gebhart/patrepeval huggingface dataset:
24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux (2006)

Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose-and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10 -20-fold higher basal LXR and - expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.
Insertion of 2 kb of bacteriophage DNA between an immunoglobulin promoter and leader exon stops somatic hypermutation in a κ transgene (1997)

Somatic hypermutation in rearranged immunoglobulin variable genes occurs in a 2kb region of DNA that is delimited on the 5' side by the promoter and on the 3' side by intron DNA. To identify sequence features that activate the mutation mechanism, we increased the distance between the promoter and the leader region to test whether the spacing of these elements was important. The promoter was separated from the leader sequence by inserting a 2 kb fragment of noncoding bacteriophage lambda DNA between the TATA box and ATG initiator codon in a kappa transgene. Mice from three founder lines were immunized, RNA and DNA were isolated from spleen and Peyer's patch B cells, and transcription of the transgene was confirmed. The frequency of mutation in endogenous heavy chain genes was high, indicating that some B cells underwent hypermutation. However, no hypermutation was found in the transgenic bacteriophage or variable region sequences. Hypermutation did occur in another kappa transgene that had a deletion of the VJ coding sequence, showing that the basic construct is functional and that the VJ exon is not necessary for the mutation mechanism. It is likely that the bacteriophage sequence is a potential substrate for mutation because other heterologous sequences have been shown to undergo mutation if placed downstream of the leader exon. The results suggest that the promoter should be contiguous with the leader exon for the mutation mechanism to function.
Soft Tissue Fixation to Bone (1994)

The initial fixation strengths of two spiked-washer designs were evaluated using human femurs and fascia lata tissue. Fascia lata was attached to the femur using the fixation devices, and then each femur-washer-fascia lata complex was loaded in tension to failure. Load-elongation curves were recorded, the initial failure load, initial failure displacement, stiffness, ultimate load, and ultimate displacement were determined for each test, and failure modes were recorded. Results indicated that the 6-spike design provided superior initial fixation strength in the 19-mm diameter size. This washer design was then compared with two commercially available fixation devices: the spiked AO washer and soft tissue fixation plate. Fixation provided by the prototypal washer design was not different in most instances from that provided by the AO fixation devices. Based on these results, important design characteristics for soft tissue spiked washers are identified and discussed.
From micro to nano contacts in biological attachment devices (2003)

Animals with widely varying body weight, such as flies, spiders, and geckos, can adhere to and move along vertical walls and even ceilings. This ability is caused by very efficient attachment mechanisms in which patterned surface structures interact with the profile of the substrate. An extensive microscopic study has shown a strong inverse scaling effect in these attachment devices. Whereas microm dimensions of the terminal elements of the setae are sufficient for flies and beetles, geckos must resort to sub-microm devices to ensure adhesion. This general trend is quantitatively explained by applying the principles of contact mechanics, according to which splitting up the contact into finer subcontacts increases adhesion. This principle is widely spread in design of natural adhesive systems and may also be transferred into practical applications.
Dissociation of Antimicrobial and Hemolytic Activities in Cyclic Peptide Diastereomers by Systematic Alterations in Amphipathicity (1999)

We have investigated the role of amphipathicity in a homologous series of head-to-tail cyclic antimicrobial peptides in efforts to delineate features resulting in high antimicrobial activity coupled with low hemolytic activity (i.e. a high therapeutic index). The peptide GS14, cyclo(VKLKVd-YPLKVKLd-YP), designed on the basis of gramicidin S (GS), exists in a preformed highly amphipathic beta-sheet conformation and was used as the base compound for this study. Fourteen diastereomers of GS14 were synthesized; each contained a different single enantiomeric substitution within the framework of GS14. The beta-sheet structure of all GS14 diastereomers was disrupted as determined by CD and NMR spectroscopy under aqueous conditions; however, all diastereomers exhibited differential structure inducibility in hydrophobic environments. Because the diastereomers all have the same composition, sequence, and intrinsic hydrophobicity, the amphipathicity of the diastereomers could be ranked based upon retention time from reversed-phase high performance liquid chromatography. There was a clear correlation showing that high amphipathicity resulted in high hemolytic activity and low antimicrobial activity in the diastereomers. The latter may be the result of increased affinity of highly amphipathic peptides to outer membrane components of Gram-negative microorganisms. The diastereomers possessing the most favorable therapeutic indices possessed some of the lowest amphipathicities, although there was a threshold value below which antimicrobial activity decreased. The best diastereomer exhibited 130-fold less hemolytic activity compared with GS14, as well as greatly increased antimicrobial activities, resulting in improvement in therapeutic indices of between 1,000- and 10,000-fold for a number of microorganisms. The therapeutic indices of this peptide were between 16- and 32-fold greater than GS for Gram-negative microorganisms and represents a significant improvement in specificity over GS. Our findings show that a highly amphipathic nature is not desirable in the design of constrained cyclic antimicrobial peptides and that an optimum amphipathicity can be defined by systematic enantiomeric substitutions.
Translational Inhibition in Vitro of Human Papillomavirus Type 16 L2 mRNA Mediated through Interaction with Heterogenous Ribonucleoprotein K and Poly(rC)-binding Proteins 1 and 2 (1998)

Human papillomavirus (HPV) type 16 belongs to the group of "high risk" HPV types that are frequently detected in anogenital cancers. The expression of HPV-16 late genes encoding the virus capsid proteins L1 and L2 is restricted to terminally differentiated epithelial cells in the superficial layers of the squamous epithelium. We have previously identified negative elements in the 3' end of L2 RNA that act in cis to reduce mRNA utilization without substantially affecting mRNA levels. The experiments reported here demonstrate the interaction of cellular proteins with an inhibitory sequence present in the coding region of the L2 mRNA. Using RNA gel shift assays and UV cross-linking, we have detected three cellular proteins interacting specifically with the sense strand of the L2 mRNA, two of which were identified as heterogeneous ribonucleoprotein K (hnRNP K) and the poly(rC) binding- protein (PCBP). Recombinant hnRNP K, PCBP-1, and PCBP-2 that were over expressed in bacteria and partially purified bound to the HPV-16 L2 mRNA in a sequence-specific manner. Interestingly, PCBP-1, PCBP-2, and hnRNP K specifically and efficiently inhibited translation of the HPV-16 L2 mRNA in vitro. Therefore, these proteins may play an important role in the regulation of HPV-16 late gene expression and virus production in vivo.
Modulation of lymphohematopoiesis in long-term cultures by gamma interferon: direct and indirect action on lymphoid and stromal cells. (1993)

Gamma interferon (IFN-gamma) is the product of multiple cell types within the bone marrow microenvironment and has been demonstrated to act as a potent inhibitor of myelopoiesis in vitro and in vivo. The action of this cytokine on lymphohematopoiesis has now been examined on both long-term bone marrow cultures and representative cloned cellular components of the bone marrow microenvironment. In myelopoietic (Dexter) cultures, the half maximal inhibitory concentration of IFN-gamma was between 1 and 10 U/mL. In comparable lymphopoietic (Whitlock/Witte) cultures, IFN-gamma inhibited the production of B-lineage lymphoid cells with a half maximal effective concentration of less than 1 U/mL. In a clonal assay for pre-B cells, IFN-gamma inhibited colony formation with a half maximal concentration of 1 to 5 U/mL. Not all B-lineage lymphoid cells displayed the same sensitivity, however. Growth of the IL-7-dependent B cell line (2E8) in methylcellulose assays was unaffected by IFN-gamma while the replication of other lymphoid lines was partially or completely inhibited. IFN-gamma induced the expression of cell surface proteins (MHC Class I and II) on both B-lineage cells and stromal cells. In cloned stromal cell lines, IFN-gamma increased the steady state mRNA levels for the cytokines interleukin-6 (IL-6) and JE, a member of the IL-8 family. These data indicate that IFN-gamma acts within the lymphohematopoietic microenvironment through both direct and indirect actions on the hemopoietic and stromal cell populations.
Power and Linearity Characteristics of GaN MISFETs on Sapphire Substrate (2004)

The improvement of device performance arising from the adoption of a MIS gate structure in GaN field-effect transistor (FET) is presented. GaN MISFET/MESFET devices were fabricated on sapphire substrate with and without the insertion of a thin SiN layer on device surface. The MISFET device showed improved device characteristic due to significant reduction in device gate leakage with respect to the standard MESFET structure. Measured power and linearity performance showed promising results. Under single-tone testing at 4 GHz, device yielded saturated output power 6.2 W/mm with 55% peak power added efficiency. When tested with two-tone signal device maintained a carrier to third order intermodulation ratio of 30 dBc up to power levels of 1.8 W/mm with 40% power added efficiency.
Human airway epithelial cells produce IP-10 (CXCL10) in vitro and in vivo upon rhinovirus infection (2005)

Human rhinovirus (HRV) infections trigger exacerbations of asthma and chronic obstructive pulmonary disease (COPD) and are associated with lymphocytic infiltration of the airways. We demonstrate that infection of primary cultures of human airway epithelial cells, or of the BEAS-2B human bronchial epithelial cell line, with human rhinovirus type 16 (HRV-16) induces expression of CXCL10 [IFN-gamma-inducible protein 10 (IP-10)], a ligand for the CXCR3 receptor found on activated type 1 T lymphocytes and natural killer cells. IP-10 mRNA reached maximal levels 24 h after HRV-16 infection then declined, whereas protein levels peaked 48 h after infection with no subsequent new synthesis. Cytosolic levels of AU-rich factor 1, a protein associated with mRNA destabilization, increased beginning 24 h after HRV-16 infection. Generation of IP-10 required virus capable of replication but was not dependent on prior induction of type 1 interferons. Transfection of synthetic double-stranded RNA into epithelial cells induced robust production of IP-10, whereas transfection of single-stranded RNA had no effect. Induction of IP-10 gene expression by HRV-16 depended upon activation of NF-kappaB, as well as other transcription factor recognition sequences further upstream in the IP-10 promoter. In vivo infection of human volunteers with HRV-16 strikingly increased IP-10 protein in nasal lavages during symptomatic colds. Levels of IP-10 correlated with symptom severity, viral titer, and numbers of lymphocytes in airway secretions. Thus IP-10 may play a role in the pathogenesis of HRV-induced colds and in HRV-induced exacerbations of COPD and asthma.
Endoscope with optical sectioning capability (1993)

The optical sectioning capability of a fiber-optic scanning microscope with a 9-cm-long gradient-index-rod lens probe has been demonstrated. A transverse resolution of 1.3 µm and a longitudinal resolution of 30 µm were achieved. The dimensions of the probe allow the device to be used as an endoscope.
Ueber die künstliche Bildung der Milchsäure und einen neuen, dem Glycocoll homologen Körper; (1850)

liefert , wohei gleichzeilig Kohlensaure
Numerical model for radio-frequency ablation of the endocardium and its experimental validation (1994)

A theoretical model for the study of the radio-frequency (RF) ablation technique is presented. The model relies on a finite-element time-domain calculation of the temperature distribution in a block of tissue, resulting from the flow of RF (< 1MHz) electrical current. A thermal damage function is used to calculate the extent of the lesion on the basis of the temperature elevation and the duration of exposure. This work extends the model proposed by Haines [1] by including a more realistic and variable geometry, the cooling effect of the blook flow and a transient analysis. Furthermore, the nonlinearity caused by the temperature dependence of the tissue properties is also considered. The complexity of the model being appreciable, an experiment demonstrating its validity is also described. While remaining workable, the experiment is sophisticated enough to lead to convincing conclusions. It consists in measuring the temperature distribution and the time-dependent electrode resistance during "ablation" of a tissue-equivalent material. Various electrode configurations and electrical excitations are investigated. In all cases, the experimental results agree reasonably well with the numerical calculations. This confirms that the model is accurate for the investigation of RF ablation.
Metabolic Signature Identifies Novel Targets for Drug Resistance in Multiple Myeloma (2015)

Drug resistance remains a major clinical challenge for cancer treatment. Multiple myeloma is an incurable plasma cell cancer selectively localized in the bone marrow. The main cause of resistance in myeloma is the minimal residual disease cells that are resistant to the original therapy, including bortezomib treatment and high-dose melphalan in stem cell transplant. In this study, we demonstrate that altered tumor cell metabolism is essential for the regulation of drug resistance in multiple myeloma cells. We show the unprecedented role of the metabolic phenotype in inducing drug resistance through LDHA and HIF1A in multiple myeloma, and that specific inhibition of LDHA and HIF1A can restore sensitivity to therapeutic agents such as bortezomib and can also inhibit tumor growth induced by altered metabolism. Knockdown of LDHA can restore sensitivity of bortezomib resistance cell lines while gain-of-function studies using LDHA or HIF1A induced resistance in bortezomib-sensitive cell lines. Taken together, these data suggest that HIF1A and LDHA are important targets for hypoxia-driven drug resistance. Novel drugs that regulate metabolic pathways in multiple myeloma, specifically targeting LDHA, can be beneficial to inhibit tumor growth and overcome drug resistance.
Backbone dynamics of the human MIA protein studied by 15N NMR relaxation: Implications for extended interactions of SH3 domains (2003)

The melanoma inhibitory activity (MIA) protein is a clinically valuable marker in patients with malignant melanoma as enhanced values diagnose metastatic melanoma stages III and IV. Here, we report the backbone dynamics of human MIA studied by (15)N NMR relaxation experiments. The folded core of human MIA is found to be rigid, but several loops connecting beta-sheets, such as the RT-loop for example, display increased mobility on picosecond to nanosecond time scales. One of the most important dynamic features is the pronounced flexibility of the distal loop, comprising residues Asp 68 to Ala 75, where motions on time scales up to milliseconds occur. Further, significant exchange contributions are observed for residues of the canonical binding site of SH3 domains including the RT-loop, the n-Src loop, for the loop comprising residues 13 to 19, which we refer to as the"disulfide loop", in part for the distal loop, and the carboxyl terminus of human MIA. The functional importance of this dynamic behavior is discussed with respect to the biological activity of several point mutations of human MIA. The results of this study suggest that the MIA protein and the recently identified highly homologous fibrocyte-derived protein (FDP)/MIA-like (MIAL) constitute a new family of secreted proteins that adopt an SH3 domain-like fold in solution with expanded ligand interactions.
Passive Dynamic Walking (1990)

There exists a class of two-legged machines for which walking is a natural dynamic mode. Once started on a shallow slope, a machine of this class will settle into a steady gait quite comparable to human walking, without active control or en ergy input. Interpretation and analysis of the physics are straightforward; the walking cycle, its stability, and its sensi tivity to parameter variations are easily calculated. Experi ments with a test machine verify that the passive walking effect can be readily exploited in practice. The dynamics are most clearly demonstrated by a machine powered only by gravity, but they can be combined easily with active energy input to produce efficient and dextrous walking over a broad range of terrain.
Imaging amyloid deposition in Lewy body diseases (2008)

Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that beta-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
Cloning and characterization of subunit genes of ribonucleotide reductase, a cell-cycle-regulated enzyme, from Plasmodium falciparum. (1993)

Ribonucleotide reductase (EC 1.17.4.1; RNR), a cell-cycle-regulated enzyme, catalyzes the rate-limiting step in the de novo synthesis of deoxyribonucleotides by the reduction of the corresponding ribonucleotides. The important role of the RNR in DNA synthesis and cell division makes this enzyme an excellent target for chemotherapy. However, nothing is known about this enzyme from the malaria parasite Plasmodium falciparum. We have isolated cDNA clones encoding both the large and small RNR subunits. The sequences of full-length clones of the large and small RNR subunits revealed an open reading frame encoding 806 and 349 amino acids, respectively, and showed significant identity with other RNR sequences in the data base. RNA blot analysis showed that the size of the large and small RNR subunit transcripts are 5.4 kb and 2.2 kb, respectively. Both the RNR subunit transcripts fluctuate in level during the cell cycle, reaching a peak preceding maximal DNA synthesis activity. An oligodeoxynucleotide phosphorothioate that is complementary to sequences around the translational initiation codon of the small RNR subunit showed significant inhibition of growth, as measured by the inhibition in DNA synthesis.
Formation and Structure of Porous Gel Networks from Si(OMe)4 in the Presence of A(CH2)nSi(OR)3 (A = Functional Group) (1998)

Monolithic silica aerogels modified by functional organic groups were prepared by sol−gel processing of Si(OMe)4/A(CH2)nSi(OR)3 mixtures under identical experimental conditions, followed by drying of the wet gels with supercritical CO2. The employed functional groups A were SH (n = 3), (n = 3), OC(O)C(Me)CH2 (n = 3), NCO (n = 3), Cl (n = 3), NHC(O)OMe (n = 3), and PPh2 (n = 2). These groups were retained in the aerogels except the isocyanate groups, which reacted with methanol to the corresponding carbamate. The properties of the obtained aerogels are rather independent of the kind of functional group, but strongly depend on the Si(OMe)4/A(CH2)nSi(OR)3 ratio, which was varied between 9:1 and 6:4. The density of the aerogels was 0.2−0.3 g cm-3; some aerogels with lower densities were also prepared for comparison. Gelling of the precursor mixtures is drastically slowed with an increasing portion of A(CH2)nSi(OR)3, and the water consumption is retarded. During supercritical drying, shrinkage of ∼10% was observed for the aerogels prepared from the 9:1 precursor mixtures. Increasing the portion of A(CH2)nSi(OR)3 or decreasing the aerogel density lead to a larger shrinkage and an incomplete incorporation of the functional organic groups. The chemical composition of the resulting aerogels was investigated by infrared (IR) and Raman spectroscopy, elemental analysis, and titration of the functional groups, and their structure by nitrogen sorption and small-angle X-ray scattering (SAXS). The Brunauer−Emmett−Teller (BET) surface areas generally decreased with an increasing portion of A(CH2)nSi(OR)3, whereas the C parameter showed a saturation behavior. An analysis of the pore volumes indicated that with an increasing portion of A(CH2)nSi(OR)3 or a decreasing bulk density, the gel skeleton is increasingly compressed during the N2 sorption experiments. SAXS measurements showed larger particles upon increasing the A(CH2)nSi(OR)3/Si(OMe)4 ratio, which correlates with the observed decrease of the specific surface areas. The results were interpreted that an increasing portion of A(CH2)nSi(OR)3 has the same kinetic effects on the hydrolysis and condensation reactions and the same structural consequences for the network formation as decreasing the bulk density of an aerogel obtained from the one-component Si(OMe)4 system. The fractal dimension increased with an increasing portion of A(CH2)nSi(OR)3; it was significantly larger for A = NCO and NHC(O)OMe than for A = SH or OC(O)C(Me)CH2.