A phase 2 study of interleukin-22 and systemic corticosteroids as initial treatment for acute GVHD of the lower GI tract.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.

Flat-band Friedrich-Wintgen bound states in the continuum based on borophene metamaterials.

Many applications involve the phenomenon of a material absorbing electromagnetic radiation. By exploiting wave interference, the efficiency of absorption can be significantly enhanced. Here, we propose Friedrich-Wintgen bound states in the continuum (F-W BICs) based on borophene metamaterials to realize coherent perfect absorption with a dual-band absorption peak in commercially important communication bands. Metamaterials consist of borophene gratings and a borophene sheet that can simultaneously support a Fabry-Perot plasmon resonance and a guided plasmon mode. The formation and dynamic modulation of the F-W BIC can be achieved by adjusting the width or carrier density of the borophene grating, while the strong coupling leads to the anti-crossover behavior of the absorption spectrum. Due to the weak angular dispersion originating from the intrinsic flat-band characteristic of the deep sub-wavelength periodic structure, the proposed plasmonic system exhibits almost no change in wavelength and absorption at large incident angles (within 70 degrees). In addition, we employ the temporal coupled-mode theory including near- and far-field coupling to obtain strong critical coupling, successfully achieve coherent perfect absorption, and can realize the absorption switch by changing the phase difference between the two coherent beams. Our findings can offer theoretical support for absorber design and all-optical tuning.

A Class of Readily Tunable Planar-Chiral Cyclopentadienyl Rhodium(III) Catalysts for Asymmetric C-H Activation.

Chiral half-sandwich cyclopentadienyl rhodium(III) (CpRhIII ) complexes are powerful catalysts for promoting asymmetric C-H activation reactions. Their preparation normally involved linking or embedding the Cp motif to or into a certain chiral backbone to forge the so-called chiral Cp ligand. However, preparation of a planar-chiral CpRhIII catalyst bearing a non-chiral Cp ligand remains a formidable challenge and is rarely reported. We describe herein an unusual class of planar-chiral rhodium catalysts bearing non-chiral Cp ligands. Different from existing ones, this catalyst is readily tunable. Ten planar-chiral only CpRhIII catalysts were prepared with ease, and successfully used in two enantioselective C-H activation reactions. Given its convenient synthesis and high structural tunability, these catalysts are expected to find more utilities in asymmetric C-H activation.

An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis.

BACKGROUND AND AIMS: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS: A phase-2 dose-escalating study was carried out. F-652 (10 µg/kg, 30 µg/kg, or 45 µg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS: F-652 is safe in doses up to 45 µg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.

Dual-Emission Reverse Change Ratio Photoluminescence Sensor Based on a Probe of Nitrogen-Doped Ti3C2 Quantum Dots@DAP to Detect H2O2 and Xanthine.

Titanium carbide quantum dots (Ti3C2 QDs) derived from two-dimensional (2D) Ti3C2Tx (MXene) are the rising-star material recently. Herein, nitrogen-doped Ti3C2 QDs (N-Ti3C2 QDs) were synthesized via a solvothermal method. The obtained N-Ti3C2 QDs exhibited excitation-dependent photoluminescence, antiphotobleaching, and dispersion stability. Furthermore, by combining the N-Ti3C2 QDs and DAP (2,3-diaminophenazine, the oxidative product of o-phenylenediamine) as a composite nanoprobe (N-Ti3C2 QDs@DAP), we developed a dual-emission reverse change ratiometric sensor to quantitatively monitor H2O2 based on photoinduced electron-transfer effects, where N-Ti3C2 QDs acted as the donor and DAP as the acceptor. On the basis of the xanthine converting into H2O2 through the catalysis of xanthine oxidase, the N-Ti3C2 QDs@DAP nanoprobe was also exploited for xanthine sensing. As a result, the proposed assay was demonstrated to be highly sensitive for H2O2 and xanthine with detection limits of 0.57 and 0.34 µM, respectively. In a word, we have investigated the application of N-Ti3C2 QDs in H2O2 and xanthine sensing and opened a new and exciting avenue for the N-Ti3C2 QDs in biosensing.

An electrochemical and fluorescence dual-signal assay based on Fe3O4@MnO2 and N-doped carbon dots for determination of hydrogen peroxide.

A novel electrochemical and fluorescence dual-signal assay was developed for the determination of hydrogen peroxide (H2O2) based on Fe3O4@MnO2 and N-doped carbon dots (NCDs). Fe3O4@MnO2 was not only applied as the recognizer for H2O2 but also served as the fluorescence quencher and electrochemical enhancer. This permits the dual-signal readout of the analytical system. In the absence of H2O2, the NCDs were quenched by Fe3O4@MnO2, and the oxidation of the electrochemical probe ferrocene (Fc) was catalyzed by Fe3O4@MnO2. In the presence of H2O2, MnO2 was reduced to Mn2+, leading to the fluorescence recovery of NCDs and the reduction in the oxidation signal of Fc. By combining the electrochemical method and the fluorescence assay, more comprehensive and valuable information for H2O2 determination was provided to meet different analytical demands. The method exhibits good repeatability and selectivity with a detection limit of 1.0 µM for the fluorescence assay and 0.6 µM for the electrochemical method. The proposed approach holds great potential for probing released targets from living cells. Graphical abstract.

A label-free electrochemical magnetic aptasensor based on exonuclease III-assisted signal amplification for determination of carcinoembryonic antigen.

A novel label-free and exonuclease III (Exo III)-assisted signal amplification electrochemical aptasensor was constructed for the determination of carcinoembryonic antigen (CEA) via magnetic field-induced self-assembly of magnetic biocomposites (Fe3O4@Au NPs-S1-S2-S3). The magnetic biocomposites were acquired by modifying double-stranded DNA (S1-S2-S3) on the surface of Fe3O4@Au nanoparticles (Fe3O4@Au NPs). Among them, Fe3O4@Au NPs were used as carriers for magnetic separation, thiolated single-stranded DNA (S1) provided signal sequence, CEA aptamer (S2) worked as a recognition element, and complementary strand (S3) was used to form double strands. In the presence of CEA, S2 bonded with CEA competitively; the exposed S1 could not be cleaved since Exo III was inactive against ssDNA. The G-quadruplex/hemin complexes finally formed with the existence of K+, and the high electrochemical signal of G-quadruplex/hemin complexes was recorded by differential pulse voltammetry (DPV) at - 0.6 V. Conversely, in the absence of CEA, dsDNA was cleaved from the 3' blunt end by Exo III; the disappearance of G-rich sequence blocked the generation of the signal. This method exhibited good selectivity and sensitivity for the determination of CEA; the linear range was from 0.1 to 200 ng mL-1 and the limit of detection was 0.4 pg mL-1. Graphical abstract.

A label-free electrochemical biosensor based on magnetic biocomposites with DNAzyme and hybridization chain reaction dual signal amplification for the determination of Pb2.

A highly sensitive and selective electrochemical biosensor for Pb2+ with a dual-amplification strategy is proposed. The first amplification step was realized by the cycle of Pb2+ and 8-17 DNAzyme (S2), and the hybridization chain reaction (HCR) triggered by S1 further amplified the electrochemical signal. Fe3O4@Au NPs, as a multifunctional magnetic carrier, is not only manifested in the construction of a magnetically controlled electrochemical response interface, but also has significant contribution in the purifying system, reducing interference, increasing the specific surface area, and the DNA loading. The magnetic nanocomposites were characterized by TEM as spheres with particle size of around 39 nm. When there was no Pb2+, long double-strand DNA (dsDNA) is formed on the surface of Fe3O4@Au NPs by the S1-triggered HCR; in the presence of Pb2+, S2 is activated and S1 on the surface of magnetic biocomposites (Fe3O4@Au NPs-S1) is continuously cleaved with the cycle of Pb2+ and S2, leading to a significant decrease of methylene blue (MB) absorbed on dsDNA. Such reverse dual-signal amplification strategy effectively increased the current difference and improved the sensitivity of the proposed sensor. The electrochemical signal of MB was obtained by differential pulse voltammetry (DPV) with preconcentration, showing a linear response toward Pb2+ ranging from 50 pM to 1 µM with a detection limit of 15 pM. The proposed method has feasible applications in detecting other heavy metal ions based on other metal-dependent DNAzyme. Graphical Abstract.

Chiral Bicyclo[2.2.2]octane-Fused CpRh Complexes: Synthesis and Potential Use in Asymmetric C-H Activation.

A new class of chiral cyclopentadienyl rhodium(I) complexes (CpRhI ) bearing C2 -symmetric chiral bridged-ring-fused Cp ligands was prepared. The complexes were successfully applied to the asymmetric C-H activation reaction of N-methoxybenzamides with quinones, affording a series of chiral hydrophenanthridinones in up to 82 % yield with up to 99 % ee. Interestingly, structure analysis reveals that the side wall of the optimal chiral CpRhI catalyst is vertically more extended, horizontally less extended, and closer to the metal center in comparison with the classic binaphthyl and spirobiindanyl CpRhI complexes, and may thus account for its superior catalytic performance.

Dependence of the Bacillus subtilis biofilm expansion rate on phenotypes and the morphology under different growing conditions.

Biofilms are communities of tightly associated bacteria encased in an extracellular matrix and attached to surfaces of various objects, such as liquid or solid surfaces. Here we use the multi-channel wide field stereo fluorescence microscope to characterize growth of the Bacillus subtilis biofilm, in which the bacterial strain was triple fluorescence labeled for three main phenotypes: motile, matrix producing and sporulating cells. We used the feature point matching approach analyzing time lapse experimental movies to study the biofilm expansion rate. We found that the matrix producing cells dominate the biofilm expansion, at the biofilm edge, the expansion rate of matrix producing cells was almost the same as the velocity of the whole biofilm; however, the motile and sporulating cells were nearly rest. We also found that the biofilm expansion rate evolution relates to cell differentiation and biofilm morphology, and other micro-environments can influence the biofilm growth, such as nutrient, substrate hardness and colony competition. From our work, we get a deeper understanding of the biofilm growth, which can help us to control and to further disperse the biofilm.

A versatile fluorometric aptasensing scheme based on the use of a hybrid material composed of polypyrrole nanoparticles and DNA-silver nanoclusters: application to the determination of adenosine, thrombin, or interferon-gamma.

The authors describe a versatile aptasensing scheme based on the use of polypyrrole nanoparticles (PPyNPs) and DNA-silver nanoclusters (DNA-AgNCs) for multiple target detection. The DNA-AgNCs consist of two functional domains, viz. (a) a nucleation domain for attaching the metal core of the nanoclusters, and (b) a recognition domain which consists of a single-stranded aptamer. In the absence of analytes, the single-strand recognition domain will be absorbed onto the surface of the PPyNPs through π stacking and hydrophobic interactions. As a result, the red fluorescence of the DNA-AgNCs (with excitation/emission peaks at 535/625 nm) is quenched by the PPyNPs. On introducing the analytes, the DNA-AgNCs will bind them. This leads to the desorption of DNA-AgNCs and the recovery of the red fluorescence. Based on the above strategy, a versatile, sensitive and selective aptasensor was established for detection of adenosine, thrombin and interferon-gamma. The method was applied to the detection of the above targets in (spiked) serum samples and gave satisfactory results, with detection limit of 0.58 nM for IFN-γ, 0.39 nM for adenosine, and 2.2 nM for thrombin. The use of PPyNPs results in uniquely low non-specific absorption and in improved analytical results in case of real-sample analysis when compared to previously reported methods. Graphical abstract Schematic illustration of DNA-silver nanoclusters and polypyrrole nanoparticles in an aptasensor for detection of multiple targets.

Dihydropyrazole Derivatives Containing Benzo Oxygen Heterocycle and Sulfonamide Moieties Selectively and Potently Inhibit COX-2: Design, Synthesis, and Anti-Colon Cancer Activity Evaluation.

Cyclooxygenase-2 (COX-2) as a rate-limiting metabolism enzyme of arachidonic acid has been found to be implicated in tumor occurrence, angiogenesis, metastasis as well as apoptosis inhibition, regarded as an attractive therapeutic target for cancer therapy. In our research, a series of dihydropyrazole derivatives containing benzo oxygen heterocycle and sulfonamide moieties were designed as highly potent and selective COX-2 inhibitors by computer-aided drug analysis of known COX-2 inhibitors. A total of 26 compounds were synthesized and evaluated COX-2 inhibition and pharmacological efficiency both in vitro and in vivo with multi-angle of view. Among them, compound 4b exhibited most excellent anti-proliferation activities against SW620 cells with IC50 of 0.86 ± 0.02 µM than Celecoxib (IC50 = 1.29 ± 0.04 µM). The results favored our rational design intention and provides compound 4b as an effective COX-2 inhibitor available for the development of colon tumor therapeutics.

Enantioselective Synthesis of C-N Axially Chiral N-Aryloxindoles by Asymmetric Rhodium-Catalyzed Dual C-H Activation.

The first enantioselective Satoh-Miura-type reaction is reported. A variety of C-N axially chiral N-aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium-catalyzed dual C-H activation reaction of N-aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C-N axially chiral compounds by such a C-H activation strategy.

Solvent-Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII -Catalyzed C-H Activation.

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N-methoxy benzamides and α,α-difluoromethylene alkynes is enabled by C-H activation with a chiral CpRhIII catalyst. Remarkably, product formation is solvent-dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in i PrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E-configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z-configured monofluoroalkene upon protonation in the i PrCN system and into an alkyne by an unusual anti ß-F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z-monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.

Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors.

A series of novel benzohydrazide derivatives containing dihydropyrazoles have been synthesized as potential epidermal growth factor receptor (EGFR) kinase inhibitors and their biological activities as potential antiproliferative agents have been evaluated. Among these compounds, compound H20 exhibited the most potent antiproliferative activity against four cancer cell line variants (A549, MCF-7, HeLa, HepG2) with IC50 values of 0.46, 0.29, 0.15 and 0.21 µM respectively, which showed the most potent EGFR inhibition activities (IC50 = 0.08 µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity and activity relationship (SAR) of these benzohydrazide derivatives. These results suggested that compound H20 may be a promising anticancer agent.

Sulfonamide derivatives containing dihydropyrazole moieties selectively and potently inhibit MMP-2/MMP-9: Design, synthesis, inhibitory activity and 3D-QSAR analysis.

New series of sulfonamide derivatives containing a dihydropyrazole moieties inhibitors of MMP-2/MMP-9 were discovered using structure-based drug design. Synthesis, antitumor activity, structure-activity relationship and optimization of physicochemical properties were described. In vitro the bioassay results revealed that most target compounds showed potent inhibitory activity in the enzymatic and cellular assays. Among the compounds, compound 3i exhibited the most potent inhibitory activity with IC50 values of 0.21 µM inhibiting MMP-2 and 1.87 µM inhibiting MMP-9, comparable to the control positive compound CMT-1 (1.26 µM, 2.52 µM). Docking simulation was performed to position compound 3i into the MMP-2 active site to determine the probable binding pose. Docking simulation was further performed to position compound 3i into the MMP-2 active site to determine the probable binding model the 3D-QSAR models were built for reasonable design of MMP-2/MMP-9 inhibitors at present and in future.

Design, synthesis, biological evaluation and molecular modeling of dihydropyrazole sulfonamide derivatives as potential COX-1/COX-2 inhibitors.

Novel dihydropyrazole sulfonamide derivatives (30-56) were designed, synthesized, and evaluated for their biological activities as COX-1 and COX-2 inhibitors. In vitro biological evaluation against three human tumor cell lines revealed that most target compounds showed antiproliferative activities. Among the compounds, compound 48 exhibited the most potent and selective COX-2 inhibitor (COX-2 IC50=0.33 µM; COX-1 IC50=68.49 µM) relative to the reference drugs celecoxib (IC50=0.052 µM). Docking simulation was performed to position compound 48 into the COX-2 active site and the result showed that compound 48 could bind well at the COX-2 active site and it indicated that compound 48 could be a potent and selective COX-2 inhibitor.

IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium.

IL-22 is an epithelial cell survival cytokine that is currently under development for the treatment of acute liver damage. Here, we used a mouse model of renal ischemia/reperfusion (I/R) injury to investigate whether IL-22 has therapeutic potential for the treatment of AKI. The action of IL-22 is mediated by binding to IL-22R1 and leads to STAT3 activation. Under physiologic conditions, renal expression of IL-22R1 was detected only in the brush border of the renal proximal tubular epithelial cells (RPTECs). Renal I/R elevated serum IL-22 levels slightly but did not induce STAT3 phosphorylation in RPTECs. IL-22-deficient mice had slightly increased I/R-induced injury compared with wild-type mice. In contrast, treatment with IL-22 or overexpression of IL-22 by either gene targeting (IL-22 transgenic mice) or administration of adenovirus expressing IL-22 increased STAT3 phosphorylation in RPTECs, ameliorated I/R-induced renal inflammation and tubular cell injury, and preserved renal functions. Overexpression of IL-22 increased the phosphorylation of STAT3 and Akt, upregulated antiapoptotic genes (e.g., Bcl-2), and downregulated proapoptotic genes (e.g., Bad) in the kidneys of mice subjected to I/R. Notably, phosphorylation of Akt increased and expression of Bad decreased in proximal tubular cells under these conditions. Furthermore, compared with wild-type mice, IL-22 transgenic mice had increased survival rates, whereas IL-22-deficient mice had reduced survival rates after I/R injury. In summary, renal expression of IL-22R1 is restricted to RPTECs, and treatment with IL-22 protects against renal I/R injury by activating STAT3 and AKT, suggesting that IL-22 has therapeutic potential for the treatment of AKI.

A Survey on Information Bottleneck.

This survey is for the remembrance of one of the creators of the information bottleneck theory, Prof. Naftali Tishby, passing away at the age of 68 on August, 2021. Information bottleneck (IB), a novel information theoretic approach for pattern analysis and representation learning, has gained widespread popularity since its birth in 1999. It provides an elegant balance between data compression and information preservation, and improves its prediction or representation ability accordingly. This survey summarizes both the theoretical progress and practical applications on IB over the past 20-plus years, where its basic theory, optimization, extensive models and task-oriented algorithms are systematically explored. Existing IB methods are roughly divided into two parts: traditional and deep IB, where the former contains the IBs optimized by traditional machine learning analysis techniques without involving any neural networks, and the latter includes the IBs involving the interpretation, optimization and improvement of deep neural works (DNNs). Specifically, based on the technique taxonomy, traditional IBs are further classified into three categories: Basic, Informative and Propagating IB; While the deep IBs, based on the taxonomy of problem settings, contain Debate: Understanding DNNs with IB, Optimizing DNNs Using IB, and DNN-based IB methods. Furthermore, some potential issues deserving future research are discussed. This survey attempts to draw a more complete picture of IB, from which the subsequent studies can benefit.

Multitask Image Clustering via Deep Information Bottleneck.

Multitask image clustering approaches intend to improve the model accuracy on each task by exploring the relationships of multiple related image clustering tasks. However, most existing multitask clustering (MTC) approaches isolate the representation abstraction from the downstream clustering procedure, which makes the MTC models unable to perform unified optimization. In addition, the existing MTC relies on exploring the relevant information of multiple related tasks to discover their latent correlations while ignoring the irrelevant information between partially related tasks, which may also degrade the clustering performance. To tackle these issues, a multitask image clustering method named deep multitask information bottleneck (DMTIB) is devised, which aims at conducting multiple related image clustering by maximizing the relevant information of multiple tasks while minimizing the irrelevant information among them. Specifically, DMTIB consists of a main-net and multiple subnets to characterize the relationships across tasks and the correlations hidden in a single clustering task. Then, an information maximin discriminator is devised to maximize the mutual information (MI) measurement of positive samples and minimize the MI of negative ones, in which the positive and negative sample pairs are constructed by a high-confidence pseudo-graph. Finally, a unified loss function is devised for the optimization of task relatedness discovery and MTC simultaneously. Empirical comparisons on several benchmark datasets, NUS-WIDE, Pascal VOC, Caltech-256, CIFAR-100, and COCO, show that our DMTIB approach outperforms more than 20 single-task clustering and MTC approaches.