ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline

H3K9 trimethylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that in male meiosis, ATF7IP2 amasses on autosomal and X-pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X-pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase I. Analyses of ATF7IP2-deficient meiosis reveal the protein's essential roles in the maintenance of MSCI, suppression of retrotransposons, and global up-regulation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition

Sonazoid-enhanced intraoperative ultrasonography in patients with gall bladder diseases: A preliminary study

Background:Ultrasonography using Sonazoid, a novel contrast agent containing microbubbles, is a useful diagnostic modality for intrahepatic mass lesions with specific characteristics in two phases: contrast enhancement of early vascular perfusion and perfusion defect of the lesion in the late phase. To improve the diagnostic accuracy of intraoperative ultrasonography (IOUS) in biliary neoplasms, particularly gall bladder, we investigated the usefulness of the Sonazoid contrast agent in a preliminary study.Subjects and Methods:We examined IOUS images of 23 patients with gall bladder disease. Sonazoid was administered intravenously, and early arterial and venous phase images of the tumor were obtained during laparotomy.Results:Tumors included the localized type of adenomyomatosis in the fundus of the gallbladder (GAM) in seven patients as benign controls, adenomatous diseases in three, and gallbladder carcinoma (GC) in 13. Sonazoid IOUS scanning was performed in all patients, with no adverse effects. Although GC showed high enhancement in 77% of the tumors, GAM and adenoma also showed mild enhancement in more than half of them. Pseudo-positivity was observed in one case of hyperplastic polyps, and pseudo-negativity was observed in two patients. Cholesterol polyps and a suspicious lesion of liver metastasis by the computed tomography were not enhanced with Sonazoid treatment.Conclusion:Although there remains a problem of pseud-positivity in the intracystic lesions, Sonazoid IOUS may be a useful tool to detect vascularity and its location or extension of gallbladder diseases; however, neither significance of differential diagnosis with benign diseases nor other clinical significance was found

Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model

阿尔茨海默病（Alzheimer’s Disease, AD）是一种以渐进性认知功能丧失为主要特征的神经退行性疾病，是最为常见的老年痴呆类型。随着全球人口老龄化的加剧，AD正在成为二十一世纪最大的疾病之一。该研究首次揭示sTREM2在AD中具有重要的保护功能，提出sTREM2或可用于AD治疗的新观点，同时也进一步佐证了小胶质细胞在AD治疗中的核心作用，研究为AD等神经退行性疾病的防治开辟了新思路、提供了新靶点。 厦门大学医学院博士后钟力和硕士研究生徐颖为论文共同第一作者，陈小芬教授和卜国军教授为该论文的共同通讯作者。厦门大学的文磊、孙灏、卓仁恭等教授和美国Sanford-Burnham-Prebys医学研究所的许华曦教授共同参与了该项目的研究。【Abstract】Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.Research by the authors was supported by grants from the National Natural Science Foundation of China 81370459, 31400914 (to X.C.), 81701079 (to L.Z.), 81373999, 81774377 (to L.W.), and 81601227 (to R.Z.), grants from the Natural Science Foundation of Guangdong Province 2016A030306005 (to X.C.), 2016A030310371 (to R.Z.), grants from the Fundamental Research Funds for the Central Universities 20720180055 (to X.C.), grants from the Alzheimer's Association AARG-18-56635 (to X.C.), and C4C-15-369446 (to H.X.). NIH grants RF1AG056130 (to G.B. and H.X.), R01AG035355 (to G.B.), R37AG027924 (to G.B.), and RF1AG056114 (to H.X.), grants from the Postdoctoral Science Foundation of China 2016M600503 and 2017T100469 (to L.Z.), a grant from the Tanz Family Funds (to H.X.), and a grant from the Natural Science Foundation of Fujian Province 2016J05203 (to R.Z.).该工作得到国家自然科学基金、厦门大学校长基金、广东省自然科学杰出青年基金、美国阿尔茨海默氏症协会基金和中国博士后科学基金等的资助

The discovery and follow-up of four transiting short-period sub-Neptunes orbiting M dwarfs

Sub-Neptunes with radii of 2–3 R⊕ are intermediate in size between rocky planets and Neptune-sized planets. The orbital properties and bulk compositions of transiting sub-Neptunes provide clues to the formation and evolution of close-in small planets. In this paper, we present the discovery and follow-up of four sub-Neptunes orbiting M dwarfs (TOI-782, TOI-1448, TOI-2120, and TOI-2406), three of which were newly validated by ground-based follow-up observations and statistical analyses. TOI-782 b, TOI-1448 b, TOI-2120 b, and TOI-2406 b have radii of Rp = 2.740 +0.082-0.079 R⊕, 2.769+0.073-0.068 R⊕, 2.120 ± 0.067 R⊕, and 2.830+0.068-0.066 R⊕ and orbital periods of P = 8.02, 8.11, 5.80, and 3.08 days, respectively. Doppler monitoring with the Subaru/InfraRed Doppler instrument led to 2σ upper limits on the masses of <19.1 M⊕, <19.5 M⊕, <6.8 M⊕, and <15.6 M⊕ for TOI-782 b, TOI-1448 b, TOI-2120 b, and TOI-2406 b, respectively. The mass–radius relationship of these four sub-Neptunes testifies to the existence of volatile material in their interiors. These four sub-Neptunes, which are located above the so-called "radius valley," are likely to retain a significant atmosphere and/or an icy mantle on the core, such as a water world. We find that at least three of the four sub-Neptunes (TOI-782 b, TOI-2120 b, and TOI-2406 b), orbiting M dwarfs older than 1 Gyr, are likely to have eccentricities of e ∼ 0.2–0.3. The fact that tidal circularization of their orbits is not achieved over 1 Gyr suggests inefficient tidal dissipation in their interiors.Peer reviewe