To figure out what makes some people more vulnerable to severe cases of covid-19, we need to rethink what we know about infection

In July 2019, a sophisticated backdoor trojan in Google Play was reported. We conducted an inquiry of our own, discovering a long-term campaign, which we dubbed “PhantomLance”, its earliest registered domain dating back to December 2015.

ABSTRACT

Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery.

IMPORTANCE PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such "antiviral" compartments. To understand this enigma, we investigate the cross talk between PML-NB components and viral RCs to find the missing link connecting both compartments to promote efficient viral replication and gene expression. Taken together, the current concept is more intricate than originally believed, since viruses apparently take advantage of several specific PML-NB-associated proteins to promote productive infection. Simultaneously, they efficiently inhibit antiviral measures to maintain the viral infectious program. Our data provide evidence that SUMOylation of the viral RC marker protein E2A represents the basis of this virus-host interface and regulates various downstream events to support HAdV productive infection. These results are the basis of our current attempts to generate and screen for specific E2A SUMOylation inhibitors to constitute novel therapeutic approaches to limit and prevent HAdV-mediated diseases and mortality of immunosuppressed patients.

Objective

To use the variations in neurology consultations requested by emergency department (ED) physicians to identify opportunities to implement multidisciplinary interventions in an effort to reduce ED overcrowding.

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and...

Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part, by the presence of specialized PML nuclear bodies called ALT-associated PML bodies (APBs). APBs localize to and cluster telomeric ends together with telomeric and DNA damage factors, which led to the proposal that these bodies act as a platform on which ALT can occur. However, the necessity of APBs and their function in the ALT pathway has remained unclear. Here, we used CRISPR/Cas9 to delete PML and APB components from ALT-positive cells to cleanly define the function of APBs in ALT. We found that PML is required for the ALT mechanism, and that this necessity stems from APBs’ role in localizing the BLM–TOP3A–RMI (BTR) complex to ALT telomere ends. Strikingly, recruitment of the BTR complex to telomeres in a PML-independent manner bypasses the need for PML in the ALT pathway, suggesting that BTR localization to telomeres is sufficient to sustain ALT activity.

Background:

The recent expansion of treatment options in acute myeloid leukemia (AML) has necessitated a greater understanding of patient preferences for treatment benefits, about which little is known.

Trong khi nhiều dự án BĐS bị ảnh hưởng bởi đại dịch covid-19 thì dự án hỗn hợp văn phòng dịch vụ và nhà ở Dreamland Bonanza (23 phố Duy Tân, Cầu Giấy, Hà Nội) do Công ty Cổ phần Đầu tư bất động sản Vinaland làm chủ đầu tư, đã đảm bảo các điều kiện thi công an toàn, về đích đúng tiến độ và bàn giao cho khách hàng vào ngày 11/5/2020.

Just in time for Mother's Day/continued at-home quarantine comes this 750mL 'My Personal Bottomless Mimosa' glass from BigMouth, Inc and available on Amazons. The surprisingly all-glass drinkware (but still hand-wash only on account of the decorations) combines the shape of a champagne bottle with a mimosa glass to holds 8 (read: 2-3) servings, and is perfect for letting the rest of your family know you're not to be bothered for the rest of the day because it may still be early here but, dammit, it's 5 o'clock somewhere that's nine and half hours ahead. Thanks to Tracey H, who informed me she can't count the number of times she's been asked to leave a bottomless brunch for really putting its bottomlessness to the test. Heck yeah, that's called doing God's work.

To figure out what makes some people more vulnerable to severe cases of covid-19, we need to rethink what we know about infection

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npj Microgravity, Published online: 16 March 2020; doi:10.1038/s41526-020-0099-7

Edge Code is an Adobe branded release of the Brackets project: a lightweight code editor with next-wave features.

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