Shoji Notomi | Kyushu University (original) (raw)

Papers by Shoji Notomi

Research paper thumbnail of Photoreceptor cell apoptosis in primary retinal cell cultures with blood clots

<p>(A) Schematic image of the double chamber co-culture system of primary retinal cells and... more <p>(A) Schematic image of the double chamber co-culture system of primary retinal cells and blood clots. (B) and (C) The viability of primary retinal cells in the lower chamber was accessed by calcein AM or MitoTracker CMTMRos after 24 h of culture with addition of a clot in the upper chamber (calcein in green, CMTMRos in red, recoverin in blue). The frequency of calcein<sup>+</sup> or CMTMRos<sup>+</sup> photoreceptors significantly decreased after incubation with clots. Apyrase treatment significantly rescued photoreceptors. (D<b>)</b> The ATP levels of culture medium in the lower chamber were significantly increased by clot exposure, and reversed by apyrase treatment. (E<b>)</b> The ATP levels in plasma and blood. <i>n = </i>10 per group; **<i>P<</i>0.01. Scale bar: 20 µm.</p

Research paper thumbnail of The pro-cell death RIP1 kinase mediates angiogenesis by facilitating M2-like macrophages

Investigative Ophthalmology & Visual Science, 2018

Research paper thumbnail of Involovement of P2X7 receptor and therapeutic efficacy of Brilliant Blue G in a mouse model of subretinal hemorrhage

Investigative Ophthalmology & Visual Science, 2012

Research paper thumbnail of Decreased Proteasomal Activity Causes Retinal Degeneration in Mice

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa

PNAS Nexus, 2022

Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods thr... more Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s)— tissue-resident microglia and/or peripheral monocyte-derived macrophages (mφ)— are implicated in the progression of the disease. Here, we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mφ by Ccl2 deficiency or immune modulation via intravenous nanoparticle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell ...

Research paper thumbnail of One-year efficacy of “rescue photodynamic therapy” for patients with typical age-related macular degeneration, polypoidal choroidal vasculopathy, and pachychoroid neovasculopathy refractory to anti-vascular endothelial growth factor therapy

Graefe's Archive for Clinical and Experimental Ophthalmology, 2022

Purpose This study aimed to evaluate the one-year outcomes of photodynamic therapy (PDT) as a res... more Purpose This study aimed to evaluate the one-year outcomes of photodynamic therapy (PDT) as a rescue treatment for age-related macular degeneration (AMD) refractory to anti-vascular endothelial growth factor (VEGF) therapy. Methods Patients with AMD refractory to anti-VEGF therapy, treated with “rescue-PDT” were retrospectively investigated. The time of PDT was defined as the baseline value. Baseline characteristics including sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), and foveal choroidal thickness (FCT) were examined. The changes in BCVA, CMT, and recurrence were also assessed at the 1-year follow-up. The logMAR VA change of 0.3 or more was defined as “improved” or “declined.” Results Twenty-three consecutive eyes (typical AMD: 10 eyes, polypoidal choroidal vasculopathy: 10 eyes, and pachychoroid neovasculopathy: 3 eyes), which underwent “rescue-PDT,” were analyzed in this study. The BCVA was improved in three patients and maintained in 20 patie...

Research paper thumbnail of Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçet’s disease and sarcoidosis

Graefe's Archive for Clinical and Experimental Ophthalmology, 2022

Research paper thumbnail of TNFRSF10A downregulation induces retinal pigment epithelium degeneration during the pathogenesis of age-related macular degeneration and central serous chorioretinopathy

Human Molecular Genetics, 2022

Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common dise... more Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common diseases that can cause vision loss in older and younger populations. These diseases share pathophysiological conditions derived from retinal pigment epithelium (RPE) dysfunction. Tumor necrosis factor receptor superfamily 10A (TNFRSF10A)-LOC389641 with the same lead single-nucleotide polymorphism (SNP) (rs13278062) is the only overlapped susceptibility locus found in both AMD and CSC through genome-wide association studies. This lead SNP has been reported to alter the transcriptional activity of TNFRSF10A. This study aimed to elucidate the function of TNFRSF10A in RPE degeneration using human primary RPE cells and Tnfrsf10 knockout (Tnfrsf10−/−) mice. TNFRSF10A was found to be localized in human RPE. In vitro assays revealed that a T allele of rs13278062, the risk allele for AMD and CSC, downregulated TNFRSF10A transcription in RPE, leading to decreased cell viability and increased apoptosi...

Research paper thumbnail of Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

Cell Death & Disease, 2015

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-i... more Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL − / −), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL − / − mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasLtriggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

Research paper thumbnail of Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death

Cell death & disease, 2015

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disor... more Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. In...

Research paper thumbnail of Therapeutic effect of prolonged treatment with topical dorzolamide for cystoid macular oedema in patients with retinitis pigmentosa

British Journal of Ophthalmology, 2013

To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic a... more To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic anhydrase inhibitor) for cystoid macular oedema (CME) associated with retinitis pigmentosa (RP). 18 eyes in 10 patients with CME secondary to RP were included. Baseline visual acuity, visual field and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each affected eye. Patients underwent follow-up examinations at 1, 3, 6, 12 and 18 months after treatment. The response to treatment was monitored by the Humphrey field analyser (HFA: the central 10-2 program); in addition, foveal thickness was measured by OCT. Evaluation of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;macular sensitivity&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; was calculated by HFA as the average of 12 central points. The &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;macular sensitivity&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; in 10 eyes in which CME was almost completely resolved was significantly improved (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In eight of the nine eyes in which CME was almost completely resolved within 6 months, the therapeutic efficacy persisted through 18 months. Five eyes which were almost completely resolved or showed an initial response within 6 months experienced recurrence of CME. The prolonged (longer than 1 year) use of topical dorzolamide is effective for the treatment of CME in patients with RP. Therefore, we propose topical dorzolamide treatment as a first choice.

Research paper thumbnail of Guidelines for the use and interpretation of assays for monitoring autophagy

Research paper thumbnail of The Regulatory Roles of Apoptosis-Inducing Factor in the Formation and Regression Processes of Ocular Neovascularization

The American Journal of Pathology, 2012

Research paper thumbnail of Critical Involvement of Extracellular ATP Acting on P2RX7 Purinergic Receptors in Photoreceptor Cell Death

The American Journal of Pathology, 2011

Research paper thumbnail of MutT Homolog-1 Attenuates Oxidative DNA Damage and Delays Photoreceptor Cell Death in Inherited Retinal Degeneration

The American Journal of Pathology, 2012

Research paper thumbnail of Dysfunctional autophagosome and phagosome in age-related macular degeneration (AMD)

Investigative Ophthalmology & Visual Science, 2015

Research paper thumbnail of Erratum

Research paper thumbnail of Relation between Sustained Chronic Inflammatory Reaction and Oxidative Damage in an Animal Model of Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Sustained Chronic Inflammatory Reaction In Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science, 2012

Research paper thumbnail of Cell Injury , Repair , Aging , and Apoptosis Critical Involvement of Extracellular ATP Acting on P 2 RX 7 Purinergic Receptors in Photoreceptor Cell Death

From the Department of Ophthalmology,* and the Morphology Core Unit, Graduate School of Medical S... more From the Department of Ophthalmology,* and the Morphology Core Unit, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Ophthalmology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan; INSERM, U848, Villejuif, France; the Metabolomics Platform, Institut Gustave Roussy, Villejuif, France; the Centre de Recherche des Cordeliers, Paris, France; the Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France; and the Sorbonne Paris Cité Faculté de Médicine, Université Paris Descartes, Paris, France

Research paper thumbnail of Photoreceptor cell apoptosis in primary retinal cell cultures with blood clots

<p>(A) Schematic image of the double chamber co-culture system of primary retinal cells and... more <p>(A) Schematic image of the double chamber co-culture system of primary retinal cells and blood clots. (B) and (C) The viability of primary retinal cells in the lower chamber was accessed by calcein AM or MitoTracker CMTMRos after 24 h of culture with addition of a clot in the upper chamber (calcein in green, CMTMRos in red, recoverin in blue). The frequency of calcein<sup>+</sup> or CMTMRos<sup>+</sup> photoreceptors significantly decreased after incubation with clots. Apyrase treatment significantly rescued photoreceptors. (D<b>)</b> The ATP levels of culture medium in the lower chamber were significantly increased by clot exposure, and reversed by apyrase treatment. (E<b>)</b> The ATP levels in plasma and blood. <i>n = </i>10 per group; **<i>P<</i>0.01. Scale bar: 20 µm.</p

Research paper thumbnail of The pro-cell death RIP1 kinase mediates angiogenesis by facilitating M2-like macrophages

Investigative Ophthalmology & Visual Science, 2018

Research paper thumbnail of Involovement of P2X7 receptor and therapeutic efficacy of Brilliant Blue G in a mouse model of subretinal hemorrhage

Investigative Ophthalmology & Visual Science, 2012

Research paper thumbnail of Decreased Proteasomal Activity Causes Retinal Degeneration in Mice

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa

PNAS Nexus, 2022

Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods thr... more Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s)— tissue-resident microglia and/or peripheral monocyte-derived macrophages (mφ)— are implicated in the progression of the disease. Here, we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mφ by Ccl2 deficiency or immune modulation via intravenous nanoparticle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell ...

Research paper thumbnail of One-year efficacy of “rescue photodynamic therapy” for patients with typical age-related macular degeneration, polypoidal choroidal vasculopathy, and pachychoroid neovasculopathy refractory to anti-vascular endothelial growth factor therapy

Graefe's Archive for Clinical and Experimental Ophthalmology, 2022

Purpose This study aimed to evaluate the one-year outcomes of photodynamic therapy (PDT) as a res... more Purpose This study aimed to evaluate the one-year outcomes of photodynamic therapy (PDT) as a rescue treatment for age-related macular degeneration (AMD) refractory to anti-vascular endothelial growth factor (VEGF) therapy. Methods Patients with AMD refractory to anti-VEGF therapy, treated with “rescue-PDT” were retrospectively investigated. The time of PDT was defined as the baseline value. Baseline characteristics including sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), and foveal choroidal thickness (FCT) were examined. The changes in BCVA, CMT, and recurrence were also assessed at the 1-year follow-up. The logMAR VA change of 0.3 or more was defined as “improved” or “declined.” Results Twenty-three consecutive eyes (typical AMD: 10 eyes, polypoidal choroidal vasculopathy: 10 eyes, and pachychoroid neovasculopathy: 3 eyes), which underwent “rescue-PDT,” were analyzed in this study. The BCVA was improved in three patients and maintained in 20 patie...

Research paper thumbnail of Increased vitreous levels of B cell activation factor (BAFF) and soluble interleukin-6 receptor in patients with macular edema due to uveitis related to Behçet’s disease and sarcoidosis

Graefe's Archive for Clinical and Experimental Ophthalmology, 2022

Research paper thumbnail of TNFRSF10A downregulation induces retinal pigment epithelium degeneration during the pathogenesis of age-related macular degeneration and central serous chorioretinopathy

Human Molecular Genetics, 2022

Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common dise... more Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common diseases that can cause vision loss in older and younger populations. These diseases share pathophysiological conditions derived from retinal pigment epithelium (RPE) dysfunction. Tumor necrosis factor receptor superfamily 10A (TNFRSF10A)-LOC389641 with the same lead single-nucleotide polymorphism (SNP) (rs13278062) is the only overlapped susceptibility locus found in both AMD and CSC through genome-wide association studies. This lead SNP has been reported to alter the transcriptional activity of TNFRSF10A. This study aimed to elucidate the function of TNFRSF10A in RPE degeneration using human primary RPE cells and Tnfrsf10 knockout (Tnfrsf10−/−) mice. TNFRSF10A was found to be localized in human RPE. In vitro assays revealed that a T allele of rs13278062, the risk allele for AMD and CSC, downregulated TNFRSF10A transcription in RPE, leading to decreased cell viability and increased apoptosi...

Research paper thumbnail of Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium

Cell Death & Disease, 2015

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-i... more Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL − / −), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL − / − mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasLtriggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

Research paper thumbnail of Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death

Cell death & disease, 2015

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disor... more Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. In...

Research paper thumbnail of Therapeutic effect of prolonged treatment with topical dorzolamide for cystoid macular oedema in patients with retinitis pigmentosa

British Journal of Ophthalmology, 2013

To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic a... more To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic anhydrase inhibitor) for cystoid macular oedema (CME) associated with retinitis pigmentosa (RP). 18 eyes in 10 patients with CME secondary to RP were included. Baseline visual acuity, visual field and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each affected eye. Patients underwent follow-up examinations at 1, 3, 6, 12 and 18 months after treatment. The response to treatment was monitored by the Humphrey field analyser (HFA: the central 10-2 program); in addition, foveal thickness was measured by OCT. Evaluation of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;macular sensitivity&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; was calculated by HFA as the average of 12 central points. The &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;macular sensitivity&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; in 10 eyes in which CME was almost completely resolved was significantly improved (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In eight of the nine eyes in which CME was almost completely resolved within 6 months, the therapeutic efficacy persisted through 18 months. Five eyes which were almost completely resolved or showed an initial response within 6 months experienced recurrence of CME. The prolonged (longer than 1 year) use of topical dorzolamide is effective for the treatment of CME in patients with RP. Therefore, we propose topical dorzolamide treatment as a first choice.

Research paper thumbnail of Guidelines for the use and interpretation of assays for monitoring autophagy

Research paper thumbnail of The Regulatory Roles of Apoptosis-Inducing Factor in the Formation and Regression Processes of Ocular Neovascularization

The American Journal of Pathology, 2012

Research paper thumbnail of Critical Involvement of Extracellular ATP Acting on P2RX7 Purinergic Receptors in Photoreceptor Cell Death

The American Journal of Pathology, 2011

Research paper thumbnail of MutT Homolog-1 Attenuates Oxidative DNA Damage and Delays Photoreceptor Cell Death in Inherited Retinal Degeneration

The American Journal of Pathology, 2012

Research paper thumbnail of Dysfunctional autophagosome and phagosome in age-related macular degeneration (AMD)

Investigative Ophthalmology & Visual Science, 2015

Research paper thumbnail of Erratum

Research paper thumbnail of Relation between Sustained Chronic Inflammatory Reaction and Oxidative Damage in an Animal Model of Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science, 2013

Research paper thumbnail of Sustained Chronic Inflammatory Reaction In Retinitis Pigmentosa

Investigative Ophthalmology & Visual Science, 2012

Research paper thumbnail of Cell Injury , Repair , Aging , and Apoptosis Critical Involvement of Extracellular ATP Acting on P 2 RX 7 Purinergic Receptors in Photoreceptor Cell Death

From the Department of Ophthalmology,* and the Morphology Core Unit, Graduate School of Medical S... more From the Department of Ophthalmology,* and the Morphology Core Unit, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; the Department of Ophthalmology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan; INSERM, U848, Villejuif, France; the Metabolomics Platform, Institut Gustave Roussy, Villejuif, France; the Centre de Recherche des Cordeliers, Paris, France; the Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France; and the Sorbonne Paris Cité Faculté de Médicine, Université Paris Descartes, Paris, France