ABSTRACT
We demonstrate the 1,600-km transmission at nearly 1-Tb/s/λ signals with a capacity of 21.5 Tb/s. Probabilistic shaping was newly applied to high-speed coherent optical Nyquist pulse transmission systems to maximize the transmission capacity. Employing a 160-GBd PS-32 QAM format, WDM signals at nearly 1-Tb/s/λ were successfully transmitted over 1,600 km with a capacity of 21.5 Tb/s.
ABSTRACT
The total capacity of optical submarine cable systems as a global communication infrastructure must be continuously enlarged. Multi-core fibers (MCFs) have been studied as methods to maximize the total cable capacity under electrical power and cable space limitations. In particular, standard cladding MCFs, which are expected to have high productivity and mechanical reliability, are attractive for early deployment in submarine cable systems. In this paper, we demonstrate high-capacity trans-Pacific class transmission using standard cladding uncoupled 4-core fibers, achieving a transmission capacity of 55.94 Tbit/s over 12,040 km. In addition, based on the results of this and our previous coupled MCF transmission experiments, we summarize the characteristics of coupled and uncoupled MCFs applied to optical submarine cable systems.
ABSTRACT
BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.
Subject(s)
Adenosine Triphosphate/metabolism , Aquaporin 4/immunology , Astrocytes/immunology , Autoantibodies/pharmacology , Neuralgia/immunology , Neuromyelitis Optica/immunology , Animals , Astrocytes/drug effects , Astrocytes/metabolism , HEK293 Cells , Humans , Neuralgia/metabolism , Neuromyelitis Optica/metabolism , RatsABSTRACT
BACKGROUND: Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. METHODS: We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-ß (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study. RESULTS: Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-ß unresponsiveness than those with low Sema4A levels. CONCLUSIONS: Sema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.
Subject(s)
Inflammation/immunology , Multiple Sclerosis, Relapsing-Remitting/immunology , Semaphorins/immunology , Th17 Cells/immunology , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Semaphorins/bloodABSTRACT
For weakly coupled mode-division multiplexed (MDM) transmission systems, we design and implement optical coherent receiver prototypes with real-time multiple-input multiple-output (MIMO) digital signal processing to equalize two degenerate linearly polarized modes with dual polarization. Using field programmable gate array circuits, we implement real-value 8 × 2 MIMO adaptive equalization with externally separated phase compensators based on the least mean square algorithm, which enables not only training equalization but also fast carrier-phase tracking. With the optical coherent MIMO receiver prototype, we demonstrate real-time weakly coupled 10 × MDM wavelength-division multiplexed dual-polarization quadrature phase shift keying transmission over 48-km few-mode fibers. This report shows a record number of multiplexed spatial modes, namely, 10 modes with dual polarization, in real-time MDM transmission experiments.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Animals , Humans , Mice , Food Additives , Succinic Acid , Signal Transduction , Mice, Inbred C57BLSubject(s)
COVID-19 Vaccines , COVID-19 , Humans , SARS-CoV-2 , COVID-19/prevention & control , Vaccination , Antibodies, ViralABSTRACT
We describe a 2048 QAM single-carrier coherent optical transmission over 150 km in detail. The OSNR at the transmitter was increased by 5 dB and the phase noise at the receiver was reduced from 0.35 to 0.17 degrees compared with a previous 1024 QAM transmission. Furthermore, we employed an A/D converter with a higher ENOB (7 bit) to guarantee the SNR of the digital QAM data, and introduced a polarization-demultiplexing algorithm to fast track the polarization state transition. As a result, a 66 Gbit/s polarization-multiplexed 2048 QAM signal was successfully transmitted within an optical bandwidth of 3.6 GHz including a pilot tone, and a potential SE of 15.3 bit/s/Hz under a 20% FEC overhead was achieved.
ABSTRACT
We demonstrate an 80 Gbit/s, 5 Gsymbol/s 256 QAM coherent optical transmission by employing an injection-locked homodyne detection circuit based on both fiber lasers and LDs. With either circuit, low phase noise carrier-phase synchronization between the transmitted data signal and an LO were achieved with a phase noise variance of only 0.2 degrees. As a result, we have successfully transmitted an 80 Gbit/s data signal over 150 km with a simple receiver configuration. This is the highest QAM multiplicity yet realized with injection-locked homodyne detection.
ABSTRACT
We report the first 1024 QAM polarization-multiplexed transmission at 3 Gsymbol/s over a 55 km 7-core fiber, with a total bit rate of 420 Gbit/s (60 Gbit/s x 7 cores). The potential spectral efficiency per core reached 15.6 bit/s/Hz, which corresponds to an aggregate spectral efficiency as high as 109 bit/s/Hz in a multi-core single-mode fiber.
ABSTRACT
OBJECTIVES: This study aimed to evaluate whether switching disease-modifying therapies (DMTs) from sphingosine-1 phosphate (S1P) receptor modulators to either natalizumab (NTZ) or dimethyl fumarate (DMF) could restore the effectiveness of SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis (MS). METHODS: This study included 9 controls and 33 patients with MS: 7 patients treated with DMF, 7 patients treated with NTZ, 9 patients treated with S1P receptor modulators, and 10 patients who had switched DMTs from S1P receptor modulators to DMF or NTZ by the second vaccine dose. The patients who had switched DMTs were classified into two groups, based on whether their lymphocyte counts were above or below 1000/µL at the time of vaccination. In addition, relapses within 6 months after switching DMTs were also evaluated in these patients. Six months after the second dose of the vaccination, anti-SARS-CoV-2 spike antibodies were evaluated in all participants, and spike specific CD4+ T cells were also assessed in patients who had switched DMTs from S1P receptor modulators. RESULTS: Patients treated with S1P receptor modulators had lower levels of anti-SARS-CoV-2 spike antibodies than the controls and patients treated with DMF and NTZ. On the other hand, in patients who had switched DMTs from S1P receptor modulators, a recovery of lymphocyte counts above 1000/µL resulted in restored humoral and cellular immune responses to the vaccination. There were no neurological relapses in patients who had switched DMTs from S1P receptor modulators to NTZ. CONCLUSION: SARS-CoV-2 mRNA vaccination is expected to be effective in patients whose lymphocyte counts have recovered due to switching DMTs from S1P receptor modulators. Switching DMTs from S1P receptor modulators to NTZ before vaccination may be beneficial in achieving efficacy for SARS-CoV-2 mRNA vaccination, with a reduced risk of relapse.
Subject(s)
COVID-19 , Dimethyl Fumarate , Multiple Sclerosis , Natalizumab , SARS-CoV-2 , Humans , Female , Dimethyl Fumarate/therapeutic use , Male , Adult , Natalizumab/therapeutic use , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/drug therapy , COVID-19/prevention & control , COVID-19/immunology , SARS-CoV-2/immunology , Sphingosine 1 Phosphate Receptor Modulators/therapeutic use , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Immunosuppressive Agents/therapeutic use , Vaccination/methods , Drug Substitution , Antibodies, Viral/bloodABSTRACT
A 67-year-old man presented slowly progressive weakness of the extremities visited our hospital. Nerve conduction study showed axonal neuropathy and needle electromyography showed neurogenic changes with denervation findings in multiple limb muscles. While he was diagnosed as Probable amyotrophic lateral sclerosis (ALS), which is defined by the Awaji criteria for diagnosis of ALS, he did not develop either respiratory muscle paralysis or bulbar palsy, which are characteristic symptoms of sporadic ALS. Genetic testing revealed a novel gene variant in senataxin (SETX), the causative gene of ALS4. We could not make a definite diagnosis of ALS4 because he had no relatives who could perform genetic testing (segregation study). However, we considered the variant can be pathogenic because it was not previously reported and absent in at least 1,000 healthy control individuals, the variant site was highly conserved in mammals, and it may impair the function of senataxin protein (in silico analysis).
Subject(s)
Amyotrophic Lateral Sclerosis , Bulbar Palsy, Progressive , Aged , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/genetics , DNA Helicases/genetics , Electromyography , Humans , Male , Multifunctional Enzymes/genetics , Muscle, Skeletal/pathology , RNA Helicases/geneticsABSTRACT
A 61-year-old man presented with slowly progressive cognitive decline. Brain MRI revealed left frontal lobe lesions with gadolinium enhancement along pia mater. Brain biopsy was performed and histopathological findings was compatible with the diagnosis of IgG4-related disease (IgG4-RD). Serum IgG4 level was within a normal range, and no other systemic organs were suggested to be involved by clinical symptoms or laboratory findings. Intravenous methylprednisolone therapy followed by oral prednisone induction markedly improved the cognitive functions and MRI findings detected at the initial diagnosis. Our case highlights the importance of including IgG4-RD as one of the differential diagnosis when encountering the patients suffering from isolated cranial lesions even in the absence of normal serum IgG4 level.
Subject(s)
Immunoglobulin G4-Related Disease , Contrast Media , Gadolinium , Humans , Immunoglobulin G , Immunoglobulin G4-Related Disease/diagnosis , Male , Methylprednisolone , Middle AgedABSTRACT
BACKGROUND AND OBJECTIVES: Recently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated. METHODS: Clinical samples were obtained from 32 patients with aquaporin-4 antibody-positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed. RESULTS: Enhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed. DISCUSSION: Our study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.
Subject(s)
Cell-Free Nucleic Acids , Neuromyelitis Optica , Humans , Interferons , Leukocytes, Mononuclear , Neutrophils/pathologyABSTRACT
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease characterized by the presence of pathogenic autoantibodies, anti-aquaporin 4 (AQP4) antibodies. Recently, HLA-DQA1*05:03 was shown to be significantly associated with NMOSD in a Japanese patient cohort. However, the specific mechanism by which HLA-DQA1*05:03 is associated with the development of NMOSD has yet to be elucidated. In the current study, we revealed that HLA-DQA1*05:03 exhibited significantly higher cell surface expression levels compared to other various DQA1 alleles, and that its expression strongly depended on the amino acid sequence of the α1 domain, with a preference for leucine at position 75. Moreover, in silico analysis indicated that the HLA-DQ encoded by HLA-DQA1*05:03 preferentially presents immunodominant AQP4 peptides, and that the peptide major histocompatibility complexes (pMHCs) are more energetically stable in the presence of HLA-DQA1*05:03 than other HLA-DQA1 alleles. In silico 3D structural models were also applied to investigate the validity of the energetic stability of pMHCs. Taken together, our findings indicate that HLA-DQA1*05:03 possesses a distinct property to play a pathogenic role in the development of NMOSD.
Subject(s)
Aquaporin 4/metabolism , Cell Membrane/metabolism , HLA-DQ alpha-Chains/metabolism , Immunodominant Epitopes , Neuromyelitis Optica/metabolism , Amino Acid Sequence , Aquaporin 4/immunology , Autoantibodies/blood , Cell Membrane/immunology , HEK293 Cells , HLA-DQ alpha-Chains/genetics , HLA-DQ alpha-Chains/immunology , Humans , Immunoglobulin G/blood , Models, Molecular , Neuromyelitis Optica/diagnosis , Neuromyelitis Optica/genetics , Neuromyelitis Optica/immunology , Protein Binding , Protein DomainsABSTRACT
Although recent studies indicate the involvement of monocytes in accelerating the lesion formation of neuromyelitis optica spectrum disorder (NMOSD), the precise mechanism of the innate immune system activation remains elusive. Thus, in this study, we aimed to clarify the mechanisms of NMOSD pathogenesis from the viewpoint of innate immunity activation. We established anti-AQP4 recombinant autoantibodies (Ab) from plasmablasts in NMOSD patient's CSF. Human astrocytes treated with anti-AQP4 Ab produced a significant amount of CCL2 and contributed to the efficient recruitment of monocytes. Moreover, mitochondrial DNA (mtDNA), which activated monocytes via Toll-like receptor 9 (TLR9), was released from astrocytes treated with anti-AQP4 Ab. MtDNA further enhanced CCL2 production by monocytes, and it was demonstrated that mtDNA concentration correlated with the efficiency of monocyte recruitment in the CSF of NMOSD patients. In conclusion, these observations highlight that mtDNA which was released from astrocytes damaged by anti-AQP4 Ab has a central role in establishing the inflammatory loop of monocyte recruitment and activation via an innate immunity pathway.