High‐Performance Tandem Organic Solar Cells Using HSolar as the Interconnecting Layer

Tandem structure provides a practical way to realize high efficiency organic photovoltaic cells, it can be used to extend the wavelength coverage for light harvesting. The interconnecting layer (ICL) between subcells plays a critical role in the reproducibility and performance of tandem solar cells, yet the processability of the ICL has been a challenge. In this work the fabrication of highly reproducible and efficient tandem solar cells by employing a commercially available material, PEDOT:PSS HTL Solar (HSolar), as the hole transporting material used for the ICL is reported. Comparing with the conventional PEDOT:PSS Al 4083 (c‐PEDOT), HSolar offers a better wettability on the underlying nonfullerene photoactive layers, resulting in better charge extraction properties of the ICL. When FTAZ:IT‐M and PTB7‐Th:IEICO‐4F are used as the subcells, a power conversion efficiency (PCE) of 14.7% is achieved in the tandem solar cell. To validate the processability of these tandem solar cells, three other research groups have successfully fabricated tandem devices using the same recipe and the highest PCE obtained is 16.1%. With further development of donor polymers and device optimization, the device simulation results show that a PCE > 22% can be realized in tandem cells in the near future.     

Linoleic acid inhibits Pseudomonas aeruginosa biofilm formation by activating diffusible signal factor‐mediated quorum sensing

Bacterial biofilm formation causes serious problems in various fields of medical, clinical, and industrial settings. Antibiotics and biocide treatments are typical methods used to remove bacterial biofilms, but biofilms are difficult to remove effectively from surfaces due to their increased resistance. An alternative approach to treatment with antimicrobial agents is using biofilm inhibitors that regulate biofilm development without inhibiting bacterial growth. In the present study, we found that linoleic acid (LA), a plant unsaturated fatty acid, inhibits biofilm formation under static and continuous conditions without inhibiting the growth of Pseudomonas aeruginosa. LA also influenced the bacterial motility, extracellular polymeric substance production, and biofilm dispersion by decreasing the intracellular cyclic diguanylate concentration through increased phosphodiesterase activity. Furthermore, quantitative gene expression analysis demonstrated that LA induced the expression of genes associated with diffusible signaling factor‐mediated quorum sensing that can inhibit or induce the dispersion of P. aeruginosa biofilms. These results suggest that LA is functionally and structurally similar to a P. aeruginosa diffusible signaling factor (cis‐2‐decenoic acid) and, in turn, act as an agonist molecule in biofilm dispersion.     

How to regulate neutrophils in gout

Most research in gout has concentrated on the proinflammatory mechanisms to explain the inflammation that is generated when leucocytes are in contact with monosodium urate crystals. However, the episodic nature of gout and the absence of inflammation even when crystals are present suggest that there are natural counter-regulatory mechanisms to limit the inflammatory response. Gagné and colleagues showed that myeloid inhibitory C-type lectin, a C-type lectin inhibitory receptor expressed on neutrophils, modulates monosodium urate-induced neutrophil responses in vitro.Neutrophil recruitment and activation play a key role in the acute inflammatory response to monosodium urate (MSU) crystals. In acute gout, our current treatments such as nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids all act on different steps of neutrophil activation. These drugs form part of the first treatment objective in gout – to relieve the painful symptoms of the acute attack – but do not address the second objective, which is to treat the underlying metabolic disorder hyperuricemia. Can neutrophil activation be manipulated or regulated? Are there signals that can be modulated and can this be of clinical relevance?The article by Gagné and colleagues provides evidence for an inhibitory pathway of neutrophil activation that acts through a recently described C-type lectin receptor called the myeloid inhibitory C-type lectin (MICL) [1]. This membrane receptor, also known as CLEC12A, inhibits neutrophil activation when it is engaged. C-type lectin receptors form a large family of proteins that have a common type of carbohydrate-binding domain that mediate cell adhesion and ligand binding in a calcium-dependent manner. Members of the C-type lectin receptors are known to participate in immune regulation, with well-known examples including Dectin-1 (CLE7A), DC-sign (CD209 or CLEC4L) and natural killer cell receptors (Ly49 or KLRA1). The MICL protein is encoded on chromosome 12p13, closely linked to the natural killer gene complex. MICL contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif and is expressed mainly on neutrophils and monocytes. Previous work has shown that the receptor could inhibit cellular activation [2]. The ligands that lead to MICL activation are currently unknown, as there is only a small body of data to show that the receptor interacts with ligands expressed in the bone marrow, thymus and kidney [3].In their studies, Gagné and colleagues showed that MSU crystals as well as a MICL-specific antibody downmodulated MICL expression on neutrophils. Reducing the expression of MICL by transfecting small interfering RNA or by antibody modulation of the receptor led to enhanced production of IL-8 when MSU was added to neutrophils, but no changes in IL-1β secretion were observed. The mechanisms of MICL signaling probably involve tyrosine phosphorylation as well as calcium flux, differing from previous results that showed MICL associated with the phosphatases SHP-1 and SHP-2 [2]. Finally, the addition of colchicine to neutrophils abrogated the negative effect of MSU on MICL expression.These results showed that reduced MICL expression is associated with augmented inflammatory responses from neutrophils, and a higher level of neutrophil MICL expression is associated with a reduced IL-8 production in vitro. As IL-8 is a major neutrophil chemoattractant, this can have important effects on neutrophil recruitment to an inflammatory site in gout. By extrapolation, if MICL expression or signaling could be enhanced or maintained during inflammation, the inhibitory signal may be reinforced and thereby downregulate inflammation. The effect of colchicine in this system is to elevate the expression of MICL, thereby increasing the inhibitory signaling mechanisms that counteract the inflammatory process.A number of caveats need to be mentioned in the interpretation of these results. The data presented were based on in vitro models of inflammation using MSU, and we need to see how this works in vivo before coming to any conclusions, as we have had examples where the in vivo results did not recapitulate the in vitro findings. They convincingly showed that reducing MICL expression on the surface of neutrophils enhanced the proinflammatory signature, but they did not show the converse – that enhanced MICL signaling can further downmodulate inflammation. Furthermore, the ligands that bind and activate MICL are unknown, so we have no idea what is the signal or how to reinforce or manipulate this signaling system. The results presented show that MSU had dual effects on neutrophils – the first is to downregulate MICL expression, and the second is to activate IL-8 production. How are these two mechanisms linked? If MSU acts mainly on the cell membrane internalization of MICL, what is the trigger for the IL-8 secretion? Notwithstanding these uncertainties, the finding that MICL modulates neutrophil activation in gout suggests that there are a number of counter-regulatory mechanisms in operation during an inflammatory process. Identifying these mechanisms may help us to understand the nature of gout as well as open up new therapeutic perspectives.     

Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy

Background

Candidia esophagitis (CE) is an AIDS-defining condition, usually occurring in individuals with low CD4 counts of <200 cells/µL. Endoscopy is a valuable definitive diagnostic method for CE but may not be indicated for asymptomatic patients or for those with high CD4 counts or without oral candidiasis. This study assessed such patients to clarify the factors associated with CE and its severity on endoscopy in the highly active antiretroviral therapy (HAART) era.

Methodology/ Principal Findings

A total of 733 HIV-infected patients who underwent upper gastrointestinal (GI) endoscopy were analyzed. Sexual behavior, CD4⁺ count, HIV-RNA viral load (VL), history of HAART, GI symptoms, GI diseases, and oral candidiasis were assessed. Endoscopic severity of CE was classified as mild (Kodsi''s grade I/II) or severe (grade III/IV). Of the 733 subjects, 62 (8.46%) were diagnosed with CE (mild, n = 33; severe, n = 29). Of them, 56.5% (35/62) had no GI symptoms, 30.6% (19/62) had CD4 + ≥200 cells/μL, and 55.3% (21/38) had no oral candidiasis. Univariate analysis found lower CD4+ counts, higher HIV VL, and no history of HAART to be significantly associated with CE. With lower CD4⁺ counts and higher HIV VL, CE occurrence increased significantly (P<0.01 for trend in odds). Multivariate analysis showed low CD4+ counts and high HIV VL to be independently associated with CE. Of the severe CE patients, 55.2% (16/29) had no GI symptoms and 44.4% (8/18) had no oral candidiasis. Median CD4⁺ counts in severe cases were significantly lower than in mild cases (27 vs. 80; P = 0.04).

Conclusions

Low CD4+ counts and high HIV VL were found to be factors associated with CE, and advanced immunosuppression was associated with the development of severity. Endoscopy is useful as it can detect CE, even severe CE, in patients without GI symptoms, those with high CD4 counts, and those without oral candidiasis.     

Circadian phase‐dependent effect of nitric oxide on L‐type voltage‐gated calcium channels in avian cone photoreceptors

Nitric oxide (NO) plays an important role in phase‐shifting of circadian neuronal activities in the suprachiasmatic nucleus and circadian behavior activity rhythms. In the retina, NO production is increased in a light‐dependent manner. While endogenous circadian oscillators in retinal photoreceptors regulate their physiological states, it is not clear whether NO also participates in the circadian regulation of photoreceptors. In this study, we demonstrate that NO is involved in the circadian phase‐dependent regulation of L‐type voltage‐gated calcium channels (L‐VGCCs). In chick cone photoreceptors, the L‐VGCCα1 subunit expression and the maximal L‐VGCC currents are higher at night, and both Ras‐mitogen‐activated protein kinase (MAPK)‐extracellular signal‐regulated kinase (Erk) and Ras‐phosphatidylinositol 3 kinase (PI3K)‐protein kinase B (Akt) are part of the circadian output pathways regulating L‐VGCCs. The NO‐cGMP‐protein kinase G (PKG) pathway decreases L‐VGCCα1 subunit expression and L‐VGCC currents at night, but not during the day, and exogenous NO donor or cGMP decreases the phosphorylation of Erk and Akt at night. The protein expression of neural NO synthase (nNOS) is also under circadian control, with both nNOS and NO production being higher during the day. Taken together, NO/cGMP/PKG signaling is involved as part of the circadian output pathway to regulate L‐VGCCs in cone photoreceptors.

     

Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs

Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.     

Leucine-rich repeat-containing G-protein coupled receptor 5/GPR49 activates G12/13-Rho GTPase pathway

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach. LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα_12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G_12/13 signaling.