Inhibition of DXR in the MEP pathway with lipophilic N-alkoxyaryl FR900098 analogs.

In Mycobacterium tuberculosis (Mtb) and Plasmodium falciparum (Pf), the methylerythritol phosphate (MEP) pathway is responsible for isoprene synthesis. This pathway and its products are vital to bacterial/parasitic metabolism and survival, and represent an attractive set of drug targets due to their essentiality in these pathogens but absence in humans. The second step in the MEP pathway is the conversion of 1-deoxy-d-xylulose-5-phosphate (DXP) to MEP and is catalyzed by 1-deoxy-d-xylulose-5-phosphate reductoisomerase (DXR). Natural products fosmidomycin and FR900098 inhibit DXR, but are too polar to reach the desired target inside some cells, such as Mtb. Synthesized FR900098 analogs with lipophilic substitution in the position α to the phosphorous atom showed promise, resulting in increased activity against Mtb and Pf. Here, an α substitution, consisting of a 3,4-dichlorophenyl substituent, in combination with various O-linked alkylaryl substituents on the hydroxamate moiety is utilized in the synthesis of a novel series of FR900098 analogs. The purpose of the O-linked alkylaryl substituents is to further enhance DXR inhibition by extending the structure into the adjacent NADPH binding pocket, blocking the binding of both DXP and NADPH. Of the initial O-linked alkylaryl substituted analogs, compound 6e showed most potent activity against Pf parasites at 3.60 µM. Additional compounds varying the phenyl ring of 6e were synthesized. The most potent phosphonic acids, 6l and 6n, display nM activity against PfDXR and low µM activity against Pf parasites. Prodrugs of these compounds were less effective against Pf parasites but showed modest activity against Mtb cells. Data from this series of compounds suggests that this combination of substituents can be advantageous in designing a new generation of antimicrobials.

Thiocarbonyl-Based Hole Transport Materials with Enhanced Defect Passivation Ability for Efficient and Stable Perovskite Solar Cells.

Organic hole transporting materials (HTMs) are extensively studied in perovskite solar cells (PSCs). The HTMs directly contact the underlying perovskite material, and they play additional roles apart from hole transporting. Developing organic HTMs with defect passivation function has been proved to be an efficient strategy to construct efficient and stable PSCs. In this work, new organic molecules with thiocarbonyl (C═S) and carbonyl (C═O) functional groups are synthesized and applied as HTMs (named FN-S and FN-O). FN-S with C═S can be facilely obtained from FN-O containing C═O. Notably, the C═S in FN-S results in superior defect passivation ability compared to FN-O. Moreover, FN-S exhibits excellent hole extraction/transport capability. Conventional PSCs using FN-S as HTM show an impressive power conversion efficiency (PCE) of 23.25%, with excellent long-term stability and operational stability. This work indicates that simply converting C═O to C═S is an efficient way to improve the device performance by strengthening the defect passivation functionality.

Improvement of Perovskite Solar Cells Efficiency by Management of the Electron Withdrawing Groups in Hole Transport Materials: Theoretical Calculation and Experimental Verification.

Management of functional groups in hole transporting materials (HTMs) is a feasible strategy to improve perovskite solar cells (PSCs) efficiency. Therefore, starting from the carbazole-diphenylamine-based JY7 molecule, JY8 and JY9 molecules are incorporated into the different electron-withdrawing groups of fluorine and cyano groups on the side chains. The theoretical results reveal that the introduction of electron-withdrawing groups of JY8 and JY9 can improve these highest occupied molecular orbital (HOMO) energy levels, intermolecular stacking arrangements, and stronger interface adsorption on the perovskite. Especially, the results of molecular dynamics (MD) indicate that the fluorinated JY8 molecule can yield a preferred surface orientation, which exhibits stronger interface adsorption on the perovskite. To validate the computational model, the JY7-JY9 are synthesized and assembled into PSC devices. Experimental results confirm that the HTMs of JY8 exhibit outstanding performance, such as high hole mobility, low defect density, and efficient hole extraction. Consequently, the PSC devices based on JY8 achieve a higher PCE than those of JY7 and JY9. This work highlights the management of the electron-withdrawing groups in HTMs to realize the goal of designing HTMs for the improvement of PSC efficiency.

Novel Conversions of a Multifunctional, Bio-sourced Lactone Carboxylic Acid.

The plant-derived compounds furfuryl alcohol and itaconic anhydride are known to undergo a Diels-Alder reaction at room temperature and in bulk to efficiently give an alkene-containing lactone carboxylic acid. Reported here is the conversion of this substance to a variety of derivatives via hydrogenation, epoxidation, or halolactonization reactions. Most notable is the formation of a set of three related acrylate or methacrylate esters (see graphical abstract) produced by direct acylative ring opening of ether bonds using Sc(OTf)3 and (meth)acrylic anhydride. These esters are viewed as promising candidates for use as biorenewable monomers in reversible addition-fragmentation chain transfer (RAFT) polymerization reactions.

Theoretical calculations and experimental investigation toward the π-conjugated modulation in arylamine derivative-based hole transporting materials for perovskite solar cells.

Excellent hole transporting materials (HTMs) are beneficial to promote the performance of perovskite solar cells (PSCs). Herein, starting from the modulation of the π-conjugated groups of carbazole-diphenylamine derivatives, HTMs CY1 and CY2 were designed and investigated using density functional theory and Marcus theory. Theoretical simulations show that CY1 and CY2 exhibit appropriate HOMO/LUMO energy levels, small recombination energy, good optical properties and molecular stability. Compared with CY1, CY2 with a larger π-conjugated group on its side chain can yield a higher hole mobility and better charge separation. The experimental results confirm that CY2 in PSCs exhibits superior properties such as good hole transporting ability, good film morphology, and efficient charge extraction and dissociation at perovskite/HTM inerfaces. Therefore, a PSC device with CY2 yields a higher efficiency than those of CY1- and Spiro-OMeTAD-based devices. Hence, the results demonstrate that the strategy of the extended π-π conjugation on a side chain is a practicable approach to design potential HTMs for application in PSCs.

Do visual and step height factors cause imbalance during bipedal and unipedal stances? A plantar pressure perspective.

Objective: The plantar pressure analysis technique was used to explore the static balance ability and stability of healthy adult males under the influence of visual and step height factors during bipedal and unipedal stances. Methods: Thirty healthy adult males volunteered for the study. Experiments used the F-scan plantar pressure analysis insoles to carry out with eyes open (EO) and eyes closed (EC) at four different step heights. The plantar pressure data were recorded for 10 s and pre-processed to derive kinematic and dynamic parameters. Results: For unipedal stance, most of kinematic parameters of the subjects' right and left feet were significantly greater when the eyes were closed compared to the EO condition and increased with step height. The differences in toe load between right and left feet, open and closed eyes were extremely statistically significant (p < 0.001). The differences in midfoot load between the EO and EC conditions were statistically significant (p = 0.024) and extremely statistically significant between the right and left feet (p < 0.001). The difference in rearfoot load between EO and EC conditions was extremely statistically significant (p < 0.001) and statistically significant (p = 0.002) between the right and left feet. For bipedal stance, most of kinematic parameters of the subjects' EO and EC conditions were statistically significant between the right and left feet and increased with step height. The overall load's difference between EO and EC states was statistically significant (p = 0.003) for both feet. The overall load's difference between the right and left feet was extremely statistically significant (p < 0.001) in the EC state. The differences between the right and left feet of the forefoot and rearfoot load with EO and EC suggested that the right foot had a smaller forefoot load, but a larger rearfoot load than the left foot (p < 0.001). The differences between the forefoot and rearfoot load of the subjects' both feet with EO and EC were extremely statistically significant (p < 0.001). Conclusion: Both visual input and step height factors, even the dominant foot, act on kinematic and dynamic parameters that affect the maintenance of static balance ability.

Probabilistic Regularized Extreme Learning for Robust Modeling of Traffic Flow Forecasting.

The adaptive neurofuzzy inference system (ANFIS) is a structured multioutput learning machine that has been successfully adopted in learning problems without noise or outliers. However, it does not work well for learning problems with noise or outliers. High-accuracy real-time forecasting of traffic flow is extremely difficult due to the effect of noise or outliers from complex traffic conditions. In this study, a novel probabilistic learning system, probabilistic regularized extreme learning machine combined with ANFIS (probabilistic R-ELANFIS), is proposed to capture the correlations among traffic flow data and, thereby, improve the accuracy of traffic flow forecasting. The new learning system adopts a fantastic objective function that minimizes both the mean and the variance of the model bias. The results from an experiment based on real-world traffic flow data showed that, compared with some kernel-based approaches, neural network approaches, and conventional ANFIS learning systems, the proposed probabilistic R-ELANFIS achieves competitive performance in terms of forecasting ability and generalizability.

SARS-CoV-2 infection of intestinal epithelia cells sensed by RIG-I and DHX-15 evokes innate immune response and immune cross-talk.

SARS-CoV-2 causes a spectrum of clinical symptoms from respiratory damage to gastrointestinal disorders. Intestinal infection of SARS-CoV-2 triggers immune response. However, the cellular mechanism that how SARS-CoV-2 initiates and induces intestinal immunity is not understood. Here, we exploited SARS-CoV-2-GFP/ΔN trVLP pseudo-virus system and demonstrated that RIG-I and DHX15 are required for sensing SARS-CoV-2 and inducing cellular immune response through MAVS signaling in intestinal epithelial cells (IECs) upon SARS-CoV-2 infection. NLRP6 also engages in the regulation of SARS-CoV-2 immunity by producing IL-18. Furthermore, primary cellular immune response provoked by SARS-CoV-2 in IECs further cascades activation of MAIT cells and produces cytotoxic cytokines including IFN-γ, granzyme B via an IL-18 dependent mechanism. These findings taken together unveil molecular basis of immune recognition in IECs in response to SARS-CoV-2, and provide insights that intestinal immune cross-talk with other immune cells triggers amplified immunity and probably contributes to immunopathogenesis of COVID-19.

A HER2 target antibody drug conjugate combined with anti-PD-(L)1 treatment eliminates hHER2+ tumors in hPD-1 transgenic mouse model and contributes immune memory formation.

PURPOSE: Disitamab vedotin (RC48) is an HER2-directed antibody-drug conjugate, emerging as an effective strategy for cancer therapy, which not only enhances antitumor immunity in previous animal models but also improves clinical outcomes for patients such as with gastric cancer, urothelium carcinoma, and HER2 low-expressing breast cancer. Here, we explore the combination therapeutic efficacy of this novel HER2-targeting ADC with immune checkpoint inhibitors in a human HER2-expressing syngeneic breast cancer model. METHODS: The human HER2+ cancer cell line is constructed by stable transfection and individual clones were isolated by single-cell sorting. Flow cytometry was performed to determine its binding activity. Cytotoxic effect was determined using an MTT assay with the supplement of RC48. Human PD-1 transgenic mice were used to analyze the in vivo antitumor effects of the ADC and its combination therapy with PD-1/PD-L1 antibody. RESULTS: The combination of RC48 and PD-1/PD-L1 immune checkpoint inhibition significantly enhanced tumor suppression and antitumor immunity. Tumor rejection in the synergistic groups was accompanied by massive T cell infiltration and immune marker activation. Furthermore, the combination therapy promoted immunological memory formation in the tumor eradication animals, protecting them from tumor rechallenge. CONCLUSION: A novel HER2-targeting ADC combined with immune checkpoint inhibitors can achieve remarkable effects in mice and elicit long-lasting immune protection in a hHER2+ murine breast cancer model. This study provides insights into the efficacy of RC48 therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.

Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody.

INTRODUCTION: Overexpression of c-Met, or hepatocyte growth factor (HGF) receptor, is commonly observed in tumor biopsies and often associated with poor patient survival, which makes HGF/c-Met pathway an attractive molecular target for cancer therapy. A number of antibody-based therapeutic strategies have been explored to block c-Met or HGF in cancers; however, clinical efficacy has been very limited, indicating that blockade of c-Met signal alone is not sufficient. Thus, an alternative approach is to develop an immunotherapy strategy for c-Met-overexpressing cancers. c-Met/CD3 bispecific antibody (BsAb) could bridge CD3-positive T lymphocytes and tumor cells to result in potent tumor cell killing. MATERIALS AND METHODS: A bispecific antibody, BS001, which binds both c-Met and CD3, was generated using a novel BsAb platform. Western blotting and T cells-mediated killing assays were utilized to evaluate the BsAb's effects on cell proliferation, survival and signal transduction in tumor cells. Subcutaneous tumor mouse models were used to analyze the in vivo anti-tumor effects of the bispecific antibody and its combination therapy with PD-L1 antibody. RESULTS: BS001 showed potent T-cell mediated tumor cells killing in vitro. Furthermore, BS001 inhibited phosphorylation of c-Met and downstream signal transduction in tumor cells. In A549 lung cancer xenograft model, BS001 inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. In vivo combination therapy of BS001 with Atezolizumab (an anti-programmed cell death protein1-ligand (PD-L1) antibody) showed more potent tumor inhibition than monotherapies. Similarly, in SKOV3 xenograft model, BS001 showed a significant efficacy in tumor growth inhibition and tumor recurrence was not observed in more than half of mice treated with a combination of BS001 and Pembrolizumab. CONCLUSION: c-Met/CD3 bispecific antibody BS001 exhibited potent anti-tumor activities in vitro and in vivo, which was achieved through two distinguished mechanisms: through antibody-mediated tumor cell killing by T cells and through inhibition of c-Met signal transduction.

Morphology Design of Co-electrospinning MnO-VN/C Nanofibers for Enhancing the Microwave Absorption Performances.

To enhance microwave loss abilities, constructing composites with one-dimensional (1D) structure is an excellent scheme. In this work, a high-efficiency microwave absorber of MnO nanograins decorated vanadium nitride/carbon nanofibers (MnO-VN/C NFs) was successfully prepared for the first time via co-electrospinning technology and subsequent nitriding treatment. Studying in detail the specific relationship between nitriding time and the morphology of the as-prepared NFs, the precipitations of MnO nanoparticles with tailored structures were attached on the surface of VN/C NFs to optimize their electromagnetic parameters. When the nitriding time was 2.0 h at 600 °C, the MnO-VN/C NFs displayed good microwave absorption performances: the minimum reflection loss (RL) value was -63.2 dB at 8.8 GHz, and the bandwidth of RL < -10 dB was up to 6.4 GHz from 11.6 to 18 GHz at the thickness of 2.8 mm. Meanwhile, the absorption bandwidth (RL< -10 dB) could cover the whole X and Ku band by adjusting the thickness, respectively. The outstanding performances could be attributed to the good impedance matching and various loss pathways including conductive loss and interfacial and dipole polarizations. In these regards, MnO-VN/C NFs are likely to be utilized as a high-efficiency microwave absorber. And the strategy in this work can provide great help to design other 1D structural microwave absorbers with a broader absorbing band.

A CO2-responsive hydrogel film for optical sensing of dissolved CO2.

CO2-monitoring plays an important role in medicine, environmental sciences, and food industries. Here, a new CO2-responsive hydrogel film was fabricated from branched polyethyleneimine (BPEI) and partially oxidized dextran (PO-Dex) via layer-by-layer (LBL) assembly, based on the in situ Schiff base reaction between the two polymers. The swelling behaviours of the films were studied using Fabry-Perot fringes on their reflection spectra. Like ordinary hydrogels, the BPEI/PO-Dex films swell in water. In addition, they swell to a larger degree when CO2 is introduced, due to the reaction between CO2 and the amino groups in BPEI. The CO2-induced swelling can be reported by the shift of the Fabry-Perot fringes on their reflection spectra; therefore, the BPEI/PO-Dex film can be used as an optical sensor for dissolved CO2. In the new sensor, the BPEI/PO-Dex film acts as a CO2-sensing material and Fabry-Perot cavity simultaneously. The introduction of ordered structure is no longer required. The response of the sensor to CO2 is linear and reversible. Unlike other hydrogel-based sensors that suffer from a slow response, the new sensor can respond to CO2 quickly, making it applicable for real-time, continuous monitoring of CO2 levels in solution.

Improved recombinant protein production by regulation of transcription and protein transport in Chinese hamster ovary cells.

OBJECTIVES: To identify genes that affected protein expression in Chinese hamster ovary (CHO) cells was significant, and we identified the changes in the transcriptome and the functional gene sets that would contribute to increase expression of recombinant protein. RESULTS: Here two sub-clones from a methotrexate-treated parental recombinant CHO cell line were selected. The two sub-clones, with different expression levels (qp were 42.8 pg/cell/day and 14.0 pg/cell/day), were analyzed through RNA-seq. More than 600 genes were identified as differently expressed, and we found that the differentially expressed genes were involved in processes such as RNA processing, transcription, protein catabolism, and protein transport. Among these, we cloned genes encoding proteins that were involved in transcription and protein transport to investigate their effect on protein production. CONCLUSIONS: We found that some genes involved in transcription and protein transport would improve recombinant protein production in CHO cells.

Genotyping of human rhinovirus in adult patients with acute respiratory infections identified predominant infections of genotype A21.

Human rhinovirus (HRV) is an important causative agent of acute respiratory tract infections (ARTIs). The roles of specific HRV genotypes in patients suffering from ARTIs have not been well established. We recruited 147 adult inpatients with community-acquired pneumonia (CAP) and 291 adult outpatients with upper ARTIs (URTIs). Respiratory pathogens were screened via PCR assays. HRV was detected in 42 patients, with 35 species A, five B and two C. Seventeen genotypes were identified, and HRV-A21 ranked the highest (9/42, 21.4%). The HRV-A21-positive infections were detected in four patients with CAP and in five with URTIs, all without co-infections. The HRV-A21 genome sequenced in this study contained 12 novel coding polymorphisms in viral protein (VP) 1, VP2 EF loop, VP3 knob and 3D regions. The infections of HRV-A21 virus obtained in this study could not be neutralized by antiserum of HRV-A21 prototype strain (VR-1131), indicating remarkable antigenic variation. Metagenomic analysis showed the HRV-A21 reads were dominant in bronchoalveolar lavage fluid of the three HRV-A21-positive patients with severe CAP, in which two dead. Our results highlight an unexpected infection of genotype HRV-A21 in the clinic, indicating the necessity of precise genotyping and surveillance of HRVs to improve the clinical management of ARTIs.

Quinone-modified NH2-MIL-101(Fe) composite as a redox mediator for improved degradation of bisphenol A.

A novel quinone-modified metal-organic frameworks NH2-MIL-101(Fe) was synthesized using a simple chemical method under mild condition. The introduced 2-anthraquinone sulfonate (AQS) can be covalently modified with NH2-MIL-101(Fe) and acts as a redox mediator to enhance the degradation of bisphenol A (BPA) via persulfate activation. The obtained AQS-NH-MIL-101(Fe) was characterized by Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, X-ray photoelectron spectra, cyclic voltammetry and electrochemical impedance spectroscopy. AQS-NH-MIL-101(Fe) exhibited better catalytic performance compared with NH2-MIL-101(Fe) and NH2-MIL-101(Fe) with free AQS (NH2-MIL-101(Fe)/AQS). That is, AQS-NH-MIL-101(Fe) was proved to be the most effective in that more than 97.7% of BPA was removed. The degradation rate constants (k) of AQS-NH-MIL-101(Fe) was 9-fold higher than that of NH2-MIL-101(Fe) and 7-fold higher than NH2-MIL-101(Fe)/AQS, indicating that AQS is a great electron-transfer mediator when modified with NH2-MIL-101(Fe). Based on the above results, the possible mechanism of catalytic reaction has been investigated in view of the trapping experiments. In addition, the AQS-NH-MIL-101(Fe) catalyst exhibited excellent stability and can be used several times without significant deterioration in performance.

Core-shell Fe3O4@MIL-101(Fe) composites as heterogeneous catalysts of persulfate activation for the removal of Acid Orange 7.

In this study, a novel core-shell Fe3O4@MIL-101 (MIL stands for Materials of Institute Lavoisier) composite was successfully synthesized by hydrothermal method and was fully characterized by X-ray diffraction, transmission electron microscopy, Fourier-transform infrared spectra, and X-ray photoelectron spectroscopy. The composite was introduced as a catalyst to generate powerful radicals from persulfate for the removal of Acid Orange 7 in an aqueous solution. Effects of the central metal ions of MIL-101, amino group content of MIL-101, and pH were evaluated in batch experiments. It was found that both hydroxyl and sulfate radicals were generated; importantly, sulfate radicals were speculated to serve as the dominant active species in the catalytic oxidation of Acid Orange 7. In addition, a possible mechanism was proposed. This study provides new physical insights for the rational design of advanced metal-organic frameworks (MOF)-based catalysts for improved environmental remediation.

A preliminary study on the potential of Mycoplasma pneumoniae to induce dyskaryotic change in respiratory epithelium in adult community-acquired pneumonia.

BACKGROUND: This study aimed to explore the cellular morphology of respiratory epithelium in Mycoplasma pneumonia (MpP) patients. MATERIALS AND METHODS: The cast-off cell morphological findings from bronchoscopic brushings in MpP and community-acquired pneumonia (CAP) caused by typical pathogens were reviewed. RESULTS: Compared with the CAP group, cellular dysplasia in respiratory tract epithelial brushings was significantly greater in MpP patients (P = 0.033). CONCLUSION: Unique biological characteristics and mechanisms of pathogenesis of Mycoplasma pneumoniae (Mp) may result in dyskaryotic changes in respiratory epithelium in adult MpP.

Unusual complication of multiple splenic abscesses arising from a feeding jejunostomy tube subsequent to total gastrectomy: A case report and literature review.

Splenic abscess is a rare clinical entity. The present study reports a case of a patient that suffered from splenic abscess secondary to septicemia resulting from Klebsiella pneumoniae infection following the removal of the feeding jejunostomy tube that was utilized subsequent to the patient undergoing total gastrectomy as part of the treatment regimen for gastric adenocarcinoma. The early clinical presentation was nonspecific and multiple splenic abscesses were subsequently identified. To reduce the risks of an additional surgical procedure in this particular patient, laparoscopic assisted splenotomy and catheter drainage were performed. Due to the severe complications that occurred in the present patient, no adjuvant chemotherapy was administered. Therefore, the unusual complication of splenic abscess subsequent to total gastrectomy should be noted, and the routine feeding jejunostomy tube placement at the time of total gastrectomy should be discussed and re-assessed.

Cu-N dopants boost electron transfer and photooxidation reactions of carbon dots.

The broadband light-absorption ability of carbon dots (CDs) has inspired their application in photocatalysis, however this has been impeded by poor electron transfer inside the CDs. Herein, we report the preparation of Cu-N-doped CDs (Cu-CDs) and investigate both the doping-promoted electron transfer and the performance of the CDs in photooxidation reactions. The Cu-N doping was achieved through a one-step pyrolytic synthesis of CDs with Na2 [Cu(EDTA)] as precursor. As confirmed by ESR, FTIR, and X-ray photoelectron spectroscopies, the Cu species chelates with the carbon matrix through Cu-N complexes. As a result of the Cu-N doping, the electron-accepting and -donating abilities were enhanced 2.5 and 1.5 times, and the electric conductivity was also increased to 171.8 µs cm(-1) . As a result of these enhanced properties, the photocatalytic efficiency of CDs in the photooxidation reaction of 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate is improved 3.5-fold after CD doping.

Rapid production of HIV-1 neutralizing antibodies in baculovirus infected insect cells.

Broadly neutralizing antibodies have been shown promise as prophylactic and therapeutic agents to provide passive protection against human immunodeficiency virus type 1 (HIV-1) infection. Such protein based microbicides are traditionally produced using mammalian cell expression system, which is not able to satisfy the increasing demand of these proteins in large scale. In this report, two of HIV-1 broadly neutralizing antibodies, b12 and VRC01, were successfully expressed in Sf9 insect cells by co-infection with baculoviruses respectively expressing the light and heavy chain of the antibodies. The purified antibodies are fully assembled as H2L2 (two heavy chains plus two light chains) heterodimer linked by covalent bonds. The b12 and VRC01 generated from insect cells reacted well to HIV-1 gp120, and their antigen binding ability is comparable to the mammalian cell-derived b12 as determined by ELISA and flow cytometry. Our data suggest that baculovirus/insect cell expression system can be utilized as an alternative to the mammalian expression system for the rapid production of HIV-1 broadly neutralizing antibodies.