gebhart/patrepeval huggingface dataset:
The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2 (1996)

The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression. Recently, Mdm2 has been found to bind several other proteins that function to regulate cell cycle progression, including the E2F-1/DP1 transcription factor complex and the retinoblastoma tumor-suppressor protein. To determine whether Mdm2 plays a role in cell cycle control or tumorigenesis that is distinct from its ability to modulate p53 function, we have examined and compared both the in vitro growth characteristics of p53-deficient and Mdm2/p53-deficient fibroblasts, and the rate and spectrum of tumor formation in p53-deficient and Mdm2/p53-deficient mice. We find no difference between p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts either in their rate of proliferation in culture or in their survival frequency when treated with various genotoxic agents. Cell cycle studies indicate no difference in the ability of the two cell populations to enter S phase when treated with DNA-damaging agents or nucleotide antimetabolites, and p53-deficient fibroblasts and Mdm2/p53-deficient fibroblasts exhibit the same rate of spontaneous immortalization following long-term passage in culture. Finally, p53-deficient mice and Mdm2/p53-deficient mice display the same incidence and spectrum of spontaneous tumor formation in vivo. These results demonstrate that deletion of Mdm2 has no additional effect on cell proliferation, cell cycle control, or tumorigenesis when p53 is absent.
Tetracyclines affect prion infectivity (2002)

Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, protease-resistant forms of the prion protein (PrP) termed PrP(Sc) are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Based on previous findings that tetracyclines revert abnormal physicochemical properties and abolish neurotoxicity of PrP peptides in vitro, we tested the ability of these compounds to interact with PrP(Sc) from patients with the new variant of Creutzfeldt-Jakob disease (vCJD) and cattle with bovine spongiform encephalopathy (BSE). The incubation with tetracycline hydrochloride or doxycycline hyclate at concentrations ranging from 10 microM to 1 mM resulted in a dose-dependent decrease in protease resistance of PrP(Sc). This finding prompted us to investigate whether tetracyclines affect prion infectivity by using an animal model of disease. Syrian hamsters were injected intracerebrally with 263K scrapie-infected brain homogenate that was coincubated with 1 mM tetracycline hydrochloride, 1 mM doxycycline hyclate, or vehicle solution before inoculation. Hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. These effects were paralleled by a delay in the appearance of magnetic-resonance abnormalities in the thalamus, neuropathological changes, and PrP(Sc) accumulation. When tetracycline was preincubated with highly diluted scrapie-infected inoculum, one third of hamsters did not develop disease. Our data suggest that these well characterized antibiotics reduce prion infectivity through a direct interaction with PrP(Sc) and are potentially useful for inactivation of BSE- or vCJD-contaminated products and prevention strategies.
Depolymerization of High Molecular Weight into a Predicted Low Molecular Weight Chitosan and Determination of the Degree of Deacetylation Coupled with Other Tests to Guarantee its Quality for Research Use (2018)

Low molecular weight chitosan (LMWC) is a semi synthetic biopolymer with potential uses as a pharmaceutical excipient, though, consistent and reliable grades of pure LMWC are scarce. Credible and competent preparation and characterization methods are, therefore, of utmost importance to specialized laboratories. Although acid hydrolysis of chitosan is already known, existing protocols produce oligomer mixtures of high polydispersity and fail to predict the ensuing molecular weights. We, herein, optimize a mild acid-catalyzed depolymerization of high molecular weight chitosan (HMWC) of 100kDa and 93% degree of deacetylation, and develop a standardized protocol that enables the predetermination of resultant molecular weight and re-acetylation in the ranges of 1.4-28.1 kDa and 55.1-81.1%, respectively. Molecular weight measurements were extracted and verified based on dynamic viscosity readings and dynamic light scattering. Degree of deacetylation was calculated by H1 NMR. These protocols were found to be efficient, time and cost-effective, reproducible, and gave LMWC with the desired quality and yield for research purposes.
Optimization of Transmission Conditions in Waveform Relaxation Techniques for RC Circuits (2014)

Waveform relaxation techniques have become increasingly important with the wide availability of parallel computers with a large number of processors. A limiting factor for classical waveform relaxation, however, is the convergence speed for an important class of problems, especially if long time windows are considered. In contrast, the optimized waveform relaxation algorithm discussed in this paper is well suited to address this problem. Today several numerical analyses have shown that optimized waveform relaxation algorithms can overcome slow convergence over long time windows. However, the optimized waveform relaxation techniques require the determination of optimized parameters. In this paper, we present a theoretical foundation for the determination of the optimized parameters for an important class of RC circuits.
Room-temperature continuous-wave operation of lateral current injection wavelength-scale embedded active-region photonic-crystal laser (2012)

We have developed a wavelength-scale embedded active-region photonic-crystal laser using lateral p-i-n structure. Zn diffusion and Si ion implantation are used for p- and n-type doping. Room-temperature continuous-wave lasing behavior is clearly observed from the injection current dependence of the output power, 3dB-bandwidth of the peak, and lasing wavelength. The threshold current is 390 μA and the estimated effective threshold current is 9.4 μA. The output power in output waveguide is 1.82 μW for a 2.0-mA current injection. These results indicate that the embedded active-region structure effectively reduce the thermal resistance. Ultrasmall electrically driven lasers are an important step towards on-chip photonic network applications.
ChemInform Abstract: The Complex Formation of Cadmium(II) and Mercury(II) with Aliphatic Dipeptides. (1982)

Abstract Mittels pH‐Titrationsmethoden werden die Stabilitätskonstanten für die Komplexe zwischen Cd(II) bzw. Hg(II) und den Dipeptiden Gly‐Gly, Gly‐d,l‐Ala, Gly‐d,l‐Leu, Gly‐Pro, d,l‐Ala‐Gly, d,l‐Leu‐Gly, Pro‐Gly, d,l‐Ala‐d,l‐Ala, d,l‐Ala‐d,l‐Leu, Pro‐ Ala, Pro‐Leu bestimmt und der Einfluß der Seitenketten auf die Stabilität der Komplexe diskutiert.
4CMenB vaccine induces elite cross-protective human antibodies that compete with human factor H for binding to meningococcal fHbp (2020)

Neisseria meningitidis serogroup B (MenB) is the leading cause of meningococcal meningitis and sepsis in industrialized countries, with the highest incidence in infants and adolescents. Two recombinant protein vaccines that protect against MenB are now available (i.e. 4CMenB and MenB-fHbp). Both vaccines contain the Factor H Binding Protein (fHbp) antigen, which can bind the Human Factor H (fH), the main negative regulator of the alternative complement pathway, thus enabling bacterial survival in the blood. fHbp is present in meningococcal strains as three main variants which are immunologically distinct. Here we sought to obtain detailed information about the epitopes targeted by anti-fHbp antibodies induced by immunization with the 4CMenB multicomponent vaccine. Thirteen anti-fHbp human monoclonal antibodies (mAbs) were identified in a library of over 100 antibody fragments (Fabs) obtained from three healthy adult volunteers immunized with 4CMenB. Herein, the key cross-reactive mAbs were further characterized for antigen binding affinity, complement-mediated serum bactericidal activity (SBA) and the ability to inhibit binding of fH to live bacteria. For the first time, we identified a subset of anti-fHbp mAbs able to elicit human SBA against strains with all three variants and able to compete with human fH for fHbp binding. We present the crystal structure of fHbp v1.1 complexed with human antibody 4B3. The structure, combined with mutagenesis and binding studies, revealed the critical cross-reactive epitope. The structure also provided the molecular basis of competition for fH binding. These data suggest that the fH binding site on fHbp v1.1 can be accessible to the human immune system upon immunization, enabling elicitation of human mAbs broadly protective against MenB. The novel structural, biochemical and functional data are of great significance because the human vaccine-elicited mAbs are the first reported to inhibit the binding of fH to fHbp, and are bactericidal with human complement. Our studies provide molecular insights into the human immune response to the 4CMenB meningococcal vaccine and fuel the rationale for combined structural, immunological and functional studies when seeking deeper understanding of the mechanisms of action of human vaccines.
Quadruplex Integrated DNA (QuID) Nanosensors for Monitoring Dopamine (2015)

Dopamine is widely innervated throughout the brain and critical for many cognitive and motor functions. Imbalances or loss in dopamine transmission underlie various psychiatric disorders and degenerative diseases. Research involving cellular studies and disease states would benefit from a tool for measuring dopamine transmission. Here we show a Quadruplex Integrated DNA (QuID) nanosensor platform for selective and dynamic detection of dopamine. This nanosensor exploits DNA technology and enzyme recognition systems to optically image dopamine levels. The DNA quadruplex architecture is designed to be compatible in physically constrained environments (110 nm) with high flexibility, homogeneity, and a lower detection limit of 110 µM.
Mechanisms for unbounded, conflict-robust hardware transactional memory (2010)

COPYRIGHT 2010 Colin BlundellThis dissertation is dedicated to my wife, Angelina. Without you, this would not have been possible. iii Acknowledgements This dissertation would not have been possible without the love and support of my family. My deepest thanks go to my wife, Angelina. The opportunity to meet her has been the greatest reward of my decision to go to graduate school. She is both the source of my success and the reason that this success has meaning. I also thank Jacob for the joy that he has brought to my life and Merlin for his constant good humor, support, and loyalty. The support of my mother, father, and brother has been instrumental in me reaching this point. They have shared in the joy of my successes and have helped me weather the setbacks. The foundation of my later success was laid in my parents ’ teaching when I was young. My brother David has been there with me through the ups and downs of our entire lives; he is the best friend a brother could ever hope for.
The Study of Active Noise Control Method for Moving Target in Noisy Space (2011)

For the noise problem of moving target in noisy space, This work is dedicated to developing a novel and promising solution based on the moving target tracking technology and the active noise control (ANC) technology. The development process began with the simplified sound field interaction model, the “auto position tracking near head space ANC” strategy has been proposed from the modelling study. Furthermore, the primary experimental system that consists of the acoustic positioning and tracking subsystem for tracking the control point and the ANC subsystem for generating the anti-noise signal is presented, with the emphasis on the development of the improved TDC-FXLMS ANC algorithm. Finally, the performance of the auto-position tracking near head space ANC device is evaluated by carrying out the primary experiments on an experimental evaluation system.
Diode laser based light sources for shifted excitation resonance Raman difference spectroscopy in the spectral range between 450 nm and 532 nm (2022)

Exciting the Raman effect at a wavelength in resonance with the absorption spectrum of the sample, typically in the visible spectral range, can increase the strength of Raman lines by orders of magnitude. Particularly in this case, the lines can be obscured by fluorescence but also by background light. Shifted excitation Raman difference spectroscopy (SERDS) can recover Raman signatures. This method uses an excitation light source with alternating operation of two neighboring, spectrally stabilized, narrow emission wavelengths. Only the Raman lines follow that change in the excitation wavelength and can be separated from the background. Up to now, internally wavelength stabilized dual wavelength diode lasers for the blue and green spectral range are unavailable. Other concepts, as presented in this work, had to be evaluated. First, the combination of two external cavity stabilized GaN diode lasers will be presented. Low reflection coated laser diodes are externally wavelength stabilized using VBGs and their beams are superimposed. Output powers in the 10- mW range for emission wavelengths of 454 nm and 456 nm will be presented. Second, devices based on frequency doubled GaAs diode lasers will be tested. The wavelength shift is realized by thermal tuning of the heat sink or by applying a current to internal heater elements in the GaAs-DBR-RW-lasers. In this case output powers, up to 50 mW at 488 nm or 515 nm were achieved. Third, dual wavelength Y-branch diode lasers at 1064 nm were frequency converted towards 532 nm with output powers in the 10-mW range using customized SHG waveguide crystals.
Soft-Tissue Imaging in a Human Mummy: Propagation-based Phase-Contrast CT (2018)

Purpose To evaluate phase-contrast CT as a noninvasive alternative to histology in the study of ancient soft tissue. Materials and Methods The imaging was performed between May 8 and June 13, 2017. A mummified human hand from ancient Egypt was imaged in a laboratory phase-contrast CT arrangement with propagation-based imaging. The experimental arrangement for propagation-based imaging included a microfocus x-ray source, a rotation stage for the sample, and an x-ray detector. The mummified hand was imaged in two different modes. First, a CT scan of the whole hand was performed in an overview arrangement. Then, a detailed scan of the tip of the middle finger was performed. With imaging distances tailored for a large magnification and to maximize the phase-contrast signal, the estimated resolution in the final images was 6-9 µm. Results The overview CT allowed identification of the tendons of the hand, as well as identification of arteries and nerves in the dehydrated soft tissue. In the detailed phase-contrast setting, virtual histology of the soft tissues of the fingertip could be performed. Blood vessels in the nail bed and the microanatomy of the bone marrow and hypodermis were imaged, and the layers of the skin could be distinguished. Round structures in the adipose tissue were identified as the remains of adipocytes. Conclusion Laboratory phase-contrast CT enables imaging of the anatomy and microanatomy of mummified soft tissue with sub-10-µm resolution and may serve as a complement or alternative to the classic invasive histologic methods used in soft-tissue paleopathology. © RSNA, 2018 Online supplemental material is available for this article.
Charge-based scanning probe readback of nanometer-scale ferroelectric domain patterns at megahertz rates (2009)

We present a method for data storage in continuous ferroelectric (FE) media, applicable to storage systems based on one or more scanning probes. Written FE domains are read back in a destructive fashion by applying a constant voltage of magnitude greater than the coercive voltage, as is done in FE random access memory (FeRAM). The resulting flow of screening charges through the readback amplifier provides sufficient signal to allow readback of domains of minimum dimension of the order of 10 nm at MHz rates, orders of magnitude faster than previously demonstrated techniques for readback of domains in continuous FE media.
Phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK). (2020)

TPS761 Background: Randomized data from the interferon era demonstrated modest survival benefits of cytoreductive nephrectomy (CN) in patients with advanced renal cell carcinoma (aRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN especially in IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in aRCC now includes first-line combination immunotherapy. Data from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and objective response rate with ipilimumab and nivolumab (I/N) compared to sunitinib. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an ‘abscopal effect’, leading to enhanced systemic anti-tumour immune response. We hypothesize that SBRT to the primary kidney mass in aRCC patients will enhance the efficacy of I/N compared to standard of care I/N alone. Methods: This phase II trial randomizes untreated aRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven aRCC (any histology), IMDC intermediate/poor risk disease, and who decline or are unsuitable for CN. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include blood immune signatures and stool microbiome. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Clinical trial information: NCT04090710.
Pulsed Laser Deposition of Metal Oxide Nanoparticles, Agglomerates, and Nanotrees for Chemical Sensors (2015)

Pulsed laser deposition (PLD) was used to prepare WO3, ZnO-modified SnO2, and V2O5 nanostructures as gas sensing materials on top of commercial SGX Sensortech MEMS microheater platforms. The layers were formed of different types of nanostructures including nanoparticles, agglomerates, and nanotrees with fractal-like growth. Clear dependency between the deposition parameters, structural morphology, and gas sensing performance was found. The sensing materials were found to be sensitive to different types of gaseous species, so that WO3 and SnO2 had very good response up to 600% to 50 ppm NO, and V2O5 up to -35% to 20 ppm NH3, respectively.
Protection of the Hydroxyphosphinyl Function of Phosphinic Dipeptides by Adamantyl. Application to the Solid-Phase Synthesis of Phosphinic Peptides (1996)

To develop solid-phase synthesis of phosphinic peptides, different FmocXaaPsi{PO(OAd)CH(2)}XaaOH building blocks have been prepared, where Fmoc is (fluorenylmethoxy)carbonyl. In this respect, the protection of the hydroxyphosphinyl function in these phosphinic dipeptides by the adamantyl group turns out to be convenient. The phosphinic adamantyl esters are completely stable in basic conditions and can be removed under relatively mild acidic conditions. Using these building blocks, despite the bulkiness of the adamantyl group, no particular problem of coupling was observed during the solid-phase synthesis of phosphinic peptides by the Fmoc strategy. The developed methodology is of particular interest to facilitate the development of potent inhibitors of zinc-metalloproteases.
Intranasal Insulin Transport is Preserved in Aged SAMP8 Mice and is Altered by Albumin and Insulin Receptor Inhibition (2017)

Insulin delivered to the level of the cribriform plate (intranasal insulin) is being investigated for its ability to enhance memory in people with Alzheimer's disease (AD). Recent work has shown intranasal insulin can be detected in young CD-1 mice within 5 min and is still present 60 min after injection. The current study determined whether intranasal insulin transport and the subsequent brain distribution of insulin varies in young, healthy mice (CD-1) compared to those with an AD-like phenotype (aged SAMP8) or those pre-disposed to develop such a phenotype (young SAMP8). We showed transport does not vary among these three mouse cohorts, suggesting that intranasal uptake and brain pharmacokinetics do not differ with AD-like signs or the genetic predisposition to developing them. We found that co-administration with bovine serum albumin increased levels of insulin in most brain regions. In addition, the insulin receptor inhibitor, S961, decreases the amount of insulin transported throughout the brain after intranasal injection. These results show insulin delivery to the brain by intranasal administration can be modified with agents such as albumin, may be dependent on the insulin receptor, and is not affected by an AD-like phenotype as presented by the SAMP8 mouse.
Biosynthesis of lanthionine-constrained agonists of G protein-coupled receptors (2020)

The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehydroamino acids to cysteines forming (methyl)lanthionines. The leader peptide also guides the export of the formed lanthionine-containing precursor peptide out of Gram-positive bacteria via a lanthipeptide transporter. An engineered cleavage site in the C-terminus of the leader peptide allows to cleave off the leader peptide yielding the modified peptide of interest. Lanthipeptide GPCR agonists are an emerging class of therapeutics of which a few examples have demonstrated high efficacy in animal models of a variety of diseases. One lanthipeptide GPCR agonist has successfully passed clinical Phase Ia.