Akt regulates L-type Ca2+ channel activity by modulating Cavα1 protein stability

The insulin IGF-1–PI3K–Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca2+ channel (LTCC) protein density. The pore-forming channel subunit Cavα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cavα1 protein levels. Our findings show that Akt-dependent phosphorylation of Cavβ2, the LTCC chaperone for Cavα1, antagonizes Cavα1 protein degradation by preventing Cavα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca2+ entry, Ca2+ handling, and contractility

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Targeted gene sanger sequencing should remain the first-tier genetic test for children suspected to have the five common X-linked inborn errors of immunity

DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.The Hong Kong Society for Relief of Disabled Children and Jeffrey Modell Foundation.http://www.frontiersin.org/Immunologyam2023Paediatrics and Child Healt

The Padul mammoth finds - On the southernmost record of Mammuthus primigenius in Europe and its southern spread during the Late Pleistocene

Fossil remains of at least four mature to old mature male individuals of Mammuthus primigenius have been discovered in a peat-bog of Late Pleistocene age, situated near to the town of Padul in the Granada Basin (Southern Spain). Radiocarbon dates indicate the presence of woolly mammoth in Southern Spain between 35.8 and 25.7 ka BP (40.4-30.6 cal ka BP), a time span corresponding with the later part of MIS 3. The Padul mammoths did not differ morphometrically from individuals of contemporaneous populations of other European regions, but represent the westernmost portion of an extended and continuous Holarctic belt of mammoth distribution. The area immediately northwest of the Pyrenees including a slender belt of dry land along the coast of the Bay of Biscay is considered the immigration route of M. primigenius into the Iberian Peninsula. The southernmost extent of Iberian woolly mammoths correlates with periods of particularly dry and cold climatic conditions, where they are documented in terrestrial and marine sediment sequences of the region. The southern expansion of M. primigenius during the Late Pleistocene extended to similar latitudes in Europe. Asia and North America, paralleling the distribution of suitable steppe- or tundra-steppe like environments. The woolly mammoth's southernmost advances were limited by the vegetational character of corresponding landscapes, by the configuration of marine shore lines and high mountain chains and by the extension of semideserts and deserts. Phases of mammoth dispersal into the Iberian and Italian Peninsulas during the later part of MIS 3 and early MIS 2 can be roughly correlated with the southern distribution of the species in the eastern Palaearctic. Along the eastern coast of the Pacific Ocean, the topography and glaciation of the Rocky Mountains range prevented a similar dispersal of woolly mammoths into western North America. The expansion of Late Pleistocene M. primigenius within the inner-continental areas of Eurasia and North America differs chronologically from those at the continental margins