gebhart/patrepeval huggingface dataset:
Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer (2023)

Overcoming PARPi resistance is a high clinical priority. We established and characterized comparative in vitro models of acquired PARPi resistance, derived from either a <i>BRCA1</i>-proficient or <i>BRCA1</i>-deficient isogenic background by long-term exposure to olaparib. While parental cell lines already exhibited a certain level of intrinsic activity of multidrug resistance (MDR) proteins, resulting PARPi-resistant cells from both models further converted toward MDR. In both models, the PARPi-resistant phenotype was shaped by (i) cross-resistance to other PARPis (ii) impaired susceptibility toward the formation of DNA-platinum adducts upon exposure to cisplatin, which could be reverted by the drug efflux inhibitors verapamil or diphenhydramine, and (iii) reduced PARP-trapping activity. However, the signature and activity of ABC-transporter expression and the cross-resistance spectra to other chemotherapeutic drugs considerably diverged between the <i>BRCA1</i>-proficient vs. <i>BRCA1-</i>deficient models. Using dual-fluorescence co-culture experiments, we observed that PARPi-resistant cells had a competitive disadvantage over PARPi-sensitive cells in a drug-free medium. However, they rapidly gained clonal dominance under olaparib selection pressure, which could be mitigated by the MRP1 inhibitor MK-751. Conclusively, we present a well-characterized in vitro model, which could be instrumental in dissecting mechanisms of PARPi resistance from HR-proficient vs. HR-deficient background and in studying clonal dynamics of PARPi-resistant cells in response to experimental drugs, such as novel olaparib-sensitizers.
Microbial activity response to hydrogen injection in thermophilic anaerobic digesters revealed by genome-centric metatranscriptomics (2018)

This is the first study investigating biogas reactor metatranscriptome dynamics following hydrogen injection for biomethanation and carbon fixation to short-chain fatty acids purposes. The same microbes showed different patterns of metabolic regulation in the two reactor configurations. It was observed an effect of the specialized acidogenic reactor on the overall microbial consortium composition and activity in the two-stage digester. There were also suggested the main species responsible for methanation, short-chain fatty acids production, and electron transport chain mechanisms, in both reactor configurations.
Passive and active mechanical properties of biotemplated ceramics revisited (2016)

Living nature and human technology apply different principles to create hard, strong and tough materials. In this review, we compare and discuss prominent aspects of these alternative strategies, and demonstrate for selected examples that nanoscale-precision biotemplating is able to produce uncommon mechanical properties as well as actuating behavior, resembling to some extent the properties of the original natural templates. We present and discuss mechanical testing data showing for the first time that nanometer-precision biotemplating can lead to porous ceramic materials with deformation characteristics commonly associated with either biological or highly advanced technical materials. We also review recent findings on the relation between hierarchical structuring and humidity-induced directional motion. Finally, we discuss to which extent the observed behavior is in agreement with previous results and theories on the mechanical properties of multiscale hierarchical materials, as well as studies of highly disperse technical materials, together with an outlook for further lines of investigation.
Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: A cellular model of insulin resistance (2010)

Obesity and type 2 diabetes mellitus represent a significant global health crisis. These two interrelated diseases are typified by perturbed insulin signaling in the hypothalamus. Using novel hypothalamic cell lines, we have begun to elucidate the molecular and intracellular mechanisms involved in the hypothalamic control of energy homeostasis and insulin resistance. In this review, we present evidence of insulin and glucose signaling pathways that lead to changes in neuropeptide gene expression. We have identified some of the molecular mechanisms involved in the control of de novo hypothalamic insulin mRNA expression. And finally, we have defined key mechanisms involved in the etiology of cellular insulin resistance in hypothalamic neurons that may play a fundamental role in cases of high levels of insulin or saturated fatty acids, often linked to the exacerbation of obesity and diabetes.
Pro-atrial natriuretic peptide is a prognostic marker in sepsis, similar to the APACHE II score: an observational study (2004)

Pro-ANP appears to be a valuable tool for individual risk assessment in sepsis patients and for stratification of high-risk patients in future intervention trials. Further studies are needed to validate our results.
DNA Recognition by Cys<sub>2</sub>His<sub>2</sub> Zinc Finger Proteins (2000)

Cys2His2 zinc fingers are one of the most common DNA-binding motifs found in eukaryotic transcription factors. These proteins typically contain several fingers that make tandem contacts along the DNA. Each finger has a conserved beta beta alpha structure, and amino acids on the surface of the alpha-helix contact bases in the major groove. This simple, modular structure of zinc finger proteins, and the wide variety of DNA sequences they can recognize, make them an attractive framework for attempts to design novel DNA-binding proteins. Several studies have selected fingers with new specificities, and there clearly are recurring patterns in the observed side chain-base interactions. However, the structural details of recognition are intricate enough that there are no general rules (a "recognition code") that would allow the design of an optimal protein for any desired target site. Construction of multifinger proteins is also complicated by interactions between neighboring fingers and the effect of the intervening linker. This review analyzes DNA recognition by Cys2His2 zinc fingers and summarizes progress in generating proteins with novel specificities from fingers selected by phage display.
Luciferase‐based quantification of membrane fusion induced by <scp>SARS‐CoV‐2</scp> S protein (2022)

The ongoing COVID-19 pandemic is caused by SARS-CoV-2. Although several effective vaccines that target the Spike protein on the viral surface have been deployed, additional therapeutic agents are urgently needed. Here, we developed a system to measure the Spike protein function by quantifying cellular membrane fusion induced by the Spike protein. The system enables the evaluation of the effects of drugs and neutralizing antibodies against SARS-CoV-2 without using live viruses. Furthermore, the system characterizes membrane fusion activity of the Spike protein of each variant to reveal that Delta variant has more potent than Wuhan and Omicron. Our system could lead to develop high-throughput screening for drug candidates and neutralization antibodies that target virus entry and characterize Spike proteins from variants.
Redetermination of the structure of bi(9,10-dihydro-9,10-anthracenediyl) at 198 K (1990)

C 28 H 20 cristallise dans Pbca avec a=8,101, b=12,034, c=18,753 A, Z=4, T=198 K; affinement jusqu'a R=0,0416. La molecule est composee de deux unites anthracene liees par deux liaisons. Les deux liaisons symetriquement equivalentes, c(9)-c(10') et c(10)-c(9') sont inhabituellement longues, 1,618 A, comparativement a une longueur C(sp 3 )-C(sp 3 ) qui est de 1,54 A
Metastasis suppressor <scp>NME</scp>1 regulates melanoma cell morphology, self‐adhesion and motility via induction of fibronectin expression (2015)

Expression of the metastasis suppressor NME1 in melanoma is associated with reduced cellular motility and invasion in vitro and metastasis in vivo, but the underlying molecular mechanisms are not completely understood. Herein, we report a novel mechanism through which NME1 controls melanoma cell morphology via upregulation of the extracellular matrix (ECM) protein fibronectin. Expression of NME1 strongly suppressed cell motility in melanoma cell lines 1205LU and M14. The resulting sedentary phenotype was associated with a more flattened appearance and marked increases in actin stress fibre and focal adhesion formation. NME1-induced focal adhesions were colocalized with dense deposits of fibronectin, which were absent or minimal in the corresponding NME1-deficient parental lines. NME1 was a strong inducer of fibronectin mRNA and protein expression, shown with reciprocal approaches of forced NME1 expression and shRNA-mediated knock-down. Increased synthesis and ECM deposition of fibronectin was necessary for NME1-induced cell spreading, as knock-down of fibronectin opposed the effects of NME1 on cell morphology. Fibronectin knock-down also reversed the ability of NME1 to promote aggregation when cells were plated on a non-adherent substratum. Similarly, inhibiting activation of the fibronectin receptor integrin α4β1 with an anti-α4 antibody reversed the motility-suppressing effect of NME1. A positive correlation was observed between NME1 and fibronectin mRNA in clinical biopsies of normal skin, benign nevi and primary melanomas, but not in metastatic forms, suggesting the NME1/fibronectin axis represents a barrier to melanoma progression. In summary, these findings indicate fibronectin is an important effector of the motility-suppressing function of NME1 in melanoma cells.
Prevalence, conservation and functional analysis of Yersinia and Escherichia CRISPR regions in clinical Pseudomonas aeruginosa isolates (2010)

Here, we report the characterization of 122 Pseudomonas aeruginosa clinical isolates from three distinct geographical locations: Dartmouth Hitchcock Medical Center in New Hampshire, USA, the Charles T. Campbell Eye Microbiology Lab at the University of Pittsburgh Medical Center, USA, and the Aravind Eye Hospital in Madurai, India. We identified and located clustered regularly interspaced short palindromic repeats (CRISPR) in 45/122 clinical isolates and sequenced these CRISPR, finding that Yersinia subtype CRISPR regions (33 %) were more prevalent than the Escherichia CRISPR region subtype (6 %) in these P. aeruginosa clinical isolates. Further, we observed 132 unique spacers from these 45 CRISPR that are 100 % identical to prophages or sequenced temperate bacteriophage capable of becoming prophages. Most intriguingly, all of these 132 viral spacers matched to temperate bacteriophage/prophages capable of inserting into the host chromosome, but not to extrachromosomally replicating lytic P. aeruginosa bacteriophage. We next assessed the ability of the more prevalent Yersinia subtype CRISPR regions to mediate resistance to bacteriophage infection or lysogeny by deleting the entire CRISPR region from sequenced strain UCBPP-PA14 and six clinical isolates. We found no change in CRISPR-mediated resistance to bacteriophage infection or lysogeny rate even for CRISPR with spacers 100 % identical to a region of the infecting bacteriophage. Lastly, to show these CRISPR and cas genes were expressed and functional, we demonstrated production of small CRISPR RNAs. This work provides both the first examination to our knowledge of CRISPR regions within clinical P. aeruginosa isolates and a collection of defined CRISPR-positive and -negative strains for further CRISPR and cas gene studies.
Epidemic Keratoconjunctivitis-Causing Adenoviruses Induce MUC16 Ectodomain Release To Infect Ocular Surface Epithelial Cells (2016)

Human adenoviruses (HAdV), species D in particular (HAdV-D), are frequently associated with epidemic keratoconjunctivitis (EKC). Although the infection originates at the ocular surface epithelium, the mechanisms by which HAdV-Ds bypass the membrane-associated mucin (MAM)-rich glycocalyx of the ocular surface epithelium to trigger infection and inflammation remain unknown. Here, we report that an EKC-causing adenovirus (HAdV-D37), but not a non-EKC-causing one (HAdV-D19p), induces ectodomain release of MUC16-a MAM with barrier functions at the ocular surface-from cultured human corneal and conjunctival epithelial cells. HAdV-D37, but not HAdV-D19p, is also found to decrease the glycocalyx barrier function of corneal epithelial cells, as determined by rose bengal dye penetrance assays. Furthermore, results from quantitative PCR (qPCR) amplification of viral genomic DNA using primers specific to a conserved region of the E1B gene show that, in comparison to infection by HAdV-D19p, infection by HAdV-D37 is significantly increased in corneal epithelial cells. Collectively, these results point to a MUC16 ectodomain release-dependent mechanism utilized by the EKC-causing HAdV-D37 to initiate infection at the ocular surface. These findings are important in terms of understanding the pathogenesis of adenoviral keratoconjunctivitis. Similar MAM ectodomain release mechanisms may be prevalent across other mucosal epithelia in the body (e.g., the airway epithelium) that are prone to adenoviral infection. IMPORTANCE Human adenoviruses (HAdVs) are double-stranded DNA viruses that cause infections across all mucosal tissues in the body. At the ocular surface, HAdVs cause keratoconjunctivitis (E. Ford, K. E. Nelson, and D. Warren, Epidemiol Rev 9:244-261, 1987, and C. M. Robinson, D. Seto, M. S. Jones, D. W. Dyer, and J. Chodosh, Infect Genet Evol 11:1208-1217, 2011, doi:10.1016/j.meegid.2011.04.031)-a highly contagious infection that accounts for nearly 60% of conjunctivitis cases in the United States (R. P. Sambursky, N. Fram, and E. J. Cohen, Optometry 78:236-239, 2007, doi:10.1016/j.optm.2006.11.012, and A. M. Pihos, J Optom 6:69-74, 2013, doi:10.1016/j.optom.2012.08.003). The infection begins with HAdV entry within ocular surface epithelial cells; however, the mechanisms used by HAdVs to transit the otherwise protective mucosal barrier of ocular surface epithelial cells prior to entry remain unknown. Here, we report that the highly virulent keratoconjunctivitis-causing HAdV-D37 induces release of the extracellular domain (ectodomain) of MUC16, a major component of the mucosal barrier of ocular surface epithelial cells, prior to infecting underlying cells. Currently, there is no specific treatment for controlling this infection. Understanding the early steps involved in the pathogenesis of keratoconjunctivitis and using this information to intercept adenoviral entry within cells may guide the development of novel strategies for controlling the infection.
D223 Liquefaction of photovoltaic module to recover useful resources (2015)

Due to recent rapid spread of photovoltaic system, large amounts of waste photovoltaic modules will be discarded in Japan in two decades. In this study, liquefaction of ethylene-vinyl acetate (EVA) was carried out in several solvents under mild condition to recover useful resources. EVA was liquefied completely in cresol mixture solvent with a small amount of sulfuric acid at 200 ℃ for 60 min. Liquefaction of EVA was accelerated by increase of acid additives. Useful metals and high-purity silicon could be recovered easily as solid residue by using a mesh, because EVA was liquefied and fluidized.
Can template-based protein models guide the design of sequence fitness for enhanced thermal stability of single domain antibodies? (2015)

We investigate the practical use of comparative (template-based) protein models in replica-exchange simulations of single-domain antibody (sdAb) chains to evaluate if the models can correctly predict in rank order the thermal susceptibility to unfold relative to experimental melting temperatures. The baseline model system is the recently determined crystallographic structure of a llama sdAb (denoted as A3), which exhibits an unusually high thermal stability. An evaluation of the simulation results for the A3 comparative model and crystal structure shows that, despite the overall low Cα root-mean-square deviation between the two structures, the model contains misfolded regions that yields a thermal profile of unraveling at a lower temperature. Yet comparison of the simulations of four different comparative models for sdAb A3, C8, A3C8 and E9, where A3C8 is a design of swapping the sequence of the complementarity determining regions of C8 onto the A3 framework, discriminated among the sequences to detect the highest and lowest experimental melting transition temperatures. Further structural analysis of A3 for selected alanine substitutions by a combined computational and experimental study found unexpectedly that the comparative model performed admirably in recognizing substitution 'hot spots' when using a support-vector machine algorithm.
La mesure d’amplitudes complexes par interférométrie à décalage multi-latéral (2009)

Numerous wave front sensors have been proposed. Among the most used for the measurement of classical aberrations, lateral shearing interferometers are well-known. The purpose of this study was to measure more complex wave fronts: the first stage of complexity was the addition of discontinuities (for example a phase step). The measurement of this kind of surfaces proved useful for coherently combining laser fibers during the CAN project (Coherent Amplification Network). It aims at demonstrating the combining of 64 passive fibers. Moreover, thanks to special features of the interferometer, we theoretically and experimentally showed a step-selective measurement method, which enables to analyze slowly-varying, continuous aberrations separately from steps. Finally, the complete information extraction makes it possible to measure both the phase and the amplitude of a luminous wave and thus to completely characterize the wave at a point. More than a wave front sensor, the interferometer is then a complex amplitude sensor, that is an electromagnetic field sensor. This measurement ability was demonstrated by the characterization of sub-wavelength gratings. Moreover, we showed that the analysis of scalar electric fields in the presence of phase dislocations (or vortex) was possible. This paves the way of new applications, such as non-intrusive measurement of surfaces or flows, which strongly modify the phase of the incident beam.
Role of the ammonium group in the diffusion of quaternary ammonium compounds in Streptococcus mutans biofilms (2007)

These results suggest that the interactions between the quaternary ammonium groups and the EPS matrices are not the prime contribution of the strong CPC binding, and the alkyl chain length plays a role in this association, likely through hydrophobic interactions.
Trends and Effects of Child Restraint Systems Based on Volvo's Swedish Accident Database (1997)

&lt;div class="htmlview paragraph"&gt;A positive trend to more frequent use of child restraint systems (CRS) in Sweden, during the last 20 years, is shown in this report. During the same period, the overall injury risk, for different age groups of child occupants, has decreased substantially. This indicates the high effectiveness of the child restraint systems.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;Children need car occupant safety systems specially designed for their size. This paper clearly states the need for child safety systems and discusses benefits and drawbacks with regard to different restraints, ages and injuries.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;The analysis points out, that when a crash occurs, the maximum effect of a child restraint system is not reached, if the child is not using the correct system for their size.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;There is even a tendency that the injury risk increases when children switch from one restraint system to another, i.e. are at the youngest ages for which the specific restraint is recommended.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;The background data used, is based on Volvo's traffic accident research. The report is founded on crashes in Sweden which occurred between 1976 and 1996 and comprises a total of 25.000 crashes. This analysis is based on a subset of 4242 child occupants between 0 and 15 years of age, restrained and unrestrained.&lt;/div&gt;
Structure Determination, Functional Characterization, and Biosynthetic Implications of Nybomycin Metabolites from a Mining Reclamation Site-Associated <i>Streptomyces</i> (2019)

We report the isolation and characterization of three new nybomycins (nybomycins B-D, <b>1</b>-<b>3</b>) and six known compounds (nybomycin, <b>4</b>; deoxynyboquinone, <b>5</b>; α-rubromycin, <b>6</b>; β-rubromycin, <b>7</b>; γ-rubromycin, <b>8</b>; and [2α(1<i>E</i>,3<i>E</i>),4β]-2-(1,3-pentadienyl)-4-piperidinol, <b>9</b>) from the Rock Creek (McCreary County, KY) underground coal mine acid reclamation site isolate <i>Streptomyces</i> sp. AD-3-6. Nybomycin D (<b>3</b>) and deoxynyboquinone (<b>5</b>) displayed moderate (<b>3</b>) to potent (<b>5</b>) cancer cell line cytotoxicity and displayed weak to moderate anti-Gram-(+) bacterial activity, whereas rubromycins <b>6</b>-<b>8</b> displayed little to no cancer cell line cytotoxicity but moderate to potent anti-Gram-(+) bacterial and antifungal activity. Assessment of the impact of <b>3</b> or <b>5</b> cancer cell line treatment on 4E-BP1 phosphorylation, a predictive marker of ROS-mediated control of cap-dependent translation, also revealed deoxynyboquinone (<b>5</b>)-mediated downstream inhibition of 4E-BP1p. Evaluation of <b>1</b>-<b>9</b> in a recently established axolotl embryo tail regeneration assay also highlighted the prototypical telomerase inhibitor γ-rubromycin (<b>8</b>) as a new inhibitor of tail regeneration. Cumulatively, this work highlights an alternative nybomycin production strain, a small set of new nybomycin metabolites, and previously unknown functions of rubromycins (antifungal activity and inhibition of tail regeneration) and also provides a basis for revision of the previously proposed nybomycin biosynthetic pathway.
Spatial Error and Convergence in Streamline Simulation (2005)

Abstract Streamline models are routinely used for waterflood optimization and management, and are being extended to more complex processes, e.g., compositional simulation. Despite these new developments, no systematic study has examined the underlying numerical spatial and temporal discretization errors in streamline simulation and their convergence. Such studies are a prerequisite to determining the optimal density of streamlines during simulation and ensuring the resulting accuracy of the solution. In this paper we first examine transverse spatial errors, e.g., errors due to the number or placement of streamlines. We provide an analytic proof and a numeric demonstration of the order of spatial convergence of the mass balance discretization error. Both global and local calculations are performed, and demonstrate the impact of stagnation regions on the order of convergence. A second transverse error arises for faulted grids, where lack of flux continuity at cell faces can lead to incorrect trajectories. These trajectory errors are of zeroth order, and can only be resolved by introducing additional degrees of freedom into the streamline velocity model. Longitudinal spatial errors also arise, and are associated with the inaccurate calculation of time of flight across cells. We show that the commonly used algorithm for corner point cells leads to inaccurate time of flight calculations for stratigraphic grids, depending upon aspect ratio. We provide a simple and exact means of calculating the time of flight for arbitrary corner point cells, or unstructured grids, in two or three dimensions, for either compressible or incompressible flow. Finally, using this new time of flight formulation, we analyze a series of cross-sectional finite difference simulations to identify grid orientation errors in the numerical calculation of flux and spatial error.