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Somatic cell nuclear transfer (SCNT) in mammals is an inefficient process that is frequently associated with abnormal phenotypes, especially in placentas. Recent studies demonstrated that mouse SCNT placentas completely lack histone methylation (H3K27me3)-dependent imprinting, but how it affects placental development remains unclear. Here, we provide evidence that the loss of H3K27me3 imprinting is responsible for abnormal placental enlargement and low birth rates following SCNT, through upregulation of imprinted miRNAs. When we restore the normal paternal expression of H3K27me3-dependent imprinted genes ( Sfmbt2 , Gab1 , and Slc38a4 ) in SCNT placentas by maternal knockout, the placentas remain enlarged. Intriguingly, correcting the expression of clustered miRNAs within the Sfmbt2 gene ameliorates the placental phenotype. Importantly, their target genes, which are confirmed to cause SCNT-like placental histology, recover their expression level. The birth rates increase about twofold. Thus, we identify loss of H3K27me3 imprinting as an epigenetic error that compromises embryo development following SCNT. Somatic cell nuclear transfer (SCNT) frequently results in abnormal placenta development in cloned mice. Here the authors show that loss of histone methylation (H3K27me3) imprinting in clustered Sfmbt2 miRNAs contributes to SCNT placenta defect.

Hand-rearing of marine mammals is an essential technique for the husbandry of orphans in captivity or the wild, especially endangered cetacean species. The purpose of the present study was to establish a method for successful hand-rearing and evaluate the nutritional state of neonatal finless porpoises. Two neonate finless porpoises maternally neglected at 5 days of age (Day 5) (neonate A, animal A) and Day 4 (neonate B, animal B) were hand reared. The amount of each tube feeding and daily number of nursings for animals A and B during the lactation period were gradually increased to 1,355 and 1,120 ml and 16 and 14 times, respectively. The mean daily caloric intake during the lactation period and average increase in body weight of animals A and B were 2,048 ± 207 and 2,206 ± 169 kcal and 65.4 and 66.9 g/day, respectively. Hypoproteinemia and hypertriglyceridemia were observed in the two neonates during the early stage of hand-rearing. The plasma concentrations of 24 free amino acids in the neonatal porpoises were significantly higher compared with adult porpoises. Plasma valine, leucine, and isoleucine levels in the neonates were dramatically higher than those in adults. Hyperlipoproteinemia, characterized by a higher percentage of very-low-density lipoprotein and the appearance of midband, was also observed in the two neonates, along with hypertriglyceridemia. A hand-rearing method for finless porpoises was successfully established in this research. Nutritional evaluation of serum protein, free amino acids, and lipid components is needed to improve the survivability of hand-reared neonatal porpoises. The hand-rearing method established in the present study is an essential technique for the husbandry of finless porpoises and can be applied to the conservation of other members of the porpoise family, including vaquita and Yangtze finless porpoises, which are the most endangered dolphins in the world.

During infection of macrophages, the pathogenic bacterium Legionella pneumophila secretes effector proteins that induce the conversion of the plasma membrane-derived vacuole into an endoplasmic reticulum (ER)-like replicative vacuole. These ER-like vacuoles are ultimately fused with the ER, where the pathogen replicates. Here we show that the L. pneumophila effector Lpg1137 is a serine protease that targets the mitochondria and their associated membranes. Lpg1137 binds to and cleaves syntaxin 17, a soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that is known to participate in the regulation of mitochondrial dynamics through interaction with the mitochondrial fission factor Drp1 in fed cells and in autophagy through interaction with Atg14L and other SNAREs in starved cells. Cleavage of syntaxin 17 inhibits not only autophagy but also staurosporine-induced apoptosis occurring in a Bax, Drp1-dependent manner. Thus, L. pneumophila can shut down ER–mitochondria communication through cleavage of syntaxin 17. The pathogenic bacterium Legionella pneumophila replicates within macrophages. Here, the authors show that L. pneumophila secretes an effector protein that cleaves the host protein syntaxin 17, thus inhibiting autophagy and staurosporine-induced apoptosis in the host cell.

ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2 -knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes—'extra-renal urate underexcretion' and genuine 'urate overproduction'—providing a new concept valuable for the treatment of hyperuricemia and gout. Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichida et al . show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.

Gout is a common disease which results from hyperuricemia. We have reported that the dysfunction of urate exporter ABCG2 is the major cause of renal overload (ROL) hyperuricemia, but its involvement in renal underexcretion (RUE) hyperuricemia, the most prevalent subtype, is not clearly explained so far. In this study, the association analysis with 644 hyperuricemia patients and 1,623 controls in male Japanese revealed that ABCG2 dysfunction significantly increased the risk of RUE hyperuricemia as well as overall and ROL hyperuricemia, according to the severity of impairment. ABCG2 dysfunction caused renal urate underexcretion and induced hyperuricemia even if the renal urate overload was not remarkable. These results show that ABCG2 plays physiologically important roles in both renal and extra-renal urate excretion mechanisms. Our findings indicate the importance of ABCG2 as a promising therapeutic and screening target of hyperuricemia and gout.

The AIDH is a project as a historical epidemiology. The AIDH aims to collect, maintain, and manage past epidemiological materials and to offer these materials to persons who are interested in the history and in the fields of tropical medicine and global health. In this paper, we introduce our purpose and activities and show a hypothesis about lymphatic filariasis with Brugia malayi in Japan as a case of historical epidemiology. We hope to build fruitful ties between historians and scholars of tropical medicine and global health workers through an interdisciplinary approach to the history of control of infectious diseases.

Dysfunctions of primary cilia and cilia‐derived sensory organelles underlie a multitude of human disorders, including retinal degeneration, yet membrane targeting to the cilium remains poorly understood. Here, we show that the newly identified ciliary targeting VxPx motif present in rhodopsin binds the small GTPase Arf4 and regulates its association with the trans‐Golgi network (TGN), which is the site of assembly and function of a ciliary targeting complex. This complex is comprised of two small GTPases, Arf4 and Rab11, the Rab11/Arf effector FIP3, and the Arf GTPase‐activating protein ASAP1. ASAP1 mediates GTP hydrolysis on Arf4 and functions as an Arf4 effector that regulates budding of post‐TGN carriers, along with FIP3 and Rab11. The Arf4 mutant I46D, impaired in ASAP1‐mediated GTP hydrolysis, causes aberrant rhodopsin trafficking and cytoskeletal and morphological defects resulting in retinal degeneration in transgenic animals. As the VxPx motif is present in other ciliary membrane proteins, the Arf4‐based targeting complex is most likely a part of conserved machinery involved in the selection and packaging of the cargo destined for delivery to the cilium.

Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function ( P = 6.14 × 10 −3 ). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 × 10 −6 ). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.

In the mouse testis, sperm originate from spermatogonial stem cells (SSCs). SSCs give rise to spermatogonial progenitors, which expand their population until entering the differentiation process that is precisely regulated by a fixed time-scaled program called the seminiferous cycle. Although this expansion process of progenitors is highly important, its regulatory mechanisms remain unclear. NANOS3 is an RNA-binding protein expressed in the progenitor population. We demonstrated that the conditional deletion of Nanos3 at a later embryonic stage results in the reduction of spermatogonial progenitors in the postnatal testis. This reduction was associated with the premature differentiation of progenitors. Furthermore, this premature differentiation caused seminiferous stage disagreement between adjacent spermatogenic cells, which influenced spermatogenic epithelial cycles, leading to disruption of the later differentiation pathway. Our study suggests that NANOS3 plays an important role in timing progenitor expansion to adjust to the proper differentiation timing by blocking the retinoic acid (RA) signaling pathway.

The purpose of this study was to try to clarify relative relationships among deviations on each tooth of gears by using the graph theory. Our previous study proposed a method to derive correlation coefficients among the tooth helix deviations and applied it to a ground helical gear. In addition, the coefficients were used as edges, and a network image of the relative helix deviations was generated. In this paper, this method was applied to the analysis of super-finished helical gears, and the phase relationship among the helix deviations was derived. Furthermore, this paper proposed a method, which enables us to derive the magnitude of helix deviation as a norm of signal, which disappeared from the phase network. Then, the derived magnitude was added to the network as the intensity of the vertices. As a result of the application of the proposed method to an analysis of the ground and super-finished helical gears, it was found that the newly created network images were able to show the different characteristics between the gear-finishing processes.