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Epigenetic modifications undergo drastic erasure and reestablishment after fertilization. This reprogramming is required for proper embryonic development and cell differentiation. In mammals, some histone modifications are not completely reprogrammed and play critical roles in later development. In contrast, in nonmammalian vertebrates, most histone modifications are thought to be more intensively erased and reestablished by the stage of zygotic genome activation (ZGA). However, histone modifications that escape reprogramming in nonmammalian vertebrates and their potential functional roles remain unknown. Here, we quantitatively and comprehensively analyzed histone modification dynamics during epigenetic reprogramming in Japanese killifish, medaka (Oryzias latipes) embryos. Our data revealed that H3K27ac, H3K27me3, and H3K9me3 escape complete reprogramming, whereas H3K4 methylation is completely erased during cleavage stage. Furthermore, we experimentally showed the functional roles of such retained modifications at early stages: (i) H3K27ac premarks promoters during the cleavage stage, and inhibition of histone acetyltransferases disrupts proper patterning of H3K4 and H3K27 methylation at CpG-dense promoters, but does not affect chromatin accessibility after ZGA; (ii) H3K9me3 is globally erased but specifically retained at telomeric regions, which is required for maintenance of genomic stability during the cleavage stage. These results expand the understanding of diversity and conservation of reprogramming in vertebrates, and unveil previously uncharacterized functions of histone modifications retained during epigenetic reprogramming.

Background Inflammatory bowel disease (IBD) patients frequently have zinc deficiency and that IBD patients with zinc deficiency are at higher risk for IBD-related complications and surgery. We reported the efficacy of zinc replacement therapy for IBD patients with zinc deficiency at ECCO2020, and now we report the results of our analysis with an extended observation period and an additional number of patients. Methods IBD patients with zinc deficiency who received zinc acetate hydrate (ZAH) from March 2017 to November 2021 were registered in this 2-center（Hokkaido University Hospital and Sapporo Higashi Tokushukai Hospital）, retrospective, observational study. Results One hundred twenty patients with Crohn’s disease (CD, n=82) or ulcerative colitis (UC, n=38) were registered. Median serum zinc level and CDAI in CD patients significantly improved (59.0-92.3 μg/dL, P Median serum zinc level and partial Mayo scores (PMS) in UC patients significantly improved (63.0-94.0μg/dL, P Logistic regression analysis identified “dose of ZAH ≥75 mg/day” as a factor contributing to normalization of serum zinc concentration and “serum zinc level ≥65 μg/dl before ZAH administration” as a factor contributing to improvement of disease activity. In both CD and UC, there was a significant correlation between serum zinc level and CDAI, CRP, and serum albumin level before ZAH administration. Conclusion ZAH administration to IBD patients with zinc deficiency is effective in improving zinc deficiency and may contribute to improving disease activity in IBD.

Recent development of targeted manipulation of histone modification enables us to experimentally and directly test the functional relevance of histone modifications accumulated at specific genomic regions. In particular, dCas9 epigenome editing has been widely used for site-specific manipulation of epigenetic modification. Here, we describe how to apply dCas9 epigenome editing in fish (medaka, Oryzias latipes) embryos and how to analyze induced changes in histone modification.

In the internet era, the digital architecture that keeps us connected and informed may also amplify the spread of misinformation. This problem is gaining global attention, as evidence accumulates that misinformation may interfere with democratic processes and undermine collective responses to environmental and health crises. In an increasingly polluted information ecosystem, understanding the factors underlying the generation and spread of misinformation is becoming a pressing scientific and societal challenge. Here, we studied the global spread of (mis-)information on spiders using a high-resolution global database of online newspaper articles on spider-human interactions, covering stories of spider-human encounters and biting events published from 2010-20204. We found that 47% of articles contained errors and 43% were sensationalist. Moreover, we show that the flow of spider-related news occurs within a highly interconnected global network and provide evidence that sensationalism is a key factor underlying the spread of misinformation. info:eu-repo/semantics/publishedVersion

SummaryReprograming of epigenetic modifications after fertilization is required for proper embryonic development and cell differentiation. However, histone modifications that escape reprogramming in non-mammalian vertebrates and their potential functional roles are poorly understood. Here, we quantitatively analyzed histone modification dynamics during reprogramming in Japanese Killifish, medaka (Oryzias latipes) embryos, and revealed that H3K27ac, H3K27me3 and H3K9me3 are retained, while H3K4 methylation is completely erased. Furthermore, we experimentally demonstrated the functional roles of such retained modifications at early stages; H3K27ac at promoters is required for proper patterning of H3K4 and H3K27 methylation at zygotic genome activation (ZGA) and specific retention of H3K9me3 at telomeric regions maintains genomic stability during cleavage stage. These results expand the understanding of diversity and conservation of reprogramming in vertebrates and unveil previously uncharacterized functions of histone modifications retained during epigenetic reprogramming.

Due to the significant growing demand for water, it is urgent to those in the food industry to consider a more rational and sustainable use of such a scarce natural resource. This chapter highlights alternative food processing methods that contemplate recycling and reusing water. Based on a systematic literature review, it highlights the adoption of cleaner production methods. The chapter focus on the meat and fresh produce sectors where evidence shows that water sustainability related methods is the most needed. Suggestions are proposed to minimize water waste through the treatment of effluents and decrease the impact of effluent pollution on the environment. In so doing, clear environmental and economic benefits could be achieved through the reduction of costs and value-adding to the final product. Yet, the implementation of Cleaner Production Methods would require support from the industry, policymakers, and consumers to encourage the recycling and reuse of water.

Background Endoscopy is the standard modality for inflammatory bowel disease, but it is invasive and poorly tolerated. On the other hand, trans-abdominal ultrasonography (US) is minimally invasive, inexpensive, and has excellent characteristics not found in other examinations, such as the ability to detect minute changes in the intestinal wall. It would be clinically useful if US could predict clinical relapse. Methods Of 185 patients with CD who underwent US between April 2011 and April 2021, we retrospectively evaluated 75 patients who were in clinical remission (CDAI < 150) at the time of their first US at our hospital for clinical relapse and maintenance of remission at 1 year after the procedure. The severity of US was evaluated by US-CD (0-52 points in total), which divided the intestine into four segments(ileum, right-sided colon, transverse colon, and left-sided colon) and was calculated the following US parameters: bowel wall thickness (BWT) (0–3), loss of stratification (0–2), degree of blood flow signaling by a color Doppler study (0–3), presence of increasing echogenicity mesentery (0–2), and intestinal stenosis (0–3). US images were analyzed and interpreted in a consensus manner by two technologists with more than 10 years of experience, blinded to the patient's clinical information. Results Of the 75 cases, 58 were males and 17 were females with a median age of 30 years (range 18-58), median BMI of 20.6 kg/square meter (range 16.2-32.5), 23 cases were ileal type, 47 cases were ileocolonic type, and 5 cases were colonic type. Sixty-eight patients remained in clinical remission during the observation period, and 7 patients had clinical relapse (CDAI > 150). The median CDAI at US was 71 (range 14-143), median CDAI at relapse was 189 (range 151-288), and median observation period was 365 days (range 6-365). The median time to relapse was 193 days (range 166-288). ROC analysis was performed on the US-CD, and the highest AUC of 0.820 was obtained when the cutoff value was 11. Six patients in the relapse group and 20 patients in the remission maintenance group had US-CD of 11 or higher, and 1 patient in the relapse group and 48 patients in the remission maintenance group had a score of less than 11. The sensitivity was 85.7%, specificity was 70.6%, positive predictive value was 23.1%, and negative predictive value was 98%. Logistic regression analysis identified "US-CD 11 or higher" as a factor contributing to clinical relapse (p=0.018). Conclusion US-CD ≥11 is a prognostic predictor of clinical relapse in CD.

Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Background Reversible cerebral vasoconstriction syndrome (RCVS) is a transient cerebrovascular disorder putatively caused by some immunosuppressive agents. Case report We recently encountered a 47-year-old female patient diagnosed with dilated cardiomyopathy who developed RCVS after heart transplantation. A triple-drug regimen consisting of tacrolimus, mycophenolate mofetil, and a corticosteroid was started after surgery. On postoperative day (POD) 11, the patient developed a severe headache, although computed tomography of the head demonstrated no signs of hemorrhage or infarction. At first, both a painkiller and migraine drugs were regularly administered to the patient. On POD 21, however, she developed an unbearable headache with a visual field defect and mild hemiparesis of the right hand. Magnetic resonance imaging (MRI) of the brain revealed a cerebral infarction in the left occipital lobe with diffuse vasoconstriction of both the middle and posterior cerebral arteries. A diagnosis of RCVS was made and tacrolimus, a drug suspected to cause RCVS, was discontinued. In its place, two doses of basiliximab followed by everolimus, both of which are alternatives for tacrolimus, were given. The corticosteroid dose was also increased. Furthermore, to release vasoconstriction, both verapamil and diltiazem were administered. On POD 27, cerebrovascular constrictions were shown to be relieved on brain MRI and the patient's neurological symptoms subsequently almost completely diminished. Conclusion RCVS should always be considered as a cause of headache in heart transplant recipients because tacrolimus, an immunosuppressive agent, may trigger RCVS. This will allow rapid intervention that is essential for avoiding irreversible neurological deficits.

Background Late renal function dysfunction is an increasingly recognized complication in continuous flow left ventricular assist device (CF-LVAD) patients. Although hemolysis is prevalent in CF-LVAD patients and hemolysis may deteriorate renal function, the influence of persistent hemolysis on renal function in CF-LVAD patients remains to be investigated. Purpose To investigate the influence of persistent hemolysis on renal function in CF-LVAD patients, using lactate dehydrogenase (LDH) as a sensitive marker of hemolysis. Methods Excluding patients who died or underwent pump exchange for pump thrombosis, we retrospectively reviewed 65 consecutive adults who underwent HeartMateII implantation in our center from May 2011 to October 2017. Patient characteristics, chronotropic change of estimated glomerular filtration rate (eGFR) and LDH values weekly for 4 weeks and every 4 weeks between 4 and 48 weeks after implantation were collected. Then, calculating mean LDH during 48 weeks after implantation, study population was divided into low and high mean LDH groups at the median value of mean LDH. Results The median value of mean LDH was 304 U/l. Compared with low LDH patients, though high LDH patients were more likely female and had smaller body surface area, there were no significant difference in pre-operative eGFR between the groups (66.0±23.7 vs. 70.2±25.7 ml/min/1.73m2, p=0.495). After 40 weeks after implantation, high LDH patients had significantly lower eGFR than low LDH patients (71.0±23.7 vs. 87.1±31.4 ml/min/1.73m2, p=0.024). In multivariate linear regression analysis, mean LDH [parameter estimate: −0.10 (95% CI: −0.17 to −0.04), p=0.003] and post-operative pulse pressure [parameter estimate: 0.71 (95% CI: 0.05 to 1.37), p=0.036] were significantly associated with eGFR change during 48 weeks after HeartMateII implantation. Univariate and multivariate linear regression analysis for eGFR change Univariate parameter estimate 95% CI p value Multivariate parameter estimate 95% CI p value Bilirubin, mg/dl 9.97 3.82 to 16.13 0.002 6.55 −0.43 to 13.53 0.065 BNP, pg/ml 0.01 0.00 to 0.02 0.044 0.00 −0.01 to 0.01 0.528 Mean LDH during 4 to 48 weeks, U/l −0.11 −0.18 to −0.05 Conclusions High mean LDH and low pulse pressure were associated with a significant decrease in eGFR late after HeartMateII implantation. Subclinical persistent hemolysis may be associated with late renal function deterioration in CF-LVAD patients.

Background Epigenetic modifications have a central role in transcriptional regulation. While several studies using next-generation sequencing have revealed genome-wide associations between epigenetic modifications and transcriptional states, a direct causal relationship at specific genomic loci has not been fully demonstrated, due to a lack of technology for targeted manipulation of epigenetic modifications. Recently, epigenome editing techniques based on the CRISPR-Cas9 system have been reported to directly manipulate specific modifications at precise genomic regions. However, the number of editable modifications as well as studies applying these techniques in vivo is still limited. Results Here, we report direct modification of the epigenome in medaka (Japanese killifish, Oryzias latipes) embryos. Specifically, we developed a method to ectopically induce the repressive histone modification, H3K27me3 in a locus-specific manner, using a fusion construct of Oryzias latipes H3K27 methyltransferase Ezh2 (olEzh2) and dCas9 (dCas9-olEzh2). Co-injection of dCas9-olEzh2 mRNA with single guide RNAs (sgRNAs) into one-cell-stage embryos induced specific H3K27me3 accumulation at the targeted loci and induced downregulation of gene expression. Conclusion In this study, we established the in vivo epigenome editing of H3K27me3 using medaka embryos. The locus-specific manipulation of the epigenome in living organisms will lead to a previously inaccessible understanding of the role of epigenetic modifications in development and disease. Electronic supplementary material The online version of this article (10.1186/s13072-019-0263-z) contains supplementary material, which is available to authorized users.

Purpose: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world. Methods: We performed a secondary analysis of data from the prospective ICON audit, in which all adult ( >16 years ) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - 80 years. Sepsis was defined as infection plus at least one organ failure. Results: A total of 2963 patients had sepsis, with similar proportions across the age groups (80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients 70 years was independently associated with increased risk of dying. Conclusions: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years. (C) 2019 Elsevier Inc. All rights reserved.

A ground-based augmentation system (GBAS) is a navigation system using global navigation satellite system (GNSS) that enables precision approaches and landing for aircraft. In May 2010, the International Civil Aviation Organization (ICAO) Navigation Systems Panel (NSP) working group completed development baseline standards and recommended practices (SARPs) for GBAS ground subsystems to support GBAS approach service type D (GAST-D), which refers to Category III precision approach services using the single-frequency L1-C/A signal. The Electronic Navigation Research Institute (ENRI) developed a prototype of the GAST-D ground subsystem to operationally validate the development baseline SARPs. Owing to the fact that ionospheric delays with large spatial gradients represent one of the most significant risks to the integrity of the GAST-D operation, the system was installed in a low magnetic latitude region where plasma bubble causes steep spatial gradients in the ionospheric delay. Preliminary results were reported to the NSP working group before the development baseline SARPs were approved in December 2016 with an expectation that they would go into effect in 2018. Here, we report the development of a prototype for a GAST-D ground subsystem to validate the development baseline SARPs and preliminarily evaluate the system’s performance.

The acetyl bromide lignin (ABL) has been shown to provide a similar relationship between lignin concentration and fiber degradability for grasses and legumes. In contrast, the acid detergent lignin (ADL) method results in different regression equations for grasses and legumes with a larger slope for grasses. The difference may be due to solubilization and loss of lignin in the grasses during the acid detergent fiber (ADF) procedure. While ADL and ABL values for legumes were about the same, ADL values for grasses were about half of those for ABL, supporting the theory that lignin was lost in grasses in the ADL method. We estimated this loss at about 60 %, so multiplying the ADL in grasses by 2.4 would yield the actual lignin concentrations. Applying this multiplier to ADL in grasses, but not in legumes, resulted in analogous regression lines for forage degradability, that were similar to those obtained with the ABL method. The nutritional entity ABL behaves uniformly for grasses and legumes and may properly determine measures of lignin, allowing further research on the mechanisms by which lignin acts as a barrier to enzymatic degradation of forage cell wall polysaccharides, which may provide information on the potential nutritive value of specific plants for herbivores.

The Trans-Pacific Partnership (TPP), signed in February 2016, is the most ambitious free trade deal of the postwar era. The 12 TPP countries account for nearly 40 percent of the world's economy. Coupled with the Transatlantic Trade and Investment Partnership—which is still being negotiated between the United States and the European Union—the TPP represents an attempt by the Obama Administration to lead in promoting regional trade and investment arrangements despite the failure of the Doha Round to reach a comprehensive global trade deal under the auspices of the World Trade Organization. Although the agreement among the 12 TPP countries has been reached, ratification by their legislatures is pending. Ratification by the US Congress remains uncertain due to complex economic and political factors in the United States, including the presidential election of 2016.

This study evaluated the control of streptococcosis outbreaks in Brazil, isolated from diseased sorubim and identified as Lactococcus garvieae by genetic sequencing. This report determined the potential for lactococcosis control in sorubim Pseudoplatystoma sp. with two vaccines: an aqueous-based, whole-cell inactivated vaccine (bacterin) and an oil-adjuvanted bacterin. Their efficacy was evaluated at 30 days post-vaccination (d.p.v.) by challenge with L. garvieae, and the antibody production response at 15, 30 and 60 d.p.v. and the non-specific immune response were compared amongst treatments. High protection levels (P

Background:The rate of elderly people over 65 year-old increased from 22.1 % in 2008 to 27.7% in 2017 in Japan, also from 27.1 % to 32.3 % in our super-aging area1, 2. The number of total and unilateral knee arthroplasty (TKA, UKA) have increased annually in all over the world according to the larger population of elderly people due to osteoarthritis (OA)3. In fact, the numbers of primary TKA predicted increasing from six hundred fifty-six thousand cases at 2010 to one million three hundred seventy-six thousand cases at 2020 in USA4. In the other hand, rheumatoid arthritis (RA) therapy have been remarkably improved from starting to use biologic agents since 2003 in Japan5. The rate of orthopaedic surgery may reflect trends in disease severity and drug management of RA5.Objectives:The aim of study is to reveal the rate of TKA, including UKA and revision TKA in elderly people in our super-aging area of Japan.Methods:We surveyed the number and cause of primary and revision TKA and UKA in our institutes using the data of diagnosis procedure combination and the record of surgeries in the last decade.Results:Figure 1.Table 1.2008-122013-17TimesOsteoarthritis15652252*1.3Rheumatoid arthritis13181*0.6Trauma155Osteonecrosis of femoral condylar2041*2.1Revision21391.9Total17382418*1.4*p< 0.05Conclusion:The number and rate of primary TKA/UKA due to RA decreased year by year because of progression of modern medication therapy. In the other hand, in case of OA increased because of increasing of elderly people affected by knee OA in the super-aging society.References:[1]National Institute of Population and Social Security Research. Japanese Mortality Database, 2018.http://www.ipss.go.jp/[2]Yamagata prefecture, Health and longevity Promotion Section. Rate of elderly people in Yamagata prefecture, 2018.http://www.pref.yamagata.jp/ou/kikakushinko/020052/tokei/jinkel.html[3]Annual report 2017 of replacement arthroplasty in Japan. The Japanese Society For Replacement Arthroplasty The Japan Arthroplasty Register.https://jsra.info/jar-report.html[4]Kurtz SM, et al. J Bone Joint Surg Am. 96: 624-30, 2014.[5]Momohara S, et al. J Rheumatol. 41:862-5, 2014.Disclosure of Interests:None declared

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized and potentially fatal complication of cardiac transplantation that commonly involves the gastrointestinal tract. Herein, we report a case of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers mimicking PTLD in a heart recipient treated with everolimus (EVL). A 40-year-old man underwent heart transplantation for dilated cardiomyopathy 3 years prior to the current admission and was treated with tacrolimus and EVL. He was admitted to a local hospital because of fever, abdominal pain, and diarrhea. His symptoms persisted and, 3 weeks later, hematochezia occurred; thus, he was transferred to our hospital. As computed tomography and 18F-fluorodeoxyglucose positron emission tomography showed bowel-wall thickening of the terminal ileum, gastrointestinal PTLD was initially suspected. However, although colonoscopy- performed after switching EVL to mycophenolate mofetil (MMF)-showed terminal ileac ulcers, the histologic examination revealed no findings corresponding to PTLD. As EVL may delay ulcer healing, MMF was maintained for 3 months. After repeated colonoscopy showed ulcer healing, MMF was switched back to EVL for cardiac allograft vasculopathy prevention. Three weeks later, he was emergently admitted to a local hospital for life-threatening gastrointestinal bleeding from a recurrent terminal ileal ulcer, which required hemostatic forceps hemostasis. As EVL is suspected to be associated with recurrent ileal ulcers, EVL was again switched back to MMF. The ileal ulcers resolved, without recurrence in 3 months of clinical follow-up. This case demonstrates that cases of life-threatening gastrointestinal bleeding from recurrent terminal ileac ulcers can mimic PTLD in a heart recipient treated with EVL.

Background Left ventricular assist device (LVAD) therapy is the “gold standard” alternative therapy for patients with advanced heart failure. However, LVAD therapy is still uncommon in the Asia-Pacific region. Therefore, we aimed to elucidate the clinical outcomes of patients from Japan supported with the HeartMate II (HM-II) LVAD at our institution. Methods Ninety-two patients (mean 44.3 ± 12.1 years, 68 men, average body mass index 1.65 ± 0.28 m2; 81 with nonischemic cardiomyopathy) who underwent HM-II implantation for bridge to transplantation (n = 91) or for destination therapy in a clinical study (n = 1) at the National Cerebral and Cardiovascular Center between April 2013 and October 2017 were enrolled in this analysis. Preoperatively, most patients (n = 73, 79%) had an INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile of between level 2 and 4. Postoperatively, the average pump speed was 8602 ± 258 rpm and the hemodynamics were well compensated. Results Adverse events consisted of 38 (41.3%) hemolysis, 30 (32.6%) major infection, 27 (29.3%) major bleeding (6 [6.5%] with gastrointestinal bleeding), and 18 (19.6%) neurologic dysfunction events. Eighteen patients underwent heart transplantation (HTx) after an average of 32.9 ± 8.9 months of VAD support, and overall survival at both 6 months and 3 years was 96.3%. Conclusion Clinical outcome among patients with HM-II at our institution is satisfactory for both survival and adverse events. The HM-II can provide effective hemodynamic support during the extremely long waiting period for HTx in Japan.