gebhart/patrepeval huggingface dataset:
Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. (2000)

Matrix metalloproteinases (MMPs) are known to play an important role in cancer cell invasion by mediating the degradation of extracellular matrix proteins. The activity of such MMPs are regulated by tissue inhibitors of metalloproteinases (TIMPs). In this study, we investigated the immunohistochemical expression of MMP-2, MT1-MMP, TIMP-2, MMP-9, and TIMP-1 in 114 epithelial ovarian tumors (14 adenomas, 22 borderline tumors, and 78 adenocarcinomas). mRNA expression of MMP-2, MT1-MMP, and TIMP-2 was determined by RT-PCR in selected samples. The diffuse positive rates of MMP-2, MT1-MMP, TIMP-2, and MMP-9 in ovarian carcinomas were significantly higher than those in the borderline and in benign tumors. Conversely, the diffuse positive rate of TIMP-1 was higher in the benign and borderline ovarian tumors than that in ovarian carcinomas. The percentages of the cases with triple diffuse positive expression for MMP-2, MT1-MMP, and TIMP-2 within the same tumor was significantly higher in malignant tumors than those in borderline and in benign tumors. With respect to clinical stage, the triple diffuse positive rate in advanced-stage (stage II/III/IV) carcinomas was significantly higher than that in early-stage (stage I) carcinomas. A significantly higher triple diffuse positive rate was also observed in high-grade (grade 2/3) disease than in low-grade (grade 1) disease. Considerable levels of mRNA expression of MMP-2, MT1-MMP and TIMP-2 were detected in all selected samples that showed triple diffuse positive immunostaining, confirming the co-expression of MMP-2, MT1-MMP, and TIMP-2 at the transcriptional level within the same tumor. All cases with diffuse positive expression for MMP-9 showed regional or negative TIMP-1 expression. The diffuse positive rate of MMP-9 was significantly higher in ovarian carcinomas with lymph node metastasis than in those without lymph node metastasis. Our results suggest that the overexpression of MMP-2, MT1-MMP, TIMP-2, and MMP-9 and down-regulation of TIMP-1 may contribute to the development or enhanced growth capacity of ovarian tumors. Co-expression of MMP-2, MT1-MMP, and TIMP-2 within the same tumor seems to play an important role in the progression of ovarian cancer. Elevated MMP-9 expression together with low expression of TIMP-1 may also contribute to the lymph node metastasis of ovarian carcinoma cells.
Optical Biopsy of Lymph Node Morphology using Optical Coherence Tomography (2005)

Optical diagnostic imaging techniques are increasingly being used in the clinical environment, allowing for improved screening and diagnosis while minimizing the number of invasive procedures. Diffuse optical tomography, for example, is capable of whole-breast imaging and is being developed as an alternative to traditional X-ray mammography. While this may eventually be a very effective screening method, other optical techniques are better suited for imaging on the cellular and molecular scale. Optical Coherence Tomography (OCT), for instance, is capable of high-resolution cross-sectional imaging of tissue morphology. In a manner analogous to ultrasound imaging except using optics, pulses of near-infrared light are sent into the tissue while coherence-gated reflections are measured interferometrically to form a cross-sectional image of tissue. In this paper we apply OCT techniques for the high-resolution three-dimensional visualization of lymph node morphology. We present the first reported OCT images showing detailed morphological structure and corresponding histological features of lymph nodes from a carcinogen-induced rat mammary tumor model, as well as from a human lymph node containing late stage metastatic disease. The results illustrate the potential for OCT to visualize detailed lymph node structures on the scale of micrometastases and the potential for the detection of metastatic nodal disease intraoperatively.
Neuroinflammation in Alzheimer's Disease: Mechanisms, Pathologic Consequences, and Potential for Therapeutic Manipulation (2010)

The concept of neuroinflammation has evolved over the past two decades from an initially controversial viewpoint to its present status as a generally accepted idea whose mechanisms and consequences are still actively under research and debate, particularly with regard to Alzheimer's disease (AD). This review summarizes the current status of neuroinflammation research as it specifically relates to AD. Neuroinflammation is discussed mechanistically with emphasis on the role of redox signal transduction linked to the activation of central nervous system-relevant innate immune pathways. Redox signaling is presented both as a causal factor and a consequence of sustained neuroinflammation. Functional relationships are discussed that connect distinct neuroinflammatory components such as cytokines, eicosanoids, classic AD pathology (amyloid plaques and neurofibrillary tangles), and the recently emergent notion of "damage-associated molecular patterns". The interaction of these paracrine factors likely can produce positive as well as negative effects on the AD brain, ranging from plaque clearance by microglia in the short term to glial dysfunction and neuronal compromise if the neuroinflammation is chronically sustained and unmitigated. Recent disappointments in AD clinical trials of anti-inflammatory drugs are discussed with reference to possible explanations and potential avenues for future pharmacological approaches to the disease.
An efficient asymmetric synthesis of enigmols (1-deoxy-5-hydroxysphingoid bases), an important class of bioactive lipid modulators (2010)

An enantioselective synthesis of the four 2S-diastereomers of enigmol (2-amino-octadecane-3,5diols) from L-alanine is reported. The procedure described is robust, highly stereoselective at each step, and suitable for preparation of gram quantities of material.
Killing of Giardia lamblia by human milk is mediated by unsaturated fatty acids (1986)

Giardia lamblia trophozoites were killed in vitro by 1% fresh human milk in the presence of bile. A similar effect was achieved in the absence of bile with milk which had been stored for at least 24 h at 6 degrees C. This killing activity was found to be caused by unsaturated fatty acids. Depending on their chain length and the number of double bonds, the concentrations of unsaturated fatty acids required for a 50% killing effect varied between 15 and 36 microM. The saturated palmitic and stearic acids, as well as various substances related to fatty acids, showed only a slight killing effect. Bile enhanced and serum suppressed the action of fatty acids on the protozoan parasite. The possible site of interference of unsaturated fatty acids within G. lamblia and the reasons for the obvious inefficacy of dietary fatty acids in giardiasis are discussed.
A protein derived from the fusion of TAT peptide and FNK, a Bcl‐xL derivative, prevents cochlear hair cell death from aminoglycoside ototoxicity in vivo (2007)

We constructed a powerful artificial cytoprotective protein, FNK, from an antiapoptotic member of the BCL-2 family, Bcl-x(L). To test the efficacy of FNK in protecting cochlear hair cells (HCs) from aminoglycoside-induced cell death in vivo, we fused FNK with protein transduction domain, TAT, of the HIV/Tat protein to construct a fusion protein of TAT-FNK. We demonstrated that, after an intraperitoneal administration to guinea pigs, TAT-myc-FNK protein was diffusely distributed in the cochlea, most prominently in the HCs and supporting cells, followed by the spiral ganglion cells, 3 hr after the injection. We next demonstrated that TAT-FNK attenuated cochlear damage induced by an ototoxic combination of kanamycin sulfate (KM) and ethacrynic acid (EA) administered at 2 different dosages: 400 mg/kg KM + 50 mg/kg EA and 200 mg/kg KM + 40 mg/kg EA. TAT-FNK or vehicle was intraperitoneally injected from 3 hr before through 5 hr after inducing the ototoxic insults, 14 days after which auditory brainstem response (ABR) and HC loss were evaluated. In comparison with vehicle-administered controls, the TAT-FNK protein significantly attenuated ototoxic drug-induced ABR threshold shifts and the extent of HC death at either dosage. The TAT-FNK protein also significantly reduced the amount of cleaved poly-(ADP-ribose) polymerase-positive HCs 8 hr after the ototoxic insults compared with that in the vehicle-administered controls. These findings indicate that systemically administered TAT-FNK was successfully delivered to the guinea pig cochlea and effectively prevented apoptotic cell death of the cochlear HCs induced by KM and EA.
Isolation of ORC6 , a Component of the Yeast Origin Recognition Complex by a One-Hybrid System (1993)

Here a method is described to identify genes encoding proteins that recognize a specific DNA sequence. A bank of random protein segments tagged with a transcriptional activation domain is screened for proteins that can activate a reporter gene containing the sequence in its promoter. This strategy was used to identify an essential protein that interacts in vivo with the yeast origin of DNA replication. Matches between its predicted amino acid sequence and peptide sequence obtained from the 50-kilodalton subunit of the yeast origin recognition complex (ORC) established that the gene isolated here, ORC6, encodes this subunit. These observations provide evidence that ORC recognizes yeast replication origins in vivo.
Engineered genetic information processing circuits (2013)

Cells implement functions through the computation of biological information that is often mediated by genetic regulatory networks. To reprogram cells with novel capabilities, a vast set of synthetic gene circuits has recently been created. These include simple modules, such as feedback circuits, feed-forward loops, ultrasensitive networks, band-pass filters, logic gate operators and others, with each carrying a specific information processing functionality. More advanced cellular computation can also be achieved by assembling multiple simple processing modules into integrated computational cores. Further, when coupled with other modules such as sensors and actuators, integrated processing circuits enable sophisticated biological functionalities at both intra- and intercellular levels. Engineered genetic information processing circuits are transforming our ability to program cells, offering us extraordinary opportunities to explore biological mechanisms and to address real-world challenges.
The Immunosuppressive Metabolite of Leflunomide Is a Potent Inhibitor of Human Dihydroorotate Dehydrogenase (1996)

The active metabolite of leflunomide. A771726, is a novel immunosuppressive compound that has been shown to be a powerful antiproliferative agent for mononuclear and T-cells. The molecular mechanism of action for this compound has not been clearly established. In vitro cellular and enzymatic assays, however, demonstrate that leflunomide is an inhibitor of several protein tyrosine kinases, with IC50 values between 30 and 100 microM. The in vivo properties of A771726 are reminiscent of another immunosuppressive agent, brequinar sodium, which has been shown to be a nonomolar inhibitor (Ki = 10-30 nM) of the enzyme dihydroorotate dehydrogenase (DHODase). On the basis, we have investigated the effects of leflunomide and A771726 on the activity of purified recombinant human DHODase. We find that A771726 is a potent inhibitor of DHODase (Ki = 179 +/- 19 nM), while the parent compound, leflunomide, had no inhibitory effect at concentrations as high as 1 microM. Studies of the dependence of inhibition on the concentrations of the substrates ubiquinone and dihydroorotate demonstrate that A771726 is a competitive inhibitor of the ubiquinone binding site and is noncompetitive with respect to dihydroorotate. The potency of A771726 as a DHODase inhibitor is thus 100-100-fold greater than that reported for its inhibition of protein tyrosine kinases. These data suggest that an alternative explanation for the immunosuppressive efficacy of A771726 may be the potent inhibition of DHODase by this compound.
Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema (2005)

Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-gamma, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-gamma-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-gamma uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-gamma caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-gamma-induced emphysema. These interventions also ameliorated IFN-gamma-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-gamma-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-gamma-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.
Origin, diversity, and maturation of human antiviral antibodies analyzed by high-throughput sequencing (2012)

Our understanding of how antibodies are generated and function could help develop effective vaccines and antibody-based therapeutics against viruses such as HIV-1, SARS coronavirus (SARS CoV), and Hendra and Nipah viruses (henipaviruses). Although broadly neutralizing antibodies (bnAbs) against the HIV-1 were observed in patients, elicitation of such bnAbs remains a major challenge when compared to other viral targets. We previously hypothesized that HIV-1 could have evolved a strategy to evade the immune system due to absent or very weak binding of germline antibodies to the conserved epitopes that may not be sufficient to initiate and/or maintain an effective immune response. To further explore our hypothesis, we used the 454 sequence analysis of a large naïve library of human IgM antibodies which had been used for selecting antibodies against SARS CoV receptor-binding domain (RBD), and soluble G proteins (sG) of henipaviruses. We found that the human IgM repertoires from the 454 sequencing have diverse germline usages, recombination patterns, junction diversity, and a lower extent of somatic mutation. In this study, we identified antibody maturation intermediates that are related to bnAbs against the HIV-1 and other viruses as observed in normal individuals, and compared their genetic diversity and somatic mutation level along with available structural and functional data. Further computational analysis will provide framework for understanding the underlying genetic and molecular determinants related to maturation pathways of antiviral bnAbs that could be useful for applying novel approaches to the design of effective vaccine immunogens and antibody-based therapeutics.
Protected gap closing in Josephson junctions constructed on Bi2Te3 surface (2018)

On the road of searching for Majorana zero modes (MZMs) in topological insulator-based Josephson junctions, a highly sought signature is the protected full transparency of electron transport through the junctions due to the existence of the MZMs, associated with complete gap closing between the electronlike and holelike Andreev bound states (ABSs). Here we present direct experimental evidence of gap closing and full transparency in single Josephson junctions constructed on the surface of three-dimensional topological insulator (3D TI) ${\mathrm{Bi}}_{2}{\mathrm{Te}}_{3}$. Our results demonstrate that the two-dimensional (2D) surface of 3D TIs provides a promising platform for hosting and manipulating MZMs.
13-cis-Retinoic Acid Plus Interferon -2a: Highly Active Systemic Theraphy for Squamous Cell Carcinoma of the Cervix (1992)

These preliminary results indicate that systemic 13-cRA plus IFN alpha-2a is a highly active, well-tolerated therapy for locally advanced cervical cancer.
Deep-level emissions in GaAsN∕GaAs structures grown by metal organic chemical vapor deposition (2007)

This work presents the deep-level photoluminescence of coherently strained GaAsN∕GaAs quantum-well (QW) structures with various GaAsN thicknesses and N contents. A broad deep-level emission at ∼1.1eV is observed, whose wavelength is redshifted as the GaAsN thickness increases. Based on its energy separation from the QW emission, this emission is attributed to a transition between the QW electron ground state and a deep level at ∼0.2eV above the GaAsN valence-band (VB) edge. This level is shown to be tied to the GaAs band edge. A transition between this level and the GaAs conduction band allows the GaAsN–GaAs band alignment to be evaluated. A type II band lineup is obtained with VB offsets of 0.03 and 0.002eV for N=0.6% and 1.8%, respectively. The decreased VB offset suggests a transition from type II to type I with increasing N content. Thermal annealing effectively removes this level and improves the QW emission. The concentration of this level is not clearly correlated with N content, suggesting that this level is induced by a low-temperature growth of the GaAsN layer to suppress the composition fluctuation. Given its energy, this level is tentatively assigned to VGa.
A functional bone morphogenetic protein system in the ovary (1999)

Bone morphogenetic proteins (BMPs) comprise a large group of polypeptides in the transforming growth factor beta superfamily with essential physiological functions in morphogenesis and organogenesis in both vertebrates and invertebrates. At present, the role of BMPs in the reproductive system of any species is poorly understood. Here, we have established the existence of a functional BMP system in the ovary, replete with ligand, receptor, and novel cellular functions. In situ hybridization histochemistry identified strong mRNA labeling for BMP-4 and -7 in the theca cells and BMP receptor types IA, IB, and II in the granulosa cells and oocytes of most follicles in ovaries of normal cycling rats. To explore the paracrine function of this BMP system, we examined the effects of recombinant BMP-4 and -7 on FSH (follicle-stimulating hormone)-induced rat granulosa cytodifferentiation in serum-free medium. Both BMP-4 and -7 regulated FSH action in positive and negative ways. Specifically, physiological concentrations of the BMPs enhanced and attenuated the stimulatory action of FSH on estradiol and progesterone production, respectively. These effects were dose- and time-dependent. Furthermore, the BMPs increased granulosa cell sensitivity to FSH. Thus, BMPs have now been identified as molecules that differentially regulate FSH-dependent estradiol and progesterone production in a way that reflects steroidogenesis during the normal estrous cycle. As such, it can be hypothesized that BMPs might be the long-sought "luteinization inhibitor" in Graafian follicles during their growth and development.
A Putative G Protein-Coupled Receptor, RDC1, Is a Novel Coreceptor for Human and Simian Immunodeficiency Viruses (2000)

More than 10 G protein-coupled receptors (GPCRs) have been shown to act as coreceptors for infection of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). We have isolated HIV-1 variants infectious to primary brain-derived CD4-positive cells (BT-3 and BT-20/N) and U87/CD4 glioma cells that are resistant to T-cell line-tropic (T-tropic), macrophage-tropic (M-tropic), and T- and M-tropic (dualtropic) (X4, R5, and R5X4) HIV-1 strains. These primary brain-derived cells were also highly susceptible to HIV-2(ROD), HIV-2(SBL6669), and SIV(mndGB-1). A factor or coreceptor that determines the susceptibility of these brain-derived cells to these HIV and SIV strains has not been fully identified. To identify this coreceptor, we examined amino acid sequences of all known HIV and SIV coreceptors and noticed that tyrosine residues are well conserved in their extracellular amino-terminal domains. By this criterion, we selected 18 GPCRs as candidates of coreceptors for HIV and SIV strains infectious to these brain-derived cells. mRNA expression of an orphan GPCR, RDC1, was detected in the brain-derived cells, the C8166 T-cell line, and peripheral blood lymphocytes, all of which are susceptible to HIV-1 variants, but not in macrophages, which are resistant to them. When a CD4-expressing cell line, NP-2/CD4, which shows strict resistance to infection not only with HIV-1 but also with HIV-2 or SIV, was transduced with the RDC1 gene, the cells became highly susceptible to HIV-2 and SIV(mnd) strains but to neither M- nor T-tropic HIV-1 strains. The cells also acquired a low susceptibility to the HIV-1 variants. These findings indicate that RDC1 is a novel coreceptor for several HIV-1, HIV-2, and SIV strains which infect brain-derived cells.
Prolonged Maintenance of the Corpus Luteum of the Ewe by Continuous Infusion of Luteinizing Hormone (1971)

Continuous intravenous infusion of purified ovine LH into intact normal ewes starting on day 10-12 after heat prolonged the life-span of corpora lutea (CL) to arbitrarily chosen times of 20, 25, or 30 days in 62% of the test animals. The weights and progesterone concentratlons of the maintained CL indicate that they were endocrinologically as active as corpora lutea from nontreated control ewes on days 9-13 of the estrous cycle. Infusion of LH was less effective in maintaining CL to day 20 when begun on days 13 and 14 after heat than when begun on day 12, and totally ineffective when initiated on day 15. Furthermore, CL were not maintained to day 25 if the infusions were discontinued on day 20, indicating that ovine corpora lutea require continuous support by luteotrophic substances. Since the reproductive and endocrine systems of the experimental ewes were intact and presumably functional, we conclude that the continual administration of a pituitary luteotrophin overcame the alleged luteolytic effect of the uterus of the normal ewe. The relative importance of the pituitary gland and the uterus in controlling the maintenance and regression of corpora lutea (CL) of ewes is controversial. Denamur et a!. (1966) concluded that the presence of the pituitary gland is required for luteal maintenance only during the latter portion of the estrous cycle. In contrast, Kaltenbach et a!. (1968a) reported that hypophyseal luteotrophic substances are indispensable