The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Sphingomyelinase Restricts the Lateral Diffusion of CD4 and Inhibits Human Immunodeficiency Virus Fusion▿

Previously, we reported that treatment of cells with sphingomyelinase inhibits human immunodeficiency virus type 1 (HIV-1) entry. Here, we determined by measuring fluorescence recovery after photobleaching that the lateral diffusion of CD4 decreased 4-fold following sphingomyelinase treatment, while the effective diffusion rate of CCR5 remained unchanged. Notably, sphingomyelinase treatment of cells did not influence gp120 binding, HIV-1 attachment, or fluid-phase and receptor-mediated endocytosis. Furthermore, sphingomyelinase treatment did not affect the membrane disposition of the HIV receptor proteins CD4, CXCR4, and CCR5, as determined by Triton X-100 extraction. Restriction of CD4 diffusion by antibody cross-linking also inhibited HIV infection. We therefore interpret the decrease in CD4 lateral mobility following sphingomyelinase treatment in terms of clustering of CD4 molecules. Examination of fusion intermediates indicated that sphingomyelinase treatment inhibited HIV at a step in the fusion process after CD4 engagement. Maximal inhibition of fusion was observed following short coculture times and with target cells that express low levels of CD4. As HIV entry into cells requires the sequential engagement of viral envelope protein with CD4 and coreceptor, we propose that sphingomyelinase inhibits HIV infection by inducing CD4 clustering that prevents coreceptor engagement and HIV fusion

Tokyo Smart City Design at Shinagawa

The Tokyo smart city project is an international collaboration from 2016 to 2020 between the Eco Urban Lab of School of City and Regional Planning and School of Architecture at Georgia Tech, Global Carbon Project (GCP), the National Institute for Environmental Studies of Japan, and the Department of Urban Engineering of the University of Tokyo.The Tokyo smart city project is an international collaboration from 2016 to 2020 between the Eco Urban Lab of School of City and Regional Planning and School of Architecture at Georgia Tech, Global Carbon Project (GCP), the National Institute for Environmental Studies of Japan, and the Department of Urban Engineering of the University of Tokyo. Tokyo provides a living urban laboratory for designing complex urban settings, agglomerations of physical, cultural and technological systems. The Tokyo Smart City Studio in Spring 2020 investigates Shinagawa and its surroundings at the Tokyo Bay waterfront area in the context of new maglev high speed rail station area development, one of the biggest urban development projects in the City of Tokyo of the next decade. The operation of the new high-speed maglev rail station from 2030 will make Shinagawa a 70-70 new gateway, 70 minutes from Tokyo to Osaka for a region with 70 million population. The new infrastructure will compress the concept of space and time, and will change the inter-cities relation. Its future city vision will have profound impact to the urban forms, functions and experiences of the city. The project aims to develop a test bed of urban systems design to demonstrate how a smart community is designed, evaluated, and implemented in Japan by incorporating governmental agencies, stakeholders and communities, with focuses on urban design and modeling, urban analytics of big data, Internet of Things (IoT), smart mobility and eco urban performance evaluation

The Envelope Cytoplasmic Tail of HIV-1 Subtype C Contributes to Poor Replication Capacity through Low Viral Infectivity and Cell-to-Cell Transmission.

The cytoplasmic tail (gp41CT) of the HIV-1 envelope (Env) mediates Env incorporation into virions and regulates Env intracellular trafficking. Little is known about the functional impact of variability in this domain. To address this issue, we compared the replication of recombinant virus pairs carrying the full Env (Env viruses) or the Env ectodomain fused to the gp41CT of NL4.3 (EnvEC viruses) (12 subtype C and 10 subtype B pairs) in primary CD4+ T-cells and monocyte-derived-macrophages (MDMs). In CD4+ T-cells, replication was as follows: B-EnvEC = B-Env>C-EnvEC>C-Env, indicating that the gp41CT of subtype C contributes to the low replicative capacity of this subtype. In MDMs, in contrast, replication capacity was comparable for all viruses regardless of subtype and of gp41CT. In CD4+ T-cells, viral entry, viral release and viral gene expression were similar. However, infectivity of free virions and cell-to-cell transmission of C-Env viruses released by CD4+ T-cells was lower, suggestive of lower Env incorporation into virions. Subtype C matrix only minimally rescued viral replication and failed to restore infectivity of free viruses and cell-to-cell transmission. Taken together, these results show that polymorphisms in the gp41CT contribute to viral replication capacity and suggest that the number of Env spikes per virion may vary across subtypes. These findings should be taken into consideration in the design of vaccines

Genetic structure and natal origins of immature hawksbill turtles (Eretmochelys imbricata) in Brazilian waters

Understanding the connections between sea turtle populations is fundamental for their effective conservation. Brazil hosts important hawksbill feeding areas, but few studies have focused on how they connect with nesting populations in the Atlantic. Here, we (1) characterized mitochondrial DNA control region haplotypes of immature hawksbills feeding along the coast of Brazil (five areas ranging from equatorial to temperate latitudes, 157 skin samples), (2) analyzed genetic structure among Atlantic hawksbill feeding populations, and (3) inferred natal origins of hawksbills in Brazilian waters using genetic, oceanographic, and population size information. We report ten haplotypes for the sampled Brazilian sites, most of which were previously observed at other Atlantic feeding grounds and rookeries. Genetic profiles of Brazilian feeding areas were significantly different from those in other regions (Caribbean and Africa), and a significant structure was observed between Brazilian feeding grounds grouped into areas influenced by the South Equatorial/North Brazil Current and those influenced by the Brazil Current. Our genetic analysis estimates that the studied Brazilian feeding aggregations are mostly composed of animals originating from the domestic rookeries Bahia and Pipa, but some contributions from African and Caribbean rookeries were also observed. Oceanographic data corroborated the local origins, but showed higher connection with West Africa and none with the Caribbean. High correlation was observed between origins estimated through genetics/rookery size and oceanographic/rookery size data, demonstrating that ocean currents and population sizes influence haplotype distribution of Brazil’s hawksbill populations. The information presented here highlights the importance of national conservation strategies and international cooperation for the recovery of endangered hawksbill turtle populations