Hepatic T-cell senescence and exhaustion are implicated in the progression of fatty liver disease in patients with type 2 diabetes and mouse model with nonalcoholic steatohepatitis.

Immunosenescence and exhaustion are involved in the development and progression of type 2 diabetes (T2D) and metabolic liver diseases, including fatty liver, fibrosis, and cirrhosis, in humans. However, the relationships of the senescence and exhaustion of T cells with insulin resistance-associated liver diseases remain incompletely understood. To better define the relationship of T2D with nonalcoholic fatty liver disease, 59 patients (mean age 58.7 ± 11.0 years; 47.5% male) with T2D were studied. To characterize their systemic immunophenotypes, peripheral blood mononuclear cells were analyzed using flow cytometry. Magnetic resonance imaging (MRI)-based proton density fat fraction and MRI-based elastography were performed using an open-bore, vertical-field 3.0 T scanner to quantify liver fat and fibrosis, respectively. The participants with insulin resistance had a significantly larger population of CD28 - CD57+ senescent T cells among the CD4+ and CD8 + T cells than those with lower Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values. The abundances of senescent CD4+ and CD8 + T cells and the HOMA-IR positively correlated with the severity of liver fibrosis, assessed using MRI-based elastography. Interleukin 15 from hepatic monocytes was found to be an inducer of bystander activation of T cells, which is associated with progression of liver disease in the participants with T2D. Furthermore, high expression of genes related to senescence and exhaustion was identified in CD4+ and CD8 + T cells from the participants with nonalcoholic steatohepatitis or liver cirrhosis. Finally, we have also demonstrated that hepatic T-cell senescence and exhaustion are induced in a diet or chemical-induced mouse model with nonalcoholic steatohepatitis. In conclusion, we have shown that T-cell senescence is associated with insulin resistance and metabolic liver disease in patients with T2D.

Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion.

BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer. METHODS: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively. RESULTS: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production. CONCLUSIONS: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.

Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice.

BACKGROUND: Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass. METHODS: MKO mice with lower muscle OxPhos were fed a normal chow or high-fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation. RESULTS: MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response-related genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in grip strength and a higher drop rate in the wire hanging test (P < 0.01). Micro-computed tomography and von Kossa staining revealed that MKO mice developed a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic analysis of the BM revealed that mitochondrial stress responses in skeletal muscles induce an inflammatory response and adipogenesis in the BM and that the CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in MKO mice. In humans, patients with low body mass index (BMI = 17.2 ± 0.42 kg/m2 ) harboured a larger population of proinflammatory and cytotoxic senescent T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in the vastus lateralis, compared with controls with a normal BMI (23.7 ± 0.88 kg/m2 ) (P < 0.01). CONCLUSIONS: Defects in muscle mitochondrial OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.

Metabolite Changes during the Transition from Hyperthyroidism to Euthyroidism in Patients with Graves' Disease.

BACKGRUOUND: An excess of thyroid hormones in Graves' disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment. METHODS: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data. RESULTS: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways. CONCLUSION: In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

Immunometabolic signatures predict recovery from thyrotoxic myopathy in patients with Graves' disease.

BACKGROUND: Thyroid hormone excess induces protein energy wasting, which in turn promotes muscle weakness and bone loss in patients with Graves' disease. Although most studies have confirmed a relationship between thyrotoxicosis and muscle dysfunction, few have measured changes in plasma metabolites and immune cells during the development and recovery from thyrotoxic myopathy. The aim of this study was to identify specific plasma metabolites and T-cell subsets that predict thyrotoxic myopathy recovery in patients with Graves' disease. METHODS: One hundred patients (mean age, 40.0 ± 14.2 years; 67.0% female), with newly diagnosed or relapsed Graves' disease were enrolled at the start of methimazole treatment. Handgrip strength and Five Times Sit to Stand Test performance time were measured at Weeks 0, 12, and 24. In an additional 35 patients (mean age, 38.9 ± 13.5 years; 65.7% female), plasma metabolites and immunophenotypes of peripheral blood were evaluated at Weeks 0 and 12, and the results of a short physical performance battery assessment were recorded at the same time. RESULTS: In both patient groups, methimazole-induced euthyroidism was associated with improved handgrip strength and lower limb muscle function at 12 weeks. Elevated plasma metabolites including acylcarnitines were restored to normal levels at Week 12 regardless of gender, body mass index, or age (P trend <0.01). Senescent CD8+ CD28- CD57+ T-cell levels in peripheral blood were positively correlated with acylcarnitine levels (P < 0.05) and decreased during thyrotoxicosis recovery (P < 0.05). High levels of senescent CD8+ T cells at Week 0 were significantly associated with small increases in handgrip strength after 12 weeks of methimazole treatment (P < 0.05), but not statistically associated with Five Times Sit to Stand Test performance. CONCLUSIONS: Restoring euthyroidism in Graves' disease patients was associated with improved skeletal muscle function and performance, while thyroid hormone-associated changes in plasma acylcarnitines levels correlated with muscle dysfunction recovery. T-cell senescence-related systemic inflammation correlated with plasma acylcarnitine levels and was also associated with small increases in handgrip strength.

Interleukin-10 Attenuates Liver Fibrosis Exacerbated by Thermoneutrality.

Background: Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs). Methods: The carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes. Results: Under TN conditions, mice with CCl4-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl4 administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation. Conclusions: BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl4-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT-liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.

Effect of Salivary Exosomal miR-25-3p on Periodontitis With Insulin Resistance.

Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.

Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.

Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.

Strong alkaline condition is preferable for producing 7,10-dihydroxy-8(E)-hexadecenoic acid from palmitoleic acid by Pseudomonas aeruginosa KNU-2B.

Microbial bioconversion of a given substrate is considered an efficient and eco-friendly tool for value-added industrial compound generation from natural products. Among natural products, unsaturated fatty acids have been used as substrates to produce various functional hydroxy fatty acids. In this study, we report the production of 7,10-dihydroxy-8(E)-hexadecenoic acid (DHD) from palmitoleic acid by a new strain, Pseudomonas aeruginosa KNU-2B. KNU-2B efficiently produced DHD from palmitoleic acid and required a strong alkaline condition for maximum DHD production. The maximum DHD amount produced under pH 10.0 and 48-h incubation at 27 °C and 150 rpm was 219.5 mg/100 mL culture. Other important nutritional factors were also investigated to obtain optimum DHD production.

Production of 7,10,12-trihydroxy-8(E)-octadecenoic acid from ricinoleic acid by Pseudomonas aeruginosa KNU-2B.

Microbial production of hydroxy fatty acids (HFAs) was widely studied because of important biological properties of HFAs. Among microorganisms producing HFAs, Pseudomonas aeruginosa PR3 was well known to produce various HFAs from different unsaturated fatty acids. Recently, a new variant species of P. aeruginosa PR3 was isolated and characterized, showing improved efficiency for producing 7,10-dihydroxy-8(E)-octadecenoic acid from oleic acid. In this study, we report the production of 7,10,12-trihydroxy-8(E)-octadecenoic acid (TOD) from ricinoleic acid by the newly isolated P. aeruginosa KNU-2B. TOD was efficiently produced from ricinoleic acid by KNU-2B with the maximum conversion yield of 56.7% under the optimum reaction conditions of pH 8.0 and 48-h incubation at 27 °C, 150 rpm. Under optimized reaction conditions, maximum TOD production reached 340.3 mg/100 mL of the culture. However, requirement of nutritional factors by KNU-2B for production of TOD were considerably different from those by PR3 strain.

Segmented retinal layer analysis of chiasmal compressive optic neuropathy in pituitary adenoma patients.

AIMS: To evaluate changes in the segmented retinal layers of pituitary adenoma (PA) patients and to identify the relationship between these changes and visual function. METHODS: A total of 47 (PA patients) and 22 (healthy subjects) eyes were reviewed from the medical records. The PA patients performed a visual field (VF) test before surgery and 1 month after surgery. By optical coherence tomography scanning, eight retinal layers were measured: retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer, outer nuclear layer, retinal pigment epithelium, and photoreceptor layer. RESULTS: The PA group showed reduced RNFL, GCL, and IPL thicknesses (p = 0.004,< 0.001,< 0.001) and thicker INL thickness (p = 0.012) than did the controls. The mean deviation of preoperative VF in the PA group was positively correlated with RNFL, GCL, and IPL thicknesses (R = 0.664, 0.720, 0.664; p < 0.001,< 0.001,< 0.001) and negatively correlated with the INL thickness (R = -0.400; p = 0.010). Among the 47 eyes, 32 eyes (68%) were included for subgroup analysis. Preoperative RNFL, GCL, and IPL thicknesses were thicker in the postoperatively improved VF group (p = 0.019, 0.009, 0.005). The preoperative cutoff values for visual recovery were 23.6 µm for RNFL thickness, 30.6 µm for GCL thickness, and 28.9 µm for IPL thickness. CONCLUSION: During chiasmal compression, the thickening of the INL has presented in addition to thinning of the inner retinal layers. Also, changes in retinal anatomical structures are related to the extent of VF defect and can be used as a predictor of postoperative visual recovery.

T-cell senescence contributes to abnormal glucose homeostasis in humans and mice.

Chronic inflammation is a driving force for the development of metabolic disease including diabetes and obesity. However, the functional characteristics of T-cell senescence in the abnormal glucose homeostasis are not fully understood. We studied the patients visiting a hospital for routine health check-ups, who were divided into two groups: normal controls and people with prediabetes. Gene expression profiling of peripheral blood mononuclear cells from normal controls and patients with type 2 diabetes was undertaken using microarray analysis. We also investigated the immunometabolic characteristics of peripheral and hepatic senescent T cells in the normal subjects and patients with prediabetes. Moreover, murine senescent T cells were tested functionally in the liver of normal or mice with metabolic deterioration caused by diet-induced obesity. Human senescent (CD28-CD57+) CD8+ T cells are increased in the development of diabetes and proinflammatory cytokines and cytotoxic molecules are highly expressed in senescent T cells from patients with prediabetes. Moreover, we demonstrate that patients with prediabetes have higher concentrations of reactive oxygen species (ROS) in their senescent CD8+ T cells via enhancing capacity to use glycolysis. These functional properties of senescent CD8+ T cells contribute to the impairment of hepatic insulin sensitivity in humans. Furthermore, we found an increase of hepatic senescent T cells in mouse models of aging and diet-induced obesity. Adoptive transfer of senescent CD8+ T cells also led to a significant deterioration in systemic abnormal glucose homeostasis, which is improved by ROS scavengers in mice. This study defines a new clinically relevant concept of T-cell senescence-mediated inflammatory responses in the pathophysiology of abnormal glucose homeostasis. We also found that T-cell senescence is associated with systemic inflammation and alters hepatic glucose homeostasis. The rational modulation of T-cell senescence would be a promising avenue for the treatment or prevention of diabetes.

The diluted atropine for inhibition of myopia progression in Korean children.

AIM: To evaluate the efficacy and safety of three different concentrations of diluted atropine for the control of myopia in Korean children, and to assess the risk factors associated with rapid myopia progression. METHODS: A total of 285 children, with refractive errors within the range of -6 diopters (D) between 5 and 14 years of age were included. After using 0.01%, or 0.025%, or 0.05% atropine, for about 1y, changes in refraction, axial lengths and frequency of adverse events were analyzed. Logistic regression analyses were performed to evaluate the risk factors associated with rapid myopia progression. RESULTS: The changes in the mean spherical equivalent values were -0.134 D/mo in the before atropine group, -0.070 D/mo in the 0.01% atropine group, -0.047 D/mo in the 0.025% atropine group, and -0.019 D/mo in the 0.05% atropine group, with significant differences between the groups (P<0.001). The axial elongation was 0.046 mm/mo, 0.037 mm/mo, 0.025 mm/mo, and 0.019 mm/mo respectively, with significant differences between the groups (P=0.003). The incidence of photophobia and near vision difficulty was not different among the three atropine groups (P=0.425 and P=0.356, respectively). Multivariate logistic regression analyses showed that only highly myopic parents were a significant predictive factor of rapid myopia progression in Korean children (odds ratio, 8.155; 95% confidence interval, 3.626-18.342; P<0.001). CONCLUSION: Treatment with 0.01%, 0.025% and 0.05% atropine solution inhibits myopia progression in Korean children in a dose-dependent manner. Children with highly myopic parents preferentially shows a rapid myopia progression rate.

Three Dimensional Evaluation of Posterior Pole and Optic Nerve Head in Tilted Disc.

For over a century, tilted disc syndrome (TDS) has been defined vaguely. The lack of consensus of the terminology arises from the lack of understanding of the pathogenesis of this condition. Also, myopic discs with temporal crescents or peripapillary atrophy (PPA) are histologically indistinguishable from TDS. Therefore, we examined the morphological background of the extreme ONH appearances such as the myopic tilted disc and the TDS by analyzing the posterior segment of the eye from a three-dimensional (3D) perspective. 107 eyes of 107 subjects were classified into 3 groups with respect to the optic disc torsion degrees: (1) mild torsion (0-30 degrees; 35 eyes) and (2) moderate torsion (30-60 degrees; 35 eyes) and (3) severe torsion (60-90 degrees; 37 eyes). SSOCT images were analyzed in coronal view, which supplements anterior-posterior depth (z axis in Cartesian coordinates). The amount of optic disc torsion was significantly correlated with Disc-DPE angle and Fovea-Disc depth (r = 0.548, P < 0.001 and r = 0.544, P < 0.001). In conclusion, we describe specific types of posterior sclera configuration that corresponds to the increasing degree of optic disc torsion, even in the extreme ONH appearances such as the myopic tilted disc and the TDS. These findings suggest that the optic disc appearance is determined by the configuration of the posterior sclera.

Effects of the Rho-Kinase Inhibitor Y-27632 on Extraocular Muscle Surgery in Rabbits.

PURPOSE: To evaluate the effect of the Rho-kinase inhibitor Y-27632 on postoperative inflammation and adhesion following extraocular muscle surgery in rabbits. METHODS: The superior rectus muscle reinsertion was performed on both eyes of 8 New Zealand white rabbits. After reinsertion, the rabbits received subconjunctival injections of the Rho-kinase inhibitor and saline on each eye. To assess acute and late inflammatory changes, Ki-67, CD11ß+, and F4/80 were evaluated and the sites of muscle reattachment were evaluated for a postoperative adhesion score and histopathologically for collagen formation. RESULTS: F4/80 antibody expression was significantly different in the Rho-kinase inhibitor-injected group at both postoperative day 3 and week 4 (p = 0.038, 0.031). However, Ki-67 and CD11ß+ were not different the between two groups. The difference in the SRM/conjunctiva adhesion score between the two groups was also significant (p = 0.034). Conclusion. Intraoperative subconjunctival injection of the Rho-kinase inhibitor may be effective for adjunctive management of inflammation and fibrosis in rabbit eyes following extraocular muscle surgery.

Sequential processing: control of nanomorphology in bulk heterojunction solar cells.

Bulk heterojunction organic photovoltaic devices based on poly[N-9''-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole) (PCDTBT)/[6,6]-phenyl C(70) butyric acid methyl ester (PC(70)BM) can be successfully fabricated by a sequential solution deposition process. When the top layer is deposited from an appropriate cosolvent, the PC(70)BM penetrates a predeposited bottom layer of PCDTBT during the spin-casting process, resulting in an interdiffused structure with a layer-evolved bulk heterojunction (LE-BHJ) nanomorphology. The PCDTBT:PC(70)BM LE-BHJ solar cells prepared with an optimized cosolvent ratio have comparable power conversion efficiency to the conventional BHJ solar cells. The nanomorphology of the optimized PCDTBT:PC(70)BM LE-BHJ mixture was found to have better vertical connectivity than the conventional BHJ material.

Spontaneous formation of bulk heterojunction nanostructures: multiple routes to equivalent morphologies.

Bulk heterojunction (BHJ) layers based on poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) were fabricated by two methods: codeposition of P3HT/PCBM from a common solvent (conventional BHJ) and by sequential, layer-by-layer deposition of P3HT/PCBM from separate solvents (layer-evolved BHJ). Thermally annealed layer-evolved BHJ solar cells show power conversion efficiencies and electron/hole mobilities comparable to conventional BHJ solar cells. The nanomorphology of both active layers is compared in situ by transmission electron microscopy (TEM) using a multilayer cross-sectional sample architecture. No significant difference is observed between the nanomorphology of the conventional BHJ and layer-evolved BHJ material implying that the bulk heterojunction forms spontaneously and that it is the lowest energy state of the two component system.

Effect of processing additive on the nanomorphology of a bulk heterojunction material.

The bulk heterojunction (BHJ) material Si-PDTBT:PC(70)BM is sensitive to the use of a small amount of 1-chloronaphthalene (CN) as a processing additive; CN as a cosolvent (e.g., 4% in chlorobenzene) causes in a factor of 2 increase in the power conversion efficiency of BHJ solar cells. The morphology of the BHJ material, prepared with and without the CN additive is studied with top-down transmission electron microscopy, cross-sectional transmission electron microscopy, and atomic force microscopy. The improved performance is the result of changes in the nanoscale morphology. Field-effect transistor measurements are consistent with the observed changes in morphology.