The gradient of the Casimir force between a Si-SiO 2 -graphene substrate and an Au-coated sphere is measured by means of a dynamic atomic force microscope operated in the frequency shift technique. It is shown that the presence of graphene leads to up to 9% increase in the force gradient at the shortest separation considered. This is in qualitative agreement with the predictions of Lifshitz theory using the dielectric permittivities of Si and SiO 2 and the Dirac model of graphene.

This article reviews current achievements in the field of chemoinformatics and their impact on modern drug discovery processes. The main data mining approaches used in cheminformatics, such as descriptor computations, structural similarity matrices, and classification algorithms, are outlined. The applications of cheminformatics in drug discovery, such as compound selection, virtual library generation, virtual high throughput screening, HTS data mining, and in silico ADMET are discussed. At the conclusion, future directions of chemoinformatics are suggested.

Combinatorial organic synthesis (combinatorial chemistry or CC) and ultrahigh-throughput screening (UHTS) are speeding up drug discovery by increasing capacity for making and screening large numbers of compounds. However, a key problem is to select the smaller set of "representative" compounds from a virtual library to make or screen. Our approach is to select drug-like as well as structurally diverse compounds. The compounds, which are not very drug-like, are less taken into account or excluded even if they contribute to the diversity of the collection. Hence, the first step in the compound selection is to rank compounds in drug-like "degree". To quantify the drug-like "degree", drug-like index (DLI) is introduced in this paper. A compound's DLI is calculated based upon the knowledge derived from known drugs selected from Comprehensive Medicinal Chemistry (CMC) database. The paper describes the way of this knowledge base is formed and the procedure for selecting drug-like compounds.

E2F transcription factor 1 (E2F1) is an important regulator of metabolic diseases, however its role in liver function remains elusive. This study unraveled a regulatory cascade involving E2F1, early growth response-1 (Egr-1), nuclear receptor small heterodimer partner (SHP, NR0B2), and EIA-like inhibitor of differentiation 1 (EID1) in cholestatic liver fibrosis. Liver E2F1 mRNA and protein expression was strongly upregulated in human nonalcoholic steatohepatitis (NASH) and alcohol cirrhosis; the latter was inversely correlated with diminished SHP expression. E2F1 was also highly induced by 3, 5- diethoxycarbonyl-1, 4-dihydrocollidine (DDC) feeding and bile-duct ligation (BDL) in mice. E2F1−/− mice exhibited reduced biliary fibrosis by DDC as determined by Masson Trichrome and Picro Sirius red staining, and decreased serum bile acid (BA), BA pool size, and fecal BA excretion. In addition, cholestatic liver fibrosis induced by BDL, as determined by immunohistochemistry analysis of a1 collagen expression, was increased in SHP−/− mice but attenuated in hepatocyte SHP-overexpressed transgenic (STG) mice. Egr-1 exhibited marked induction in livers of SHP−/− mice compared to the wild type mice in both sham and BDL groups, and reduction in STG livers. Egr-1 promoter was activated by E2F1, and the activation was abrogated by expression of SHP and its co-repressor EID1 in hepatoma cells Huh7, Hepa1, and stellate cells LX2. ChIP assays further confirmed the association of E2F1, SHP and EID1 proteins with the Egr-1 promoter, and their direct protein interactions were determined by GST pull-down assays. Interestingly, E2F1 activated Egr-1 expression in a biphasic fashion as described in both human and mouse hepatocytes. Conclusion E2F1 is a fibrogenic gene and could serve as a potential new diagnostic marker for non-alcoholic and alcoholic liver fibrosis/cirrhosis.

We report precision measurements of the Casimir interaction at larger separation distances between the Au-coated surfaces of a sphere and a plate in ultrahigh vacuum using a much softer cantilever of the dynamic atomic force microscope-based setup and two-step cleaning procedure of the vacuum chamber and test body surfaces by means of UV light and Ar-ion bombardment.Compared to the previously performed experiment, two more measurement sets for the gradient of the Casimir force are provided which confirmed and slightly improved the results. Next, additional measurements have been performed with a factor of two larger oscillation amplitude of the cantilever. This allowed obtaining meaningful results at much larger separation distances. The comparison of the measurement data with theoretical predictions of the Lifshitz theory using the dissipative Drude model to describe the response of Au to the low-frequency electromagnetic field fluctuations shows that this theoretical approach is experimentally excluded over the distances from 250 to 1100 nm (i.e., a major step forward has been made as compared to the previous work where it was excluded up to only 820 nm). The theoretical approach using the dissipationless plasma model at low frequencies is shown to be consistent with the data over the entire measurement range from 250 to 1300 nm. The possibilities to explain these puzzling results are discussed. * Umar.Mohideen@ucr.edu arXiv:1911.00703v2 [quant-ph]

We performed measurements of the gradient of the Casimir force between Au-coated surfaces of a sphere and a plate by means of significantly upgraded dynamic atomic force microscope (AFM) based technique. By introducing combined cleaning procedure of interior surfaces of the vacuum chamber and the test bodies by means of UV light and Ar ions, we reached higher vacuum and eliminated the role of electrostatic patches. Furthermore, the use of much softer cantilever allowed a sixfold decrease of the systematic error in measuring the force gradient. The experimental data are compared with theoretical predictions of the Lifshitz theory taking into account corrections due to the inaccuracy of the proximity force approximation and that due to surface roughness. It is shown that the theoretical approach accounting for the relaxation properties of free electrons is excluded by the data up to a larger than previous sphere-plate separation of 820 nm, whereas an alternative approach is found in a very good agreement with the data. Importance of these results in connection with the foundations of quantum statistical physics is discussed. * Umar.Mohideen@ucr.edu

SummaryAdvanced techniques for observing protein localization in live bacteria show that the distributions are dynamic. For technical reasons, most such techniques have not been applied to outer membrane proteins in Gram-negative bacteria. We have developed two novel live-cell imaging techniques to observe the surface distribution of LamB, an abundant integral outer membrane protein in Escherichia coli responsible for maltose uptake and for attachment of bacteriophage lambda. Using fluorescently labelled bacteriophage lambda tails, we quantitatively described the spatial distribution and dynamic movement of LamB in the outer membrane. LamB accumulated in spiral patterns. The distribution depended on cell length and changed rapidly. The majority of the protein diffused along spirals extending across the cell body. Tracking single particles, we found that there are two populations of LamB -one shows very restricted diffusion and the other shows greater mobility. The presence of two populations recalls the partitioning of eukaryotic membrane proteins between 'mobile' and 'immobile' populations. In this study, we have demonstrated that LamB moves along the bacterial surface and that these movements are restricted by an underlying dynamic spiral pattern.

Endothelial activation is a hallmark of the high-glucose (HG)-induced retinal inflammation associated with diabetic retinopathy (DR). However, precisely how HG induces retinal endothelial activation is not fully understood. We hypothesized that HG-induced upregulation of lysyl oxidase (LOX), a collagen-cross-linking enzyme, in retinal capillary endothelial cells (ECs) enhances subendothelial basement membrane (BM) stiffness, which, in turn, promotes retinal EC activation. Diabetic C57BL/6 mice exhibiting a 70 and 50% increase in retinal intercellular adhesion molecule (ICAM)-1 expression and leukocyte accumulation, respectively, demonstrated a 2-fold increase in the levels of BM collagen IV and LOX, key determinants of capillary BM stiffness. Using atomic force microscopy, we confirmed that HG significantly enhances LOX-dependent subendothelial matrix stiffness in vitro, which correlated with an ∼2.5-fold increase in endothelial ICAM-1 expression, a 4-fold greater monocyte-EC adhesion, and an ∼2-fold alteration in endothelial NO (decrease) and NF-kB activation (increase). Inhibition of LOX-dependent subendothelial matrix stiffening alone suppressed HG-induced retinal EC activation. Finally, using synthetic matrices of tunable stiffness, we demonstrated that subendothelial matrix stiffening is necessary and sufficient to promote EC activation. These findings implicate BM stiffening as a critical determinant of HG-induced retinal EC activation and provide a rationale for examining BM stiffness and underlying mechanotransduction pathways as therapeutic targets for diabetic