of bacteria from blood culture broths, (ii) rapid turn-around time (30 min), (iii) simplicity of the procedure, and (iv) relative low cost.
Reinforcement learning with natural language signals (2016)

Thesis: S.M., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2016.