gebhart/patrepeval huggingface dataset:
Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: Possible implications for diagnosis and treatment (2006)

Degeneration of the locus ceruleus (LC) and decreased cortical levels of norepinephrine are common findings in Alzheimer's disease (AD), but their significance is unknown. Because the noradrenergic system is accessible to pharmacological intervention, the role of LC degeneration and noradrenergic dysfunction in the pathogenesis and clinical manifestations of AD needs clarification. Hypothetically, loss of noradrenergic innervation could cause microvascular dysfunction and manifest as ischemia. The objectives of this study were to develop a scale for assessment of LC degeneration and to determine whether degeneration of the LC correlates quantitatively with either duration of clinical dementia, overall severity of AD pathology or with measures of ischemic non-focal white matter disease (WMD) in AD. This report is a pathological follow-up of a clinical longitudinal dementia study of 66 consecutive cases of AD without admixture of vascular dementia (VaD) from the Lund Longitudinal Dementia Study, neuropathologically diagnosed between 1990 and 1999. Ten cases of VaD were included for comparative purposes. No correlation between degree of LC degeneration and duration of dementia, AD or WMD severity was found. LC degeneration was significantly more severe in the AD group than in the VaD group. Even though LC degeneration was not associated with WMD or the severity of AD pathology in this AD material, we suggest that clinical studies on the consequences of noradrenergic dysfunction are warranted. Treatment augmenting noradrenergic signaling is available and safe. The marked difference in the level of LC degeneration between AD and VaD cases suggests that LC degeneration could be used as a diagnostic marker of AD.
Identification and cloning of a fur regulatory gene in Yersinia pestis (1991)

Yersinia pestis is one of many microorganisms responding to environmental iron concentrations by regulating the synthesis of proteins and an iron transport system(s). In a number of bacteria, expression of iron uptake systems and other virulence determinants is controlled by the Fur regulatory protein. DNA hybridization analysis revealed that both pigmented and nonpigmented cells of Y. pestis possess a DNA locus homologous to the Escherichia coli fur gene. Introduction of a Fur-regulated beta-galactosidase reporter gene into Y. pestis KIM resulted in iron-responsive beta-galactosidase activity, indicating that Y. pestis KIM expresses a functional Fur regulatory protein. A cloned 1.9-kb ClaI fragment of Y. pestis chromosomal DNA hybridized specifically to the fur gene of E. coli. The coding region of the E. coli fur gene hybridized to a 1.1-kb region at one end of the cloned Y. pestis fragment. The failure of this clone to complement an E. coli fur mutant suggests that the 1.9-kb clone does not contain a functional promoter. Subcloning of this fragment into an inducible expression vector restored Fur regulation in an E. coli fur mutant. In addition, a larger 4.8-kb Y. pestis clone containing the putative promoter region complemented the Fur- phenotype. These results suggest that Y. pestis possesses a functional Fur regulatory protein capable of interacting with the E. coli Fur system. In Y. pestis Fur may regulate the expression of iron transport systems and other virulence factors in response to iron limitation in the environment. Possible candidates for Fur regulation in Y. pestis include genes involved in ferric iron transport as well as hemin, heme/hemopexin, heme/albumin, ferritin, hemoglobin, and hemoglobin/haptoglobin utilization.
Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(iii) ylides (2016)

Synthesis of non-activated electron-rich and sterically hindered <sup>18</sup>F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(III) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [<sup>18</sup>F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(III) can be modeled well by appropriately selected dispersion-corrected density functional methods. Modeling of the reaction pathways show that fluoride-iodonium(III) adduct intermediates are strongly activated and highly regioselective for reductive elimination of the desired [<sup>18</sup>F]fluoroarenes (difference in barriers, ΔΔ<i>G</i><sup>‡</sup> > 25 kcal·mol<sup>-1</sup>). The advantage of spirocyclic auxiliaries is further supported by NMR spectroscopy studies, which bolster evidence for underlying decomposition processes which can be overcome for radiofluorination of iodonium(III) precursors. Using a novel adamantyl auxiliary, sterically hindered iodonium ylides have been developed to enable highly efficient radiofluorination of electron-rich arenes, including fragments of pharmaceutically relevant nitrogen-containing heterocycles and tertiary amines. Furthermore, this methodology has been applied for the syntheses of the radiopharmaceuticals 6-[<sup>18</sup>F]fluoro-<i>meta</i>-tyrosine ([<sup>18</sup>F]FMT, 11 ± 1% isolated radiochemical yield, non-decay-corrected (RCY, n.d.c.; <i>n</i> = 3), and <i>meta</i>-[<sup>18</sup>F]fluorobenzylguanidine ([<sup>18</sup>F]mFBG, 14 ± 1% isolated RCY, n.d.c., <i>n</i> = 3) which cannot be directly radiolabeled using conventional nucleophilic aromatic substitution with [<sup>18</sup>F]fluoride.
Bacillus megaterium spore protease: purification, radioimmunoassay, and analysis of antigen level and localization during growth, sporulation, and spore germination (1982)

The protease which initiates the massive protein degradation early in bacterial spore germination has been purified from Bacillus megaterium spores. The enzyme has a molecular weight of 160,000 and contains four apparently identical subunits, but only the tetramer is enzymatically active. A radioimmunoassay has been developed for this enzyme and has been used to show that the protease is absent from growing cells, but appears early in sporulation within the developing forespore. In contrast, the protease antigen disappears rapidly during spore germination, in parallel with the loss in enzyme activity.
Isolation and characterization of temperature-sensitive RNA polymerase II mutants of Saccharomyces cerevisiae. (1987)

Three independent, recessive, temperature-sensitive (Ts-) conditional lethal mutations in the largest subunit of Saccharomyces cerevisiae RNA polymerase II (RNAP II) have been isolated after replacement of a portion of the wild-type gene (RPO21) by a mutagenized fragment of the cloned gene. Measurements of cell growth, viability, and total RNA and protein synthesis showed that rpo21-1, rpo21-2, and rpo21-3 mutations caused a slow shutoff of RNAP II activity in cells shifted to the nonpermissive temperature (39 degrees C). Each mutant displayed a distinct phenotype, and one of the mutant enzymes (rpo21-1) was completely deficient in RNAP II activity in vitro. RNAP I and RNAP III in vitro activities were not affected. These results were consistent with the notion that the genetic lesions affect RNAP II assembly or holoenzyme stability. DNA sequencing revealed that in each case the mutations involved nonconservative amino acid substitutions, resulting in charge changes. The lesions harbored by all three rpo21 Ts- alleles lie in DNA sequence domains that are highly conserved among genes that encode the largest subunits of RNAP from a variety of eucaryotes; one mutation lies in a possible Zn2+ binding domain.
Maternal or Paternal Exposure to Cannabinoids Affects Central Neurotransmitter Levels and Reproductive Function in Male Offspring (1999)

A single prenatal exposure to cannabinol or cannabidiol reduced brain norepinephrine and dopamine and hypothalamic NE concentrations, but increased brain levels of serotonin and its metabolite, 5-hydroxyindoleacetic acid. In addition, testicular testosterone concentrations and seminal vesicles weights were reduced in animals exposed to CBN. In contrast, seminal vesicles weights were increased in CBD-exposed males. Prenatal exposure to the major psychoactive component of marihuana, δ9-tetrahydrocannabinol on one of the last four days of gestation did not affect these parameters. The F1 male offspring of male mice treated with CBN, CBD, or THC presented evidence of reduced fertility and testicular chromosomal abnormalities. In addition, two of the F1 male offspring of the THC-treated mice sired litters containing pups with severe congenital malformations. These findings indicate that maternal or paternal exposure to cannabinoids can influence developmental and reproductive functions in offspring. Thus, cannabinoids appear to be both mutagenic and teratogenic in mice.
Enamel matrix, cementum development and regeneration (1997)

Studies during the last 20 years have indicated that enamel-related proteins are involved in the formation of cementum. In the present article, this relation is further explored. Attention is called to the fact that coronal acellular extrinsic fiber cementum is formed on the enamel surface in a number of species. The composition of the enamel matrix proteins and the expression of these proteins during root formation are briefly reviewed. The dominating constituent of the enamel matrix, amelogenin, is shown by means of immunohistochemistry to be expressed in human teeth during root formation. Amelogenin was also found to be present in Tomes' granular layer of human teeth. When mesenchymal cells of the dental follicle were exposed to the enamel matrix a non-cellular hard tissue matrix was formed at the enamel surface. Application of porcine enamel matrix in experimental cavities in the roots of incisors of monkeys induced formation of acellular cementum that was well attached to the dentin. In control cavities without enamel matrix, a cellular, poorly attached hard tissue was formed. The present studies provide additional support to the idea that enamel matrix proteins are involved in the formation of acellular cementum and also that they have the potential to induce regeneration of the same type of cementum.
Angiotensin II Type 1 Receptor–Mediated Peroxide Production in Human Macrophages (1999)

Our previous experiments demonstrated upregulation of the renin-angiotensin system in macrophages, including angiotensin II type 1 (AT1) and type 2 (AT2) receptors, during transformation from monocytes. We investigated the role of angiotensin II in oxidative stress of monocytes/macrophages, which plays a role in the advance of atherosclerosis. THP1, a human monocytic leukemia cell line, was differentiated to macrophages by adding of phorbol 12-myristate 13-acetate for 24 hours. The intracellular production of peroxide was measured by a cytofluorometric assay with 2', 7'-dichlorofluorescein-diacetate with a flow cytometer scan. Peroxide was detected in monocytes and upregulated during the transformation to macrophages by 3.18+/-0.52 times in relative fluorescein of peak value (P<0.01). Angiotensin II (1 micromol/L) induced oxidative stress in macrophages, with the peak at 15 minutes by 451+/-223%, and returned to the control level within 1 hour. EC50 was 5.4x10(-9) mol/L. AT1 antagonist (CV11974, 1 micromol/L) significantly decreased angiotensin II-induced oxidative stress in macrophages, but AT2 antagonist (PD123319, 1 micromol/L) did not. Of interest, AT1 antagonist also decreased basal levels of peroxide production in macrophages in a dose-dependent manner. These results suggest that upregulation of the expression of AT1 receptor in macrophages contributes in part to upregulation of peroxide production. AT1 receptor antagonists may be useful to suppress oxidative stress of macrophages in atherosclerotic lesions.
Naturally processed and concealed HLA‐A2.1‐restricted epitopes from tumor‐associated antigen tyrosinase‐related protein‐2 (2000)

In this study, a computer-assisted reverse immunology approach was utilized in order to identify potentially antigenic peptides derived from the differentiation antigen TRP-2, a melanosomal protein frequently expressed in melanoma. Among the seven peptides complying with HLA-A2.1-binding motifs, two induced specific CD8+ cytotoxic T lymphocytes. HLA-A2.1+ melanoma cells expressing TRP-2 were lysed by clones specific for TRP-2360–368 (TLDSQVMSL) peptide, thus identifying it as a naturally processed epitope. Other T-cell clones directed against TRP-2476–484 (VMGTLVALV) were unable to lyse HLA-matched TRP-2+ cell lines. The role of intracellular proteolytic processing in the generation of this epitope was investigated by transfecting mini-genes encoding the TRP-2476–484 peptide alone or carrying N- or C-terminal extensions. Specific T-cell clones recognized target cells expressing the cytotoxic T-lymphocyte (CTL)-defined epitope or its C-terminally extended precursor, but failed to recognize cells expressing the N-terminally extended TRP-2476–484 peptide, suggesting the presence of a negative processing signal (NPS). Regarding C-terminus-flanking regions, mutational analysis indicates that the GLY485 residue plays a key role in the processing of the TRP-2476–484 epitope. Interestingly, proteasome inhibitors preventing the generation of the MART-1/Melan-A27–35 immunodominant melanoma tumor-associated antigen (TAA) promoted detectable presentation of TRP-2476–484 epitope in HLA-A2.1+ and TRP-2+ tumor lines, as witnessed by cytokine release by specific T-cell clones. Int. J. Cancer 87:241–246, 2000. © 2000 Wiley-Liss, Inc.
Therapeutic PD-1 Pathway Blockade Augments with Other Modalities of Immunotherapy T-Cell Function to Prevent Immune Decline in Ovarian Cancer (2013)

The tumor microenvironment mediates induction of the immunosuppressive programmed cell death-1 (PD-1) pathway, and targeted interventions against this pathway can help restore antitumor immunity. To gain insight into these responses, we studied the interaction between PD-1 expressed on T cells and its ligands (PD-1:PD-L1, PD-1:PD-L2, and PD-L1:B7.1), expressed on other cells in the tumor microenvironment, using a syngeneic orthotopic mouse model of epithelial ovarian cancer (ID8). Exhaustion of tumor-infiltrating lymphocytes (TIL) correlated with expression of PD-1 ligands by tumor cells and tumor-derived myeloid cells, including tumor-associated macrophages (TAM), dendritic cells, and myeloid-derived suppressor cells (MDSC). When combined with GVAX or FVAX vaccination (consisting of irradiated ID8 cells expressing granulocyte macrophage colony-stimulating factor or FLT3 ligand) and costimulation by agonistic α-4-1BB or TLR 9 ligand, antibody-mediated blockade of PD-1 or PD-L1 triggered rejection of ID8 tumors in 75% of tumor-bearing mice. This therapeutic effect was associated with increased proliferation and function of tumor antigen-specific effector CD8(+) T cells, inhibition of suppressive regulatory T cells (Treg) and MDSC, upregulation of effector T-cell signaling molecules, and generation of T memory precursor cells. Overall, PD-1/PD-L1 blockade enhanced the amplitude of tumor immunity by reprogramming suppressive and stimulatory signals that yielded more powerful cancer control.
Transcriptome-Wide Assessment of Human Brain and Lymphocyte Senescence (2008)

Results affirm that deteriorating mitochondrial gene expression is a common theme in senescence, but also highlight novel pathways and features of gene architecture that may be important for understanding the molecular consequences of aging.
Learning Phrase Representations using RNN Encoder-Decoder for Statistical Machine Translation (2014)

In this paper, we propose a novel neural network model called RNN Encoder-Decoder that consists of two recurrent neural networks (RNN). One RNN encodes a sequence of symbols into a fixed-length vector representation, and the other decodes the representation into another sequence of symbols. The encoder and decoder of the proposed model are jointly trained to maximize the conditional probability of a target sequence given a source sequence. The performance of a statistical machine translation system is empirically found to improve by using the conditional probabilities of phrase pairs computed by the RNN Encoder-Decoder as an additional feature in the existing log-linear model. Qualitatively, we show that the proposed model learns a semantically and syntactically meaningful representation of linguistic phrases.
MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias (2011)

Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers.
Peroxynitrite Decomposition with FeTMPyP Improves Plasma-Induced Vascular Dysfunction and Infarction during Mild but not Severe Hyperglycemic Stroke (2012)

We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA (n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)(A) (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP (n=12) or vehicle (n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma (P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA (P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.
Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection (2012)

Staphylococcus aureus is a frequent cause of skin infection and sepsis in humans. Preclinical vaccine studies with S. aureus have used a mouse model with intraperitoneal challenge and survival determination as a measure for efficacy. To appreciate the selection of protective antigens in this model, we sought to characterize the pathological attributes of S. aureus infection in the peritoneal cavity. Testing C57BL/6J and BALB/c mice, >10(9) CFU of S. aureus Newman were needed to produce a lethal outcome in 90% of animals infected via intraperitoneal injection. Both necropsy and histopathology revealed the presence of intraperitoneal abscesses in the vicinity of inoculation sites. Abscesses were comprised of fibrin as well as collagen deposits and immune cells with staphylococci replicating at the center of these lesions. Animals that succumbed to challenge harbored staphylococci in abscess lesions and in blood. The establishment of lethal infections, but not the development of intraperitoneal abscesses, was dependent on S. aureus expression of alpha-hemolysin (Hla). Active immunization with nontoxigenic Hla(H35L) or passive immunization with neutralizing monoclonal antibodies protected mice against early lethal events associated with intraperitoneal S. aureus infection but did not affect the establishment of abscess lesions. These results characterize a mouse model for the study of intraperitoneal abscess formation by S. aureus, a disease that occurs frequently in humans undergoing continuous ambulatory peritoneal dialysis for end-stage renal disease.
A computer algorithm to determine the recognition site of restriction enzymes (1987)

A new algorithm is proposed to determine the type-II restriction endonucleases' recognition site knowing the digested DNA sequence and fragment lengths in an actual case. The algorithm is implemented for the Commodore 64 microcomputer.
Context-Dependent Hormone-Refractory Progression Revealed through Characterization of a Novel Murine Prostate Cancer Cell Line (2005)

Insights into the molecular basis of hormone-refractory prostate cancer have principally relied on human prostate cancer cell lines, all of which were derived from patients who had already failed hormonal therapy. Recent progress in developing genetically engineered mouse prostate cancer models provides an opportunity to isolate novel cell lines from animals never exposed to hormone ablation, avoiding any potential bias conferred by the selective pressure of the castrate environment. Here we report the isolation of such a cell line (Myc-CaP) from a c-myc transgenic mouse with prostate cancer. Myc-CaP cells have an amplified androgen receptor gene despite no prior exposure to androgen withdrawal and they retain androgen-dependent transgene expression as well as androgen-dependent growth in soft agar and in mice. Reexpression of c-Myc from a hormone-independent promoter rescues growth in androgen-depleted agar but not in castrated mice, showing a clear distinction between the molecular requirements for hormone-refractory growth in vitro versus in vivo. Myc-CaP cells represent a unique reagent for dissecting discreet steps in hormone-refractory prostate cancer progression and show the general utility of using genetically engineered mouse models for establishing new prostate cancer cell lines.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - management in adults. (2010)

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive hereditary diseases. The impairment of cortisol synthesis leads to excessive stimulation of the adrenal glands by adrenocorticotropic hormone (ACTH), adrenal hyperplasia, and excessive androgen synthesis. The syndrome is characterised by a considerable correlation between the genotype and the phenotype with the type of CYP21A2 gene mutation affecting the severity of 21-hydroxylase deficiency. The clinical manifestations of CAH in adults result from adrenocortical and adrenomedullary insufficiency, hyperandrogenism, and the adverse effects of glucocorticosteroids used for the treatment of the condition. Non-classic CAH may sometimes be asymptomatic. In patients with classic CAH obesity, hyperinsulinaemia, insulin resistance, and hyperleptinaemia are more often seen than in the general population. These abnormalities promote the development of metabolic syndrome and its sequelae, including endothelial dysfunction, and cardiovascular disease. Long-term glucocorticosteroid treatment is also a known risk factor for osteoporosis. Patients with CAH require constant monitoring of biochemical parameters (17a-hydroxyprogesterone and androstenedione), clinical parameters (body mass, waist circumference, blood pressure, glucose, and lipids), and bone mineral density by densitometry. The principal goal of treatment in adults with CAH is to improve quality of life, ensure that they remain fertile, reduce the manifestations of hyperandrogenisation in females, and minimise the adverse effects of glucocorticosteroid treatment. Patients with classic CAH require treatment with glucocorticosteroids and, in cases of salt wasting, also with a mineralocorticosteroid. Radical measures, such as bilateral adrenalectomy, are very rarely needed. Asymptomatic patients with non-classic CAH require monitoring: treatment is not always necessary. Medical care for patients with CAH should be provided by reference centres, as the management of such patients requires collaboration between an endocrinologist, diabetologist, gynaecologist, andrologist, urologist, and psychologist.