Spleen tyrosine kinase inhibitor R406 has both antiviral and anti-inflammatory effects on severe influenza A infection.

Death due to severe influenza is usually a fatal complication of a dysregulated immune response more than the acute virulence of an infectious agent. Although spleen tyrosine kinase (SYK) as a critical immune signaling molecule and therapeutic target plays roles in airway inflammation and acute lung injury, the role of SYK in influenza virus infection is not clear. Here, we investigated the antiviral and anti-inflammatory effects of SYK inhibitor R406 on influenza infection through a coculture model of human alveolar epithelial (A549) and macrophage (THP-1) cell lines and mouse model. The results showed that R406 treatment increased the viability of A549 and decreased the pathogenicity and mortality of lethal influenza virus in mice with influenza A infection, decreased levels of intracellular signaling molecules under the condition of inflammation during influenza virus infection. Combination therapy with oseltamivir further ameliorated histopathological damage in the lungs of mice and further delayed the initial time to death compared with R406 treatment alone. This study demonstrated that phosphorylation of SYK is involved in the pathogenesis of influenza, and R406 has antiviral and anti-inflammatory effects on the treatment of the disease, which may be realized through multiple pathways, including the already reported SYK/STAT/IFNs-mediated antiviral pathway, as well as TNF-α/SYK- and SYK/Akt-based immunomodulation pathway.

A Comparison of Etiology, Pathogenesis, Vaccinal and Antiviral Drug Development between Influenza and COVID-19.

Influenza virus and coronavirus, two kinds of pathogens that exist widely in nature, are common emerging pathogens that cause respiratory tract infections in humans. In December 2019, a novel coronavirus SARS-CoV-2 emerged, causing a severe respiratory infection named COVID-19 in humans, and raising a global pandemic which has persisted in the world for almost three years. Influenza virus, a seasonally circulating respiratory pathogen, has caused four global pandemics in humans since 1918 by the emergence of novel variants. Studies have shown that there are certain similarities in transmission mode and pathogenesis between influenza and COVID-19, and vaccination and antiviral drugs are considered to have positive roles as well as several limitations in the prevention and control of both diseases. Comparative understandings would be helpful to the prevention and control of these diseases. Here, we review the study progress in the etiology, pathogenesis, vaccine and antiviral drug development for the two diseases.

TD-DFT benchmark for UV-visible spectra of fused-ring electron acceptors using global and range-separated hybrids.

Non-fullerene acceptors, especially acceptor-donor-acceptor structured fused-ring electron acceptors (FREAs), have attracted widespread attention in organic solar cells because of their versatile molecular design in fine-tuning light absorption and energy levels. We report the accuracy of Time-Dependent Density Functional Theory (TD-DFT) for FREAs by comparing their theoretically predicted vertical absorption wavelength (λver-abso) with the experimental maximum absorption (λmax). The λver-abso values of 50 molecules obtained from major types of FREAs have been investigated using TD-DFT by considering the solvent effects. The values of λver-abso predicted with a pure density functional (PBE), global hybrids (B3LYP and PBE0) and range-separated schemes (CAM-B3LYP and LC-ωPBE) follow the exact exchange percentage included at an intermediate inter-electronic distance. Global hybrids outperform all other schemes. The mean absolute error provided is 22 nm by PBE0 and 38 nm by B3LYP for the whole set of molecules. The maximum deviation of 92 nm provided by B3LYP and 69 nm provided by PBE0 confirms that PBE0 is more appropriate for predicting the absorption wavelengths when designing new FREAs. By applying linear regression analysis to obtain the calibration curve, we found that the range-separated methods provide an equal or even more consistent description of FREA excited states. For the whole set of molecules, linearly corrected data yield an average error of 25 and 27 nm for CAM-B3LYP and LC-ωPBE, respectively. Consequently, when a statistical analysis technique is applicable for a certain series of FREAs, a theoretical method permits a chemically comprehensive and empirically good explanation of UV/Vis spectra for newly-designed FREAs.

Enhancing Adhesion and Reducing Ohmic Contact through Nickel-Silicon Alloy Seed Layer in Electroplating Ni/Cu/Ag.

Due to the lower cost compared to screen-printed silver contacts, the Ni/Cu/Ag contacts formed by plating have been continuously studied as a potential metallization technology for solar cells. To address the adhesion issue of backside grid lines in electroplated n-Tunnel Oxide Passivating Contacts (n-TOPCon) solar cells and reduce ohmic contact, we propose a novel approach of adding a Ni/Si alloy seed layer between the Ni and Si layers. The metal nickel layer is deposited on the backside of the solar cells using electron beam evaporation, and excess nickel is removed by H2SO4:H2O2 etchant under annealing conditions of 300-425 °C to form a seed layer. The adhesion strength increased by more than 0.5 N mm-1 and the contact resistance dropped by 0.5 mΩ cm2 in comparison to the traditional direct plating Ni/Cu/Ag method. This is because the resulting Ni/Si alloy has outstanding electrical conductivity, and the produced Ni/Si alloy has higher adhesion over direct contact between the nickel-silicon interface, as well as enhanced surface roughness. The results showed that at an annealing temperature of 375 °C, the main compound formed was NiSi, with a contact resistance of 1 mΩ cm-2 and a maximum gate line adhesion of 2.7 N mm-1. This method proposes a new technical solution for cost reduction and efficiency improvement of n-TOPCon solar cells.

Asymmetric Non-Fullerene Acceptor Derivatives Incorporated Ternary Organic Solar Cells.

Incorporating ITIC derivatives as guest acceptors into binary host systems is an effective strategy for constructing high-performance ternary organic solar cells (TOSCs). In this work, we introduced A-D-A type ITIC derivatives PTBTT-4F (asymmetric) and PTBTP-4F (symmetric) into the PM6:BTP-BO-4F (Y6-BO) binary blend and investigated the impacts of two guest acceptors on the performance of TOSCs. Differentiated device performance was observed, although PTBTT-4F and PTBTP-4F presented similar chemical structures and comparable absorptions. The PTBTT-4F ternary devices exhibited an improved power conversion efficiency (PCE) of 17.67% with increased open circuit (VOC) and current density (JSC), whereas the PTBTP-4F-based ternary devices yielded a relatively lower PCE of 16.34%. PTBTT-4F showed much better compatibility with the host acceptor BTP-BO-4F, so that they formed a well-mixed alloy phase state; more precise phase separation and increased crystallinity were thus induced in the ternary blends, leading to reduced molecular recombination and improved charge mobilities, which contributed to improved fill factors of the ternary devices. In addition, the optimized PTBTT-4F devices exhibited good performance tolerance of the photoactive layer thickness, as they even delivered a PCE of 15.25% when the active layer was as thick as up to ∼300 nm.

Deficiency of C-reactive protein or human C-reactive protein transgenic treatment aggravates influenza A infection in mice.

C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-γ concentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRP transgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.

An unfused-ring acceptor with high side-chain economy enabling 11.17% as-cast organic solar cells.

Side-chain engineering on nonfullerene acceptors (NFAs) is crucial for modulating their solubility and crystallinity as well as packing behaviours in active layers to pursue high-performance organic solar cells (OSCs). High weight ratios of side chains are generally used by NFAs for the desired device efficiencies. Side-chain economy has seldom been discussed despite increased cost and difficulties in synthesis when optimizing the molecular design. Herein, we introduce 7H-dibenzo[c,g]carbazole (DCB) as an electron-donating core to design unfused-ring acceptors (UFAs) with a dramatically low weight ratio of side chains. DCB-4F has thus been designed and compared with the carbazole cored analogue (CB-4F). The unique conformation of the DCB core endows DCB-4F with higher solubility (8.2 mg mL-1 in chloroform) compared to CB-4F (2.2 mg mL-1) when using the same side chains. Featuring a lowest unoccupied molecular orbital (LUMO) level of -3.86 eV and an optical bandgap of 1.55 eV, the DCB-4F film exhibits an absorption profile (maximum 667 nm) complementary to polymer donor PM6. The PM6:DCB-4F as-cast OSCs deliver a power conversion efficiency (PCE) of 9.56% with a high open-circuit voltage (VOC) of 1.00 V. By adding 10 wt% PC71BM into the casting solutions, a greatly improved PCE of 11.17% is readily achieved, which is one of the highest PCEs for as-cast single-junction UFA-based devices. The PM6:DCB-4F based blends show homogeneous nano-fiberous morphology and higher hydrophobicity. The design of conformation-tuned NFAs using sterically hindered DCB-like cores is promising to achieve highly efficient as-cast OSCs.

Over 15% Efficiency in Ternary Organic Solar Cells by Enhanced Charge Transport and Reduced Energy Loss.

In this study, an efficient ternary bulk-heterojunction (BHJ) organic solar cell (OSC) is demonstrated by incorporating two acceptors, PC61BM and ITC6-4F, with a polymer donor (PM6). This reveals that the addition of PC61BM not only enhances the electron mobility of the derived BHJ blend but also facilitates exciton dissociation, resulting in a more balanced charge transport alongside with reduced trap-assisted charge recombination. Consequently, as compared to the pristine PM6/ITC6-4F device, the optimal ternary OSC is revealed to deliver an improved power conversion efficiency (PCE) of 15.11% with a boosted JSC, VOC, and fill factor (FF) simultaneously. The resultant VOC and FF are among the highest values recorded in the literature for the ternary OSCs with a PCE exceeding 15%. This result thus suggests that besides improving the charge transport characteristics in devices, incorporating a fullerene derivative as part of the acceptor can also improve the resultant VOC, which can reduce the energy loss to realize efficient organic photovoltaics.

AA28-67 domain within MyD88 suppresses c-myc activity and expression to regulate differentiation and function of dendritic cells.

The mechanism by which c-myc expression in undifferentiated cells rapidly declines following induction of differentiation is poorly characterized. We demonstrate here that MyD88, which can activate NF-kappaB and MAPK, also suppresses c-myc activity and expression. The aa 28-67 domain, a highly conserved region within MyD88, plays a critical role in the MyD88-mediated inhibition. Indeed, deletion of the aa 28-67 domain (MyD88 Delta 28-67) or mutation of the highly conserved amino acid residue phenylalanine (aa 36) to aspartic acid (MyD88 Delta F36D) significantly promoted c-myc activity and expression. Additionally, we found that MyD88 Delta 28-67-mediated c-myc activity and expression could be abrogated using PI3K inhibitor, suggesting that the PI3K/Akt signaling pathway may be involved in MyD88-mediated suppression of c-myc. Compared to MyD88-transduced DCs, MyD88 Delta 28-67- and MyD88 Delta F36D-transduced DCs derived from MyD88-/- bone marrow cells had lower antigen-presenting ability. Thus, MyD88 induces the differentiation and maturation of DCs not only by activating NF-kappaB and MAPK but also via suppressing c-myc activity and expression.

Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells.

An elevated number of Gr-1(+)CD11b(+) myeloid-derived suppression cells (MDSCs) has been described in mice and human bearing tumor and associated with immune suppression. Arginase I production by MDSCs in the tumor environment may be a central mechanism for immunosuppression and tumor evasion. In this study and before, we found that Gr-1(+)CD11b(+) MDSCs from ascites and spleen of mice bearing ovarian 18D carcinoma express a high level of PD-1, CTLA-4, B7-H1 and CD80 while other co-stimulatory molecules, namely CD40, B7-DC and CD86 are not detected. Further studies showed that PD-1 and CTLA-4 on the Gr-1(+)CD11b(+) MDSCs regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 and CTLA4 molecules could significantly reduce arginase I activity and expression induced with tumor-associated factor. Similar results were also observed while their ligands B7-H1 and/or CD80 were blocked or silenced. Furthermore, CD80 deficiency also decreased the arginase I expression and activity. Antibody blockade or silencing of PD-1, CTLA-4 or both reduced the suppressive potential of PD-1+CTLA-4+MDSCs. Blockade of PD-1, CTLA-4 or both also slowed tumor growth and improved the survival rate of tumor-bearing mice. Thus, there may exist a coinhibitory and costimulatory molecules-based immuno-regulating net among MDSCs.

B7-H1 on myeloid-derived suppressor cells in immune suppression by a mouse model of ovarian cancer.

Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and are associated with immune suppression. Here, we described high level of expression of B7-H1 (CD274), PD-1 (CD279) and CTLA4 (CD152) by Gr-1(+)CD11b(+) MDSCs obtained from both ascites and spleens of mice bearing the 1D8 ovarian carcinoma, whereas B7-DC (CD273), CD40 and CD86 were absent. In contrast, B7-H1, PD-1 and CTLA-4 expression was not detected on Gr-1(+)CD11b(+) cells from naive mice. Expression of B7-H1 by Gr-1(+)CD11b(+) cells from naive mice could be induced by co-culture with 1D8 ovarian carcinoma cells. Gr-1(+)CD11b(+) cells derived from 1D8 tumor-bearing mice markedly suppressed antigen-specific immune responses, whereas Gr-1(+)CD11b(+) cells from naive mice did not. siRNA-mediated knockdown of B7-H1 in Gr-1(+)CD11b(+) cells of 1D8 tumor-bearing mice alleviated suppression of antigen-specific immune responses. Suppression of antigen-specific immune responses via B7-H1 on Gr-1(+)CD11b(+) myeloid cells was mediated by CD4(+)CD25(+) Foxp3(+) T regulatory cells and required PD-1. Antibody blockade of either B7-H1 or PD-1 retarded the growth of 1D8 tumor in mice. This suggests that expression of B7-H1 on Gr-1(+)CD11b(+) myeloid cells triggered by the 1D8 mouse model of ovarian carcinoma suppresses antigen-specific immunity via interaction with PD-1 on CD4(+)CD25(+) Foxp3(+) regulatory T cells.

Dithieno[3,2-b:2',3'-d]pyrrol Fused Nonfullerene Acceptors Enabling Over 13% Efficiency for Organic Solar Cells.

A new electron-rich central building block, 5,5,12,12-tetrakis(4-hexylphenyl)-indacenobis-(dithieno[3,2-b:2',3'-d]pyrrol) (INP), and two derivative nonfullerene acceptors (INPIC and INPIC-4F) are designed and synthesized. The two molecules reveal broad (600-900 nm) and strong absorption due to the satisfactory electron-donating ability of INP. Compared with its counterpart INPIC, fluorinated nonfullerene acceptor INPIC-4F exhibits a stronger near-infrared absorption with a narrower optical bandgap of 1.39 eV, an improved crystallinity with higher electron mobility, and down-shifted highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels. Organic solar cells (OSCs) based on INPIC-4F exhibit a high power conversion efficiency (PCE) of 13.13% and a relatively low energy loss of 0.54 eV, which is among the highest efficiencies reported for binary OSCs in the literature. The results demonstrate the great potential of the new INP as an electron-donating building block for constructing high-performance nonfullerene acceptors for OSCs.

Delivery of telomerase reverse transcriptase small interfering RNA in complex with positively charged single-walled carbon nanotubes suppresses tumor growth.

PURPOSE: To determine whether -CONH-(CH(2))(6)-NH(3)(+)Cl(-) functionalized single-walled carbon nanotubes (SWNT) carrying complexed small interfering RNA (siRNA) can enter into tumor cells, wherein they release the siRNA to silence the targeted gene. EXPERIMENTAL DESIGN: -CONH-(CH(2))(6)-NH(3)(+)Cl(-) was used to mediate the conjugation of telomerase reverse transcriptase (TERT) siRNA to SWNTs. The ability of TERT siRNA delivered via SWNT complexes to silence the expression of TERT was assessed by their effects on the proliferation and growth of tumor cells both in vitro and in mouse models. RESULTS: The functionalized SWNTs -CONH-(CH(2))(6)-NH(3)(+)Cl(-) could facilitate the coupling of siRNAs that specifically target murine TERT expression to form the mTERT siRNA:SWNT+ complex. These functionalized SWNTs rapidly entered three cultured murine tumor cell lines, suppressed mTERT expression, and produced growth arrest. Injection of mTERT siRNA:SWNT+ complexes into s.c. Lewis lung tumors reduced tumor growth. Furthermore, human TERT siRNA:SWNT+ complexes also suppressed the growth of human HeLa cells both in vitro and when injected into tumors in nude mice. CONCLUSIONS: -CONH-(CH(2))(6)-NH(3)(+)Cl(-) functionalized SWNTs carry complexed siRNA into tumor cells, wherein they release the siRNA from the nanotube sidewalls to silence the targeted gene. The -CONH-(CH(2))(6)-NH(3)(+)Cl(-) functionalized SWNTs may represent a new class of molecular transporters applicable for siRNA therapeutics.

Antigen presentation by dendritic cells in tumors is disrupted by altered metabolism that involves pyruvate kinase M2 and its interaction with SOCS3.

Dendritic cell (DC) function is negatively affected by tumors and tumor-derived factors, but little is known about the underlying mechanisms. Here, we show that intracellular SOCS3 in DCs binds to pyruvate kinase type M2 (M2-PK), which plays a critical role in ATP production through glycolysis. The interaction of SOCS3 with M2-PK reduced ATP production and impaired DC-based immunotherapy against tumors. Thus, SOCS3, which has been shown to be upregulated by tumor-derived factors, interacts with M2-PK to decrease ATP production, causing DC dysfunction. These dysfunctional DCs have a reduced ability to present antigens. Alteration of DC metabolism mediated by SOCS3 represents a novel mechanism for DC dysfunction in the tumor microenvironment.

Suppressor of cytokine signaling 3 promotes bone marrow cells to differentiate into CD8+ T lymphocytes in lung tissue via up-regulating Notch1 expression.

Suppressor of cytokine signaling 3 (SOCS3) expression in bone marrow cells (BMC) was up-regulated upon exposure to interleukin 6, lipopolysaccharide, or tumor-associated factors. But, how the up-regulated SOCS3 affects differentiation of BMCs is incompletely characterized. Here, we showed that SOCS3 promoted BMCs to intently differentiate into CD8 T cells. Importantly, lung can be as one athymus tissue for the BMCs to differentiate into CD8(+) T cells. Notch1 plays a critical role in the differentiation from SOCS3-transfected BMCs to CD8(+) T cells. We conclude that the up-regulated SOCS3 in some pathologic conditions, such as tumor and inflammation, might promote BMCs to differentiate into CD8(+) T lymphocytes in lung tissue via up-regulating Notch1 expression. This may represent a new mechanism against diseases such as tumor.

Tumor-induced suppressor of cytokine signaling 3 inhibits toll-like receptor 3 signaling in dendritic cells via binding to tyrosine kinase 2.

The suppressor of cytokine signaling (SOCS) family of negative regulatory proteins is up-regulated in response to several cytokines and pathogen-associated molecular patterns (PAMP) and suppresses cellular signaling responses by binding receptor phosphotyrosine residues. Exposure of bone marrow-derived dendritic cells (BMDC) to 1D8 cells, a murine model of ovarian carcinoma, suppresses their ability to express CD40 and stimulate antigen-specific responses in response to PAMPs and, in particular, to polyinosinic acid:poly-CMP (polyI:C) with the up-regulated SOCS3 transcript and protein levels. The ectopic expression of SOCS3 in both the macrophage cell line RAW264.7 and BMDCs decreased signaling in response to both polyI:C and IFNalpha. Further, knockdown of SOCS3 transcripts significantly enhanced the responses of RAW264.7 and BMDCs to both polyI:C and IFNalpha. Immunoprecipitation and pull-down studies show that SOCS3 binds to the IFNalpha receptor tyrosine kinase 2 (TYK2). Because polyI:C triggers autocrine IFNalpha signaling, binding of SOCS3 to TYK2 may thereby suppress the activation of BMDCs by polyI:C and IFNalpha. Thus, elevated levels of SOCS3 in tumor-associated DCs may potentially resist the signals induced by Toll-like receptor 3 ligands and type I IFN to decrease DC activation via binding with IFNalpha receptor TYK2.