Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin.

The SARS-CoV-2 Delta variant has spread rapidly worldwide. To provide data on its virological profile, we here report the first local transmission of Delta in mainland China. All 167 infections could be traced back to the first index case. Daily sequential PCR testing of quarantined individuals indicated that the viral loads of Delta infections, when they first become PCR-positive, were on average ~1000 times greater compared to lineage A/B infections during the first epidemic wave in China in early 2020, suggesting potentially faster viral replication and greater infectiousness of Delta during early infection. The estimated transmission bottleneck size of the Delta variant was generally narrow, with 1-3 virions in 29 donor-recipient transmission pairs. However, the transmission of minor iSNVs resulted in at least 3 of the 34 substitutions that were identified in the outbreak, highlighting the contribution of intra-host variants to population-level viral diversity during rapid spread.

The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in fecal material has raised the possibility of viral transmission via a fecal–oral route. This study investigated whether SARS-CoV-2 transmission via fecal aerosols in the drainage pipe system may have been the cause of COVID-19 infection in a cluster of 3 families living in a high-rise building in China.

SummaryWe report the first local transmission of the Delta SARS-CoV-2 variant in mainland China. All 167 infections could be traced back to the first index case. The investigation on daily sequential PCR testing of the quarantined subjects indicated the viral load of the first positive test of Delta infections was ∼1000 times higher than that of the 19A/19B strains infections back in the initial epidemic wave of 2020, suggesting the potential faster viral replication rate and more infectiousness of the Delta variant at the early stage of the infection. The 126 high-quality sequencing data and reliable epidemiological data indicated some minor intra-host single nucleotide variants (iSNVs) could be transmitted between hosts and finally fixed in the virus population during the outbreak. The minor iSNVs transmission between donor-recipient contribute at least 4 of 31 substitutions identified in the outbreak suggesting some iSNVs could quickly arise and reach fixation when the virus spread rapidly. Disease control measures, including the frequency of population testing, quarantine in pre-symptomatic phase and enhancing the genetic surveillance should be adjusted to account for the increasing prevalence of the Delta variant at global level.

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Members of the FOXO (forkhead O) class of transcription factors are tumor suppressors that also control aging and organismal life span. Mammalian FOXO degradation is proteasomemediated, although the ubiquitin E3 ligase for FOXO factors remains to be defined. We show that MDM2 binds to FOXO1 and FOXO3A and promotes their ubiquitination and degradation, a process apparently dependent on FOXO phosphorylation at AKT sites and the E3 ligase activity of MDM2. Binding of MDM2 to FOXO occurs through the region of MDM2 that directs its cellular trafficking and the forkhead box of FOXO1. MDM2 promotes the ubiquitination of FOXO1 in a cell-free system, and its knockdown by small interfering RNA causes accumulation of endogenous FOXO3A protein in cells and enhances the expression of FOXO target genes. In cells stably expressing a temperature-sensitive p53 mutant, activation of p53 by shifting to permissive temperatures leads to MDM2 induction and degradation of endogenous FOXO3A. These data suggest that MDM2 acts as an ubiquitin E3 ligase, downstream of p53, to regulate the degradation of mammalian FOXO factors.FOXO (forkhead O) proteins belong to the family of forkhead transcriptional factors, which are characterized by a conserved DNA binding domain termed the "Forkhead box" (1). Mammalian FOXO factors include FOXO1 (previously known as FKHR), FOXO3A (previously known as FKHRL1), FOXO4 (previously known as AFX), and FOXO6. These factors control the expression of a variety of genes that regulate essential cellular processes, such as cell cycle (2-4), apoptosis (5), oxidative stress (6, 7), atrophy (8), energy homeostasis, and glucose metabolism (9, 10). Whole organism studies in worms and flies show that FOXO factors have conserved ability to increase the organismal longevity (11). Genetic and functional analysis identifies FOXO1 as a tumor suppressor in the prostate (12). Knock-out studies show that mammalian FOXO factors act redundantly to suppress tumorigenesis in a lineage-specific fashion (13) and to maintain the long term regenerative potential of hematopoietic stem cells by regulating genes involved in the cellular response to physiological oxidative stresses (14).The transcription of FOXO factors is regulated by posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. Multiple kinases, including AKT (15, 16), serum-and glucocorticoid-induced kinase (17), casein kinase 1 (18), mammalian Ste20-like kinase 1 (19), I B kinase (20), and cyclin-dependent kinase 2 (21), catalyze FOXO phosphorylation and often promote FOXO nuclear exportation. In response to insulin and growth factors, FOXO1 and FOXO3A are ubiquitinated and degraded by the proteasome pathway after phosphorylation at known AKT sites (15,22,23). Acetyltransferases, p300 (24) and CBP (25), and SIRT1 deacetylase (26, 27) regulate the activity of FOXO through acetylation/deacetylation. The role of FOXO acetylation is controversial, but it could affect their nuclear retention (28), phosphorylation (25), and ubiquitination-medi...

Breast cancer is one of the leading causes of cancer death among women worldwide. In clinical routine, automatic breast ultrasound (BUS) image segmentation is very challenging and essential for cancer diagnosis and treatment planning. Many BUS segmentation approaches have been studied in the last two decades, and have been proved to be effective on private datasets. Currently, the advancement of BUS image segmentation seems to meet its bottleneck. The improvement of the performance is increasingly challenging, and only few new approaches were published in the last several years. It is the time to look at the field by reviewing previous approaches comprehensively and to investigate the future directions. In this paper, we study the basic ideas, theories, pros and cons of the approaches, group them into categories, and extensively review each category in depth by discussing the principles, application issues, and advantages/disadvantages. Keyword: breast ultrasound (BUS) images; breast cancer; segmentation; benchmark; early detection; computer-aided diagnosis (CAD) IntroductionBreast cancer occurs in the highest frequency in women among all cancers, and is also one of the leading causes of cancer death worldwide [1,2]. Scientists do not definitely know what causes breast cancer yet, and only know some risk factors that can increase the likelihood of developing breast cancer: getting older, genetics, radiation exposure, dense breast tissue, alcohol consumption, etc. The key of reducing the mortality is to find signs and symptoms of breast cancer at its early stage by clinic examination [3]. Breast ultrasound (BUS) imaging has become one of the most important and effective modality for the early detection of breast cancer because of its noninvasive, nonradioactive and cost-effective nature [4]; and it is most suitable for large-scale breast cancer screening and diagnosis in low-resource countries and regions. processing approaches. The category of the others [136,138,139,140,[142][143][144][145][146] is composed of three small sub-categories, each contains only few literatures. Due to the challenging nature of the task, just using single image processing technique cannot achieve desirable results; and most successful approaches employ hybrid techniques and model biological priors.The rest of the paper is organized as follows: in section 2, the fundamental issues in BUS segmentation are discussed, e.g., denoising, interaction, biological priors modeling, validation, and the possible problemsolving strategies; in sections 3 -6, we review automatic BUS image segmentation methods by presenting the principle of each category, discussing their advantages and disadvantages, and summarizing the most valuable strategies. In section 7, we discuss the approaches of three sub-categories briefly. Section 8 gives the conclusion and the future directions. Fundamental Issues of BUS Image SegmentationBUS segmentation approaches have been studied in the last two decades extensively, and many of them achieved good performances utilizin...

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