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The lipid droplet (LD) is a dynamic organelle responsible for lipid storage and metabolism that plays important roles in maintaining lipid homeostasis. However, limited strategies are available for...

Aims: Whereas intravenous administration of Toll-like receptor 4 ligand lipopolysaccharide (LPS) to human volunteers is frequently used in clinical pharmacology studies, systemic use of LPS has practical limitations. We aimed to characterize the intradermal LPS response in healthy volunteers, and as such qualify the method as local inflammation model for clinical pharmacology studies. Methods: Eighteen healthy male volunteers received 2 or 4 intradermal 5 ng LPS injections and 1 saline injection on the forearms. The LPS response was evaluated by noninvasive (perfusion, skin temperature and erythema) and invasive assessments (cellular and cytokine responses) in skin biopsy and blister exudate. Results: LPS elicited a visible response and returned to baseline at 48 hours. Erythema, perfusion and temperature were statistically significant (P Discussion: Intradermal LPS administration in humans causes an acute, localized and transient inflammatory reaction that is well-tolerated by healthy volunteers. This may be a valuable inflammation model for evaluating the pharmacological activity of anti-inflammatory investigational compounds in proof of pharmacology studies.

We developed luminescent rhenium(i) perfluorobiphenyl complexes that reacted specifically with the cysteine residue of the π-clamp sequence (FCPF) to afford novel peptide-based imaging reagents, photosensitisers for singlet oxygen and enzyme sensors.

In this work, we demonstrate bioorthogonal control of the phosphorescence and singlet oxygen photosensitisation properties of new iridium(iii) tetrazine complexes by different reaction partners; the system was exploited for organelle-specific staining and modulated photocytotoxic activity applications.

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

Scientific information on antioxidant properties and phenolic content of Nauclea latifolia used in ethnoveterinary medicine in Burkina Faso are limited. Therefore, the quantification of the antioxidant activity of different parts of this specie remains an interesting and useful task, particularly for finding new sources for natural antioxidants. The aim of this study was to evaluate the antioxidant activity and total polyphenols of Nauclea latifolia Smith (Rubiaceae) acetonic fractions from Burkina Faso. n-hexane, dichloromethane, ethyl acetate and n-butanol fractions of leaves, barks and root barks were tested for their antioxidant activities using DPPH, ABTS and FRAP methods. Folin-Ciocalteu and AlCl3 reagents were used to quantify the polyphenols. n-butanol fraction of barks (58.16 ± 0.76 mg GAE/100 mg), dichloromethane fraction of barks (51.13 ± 0.99; 26.14 mg GAE/100 mg) have presented the best total phenolic contents while the best total flavonoid contents were found in n-butanol fraction of leaves and n-hexane fraction of leaves with 4.85 ± 0.14 mg EQ/100mg and 2.92 ± 0.13 mg EQ/100mg, respectively. It was observed that n-hexane fraction of leaves was scavenge more DPPH free radicals with a value of 1011.98± 17,01 µmol EAA/g. That of n-butanol fractions of barks was showed the best ferric reduction power (3056.37 ± 96.66 µmol EAA/g) and the highest ABTS cation radicals scavenging capacity (7031.52 ± 254.98 µmol EAA/g). Nevertheless, this work encourages investigations on Burkina Faso plant species used in the ethnoveterinary medicine as sources of antioxidants. Keywords: Fraction; Ouagadougou; Barks, Total Polyphenols Contents; Radicals.

Summary Treatments that target single mediators of sepsis have failed to reduce its high mortality rate. Here we developed multifunctional tannic acid-Zn2+-gentamicin nanoparticles (TA-Zn-Gen NPs) that target multiple mediators of sepsis to improve sepsis treatment. TA-Zn-Gen NPs with lower gentamicin content possessed net negative surface charge but still bound cell-free DNA (cfDNA) with high affinity. The TA-Zn-Gen NPs exhibited five modes of anti-sepsis activity: (1) scavenged cfDNA and inhibited cfDNA-initiated activation of toll-like receptors and NF-κB signaling; (2) inhibited activated macrophage-induced macrophage recruitment; (3) scavenged reactive oxygen species (ROS) and reduced ROS-induced DNA damage and cell death; (4) inhibited nitric oxide production induced by lipopolysaccharides; and (5) potent antibacterial activity. The NPs reduced multiple organ damage and increased the survival rate of mice with severe sepsis. Together, the results demonstrate the potency of targeting multiple mediators for sepsis treatment, and support the development of multifunctional NPs for treating other intractable inflammation-related diseases.

In this study, the mechanical properties of aluminum vibration damping sheet and 1.5 GPa HPF steel sheet (SABC1470) dissimilar joining were evaluated. Joint methods of self piercing rivet (SPR), bolt/nut, flow drill screw (FDS), and blind rivet were compared to evaluate joint characteristic. In SPR Joining, buckling failure was occurred in SPR rivet caused by the strength of the 1.5 GPa HPF steel. So that, SPR hybrid joining was selected with a Al5052 alloy additional plate in lower sheet for formability and pre-hole processed on 1.5 GPa HPF steel in upper sheet. Through optimized of SPR die, the tensile shear load of the SPR hybrid joining was measured 7.53 kN. In FDS joining, failure of fastener was occurred due to the high strength of the 1.5 GPa HPF steel. FDS joining was available after pre-hole process on the 1.5 GPa HPF steel. However, delamination of the aluminum damping plate was observed and the tensile shear load was measured 3.14 kN. In bolt/nut joining, tensile shear load was measured depending on process variable (combination of plate, washer and tightening torque) and maximum tensile load was measured 5.43 kN. In blind rivet joining, the maximum tensile shear load was measured 3.64 kN, when the Al vibration damping sheet was placed on the upper plate. The large area of the blind rivet head released the concentration of stress on Al vibration damping sheet. As a result, SPR hybrid joining is considerable method because pre-hole processing is minimized and tensile shear load is higher than the other method.

The aim of this study was to investigate the effects of titanium dioxide nanotube addition on the water sorption and water solubility values of different composite resins. Titanium dioxide nanotubes were synthesized from titanium dioxide powder in anatase form and in 13 nm diameter by hydrothermal process and then functionalized with methacrylic acid. Characterization of the nanotubes was performed by scanning electron microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction and Fourier transform infrared spectroscopy. A flowable composite resin (Filtek Ultimate Flowable) and four flowable bulk-fill composite resins (Filtek Bulk Fill Flowable, SDR Bulk Fill Flowable, Venus Bulk Fill, X-tra Base) were tested. Two groups of each composite resin were prepared: groups of the resins without nanotubes; groups of the resins reinforced with 1.0 wt% functionalized titanium dioxide nanotube. Sorption and solubility in water were assessed according to ISO 4049 standards after 1, 7, 14, 21 days immersion periods. Data were analyzed using Mann-Whitney U and Kruskal-Wallis H tests (p < 0.05). Long cylindrical tubular structures with a diameter of 41.09-72.49 nm were observed in electron microscopy analysis. The band at 1636 cm( - 1) showed the existence of the vinyl (C=C) bond of methacrylic acid coordinated to the nanotubes in Fourier transform infrared spectroscopy analysis. None of the materials tested in this study exceeded the maximum sorption and solubility values established by ISO. Regarding the water solubility, negative values were obtained. TiO2 nanotube reinforcement decreased the water sorption and solubility values significantly at different evaluation periods in all composite resins except for Venus (p < 0.05).

Aims Remdesivir is a prodrug of an adenosine triphosphate analogue and is currently the only drug formally approved for the treatment of hospitalised COVID-19 patients. Nucleoside/nucleotide analogues have been shown to induce mitochondrial damage and cardiotoxicity, and this may be exacerbated by hypoxia, which frequently occurs in severe COVID-19 patients. Although there have been few reports of adverse cardiovascular events associated with remdesivir, clinical data are limited. Here, we investigated whether remdesivir induced cardiotoxicity using an in vitro human cardiac model. Methods and Results Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to remdesivir under normoxic and hypoxic conditions to simulate mild and severe COVID-19 respectively. Remdesivir induced mitochondrial fragmentation, reduced redox potential and suppressed mitochondrial respiration at levels below the estimated plasma concentration under both normoxic and hypoxic conditions. Non-mitochondrial damage such as electrophysiological alterations and sarcomere disarray were also observed. Importantly, some of these changes persisted after the cessation of treatment, culminating in increased cell death. Mechanistically, we found that inhibition of DRP1, a regulator of mitochondrial fission, ameliorated the cardiotoxic effects of remdesivir, showing that remdesivir-induced cardiotoxicity was preventable and excessive mitochondrial fission might contribute to this phenotype. Conclusions Using an in vitro model, we demonstrated that remdesivir can induce cardiotoxicity in hiPSC-CMs at clinically relevant concentrations. These results reveal previously unknown potential side-effects of remdesivir and highlight the importance of further investigations with in vivo animal models and active clinical monitoring to prevent lasting cardiac damage to patients. Translational perspective Adult cardiomyocytes have limited ability to regenerate, thus treatment-induced cardiotoxicity can potentially cause irreparable harm. Remdesivir is currently the only FDA approved treatment for COVID-19 but clinical safety data are limited. Using human pluripotent stem cell-derived cardiomyocytes, we revealed that remdesivir induced persistent mitochondrial and structural abnormalities at clinically relevant concentrations. We advise confirmatory experiments in in vivo animal models, investigations of cardioprotective strategies, and closer patient monitoring such that treatment-induced cardiotoxicity does not contribute to the long term sequelae of COVID-19 patients., Graphical Abstract Graphical Abstract

Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells. Supplementary Information The online version contains supplementary material available at 10.1007/s10456-021-09819-0.

Effects of the hot and dense plasma on the doubly excited states (DES) of the four-electron beryllium-like ions (BLI) with Z varying from 4 to 10 have been investigated by applying the stabilization method. The Debye–Huckel model has been used to describe the effective potential in the plasma. The four-electron ions are treated as an effective three-body problem by means of the method of model potential. One, four and five DESs lying above the 1s 2 2p threshold are found to exist in the ions having Z = 4 , Z = 5 and Z = 6 − 10 respectively. For the plasma-free case our results for the energy and width of the DESs are in agreement with the available results in the literature. A detailed study is made on the changes of energy and width of the DESs of the ions with varying plasma screening strength. Particular emphasis is given to explore the effects of the plasma on the whole sequence of ions.

Aims: The present work is the use of Scheffler technology to melt plastic waste to produce composite materials using an oven type receiver. The composite material in this study contains polyethylene as a matrix and sand as reinforcement. Study Design: The fusion temperature of polyethylene is about 200°C and is obtained by solar concentration. The experimental plastic melting unit in Saaba (latitude 12.38° N; longitude -1.43° E), Burkina Faso, uses two 8 m² Scheffler concentrators sharing a cubic receiver. Three types of mirrors with a reflectivity of at least 90% are used as reflecting facets to equip the Scheffler dishes at the site. Methodology: The thermal behavior of the receiver is analyzed experimentally. Temperatures are measured on the inner and outer walls as well as the internal air temperature with 5 K-type thermocouples. When the fusion temperature is reached on the inside, we introduce the plastic waste which has been previously washed, crushed, dried and weighed. Results: The installed model obtained an average energy of 1.80 kW at the receiver and an average internal temperature of 251.15°C for an average irradiance of 623 W/m² during the no-load test. During the load test, an average energy of 1.34 kW and an internal temperature of 206.4°C were reached for an average irradiance of 473 W/m² and an optical efficiency of 56%. This test led to the production of two pavers of the composite material matrix with 2.2 kg of plastic waste. Conclusion: These results show that the profiles of the primary reflector, tracking system, and tilt axis are accurate and the maximum concentrated solar flux converges on the absorbing surfaces of the receiver. The tempered panes of the absorbing surfaces is more transparent and less emissive. Thus our device contributes to the valorization of plastic waste by using a non-polluting energy source.

The undesirable sneak current path is one of the key challenges in high-density memory integration for the emerging cross-bar memristor arrays. This work demonstrates a new heterojunction design of oxide multilayer stacking with different oxygen vacancy contents to manipulate the oxidation state. We show that the bipolar resistive switching (BRS) behavior of the Pt/TiOx/Pt cross-bar structure can be changed to complementary resistive switching (CRS) by introducing a thin TiO2 layer in the middle of the TiOx layer to obtain a Pt/TiOx/TiO2/TiOx/Pt device architecture with a double-junction active matrix. In contrast to the BRS in a single-layer TiOx matrix, the device with a double-junction matrix remains in a high-resistance state in the voltage range below the SET voltage, which makes it an efficient structure to overcome the sneak path constraints of undesired half-selected cells that lead to incorrect output reading. This architecture is capable of eliminating these half-selected cells between the nearby cross-bar cells in a smaller programming voltage range. A simplified model for the switching mechanism can be used to account for the observed high-quality switching performance with excellent endurance and current retention properties.

Background and Objective Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. Methods An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. Results In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. Conclusions Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00357-0.

Chronic intermittent hypoxia (CIH), a hallmark of obstructive sleep apnea (OSA), is associated with various cardiovascular diseases. In the present study, we assessed the effect of the lipid reducing agent atorvastatin on CIH-induced myocardial oxidative stress and apoptosis in a mouse OSA model. Forty-eight C57BL/6J mice were evenly divided among normoxia + vehicle, normoxia + atorvastatin, CIH + vehicle, and CIH + atorvastatin groups. CIH consisted of a hypoxia-reoxygenation cycle in which oxygen concentrations fluctuated from 21% to 6% and back over two minutes for 8 hours each day (30 events/hour). CIH exposure continued for 12 weeks. Atorvastatin (5 mg/kg) was administered from week 6 through the end of the experiment. CIH increased malondialdehyde levels and decreased superoxide dismutase activity, total antioxidant capacity, and nuclear factor erythroid 2-related factor 2 levels in cardiac tissue, indicating a reduction in antioxidant activity. Atorvastatin significantly reversed those effects (p < 0.05). CIH also increased B-cell lymphoma 2-associated protein X and cleaved caspased-3 levels as well as the myocardial apoptotic rate, as indicated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Atorvastatin had no effect on those changes (p > 0.05). Thus, atorvastatin administration exerts antioxidant but not anti-apoptotic effects after CIH and may therefore have therapeutic potential in OSA patients with cardiovascular comorbidities.

New neutral iridium(III) complexes featuring a cubic polyhedral oligomeric silsesquioxane (POSS) unit, [Ir(N∧C)2(L1-POSS)] [HN∧C = 2-phenylpyridine (Hppy; 1), 2-phenylbenzothioazole (Hbt; 2), and 2-(1-naphthyl)benzothiazole (Hbsn; 3); L1-POSS = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-heptakis(isobutyl)POSS-propyl carbamate], were designed and synthesized. Their POSS-free counterparts, [Ir(N∧C)2(L1)] [L1 = (E)-N-(4-hydroxymethylphenyl)-1-(2-hydroxyphenyl)methanimine; HN∧C = Hppy (1a), Hbt (2a), and Hbsn (3a)], and the poly(ethylene glycol) (PEG) derivatives [Ir(N∧C)2(L1-PEG)] [L1-PEG = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-[2-[ω-methoxypoly(1-oxapropyl)]ethyl]carbamate; HN∧C = Hppy (1b), Hbt (2b), and Hbsn (3b)] were also prepared. The photophysical, photochemical, and biological properties of the POSS complexes were compared with those of their POSS-free and PEG-modified counterparts. Upon irradiation, all of these complexes displayed orange-to-red emission and long emission lifetimes under ambient conditions. The bsn complexes 3, 3a, and 3b exhibited the highest singlet oxygen (1O2) generation quantum yields (ΦΔ = 0.85-0.86) in aerated CH3CN. Laser-scanning confocal microscopy images revealed that complexes 1-3 and 1a-3a showed exclusive lipid-droplet staining upon cellular uptake, while the PEG derivatives 1b-3b displayed lysosomal localization. Complex 3 was utilized to study various lipid-droplet-related biological events including lipid-droplet accumulation under oleic acid stimulation, the movement of lipid droplets, and preadipocyte differentiation. Notably, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the ppy complexes 1 and 1b and the bt complexes 2 and 2b were noncytotoxic both in the dark and upon irradiation at 450 nm for 5 min (IC50 > 200 μM), while the bsn complexes 3, 3a, and 3b showed low dark cytotoxicity (IC50 = 52.9 to >200 μM) and high photocytotoxicity (IC50 = 1.1-5.3 μM). The cellular uptake, internalization mechanisms, and cell death pathways of these complexes were also investigated. This work not only offers promising luminescent probes for lipid droplets through the structural modification of iridium(III) complexes but also paves the way to the construction of new reagents for theranostics.

This study was conducted to determine the pH, protein concentration, mineral, phenolic, flavonoid, and organic acid contents, as well as the antioxidant activity of three batches of fruit jiaosu (F1B3, F1B4, and F1B5). The jiaosu was prepared by mixing ten types of fresh fruits, raw honey, and water (3:1:10, w/w/w), and fermented at room temperature for six months. All fruit jiaosu had low pH (2.96–3.69), and the protein concentration was ranged from 8.45 to 16.2 µg/mL. Potassium (605.0–657.2 mg/L) was found to be the most abundant mineral in all the samples, followed by magnesium, calcium, and sodium. The total phenolic and flavonoid contents were 183.1–210.5 µg gallic acid equivalent/mL and 45.2–53.8 µg quercetin equivalent/mL, respectively. Acetic acid was the major organic acid in the F1B4 and F1B5 samples (6.58 g/L and 20.7 g/L, respectively) while the F1B3 sample contained the highest amount of lactic acid (12.1 g/L). Ascorbic and citric acids were present in small amounts in all samples. All the samples showed stronger scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radicals (half-maximum inhibitory concentration, IC50: 13.6–16.8% v/v) than against hydrogen peroxide (IC50: 47.2–50.6% v/ v). The ferric reducing antioxidant power and oxygen radical absorbance capacity values for the samples were 14.9–20.9 µg ascorbic acid equivalent/mL and 23.9–25.4 mg Trolox equivalent/mL, respectively. The results indicated that the fruit jiaosu is a complex acidic solution containing proteins, minerals, phenolic compounds, and organic acids with antioxidant activities. Natural fermentation may cause variations in the organic acid content of the fruit jiaosu.

Flexible wearable electronics were developed for applications such as electronic skins, human-machine interactions, healthcare monitoring, and anti-infection therapy. But conventional materials showed impermeability, single sensing ability, and no designated therapy, which hindered their applications. Thus it was still a great challenge to develop electronic devices with multifunctional sensing properties and self-driven anti-infection therapy. Herein, flexible and breathable on-skin electronic devices for multifunctional fabric based sensing and self-driven designated anti-infection therapy were prepared successfully with cellulose nanocrystals/iron(III) ion/polyvinyl alcohol (CNC/Fe3+/PVA) composite. The resultant composite films possessed robust mechanical performances, outstanding conductivity, and distinguished breathability (3.03 kg/(m2·d)), which benefited from the multiple interactions of weak hydrogen bonds and Fe3+ chelation and synergistic effects among CNC, polyaniline (PANI), and PVA. Surprisingly, the film could be assembled as a multifunctional sensor to actively monitor real-time physical and infection related signals such as temperature, moisture, pH, NH3, and human movements even at sweat states. More importantly, this multifunctional device could act as a self-driven therapist to eliminate bacterial by the release of Fe3+, which was driven by the damage of metal coordination Fe-O bonds due to the high temperature caused by infection at wound sites. Thus, the composite films had potential versatile applications in electronic skins, smart wound dressings, human-machine interactions, and self-driven anti-infection therapy.

There have been a number of surprising reports of unexpected products when preparing heterostructures of Bi2Se3 with other 2D layers. These reports prompted us to explore the formation of metastable heterostructures containing Bi2Se3 using X-ray diffraction techniques to follow the reaction pathway. We discovered that the products formed depend on the electronic properties of the second constituent. Bi|Se layers deposited in a 2:3 ratio with enough atoms to make a single five-plane layer evolved to form thermodynamically stable Bi2Se3 as expected from the phase diagram. When the same Bi|Se layers were sequentially deposited with M|Se layers that form semiconductor layers (PbSe and 2H-MoSe2), Bi2Se3-containing heterostructures formed. When the same Bi|Se layers were deposited with M|Se layers that form metallic layers (TiSe2, VSe2, and 1T-MoSe2), BiSe-containing heterostructures formed. The amount of excess Se in the precursor controls whether [(Bi2Se3)1+δ]1[(MoSe2)]1 or [(BiSe)1+γ]1[(MoSe2)]1 forms. XPS data indicates that a mixture of both metallic 1T and semiconducting 2H-MoSe2 is present in [(BiSe)1+γ]1[(MoSe2)]1, while only semiconducting 2H-MoSe2 is present when layered with Bi2Se3. The electronic structure of adjacent layers impacts the formation of different structures from layers with similar local compositions. This provides an important additional parameter to consider when designing the synthesis of heterostructures, similar to substituent effects in molecular chemistry.

Nematode chitinases play vital roles in various physiological processes, including egg hatching, larva moulting, and reproduction. Small-molecule inhibitors of nematode chitinases have potential applications for controlling nematode pests. On the basis of the crystal structure of CeCht1, a representative chitinase indispensable to the eggshell chitin degradation of the model nematode Caenorhabditis elegans, we have discovered a series of novel inhibitors bearing a (R)-3,4-diphenyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one scaffold by hierarchical virtual screening. The crystal structures of CeCht1 complexed with two of these inhibitors clearly elucidated their interactions with the enzyme active site. Based on the inhibitory mechanism, several analogues with improved inhibitory activities were identified, among which the compound PP28 exhibited the most potent activity with a Ki value of 0.18 μM. This work provides the structural basis for the development of novel nematode chitinase inhibitors.

Recent findings have revealed that exposure to environmental contaminants may result in obesity and pose a health threat to the general public. As the activity of transient receptor potential channels (TRPs) plays a permissive role in adipogenesis, the interactions between TRPs and some food pollutants, i.e. bisphenol A, di (2-ethylhexyl) phthalate, zearalenone, and zeranol at 10 μM were investigated in the present study. TRP-V1,-V3, -C4 and -C6 are reported to be differentially expressed in the adipocyte differentiation, and immunoblotting was performed to quantify changes in these TRPs affected by the pollutants. Our result indicated that the mycoestrogen zeranol or α-zearalanol suppressed the expression of the V1 and C6 isoforms. Subsequently, confocal microscopy was used to measure the calcium inflow repressed by zeranol from 0.1 μM to 10 μM. Oil Red O staining was used to determine the differentiation of 3T3 L1 preadipocytes. Zeranol could suppress the expression of TRP-V1 and -C6 protein and inhibit the associated flow of calcium into the cytosol of 3T3 L1 cells. Its IC50 value for inhibiting calcium inflow stimulated by 40 μM capsaicin or 10 μM GSK1702934A was estimated to be around 6 μM. Reduced TRP-V1 or -C6 activity might result in promoting adipogenesis. In conclusion, this study demonstrated that zeranol could potentiate fat cell differentiation through antagonizing TRP-V1 and –C6 activities.

In selective macroautophagy/autophagy, cargo receptors are recruited to the forming autophagosome by interacting with Atg8 (autophagy-related 8)-family proteins and facilitate the selective sequestration of specific cargoes for autophagic degradation. In addition, Atg8 interacts with a number of adaptors essential for autophagosome biogenesis, including ATG and non-ATG proteins. The majority of these adaptors and receptors are characterized by an Atg8-family interacting motif (AIM) for binding to Atg8. However, the molecular basis for the interaction mode between ATG8 and regulators or cargo receptors in plants remains largely unclear. In this study, we unveiled an atypical interaction mode for Arabidopsis ATG8f with a plant unique adaptor protein, SH3P2 (SH3 domain-containing protein 2), but not with the other two SH3 proteins. By structure analysis of the unbound form of ATG8f, we identified the unique conformational changes in ATG8f upon binding to the AIM sequence of a plant known autophagic receptor, NBR1. To compare the binding affinity of SH3P2-ATG8f with that of ATG8f-NBR1, we performed a gel filtration assay to show that ubiquitin-associated domain of NBR1 outcompetes the SH3 domain of SH3P2 for ATG8f interaction. Biochemical and cellular analysis revealed that distinct interfaces were employed by ATG8f to interact with NBR1 and SH3P2. Further subcellular analysis showed that the AIM-like motif of SH3P2 is essential for its recruitment to the phagophore membrane but is dispensable for its trafficking in endocytosis. Taken together, our study provides an insightful structural basis for the ATG8 binding specificity toward a plant-specific autophagic adaptor and a conserved autophagic receptor.Abbreviations: ATG, autophagy-related; AIM, Atg8-family interacting motif; BAR, Bin-Amphiphysin-Rvs; BFA, brefeldin A; BTH, benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester; CCV, clathrin-coated-vesicle; CLC2, clathrin light chain 2; Conc A, concanamycin A; ER, endoplasmic reticulum; LDS, LIR docking site; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; LIR, LC3-interacting region; PE, phosphatidylethanolamine; SH3P2, SH3 domain containing protein 2; SH3, Src-Homology-3; UBA, ubiquitin-associated; UIM, ubiquitin-interacting motif.

Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib. This Phase 1, open-label, two-part study (Part 1 for rifampin and Part 2 for efavirenz) was conducted in healthy adult men and women. A single dose of fedratinib (500 mg) was administered on Day 1. Participants received rifampin 600 mg daily or efavirenz 600 mg daily on Days 9–18. On Day 17, a single dose of fedratinib (500 mg) was coadministered with rifampin or efavirenz. Plasma fedratinib concentrations were measured using validated liquid chromatography–tandem mass spectrometry. Maximum observed plasma fedratinib concentrations were lowered by approximately 70% and 30% during coadministration with rifampin or efavirenz, respectively, compared with fedratinib alone. Geometric means of fedratinib area under the plasma concentration–time curve from 0 to infinity were decreased by 81% (90% confidence interval [CI], 77–83%) and 47% (90% CI, 40–53%) during coadministration with rifampin or efavirenz, respectively. Fedratinib was generally well tolerated when administered alone or in combination with rifampin or efavirenz. Significant reductions in fedratinib exposure were observed in the presence of strong or moderate CYP3A4 inducers. These results suggest that agents that are strong or moderate inducers of CYP3A4 should be avoided when coadministered with fedratinib. NCT03983239 (Registration date: June 12, 2019).

Retinal nerve fiber/ganglion cell layer (RNFL/GCL) thickness measured using optical coherence tomography has been proposed as an ocular biomarker for children with attention-deficit/hyperactivity disorder (ADHD), but findings varied in different studies. This study aims to determine the association between RNFL/GCL thickness and ADHD in children by systematic review and meta-analysis. We performed a literature search in Embase, PubMed, Medline, Web of Science, and PsycINFO for relevant articles published up to February 29, 2020. All studies with original data comparing RNFL/GCL thickness in ADHD and healthy children were included. The Newcastle Ottawa Scale was used to assess bias risk and quality of evidence. Pooled estimates of the differences in thickness of RNFL or GCL between ADHD and healthy subjects were generated using meta-analysis with a random-effect model due to significant inter-study heterogeneity. Sensitivity analysis was also performed. We identified four eligible studies involving a total of 164 ADHD and 150 control subjects. Meta-analysis revealed that ADHD in children was associated with a reduction in global RNFL thickness (SMD, − 0.23; 95% CI − 0.46, − 0.01; p = 0.04). The global GCL thickness was examined in two studies with 89 ADHD and 75 control subjects, but the pooled difference in global GCL thickness between ADHD children and controls was not statistically significant (SMD, − 0.34; 95% CI − 1.25, 0.58; p = 0.47). Existing evidence suggests a possible association between ADHD and RNFL thinning in children. In view of the limited number of reports, further studies in large cohorts should be warranted.