Photodynamic Effect of Amphiphilic N∧C∧N-Coordinated Platinum(II) Complexes in Human Umbilical Vein Endothelial Cells.

Here, we report a photodynamic therapy (PDT) photosensitizer of N∧C∧N-coordinated Pt(II) complexes: [Pt(L)(solv)]+ (HL = 1,3-(2-dipyridyl)benzene) and [Pt(L)]+@HSA, which is the Pt(II) complex encapsulated in human serum albumin (HSA). The quantum yield of singlet oxygen production for [Pt(L)(solv)]+ is more than 50%, while that for [Pt(L)]+@HSA is much lower. Photoimages of human umbilical vein endothelial cells (HUVECs) treated with the Pt(II) complexes suggest that [Pt(L)(solv)]+ is delocalized in the entire cell after the fast uptake by diffusion and [Pt(L)]+@HSA is taken up by endocytosis and localized on organelles and the cell membrane. [Pt(L)(solv)]+ shows high photocytotoxicity for HUVECs, while [Pt(L)]+@HSA does not show photocytotoxicity.

Mutual oligosynaptic inhibition of group Ia afferents between the anterior and posterior parts of the deltoid in humans.

The anterior (DA) and posterior parts of the deltoid (DP) show alternating contraction during shoulder flexion and extension movements. It is expected that an inhibitory spinal reflex between the DA and DP exists. In this study, spinal reflexes between the DA and DP were examined in healthy human subjects using post-stimulus time histogram (PSTH) and electromyogram averaging (EMG-A). Electrical conditioning stimulation was delivered to the axillary nerve branch that innervates the DA (DA nerve) and DP (DP nerve) with the intensity below the motor threshold. In the PSTH study, the stimulation to the DA and DP nerves inhibited (decrease in the firing probability) 31 of 54 DA motor units and 31 of 51 DP motor units. The inhibition was not provoked by cutaneous stimulation. The central synaptic delay of the inhibition between the DA and DP nerves was 1.5 ± 0.5 ms and 1.4 ± 0.4 ms (mean ± SD) longer than those of the homonymous facilitation of the DA and DP, respectively. In the EMG-A study, conditioning stimulation to the DA and DP nerves inhibited the rectified and averaged EMG of the DP and DA, respectively. The inhibition diminished with tonic vibration stimulation to the DA and DP and recovered 20-30 min after vibration removal. These findings suggest that oligo(di or tri)-synaptic inhibition mediated by group Ia afferents between the DA and DP exists in humans.

Survey of diversity awareness and environment among members of the Pediatric Rheumatology Association of Japan.

BACKGROUND: Diversity management has gained traction in Japan. The Pediatric Rheumatology Association of Japan (PRAJ) has an Advisory Committee for Diversity Promotion with a broader focus on promoting diversity. The objectives of this study were to better understand the problems faced by PRAJ members regarding the work environment, childcare and nursing care, and work-life balance. METHODS: A web-based questionnaire was administered to members of the PRAJ and 79 responses were evaluated. RESULTS: Of the respondents, 73% were male and 27% were female. A total of 14% worked for more than 12 h on weekdays, and 22% worked for more than 60 h per week and 38% had fewer than 4 days off per month. Regarding childcare, 54% of the respondents were raising preschool children and 83% had taken parental leave for less than 1 year. A total of 17% of participants had family members in need of care. For both childcare and caregiving, the burden was greater for women. Only 18% of the respondents reported a well-balanced work-life balance, and the most common reasons for a lack of balance were not having enough time, heavy workload, and heavy housework load. CONCLUSIONS: The working hours of the respondents were long, and female members had a greater burden of childcare and caregiving, which was considered a barrier to the career development of women. In the future, there will be a need to promote a sense of equality in diverse human resources, develop support for family life, and shorten working hours.

Monosynaptic facilitation of flexor digitorum superficialis motoneurons mediated by Group Ia afferents from the extensor carpi radialis in humans.

Wrist position is known to affect the grip strength. We focused on the spinal reflex arc, which would support the movement, and investigated the effects of low-threshold afferents from the extensor carpi radialis (ECR) on the excitability of the flexor digitorum superficialis (FDS) motoneurons using the post-stimulus time-histogram (PSTH) and electromyogram-averaging (EMG-A) methods. Electrical conditioning stimulation of an intensity below the motor threshold was applied to the radial nerve branch innervating the ECR. In the PSTH study, changes in the firing probability of single motor units after electrical conditioning stimulation were investigated in seven subjects. An early and significant peak (increase in the firing probability: facilitation) was recorded for 36/60 FDS motor units. The remaining 24 motor units did not show any effects. Weak mechanical conditioning stimulation of the ECR muscle belly induced a similar peak. The central latency of the facilitation was equivalent to that of the homonymous monosynaptic facilitation. In the EMG-A study, changes in the rectified and averaged electromyograms of FDS induced by conditioning stimulation were examined in 12 subjects. An early and significant peak (facilitation) was induced by both electrical and mechanical conditioning stimulations. The facilitation decreased after withdrawal of the vibration to the ECR muscle belly. The facilitation was never induced by cutaneous nerve stimulation in the PSTH and EMG-A studies. These findings suggest that Group Ia afferents from the ECR increase the excitability of FDS motoneurons through a monosynaptic path in the spinal cord. These reflex arcs likely facilitate hand grasping movements.

Effect of thyroid hormone-disrupting chemicals on swim bladder inflation and thyroid hormone-related gene expression in Japanese medaka and zebrafish.

We compared the influence of thyroid hormone-disrupting chemicals (heptafluorobutanoic acid, PFBA and tris[1,3-dichloro-2-propyl] phosphate, TDCPP) and thyroid hormone (3,3',5-triiodo-L-thyronine, T3) on swim bladder inflation and thyroid hormone-related gene expression in Japanese medaka and zebrafish. The swim bladder of most larvae had inflated at 4 h post hatching (hph) in Japanese medaka and at 48 hph in zebrafish in controls. In both fish species, the swim bladder inflation was inhibited in larvae exposed to PFBA (lowest observed effect concentration [LOEC] in medaka: 40 mg/L; in zebrafish: 80 mg/L), TDCPP (LOEC in medaka: 1 mg/L; in zebrafish: 0.5 mg/L), and T3 (no inhibition in Japanese medaka; LOEC in zebrafish: 7.5 µg/L). We also examined the influence of PFBA, TDCPP, and T3 on the expression of thyroid stimulating hormone subunit beta (tshß) or thyroid hormone receptor alpha (trα) and beta (trß). No changes were observed in the expression of genes after PFBA and TDCPP exposure; however, T3 exposure upregulated trα and trß expression in both fish species. When the results were compared between Japanese medaka and zebrafish, swim bladder inflation in both species was found to be inhibited by exposure to thyroid hormone-disrupting chemicals. Our results show that inhibition of the swim bladder inflation at 4 hph in Japanese medaka and 48 hph in zebrafish is a potential indicator of thyroid hormone-disturbing activity of chemicals.

Summary of 17 chemicals evaluated by OECD TG229 using Japanese Medaka, Oryzias latipes in EXTEND 2016.

In June 2016, the Ministry of the Environment of Japan announced a program "EXTEND2016" on the implementation of testing and assessment for endocrine active chemicals, consisting of a two-tiered strategy. The aim of the Tier 1 screening and the Tier 2 testing is to identify the impacts on the endocrine system and to characterize the adverse effects to aquatic animals by endocrine disrupting chemicals detected in the aquatic environment in Japan. For the consistent assessment of the effects on reproduction associated with estrogenic, anti-estrogenic, androgenic, and/or anti-androgenic activities of chemicals throughout Tier 1 screening to Tier 2 testing, a unified test species, Japanese medaka (Oryzias latipes), has been used. For Tier 1 screening, the in vivo Fish Short-Term Reproduction Assay (OECD test guideline No. 229) was conducted for 17 chemicals that were nominated based on the results of environmental monitoring, existing knowledge obtained from a literature survey, and positive results in reporter gene assays using the estrogen receptor of Japanese medaka. In the 17 assays using Japanese medaka, adverse effects on reproduction (i.e., reduction in fecundity and/or fertility) were suggested for 10 chemicals, and a significant increase of hepatic vitellogenin in males, indicating estrogenic (estrogen receptor agonistic) potency, was found for eight chemicals at the concentrations in which no overt toxicity was observed. Based on these results, and the frequency and the concentrations detected in the Japanese environment, estrone, 4-nonylphenol (branched isomers), 4-tert-octylphenol, triphenyl phosphate, and bisphenol A were considered as high priority candidate substances for the Tier 2 testing.

New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs.

In the early 1960's, at Professor Bern's laboratory, University of California, Berkeley) in the US, Takasugi discovered ovary-independent, persistent vaginal changes in mice exposed neonatally to estrogen, which resulted in vaginal cancer later in life. Reproductive abnormalities in rodents were reported as a result of perinatal exposure to various estrogenic chemicals. Ten years later, vaginal cancers were reported in young women exposed in utero to the synthetic estrogen diethylstilbestrol (DES) and this has been called the "DES syndrome". The developing organism is particularly sensitive to developmental exposure to estrogens inducing long-term changes in various organs including the reproductive organs. The molecular mechanism underlying the persistent vaginal changes induced by perinatal estrogen exposure was partly demonstrated. Persistent phosphorylation and sustained expression of EGF-like growth factors, lead to estrogen receptor α (ESR1) activation, and then persistent vaginal epithelial cell proliferation. Agents which are weakly estrogenic by postnatal criteria may have major developmental effects, especially during a critical perinatal period. The present review outlines various studies conducted by four generations of investigators all under the influence of Prof. Bern. The studies include reports of persistent changes induced by neonatal androgen exposure, analyses of estrogen responsive genes, factors determining epithelial differentiation in the Müllerian duct, ESR and growth factor signaling, and polyovular follicles in mammals. This review is then expanded to the studies on the effects of environmental estrogens on wildlife and endocrine disruption in Daphnids.

Citrullinated fibrinogen is a target of auto-antibodies in interstitial lung disease in mice with collagen-induced arthritis.

Interstitial lung disease (ILD) is a very common and lethal complication of rheumatoid arthritis (RA), yet its pathogenesis is not well understood, in part due to the lack of adequate animal models. Although collagen-induced arthritis (CIA) is the most widely used animal model for RA, the lung involvement occurring in this model has scarcely been studied. To evaluate the suitability of CIA as a model for RA-associated ILD (RA-ILD), we immunized DBA/1 mice with bovine type II collagen and characterized lung disease in this model. Histologic analyses revealed patchy interstitial infiltration of inflammatory cells in the peripheral regions of the lung, notably in the subpleural region, in mice with CIA. This pattern resembled usual interstitial pneumonia in humans, which is the most prevalent pattern in RA-ILD. Among infiltrates in the lung, CD11bhi macrophages of the M2 phenotype were most prominently increased. IgG and C3 were deposited in the subpleural region where inflammatory cells infiltrated. The sera from CIA mice contained auto-antibodies against citrullinated proteins, which are specific and predictive markers for RA. Protein citrullination was enhanced in the lung of CIA mice compared with naive mice, and citrullinated fibrinogen was primarily targeted by these auto-antibodies. The elevation of auto-antibodies against citrullinated proteins and their deposition in the lung with patchy subpleural preponderance suggest that CIA can serve as a model to study the pathogenesis of RA-ILD.

p63 is a cereblon substrate involved in thalidomide teratogenicity.

Cereblon (CRBN) is a primary target of thalidomide and mediates its multiple pharmacological activities, including teratogenic and antimyeloma activities. CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs. Although a number of CRL4CRBN substrates have recently been identified, the substrate involved in thalidomide teratogenicity is unclear. Here we show that p63 isoforms are thalidomide-dependent CRL4CRBN neosubstrates that are responsible, at least in part, for its teratogenic effects. The p53 family member p63 is associated with multiple developmental processes. ∆Np63α is essential for limb development, while TAp63α is important for cochlea development and hearing. Using a zebrafish model, we demonstrate that thalidomide exerts its teratogenic effects on pectoral fins and otic vesicles by inducing the degradation of ∆Np63α and TAp63α, respectively. These results may contribute to the invention of new thalidomide analogs lacking teratogenic activity.

Methyl farnesoate regulatory mechanisms underlying photoperiod-dependent sex determination in the freshwater crustacean Daphnia magna.

Freshwater zooplankton Daphnia magna has been widely used in ecotoxicology studies. During the last 20 years, it has been demonstrated that the topical application of juvenile hormone (JH) or JH analogs to mother daphnids induce male offspring production. Based on this finding, an in vivo screening validation method for chemicals with JH agonistic effect has developed. Although this screening system successfully identified a number of JH-like chemicals, molecular mechanisms underlying the male sex-determining process remain largely unknown. To address this issue, we established a reliable male- or female-producing system using Daphnia pulex WTN6 strain by changing the rearing photoperiod. Taking advantage of this rearing system, we successfully found several factors involving male sex determination such as ionotropic glutamate receptors, protein kinase C and pantothenate. Here, we used two D. magna strains that can also control the production of female or male offspring by photoperiod differences as model species for ecotoxicology studies. We demonstrated that either treatment of antagonist of ionotropic glutamate receptors or inhibitor of protein kinase C strongly suppressed male offspring production even under male-producing conditions. Moreover, we revealed that male sex-determining processes are likely diverged between D. magna and D. pulex based on the current experiment. This study provides a fine experimental method for in vivo screening not only JH agonists but also JH antagonists. Moreover, using daphnids with photoperiod-dependent sex determination manner will hugely contribute to understanding the mode-of-action of JH in daphnids.

Characterization of G protein-coupled estrogen receptors in Japanese medaka, Oryzias latipes.

The G protein-coupled estrogen receptor 1 (Gper1) is a membrane-bound estrogen receptor that mediates non-genomic action of estrogens. A Gper1-mediating pathway has been implicated in reproductive activities in fish, including oocyte growth, but Gper1 has been characterized in only a very limited number of fish species. In this study, we cloned and characterized two genes encoding medaka (Oryzias latipes) Gper1s, namely, Gper1a and Gper1b, and phylogenic and synteny analyses suggest that these genes originate through a teleost-specific whole genome duplication event. We found that Gper1a induced phosphorylation of mitogen-activated protein kinase (MAPK) in 293T cells transfected with medaka Gper1s on exposure to the natural estrogen, 17ß-estradiol (E2) and a synthetic Gper1 agonist (G-1), and treatment with both E2 and G-1 also decreased the rate of spontaneous maturation in medaka oocytes. These findings show that the processes for oocyte growth and maturation are sensitive to estrogens and are possibly mediated through Gper1a in medaka. We also show that 17α-ethinylestradiol (EE2), one of the most potent estrogenic endocrine-disrupting chemicals, and bisphenol A (BPA, a weak environmental estrogen) augmented phosphorylation of MAPK through medaka Gper1s in 293T cells. Interestingly, however, treatment with EE2 or BPA did not attenuate maturation of medaka oocytes. Our findings support that Gper1-mediated effects on oocytes are conserved among fish species, but effects of estrogenic endocrine-disrupting chemicals on oocytes acting through Gper1 may be divergent among fish species.

Summary of reference chemicals evaluated by the fish short-term reproduction assay, OECD TG229, using Japanese Medaka, Oryzias latipes.

Under the Organisation for Economic Co-operation and Development (OECD), the Ministry of the Environment of Japan (MOE) added Japanese medaka (Oryzias latipes) to the test guideline fish short-term reproduction assay (FSTRA) developed by the United States Environmental Protection Agency (US EPA) using fathead minnow (Pimephales promelas). The FSTRA was designed to detect endocrine disrupting effects of chemicals interacting with the hypothalamic-pituitary-gonadal axis (HPG axis) such as agonists or antagonists on the estrogen receptor (Esr) and/or the androgen receptor (AR) and steroidogenesis inhibitors. We conducted the FSTRA with Japanese medaka, in accordance with OECD test guideline number 229 (TG229), for 16 chemicals including four Esr agonists, two Esr antagonists, three AR agonists, two AR antagonists, two steroidogenesis inhibitors, two progesterone receptor agonists, and a negative substance, and evaluated the usability and the validity of the FSTRA (TG229) protocol. In addition, in vitro reporter gene assays (RGAs) using Esr1 and ARß of Japanese medaka were performed for the 16 chemicals, to support the interpretation of the in vivo effects observed in the FSTRA. In the present study, all the test chemicals, except an antiandrogenic chemical and a weak Esr agonist, significantly reduced the reproductive status of the test fish, that is, fecundity or fertility, at concentrations where no overt toxicity was observed. Moreover, vitellogenin (VTG) induction in males and formation of secondary sex characteristics (SSC), papillary processes on the anal fin, in females was sensitive endpoints to Esr and AR agonistic effects, respectively, and might be indicators of the effect concentrations in long-term exposure. Overall, it is suggested that the in vivo FSTRA supported by in vitro RGA data can adequately detect effects on the test fish, O. latipes, and probably identify the mode of action (MOA) of the chemicals tested.

Fluidic Patch Device to Sample Sweat for Accurate Measurement of Sweat Rate and Chemical Composition: A Proof-of-Concept Study.

Sweat sensors that can continuously sample sweat are critical for determining the time-dependent physiological responses occurring in normal daily life. Here, a new device, termed fluidic patch, for collecting human sweat samples at defined time intervals is developed, and the proof-of-concept is demonstrated. The device comprises micropumps and a disposable microfluidic patch attached to the human skin. The fluidic patch continuously collects aliquots of freshly secreted sweat accumulated in the fluidic pathway at accurately defined time windows (typically 5 min). By measuring the weight of the collected samples, the local sweat rate is calculated. The sweat sample collected can be directly subjected to a wide range of chemical analyses. For the proof-of-concept, we compared the sweat rates during passive heating in human trials using the fluidic patch and the conventional ventilated sweat capsule system. Although the sweat rate obtained using the fluidic patch highly correlated with that of the ventilated sweat capsule (R2 = 0.96, y = 1.4x - 0.05), the fluidic patch overestimated the sweat rate compared with the ventilated capsule system when the sweat rate exceeded 0.5 mg/(cm2·min). The sampled sweat was analyzed for sodium, potassium, chloride, lactate, pyruvate, and cortisol. The device could obtain the time courses of the concentrations of the abovementioned three ions; the concentrations of sodium and chloride increased linearly with the sweat rate during passive heating (R2 = 0.76 and 0.66, respectively). The device can reliably measure the sweat rate and collect sweat samples for chemical analysis. It can be utilized for real-time physiological investigations toward wider applications.

Hedgehog signaling regulates the basement membrane remodeling during folliculogenesis in the neonatal mouse ovary.

In the mouse ovary, interactions between oocytes and somatic cells are essential for folliculogenesis and subsequent follicle development. The polyovular follicle (PF), which contains more than two oocytes in a follicle, can be induced in the neonatal mouse ovary when interactions between oocytes and somatic cells are disrupted by agents such as the potent synthetic estrogen diethylstilbestrol (DES) acting through estrogen receptor (ER) ß. Hedgehog signaling is known to regulate granulosa cell proliferation, thecal cell differentiation, and follicle growth. To investigate the role of hedgehog signaling in the early folliculogenesis and in PF induction by DES, neonatal mouse ovaries were cultured with or without 10 µM cyclopamine (CPA), an inhibitor of hedgehog signaling, and grafted under the kidney capsule of adult ovariectomized host mice. The number and the incidence of PFs were significantly increased in organ-cultured ovaries post-grafting. Expression of procollagen type IV, alpha 1 (Col4a1) in organ-cultured ovaries was significantly reduced by CPA, but not by DES. The expression of two hedgehog ligands, Desert hedgehog (Dhh) and Indian hedgehog (Ihh), and a target gene, Hedgehog interacting protein (Hhip), was significantly increased by DES both in WT and ERß KO mice. Therefore, we infer that DES can affect expression of those genes through ERα but not via suppression of hedgehog signaling. Thus, PFs are induced by DES or CPA, but the induction mechanism is different. Our results revealed an important role of hedgehog signaling in basement membrane remodeling during folliculogenesis even before thecal cell differentiation.

Molecular Insights into Structural and Ligand Binding Features of Methoprene-Tolerant in Daphnids.

Juvenile hormone (JH) is an important endocrine factor regulating many biological activities in arthropods. In daphnids, methoprene-tolerant (Met) belongs to a basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family protein which has recently been confirmed as a JH receptor and can bind and be activated by JHs and JH agonists. Although the activation of the JH signaling pathway causes many physiological effects, the molecular basis for the structural feature and ligand binding properties of Daphnia Met are not fully understood. To study the ligand preference in terms of structural features of Daphnia Met, we built in silico homology models of the PAS-B domain of Daphnia Mets from cladoceran crustaceans, Daphnia pulex and D. magna. Structural comparison of two Daphnia Met PAS-B domain models revealed that the volume in the main cavity of D. magna Met was larger than that of D. pulex Met. Compared with insect Met, Daphnia Met had a less hydrophobic cavity due to polar residues in the core-binding site. Molecular docking simulations of JH and its analogs with Daphnia Met indicated that the interaction energies were correlated with each of the experimental values of in vivo JH activities based on male induction and in vitro Met-mediated transactivation potencies. Furthermore, in silico site-directed mutagenesis supported experimental findings that Thr292 in D. pulex Met and Thr296 in D. magna Met substitution to valine contribute to JH selectivity and differential species response. This study demonstrates that in silico simulations of Daphnia Met and its ligands may be a tool for predicting the ligand profile and cross species sensitivity.

Prevalence and characterization of Staphylococcus aureus isolated in raw milk from cows in Hokkaido, Japan.

The aim of this study was to characterize the phenotypes and genotypes of Staphylococcus aureus isolated from raw bovine milk in Hokkaido, Japan. S. aureus isolates were identified in 135 of 436 milk samples from cows with and without signs of mastitis from three farms in Hokkaido. These clinical isolates were characterized for antimicrobial susceptibility patterns, molecular typing using phage-open-reading frame typing (POT), coagulase gene type, virulence genes, and biofilm-associated genes and were evaluated for biofilm-forming ability. Most isolates were susceptible to the antimicrobial agents tested. The highest rate of resistance was to ampicillin. Molecular typing of all S. aureus isolates indicated a predominance of coagulase type VI and 0-17-34 POT type, and virulence genes were highly prevalent in the isolates from all farms. Moreover, a high percentage of the 0-17-34 POT type isolates showed extensive formation of biofilm. These findings will help veterinarians and farmers to understand the epidemiology of S. aureus so that they can monitor the transmission and spread of this pathogen and control it more effectively.

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance.

The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and moesin. Mutations in the moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging moesin-deficient mice develop a systemic lupus erythematosus-like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8+CD44+CD122+Ly49+ regulatory T (CD8+ Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8+ Treg cells from moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that moesin plays a key role in IL-15-mediated signaling. These findings underscore the importance of moesin in IL-15-dependent CD8+ Treg cell homeostasis and, thus, the control of self-tolerance.

Optical coherence tomography findings in unilateral peripheral cone dysfunction syndrome: a case report.

INTRODUCTION: To report a case of unilateral peripheral cone dysfunction syndrome and evaluate the associated clinicopathological changes using swept-source optical coherence tomography (SS-OCT). CASE PRESENTATION: A 39-year-old Japanese woman reported a visual field defect of 2-years duration in the right eye. The patient underwent visual field testing, full-field electroretinography (ff-ERG), SS-OCT, and a routine ophthalmologic examination. The best-corrected visual acuity was 20/20 bilaterally. The funduscopy examination was normal bilaterally. Visual field testing showed a relative paracentral scotoma in the right eye. SS-OCT scans showed an unclear interdigitation zone (IZ) throughout the posterior pole except for the foveal zone in the right eye. SS-OCT macular analysis showed thinning of the ganglion cell layer (GCL) and inner plexiform layer (IPL) corresponding to the region of the IZ defect. ff-ERG showed almost normal flash ERGs and normal rod responses bilaterally. The cone response and flicker ERG response were decreased markedly only in the right eye. CONCLUSION: To the best of our knowledge, this is the first case report of unilateral peripheral cone dysfunction syndrome in which SS-OCT showed pathological changes in the GCL and IPL. The OCT findings corresponded well to the ERG changes and visual field abnormality. Because foveolar cone photoreceptor cells are connected in a one-to-one correspondence to retinal ganglion cells without connection to the horizontal cells or amacrine cells, the GCL and IPL were not present in the fovea. Based on this analysis, we speculated that the primary lesion of peripheral cone dysfunction syndrome is not in the cone photoreceptor cells but in the horizontal cells and/or amacrine cells. The clinicopathological changes in the ganglion cells and cone photoreceptor cells might be the subsequent pathologies in the horizontal cells in peripheral cone dysfunction syndrome.

Retinoic acid signaling determines the fate of uterine stroma in the mouse Müllerian duct.

The Müllerian duct develops into the oviduct, uterus, and vagina, all of which are quite distinct in their morphology and function. The epithelial fate of these female reproductive organs in developing mice is determined by factors secreted from the stroma; however, how stromal differentiation occurs in the female reproductive organs derived from the Müllerian duct is still unclear. In the present study, roles of retinoic acid (RA) signaling in developing female reproductive tracts were investigated. Retinol dehydrogenase 10 (RDH10) and aldehyde dehydrogenase family 1 subfamily A2 (ALDH1A2) mRNAs and proteins and transactivation activity of endogenous RA were found in the stroma of proximal Müllerian ducts and gradually decreased from the proximal to caudal regions in fetal mice. In organ-cultured Müllerian ducts, retinaldehyde or RA treatment induced uterine epithelial differentiation, defined as a layer of columnar epithelial cells negative for oviductal and vaginal epithelial markers. In contrast, inhibition of RA receptor (RAR) signaling induced vaginal epithelial differentiation, characterized as vaginal epithelial marker genes-positive stratified epithelium. Grafting experiments of the organ-cultured Müllerian duct revealed irreversible epithelial fate determination. Although RAR did not directly bind to the homeobox A10 (Hoxa10) promoter region, RA-RAR signaling stimulated Hoxa10 expression. Thus, RA-RAR signaling in the Müllerian duct determines the fate of stroma to form the future uterus and vagina.

Heparin prevents oxidative stress-induced apoptosis in human decidualized endometrial stromal cells.

Clinical trials have shown that administering heparin during the luteal phase has beneficial effects on implantation and live birth rates. Heparin exerts direct effects on decidual human endometrial stromal cells (HESCs), which are independent of its anticoagulant effect. However, the accurate effects of heparin on the decidualization process remain unidentified. Here, we demonstrate that HESCs become dramatically resistant to oxidative stress upon decidualization, and we hypothesize a possible direct action of heparin on the decidualization of HESCs, which would lead to improved implantation. To test this hypothesis, we established primary HESC cultures and propagated them, and then we decidualized confluent cultures with 8-bromo-cAMP, with medroxyprogesterone acetate, and with or without heparin. We treated the cells with hydrogen peroxide (H2O2) as a source of reactive oxygen species (ROS). Adding heparin to decidualized HESCs induced prolactin secretion. Decidualized HESCs treated with heparin were prevented from undergoing apoptosis induced by oxidative stress. Heparin induced nuclear accumulation of the forkhead transcription factor FOXO1 and expression of its downstream target, the ROS scavenger superoxide dismutase 2. These results demonstrate that heparin-treated decidualized HESCs acquired further resistance to oxidative stress, suggesting that heparin may improve the implantation environment.