gebhart/patrepeval huggingface dataset:
Invited review: Drug development for tauopathies (2014)

Many different approaches to treating tauopathies are currently being explored, with a few compounds already in clinical development (including small molecules such as anti-aggregation compound LMTX and active vaccines AADvac1 and ACI-35). This review aims to summarize the status of the clinical candidates and to highlight the emerging areas of research that hold promise for drug development. Tau is post-translationally modified in several different ways (phosphorylated, acetylated, glycosylated and truncated). The extent of these modifications can be manipulated to influence tau aggregation state and pathogenesis and the enzymes involved provide tractable targets for drug intervention. In addition, modulation of tau expression levels is an attractive therapeutic approach. Finally, the recently described prion-like spreading of tau between cells opens up novel avenues from the tau drug development perspective. The review compares the merits of small-molecule and antibody-based therapies and emphasizes the need for amenable clinical biomarkers for drug development, particularly PET imaging.
LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. (2001)

Lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 is thought to be restricted to lymph vessels and has been used as such to show that tumor lymphangiogenesis occurs on overexpression of lymphangiogenic factors in mouse tumor models. However, these studies have not yet been corroborated in human tumors. Here we show, first, that LYVE-1 is not exclusive to the lymph vessels. Indeed, LYVE-1 is also present in normal hepatic blood sinusoidal endothelial cells in mice and humans. Surprisingly, LYVE-1 is absent from the angiogenic blood vessels of human liver tumors and only weakly present in the microcirculation of regenerative hepatic nodules in cirrhosis, though both vessels are largely derived from the liver sinusoids. Second, we propose a novel approach to identify lymphatics in human and murine liver. By combining LYVE-1 and Prox 1 (a transcription factor) immunohistochemistry, we demonstrate that lymphatics are abundant in cirrhosis. In contrast, in human hepatocellular carcinoma and liver metastases, they are restricted to the tumor margin and surrounding liver. The absence of intratumor lymphatics in hepatocellular carcinomas and liver metastases may impair molecular and cellular transport in these tumors. Finally, the presence of LYVE-1 in liver sinusoidal endothelia suggests that LYVE-1 has functions beyond the lymph vascular system.
ChemInform Abstract: SYNTHESIS OF SOME 3‐NITROPHTHALYL‐AMINO ACIDS AND DIPEPTIDE DERIVATIVES (1980)

Abstract Die Umsetzung von Nitrophthalsäureanhydrid (I) mit den Aminosäuren (II) führt zu den Nitrophthaloylaminosäuren (III), die sich mit PCIS in die Säurechloride (IV) überführen lassen, die mit Methanol (V) die Ester (VI) liefern.
Maize oleosin is correctly targeted to seed oil bodies in Brassica napus transformed with the maize oleosin gene. (1991)

Oleosins are small hydrophobic abundant proteins localized in the oil bodies of plant seeds. An oleosin gene from the monocotyledonous maize (Zea mays L.) was transferred into the dicotyledonous Brassica napus L. using Agrobacterium-mediated transformation. The maize oleosin gene was placed under the control of either its own promoter/terminator or the promoter/terminator of a Brassica seed storage protein (napin) gene. Southern blot analyses of individual transformed plants suggested that the oleosin gene from either construct was incorporated into the Brassica chromosomes without appreciable structural alterations. The amount of construct incorporated was from 1 to >10 copies per haploid genome, depending on the individual transformant. Maize oleosin mRNA and protein were detected only in the transformants containing the napin gene promoter/terminator constructs; these transformants were studied further. Northern blot analyses of RNA isolated from different tissues and seeds of different developmental stages indicated that the maize oleosin mRNA was present only in the maturing seed. Approximately 1% of the total protein in mature seed was represented by maize oleosin. Subcellular fractionation of the mature seed revealed that 90% or more of the maize oleosin, as well as the Brassica oleosin, was localized in the oil bodies. The results show that a monocotyledonous oleosin possesses sufficient targeting information for its proper intracellular transport in a dicotyledon and also suggest that the napin gene promoter/terminator of Brassica, or equivalent seed storage protein regulatory elements of other plant species, may be used to express genes for the genetic engineering of seed oils.
Adeno-associated virus vector integration. (2009)

Adeno-associated virus (AAV) vectors efficiently transduce various cell types and can produce long-term expression of transgenes in vivo. Although AAV vector genomes can persist within cells as episomes, vector integration has been observed in various experimental settings, either at non-homologous sites where DNA damage may have occurred or by homologous recombination. In some cases, integration is essential for the therapeutic or experimental efficacy of AAV vectors. Recently, insertional mutagenesis resulting from the integration of AAV vectors was associated with tumorigenesis in mice, a consideration that may have relevance for certain clinical applications.
Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16 (2018)

Ligand-dependent protein degradation has emerged as a compelling strategy to pharmacologically control the protein content of cells. So far, only a limited number of E3 ligases have been found to support this process. Here, we use a chemical proteomic strategy to discover that DCAF16 – a poorly characterized substrate recognition component of CUL4-DDB1 E3 ubiquitin ligases – promotes nuclear-restricted protein degradation upon modification by cysteine-directed heterobifunctional electrophilic compounds.
The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology (2007)

Loss of function of the maternally inherited allele for the UBE3A ubiquitin ligase gene causes Angelman syndrome (AS), which is characterized by severe neurological impairment and motor dysfunction. In addition, UBE3A lies within chromosome 15q11-q13 region, where maternal, but not paternal, duplications cause autism. The UBE3A gene product, E6-AP, has been shown to function both as an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator. However, the specific role of E6-AP in the brain, or how loss of function of E6-AP results in AS, is unclear. Herein, we show, using a recombinant transgenic mouse expressing a Ube3a(YFP) fusion gene, that the maternal Ube3a(YFP) allele is upregulated and preferentially expressed in neurons, and that the fusion protein, E6-AP:YFP, is enriched in the nucleus and dendrites in vivo. We also show that E6-AP:YFP localizes to the nucleus and to presynaptic and postsynaptic compartments in cultured hippocampal neurons. Furthermore, we show that cerebellar Purkinje cell number and dendritic branching are not affected in Ube3a maternal-deficient mice, but that dendritic spine development, including spine morphology, number and length, is affected on cerebellar Purkinje cells and on pyramidal neurons in the hippocampus and cortex. Collectively, these data suggest that the neurological deficits observed in AS patients and in AS mice may result from specific abnormalities in synaptic development and/or plasticity.
Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D (2004)

This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).
A quantitative assay for assessing allelic proportions by iterative gap ligation (1998)

A variety of techniques are currently available for detecting point mutations in DNA. These techniques are frequently not sensitive enough to be applied as quantitative assays in evaluation of relative occurrence of alleles in cases of polymorphism or when variations in allelic gene expression are being evaluated at the level of RNA. We report here the establishment of an iterative gap ligation (IGL) assay that is both quantitative and sensitive. The design of the assay is such that ligation of an upstream to a downstream primer across a single nucleotide gap will only occur if the gap is filled with a deoxynucleotide complementary to the wild-type or mutant sequence. Under conditions in which excess upstream primer saturates the template concurrently with limiting amounts of downstream primer quantitative ligation is absolutely dependent on provision of the appropriate gap filling nucleotide. When gap ligation occurs in a single incubation, or cycle, the amount of ligated product is a linear function of the relative amount of mutant sequence, with a sensitivity and detection limit of approximately 3% over a range of relative concentrations of 0-100%. When the reaction occurs over multiple cycles, or iterations, gap ligation becomes a non-linear function such that small changes in the relative proportions of alleles produce a disproportionately large amount of ligation. As a consequence, the sensitivity and limits of detection of the assay improve to 0.2% after only 8 cycles. The development of this assay provides a unique means of quantifying allelic polymorphisms in both DNA and RNA (after initial amplification by PCR or RT-PCR) and should be applicable to any experimental settings in which nucleic acids from tissues or mixed populations of cells are being evaluated.
Expression of the interleukin 6 gene in rheumatoid synovial fibroblasts. (1990)

A number of fibroblastoid synovial cell lines have been established from rheumatoid joints. These cell lines were shown to express the interleukin 6 (IL-6) gene constitutively, and exposure of these cells to 5 ng/ml of recombinant human interleukin 1 beta (IL-1 beta) increased IL-6 gene expression. Other recombinant human lymphokines, namely interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor had no enhancing effect on IL-6 gene expression. Dexamethasone added to the cultures at 10(-7) M concentration suppressed the constitutive expression of the IL-6 gene. At a concentration of 10(-5) M, dexamethasone partially suppressed the IL-1 enhanced expression of IL-6. The IL-6 gene probe also hybridized to RNA from unfractionated synovial fluid cells, peripheral blood T cells and non-T cells but not Epstein-Barr virus transformed peripheral blood B cells of patients with rheumatoid arthritis. Our results suggest that in rheumatoid arthritis, synovial fibroblasts actively participate in joint inflammation by lymphokine production. The coexpression of both IL-1 and IL-6 by one synovial fibroblast line suggests a mechanism for the perpetuation of synovitis.
Discovery and Evaluation of Potent P1 Aryl Heterocycle-Based Thrombin Inhibitors (2004)

In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
The histone-like H protein ofEscherichia coliis ribosomal protein S3 (1989)

We report the purification of four proteins from Escherichia coli that stimulate or inhibit inter- and/or intramolecular recombination promoted by the yeast plasmid-encoded FLP protein. The proteins are identified as the ribosomal proteins S3 (27 kDa), L2 (26 kDa), S4 (24 kDa), and S5 (16 kDa), on the basis of N-terminal sequence analysis. The S3 protein is found to be identical to H protein, an E. coli histone-like protein that is related to histone H2A immunologically and by virtue of amino acid content. The H protein/S3 identity is based on co-migration on polyacrylamide gels, heat stability, amino acid analysis, and effects on FLP-promoted recombination. These results are relevant to current studies on the structure of the E. coli nucleoid. Since the H protein has previously been found associated with the E. coli nucleoid, the results indicate that either (a) some ribosomal proteins serve a dual function in E. coli, or, more likely, (b) ribosomal proteins can and are being mis-identified as nucleoid constituents.
Control of Arabidopsis flower and seed development by the homeotic gene APETALA2. (1994)

APETALA2 (AP2) plays a central role in the establishment of the floral meristem, the specification of floral organ identity, and the regulation of floral homeotic gene expression in Arabidopsis. We show here that in addition to its functions during flower development, AP2 activity is also required during seed development. We isolated the AP2 gene and found that it encodes a putative nuclear protein that is distinguished by an essential 68-amino acid repeated motif, the AP2 domain. Consistent with its genetic functions, we determined that AP2 is expressed at the RNA level in all four types of floral organs--sepals, petals, stamens, and carpels--and in developing ovules. Thus, AP2 gene transcription does not appear to be spatially restricted by the floral homeotic gene AGAMOUS as predicted by previous studies. We also found that AP2 is expressed at the RNA level in the inflorescence meristem and in nonfloral organs, including leaf and stem. Taken together, our results suggest that AP2 represents a new class of plant regulatory proteins that may play a general role in the control of Arabidopsis development.
Molecular epidemiology of Escherichia coli producing extended-spectrum β-lactamases in Lugo (Spain): dissemination of clone O25b:H4-ST131 producing CTX-M-15 (2009)

CTX-M-type ESBLs, primarily CTX-M-14 and CTX-M-15, have emerged as the predominant types of ESBL produced by E. coli isolates in Lugo. In view of the reported findings, long-term care facilities for elderly people may represent a significant reservoir for E. coli clone O25b:H4-ST131 producing CTX-M-15. The triplex PCR developed in this work will be useful for rapid and simple detection of this clone.
Atomic Structure of the Cubic Core of the Pyruvate Dehydrogenase Multienzyme Eomplex (1992)

The highly symmetric pyruvate dehydrogenase multienzyme complexes have molecular masses ranging from 5 to 10 million daltons. They consist of numerous copies of three different enzymes: pyruvate dehydrogenase, dihydrolipoyl transacetylase, and lipoamide dehydrogenase. The three-dimensional crystal structure of the catalytic domain of Azotobacter vinelandii dihydrolipoyl transacetylase has been determined at 2.6 angstrom (A) resolution. Eight trimers assemble as a hollow truncated cube with an edge of 125 A, forming the core of the multienzyme complex. Coenzyme A must enter the 29 A long active site channel from the inside of the cube, and lipoamide must enter from the outside. The trimer of the catalytic domain of dihydrolipoyl transacetylase has a topology identical to chloramphenicol acetyl transferase. The atomic structure of the 24-subunit cube core provides a framework for understanding all pyruvate dehydrogenase and related multienzyme complexes.
S100A11 gene identified by in-house cDNA microarray as an accurate predictor of lymph node metastases of gastric cancer (2004)

Gastric cancer is one of the most common malignancies in the world, and in Asian countries its incidence and mortality rates are very high. Worldwide, Japan ranks first in the incidence of this type of cancer for both sexes. To shed light on the mechanisms underlying the development and/or progression of gastric cancer, we compared the expression profiles in gastric cancer cells obtained from surgical dissection of 20 gastric adenocarcinoma specimens with those in the corresponding non-cancerous mucosa, by cDNA microarray analysis. In total, 8,000 cDNA clones were randomly picked up and their 5'-end nucleotide sequences were determined. On the basis of sequence information, 4,608 independent clones were selected and used to produce the cDNA microarray. We identified 26 genes that were commonly up-regulated and 44 genes that were commonly down-regulated in cancerous tissues. To validate the cDNA microarray analysis, real-time PCR was performed. We found that gene S100A11 expression was associated with the development of lymph node metastases. S100A11 gene expression was clearly up-regulated in specimens from patients with lymph node metastases relative to those from patients without lymph node metastases. S100A11 gene expression status was useful to distinguish gastric cancers with lymph node metastases from those without lymph node metastasis. This genome-wide information contributes to an improved understanding of molecular changes during the development of gastric cancers. It may also help clinicians predict the development of lymph node metastases and assist researchers in identifying novel therapeutic targets for patients with gastric cancer.
Automatic cell segmentation in microscopic color images using ellipse fitting and watershed (2010)

This paper presents an efficient and innovative method for the automated counting of cells in a microscopic image. The performance of watershed-based algorithms for the segmentation of clustered cells has been well demonstrated. The strength of our algorithm lies in the fact that it incorporates knowledge of color in the image. Our method uses the watershed transform with iterative shape alignment and is shown to be more accurate in retaining cell shape. We report a sensitivity of 97% and specificity of 96% when all color bands are used. Our methods could be of value to computer-based systems designed to objectively interpret microscopic images, since they provide a means for accurate cell segmentation.
Hypoactive sexual desire disorder: can we treat it with drugs? (2010)

Hypoactive sexual desire disorder (HSDD) is a common multidimensional condition which is characterized by a decrease in sexual desire that causes marked personal distress and/or interpersonal difficulty. There are a number of potential causes and contributing factors to HSDD and a balanced approach comprising both biological and psycho-relational factors is mandatory for accurate diagnosis and tailored management in clinical practice. It is clearly evident that sex hormones play a crucial role in modulating sexual response during the entire reproductive life span of women. On the other hand, a better understanding of the neurobiological basis of sexual desire supports the idea that selective psychoactive agents may be proposed as non-hormonal treatments to restore the balance between excitatory and inhibitory stimuli leading to a normal sexual response cycle. However, there are currently no approved pharmacological treatments for premenopausal women with HSDD, while transdermal testosterone is approved in Europe for post-menopausal women who experience HSDD as a result of a bilateral oophorectomy. That being so, the ideal clinical approach remains to be established in term of efficacy and safety and further research is needed to develop specific pharmacotherapies for individualized care of women with sexual dysfunction of any age.
Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes (2014)

Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1(-/y)), we show that phosphorylation of the mRNA 5' cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1(-/y) mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
DEPLETION OF CD16+ CELLS LEADS TO INCREASED SURVIVAL OF CFSE-LABELED PERIPHERAL BLOOD STEM CELLS IN RHESUS MACAQUES (2008)

Transplantation: July 27, 2008 - Volume 86 - Issue 2S - p 410 doi: 10.1097/01.tp.0000331474.40601.7d
Layer-by-Layer Assembly of Zeolite Crystals on Glass with Polyelectrolytes as Ionic Linkers (2001)

ZSM-5 crystals and glass plates tethered with trimethylpropylammonium iodide and sodium butyrate, respectively, (denoted as Z+, Z-, G+, and G-, respectively) were prepared. Treatment of G- with Z+ suspended in ethanol results in monolayer assembly of Z+ on G- (G-/Z+) with high surface coverage. The zeolite crystals have a strong tendency to closely pack and align with the b-axis normal to the glass plate, despite large positive zeta potentials. Subsequent treatment of G-/Z+ with Z- leads to second-layer assembly of Z- on G-/Z+ (G-/Z+/Z-), but with rather poor coverage. Sequential treatment of G+ with poly(sodium 4-styrenesulfonate)(Na+PSS-), poly(diallyldimethylammonium chloride) (PDDA+Cl-), and Na+PSS- followed by Z+ yields glass plates assembled with monolayers of Z+ with very high surface coverage through the composite polyelectrolyte linkers (G+/PSS-/PDDA+/PSS-/Z+). The zeolite crystals also have a strong tendency to closely pack and align with the b-axis perpendicular to the substrate plane. The binding strength between the zeolite crystals and glass plates is much higher in G+/PSS-/PDDA+/PSS-/Z+ than in G-/Z+. Repetition of the sequential PSS-/PDDA+/PSS-/Z+ layering for five cycles yields glass plates assembled with pentalayers of ZSM-5 crystals [G+/(PSS-/PDDA+/PSS-/Z+)(5)]. The observed degrees of coverage and alignment of zeolite crystals in each layer were very high up to the third layers despite the nonuniformity of the sizes and shapes of the zeolite crystals used in this study. This report thus demonstrates the feasibility of layer-by-layer assembly of micrometer-sized zeolite crystals on glass through electrostatic interaction between surface-bound, full-fledged ionic centers, especially by use of polyelectrolyes as the linkers.
Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland (2004)

It is anticipated that availability of localized reference values for an extended range of peripheral blood lymphocyte phenotypes should supplement previously published reference values and enhance the utility of flow cytometric analysis undertaken in Switzerland.