Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery.

Background: Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown. Methods: Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes. Results: Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the 'cholesterol homeostasis' pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression. Conclusion: In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.

Total syntheses of Tetrodotoxin and 9-epiTetrodotoxin.

Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.

Asymmetric Substitution by Alkynyl Copper Driven Dearomatization and Rearomatization.

Catalytic asymmetric transformations by dearomatization have developed into a widely applicable synthetic strategy, but heavily relied on the use of arenes bearing a heteroatom. In this case, the dearomatization is facilitated by the involvement of a p-orbital electron of the heteroatom. Different from the conventional substrate-dependent model, here we demonstrate that the activation by a d-orbital electron of the transition-metal center can serve as a driving force for dearomatization, and is applied to the development of a novel asymmetric alkynyl copper facilitated remote substitution reaction. A newly modified PyBox chiral ligand enables the construction of valuable diarylmethyl and triarylmethyl skeletons in high enantioselectivities. An unexpected tandem process involving sequential remote substitution/cyclization/1,5-H shift leads to the formation of the enantioenriched C-N axis. A gram-scale reaction and various downstream transformations highlight the robustness of this method and the potential transformations of the products. Preliminary mechanistic studies reveal a mononuclear Cu-catalyzed remote substitution process.

Large dynamic range dual-mode pH sensors via dye-doped ionic liquid fiber optofluidic lasers.

We report a fiber optofluidic laser (FOFL) using an RhB-doped ionic liquid (BmimPF6) as the gain medium and explore its application for large dynamic range highly sensitive pH sensing. Due to the high Q-factor of the FOFL and the unique merits of BmimPF6, lasing emission presents a threshold of only 0.61 µJ mm-1. Particularly, lasing emission behaviors are strongly dependent on the pH value of the gain medium, i.e., in the pH range 4.28-6.37, the lasing central wavelength blue-shifts monotonically with a sensitivity as high as 5.02 nm per pH unit, which we attribute to the conversion of the cationic form of RhB to the zwitterionic form caused by the deprotonation of the COOH group. Under alkaline conditions (pH 7.20-11.17), the lasing emission intensity exhibits a significant decrease and the corresponding lasing central wavelength is also blue-shifted due to the solvent effect. The sensitivity based on the wavelength shift is 3.03 nm per pH unit, which is 4-fold higher than that of fluorescence-based sensing, while the sensitivity based on the variation of the lasing emission intensity is almost three orders of magnitude higher than that of fluorescence-based sensing. Our work presents a novel dual sensing paradigm in response to different pH conditions, which can greatly improve the reliability and discrimination of pH sensing.

Optical fiber optofluidic laser based on surfactant solubilization of rhodamine B gain in an aqueous solution.

We report a whispering gallery mode (WGM)-based fiber optofluidic laser (FOFL), in which rhodamine B (RhB) in an aqueous surfactant solution of sodium dodecylbenzene sulfonate (SDBS) is used as the laser gain medium. Here, the role of SDBS is to scatter the RhB dye molecules to effectively prevent its self-association in the aqueous solution. Therefore, the fluorescence quantum yield of the used RhB dye is improved due to the enhanced solubilization, which results in a low lasing threshold of ∼2.2 µJ/mm2 when the concentration of SDBS aqueous solution reaches up to 20 mM, on par with or even better than most of the optofluidic dye lasers using RhB as the gain medium in an organic solution. We then establish a model of solubilization capacity of SDBS micelles, which successfully addresses the mechanisms of dye-surfactant interactions in the proposed FOFL system. We further apply this FOFL platform to the case of concentration sensing of the used SDBS, which exhibits a 2-order-of-magnitude improvement in sensitivity compared to the fluorescence measurement due to the signal amplification inherent to the lasing process. The proposed FOFL platform in combination with surfactant solubilization gain medium in an aqueous solution promises to enable chip-scale coherent light sources for various environmental and bio-chemical sensing applications.

Mechanical Stabilization of a Bacterial Adhesion Complex.

The adhesions between Gram-positive bacteria and their hosts are exposed to varying magnitudes of tensile forces. Here, using an ultrastable magnetic tweezer-based single-molecule approach, we show the catch-bond kinetics of the prototypical adhesion complex of SD-repeat protein G (SdrG) to a peptide from fibrinogen ß (Fgß) over a physiologically important force range from piconewton (pN) to tens of pN, which was not technologically accessible to previous studies. At 37 °C, the lifetime of the complex exponentially increases from seconds at several pN to ∼1000 s as the force reaches 30 pN, leading to mechanical stabilization of the adhesion. The dissociation transition pathway is determined as the unbinding of a critical ß-strand peptide ("latch" strand of SdrG that secures the entire adhesion complex) away from its binding cleft, leading to the dissociation of the Fgß ligand. Similar mechanical stabilization behavior is also observed in several homologous adhesions, suggesting the generality of catch-bond kinetics in such bacterial adhesions. We reason that such mechanical stabilization confers multiple advantages in the pathogenesis and adaptation of bacteria.

Application of piconewton forces to individual filopodia reveals mechanosensory role of L-type Ca2+ channels.

Filopodia are ubiquitous membrane projections that play crucial role in guiding cell migration on rigid substrates and through extracellular matrix by utilizing yet unknown mechanosensing molecular pathways. As recent studies show that Ca2+ channels localized to filopodia play an important role in regulation of their formation and since some Ca2+ channels are known to be mechanosensitive, force-dependent activity of filopodial Ca2+ channels might be linked to filopodia's mechanosensing function. We tested this hypothesis by monitoring changes in the intra-filopodial Ca2+ level in response to application of stretching force to individual filopodia of several cell types using optical tweezers. Results show that stretching forces of tens of pN strongly promote Ca2+ influx into filopodia, causing persistent Ca2+ oscillations that last for minutes even after the force is released. Several known mechanosensitive Ca2+ channels, such as Piezo 1, Piezo 2 and TRPV4, were found to be dispensable for the observed force-dependent Ca2+ influx, while L-type Ca2+ channels appear to be a key player in the discovered phenomenon. As previous studies have shown that intra-filopodial transient Ca2+ signals play an important role in guidance of cell migration, our results suggest that the force-dependent activation of L-type Ca2+ channels may contribute to this process. Overall, our study reveals an intricate interplay between mechanical forces and Ca2+ signaling in filopodia, providing novel mechanistic insights for the force-dependent filopodia functions in guidance of cell migration.

High sensitivity pH sensing by using a ring resonator laser integrated into a microfluidic chip.

We present a chip-scale integrated pH sensor with high sensitivity by using an optofluidic ring resonator (OFRR) laser. An optical fiber with a high refractive index (RI) is employed both as an optical cavity and the sensing reactor along a microchannel, while disodium fluorescein (DSF) aqueous solution with a low RI is served as the cladding gain medium and fluorescent probes. The pump light is introduced along the fiber axis and guided by the total internal reflection at the fiber/cladding interface. The evanescent field of the pump light extends out of the fiber surface and efficiently excites the dye molecules residing in the evanescent field region of the Whispering Gallery Modes (WGMs) of the OFRRs to produce lasing emission. This pumping scheme provides a uniform excitation to the gain medium and significantly increases the signal-to-noise ratio, ensuring a low lasing threshold and highly sensitive sensing. The lasing threshold property under different pH conditions is experimentally and theoretically conducted to evaluate the sensing performance, which shows that the lasing threshold highly depends on the pH value of the cladding solution due to the increasing deprotonation process. We further verify that the intensity of the lasing emission and the pH value shows good linearity in the pH range 6.51-8.13, with a 2-order-of-magnitude sensitivity enhancement compared to fluorescence measurement. The proposed OFRR lasing platform shows excellent robustness and low sample consumption, providing a powerful sensing strategy in medicine, and hazardous/toxic/volatile sensing, which require label-free, real-time, and in situ detection.

A Portable Micro-Gas Chromatography with Integrated Photonic Crystal Slab Sensors on Chip.

The miniaturization of gas chromatography (GC) systems has made it possible to utilize the analytical technique in various on-site applications to rapidly analyze complex gas samples. Various types of miniaturized sensors have been developed for micro-gas chromatography (µGC). However, the integration of an appropriate detector in µGC systems still faces a significant challenge. We present a solution to the problem through integration of µGC with photonic crystal slab (PCS) sensors using transfer printing technology. This integration offers an opportunity to utilize the advantages of optical sensors, such as high sensitivity and rapid response time, and at the same time, compensate for the lack of detection specificity from which label-free optical sensors suffer. We transfer printed a 2D defect free PCS on a borofloat glass, bonded it to a silicon microfluidic gas cell or directly to a microfabricated GC column, and then coated it with a gas responsive polymer. Realtime spectral shift in Fano resonance of the PCS sensor was used to quantitatively detect analytes over a mass range of three orders. The integrated µGC-PCS system was used to demonstrate separation and detection of a complex mixture of 10 chemicals. Fast separation and detection (4 min) and a low detection limit (ng) was demonstrated.

Design and Experiment Using Flexible Bumps for Piezoelectric-Driven Hydraulically Amplified Braille Dot Display.

This paper describes the design of a piezoelectric-driven hydraulically amplified Braille-flexible bump device that enables the flexible formation of Braille characters. A piezoelectric vibrator is used to excite fluid resonance in a cavity, and displacement is realized by compressing the fluid, allowing Braille character dots to be formed. First, the structural design and working principle of the device, as well as the method used to drive the fluid, are explained. Expressions for the output displacement and amplification ratio of the flexible film and piezoelectric vibrator are then obtained through kinetic analysis of the system unit. Subsequently, the structural parameters that affect the output displacement and the liquid amplification are described. Finally, experimental tests of the system are explained. The results indicate that the output displacement of the contact formed by the flexible film reaches 0.214 mm, satisfying the requirements of the touch sensitivity standard for the blind, when the fluid cavity diameter measures 31 mm and the resonance frequency is 375.4 Hz. The corresponding water discharge is 8.8 mL. This study proves that constructing a Braille bump device in this way is both feasible and effective.

Preparation of IgG imprinted polymers by metal-free visible-light-induced ATRP and its application in biosensor.

Immunoglobulin G (IgG) is related to the occurrence of many diseases, such as measles and inflammatory. In this paper, IgG imprinted polymers (IgGIPs) were fabricated on the surface of nano Au/nano Ni modified Au electrode (IgGIPs/AuNCs/NiNCs/Au) via metal-free visible-light-induced atom transfer radical polymerization (MVL ATRP). The IgGIPs were prepared by IgG conjugated with fluorescein isothiocyanate (FITC-IgG) as both a template and a photocatalyst. After the templates were removed, the photocatalysts (FITC) would not remain in the polymer and avoided all the effect of catalysts on the electrode. The fabricated electrodes were examined by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). Under the optimized conditions, IgGIPs/AuNCs/NiNCs/Au was prepared and used as an electrochemical biosensor. The biosensor could be successfully applied for the determination of IgG by differential pulse voltammetry (DPV) measurement. The results showed that the proposed biosensor displayed a broader linear range and a lower detection limit for IgG determination when it was compared to those similar IgG sensors. The linear range from 1.0 × 10-6 mg L-1 to 1.0 × 101 mg L-1 was obtained with a low detection limit (LOD) of 2.0 × 10-8 mg L-1 (S/N = 3). Briefly, the biosensor in this study introduced an easy and non-toxic method for IgG determination and also provided a progressive approach for designing protein imprinted polymers.

Versatile Optofluidic Solid-Core/Liquid-Cladding Waveguide Based on Evanescent Wave Excitation.

In this paper, we present the design and operation of a solid-core/liquid-cladding (SL) waveguide excited by an evanescent wave. To do this, an optical fiber is integrated into a microfluidic channel and pumped along the fiber axis, ensuring the cladding solution is excited by the evanescent field of the guided mode at the core/cladding interface. The pump beam is guided by the total internal reflection in the fiber, providing a uniform excitation along the microfluidic channel. The evanescent wave provides precise excitation to the dye molecules in close proximity to the core/cladding interface, which significantly reduces the background fluorescence and increases the signal-to-noise ratio. Fluorescence intensity measurements of different dye concentrations and refractive indices of the cladding solution are conducted to evaluate their influences on the propagation loss, which shows that the peak intensity propagation loss can be as low as about 0.1 dB/cm. We further exemplify that the intensity of the fluorescence emission and the dye concentration show good linearity when the dye is in the low concentration region (<250 µM). A broad-band and simultaneous light source with a single pump light is also demonstrated by employing cascade SL waveguide segments through fluorescence resonance energy transfer. The proposed SL waveguide demonstrates excellent robustness and is easy to fabricate and use, providing a versatile platform for a variety of applications, such as high-sensitivity detection of low-concentration samples, multiband on-chip light sources, and simultaneous measurement of multiplexed parameters.

Reconfigurable Integrated Optofluidic Droplet Laser Arrays.

Optofluidic lasers are an emerging technology for the development of miniaturized light sources and biological and chemical sensors. However, most optofluidic lasers demonstrated to date are operated at the single optical cavity level, which limits their applications in high-throughput biochemical sensing, high-speed wavelength switching, and on-chip spectroscopic analysis. Here, we demonstrated an optofluidic droplet laser array on a silicon chip with integrated microfluidics, in which four individual droplet optical cavities are generated and controlled by a 2 × 2 nozzle array. Arrays of droplets with a diameter ranging from 115 to 475 µm can be generated, removed, and regenerated on demand. The lasing threshold of the droplet laser array is in the range of 0.63-2.02 µJ/mm2. An image-based lasing threshold analysis method is developed, which enables simultaneous lasing threshold measurement for all laser units within the laser array using a low-cost camera. Compared to the conventional spectrum-based threshold analysis method, the lasing threshold obtained from the image-based method showed consistent results. Our droplet laser array is a promising technology in the development of cost-effective and integrated coherent light source on a chip for point-of-care applications.

Optofluidic vapor sensing with free-space coupled 2D photonic crystal slabs.

We report here a compact vapor sensor based on polymer coated two-dimensional (2D) defect-free photonic crystal slabs (PCS). The sensing mechanism is based on the resonance spectral shift associated with the Fano resonance mode in the PCS due to the vapor molecule adsorption and desorption induced changes in both polymer thickness and polymer refractive index (RI). Sensitivity due to RI and thickness change were theoretically investigated respectively. With three different thicknesses of OV-101 polymer coating, sensitivity and response time were experimentally evaluated for hexane and ethanol vapors. The polymer demonstrated roughly four times higher sensitivity towards the hexane vapor than ethanol vapor. The PCS sensor with thicker polymer coating showed higher sensitivity to both hexane and ethanol vapors but exhibiting longer response time.

Effects of azo dye on simultaneous biological removal of azo dye and nutrients in wastewater.

The potential disrupting effects of Azo dye on wastewater nutrients removal deserved more analysis. In this study, 15 days exposure experiments were conducted with alizarin yellow R (AYR) as a model dye to determine whether the dye caused adverse effects on biological removal of both the dye and nutrients in acclimated anaerobic-aerobic-anoxic sequencing batch reactors. The results showed that the AYR removal efficiency was, respectively, 85.7% and 66.8% at AYR concentrations of 50 and 200 mg l-1, while higher AYR inlet (400 mg l-1) might inactivate sludge. Lower removal of AYR at 200 mg l-1 of AYR was due to the insufficient support of electron donors in the anaerobic process. However, the decolorized by-products p-phenylenediamine and 5-aminosalicylic were completely decomposed in the following aerobic stage at both 50 and 200 mg l-1 of AYR concentrations. Compared with the absence of AYR, the presence of 200 mg l-1 of AYR decreased the total nitrogen removal efficiency from 82.4 to 41.1%, and chemical oxygen demand (COD) removal efficiency initially decreased to 68.1% and then returned to around 83.4% in the long-term exposure time. It was also found that the inhibition of AYR, nitrogen and COD removal induced by a higher concentration of AYR was due to the increased intracellular reactive oxygen species production, which caused the rise of oxidation-reduction potential value and decreased ammonia monooxygenase and nitrite oxidoreductase activities.

Optofluidic droplet dye laser generated by microfluidic nozzles.

We present an optofluidic droplet dye laser that is generated by an array of microfluidic nozzles fabricated on a polycarbonate chip. A droplet resonator forms upon pressurizing the nozzle backside microfluidic channel. Multimode low-threshold lasing is observed from individual microdroplets doped with dye. Additionally, droplets can be conveniently released from the nozzle by water rinsing from the top microfluidic channel and subsequently regenerated, and thus achieve optofluidic lasers on-demand. Our work demonstrates a new approach to generating on-chip laser source and laser arrays in a simple, reproducible, reconfigurable, and low-cost fashion.

Photonic crystal bandedge membrane lasers on silicon.

We report here the design and experimental demonstration of optically pumped photonic crystal bandedge membrane lasers on silicon-on-insulator (SOI) and on bulk silicon (Si) substrates, based on heterogeneously integrated InGaAsP multi-quantum-well membrane layers transfer printed onto patterned photonic crystal cavities. Single-mode lasing under room-temperature operation was observed at 1542 nm, with excellent side mode suppression ratio greater than 31.5 dB, for the laser built on SOI substrate. For the laser built on bulk Si substrate, single-mode lasing was also achieved at 1452 nm with much lower thermal resistance, as compared to that of the laser built on SOI substrates. Such improved thermal characteristics are favorable for lasers operating potentially at higher temperatures and higher power.

In Silico Identification of a Novel Hinge-Binding Scaffold for Kinase Inhibitor Discovery.

To explore novel kinase hinge-binding scaffolds, we carried out structure-based virtual screening against p38α MAPK as a model system. With the assistance of developed kinase-specific structural filters, we identify a novel lead compound that selectively inhibits a panel of kinases with threonine as the gatekeeper residue, including BTK and LCK. These kinases play important roles in lymphocyte activation, which encouraged us to design novel kinase inhibitors as drug candidates for ameliorating inflammatory diseases and cancers. Therefore, we chemically modified our substituted triazole-class lead compound to improve the binding affinity and selectivity via a "minimal decoration" strategy, which resulted in potent and selective kinase inhibitors against LCK (18 nM) and BTK (8 nM). Subsequent crystallographic experiments validated our design. These rationally designed compounds exhibit potent on-target inhibition against BTK in B cells or LCK in T cells, respectively. Our work demonstrates that structure-based virtual screening can be applied to facilitate the development of novel chemical entities in crowded chemical space in the field of kinase inhibitor discovery.

Optical Refractive Index Sensing Based on High-Q Bound States in the Continuum in Free-Space Coupled Photonic Crystal Slabs.

High sensitivity (S) and high quality factor (Q) are desirable to achieve low detection limit in label-free optical sensors. In this paper, we theoretically demonstrate that single-layer and coupled bi-layer photonic crystal slabs (PCS) possess simultaneously high S and high Q near the bound states in the continuum (BIC). We theoretically achieved S > 800 nm/RIU and Q > 107 in refractive index sensing in the 1400-1600 nm telecom optical wavelength bands. We experimentally demonstrated an S of 94 nm/RIU and a Q of 1.2 × 104, with a detection limit of 6 × 10-5 refractive index unit. These sensor designs can find applications in biochemical sensing, environmental monitoring, and healthcare.