ABSTRACT

In numerous instances, tracking the biological significance of a nucleic acid sequence can be augmented through the identification of environmental niches in which the sequence of interest is present. Many metagenomic data sets are now available, with deep sequencing of samples from diverse biological niches. While any individual metagenomic data set can be readily queried using web-based tools, meta-searches through all such data sets are less accessible. In this brief communication, we demonstrate such a meta-metagenomic approach, examining close matches to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in all high-throughput sequencing data sets in the NCBI Sequence Read Archive accessible with the "virome" keyword. In addition to the homology to bat coronaviruses observed in descriptions of the SARS-CoV-2 sequence (F. Wu, S. Zhao, B. Yu, Y. M. Chen, et al., Nature 579:265–269, 2020, https://doi.org/10.1038/s41586-020-2008-3; P. Zhou, X. L. Yang, X. G. Wang, B. Hu, et al., Nature 579:270–273, 2020, https://doi.org/10.1038/s41586-020-2012-7), we note a strong homology to numerous sequence reads in metavirome data sets generated from the lungs of deceased pangolins reported by Liu et al. (P. Liu, W. Chen, and J. P. Chen, Viruses 11:979, 2019, https://doi.org/10.3390/v11110979). While analysis of these reads indicates the presence of a similar viral sequence in pangolin lung, the similarity is not sufficient to either confirm or rule out a role for pangolins as an intermediate host in the recent emergence of SARS-CoV-2. In addition to the implications for SARS-CoV-2 emergence, this study illustrates the utility and limitations of meta-metagenomic search tools in effective and rapid characterization of potentially significant nucleic acid sequences.

IMPORTANCE Meta-metagenomic searches allow for high-speed, low-cost identification of potentially significant biological niches for sequences of interest.

The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins, it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line "clonal origin" an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years, and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal derivation. However, older production cell lines developed before the implementation of these methods, herein referred to as "legacy cell lines," may not meet current regulatory expectations for demonstration of clonal derivation. In this article, the members of the IQ Consortium Working Group on Clonality present our position that the demonstration of process consistency and product comparability of critical quality attributes throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal derivation standards. With this commentary, we discuss advantages and limitations of genetic testing methods to support clonal derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to Investigational New Drug (IND) application and before demonstration of product and process consistency at Biologics License Applications (BLA) submission.

OBJECTIVE

To investigate factors related to glycemic management among members of a professional cycling team with type 1 diabetes over a 7-day Union Cycliste Internationale World Tour stage race.

OBJECTIVE

There is a controversy over the association between obesity and end-stage renal disease (ESRD) in people with or without type 2 diabetes; therefore, we examined the effect of BMI on the risk of ESRD according to glycemic status in the Korean population.

We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β^–/–, IL1α^–/–, and IL1R1^–/– mice. Tumors grew progressively in IL1R^–/– and IL1α^–/– mice but were often absent in IL1β^–/– mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Antibodies to IL1β prevented tumor growth in wild-type (WT) mice but not in IL1R1^–/– or IL1α^–/– mice. Antibodies to IL1α promoted tumor growth in IL1β^–/– mice and reversed the tumor-suppressive effect of anti-IL1β in WT mice. Depletion of CD8⁺ T cells and blockade of lymphocyte mobilization abrogated the IL1β^–/– tumor suppressive effect, as did crossing IL1β^–/– mice to SCID or Rag1^–/– mice. Finally, blockade of IL1β synergized with blockade of PD-1 to inhibit tumor growth in WT mice. These results suggest that IL1β promotes tumor growth, whereas IL1α inhibits tumor growth by enhancing T-cell–mediated antitumor immunity.

Dietary protein residue can result in microbial generation of various toxic metabolites in the gut, such as ammonia. A prebiotic is "a substrate that is selectively utilised by host microorganisms conferring a health benefit" (G. R. Gibson, R. Hutkins, M. E. Sanders, S. L. Prescott, et al., Nat Rev Gastroenterol Hepatol 14:491–502, 2017, https://doi.org/10.1038/nrgastro.2017.75). Prebiotics are carbohydrates that may have the potential to reverse the harmful effects of gut bacterial protein fermentation. Three-stage continuous colonic model systems were inoculated with fecal samples from omnivore and vegetarian volunteers. Casein (equivalent to 105 g protein consumption per day) was used within the systems as a protein source. Two different doses of inulin-type fructans (Synergy1) were later added (equivalent to 10 g per day in vivo and 15 g per day) to assess whether this influenced protein fermentation. Bacteria were enumerated by fluorescence in situ hybridization with flow cytometry. Metabolites from bacterial fermentation (short-chain fatty acid [SCFA], ammonia, phenol, indole, and p-cresol) were monitored to further analyze proteolysis and the prebiotic effect. A significantly higher number of bifidobacteria was observed with the addition of inulin together with reduction of Desulfovibrio spp. Furthermore, metabolites from protein fermentation, such as branched-chain fatty acids (BCFA) and ammonia, were significantly lowered with Synergy1. Production of p-cresol varied among donors, as we recognized four high producing models and two low producing models. Prebiotic addition reduced its production only in vegetarian high p-cresol producers.

IMPORTANCE Dietary protein levels are generally higher in Western populations than in the world average. We challenged three-stage continuous colonic model systems containing high protein levels and confirmed the production of potentially harmful metabolites from proteolysis, especially replicates of the transverse and distal colon. Fermentations of proteins with a prebiotic supplementation resulted in a change in the human gut microbiota and inhibited the production of some proteolytic metabolites. Moreover, we observed both bacterial and metabolic differences between fecal bacteria from omnivore donors and vegetarian donors. Proteins with prebiotic supplementation showed higher Bacteroides spp. and inhibited Clostridium cluster IX in omnivore models, while in vegetarian modes, Clostridium cluster IX was higher and Bacteroides spp. lower with high protein plus prebiotic supplementation. Synergy1 addition inhibited p-cresol production in vegetarian high p-cresol-producing models while the inhibitory effect was not seen in omnivore models.

Purpose:

Preclinical data demonstrating androgen receptor (AR)–positive (AR⁺) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR⁺ (≥10%) breast cancer.

Scabies is a frequent cutaneous infection caused by the mite Sarcoptes scabiei in a large number of mammals, including humans. As the resistance of S. scabiei against several chemical acaricides has been previously documented, the establishment of alternative and effective control molecules is required. In this study, the potential acaricidal activity of beauvericin was assessed against different life stages of S. scabiei var. suis and in comparison with dimpylate and ivermectin, two commercially available molecules used for the treatment of S. scabiei infection in animals and/or humans. The toxicity of beauvericin against cultured human fibroblast skin cells was evaluated using an MTT proliferation assay. In our in vitro model, developmental stages of S. scabiei were placed in petri dishes filled with Columbia agar supplemented with pig serum and different concentrations of the drugs. Cell sensitivity assays demonstrated low toxicity of beauvericin against primary human fibroblast skin cells. At 0.5 and 5 mM, beauvericin showed higher activity against adults and eggs of S. scabiei compared to dimpylate and ivermectin. These results revealed that the use of beauvericin is promising and might be considered for the treatment of S. scabiei infection.

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC₅₀] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC₅₀ of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

Background:

The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I–III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I–III colorectal cancer.

A gameplay trailer for a Prince of Persia reboot, called Prince of Persia: Redemption, was posted on YouTube in March 2012 and was discovered this week. 

The LinkedIn profile for the former Ubisoft employee Christophe Prelot revealed he worked on a cancelled Prince of Persia title from April 2010 to 2011 as a 3D level artist. The game was in development for the PlayStation 3, Xbox 360 and Windows PC. 

Ubisoft assistant technical director Marc-Andre Belleau in 2018 left a comment on the video asking, "Where did you get that?!"

View the video below:

Thanks ResetEra.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443408/footage-of-cancelled-prince-of-persia-redemption-from-2012-discovered/

We’re used to tweaking our digital selves to look thinner or more attractive. A new generation of Instagram filters could drastically change how we perceive ourselves

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Ready-to-connect readycables® save you time on cable assembly and are guaranteed to last 36 months

Ubisoft debuted some in-engine footage of the latest Assassin's Creed game during the Inside Xbox stream

While you're going to gaming jail, you'll want to listen to our show so you know what games to bring with you. Fallout 76 has a new update, perhaps it'll be a good choice for you. Phantasy Star Online 2 had a wonderful beta, maybe it's the way to go. Unfortunately, Metal Max Xeno: Reborn was delayed so you'll have to wait a bit for that one.

Desmond Mombeyarara, 34, was with his son when officers shot him with a stun gun

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Desmond Mombeyarara, 34, was shot with a stun gun by police on Wednesday evening after officers stopped him for allegedly speeding.

If there's a ventilator shortage, doctors and ethicists say priority should be given to people with the best chance of recovery and most years likely left to live

Contagion was a film released in 2011 about a fictional pandemic of a virus called MEV-1 which kills between 25 and 30 per cent of those it infected. Here is our review of the film originally published in September 2011, now that it's on Netflix

Host Aziz Ansari touched upon the Women's Marches, racism and immigration in his monologue.

“Hi, I’m Taylor.” With that greeting, Taylor Swift returned to the stage as the headliner of “DirectTV Now Super Saturday Night” at Club Nomadic on the eve of the Super Bowl.

Usman Khawaja said that playing India behind closed doors might end up working in favour of the hosts.

In a further amendment to the plans for Vuelta a Espana 2020, the race will not travel through Portugal.

Thousands of cyclists took over streets in the centre of the Slovenian capital Ljubljana on Friday evening to protest against the government of Prime Minister Janez Jansa and the restrictions it has imposed to fight the coronavirus.

Approved organisations will now be able to receive funds directly...

The post You Can Now Host A Fundraiser From Your Instagram Live appeared first on Man's World India.

Maryland police released body camera footage of an officer shooting and killing a man who rushed towards him with a knife.

Long victimized by poaching and deforestation, the primate species is in the midst of a surprising rebound that is sparking new hopes of recovery

New Zealand's Greg Henderson won the 201.5-km first stage of Paris-Nice between St Arnoult-en-Yvelines and Contres on Monday.

Tour de France champion Alberto Contador lost time on the leaders and suffered a painful knock to his leg when he crashed towards the end of the first stage of Paris-Nice on Monday.

Read our live coronavirus updates HERE Coronavirus: The symptoms

New video footage released by Russian authorities shows the moment a plane's emergency landing resulted in a crash which killed 41 people in Moscow in 2019.

Live coronavirus updates here

Follow our live updates HERE Coronavirus: The symptoms

Follow our live coronavirus updates HERE Coronavirus: The symptoms

Coronavirus: the symptoms Read our LIVE updates on the coronavirus here

NHS doctors and nurses on the frontline are now being asked to treat coronavirus patients without full-length gowns if necessary, ahead of expected shortages.

England's Deputy Chief Medical Officer has defended the Government's response to the coronavirus outbreak and its distribution of vital protective equipment to frontline workers.

The World Health Organisation's chief has warned that most countries are still in the early stages of their coronavirus epidemics and others are starting to see a resurgence in cases.

Kate and William have thanked the public for Prince Louis's birthday wishes by sharing an adorable behind the scenes photograph of the young royal, who turns two today.

Poorer children taking GCSEs and A-levels next year face an "impossible situation" because they have missed so much face-to-face teaching, a leading London headmaster has warned.

Several calls on Zoom, the video conferencing app whose popularity has soared since the coronavirus lockdown meant a huge rise in home working, have been disrupted by abusive footage.

A pregnant doctor and her husband are bringing a legal challenge against the Government which questions the lawfulness of current guidance and a failure to source PPE.

Previously leaked videos of US Navy pilots encountering "unexplained aerial phenomena" have been released by the Pentagon.

Virgin Media customers are still complaining about issues with their broadband despite the provider saying the issue has been fixed.