Trogocytic molting of T cell microvilli upregulates T cell receptor surface expression and promotes clonal expansion.

Although T cell activation is known to involve the internalization of the T cell antigen receptor (TCR), much less is known regarding the release of TCRs following T cell interaction with cognate antigen-presenting cells. In this study, we examine the physiological mechanisms underlying TCR release following T cell activation. We show that T cell activation results in the shedding of TCRs in T cell microvilli, which involves a combined process of trogocytosis and enzymatic vesiculation, leading to the loss of membrane TCRs and microvilli-associated proteins and lipids. Surprisingly, unlike TCR internalization, this event results in the rapid upregulation of surface TCR expression and metabolic reprogramming of cholesterol and fatty acid synthesis to support cell division and survival. These results demonstrate that TCRs are lost through trogocytic 'molting' following T cell activation and highlight this mechanism as an important regulator of clonal expansion.

SURGICAL OUTCOMES OF MYOPIC TRACTION MACULOPATHY ACCORDING TO THE INTERNATIONAL PHOTOGRAPHIC CLASSIFICATION FOR MYOPIC MACULOPATHY.

PURPOSE: To compare treatment results of myopic traction maculopathy according to the international photographic classification for myopic maculopathy. METHODS: This was a retrospective, single-surgeon-based, observational case series of 35 consecutive eyes that underwent vitrectomy for myopic traction maculopathy. Eyes were classified into nonpathologic myopia (PM) (n = 15) and PM (n = 20) groups. Main outcome measures constituted best-corrected visual acuity (BCVA) and anatomical change. RESULTS: The mean follow-up was 32.03 ± 6.85 months. Axial length correlated with myopic maculopathy category (rho = 0.6836, P < 0.001). In the total group, BCVA improved from 20/61 to 20/36 (P = 0.001). In the subgroup, BCVA improved from 20/41 to 20/22 in the non-PM group (P = 0.002), whereas from 20/82 to 20/52 in the PM group (P = 0.048). Postoperative BCVA of the PM group was inferior to that of the non-PM group (P = 0.002) and the PM group was more likely to have postoperative BCVA <20/30 (odds ratio, 17.3; 95% CI, 2.6-325.0; P = 0.012). Two cases of macular hole retinal detachment occurred after surgery in the PM group. CONCLUSION: Because there are limited benefits of vitrectomy in myopic traction maculopathy accompanied by PM, careful consideration would be necessary when determining surgery. Optical coherence tomography should not be used alone in determining vitrectomy because myopic traction maculopathy can also have PM defined mainly by fundus photographs.

T cell microvilli constitute immunological synaptosomes that carry messages to antigen-presenting cells.

Microvilli on T cells have been proposed to survey surfaces of antigen-presenting cells (APC) or facilitate adhesion under flow; however, whether they serve essential functions during T cell activation remains unclear. Here we show that antigen-specific T cells deposit membrane particles derived from microvilli onto the surface of cognate antigen-bearing APCs. Microvilli carry T cell receptors (TCR) at all stages of T cell activation and are released as large TCR-enriched, T cell microvilli particles (TMP) in a process of trogocytosis. These microvilli exclusively contain protein arrestin-domain-containing protein 1, which is directly involved in membrane budding and, in combination with vacuolar protein-sorting-associated protein 4, transforms large TMPs into smaller, exosome-sized TMPs. Notably, TMPs from CD4+ T cells are enriched with LFA-2/CD2 and various cytokines involved in activating dendritic cells. Collectively, these results demonstrate that T cell microvilli constitute "immunological synaptosomes" that carry T cell messages to APCs.

TAGLN2 polymerizes G-actin in a low ionic state but blocks Arp2/3-nucleated actin branching in physiological conditions.

TAGLN is an actin-binding protein family that comprises three isoforms with theorized roles in smooth muscle differentiation, tumour development, lymphocyte activation, and brain chemistry. However, their fundamental characteristics in regulation of the actin-based cytoskeleton are not fully understood. Here we show that TAGLN2 (including TAGLN1 and TAGLN3) extensively nucleates G-actin polymerization under low-salt conditions, where polymerization would be completely suppressed. The calponin homology domain and actin-binding loop are essential to mechanically connect two adjacent G-actins, thereby mediating multimeric interactions. However, TAGLN2 blocked the Arp2/3 complex binding to actin filaments under physiological salt conditions, thereby inhibiting branched actin nucleation. In HeLa and T cells, TAGLN2 enhanced filopodium-like membrane protrusion. Collectively, the dual functional nature of TAGLN2-G-actin polymerization and Arp2/3 complex inhibition-may account for the mechanisms of filopodia development at the edge of Arp2/3-rich lamellipodia in various cell types.

Risk of Retinal Vein Occlusion in Patients With End-Stage Renal Disease: A 12-Year, Retrospective, Nationwide Cohort Study in South Korea.

Purpose: The present study aimed to evaluate the risk of retinal vein occlusion (RVO) in Korean patients with end-stage renal disease (ESRD). Methods: In this retrospective, nationwide, propensity score-matched cohort study, subjects were randomly enrolled from the 12-year longitudinal Korean National Health Insurance Service-National Sample Cohort 2002-2013 database comprising 1 million subjects. The ESRD group comprised 988 patients newly diagnosed with ESRD from 2003 onward by washing out data from 2002. The comparison group comprised 4940 (5 for each patient with ESRD) randomly selected propensity score-matched individuals not diagnosed with ESRD. Each sampled patient was tracked until 2013 for RVO development. Multiple conditional Cox regression analysis was performed to compare the risk of RVO between the two groups. Results: The mean follow-up period was 7.37 years. The incidence of RVO was 3.95% in the ESRD group and 2.17% in the comparison group (P = 0.001). ESRD was associated with greater risk of RVO development after adjustment for possible confounders (adjusted hazard ratio [HR], 2.122; 95% confidence interval [CI], 1.396-3.226; P = 0.0004). The 50- to 60-year (adjusted HR, 2.635; 95% CI, 1.100-6.313; P = 0.0297) and 60- to 70-year (adjusted HR, 2.544; 95% CI, 1.059-6.110; P = 0.0368) age groups exhibited higher risk of RVO compared with the <40-year age group. Hyperlipidemia (adjusted HR, 1.670; 95% CI, 1.176-2.371; P = 0.0042) and hypertension (adjusted HR, 1.896; 95% CI, 1.165-3.086; P = 0.01) were also associated with RVO. Conclusions: An association between ESRD and subsequent RVO development was found after adjustment for possible confounding factors.

An Essential Role for TAGLN2 in Phagocytosis of Lipopolysaccharide-activated Macrophages.

Activated macrophages have a greater ability of phagocytosis against pathogens that is mediated by large-scale actin rearrangement. However, molecular machineries that conduct this task have not been fully identified. Here, we demonstrate an unanticipated role of TAGLN2, a 22-kDa actin-binding protein, in Toll-like receptor (TLR)-stimulated phagocytosis. TAGLN2 was greatly induced in macrophages in response to lipopolysaccharide (LPS), a ligand for TLR4, partly via the NF-κB pathway. TAGLN2-deficient macrophages (TAGLN2 -/-) showed defective phagocytic functions of IgM- and IgG-coated sheep red blood cells as well as bacteria. Cell signaling pathways involved in actin rearrangement-PI3 kinase/AKT and Ras-ERK-were also down-regulated in LPS-stimulated TAGLN2-deficient macrophages. Moreover, TAGLN2 -/- mice showed higher mortality after bacterial infection than wild-type littermates. Thus, our results revealed a novel function of TAGLN2 as a molecular armament required for host defense.

Electrochemiluminescent chemodosimeter based on iridium(III) complex for point-of-care detection of homocysteine levels.

Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease. Although a routine, rapid, and simple determination of Hcy levels is highly desired, the existing methods are practically limited because of complicated sample preparation and bulky instrumentation. Herein, we report a chemodosimetric approach for one-step analysis of Hcy levels based on the electrochemiluminescence (ECL). A rationally designed cyclometalated iridium(III) complex possessing a phenylisoquinoline main ligand underwent a selective ring-formation reaction with Hcy to generate a binding adduct, which enabled producing highly luminescent excited states, and yielded strong ECL signals on the surface of electrode without any use of enzymes or antibodies. The level of Hcy was successfully monitored by the ECL increment with a linear correlation between 0 and 40µM in 99.9% aqueous media. The approach required neither sample preparation nor bulky instrument, suggesting the point-of-care testing of Hcy levels, and is potentially useful for routine, cost-effective, and precautionary diagnosis of various cardiovascular diseases.

Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation.

Atopic dermatitis (AD) is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA) isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production.

Oral Administration of 4-Hydroxy-3-Methoxycinnamaldehyde Attenuates Atopic Dermatitis by Inhibiting T Cell and Keratinocyte Activation.

Atopic dermatitis (AD) is a skin condition caused by an imbalance of distinct subsets of T helper cells. Previously, we showed that 4-hydroxy-3-methoxycinnamaldehyde (4H3MC) inhibits T cell activation but does not induce apoptosis. Here, we examined the mechanism underlying the inhibitory effect of 4H3MC on AD both in vivo and in vitro. We sought to test the pharmacological effects of 4H3MC using a mouse model of 2, 4-'2,4-dinitrocholorobenzene' (DNCB)- and mite-induced AD. Also, we determined whether 4H3MC affects T cell differentiation and proliferation. Oral administration of 4H3MC attenuated the symptoms of DNCB- and mite-induced AD, including increased ear thickness, serum IgE levels, immune cell infiltration into inflammatory lesions, and pathogenic cytokine expression in ear tissues. In vitro, 4H3MC blocked T cell differentiation into Th1 and Th2 subtypes, as reflected by suppression of T-bet and GATA3, which are key transcription factors involved in T cell differentiation. In addition, 4H3MC downregulated T cell proliferation during Th1 and Th2 differentiation and keratinocyte activation. Collectively, these findings suggest that 4H3MC ameliorates AD symptoms by modulating the functions of effector T cells and keratinocytes.

Relationships between serum osteocalcin, leptin and the effect of weight loss by pharmacological treatment in healthy, nonsmoking Korean obese adults.

BACKGROUND: Recent studies have reported a relationship between osteocalcin (OC) levels and factors associated with energy metabolism and insulin resistance. As any detailed understanding of OC mechanisms still remains elusive, this study aimed at revealing a correlation between serum OC levels and obesity in healthy, nonsmoking, Korean obese adults who had undergone weight loss through pharmacological treatment. METHODS: 119 healthy, nonsmoking, Korean obese adults were investigated at 3 months following weight loss through pharmacological treatment. Serum OC, leptin, HOMA score, ghrelin, visceral fat mass, total body fat, and BMI were measured. RESULTS: Increase in serum OC was significantly associated with decreases in: BMI (and weight change %) (r=-0.209, p=0.023), visceral fat mass (r=-0.189, p=0.049), HOMA (r=-0.203 p=0.027), and leptin (r=-0.253 p=0.006), but not with changes in adiponectin (r=+0.029, p=NS), and Ghrelin (r=+0.019, p=NS). Decrease in leptin (ß=-0.280, p=0.002) was significantly associated with an increase in serum OC, after pharmacological weight loss treatment was adjusted for age, sex, drug type, and BMI (or visceral fat mass). CONCLUSIONS: Serum OC was significantly increased at 3 months after pharmacological weight loss. We further found that leptin levels were associated with changes in serum OC. These findings suggest a relationship between bone and adipose tissue.

Fluorescence turn-on probe for homocysteine and cysteine in water.

A simple fluorescent probe based on an ortho-hydroxy aldehyde-functionalized coumarin showed selective responses to homocysteine and cysteine by fluorescence turn-on.

Dimeric capsules with a nanoscale cavity for [60]fullerene encapsulation.

The acid-assisted and guest-induced formation of superstructures was achieved by the addition of haloacetic acids to a toluene solution of the resorcin[4]arene derivatives 1 and [60]fullerenes. The formation of dimeric superstructures that encapsulated a nanosized guest molecule was observed when appropriate acids, such as haloacetic acids, and suitable guest molecules, such as [60]fullerenes, were co-added to a toluene solution of cavitand 1 that has four pyridine units, whereas a complicated equilibrium between several species was detected without [60]fullerenes, and the formation of discrete superstructures was not monitored in the absence of haloacetic acids. The spectroscopic data indicate that the formed [60]fullerene-encapsulated complexes have the structure of 2. These complexes are self-assembled through pyridinium-anion-pyridinium interactions and by pi-pi and van der Waals interactions. The rate of decomplexation of 2 is estimated to be 3.1 s(-1) from a 2D exchange NMR spectrum. The [60]fullerene encapsulation process can be controlled by modifying the amounts of acids used, changing the temperature of the system, altering the ratio of acid/base, and even through varying the solvent polarity. Moreover, the fluorescence spectra show band-narrowing spectral changes and a retardation of the relaxation characteristics of isolated and isotropic [60]fullerenes, which indicates that the environmental change around [60]fullerene is induced upon its encapsulation.

Fluorescent chemodosimeter for selective detection of cyanide in water.

A coumarin-based fluorescent chemodosimeter with a salicylaldehyde functionality as a binding site has been developed for selective detection of cyanide anions over other anions in water at biological pH.

Understanding disparities in aggressive care preferences between patients with terminal illness and their family members.

We examined the factors associated with the disparity in aggressive care preferences between patients with terminal cancer and their family members. Two hundred forty-four consecutive pairs recruited from three university hospitals participated in this study. Each pair completed questionnaires that measured two major aggressive care preferences-admission to the intensive care unit (ICU) and the use of cardiopulmonary resuscitation (CPR). Sixty-eight percent of patients and their family members were in agreement regarding admission to the ICU and 71% agreed regarding CPR. Regarding admission to the ICU, younger, unmarried patients and patients who preferred to die in an institution were more likely to have a different preference from their family caregivers. Regarding CPR, younger patients and patients from severely dysfunctional families were more likely to have a different preference from their family caregivers. Elucidation of the factors associated with such disparities should help reduce them.

EuroQol and survival prediction in terminal cancer patients: a multicenter prospective study in hospice-palliative care units.

GOALS OF WORK: Although the EuroQol (EQ-5D) is widely used for economic evaluation, it remains unclear whether it can be combined with medical data to predict survival in patients with terminal cancer. PATIENTS AND METHODS: We carried out this prospective study on 142 terminal cancer patients in four hospice-palliative care units. Association was sought between survival time and a range of variables such as cancer site, performance, previous treatment, age, sex, pain, and EuroQol. The EQ-5D was transformed into the corresponding EQ-5D utility. For univariate analysis, we estimated differences in survival with the Gehan generalized Wilcoxon test. For those variables that were significant, we performed multivariate analysis using the Cox proportional hazard model. MAIN RESULTS: Univariate analysis showed that sex, age, performance, previous use of chemotherapy, and the EQ-5D utility provided statistically significant prognostic survival information. The median survival time was 13.0 days for the group with an EQ-5D utility score lower than -0.5 and 21.0 days for the group with an EQ-5D utility score above -0.5. In multivariate analysis with the Cox proportional hazard model, an EQ-5D utility score < or = 0.5 (RR 1.57, 95% confidence interval 1.06-2.33) was an independent negative predictor of survival. CONCLUSIONS: The EQ-5D quality-of-life assessment tool might be useful for predicting survival time for terminal cancer patients.

Her2 genotype and breast cancer progression in Korean women.

The amplification and overexpression of Her2 proto-oncogene have been found to be associated with the development and progression of human breast cancer. A polymorphic valine allele at codon 655 of the Her2 gene (Her2(V655)) was suggested by some authors to be a susceptible genetic factor for the development of breast cancer. The Her2 polymorphism at codon 655 was investigated in 304 Korean women including 177 patients with breast cancer. The association between Her2 genotype and Her2 protein overexpression was also examined in breast cancers by immunohistochemistry. Her2(V655) was not associated with a significant breast cancer risk (odds ratio (OR), 1.792; 95% confidence interval (CI), 0.459-6.991). The frequency of homozygous or heterozygous valine allele increased in stage 2 patients (OR, 1.67; 95% CI, 0.67-4.19), and patients in stages 3 and 4 (OR, 3.36; 95% CI, 0.85-13.42) compared to patients in stage 0. However, an association between the presence of the valine allele and the overexpression of Her2 protein could not be demonstrated. These results suggest that Her2 polymorphism at codon 655 is not associated with the development of breast cancer in Korean women. However, there is a possibility that the valine allele at codon 655 might be related to increased risk of breast cancer progression.