ABSTRACT

Reversible repression of HIV-1 5' long terminal repeat (5'-LTR)-mediated transcription represents the main mechanism for HIV-1 to maintain latency. Identification of host factors that modulate LTR activity and viral latency may help develop new antiretroviral therapies. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are known to regulate gene expression and possess multiple physiological functions. hnRNP family members have recently been identified as the sensors for viral nucleic acids to induce antiviral responses, highlighting the crucial roles of hnRNPs in regulating viral infection. A member of the hnRNP family, X-linked RNA-binding motif protein (RBMX), has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells. Mechanistically, RBMX binds to HIV-1 proviral DNA at the LTR downstream region and maintains the repressive trimethylation of histone H3 lysine 9 (H3K9me3), leading to a blockage of the recruitment of the positive transcription factor phosphorylated RNA polymerase II (RNA pol II) and consequential impediment of transcription elongation. This RBMX-mediated modulation of HIV-1 transcription maintains viral latency by inhibiting viral reactivation from an integrated proviral DNA. Our findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

IMPORTANCE HIV-1 latency featuring silence of transcription from HIV-1 proviral DNA represents a major obstacle for HIV-1 eradication. Reversible repression of HIV-1 5'-LTR-mediated transcription represents the main mechanism for HIV-1 to maintain latency. The 5'-LTR-driven HIV gene transcription can be modulated by multiple host factors and mechanisms. The hnRNPs are known to regulate gene expression. A member of the hnRNP family, RBMX, has been identified in this study as a novel HIV-1 restriction factor that modulates HIV-1 5'-LTR-driven transcription of viral genome in CD4⁺ T cells and maintains viral latency. These findings provide a new understanding of how host factors modulate HIV-1 infection and latency and suggest a potential new target for the development of HIV-1 therapies.

ABSTRACT

All enterococci produce a complex polysaccharide called the enterococcal polysaccharide antigen (EPA). This polymer is required for normal cell growth and division and for resistance to cephalosporins and plays a critical role in host-pathogen interaction. The EPA contributes to host colonization and is essential for virulence, conferring resistance to phagocytosis during the infection. Recent studies revealed that the "decorations" of the EPA polymer, encoded by genetic loci that are variable between isolates, underpin the biological activity of this surface polysaccharide. In this work, we investigated the structure of the EPA polymer produced by the high-risk enterococcal clonal complex Enterococcus faecalis V583. We analyzed purified EPA from the wild-type strain and a mutant lacking decorations and elucidated the structure of the EPA backbone and decorations. We showed that the rhamnan backbone of EPA is composed of a hexasaccharide repeat unit of C2- and C3-linked rhamnan chains, partially substituted in the C3 position by α-glucose (α-Glc) and in the C2 position by β-N-acetylglucosamine (β-GlcNAc). The so-called "EPA decorations" consist of phosphopolysaccharide chains corresponding to teichoic acids covalently bound to the rhamnan backbone. The elucidation of the complete EPA structure allowed us to propose a biosynthetic pathway, a first essential step toward the design of antimicrobials targeting the synthesis of this virulence factor.

IMPORTANCE Enterococci are opportunistic pathogens responsible for hospital- and community-acquired infections. All enterococci produce a surface polysaccharide called EPA (enterococcal polysaccharide antigen) required for biofilm formation, antibiotic resistance, and pathogenesis. Despite the critical role of EPA in cell growth and division and as a major virulence factor, no information is available on its structure. Here, we report the complete structure of the EPA polymer produced by the model strain E. faecalis V583. We describe the structure of the EPA backbone, made of a rhamnan hexasaccharide substituted by Glc and GlcNAc residues, and show that teichoic acids are covalently bound to this rhamnan chain, forming the so-called "EPA decorations" essential for host colonization and pathogenesis. This report represents a key step in efforts to identify the structural properties of EPA that are essential for its biological activity and to identify novel targets to develop preventive and therapeutic approaches against enterococci.

Transportation infrastructure owners manage an array of different asset types such as bridges, road pavements, earthworks and drainage. Currently, most organization management procedures are siloed by asset type; however, there are important interactions between these asset groups that need to be managed in a cross-asset way. Although these interactions are known, there is little or no quantification of these interactions. For the first time, this paper quantifies that 74% of Highways England's earthwork failures are a result of drainage-related problems, either the lack of drainage infrastructure or the poor performance of it. The analysis undertaken is an important first step not only in moving towards more connected asset management planning for earthworks and drainage, but to also provide guidance for other owners of earthwork infrastructure assets to improve their strategic asset management procedures.

Thematic collection: This article is part of the Ground-related risk to transportation infrastructure collection available at https://www.lyellcollection.org/cc/Ground-related-risk-to-transportation-infrastructure

Although enteroviruses are associated with a wide variety of diseases and conditions, their mode of replication is well conserved. Their genome is carried as a single, positive-sense RNA strand. At the 5' end of the strand is an approximately 90-nucleotide self-complementary region called the 5' cloverleaf, or the oriL. This noncoding region serves as a platform upon which host and virus proteins, including the 3B, 3C, and 3D virus proteins, assemble in order to initiate replication of a negative-sense RNA strand. The negative strand in turn serves as a template for synthesis of multiple positive-sense RNA strands. Building on structural studies of individual RNA stem-loops, the structure of the intact 5' cloverleaf from rhinovirus has recently been determined via nuclear magnetic resonance/small-angle X-ray scattering (NMR/SAXS)-based methods, while structures have also been determined for enterovirus 3A, 3B, 3C, and 3D proteins. Analysis of these structures, together with structural and modeling studies of interactions between host and virus proteins and RNA, has begun to provide insight into the enterovirus replication mechanism and the potential to inhibit replication by blocking these interactions.

The response to iron limitation of the Gram-positive soil bacterium Corynebacterium glutamicum was analyzed with respect to secreted metabolites, the transcriptome, and the proteome. During growth in glucose minimal medium, iron limitation caused a shift from lactate to pyruvate as the major secreted organic acid complemented by l-alanine and 2-oxoglutarate. Transcriptome and proteome analyses revealed that a pronounced iron starvation response governed by the transcriptional regulators DtxR and RipA was detectable in the late, but not in the early, exponential-growth phase. A link between iron starvation and thiamine pyrophosphate (TPP) biosynthesis was uncovered by the strong upregulation of thiC. As phosphomethylpyrimidine synthase (ThiC) contains an iron-sulfur cluster, limiting activities of the TPP-dependent pyruvate–2-oxoglutarate dehydrogenase supercomplex probably cause the excretion of pyruvate and 2-oxoglutarate. In line with this explanation, thiamine supplementation could strongly diminish the secretion of these acids. The upregulation of thiC and other genes involved in thiamine biosynthesis and transport is presumably due to TPP riboswitches present at the 5' end of the corresponding operons. The results obtained in this study provide new insights into iron homeostasis in C. glutamicum and demonstrate that the metabolic consequences of iron limitation can be due to the iron dependency of coenzyme biosynthesis.

IMPORTANCE Iron is an essential element for most organisms but causes problems due to poor solubility under oxic conditions and due to toxicity by catalyzing the formation of reactive oxygen species (ROS). Therefore, bacteria have evolved complex regulatory networks for iron homeostasis aiming at a sufficient iron supply while minimizing ROS formation. In our study, the responses of the actinobacterium Corynebacterium glutamicum to iron limitation were analyzed, resulting in a detailed view on the processes involved in iron homeostasis in this model organism. In particular, we provide evidence that iron limitation causes TPP deficiency, presumably due to insufficient activity of the iron-dependent phosphomethylpyrimidine synthase (ThiC). TPP deficiency was deduced from the upregulation of genes controlled by a TPP riboswitch and secretion of metabolites caused by insufficient activity of the TPP-dependent enzymes pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase. To our knowledge, the link between iron starvation and thiamine synthesis has not been elaborated previously.

Monoubiquitinated FANCI and FANCD2 constitute the ID complex, which forms a sliding clamp on DNA.

Gastric cancer (GC) is the fifth-ranked cancer type by associated mortality. The proportion of early diagnosis is low, and most patients are diagnosed at the advanced stages. First-line therapy standardly includes fluoropyrimidines and platinum compounds with trastuzumab for HER2-positive cases. For recurrent disease, there are several alternative options including ramucirumab, a monoclonal therapeutic antibody that inhibits VEGF-mediated tumor angiogenesis by binding with VEGFR2, alone or in combination with other cancer drugs. However, overall response rate following ramucirumab or its combinations is 30%–80% of the patients, suggesting that personalization of drug prescription is needed to increase efficacy of treatment. We report here original tumor RNA sequencing profiles for 15 advanced GC patients linked with data on clinical response to ramucirumab or its combinations. Three genes showed differential expression in the tumors for responders versus nonresponders: CHRM3, LRFN1, and TEX15. Of them, CHRM3 was up-regulated in the responders. Using the bioinformatic platform Oncobox we simulated ramucirumab efficiency and compared output model results with actual tumor response data. An agreement was observed between predicted and real clinical outcomes (AUC ≥ 0.7). These results suggest that RNA sequencing may be used to personalize the prescription of ramucirumab for GC and indicate potential molecular mechanisms underlying ramucirumab resistance. The RNA sequencing profiles obtained here are fully compatible with the previously published Oncobox Atlas of Normal Tissue Expression (ANTE) data.

BACKGROUND AND PURPOSE:

Detailed insight into the composition of thrombi retrieved from patients with ischemic stroke by mechanical thrombectomy might improve pathophysiologic understanding and therapy. Thus, this study searched for links between histologic thrombus composition and stroke subtypes and mechanical thrombectomy results.

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The majority of these children have tested positive for the virus or seem to carry antibodies from an earlier infection.

A 7-year-old boy from Westchester County is the second child in New York state to die from pediatric multi-symptom inflammatory syndrome tied to COVID-19 since the pandemic began. A 5-year-old boy died earlier in the week from the same syndrome at Mount Sinai Kravis Children’s Hospital in New York City.

The childhood ailment has affected at least 73 children in New York state and authorities are now looking for other potential cases across the country. Cases have also been reported in Washington, D.C., California, Delaware, Louisiana, Massachusetts, Pennsylvania, Washington state and New Jersey, where a 4-year-old died with symptoms last month.

It has been previously thought that children are less likely to suffer any serious complications from the coronavirus.

Read more at The Daily Beast.

Huge constellations of satellites like SpaceX’s Starlink could make ground-based astronomy impossible, and we’re running out of time to deal with the problem

A group of astronomers has called for legal action to stop the launch of thousands of satellites designed by companies like SpaceX and OneWeb to beam high-speed internet around the world

The International Astronomical Union has concluded a review of satellite mega constellations such as SpaceX's Starlink satellites and found they will have a major impact on large telescopes, but not naked eye astronomy

PUBG Mobile update 0.18.0 released this week but a bug appears to be causing a lot of grief for players unable to play since downloading the latest patch

While Chris destroys Anna Marie's right joycon (press R to pay respects), the rest of the cast discusses their now playing, the news of the week, and there are still far too many games releasing every week. Please save us.

Scientists set out to investigate a potential role of the gut microbiota in the development of cardio-metabolic diseases. They ended up identifying the common cholesterol-lowering drug statins as a potential microbiota-modulating therapeutic.

Obese Europeans who are treated with cholesterol lowering drugs have not only lower values of blood LDL cholesterol and markers of inflammation but in addition a more healthy gut bacteria profile than those obese who are not prescribed statins.

New research finds that sleep problems in a baby's first 12 months may not only precede an autism diagnosis, but also may be associated with altered growth trajectory in a key part of the brain, the hippocampus.

An analysis of the daily steps taken by about 5000 people in the US has found that a higher step count is linked to a lower yearly risk of death, although the effect tails off above 12,000 steps

Following China’s switch to a two-child policy, there has been a slight rise in congenital anomalies, perhaps because parents are older on average at conception

As Quebec prepares to reopen schools, doctors are poring over 15-20 cases of children with what seems to be the same illnesses reported in U.S. and Europe

According to many observations, certain virus infections may play a part in the autoimmune attack that leads to type 1 diabetes. Researchers have now produced a vaccine for these viruses in the hope that it could provide protection against the disease.

A new study has found an association between low average levels of vitamin D and high numbers of COVID-19 cases and mortality rates across 20 European countries.

People with body integrity dysphoria (BID) often feel as though one of their healthy limbs isn't meant to be a part of their bodies. They may act as though the limb is missing or even seek its amputation 'to feel complete.' Now, researchers have found that these feelings that a limb doesn't belong are mirrored in the brains of people with this condition.

Educational status appears to have positive influence on a healthy diet, particularly in low income countries, according to new research examining European nutritional data.

The brain has a powerful ability to remember and connect events separated in time. And now, in a new study in mice, scientists have shed light on how the brain can form such enduring links.

Hackers linked to Iran have targeted staff at U.S. drugmaker Gilead Sciences Inc in recent weeks, according to publicly-available web archives reviewed by Reuters and three cybersecurity researchers, as the company races to deploy a treatment for the COVID-19 virus.

Read our live coronavirus updates HERE Coronavirus: The symptoms

Read our live coronavirus updates HERE

Detectives investigating a gang responsible for trafficking young women from Brazil to work in brothels in north London have made two arrests.

Scheme by tech entrepreneur Elon Musk's SpaceX firm casts unique chain of lights in Britain's night skies

Boris Johnson is having an audience with the Queen by video link – his first conversation with the Monarch since he fell ill with coronavirus three weeks ago.

A UK police force has upped patrols around 5G masts in a bid to stop further attacks linked to coronavirus conspiracy theories.

A 44-year-old man has been charged with attempted murder after being allegedly linked to three stabbings in north London.

Some children have died of a new illness that could be linked to coronavirus, the Health Secretary has said.

Global health experts are investigating reports of a rare but serious illness affecting children and its links to coronavirus after UK medics raised the alarm.

There is now an outbreak of COVID-19 linked to Canada Post's main plant in Calgary, according to Alberta Health Services.

Hackers linked to Iran have targeted staff at U.S. drugmaker Gilead Sciences Inc in recent weeks, according to publicly-available web archives reviewed by Reuters and three cybersecurity researchers, as the company races to deploy a treatment for the COVID-19 virus. In one case, a fake email login page designed to steal passwords was sent in April to a top Gilead executive involved in legal and corporate affairs, according to an archived version on a website used to scan for malicious web addresses. Ohad Zaidenberg, lead intelligence researcher at Israeli cybersecurity firm ClearSky, who closely tracks Iranian hacking activity and has investigated the attacks, said the attempt was part of an effort by an Iranian group to compromise email accounts of staff at the company using messages that impersonated journalists.

Pandemic disrupts broadband progress as cities halt construction.

'By expanding our thinking of how oceans behaved in the past, we could gain some insights into oceans today,' says scientist at Stanford University

Police have no suspects in connection with the fires.

In addition to the QAnon accounts, Facebook also removed accounts linked to VDARE, a U.S. website known for posting anti-immigration content.

1. Evidence Builds Linking Anticoagulation to COVID-19 Survival  Medscape
2. Blood thinners may boost survival rates of Covid-infected patients: Study  ETHealthworld.com
3. Coronavirus blood-clot mystery intensifies  Nature.com
4. Coronavirus: Blood thinners could boost survival chances of patients  The Independent
5. Blood thinners may help COVID-19 patients  ABC27
6. View Full coverage on Google News