gebhart/patrepeval huggingface dataset:
Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches (2007)

During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer disease (AD). According to the most widely accepted hypothesis, production and aggregation of the amyloid beta (Abeta) peptide plays a key role in AD, and thus therapeutic interference with these processes is the subject of intense research. However, some important aspects of the disease mechanism are not yet fully understood. There is no consensus as yet on whether the disease acts through a loss- (LOF) or a gain-of-function (GOF) mechanism. While for many years, an increased production of Abeta42 was considered to be the prime culprit for the initiation of the disease process, and accordingly Abeta42 is elevated by AD-related presenilin(PS) mutations, recent data strongly suggest that PS mutations also lead to a LOF of PS towards a plethora of its substrates including amyloid precursor protein. How this PS LOF, especially decreased Abeta40 secretion due to mutant PS, impacts on the disease pathogenesis is yet to be elucidated. Secondly, vascular abnormalities--frequently observed to co-occur with AD--might also play a critical role in the initiation and aggravation of AD pathology given that the elimination of Abeta through a vascular route is an important brain Abeta clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. In this review, we will first focus on the important issue of a LOF versus a GOF mechanism for AD due to mutant PS, as well as on the possible role of vascular damage and reduced perfusion in AD. Special emphasis will be given to some of the AD mouse models that have helped to gain insights into the disease mechanism. Secondly, considering these mechanistic insights, we will discuss some therapeutic strategies which are currently in clinical or preclinical trials for AD.
Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders (2008)

Cannabidiol (CBD) is the main non-psychotropic component of the glandular hairs of Cannabis sativa. It displays a plethora of actions including anticonvulsive, sedative, hypnotic, antipsychotic, antiinflammatory and neuroprotective properties. However, it is well established that CBD produces its biological effects without exerting significant intrinsic activity upon cannabinoid receptors. For this reason, CBD lacks the unwanted psychotropic effects characteristic of marijuana derivatives, so representing one of the bioactive constituents of Cannabis sativa with the highest potential for therapeutic use.The present review reports the pharmacological profile of CBD and summarizes results from preclinical and clinical studies utilizing CBD, alone or in combination with other phytocannabinoids, for the treatment of a number of CNS disorders.
Femtosecond laser-induced formation of nanometer-width grooves on synthetic single-crystal diamond surfaces (2009)

We form periodic linear grooves in synthetic single-crystal diamond with femtosecond pulses at 800 nm. The grooves are 40 nm wide, 500 nm deep, up to 0.3 mm long, and have an average spacing of 146±7 nm. The grooves are perpendicular to the direction of the laser polarization and are formed below the threshold for ablation throughout the focal volume. The submicrometer periodicity is caused by interference between a laser-induced plasma and the incident laser beam, which locally enhances the field at the surface so the ablation threshold is exceeded. Using Raman spectroscopy we find that the structures retain the original diamond composition.
Is Cell-Free Fetal DNA From Maternal Blood Finally Ready for Prime Time? (2012)

See related article on page 890. Dr. Simpson is from the Florida International University, Miami, FL, and is Senior Vice President of Research and Global Programs with the March of Dimes Foundation, White Plains, NY; e-mail: [email protected]. Financial Disclosure Dr. Simpson has been an advisor to Bio Dx, Novartis, and Bayer.
Functional inhibition of retinoic acid response by dominant negative retinoic acid receptor mutants. (1993)

The diverse effects of retinoids on the development, growth, and homeostasis of vertebrate organisms are mediated in part by three distinct isoforms of retinoic acid receptors (RARs). These proteins, which are structurally and functionally closely related to thyroid hormone receptors and the oncogene product v-ErbA, regulate patterns of gene expression in target tissues. One approach to study the distinct effects of retinoic acid in cells is to subvert this activity of endogenous receptors by expression of dominant negative receptor derivatives. We demonstrate here that RAR alpha, RAR beta, and RAR gamma can be converted into potent negative transcriptional regulators that block wild-type RAR function. Furthermore, these mutant RARs, but not the wild-type receptors, actively repress the basal transcription level of target promoters. When expressed in transgenic mice, the most potent of these inhibitory receptor mutants is apparently able to disturb developmental processes by inducing a cleft palate in transgenic offspring.
Ultra-small-sample molecular structure detection using microslot waveguide nuclear spin resonance (2007)

We here report on the design of a planar microslot waveguide NMR probe with an induction element that can be fabricated at scales from centimeters to nanometers to allow analysis of biomolecules at nano- or picomole quantities, reducing the required amount of materials by several orders of magnitude. This device demonstrates the highest signal-to-noise ratio for a planar detector to date, measured by using the anomeric proton signal from a 15.6-nmol sample of sucrose. This probe had a linewidth of 1.1 Hz for pure water without susceptibility matching. Analysis of 1.57 nmol of ribonuclease-A shows high sensitivity in one- and two-dimensional NMR spectra. Along with reducing required sample volumes, this integrated geometry can be packed in parallel arrays and combined with microfluidic systems. Further development of this device may have broad implications not only for advancing our understanding of many intractable protein structures and their folding, molecular interactions, and dynamic behaviors, but also for high-sensitivity diagnosis of a number of protein conformational diseases.
IFN- γ Promotes Apoptosis of the Uterus and Placenta in Pregnant Rat and Human Cytotrophoblast Cells (2007)

Growth and development of placentas in all pregnancy periods and that of fetuses in late pregnancy were inhibited after administration of interferon-gamma (IFN-gamma). Apoptosis can be detected by TUNEL at the maternal-fetal interface during normal rat pregnancy. Apoptosis locations at the maternal-fetal interface changed according to the period of pregnancy. The results of immunohistochemistry and the DNA ladder assay showed that IFN-gamma could promote the apoptosis levels during the entire pregnancy, but it did not change the apoptosis locations. IFN regulatory factor-1 (IRF-1), FasL, and p53 expressions were modulated by IFN-gamma during the entire pregnancy. In vitro cell proliferation assay indicated that IFN-gamma could inhibit proliferation of human cytotrophoblast cells, and flow assay showed that this effect was mainly due to apoptosis induction. TUNEL and Hoechst staining also showed that IFN-gamma could induce apoptosis of human cytotrophoblast cells. Expression of IRF-1 was induced and expression of active caspase-3 was promoted by IFN-gamma treatment, but IFN-gamma did not affect the expression of IFNGR and p53.
Automated laser interferometric ellipsometry and precision reflectometry (1983)

A new opto-electronic ellipsometer operating on laser interferometric principles has been developed into an automated system based on a microprocessor. The latter performs the gain and offset calibrations and adjusts the various mode settings, followed by fast on-line data acquisition. Subsequently, data are processed via an interfaced minicomputer. The instrument is unique in providing absolute ellipsometric data. It permits perpendicular incidence ellipsometry, the handling of both vertically and horizontally mounted (liquid) samples, as well as precision reflectometry. Alignment is easily and quickly achieved because the signals are displayed on a cathode ray oscilloscope (CRO) screen. Some of the valuable features of this system are discussed in the light of results obtained in the visible spectrum.
ANTICOAGULANT EFFECTS OF SULPHATED POLYSACCHARIDES IN NORMAL AND ANTITHROMBIN III‐DEFICIENT PLASMAS (1980)

1 Comparison of the effects of sulphated polysaccharides on thrombin-induced clotting of normal and antithrombin III-deficient plasmas suggests the involvement of antithrombin III (AT III) in the anticoagulant activities of cellulose, dextran and xylan sulphates. 2 AT III appears to play little or no role in the anticoagulant activity of carrageenans.
Unknotting immersed surface-links and singular 2-dimensional braids by 1-handle surgeries (1999)

By a surface-link, we mean a closed oriented immersed surface F in the 4-space R whose singularities are transverse double points. An embedded surface-link is said to be unknotted if it bounds mutually disjoint handlebodies (possibly including 3-balls) in R. We define a surface-link with double points to be unknotted if it is obtained from an unknotted embedded surface-link by adding several pieces of trivial positive/negative kink, as illustrated in Fig. 1. A 3-ball h in R is called a 1-handle attached to F if F Π h is a pair of 2-disks on dh that is disjoint from the singularities of F; the surgery results an orientable surface, say F' (cf. [3, 9, 20]). We assign F' the orientation induced from that of F and consider it a surface-link. It is known that every embedded surface-link is transformed into an unknotted one by surgery along 1-handles (cf. [9]). (There are interesting researches on 1-handle surgeries for embedded surface-links in [3, 9, 10, 17, 18, 23].) This result is generalized to surface-links, which are not necessarily embedded.
Tumor Necrosis Factor α Decreases, and Interleukin-10 Increases, the Sensitivity of Human Monocytes to Dexamethasone: Potential Regulation of the Glucocorticoid Receptor (1999)

Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNFalpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNFalpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNFalpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbolmyristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNFalpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNFalpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNFalpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNFalpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNFalpha or IL-10 pretreatment; TNFalpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy.
The yeast I-Sce I meganuclease induces site-directed chromosomal recombination in mammalian cells. (1994)

Double-strand breaks in genomic DNA stimulate recombination. Until now it was not possible to induce in vivo site-directed double-strand breaks in a mammalian chromosomal target. In this article we describe the use of I-Sce I meganuclease, a very rare cutter yeast endonuclease, to induce site-directed double-strand breaks mediated recombination. The results demonstrate the potential of the I-Sce I system for chromosome manipulation in mammalian cells.
Brain activity at rest: a multiscale hierarchical functional organization (2011)

Spontaneous brain activity was mapped with functional MRI (fMRI) in a sample of 180 subjects while in a conscious resting-state condition. With the use of independent component analysis (ICA) of each individual fMRI signal and classification of the ICA-defined components across subjects, a set of 23 resting-state networks (RNs) was identified. Functional connectivity between each pair of RNs was assessed using temporal correlation analyses in the 0.01- to 0.1-Hz frequency band, and the corresponding set of correlation coefficients was used to obtain a hierarchical clustering of the 23 RNs. At the highest hierarchical level, we found two anticorrelated systems in charge of intrinsic and extrinsic processing, respectively. At a lower level, the intrinsic system appears to be partitioned in three modules that subserve generation of spontaneous thoughts (M1a; default mode), inner maintenance and manipulation of information (M1b), and cognitive control and switching activity (M1c), respectively. The extrinsic system was found to be made of two distinct modules: one including primary somatosensory and auditory areas and the dorsal attentional network (M2a) and the other encompassing the visual areas (M2b). Functional connectivity analyses revealed that M1b played a central role in the functioning of the intrinsic system, whereas M1c seems to mediate exchange of information between the intrinsic and extrinsic systems.
ATP-independent loading of the proliferating cell nuclear antigen requires DNA ends. (1993)

The proliferating cell nuclear antigen (PCNA) is a processivity subunit for eukaryotic DNA polymerase delta. We present biochemical evidence that yeast PCNA likely adopts a toroidal structure containing an inside cavity through which double-stranded DNA slides. A comparative study of DNA replication reactions on circular versus linear model substrates shows that PCNA can only interact productively with DNA polymerase delta if the substrate is linear. This combined with the observation that a large molar excess of PCNA is required for maximal stimulatory activity is consistent with a model in which PCNA slips onto the end of the DNA in an ATP-independent manner.
Experimental Models of Inflammatory Bowel Diseases (2015)

The understanding of the intestinal inflammation occurring in the inflammatory bowel diseases (IBD) has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD studies has been enabled by our improved knowledge of mucosal immunity and thus our improved ability to interpret the complex responses of mice with various causes of colitis; in addition, it has been powered by the availability of models in which the mice have specific genetic and/or immunologic defects that can be related to the origin of the inflammation. Finally, and more recently, it has been enhanced by our newly acquired ability to define the intestinal microbiome under various conditions and thus to understand how intestinal microorganisms impact on inflammation. In this brief review of murine models of intestinal inflammation we focus mainly on the most often used models that are, not incidentally, also the models that have yielded major insights into IBD pathogenesis.
Pregnancy‐associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer (2014)

Aberrant mitosis is a common feature of cancer, yet little is known about the altered genes causing mitotic defects. We screened human tumours for cells with morphological signatures of highly specific mitotic defects previously assigned to candidate genes in a genome-wide RNA interference screen carried out in HeLa cells (www.mitocheck.org). We discovered a striking enrichment of early mitotic configurations indicative of prophase/prometaphase delay in breast cancer. Promoter methylation analysis of MitoCheck candidate genes assigned to the corresponding 'mitotic delay' class linked this defect to epigenetic silencing of the gene encoding pregnancy-associated plasma protein-A (PAPPA), a secreted protease. PAPPA silencing was highly prevalent in precursor lesions and invasive breast cancer. Experimental manipulation of PAPPA protein levels in human mammary epithelial cells and in breast cancer cell lines demonstrates that progression through early mitosis is dependent on PAPPA function, and that breast cancer cells become more invasive after down-regulation of this protease. PAPPA regulates mitotic progression through modulating the IGF-1 signalling pathway resulting in activation of the forkhead transcription factor FoxM1, which drives a transcriptional cluster of essential mitotic genes. Our results show that PAPPA has a critical function in normal cell division and is targeted early in breast cancer development.
The induction of hair follicle formation in the adult hooded rat by vibrissa dermal papillae (1970)

ABSTRACT Hair follicles are essentially composed of two tissues. The inner epidermal component, which gives rise to, among other products, the keratinized hair shaft, is confluent with the surface epidermis and is ensheathed by the dermal component which is confluent with the pars papillaris of the dermis.
Reduction of the Shupe effect in fibre optic gyros;the random-wound coil (1996)

A method for reducing the Shupe effect in fibre-optic gyros is described, and verified experimentally. The unbalanced phase shifts in the gyro Sagnac intereferometer that are produced by a traversing temperature gradient are randomised by winding the coil in such a way as to scramble the relative positions of the turns.
Modified selective mapping scheme with low complexity for minimizing high peak-average power ratio in orthogonal frequency division multiplexing system (2016)

Selected mapping based orthogonal frequency division multiplexing system (OFDM) for the reduction of peak to average power ratio (PAPR) using higher number of novel phase sequences under 32-QAM
Ventilation-perfusion studies and the diagnosis of pulmonary embolism: concise communication. (1980)

Various diagnostic strategies for the assessment of pulmonary embolism were developed using the results of scintigraphic examinations in 169 patients who had both scintigraphic studies and pulmonary angiography. Likelihood ratios for several perfusion and ventilation-perfusion patterns were first obtained, and Bayes' Theorem was then applied using a range of prior probabilities for pulmonary embolism. Resulting posterior probabilities ranged from under 10% to over 90%. The former values held for patients with small perfusion defects and no ventilation study, regardless of their prior probabilities for pulmonary embolism. The latter values held for patients with average to high prior probabilities and ventilation-perfusion mismatches.
Thrombophilic state in cancer, Part I: Biology, incidence, and risk factors (2011)

The association between malignancy and thrombosis has long been appreciated but remains incompletely understood. This is the first of a two-part review of the complex, integral relationship between these two entities, and addresses the mechanisms and pathogenesis of this relationship and the clinical risk factors for thromboembolism in cancer patients.
Asymmetry of magnetic-field profiles in superconducting strips (2005)

We analyze the magnetic-field profiles ${H}_{z}(x)$ at the upper (lower) surface of a superconducting strip in an external magnetic field, with $z$ perpendicular to the plane of the strip and $x$ along its width. The external magnetic field ${H}_{a}$ is perpendicular or inclined to the plane of the strip. We show that an asymmetry of the profiles ${H}_{z}(x)$ appears in an oblique magnetic field ${H}_{a}$ and also in the case when the angular dependence of the critical current density ${j}_{c}$ in the superconductor is not symmetric relative to the $z$ axis. The asymmetry of the profiles is related to the difference $\ensuremath{\Delta}{H}_{z}(x)$ of the magnetic fields at the upper and lower surfaces of the strip, which we calculate. Measurement of this difference or, equivalently, of the asymmetry of the profiles can be used as a new tool for investigation of flux-line pinning in superconductors.
Galactose transport in Salmonella typhimurium (1977)

We have studied the various systems by which galactose can be transported in Salmonella typhimurium, in particular the specific galactose permease (GP). Mutants that contain GP as the sole galactose transport system have been isolated, and starting from these mutants we have been able to select point mutants that lack GP. The galP mutation maps close to another mutation, which results in the constitutive synthesis of GP, but is not linked to galR. Growth of wild-type strains on glaactose induces GP but not the beta-methylgalactoside permease (MGP). Strains lacking GP are able to grow slowly on galactose, and MGP is induced; however, D-fucose is a much better inducer of MGP. Induction of GP or MGP is not prevented by a pts mutation, although this mutation changes the apparent Km of MGP for galactose. pts mutations have no effect on GP. GP has a rather broad specificity: galactose, glucose, mannose, fucose, 2-deoxygalactose, and 2-deoxyglucose are substrates, but only galactose and fucose can induce this transport system.
Structure of an α‐2,6‐sialylated lipooligosaccharide from Neisseria meningitidis immunotype L1 (1998)

The recent cloning of the lipooligosaccharide (LOS) a-2,3-sialyltransferase from Neisseria meningitidis immunotype L3 permitted us to examine other immunotypes for this structural gene. We identified the gene and measured the enzyme activity in the L1 immunotype strain which had previously been reported to lack sialic acid in its LOS because it contains a terminal alpha-linked galactose which was thought not to be an acceptor for the sialyltransferase. This finding prompted us to re-examine the structure of the LOS from the L1 immunotype, which revealed the presence of sialic acid on the terminal alpha-linked galactose. Oligosaccharides derived from the LOS were shown to be sialylated by composition and methylation analysis, mass spectrometry and nuclear magnetic resonance. The detailed structural analysis showed the sialic acid to occur only at 06 of the terminal a-D-galactopyranose residue of the alpha-D-Gal-1,4-beta-D-Gal-1,4-beta-D-glc trisaccharide (Pk epitope) chain of the LOS, in the alpha-D configuration. These data are the first report of a alpha-2,6-linked sialic acid in a bacterial LOS or lipopolysaccharide, and also the first report of a sialylated Pk epitope.