gebhart/patrepeval huggingface dataset:
DNA bending and unbending by MutS govern mismatch recognition and specificity (2003)

DNA mismatch repair is central to the maintenance of genomic stability. It is initiated by the recognition of base-base mismatches and insertion/deletion loops by the family of MutS proteins. Subsequently, ATP induces a unique conformational change in the MutS-mismatch complex but not in the MutS-homoduplex complex that sets off the cascade of events that leads to repair. To gain insight into the mechanism by which MutS discriminates between mismatch and homoduplex DNA, we have examined the conformations of specific and nonspecific MutS-DNA complexes by using atomic force microscopy. Interestingly, MutS-DNA complexes exhibit a single population of conformations, in which the DNA is bent at homoduplex sites, but two populations of conformations, bent and unbent, at mismatch sites. These results suggest that the specific recognition complex is one in which the DNA is unbent. Combining our results with existing biochemical and crystallographic data leads us to propose that MutS: (i) binds to DNA nonspecifically and bends it in search of a mismatch; (ii) on specific recognition of a mismatch, undergoes a conformational change to an initial recognition complex in which the DNA is kinked, with interactions similar to those in the published crystal structures; and (iii) finally undergoes a further conformational change to the ultimate recognition complex in which the DNA is unbent. Our results provide a structural explanation for the long-standing question of how MutS achieves mismatch repair specificity.
Adaptive-optics optical coherence tomography for high-resolution and high-speed 3D retinal in vivo imaging (2005)

We have combined Fourier-domain optical coherence tomography (FD-OCT) with a closed-loop adaptive optics (AO) system using a Hartmann-Shack wavefront sensor and a bimorph deformable mirror. The adaptive optics system measures and corrects the wavefront aberration of the human eye for improved lateral resolution (~4 μm) of retinal images, while maintaining the high axial resolution (~6 μm) of stand alone OCT. The AO-OCT instrument enables the three-dimensional (3D) visualization of different retinal structures in vivo with high 3D resolution (4×4×6 μm). Using this system, we have demonstrated the ability to image microscopic blood vessels and the cone photoreceptor mosaic.
Structural and Mutational Analysis of the PhoQ Histidine Kinase Catalytic Domain (2001)

PhoQ is a transmembrane histidine kinase belonging to the family of two-component signal transducing systems common in prokaryotes and lower eukaryotes. In response to changes in environmental Mg(2+) concentration, PhoQ regulates the level of phosphorylated PhoP, its cognate transcriptional response-regulator. The PhoQ cytoplasmic region comprises two independently folding domains: the histidine-containing phosphotransfer domain and the ATP-binding kinase domain. We have determined the structure of the kinase domain of Escherichia coli PhoQ complexed with the non-hydrolyzable ATP analog adenosine 5'-(beta,gamma-imino)triphosphate and Mg(2+). Nucleotide binding appears to be accompanied by conformational changes in the loop that surrounds the ATP analog (ATP-lid) and has implications for interactions with the substrate phosphotransfer domain. The high resolution (1.6 A) structure reveals a detailed view of the nucleotide-binding site, allowing us to identify potential catalytic residues. Mutagenic analyses of these residues provide new insights into the catalytic mechanism of histidine phosphorylation in the histidine kinase family. Comparison with the active site of the related GHL ATPase family reveals differences that are proposed to account for the distinct functions of these proteins.
Two Different Pathways for the Maintenance of Trabecular Bone in Adult Male Mice (2002)

Androgens may regulate the male skeleton either directly via activation of the androgen receptor (AR) or indirectly via aromatization of androgens into estrogen and, thereafter, via activation of estrogen receptors (ERs). There are two known estrogen receptors, ER-alpha and ER-beta. The aim of this study was to investigate the relative roles of ER-alpha, ER-beta, and AR in the maintenance of trabecular bone in male mice. Seven-month-old male mice, lacking ER-alpha (ERKO), ER-beta (BERKO), or both receptors (DERKO), were orchidectomized (orx) and treated for 3 weeks with 0.7 microg/mouse per day of 17beta-estradiol or vehicle. No reduction in trabecular bone mineral density (BMD) was seen in ERKO, BERKO, or DERKO mice before orx, showing that neither ER-a nor ER-beta is required for the maintenance of a normal trabecular BMD in male mice. After orx, there was a pronounced decrease in trabecular BMD, similar for all groups, resulting in equal levels of trabecular BMD in all genotypes. This reduction was reversed completely in wild-type (WT) and BERKO mice treated with estrogen, and no significant effect of estrogen was found in ERKO or DERKO mice. In summary, the trabecular bone is preserved both by a testicular factor, presumably testosterone acting via AR and by an estrogen-induced activation of ER-alpha. These results indicate that AR and ER-alpha are redundant in the maintenance of the trabecular bone in male mice. In contrast, ER-beta is of no importance for the regulation of trabecular bone in male mice.
Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal (2005)

Acetyl-CoA carboxylases (ACC1 and ACC2) catalyze the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a pivotal role in the regulation of fatty acid metabolism. We previously reported that ACC2 null mice are viable, and that ACC2 plays an important role in the regulation of fatty acid oxidation through the inhibition of carnitine palmitoyltransferase I, a mitochondrial component of the fatty-acyl shuttle system. Herein, we used gene targeting to knock out the ACC1 gene. The heterozygous mutant mice (Acc1(+/-)) had normal fertility and lifespans and maintained a similar body weight to that of their wild-type cohorts. The mRNA level of ACC1 in the tissues of Acc1(+/-) mice was half that of the wild type; however, the protein level of ACC1 and the total malonyl-CoA level were similar. In addition, there was no difference in the acetate incorporation into fatty acids nor in the fatty acid oxidation between the hepatocytes of Acc1(+/-) mice and those of the wild type. In contrast to Acc2(-/-) mice, Acc1(-/-) mice were not detected after mating. Timed pregnancies of heterozygotes revealed that Acc(-/-) embryos are already undeveloped at embryonic day (E)7.5, they die by E8.5, and are completely resorbed at E11.5. Our previous results of the ACC2 knockout mice and current studies of ACC1 knockout mice further confirm our hypotheses that malonyl-CoA exists in two independent pools, and that ACC1 and ACC2 have distinct roles in fatty acid metabolism.
Cardiomyocytes of Noncardiac Origin in Myocardial Biopsies of Human Transplanted Hearts (2002)

These results show that regeneration by cells of noncardiac origin (differentiated into cardiomyocytes and physiologically linked to neighboring myocytes) can be detected even in small myocardial biopsies. This may lead to new diagnostic and therapeutic strategies in the treatment of myocardial infarction, inflammatory heart disease, and/or heart failure.
[The comparison of clustering methods of EEG independent components in healthy subjects and patients with post concussion syndrome after traumatic brain injury]. (2010)

The comparison of three different clustering methods of 19-channels EEG independent components in 518 healthy subjects and 87 patients with post concussion syndrome after traumatic brain injury was performed to define more exact the location of sources of pathologic brain activity. Following methods of grouping were used: clustering of independent components topographies, clustering of coordinates of equivalent dipole sources corresponding to independent components topographies and sorting of independent components using extremes of equivalent source current density computed by Standardized Low Resolution Electromagnetic Tomography (sLORETA).The comparison of power spectra of independent components revealed statically significant increase of EEG power located in frontal and temporal brain areas in delta, theta and alpha frequency bands in patients with post concussion syndrome after traumatic brain injury. The method of clustering of independent components topographies seems to be most sensitive in comparison with other two methods.
Photoinscription of channel waveguides and grating couplers in azobenzene polymer thin films (1997)

Poly(methyl methacrylate) slab waveguide materials were prepared, incorporating covalently attached azobenzene side groups. Birefringence was rapidly photoinduced in the films with linearly polarized light from an Ar<SUP>+</SUP> laser to define stable channel waveguides, and the irradiated regions were shown to be suitable for multimode guiding of light at 633 nm. This single-step photoinscription process gives a controlled refractive index variation up to 0.012 for step or graded index channels, and can be rapidly modulated or completely erased with irradiation from a circularly polarized Ar<SUP>+</SUP> laser beam. Written waveguides are stable indefinitely. Coupling in and out of the waveguides can be achieved with diffraction gratings photoinscribed in the polymer film using interfering beams from the same Ar<SUP>+</SUP> laser. These high efficiency volume and surface diffraction gratings are stable over time and light exposure at the guiding wavelength. The grating spacing can be controlled by the geometry of the interference pattern, and hence can be optimize for high efficiency in-coupling and out-coupling at any required angle. Gratings with fringe spacings from 350 nm to 2000 nm were photoinscribed, and shown to couple light in and out of birefringent channel waveguides photoinscribed in the same material. The reversibility of the channels allows the guides to be photoaddressed for switching and mode filtering.
Clostridium septicum Alpha Toxin Uses Glycosylphosphatidylinositol-anchored Protein Receptors (1999)

The alpha toxin produced by Clostridium septicum is a channel-forming protein that is an important contributor to the virulence of the organism. Chinese hamster ovary (CHO) cells are sensitive to low concentrations of the toxin, indicating that they contain toxin receptors. Using retroviral mutagenesis, a mutant CHO line (BAG15) was generated that is resistant to alpha toxin. FACS analysis showed that the mutant cells have lost the ability to bind the toxin, indicating that they lack an alpha toxin receptor. The mutant cells are also resistant to aerolysin, a channel-forming protein secreted by Aeromonas spp., which is structurally and functionally related to alpha toxin and which is known to bind to glycosylphosphatidylinositol (GPI)-anchored proteins, such as Thy-1. We obtained evidence that the BAG15 cells lack N-acetylglucosaminyl-phosphatidylinositol deacetylase-L, needed for the second step in GPI anchor biosynthesis. Several lymphocyte cell lines lacking GPI-anchored proteins were also shown to be less sensitive to alpha toxin. On the other hand, the sensitivity of CHO cells to alpha toxin was increased when the cells were transfected with the GPI-anchored folate receptor. We conclude that alpha toxin, like aerolysin, binds to GPI-anchored protein receptors. Evidence is also presented that the two toxins bind to different subsets of GPI-anchored proteins.
Pharmaceutical and Medical Aspects of Bioadhesive Systems for Drug Administration (1988)

Bioadhesion could lead to the solution of bioavailability problems resulting from a too short stay of the pharmaceutical dosage form at the absorption or activity level of the active ingredient. Bioadhesion stages are: intimate contact resulting from a good wetting of the bioadhesion surface and the swelling of the bioadhesive polymer, then penetration of the bioadhesive into the crevice of the tissue surface or interpenetration of bioadhesive chains with those of the mucus, and finally low chemical bonds. date, the most important bioadhesive polymers are polycarbophil a Carbopol 934. Methods of studying bioadhesion are described as well as the existing bioadhesive dosage forms.
Containing Pandemic Influenza with Antiviral Agents (2004)

For the first wave of pandemic influenza or a bioterrorist influenza attack, antiviral agents would be one of the few options to contain the epidemic in the United States until adequate supplies of vaccine were available. The authors use stochastic epidemic simulations to investigate the effectiveness of targeted antiviral prophylaxis to contain influenza. In this strategy, close contacts of suspected index influenza cases take antiviral agents prophylactically. The authors compare targeted antiviral prophylaxis with vaccination strategies. They model an influenza pandemic or bioterrorist attack for an agent similar to influenza A virus (H2N2) that caused the Asian influenza pandemic of 1957-1958. In the absence of intervention, the model predicts an influenza illness attack rate of 33% of the population (95% confidence interval (CI): 30, 37) and an influenza death rate of 0.58 deaths/1,000 persons (95% Cl: 0.4, 0.8). With the use of targeted antiviral prophylaxis, if 80% of the exposed persons maintained prophylaxis for up to 8 weeks, the epidemic would be contained, and the model predicts a reduction to an illness attack rate of 2% (95% Cl: 0.2, 16) and a death rate of 0.04 deaths/1,000 persons (95% CI: 0.0003, 0.25). Such antiviral prophylaxis is nearly as effective as vaccinating 80% of the population. Vaccinating 80% of the children aged less than 19 years is almost as effective as vaccinating 80% of the population. Targeted antiviral prophylaxis has potential as an effective measure for containing influenza until adequate quantities of vaccine are available.
Viral infection of human progenitor and liver-derived cells encapsulated in three-dimensional PEG-based hydrogel (2008)

We have studied the encapsulation of human progenitor cells into 3D PEG hydrogels. Replication-incompetent lentivirus promoter reporter vectors were found to efficiently detect the in vivo expression of human hepatic genes in hydrogel-encapsulated liver progenitor cells. Similarly, hydrogel-encapsulated cells could be efficiently infected with hepatitis C virus, and progeny infectious virus could be recovered from the media supernatants of the hydrogels. Provocatively, the diameters of these virus particles range from ∼50 to 100 nm, while the calculated mesh size of the 8 k hydrogel is 44.6 ± 1.7 Å. To reconcile how viral particles can penetrate the hydrogels to infect the encapsulated cells, we propose that microfractures/defects of the hydrogel result in a functional pore size of up to 20 fold greater than predicted by theoretical mesh calculations. These results suggest a new model of hydrogel structure, and have exciting implications for tissue engineering and hepatitis virus studies.
[Pathophysiology of abnormal movements in Parkinson's disease]. (2000)

Major parkinsonian motor symptoms, i.e., bradykinesia, muscular rigidity, and resting tremor, are due to abnormalities in the motor circuit of the basal ganglia caused by loss of nigrostriatal dopamine neurons. Bradykinesia results from increased activity with altered firing patterns of the output nuclei of the basal ganglia. Exaggerated long-latency reflex or decreased Ib inhibition of the spinal reflex network have been suggested to underlie rigidity, but the relationship between these reflex abnormalities and the altered activities of the basal ganglia in the parkinsonian state remains unclear. The central oscillator for parkinsonian tremor has been localized in the basal ganglia circuit, and the cerebellar system also participates in generation of the tremor. Dyskinesia and dystonia may develop from decreased activity with altered firing patterns of the output nuclei of the basal ganglia.
Trace-based just-in-time compilation for lazy functional programming languages (2013)

This thesis investigates the viability of trace-based just-in-time (JIT) compilation for optimising programs written in the lazy functional programming language Haskell. A trace-based JIT compiler optimises only execution paths through the program, which is in contrast to method-based compilers that optimise complete functions at a time. The potential advantages of this approach are shorter compilation times and more natural interprocedural optimisation. Trace-based JIT compilers have previously been used successfully to optimise programs written in dynamically typed languages such as JavaScript, Python, or Lua, but also statically typed languages like Java or the Common Language Runtime (CLR). Lazy evaluation poses implementation challenges similar to those of dynamic languages, so trace-based JIT compilation promises to be a viable approach. In this thesis we focus on program performance, but having a JIT compiler available can simplify the implementation of features like runtime inspection and mobile code. We implemented Lambdachine, a trace-based JIT compiler which implements most of the pure subset of Haskell. We evaluate Lambdachine’s performance using a set of micro-benchmarks and a set of larger benchmarks from the “spectral” category of the Nofib benchmark suite. Lambdachine’s performance (excluding garbage collection overheads) is generally about 10 to 20 percent slower than GHC on statically optimised code. We identify the two main causes for this slow-down: trace selection and impeded heap allocation optimisations due to unnecessary thunk updates.
Making Clinical Policy Explicit:Legislative Policy Making and Lessons for Developing Practice Guidelines (1993)

Promulgation of practice guidelines in medicine has increased interest in the structure of clinical policy making. It is argued that with a generic definition of policy as "the rules governing the behavior of individuals or institutions," clinical policy making is analogous to legislative policy making. Practice guidelines emphasize the advantages of making clinical policy more explicit. The structure of legislative policy making has evolved over many years to meet the challenge of making both the policies and the process of policy making explicit. Processes to promulgate clinical policies may be able to exploit this experience to improve clinical policy making and thereby retain control of the process within medicine. Generic steps are outlined for making decisions with incomplete information; synthesis of facts, vested interests, and values; involvement of stakeholders; and implementation of policy. An illustration of the use of the generic steps to make and implement a clinical policy for cesarean birth follows, with evaluations of its impact on the behavior and satisfaction of clinical stakeholders.
Metallodielectric gratings with subwavelength slots:  Optical properties (2003)

We report an experimental and theoretical study of the properties of metallodielectric gratings with subwavelength slots in the thin metal limit. These structures were fabricated using a bench top nanopatterning method that produces metallic periodic structures with subwavelength features without the need for lithographic masks by directing the deposition of metal onto prepatterned surfaces. In the size and thickness regime explored in this study two excitations are possible: surface plasmons (SP's) and Rayleigh anomalies. The transmissive and reflective properties of these structures are reported, and very good agreement between theory and experiment is achieved. The dispersion of both the Rayleigh anomalies and SPs is measured. In addition, the near-field properties of each of these excitations are calculated. Plasmon-plasmon interactions, which produce gaps in the dispersion relation for the surface waves, are observed.
FcγRIIa Is Expressed on Natural IFN-α-Producing Cells (Plasmacytoid Dendritic Cells) and Is Required for the IFN-α Production Induced by Apoptotic Cells Combined with Lupus IgG (2003)

An ongoing production of IFN-alpha may be of etiopathogenic significance in systemic lupus erythematosus (SLE). It may be due to the natural IFN-producing cells (NIPC), also termed plasmacytoid dendritic cells (PDC), activated by immune complexes that contain nucleic acids derived from apoptotic cells. We here examined the role of FcgammaR in the IFN-alpha production in vitro by PBMC induced by the combination of apoptotic U937 cells and autoantibody-containing IgG from SLE patients (SLE-IgG). The Fc portion of the SLE-IgG was essential to induce IFN-alpha production, because Fab fragments or F(ab')(2) were ineffective. Normal, especially heat-aggregated, IgG inhibited the IFN-alpha production, suggesting a role for FcgammaR on PBMC. Using blocking anti-FcgammaR Abs, the FcgammaRIIa,c (CD32) but not FcgammaRI or FcgammaRIII were shown to be involved in the IFN-alpha induction by apoptotic cells combined with SLE-IgG, but not by HSV or CpG DNA. In contrast, the action of all of these inducers was inhibited by the anti-FcgammaRIIa,b,c mAb AT10 or heat-aggregated IgG. Flow cytometric analysis revealed that approximately 50% of the BDCA-2-positive PBMC, i.e., NIPC/PDC, expressed low but significant levels of FcgammaRII, as did most of the actual IFN-alpha producers activated by HSV. RT-PCR applied to NIPC/PDC purified by FACS demonstrated expression of FcgammaRIIa, but not of FcgammaRIIb or FcgammaRIIc. We conclude that FcgammaRIIa on NIPC/PDC is involved in the activation of IFN-alpha production by interferogenic immune complexes, but may also mediate inhibitory signals. The FcgammaRIIa could therefore have a key function in NIPC/PDC and be a potential therapeutic target in SLE.
Purification and characterization of two serine carboxypeptidases from Aspergillus niger and their use in C-terminal sequencing of proteins and peptide synthesis (1992)

A procedure was developed to prepare in large amounts two carboxypeptidases, CPD-I and CPD-II, from Aspergillus niger. They were each shown to be serine proteases and single-chain monomers with molecular masses of ca. 81 kDa and containing 22% carbohydrates. Amino acid analysis, carbohydrate determination, and N-terminal sequencing (20 to 25 residues) were performed on each enzyme. CPD-I showed sequence homologies with malt carboxypeptidase II, while the N terminus of CPD-II was different from that of any known serine carboxypeptidase. Like carboxypeptidase Y from Saccharomyces cerevisiae and carboxypeptidase III from malt, CPD-II contained a free sulfhydryl group that could play a role in catalysis. Both A. niger enzymes had pH optima of about 4 and were unstable above pH 7. Their specificities for substrate positions P1 and P'1 were characterized by use of, as substrates, a series of N-blocked amino acid esters and dipeptides. Both enzymes were specific for Arg, Lys, and Phe in P1. CPD-I preferred hydrophobic residues in P'1, while CPD-II was highly specific for Arg and Lys in this position. Each displayed an original specificity when P1 and P'1 were considered together. The specificities were also studied by analyzing the time course of the release of amino acids from eight different peptides of various lengths. CPD-I and CPD-II appeared to be quite suitable for C-terminal sequence studies as well as for the synthesis of peptide bonds. The latter was studied with two peptide esters as aminolysis substrates and a series of amino acid amides as nucleophiles.(ABSTRACT TRUNCATED AT 250 WORDS)
Three‐Dimensional Nanostructured Substrates toward Efficient Capture of Circulating Tumor Cells (2009)

Zellfänger: Eine dreidimensionale Nanostruktur aus säulenartig angeordneten Si-Nanostäben (SiNPs), die mit dem Antikörper anti-EpCAM (EpCAM: Epithelzelladhäsionsmolekül) bedeckt sind, zeigt verstärkte lokale topographische Wechselwirkungen zwischen nanoskaligen Zelloberflächenkomponenten und dem Substrat. Dies erhöht die Effizienz der Zellfixierung bei der Isolierung lebensfähiger Krebszellen aus Vollblutproben (siehe Schema und REM-Bild einer fixierten Krebszelle).