ADH1B, the adipocyte-enriched alcohol dehydrogenase, plays an essential, cell-autonomous role in human adipogenesis.

Alcohol dehydrogenase 1B (ADH1B) is a primate-specific enzyme which, uniquely among the ADH class 1 family, is highly expressed both in adipose tissue and liver. Its expression in adipose tissue is reduced in obesity and increased by insulin stimulation. Interference with ADH1B expression has also been reported to impair adipocyte function. To better understand the role of ADH1B in adipocytes, we used CRISPR/Cas9 to delete ADH1B in human adipose stem cells (ASC). Cells lacking ADH1B failed to differentiate into mature adipocytes manifested by minimal triglyceride accumulation and a marked reduction in expression of established adipocyte markers. As ADH1B is capable of converting retinol to retinoic acid (RA), we conducted rescue experiments. Incubation of ADH1B-deficient preadipocytes with 9-cis-RA, but not with all-transretinol, significantly rescued their ability to accumulate lipids and express markers of adipocyte differentiation. A homozygous missense variant in ADH1B (p.Arg313Cys) was found in a patient with congenital lipodystrophy of unknown cause. This variant significantly impaired the protein's dimerization, enzymatic activity, and its ability to rescue differentiation in ADH1B-deficient ASC. The allele frequency of this variant in the Middle Eastern population suggests that it is unlikely to be a fully penetrant cause of severe lipodystrophy. In conclusion, ADH1B appears to play an unexpected, crucial and cell-autonomous role in human adipocyte differentiation by serving as a necessary source of endogenous retinoic acid.

High-Q lasing via all-dielectric Bloch-surface-wave platform.

Controlling the propagation and emission of light via Bloch surface waves (BSWs) has held promise in the field of on-chip nanophotonics. BSW-based optical devices are being widely investigated to develop on-chip integration systems. However, a coherent light source that is based on the stimulated emission of a BSW mode has yet to be developed. Here, we demonstrate lasers based on a guided BSW mode sustained by a gain-medium guiding structure microfabricated on the top of a BSW platform. A long-range propagation length of the BSW mode and a high-quality lasing emission of the BSW mode are achieved. The BSW lasers possess a lasing threshold of 6.7 µJ/mm2 and a very narrow linewidth reaching a full width at half maximum as small as 0.019 nm. Moreover, the proposed lasing scheme exhibits high sensitivity to environmental changes suggesting the applicability of the proposed BSW lasers in ultra-sensitive devices.

Chiroptical Response Inversion and Enhancement of Room-Temperature Exciton-Polaritons Using 2D Chirality in Perovskites.

Although chiral semiconductors have shown promising progress in direct circularly polarized light (CPL) detection and emission, they still face potential challenges. A chirality-switching mechanism or approach integrating two enantiomers is needed to discriminate the handedness of a given CPL; additionally, a large material volume is required for sufficient chiroptical interaction. These two requirements pose significant obstacles to the simplification and miniaturization of the devices. Here, room-temperature chiral polaritons fulfilling dual-handedness functions and exhibiting a more-than-two-order enhancement of the chiroptical signal are demonstrated, by embedding a 40 nm-thick perovskite film with a 2D chiroptical effect into a Fabry-Pérot cavity. By mixing chiral perovskites with different crystal structures, a pronounced 2D chiroptical effect is accomplished in the perovskite film, featured by an inverted chiroptical response for counter-propagating CPL. This inversion behavior matches the photonic handedness switch during CPL circulation in the Fabry-Pérot cavity, thus harvesting giant enhancement of the chiroptical response. Furthermore, affected by the unique quarter-wave-plate effects, the polariton emission achieves a chiral dissymmetry of ±4% (for the emission from the front and the back sides). The room-temperature polaritons with the strong dissymmetric chiroptical interaction shall have implications on a fundamental level and future on-chip applications for biomolecule analysis and quantum computing.

Angular Control of Circularly Polarized Emission from Achiral Molecules via Magnetic Dipoles Sustained in a Chiral Metamirror.

Circularly polarized emission (CPE) plays an important role in the designs of advanced displays and photonic integrated circuits. Unfortunately, the control of CPE handedness is limited by the chiral metasurfaces employed to emit chiral light. Particularly, the switching of the handedness with chiral metasurfaces relies on flipping the metasurfaces, which adds some constraints to practical applications. Herein, we propose an angle-sensitive chiral metamirror with Mie resonators to realize handedness switching. The Mie resonator supports a magnetic dipole having large field enhancement. This chiral metamirror is applied to excite CPEs with opposite handedness at emission angles within 10°. In contrast to the conventional methods, this work proposes a more efficient approach to manipulate the handedness of CPE.

Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases.

ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.

The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes.

Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL) proteins are key regulators of necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic-independent functions of RIPK3 and MLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 and MLKL in adipocyte differentiation. Mlkl-KO abolished white adipocyte differentiation via a strong expression of Wnt10b, a ligand of the Wnt/ß-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of Ripk3. Conversely, Mlkl and Ripk3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.

Ligand Engineering and Recrystallization of Perovskite Quantum-Dot Thin Film for Low-Threshold Plasmonic Lattice Laser.

Solution-process perovskite quantum dots (QDs) are promising materials to be utilized in photovoltaics and photonics with their superior optical properties. Advancements in top-down nanofabrication for perovskite are thus important for practical photonic and plasmonic devices. However, different from the chemically synthesized nano/micro-structures that show high quality and low surface roughness, the perovskite QD thin film prepared by spin-coating or the drop-casting process shows a large roughness and inhomogeneity. Low-roughness and low-optical loss perovskite QD thin film is highly desired for photonic and optoelectronic devices. Here, this work presents a pressure-assisted ligand engineering/recrystallization process for high-quality and well-thickness controlled CsPbBr3 QD film and demonstrates a low-threshold and single-mode plasmonic lattice laser. A recrystallization process is proposed to prepare the QD film with a low roughness (RMS = 1.3 nm) and small thickness (100 nm). Due to the low scattering loss and strong interaction between gain media and plasmonic nanoparticles, a low lasing threshold of 16.9 µJ cm-2 is achieved. It is believed that this work is not only important to the plasmonic laser field but also provides a promising and general nanofabrication method of solution-processed QDs for various photonic and plasmonic devices.

Integration of on-chip perovskite nanocrystal laser and long-range surface plasmon polariton waveguide with etching-free process.

Perovskite materials prepared in the form of solution-processed nanocrystals and used in top-down fabrication techniques are very attractive to develop low-cost and high-quality integrated optoelectronic circuits. Particularly, integrated miniaturized coherent light sources that can be connected to light-guiding structures on a chip are highly desired. To control light propagating on a small footprint with low-loss optical modes, long-range surface plasmon polariton (LRSPP) waveguides are employed. Herein, we demonstrate an on-chip fabricated photonic-plasmonic hybrid system consisting of a perovskite lasing structure coupled to an LRSPP waveguide achieving a low lasing threshold and a propagation length over 100 µm. Preventing perovskite material degradation and the formation of surface roughness of the laser cavity during fabrication is made possible by designing a fabrication technique without any etching step.

Sensitive Oligonucleotide Detection Using Resonant Coupling between Fano Resonance and Image Dipoles of Gold Nanoparticles.

The surface plasmon resonance (SPR)-based sensor has been widely used for biodetection. One of the attractive roles is the gold nanostructure with Fano resonance. Its sharp resonant profile takes advantage of the high figure of merit (FoM) in high-sensitivity detection. However, it is still difficult to detect small molecules at low concentrations due to the extremely low refractive index changes on the metallic surface. We propose using the coupling of image dipoles of gold nanoparticles (AuNPs) and Fano resonance of periodic capped gold nanoslits (CGNs) for sensitive small-molecule detections. The coupling mechanism was verified by three-dimensional finite-difference time-domain calculations and experiments. AuNPs on CGN form image dimer assemblies and induce image dipole with resonance wavelengths ranging from 730 to 550 nm. The surface plasmon polaritons (SPPs) interact with the image dipole of the AuNP on the CGNs and then scatter out through the periodic gold caps. The experimental results show that the peak intensity of grating resonance is decreased by the effect of image dipole and exhibits the maximum intensity change when the Fano resonance matches the resonance of image dipole. The 50 nm AuNPs can be detected with a surface density of less than one particle/µm2 by using the intensity change as the signal. With the resonant coupling between Fano resonance and image dipole extinction, the oligonucleotide with a molecular weight of 5.5 kDa can be detected at a concentration of 100 fM. The resonant coupling dramatically pushes the sensitivity boundary, and we report the limit of detection (LOD) to be 3 orders of magnitude lower than that of the prism-based SPR. This study provides a promising and efficient method for detecting low concentrations of small molecules such as aptamers, miRNA, mRNA, and peptides.

MRCK-Alpha and Its Effector Myosin II Regulatory Light Chain Bind ABCB4 and Regulate Its Membrane Expression.

ABCB4, is an adenosine triphosphate-binding cassette (ABC) transporter localized at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine secretion into bile. Gene variations of ABCB4 cause different types of liver diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3). The molecular mechanisms underlying the trafficking of ABCB4 to and from the canalicular membrane are still unknown. We identified the serine/threonine kinase Myotonic dystrophy kinase-related Cdc42-binding kinase isoform α (MRCKα) as a novel partner of ABCB4. The role of MRCKα was explored, either by expression of dominant negative mutant or by gene silencing using the specific RNAi and CRISPR-cas9 strategy in cell models. The expression of a dominant-negative mutant of MRCKα and MRCKα inhibition by chelerythrine both caused a significant increase in ABCB4 steady-state expression in primary human hepatocytes and HEK-293 cells. RNA interference and CRISPR-Cas9 knockout of MRCKα also caused a significant increase in the amount of ABCB4 protein expression. We demonstrated that the effect of MRCKα was mediated by its downstream effector, the myosin II regulatory light chain (MRLC), which was shown to also bind ABCB4. Our findings provide evidence that MRCKα and MRLC bind to ABCB4 and regulate its cell surface expression.

Near-Zero-Index Slabs on Bloch Surface Wave Platform for Long-Range Directional Couplers and Optical Logic Gates.

Near-zero-index materials and structures, with their extraordinary optical behaviors of phase-free propagation resulting in directional radiation, provide a possible approach for directional coupling and optical logic gates in photonic integrated circuits. However, the radiation from the near-zero-index structures is limited to a short range of a few hundreds of nanometers. A Bloch surface wave (BSW), an electromagnetic surface wave that can be excited at the interface between an all-dielectric multilayer and a dielectric medium with a low-loss optical mode, provides a solution to increase the propagation length. In this work, we present a nanostructured near-zero-index slab integrated on the all-dielectric metal-free BSW platform for long-range surface wave radiation. By employing the long-range directional surface-wave radiation, a directional coupler and optical logic gates based on the BSW near-zero-index slabs are realized. The proposed directional couplers achieve long coupling distances (the electric-field magnitude ratio between the input slab and output slab is 0.22 with a 50 µm coupling distance), which is 2 orders of magnitude longer than that of conventional directional couplers based on evanescent wave coupling. By controlling the interference pattern of the BSW between the slabs, the XOR logic gate is experimentally demonstrated with a significant extinction ratio of 27.9 dB at telecommunications wavelengths. The BSW near-zero-index logic gates and the directional coupler with long-range light propagation provide an approach to the development of photonic integrated circuits and metal-free surface wave-based applications.

The Ca2+- and phospholipid-binding protein Annexin A2 is able to increase and decrease plasma membrane order.

Annexin A2 (AnxA2) is a calcium- and phospholipid-binding protein that plays roles in cellular processes involving membrane and cytoskeleton dynamics and is able to associate to several partner proteins. However, the principal molecular partners of AnxA2 are negatively charged phospholipids such as phosphatidylserine and phosphatidyl-inositol-(4,5)-phosphate. Herein we have studied different aspects of membrane lipid rearrangements induced by AnxA2 membrane binding. X-ray diffraction data revealed that AnxA2 has the property to stabilize lamellar structures and to block the formation of highly curved lipid phases (inverted hexagonal phase, HII). By using pyrene-labelled cholesterol and the environmental probe di-4-ANEPPDHQ, we observed that in model membranes, AnxA2 is able to modify both, cholesterol distribution and lipid compaction. In epithelial cells, we observed that AnxA2 localizes to membranes of different lipid order. The protein binding to membranes resulted in both, increases and/or decreases in membrane order depending on the cellular membrane regions. Overall, AnxA2 showed the capacity to modulate plasma membrane properties by inducing lipid redistribution that may lead to an increase in order or disorder of the membranes.

Lithographic in-mold patterning for CsPbBr3 nanocrystals distributed Bragg reflector single-mode laser.

Extensive studies on lead halide perovskites have shown that these materials are excellent candidates as gain mediums. Recently, many efforts have been made to incorporate perovskite lasers in integrated optical circuits. Possible solutions would be to utilize standard lithography with an etching/lift-off process or a direct laser etching technique. However, due to the fragile nature of the lead halide perovskites which gives rise to significant material deterioration during the lithography and etching processes, realizing a small-size, low-roughness, and single-mode laser remains a challenge. Here, a lithographic in-mold patterning method realized by nanocrystal concentration control and a multi-step filling-drying process is proposed to demonstrate CsPbBr3 nanocrystals distributed-Bragg-reflector (DBR) waveguide lasers. This method realizes the patterning of the CsPbBr3 nanocrystal laser cavity and DBR grating without lift-off and etching processes, and the smallest fabricated structures are obtained in a few hundred nanometers. The single-mode lasing is demonstrated at room temperature with a threshold of 23.5 µJ cm-2. The smallest full width at half maximum FWHM of the laser output is 0.4 nm. Due to the fabrication process and the DBR laser geometry, the lasers can be fabricated in a compact array, which is important for incorporating perovskite-based lasers in complex optoelectronic circuits.

RAB10 Interacts with ABCB4 and Regulates Its Intracellular Traffic.

ABCB4 (ATP-binding cassette subfamily B member 4) is an ABC transporter expressed at the canalicular membrane of hepatocytes where it ensures phosphatidylcholine secretion into bile. Genetic variations of ABCB4 are associated with several rare cholestatic diseases. The available treatments are not efficient for a significant proportion of patients with ABCB4-related diseases and liver transplantation is often required. The development of novel therapies requires a deep understanding of the molecular mechanisms regulating ABCB4 expression, intracellular traffic, and function. Using an immunoprecipitation approach combined with mass spectrometry analyses, we have identified the small GTPase RAB10 as a novel molecular partner of ABCB4. Our results indicate that the overexpression of wild type RAB10 or its dominant-active mutant significantly increases the amount of ABCB4 at the plasma membrane expression and its phosphatidylcholine floppase function. Contrariwise, RAB10 silencing induces the intracellular retention of ABCB4 and then indirectly diminishes its secretory function. Taken together, our findings suggest that RAB10 regulates the plasma membrane targeting of ABCB4 and consequently its capacity to mediate phosphatidylcholine secretion.

Enhancing Raman signals from bacteria using dielectrophoretic force between conductive lensed fiber and black silicon.

An osmium-coated lensed fiber (OLF) probe combined with a silver-coated black silicon (SBS) substrate was used to generate a dielectrophoretic (DEP) force that traps bacteria and enables Raman signal detection from bacteria. The lensed fiber coated with a 2-nm osmium layer was used as an electrode for the DEP force and also as a lens to excite Raman signals. The black silicon coated with a 150-nm silver layer was used both as the surface-enhanced Raman scattering (SERS) substrate and the counter electrode. The enhanced Raman signal was collected by the same OLF probe and further analyzed with a spectrometer. For Raman measurements, a drop of bacterial suspension was placed between the OLF probe and the SBS substrate. By controlling the frequency of an AC voltage on the OLF probe and SBS substrate, a DEP force at 1 MHz concentrated bacteria on the SBS surface and removed the unbound micro-objects in the solution at 1 kHz. A bacteria concentration of 6 × 104 CFU/mL (colony forming units per mL) could be identified in less than 15 min, using a volume of only 1 µL, by recording the variation of the Raman peak at 740 cm-1.

Molecular dynamics study of water confined in MIL-101 metal-organic frameworks.

Molecular dynamics simulations of water adsorbed in Material Institute Lavoisier MIL-101(Cr) metal-organic frameworks are performed to analyze the kinetic properties of water molecules confined in the framework at 298.15 K and under different vapor pressures and clarify the water adsorption mechanism in MIL-101(Cr). The terahertz frequency-domain spectra (THz-FDS) of water are calculated by applying fast Fourier transform to the configurational data of water molecules. According to the characteristic frequencies in the THz-FDS, the dominant motions of water molecules in MIL-101(Cr) can be categorized into three types: (1) low-frequency translational motion (0-0.5 THz), (2) medium-frequency vibrational motion (2-2.5 THz), and (3) high-frequency vibrational motion (>6 THz). Each type of water motion is confirmed by visualizing the water configuration in MIL-101(Cr). The ratio of the number of water molecules with low-frequency translational motion to the total number of water molecules increases with the increase in vapor pressure. In contrast, that with medium-frequency vibrational motion is found to decrease with vapor pressure, exhibiting a pronounced decrease after water condensation has started in the cavities. That with the high-frequency vibrational motion is almost independent of the vapor pressure. The interactions between different types of water molecules affect the THz-FDS. Furthermore, the self-diffusion coefficient and the velocity auto-correlation function are calculated to clarify the adsorption state of the water confined in MIL-101(Cr). To confirm that the general trend of the THz-FDS does not depend on the water model, the simulations are performed using three water models, namely, rigid SPC/E, flexible SPC/E, and rigid TIP5PEw.

Molecular Regulation of Canalicular ABC Transporters.

The ATP-binding cassette (ABC) transporters expressed at the canalicular membrane of hepatocytes mediate the secretion of several compounds into the bile canaliculi and therefore play a key role in bile secretion. Among these transporters, ABCB11 secretes bile acids, ABCB4 translocates phosphatidylcholine and ABCG5/G8 is responsible for cholesterol secretion, while ABCB1 and ABCC2 transport a variety of drugs and other compounds. The dysfunction of these transporters leads to severe, rare, evolutionary biliary diseases. The development of new therapies for patients with these diseases requires a deep understanding of the biology of these transporters. In this review, we report the current knowledge regarding the regulation of canalicular ABC transporters' folding, trafficking, membrane stability and function, and we highlight the role of molecular partners in these regulating mechanisms.

Effect of CFTR correctors on the traffic and the function of intracellularly retained ABCB4 variants.

BACKGROUND & AIM: ABCB4 is expressed at the canalicular membrane of hepatocytes. This ATP-binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors. METHODS: The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4. RESULTS: We observed that the correctors C10, C13, and C17, as well as the combinations of C3 + C18 and C4 + C18, allowed the rescue of maturation and canalicular localization of four distinct traffic-defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and/or ATP-binding sites of the transporter. CONCLUSION: Our results illustrate the uncoupling between the traffic and the activity of ABCB4 because the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.

Modulating Ni/Ce Ratio in NiyCe100-yOx Electrocatalysts for Enhanced Water Oxidation.

Oxygen evolution reaction (OER) is the key reaction for water splitting, which is used for hydrogen production. Oxygen vacancy engineering is an effective method to tune the OER performance, but the direct relationship between the concentration of oxygen vacancy and OER activity is not well understood. Herein, a series of NiyCe100-yOx with different concentration of oxygen vacancies were successfully synthesized. The larger concentration of oxygen vacancies in Ni75Ce25Ox and Ni50Ce50Ox result in their lower Tafel slopes, small mass-transfer resistance, and larger electrochemical surface areas of the catalysts, which account for the higher OER activities for these two catalysts. Moreover, with a fixed current density of 10 mA/cm2, the potential remains stable at 1.57 V for more than 100 h, indicating the long-term stability of the Ni75Ce25Ox catalyst.

Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency.

BACKGROUND & AIM: The canalicular bile salt export pump (BSEP/ABCB11) of hepatocytes is the main adenosine triphosphate (ATP)-binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in ABCB11 cause several cholestatic diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) often lethal in absence of liver transplantation. We investigated in vitro the effect and potential rescue of a BSEP mutation by ivacaftor, a clinically approved cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) potentiator. METHODS: The p.T463I mutation, identified in a PFIC2 patient and located in a highly conserved ABC transporter motif, was studied by 3D structure modelling. The mutation was reproduced in a plasmid encoding a rat Bsep-green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin-Darby canine kidney (MDCK) clones co-expressing the rat sodium-taurocholate co-transporting polypeptide (Ntcp/Slc10A1). RESULTS: As the wild-type protein, BsepT463I was normally targeted to the canalicular membrane of Can 10 cells. As predicted by 3D structure modelling, taurocholate transport activity was dramatically low in MDCK clones expressing BsepT463I . Ivacaftor treatment increased by 1.7-fold taurocholate transport activity of BsepT463I (P < .0001), reaching 95% of Bsepwt activity. These data suggest that the p.T463I mutation impairs ATP-binding, resulting in Bsep dysfunction that can be rescued by ivacaftor. CONCLUSION: These results provide experimental evidence of ivacaftor therapeutic potential for selected patients with PFIC2 caused by ABCB11 missense mutations affecting BSEP function. This could represent a significant step forward for the care of patients with BSEP deficiency.