Fast QoT estimation method using cascaded artificial neural network for real-time path provisioning in IMDD based all-optical networks.

We propose a fast quality of transmission (QoT) estimation method based on cascaded artificial neural networks (ANNs) for intensity modulation-direct detection (IMDD) systems. The proposed method can calculate the bit error rate of three-span 36 km transmission within 0.7 seconds while taking account of the deterministic waveform distortion caused by the chromatic dispersion and self-phase modulation (SPM).

Simultaneous reception of AMCC signals and QPSK signals by a single coherent receiver with DSP.

This paper investigates an auxiliary management and control channel (AMCC) signal extraction method using digital signal processing (DSP) blocks with 3-step moving averaging that allows a single coherent receiver to receive main signal and AMCC signal simultaneously. Receiver sensitivity characteristics versus the modulation index (MI) and average number of the proposed DSP blocks are elucidated. Based on the results, we discuss a policy for designing the parameters. Experiments apply the design policy to achieve receiver sensitivity of -41.8 dBm with both 25 Gbit/s QPSK main signal and 128 kbit/s AMCC signal; the main signal sensitivity penalty is just 0.2 dB.

Utility of autologous fecal microbiota transplantation and elucidation of microbiota in diversion colitis.

Objectives: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

Increase in muscle mass associated with the prebiotic effects of 1-kestose in super-elderly patients with sarcopenia.

Sarcopenia causes functional disorders and decreases the quality of life. Thus, it has attracted substantial attention in the aging modern world. Dysbiosis of the intestinal microbiota is associated with sarcopenia; however, it remains unclear whether prebiotics change the microbiota composition and result in the subsequent recovery of muscle atrophy in elderly patients with sarcopenia. This study aimed to assess the effects of prebiotics in super-elderly patients with sarcopenia. We analyzed the effects of 1-kestose on the changes in the intestinal microbiota and body composition using a next-generation sequencer and a multi-frequency bioimpedance analysis device. The Bifidobacterium longum population was significantly increased in the intestine after 1-kestose administration. In addition, in all six patients after 12 weeks of 1-kestose administration, the skeletal muscle mass index was greater, and the body fat percentage was lower. This is the first study to show that administration of a prebiotic increased the population of B. longum in the intestinal microbiota and caused recovery of muscle atrophy in super-elderly patients with sarcopenia.

Lactobacillus crispatus promotes invasion of the HTR-8/SVneo trophoblast cell line.

INTRODUCTION: Recent studies have shown that the endometrium possesses unique microbiomes, including Lactobacillus. However, the roles of these microbes are currently unknown, especially in placentation and the early stage of pregnancy. METHODS: The immortalized human first-trimester trophoblast cell line HTR-8/SVneo was cultured in the presence or absence of Lactobacillus crispatus. Invasive and migrative activities were directly evaluated using an optical microscope and a time-lapse imaging system. Protein levels of the invasion-related protein matrix metalloproteinase (MMP)-1, MMP-2, and MMP-9 were evaluated using ELISA. RESULTS: Matrigel invasion of HTR-8/SVneo cells was significantly increased by L. crispatus, though migration was not affected. The culture supernatant of L. crispatus also promoted invasion. Additionally, levels of the active forms of MMP-1 and MMP-2 in the cell culture medium were upregulated by L. crispatus treatment, but that of MMP-9 was not changed. DISCUSSION: L. crispatus promotes trophoblast invasion with an increase in MMP-1 and MMP-2 activation. Our results might explain why Lactobacillus dominance in the endometrium seems beneficial for implantation. Nevertheless, further research is required to determine whether the promotion of trophoblast invasion by L. cripatus is favorable for successful placentation at the early stage of pregnancy.

Symmetric 10 Gbit/s 40-km reach DSP-based TDM-PON with a power budget over 50†dB.

This paper introduces the concept of a symmetric 10 Gbit/s high power-budget TDM-PON based on digital coherent technology and confirms its feasibility through a bidirectional transmission experiment with a transmission distance of 40 km and power budget of more than 50 dB. Burst-mode upstream 10 Gbit/s binary-phase-shift-keying (BPSK) signals synchronized by the clock recovered from downstream 10 Gbit/s NRZ signals are detected by using an optical pre-amplifier and coherent detection based on real-time burst-mode digital signal processing (DSP) in the optical line terminal (OLT). The real-time DSP implements coefficient handover in the adaptive equalizer to allow the reception of burst-mode upstream BPSK signals with short preamble length. An experimental bit error performance evaluation of the real-time burst-mode DSP yields the receiver sensitivity of -45.1 dBm for upstream burst-mode BPSK with a preamble length of 1.3 µs. For downstream signals, the receiver sensitivity of -38.9 dBm is achieved by using a chirp-controlled transmitter with optical post-amplifier so as to avoid the signal distortion created by the chromatic dispersion of single mode fiber (SMF) when the launched power is increased.

Small extracellular vesicles derived from interferon-γ pre-conditioned mesenchymal stromal cells effectively treat liver fibrosis.

Mesenchymal stromal cells (MSCs) are used for ameliorating liver fibrosis and aiding liver regeneration after cirrhosis; Here, we analyzed the therapeutic potential of small extracellular vesicles (sEVs) derived from interferon-γ (IFN-γ) pre-conditioned MSCs (γ-sEVs). γ-sEVs effectively induced anti-inflammatory macrophages with high motility and phagocytic abilities in vitro, while not preventing hepatic stellate cell (HSC; the major source of collagen fiber) activation in vitro. The proteome analysis of MSC-derived sEVs revealed anti-inflammatory macrophage inducible proteins (e.g., annexin-A1, lactotransferrin, and aminopeptidase N) upon IFN-γ stimulation. Furthermore, by enabling CX3CR1+ macrophage accumulation in the damaged area, γ-sEVs ameliorated inflammation and fibrosis in the cirrhosis mouse model more effectively than sEVs. Single cell RNA-Seq analysis revealed diverse effects, such as induction of anti-inflammatory macrophages and regulatory T cells, in the cirrhotic liver after γ-sEV administration. Overall, IFN-γ pre-conditioning altered sEVs resulted in efficient tissue repair indicating a new therapeutic strategy.

Molecular Mechanisms and Treatment of Sarcopenia in Liver Disease: A Review of Current Knowledge.

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass and strength that occurs with aging or in association with various diseases. The condition is prevalent worldwide and occurs more frequently in patients with chronic diseases owing to the intrinsic relationship of muscles with glucose, lipid, and protein metabolism. Liver cirrhosis is characterized by the progression of necro-inflammatory liver diseases, which leads to fibrosis, portal hypertension, and a catabolic state, which causes loss of muscle tissue. Sarcopenia is of significant concern in the state of liver cirrhosis because sarcopenia has been associated with higher mortality, increased hospital admissions, worse post-liver transplant outcomes, decreased quality of life, and increased risk for other complications associated with cirrhosis. Therefore, sarcopenia is also an important feature of liver cirrhosis, representing a negative prognostic factor and influencing mortality. An increased understanding of sarcopenia could lead to the development of novel therapeutic approaches that could help improve the cognitive impairment of cirrhotic patients; therefore, we present a review of the mechanisms and diagnosis of sarcopenia in liver disease and existing therapeutic approaches.

Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH.

The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-l-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH.

Tumor Endothelial Cell-Mediated Antigen-Specific T-cell Suppression via the PD-1/PD-L1 Pathway.

Tumor endothelial cells (TEC) play multiple roles in the regional specialization of vascular structure and physiology. Because TECs in the tumor microenvironment come in contact with circulating immune cells, they might influence not only trafficking but also the antitumor cellular immune response. In a mouse tumor implantation model with B16 melanoma cells, TECs expressed MHC class II, costimulating molecules, and programmed death-ligand 1 (PD-L1), suggesting that they are antigen (Ag)-presenting cells with suppressive activity. Furthermore, TECs were able to take up and present tumor-derived ovalbumin (OVA) peptide on MHC class I molecules. In functional assays, B16-OVA tumor-derived TECs significantly suppressed the proliferation and Ag-specific cytotoxicity of OVA-specific CD8+ T cells relative to those of B16 tumor-derived TECs. This suppressive activity required cell-cell contact and was abrogated by PD-L1 blockade. TECs impaired proinflammatory cytokine production of CD8+ T cells, including IL2, TNFα, and IFNγ. B16-OVA tumor-derived TECs induced immunosuppressive CD4+ T cells that suppressed OVA-specific CD8+ T-cell proliferation via inhibitory cytokines, including IL10 and TGFß. Deficiency of PD-L1 in TECs, but not in hematopoietic cells, impaired suppression and apoptosis of tumor-infiltrating CD8+ T cells, resulting in inhibition of tumor development in vivo model. These data suggest that TECs might regulate the immune response of tumor Ag-specific CD8+ T cells via the PD-1/PD-L1 pathway and induce immune suppressive CD4+ T cells in an Ag-specific manner, contributing to tumor immune evasion. IMPLICATIONS: The findings of this study might encourage the further development of novel anticancer therapies and strategies.

Variation in small bowel transit time on capsule endoscopy.

BACKGROUND: Small bowel motility remains inadequately understood because of the complex and various functions as well as its anatomical position. The aimed of the study was to investigate the small bowel transit time (SBTT) of capsule endoscopy (CE) and to analyze the clinical factors affecting SBTT. METHODS: SBTT was analyzed in patients who underwent small bowel CE. Factors contributing to SBTT and CE retention were investigated. RESULTS: Among 397 patients enrolled in this study, 336 (84.6%) completed CE. The mean SBTT (± standard deviation) was 282.1±132.2 min. According to the univariate and multivariate analyses, aging and small bowel stenosis extended SBTT. In 38 patients who underwent multiple CE studies, considerable variation in SBTT were observed [mean of standard deviations (SDs) =97.97 min, SD of the SDs =81.99 min]. CE retention was observed in 61 patients (13.3%), and it was statistically associated to small bowel lesion. CONCLUSIONS: Aging and small bowel stenosis were associated with longer SBTT. Furthermore, SBTT analyzed by CE should be interpreted carefully considering the intra-individual differences in SBTT.

Development of a non-alcoholic steatohepatitis model with rapid accumulation of fibrosis, and its treatment using mesenchymal stem cells and their small extracellular vesicles.

INTRODUCTION: Currently, there are no approved drugs for treating non-alcoholic steatohepatitis (NASH); however, mesenchymal stem cells (MSCs) and their small extracellular vesicles (sEVs), which possess immunomodulatory activities, are potential candidates. This study aimed to develop a mouse model of NASH with rapid accumulation of fibrosis using the pre-established melanocortin type-4 receptor knockout (Mc4r-KO) NASH mouse model and lipopolysaccharide (LPS), and to evaluate the therapeutic effect of MSCs and their sEVs. METHODS: Mc4r-KO mice (8 weeks old, male) were fed a western diet (WD) for 8 weeks. Next, the mice were intraperitoneally injected with lipopolysaccharide (LPS) twice a week for 4 weeks while continuing the WD. To confirm the therapeutic effect of MSCs and sEVs, human adipose tissue-derived MSCs or their sEVs were administered 12 weeks after initiation of the WD, and serum testing, quantitative analysis of fibrosis, and quantitative reverse transcription-polymerase chain reaction qRT-PCR were performed. RESULTS: By providing a WD combined with LPS treatment, we successfully developed a NASH model with rapid accumulation of fibrosis. Both human MSCs and their sEVs decreased serum alanine transaminase levels and inflammatory markers based on qRT-PCR. Histological analysis showed that MSC or sEV treatment did not affect fat accumulation. However, an improvement in fibrosis in the groups treated with MSCs and their sEVs was observed. Furthermore, after administering MSCs and sEVs, there was a significant increase in anti-inflammatory macrophages in the liver. CONCLUSION: We successfully developed a NASH model with rapid accumulation of fibrosis and confirmed the anti-inflammatory and anti-fibrotic effects of MSCs and their sEVs, which may be options for future therapy.

Advanced squamous cell carcinoma in an asymptomatic, large, epiphrenic esophageal diverticulum.

An asymptomatic epiphrenic diverticulum (ED) was diagnosed in a man undergoing annual esophagogastroduodenoscopy (EGD) at another hospital 40 years before he presented to our hospital at age 63 years for his annual EGD. However, because substantial food retention was found in the ED, we could not confirm a lesion. After the retained food was removed endoscopically, a second EGD showed a reddish, flat lesion with an elevated mass within the ED. Endoscopic ultrasonography indicated that the elevated mass was deep in the submucosal layer. An esophagram showed that the ED was approximately 80 mm in diameter, which is considered large. An endoscopic biopsy of the lesion confirmed squamous cell carcinoma. Total esophagectomy was performed. Microscopic examination revealed well-differentiated to moderately differentiated squamous cell carcinoma invading the adventitia at the elevated lesion. The final pathological stage was pT3N0M0. There was no evidence of recurrence for 3 years during the quarterly follow-up examinations. To our knowledge, this case involved the longest asymptomatic term (40 years) since the ED was detected. A review of 18 reported cases of carcinoma in an ED indicated that advanced cancer has a poor prognosis. Periodic follow-up of ED patients is essential for early diagnosis.

Mesenchymal stem cell therapies for liver cirrhosis: MSCs as "conducting cells" for improvement of liver fibrosis and regeneration.

Mesenchymal stem cells (MSCs) can be cultured relatively easily and can be obtained not only from the bone marrow, but also from medical waste such as adipose tissue and umbilical cord tissue. Because of its low antigenicity, allogeneic MSC injection is safe. MSCs have been evaluated in more than 900 clinical trials in a variety of fields, with more than 50 clinical trials related to liver diseases. Experiments have suggested that MSCs function as "conducting cells" to affect various "effective cells" such as T cells, B cells, and macrophages. Recent clinical trials have focused on allogeneic MSCs. Thus, studies are needed to determine the most effective cell source, culture conditions, cell numbers, administration frequency, administration route, cost, safety, and liver disease treatments. Recently, the functions of exosomes have gained attention, and cell-free therapy may become possible as an alternative therapy for liver disease. In this review, we introduce general information, mechanism, representative clinical study data, recently started or planned clinical trials, and possibility of cell-free therapy of MSCs.

Colorectal neuroendocrine carcinoma: A case report and review of the literature.

BACKGROUND: Colorectal neuroendocrine carcinoma (NEC) is a rare tumor that demonstrates aggressive growth pattern with ingrowth into the tract, metastasis to the other organs, and invasion to the surrounding organs; these clinical characteristics result in poor prognosis. Surgical resection appears as an effective approach; however, because it is difficult to accurately diagnose NEC during the early stage and owing to its aggressive growth pattern, development of a reliable standard chemotherapy regimen and management strategies are essential. CASE SUMMARY: Here, we report the case of patient with NEC showing an aggressive growth pattern that resulted in the rupture of the tumor to the outside the colon after stenting of the internal colonic stenosis. In addition, the tumor invaded into the duodenum, thereby causing duodenal stenosis that required an additional stent in the duodenum. This aggressive growth pattern is one of the main features of the NEC that is different from adenocarcinoma. To clarify the clinical characteristics, we reviewed 60 recently reported cases, including data on tumor location, size, treatment, and prognosis. CONCLUSION: We consider that the information presented here is of great significance for the diagnosis, treatment, and management of symptoms of the patients with NEC.

Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation.

Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.

Isolation of tumor endothelial cells from murine cancer.

Tumor endothelial cells (TECs), which constitute the lining of the tumor blood vessels, have various characteristics as tumor constituent cells. In this study, we describe a novel method for the isolation of highly pure, fresh TECs, which form a small population within the tumor. Tumors were first dissected from tumor-bearing mice and digested to a single cell suspension with Collagenase Type II; the single cells were then separated by density gradient centrifugation. TECs were enriched by CD31-positive selection using magnetic activated cell sorting and subsequently purified by fluorescence activated cell sorting. The high purity of the obtained cells was verified by flow cytometry. Upon cell culture, the isolated cells showed a polygonal shape and a cobblestone appearance, which are features of the endothelial cells. Furthermore, a functional assay revealed that the TECs suppressed the proliferation of CD8+ T cells in vitro. We believe that the isolation method described in this study will enable the further elucidation of the characteristics of TECs.

Sendai virus C protein limits NO production in infected RAW264.7 macrophages.

To suppress virus multiplication, infected macrophages produce NO. However, it remains unclear how infecting viruses then overcome NO challenge. In the present study, we report the effects of accessory protein C from Sendai virus (SeV), a prototypical paramyxovirus, on NO output. We found that in RAW264.7 murine macrophages, a mutant SeV without C protein (4C(-)) significantly enhanced inducible NO synthase (iNOS) expression and subsequent NO production compared to wild type SeV (wtSeV). SeV 4C(-) infection caused marked production of IFN-ß, which is involved in induction of iNOS expression via the JAK-STAT pathway. Addition of anti-IFN-ß Ab, however, resulted in only marginal suppression of NO production. In contrast, NF-κB, a primarily important factor for transcription of the iNOS gene, was also activated by 4C(-) infection but not wtSeV infection. Induction of NO production and iNOS expression by 4C(-) was significantly suppressed in cells constitutively expressing influenza virus NS1 protein that can sequester double-stranded (ds)RNA, which triggers activation of signaling pathways leading to activation of NF-κB and IRF3. Therefore, C protein appears to suppress NF-κB activation to inhibit iNOS expression and subsequent NO production, possibly by limiting dsRNA generation in the context of viral infection.

TGF-ß1 inhibits the production of IFN in response to CpG DNA via ubiquitination of TNF receptor-associated factor (TRAF) 6.

The effect of TGF-ß1 on CpG DNA-induced type I IFN production was examined by reconstituting a series of signaling molecules in TLR 3 signaling. TGF-ß1 inhibited CpG DNA-induced IFN-α4 productivity in HeLa cells. Transfection of IFN regulatory factor (IRF)7 but not TNF receptor-associated factor (TRAF)6 and TRAF3 into cells triggered IFN-α4 productivity, and TGF-ß1 inhibited IRF7-mediated type I IFN production in the presence of TRAF6. TGF-ß1 induced ubiquitination of TRAF6, although CpG DNA did not induce it. Moreover, TGF-ß1 accelerated the ubiquitination of TRAF6 in the presence of CpG DNA. TGF-ß1 ubiquitinated TRAF6 at K63 but not K48. TGF-ß1 also induced ubiquitination of IRF7. Further, TGF-ß1 did not impair the interaction of IRF7 and TRAF6. CpG DNA induced the phosphorylation of IRF7 in the presence of TRAF6, whereas TGF-ß1 inhibited the IRF7 phosphorylation. Blocking of TRAF6 ubiquitination abolished the inhibition of CpG DNA-induced type I IFN production by TGF-ß. Taken together, TGF-ß was suggested to inhibit CpG DNA-induced type I IFN production transcriptionally via ubiquitination of TRAF6.

Involvement of redox balance in in vitro osteoclast formation of RAW 264.7 macrophage cells in response to LPS.

Here we report that LPS induces osteoclast (OC) formation in murine RAW 264.7 macrophage cells in RPMI-1640 medium but not in α-minimum essential medium (α-MEM) as the original culture medium. LPS-induced OC formation in both media was examined to clarify the differential response. Receptor activator of NF-κB ligand induced OC formation in either α-MEM or RPMI-1640 medium. However, LPS-induced OC formation in RAW 264.7 cells maintained in RPMI-1640 medium, but not α-MEM, which was also supported by mouse bone marrow-derived macrophages, although they were less sensitive to LPS than RAW 264.7 cells. LPS augmented the expression of nuclear factor of activated T-cells (NFATc1) as a key transcription factor of osteoclastogenesis in cells maintained in RPMI-1640 medium, but reduced it in cells maintained in α-MEM. A high concentration of LPS was cytotoxic against cells maintained in α-MEM. Glutathione exclusively present in RPMI-1640 medium prevented LPS-induced cell death in α-MEM and augmented LPS-induced NFATc1 expression, followed by enhanced LPS-induced OC formation. LPS induced higher generation of reactive oxygen species in α-MEM than RPMI-1640 medium. An antioxidant enhanced LPS-induced OC formation, whereas a pro-oxidant reduced it. Taken together, redox balance in the culture condition was suggested to regulate in vitro LPS-induced OC formation.