The genome and transcriptome of Japanese flounder provide insights into flatfish asymmetry

Flatfish have the most extreme asymmetric body morphology of vertebrates. During metamorphosis, one eye migrates to the contralateral side of the skull, and this migration is accompanied by extensive craniofacial transformations and simultaneous development of lopsided body pigmentation(1-5). The evolution of this developmental and physiological innovation remains enigmatic. Comparative genomics of two flatfish and transcriptomic analyses during metamorphosis point to a role for thyroid hormone and retinoic acid signaling, as well as phototransduction pathways. We demonstrate that retinoic acid is critical in establishing asymmetric pigmentation and, via cross-talk with thyroid hormones, in modulating eye migration. The unexpected expression of the visual opsins from the phototransduction pathway in the skin translates illumination differences and generates retinoic acid gradients that underlie the generation of asymmetry. Identifying the genetic underpinning of this unique developmental process answers long-standing questions about the evolutionary origin of asymmetry, but it also provides insight into the mechanisms that control body shape in vertebrates.National Natural Science Foundation of China [31130057, 31461163005, 31530078, 31472269, 31472262, 31472273]; State 863 High Technology R&D Project of China [2012AA092203, 2012AA10A408, 2012AA10A403-2]; Education and Research of Guangdong Province [2013B090800017]; Taishan Scholar Climb Project Fund of Shandong of China; Taishan Scholar Project Fund of Shandong of China for Young Scientists; Shanghai Universities First-class Disciplines Project of Fisheries; Program for Professor of Special Appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning; Shanghai Municipal Science, Special Project on the Integration of Industryinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/publishedVersio

Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation

金沢大学医薬保健研究域医学系Mitochondrial DNA (mtDNA) mutations are found in many types of cancers and suspected to be involved in carcinogenesis, although the mechanism has not been elucidated. In this study, we report that consecutive C-to-T mutations (hypermutations), a unique feature of mutations induced by APOBECs, are found in mtDNA from cervical dysplasia and oropharyngeal cancers. In vitro, we found that APOBEC3A (A3A) and 3B (A3B) expression, as well as mtDNA hypermutation, were induced in a cervical dysplastic cell line W12 when cultured in a differentiating condition. The ectopic expression of A3A or A3B was sufficient to hypermutate mtDNA. Fractionation of W12 cell lysates and immunocytochemical analysis revealed that A3A and A3B could be contained in mitochondrion. These results suggest that mtDNA hypermutation is induced upon keratinocyte differentiation, and shed light on its molecular mechanism, which involves A3s. The possible involvement of mtDNA hypermutations in carcinogenesis is also discussed. © 2018 The Author(s)

Does Selective Posterior Tibial Slope Technique in Cruciate-Retaining Total Knee Arthroplasty Result in the Elimination of Posterior Cruciate Ligament Management?

In cruciate-retaining total knee arthroplasty (CR-TKA), intraoperative posterior cruciate ligament (PCL) management is necessary because retention of optimum PCL tension with high reproducibility is difficult. If PCL management is not performed appropriately, problems such as postoperative pain, poor range of motion, and a feeling of instability may occur. The posterior tibial slope (PTS) has a major influence on the tension of the PCL in CR-TKA. Changes in femoral posterior condylar offset also influences PCL tension in CR-TKA. We designed a surgical procedure in which the PTS is adjusted in association with the posterior condylar offset during surgery. The postoperative clinical results of the primary total knee arthroplasty 159 knee performed by this procedure were favorable. In addition, none of the knees required management of PCL. In our procedure, PCL management, which is the main problem in CR-TKA, is not necessary, and this may be the main advantage of the new procedure

Castrated autoimmune glomerulonephritis mouse model shows attenuated glomerular sclerosis with altered parietal epithelial cell phenotype

Sex hormones help in maintaining proper immunity as well as renal homeostasis in mammals, and these multi-functional properties characterize the onset of sex-dependent diseases. To clarify the contribution of sex hormones to autoimmune disease-related renal pathogenesis, BXSB/MpJ-Yaa was investigated as a murine autoimmune glomerulonephritis model. BXSB/MpJ-Yaa and its wild-type, BXSB/MpJ-Yaa(+) were castrated or sham-operated at three weeks and examined until six months of age. Both castrated strains showed significantly lower serum testosterone levels and body weights than sham-operated mice. Castration did not change the disease phenotypes in BXSB/MpJ-Yaa(+). At three months, both sham-operated and castrated BXSB/MpJ-Yaa manifested splenomegaly, autoantibody production, and glomerulonephritis, and castrated BXSB/MpJ-Yaa tended to show heavier spleen weights than the sham-operated group. At six months, both the treated BXSB/MpJ-Yaa showed equivalent autoimmune disease conditions; however, castrated mice clearly showed milder glomerular sclerotic lesions than the sham-operated groups. Urinary albumin excretion in castrated BXSB/MpJ-Yaa was significantly milder than in sham-operated mice at four months, but those of both the treated BXSB/MpJ-Yaa were comparable at six months. The examined renal histopathological indices in parietal epithelial cells were remarkably altered by castration. Briefly, castration decreased the height of parietal epithelial cells and total parietal epithelial cell number in BXSB/MpJ-Yaa at six months. For immunostaining, parietal epithelial cells facing the injured glomeruli of BXSB/MpJ-Yaa expressed CD44, an activated parietal epithelial cell marker, and CD44-positive parietal epithelial cells showed nuclear localization of the androgen receptor and proliferation marker Ki67. CD44- or Ki67-positive parietal epithelial cells were significantly fewer in castrated group than in sham-operated BXSB/MpJ-Yaa at six months. Further, quantitative indices for CD44-positive parietal epithelial cell number and frequency in renal corpuscles positively correlated with glomerular sclerotic severity in BXSB/MpJ-Yaa. In conclusion, androgen seemed to have an effect on both systemic immunity and renal morpho-function; however, the effect on the latter could be more clearly observed in BXSB/MpJ-Yaa, as parietal epithelial cell activation resulted in glomerular sclerosis

Efficacy of Long-term Flecainide Therapy in Patients with Paroxysmal Atrial Fibrillation —Analysis Based on Time of Onset—

This study sought to evaluate the efficacy of long-term flecainide therapy in maintaining sinus rhythms in patients with paroxysmal atrial fibrillation (AF. based on time of onset. Flecainide (150 mg/day. was administered as an antiarrhythmic drug to a total of 70 patients (54 men and 16 women: mean age 65 ± 10 years. after sinus rhythm was restored spontaneously or by electrical and/or pharmacological cardioversion. Paroxysmal AF was divided into three categories based on time of onset: diurnal type (N = 11), nocturnal type (N = 13), and mixed type (N = 46). The mean follow-up period was 37.7 ± 17.7 months. The duration of sinus rhythm maintenance in patients with diurnal and nocturnal paroxysmal AF was 32.4 ± 10.4 months and 20.8 ± 8.3 months, respectively; the duration of sinus rhythm maintenance in those with mixed paroxysmal AF was only 7.2 ± 2.1 months. Significant differences were observed in duration between diurnal and mixed cases (mean ± S.E., P < 0.05). Actuarial recurrence-free rates at 1, 3, 6, 9 and 12 months were 90.9%, 63.6%, 63.6%, 54.5%, and 54.5%, respectively, for diurnal cases; 84.6%, 76.9%, 53.8%, 38.5%, and 30.8%, respectively, for nocturnal cases; and 58.7%, 39.1%, 28.3%, 21.7%, and 15.2% respectively, for mixed cases. Significant differences in rates at 12 months were observed between diurnal and mixed cases (P < 0.05). These results suggest that flecainide is highly effective in preventing AF recurrence in patients with diurnal paroxysmal AF

Expression of Indian hedgehog signaling in murine oviductal infundibulum and its relationship with epithelial homeostasis

Homeostasis of the oviductal infundibulum epithelium is continuously regulated by signaling pathways under physiological and pathological conditions. Herein, we investigated the expression of hedgehog (Hh) signaling-related components in the murine oviductal infundibulum, which is known to maintain homeostasis in the adult epithelium. Additionally, using autoimmune disease-prone MRL/MpJ-Fas(lpr/lpr) (MRL/lpr) mice showing abnormal morphofunction of the ciliated epithelium of the infundibulum related to the oviductal inflammation, we examined the relationship between Hh signaling and pathology of the infundibulum. The expression and localization of Pax8, a marker for progenitor cells in the oviductal epithelium, and Foxj1, a marker for ciliogenesis, were examined in the infundibulum. The results showed that Pax8 was downregulated and Foxj1 was upregulated with aging, suggesting that homeostasis of the infundibulum epithelium of MRL/lpr mice was disturbed at 6 months of age. In all mice, the motile cilia of ciliated epithelial cells in the infundibulum harbored Hh signaling pathway-related molecules: patched (Ptch), smoothened (Smo), and epithelial cells harbor Gli. In contrast, Ptch, Smo, and Gli2 were significantly downregulated in the infundibulum of MRL/lpr mice at 6 months of age. The expression levels of Pax8 and Foxj1 were significantly positively correlated with those of Ptch1, Smo, and Gli2. Hh signaling is thought to be involved in homeostasis of the ciliated epithelium in the infundibulum. In MRL/lpr mice, which show exacerbated severe systemic autoimmune abnormalities, molecular alterations in Hh signaling-related components are considered to interact with local inflammation in the infundibulum, leading to disturbances in epithelial homeostasis and reproductive function

Compartmentalization of interleukin 36 subfamily according to inducible and constitutive expression in the kidneys of a murine autoimmune nephritis model

The interleukin (IL) 36 subfamily belongs to the IL-1 family and is comprised of agonists (IL-36 alpha, IL-36 beta, IL-36 gamma) and antagonists (IL-36Ra, IL-38). We previously reported IL-36 alpha overexpression in renal tubules of chronic nephritis mice. To understand the localization status and biological relationships among each member of the IL-36 subfamily in the kidneys, MRL/MpJ-Fas(lpr/lpr) mice were investigated as autoimmune nephritis models using pathology-based techniques. MRL/MpJ-Fas(lpr/lpr) mice exhibited disease onset from 3 months and severe nephritis at 6-7 months (early and late stages, respectively). Briefly, IL-36 gamma and IL-36Ra were constitutively expressed in murine kidneys, while the expression of IL-36 alpha, IL-36 beta, IL-36Ra, and IL-38 was induced in MRL/MpJ-Fas(lpr/lpr) mice. IL-36 alpha expression was significantly increased and localized to injured tubular epithelial cells (TECs). CD44(+)-activated parietal epithelial cells (PECs) also exhibited higher IL-36 alpha-positive rates, particularly in males. IL-36 beta and IL-38 are expressed in interstitial plasma cells. Quantitative indices for IL-36 alpha and IL-38 positively correlated with nephritis severity. Similar to IL-36 alpha, IL-36Ra localized to TECs and PECs at the late stage; however, MRL/MpJ-Fas(lpr/lpr) and healthy MRL/MpJ mice possessed IL-36Ra(+) smooth muscle cells in kidney arterial tunica media at both stages. IL-36 gamma was constitutively expressed in renal sympathetic axons regardless of strain and stage. IL-36 receptor gene was ubiquitously expressed in the kidneys and was induced proportional to disease severity. MRL/MpJ-Fas(lpr/lpr) mice kidneys possessed significantly upregulated IL-36 downstream candidates, including NF-kappa B- or MAPK-pathway organizing molecules. Thus, the IL-36 subfamily contributes to homeostasis and inflammation in the kidneys, and especially, an IL-36 alpha-dominant imbalance could strongly impact nephritis deterioration

Altered Renal Pathology in an Autoimmune Disease Mouse Model After Induction of Diabetes Mellitus

Diabetes mellitus (DM) is a predisposing factor for renal disorder progression and is referred to as diabetic kidney disease (DKD). However, there are no reports of DKD with an underlying autoimmune disorder. In this study, we compared the pathophysiological changes caused by DM induction after streptozotocin (STZ) injection in comparison with that in a control group receiving citrate buffer (CB) in the autoimmune disease model mice "BXSB/MpJ-Yaa" (Yaa) and the wild-type strain BXSB/MpJ. Both strains showed hyperglycemia after 12 weeks of STZ injection. Interestingly, the Yaa group developed membranous and proliferative glomerulonephritis, which tended to be milder glomerular lesions in the STZ group than in the CB group, as indicated by a decreased mesangial area and ameliorated albuminuria. Statistically, the indices for hyperglycemia and autoimmune abnormalities were negatively and positively correlated with the histopathological parameters for mesangial matrix production and glomerular proliferative lesions, respectively. STZ treatment induced renal tubular anisonucleosis and dilations in both strains, and they were more severe in Yaa. Significantly decreased cellular infiltration was observed in the Yaa group compared to the CB group. Thus, in DKD related to autoimmune nephritis, hyperglycemia modifies its pathology by decreasing the mesangial area and interstitial inflammation and aggravating renal tubular injury

Age-related changes in bone morphology, function, and cell populations in inbred C57BL/6N mice

Bones play crucial roles in controlling motility, regulating electrolyte metabolism, and hematopoiesis. We examined age-related changes in bone morphofunction using 3-, 6-, and 13-month-old male C57BL/6N mice. Tibia weight and length generally increased with age. Phosphorus, hemoglobin, and hematocrit measurements in blood, indices of electrolyte metabolism and hematopoiesis, significantly decreased with age. Bone histology showed that osteocyte and osteoblast numbers in the tibia were significantly correlated with decreases in hemoglobin levels and hematocrit values. Furthermore, platelet levels in blood increased with age, negatively correlating with osteoblast and osteoclast number. Thus, we have demonstrated age-related changes in bone morphofunction in healthy mice, particularly quantitative alternations of bone-composing cells and hematopoietic activities

Feature Article: Altered morpho-functional features of bones in autoimmune disease-prone BXSB/MpJ-Yaa mice

Bones play crucial roles in motility, electrolyte metabolism, and immunity. Clinical cases have suggested bone dysfunction in several systemic autoimmune diseases. This study exhibited altered bone morpho-functions in BXSB/MpJ-Yaa as a murine autoimmune disease model. During clinical examinations, the serum Ca level was significantly higher in BXSB/MpJ-Yaa than the healthy control BXSB/MpJ at the early stage (two to four months), but that in BXSB/MpJ-Yaa decreased with advancing age. Further, the increase of urinary Ca with nephritis and white blood cells with mild anemia proceeded in BXSB/MpJ-Yaa with advancing age. The thyroid and parathyroid gland morphologies and serum parathormone level did not differ among strains, but the tibia was smaller in BXSB/MpJ-Yaa than in BXSB/MpJ especially during the late stage (six months). Histologically, osteoclasts and osteoblasts showed increased and decreased tendencies, respectively, in BXSB/MpJ-Yaa during the early stage, and osteoclasts and bone area significantly increased and decreased, respectively, compared with BXSB/MpJ at later stages. The bone morphological indices were affected by the expression of BXSB/MpJ-Yaa mutation genes and inflammatory genes in BXSB/MpJ-Yaa. In conclusion, systemic autoimmune diseases in BXSB/MpJ-Yaa are associated with the morpho-functional abnormalities of bones, calcium dynamics, and hematopoiesis, and each factor contributes to forming the phenotypes in this disease. Impact statement Bone disease, such as osteoporosis and rheumatoid arthritis, increases because of the progression of an aging society. Autoimmune disease are important and predisposing factors for the pathogenesis of the bone disease; however, the pathological mechanism is unclear. We have demonstrated that systemic autoimmune disease in BXSB/MpJ-Yaa is closely associated with the morpho-functional abnormalities of bones including bone marrow and has complicated pathology. The abnormalities are characterized by altered regulations of serum calcium, anemia tendency, and hematopoiesis with increased WBCs and decreased PLs, short length and low mass of long bones, imbalance in the populations of osteoclasts and osteoblasts, and increased expression of candidate genes for causing and/or exacerbating their phenotypes. Therefore, BXSB/MpJ-Yaa serves as a model to elucidate bone phenotypes in systemic autoimmune disease that would be affected by the factors in the bone as well as the other immune and/or mineral metabolism organs both in human and experimental medicine