Key Points

Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV.

IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

A ubiquitous structural feature in biological systems is texture in extracellular matrix that gains functions when hardened, for example, cell walls, insect scales, and diatom tests. Here, we develop patterned liquid crystal elastomer (LCE) particles by recapitulating the biophysical patterning mechanism that forms pollen grain surfaces. In pollen grains, a...

Hypoxia is a hallmark of solid cancers, supporting proliferation, angiogenesis, and escape from apoptosis. There is still limited understanding of how cancer cells adapt to hypoxic conditions and survive. We analyzed transcriptome changes of human lung and breast cancer cells under chronic hypoxia. Hypoxia induced highly concordant changes in transcript abundance, but divergent splicing responses, underlining the cell type-specificity of alternative splicing programs. While RNA-binding proteins were predominantly reduced, hypoxia specifically induced muscleblind-like protein 2 (MBNL2). Strikingly, MBNL2 induction was critical for hypoxia adaptation by controlling the transcript abundance of hypoxia response genes, such as vascular endothelial growth factor A (VEGFA). MBNL2 depletion reduced the proliferation and migration of cancer cells, demonstrating an important role of MBNL2 as cancer driver. Hypoxia control is specific for MBNL2 and not shared by its paralog MBNL1. Thus, our study revealed MBNL2 as central mediator of cancer cell responses to hypoxia, regulating the expression and alternative splicing of hypoxia-induced genes.

Interferon-regulated myxovirus resistance protein B (MxB) is an interferon-induced GTPase belonging to the dynamin superfamily. It inhibits infection with a wide range of different viruses, including HIV-1, by impairing viral DNA entry into the nucleus. Unlike the related antiviral GTPase MxA, MxB possesses an N-terminal region that contains a nuclear localization signal and is crucial for inhibiting HIV-1. Because MxB previously has been shown to reside in both the nuclear envelope and the cytoplasm, here we used bioinformatics and biochemical approaches to identify a nuclear export signal (NES) responsible for MxB's cytoplasmic location. Using the online computational tool LocNES (Locating Nuclear Export Signals or NESs), we identified five putative NES candidates in MxB and investigated whether their deletion caused nuclear localization of MxB. Our results revealed that none of the five deletion variants relocates to the nucleus, suggesting that these five predicted NES sequences do not confer NES activity. Interestingly, deletion of one sequence, encompassing amino acids 505–527, abrogated the anti-HIV-1 activity of MxB. Further mutation experiments disclosed that amino acids 515–519, and Pro-515 in particular, regulate MxB oligomerization and its binding to HIV-1 capsid, thereby playing an important role in MxB-mediated restriction of HIV-1 infection. In summary, our results indicate that none of the five predicted NES sequences in MxB appears to be required for its nuclear export. Our findings also reveal several residues in MxB, including Pro-515, critical for its oligomerization and anti-HIV-1 function.

Virus-like-particle (VLP) influenza vaccines can be given intramuscularly (i.m.) or intranasally (i.n.) and may have advantages over split-virion formulations in the elderly. We tested a plant-made VLP vaccine candidate bearing the viral hemagglutinin (HA) delivered either i.m. or i.n. in young and aged mice. Young adult (5- to 8-week-old) and aged (16- to 20-month-old) female BALB/c mice received a single 3-μg dose based on the HA (A/California/07/2009 H1N1) content of a plant-made H1-VLP (i.m. or i.n.) split-virion vaccine (i.m.) or were left naive. After vaccination, humoral and splenocyte responses were assessed, and some mice were challenged. Both VLP and split vaccines given i.m. protected 100% of the young animals, but the VLP group lost the least weight and had stronger humoral and cellular responses. Compared to split-vaccine recipients, aged animals vaccinated i.m. with VLP were more likely to survive challenge (80% versus 60%). The lung viral load postchallenge was lowest in the VLP i.m. groups. Mice vaccinated with VLP i.n. had little detectable immune response, but survival was significantly increased. In both age groups, i.m. administration of the H1-VLP vaccine elicited more balanced humoral and cellular responses and provided better protection from homologous challenge than the split-virion vaccine.

In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33–amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS.

Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc₁ complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and Plasmodium vivax, their activity against the zoonotic agent Plasmodium knowlesi is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against P. knowlesi in vitro and compared this with their activity against P. falciparum tested under identical conditions. We demonstrated that ELQs are potent against P. knowlesi (50% effective concentration, <117 nM) and equally effective against P. falciparum. We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against P. knowlesi than P. falciparum, while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against P. falciparum. However, against P. knowlesi, no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species.

Ngôi nhà 2,5 tầng sử dụng màu sắc và vật liệu đặc trưng của Hội An kết hợp cùng lối thiết kế hiện đại mang lại cho gia chủ cảm giác vừa mới mẻ, vừa gần gũi. Những hình ảnh về thiết kế nhà được chia sẻ trên mạng xã hội và nhận được nghìn lượt "like" chỉ sau vài giờ.

Negotiating isn’t that dissimilar from playing a game – it involves reading your opponent, strategizing, and then striking.

SEGA announced Yakuza: Like a Dragon will be a launch title for the Xbox Series X, and it will also be coming to the Xbox One and Windows PC via Steam. The game has previously been confirmed to launch in the west for the PlayStation 4. 

The Xbox Series X and Xbox One version of the game will support Smart Delivery and cross-save functionality.

View the Yakuza: Like a Dragon Xbox Series X cinematic trailer below:

Here is an overview of the game:

The Story Begins…

Yakuza: Like a Dragon is, at its core, an underdog story about fighting for what you believe in, even when you’re at rock bottom. Our new main protagonist, Ichiban Kasuga, a low-ranking grunt of a low-ranking yakuza family, takes the fall for a crime he didn’t commit in order to protect his patriarch and father-figure, Masumi Arakawa. After serving an 18-year prison sentence, he returns to society to discover that the clan he once belonged to has been destroyed, its few remaining members are being hunted in the streets, and learns that his former patriarch may be the man responsible for it all. Facing an unimaginable sense of betrayal, loss, and confusion, he sets out to discover the truth. This is where Yakuza: Like a Dragon’s story begins.

A Truly Outrageous RPG Like You’ve Never Seen Before

Along with the all-new cast and setting, Yakuza: Like a Dragon introduces a new dynamic RPG combat system that takes the genre somewhere it’s never been before – present-day Japan. Ichiban is a diehard RPG fan, so to help him stay focused in fights, he imagines the battlefield as if he was living in one of his favorite games. In Yakuza: Like a Dragon, players will level up 19 different ‘Jobs’ far from traditional RPG fare – not Warriors or Mages, but Bodyguards and Musicians, with completely unique strengths and skills. Get ready to step into Ichiban’s shoes and crack some skulls in style!

Welcome to the Underworld Playground

Even with so many changes, Yakuza: Like a Dragon still retains the core Yakuza experience, and a large part of that is the seemingly endless supply of hilarious minigames and substories spread throughout the city. Over 50 substories and a collection of never-before-seen minigames, as well as the return of fan-favorites like Karaoke and SEGA Arcades will ensure that players will enjoy their time in Yokohama to the fullest.

Yakuza: Like a Dragon is everything that fans know and love about the series, with several over the top twists for the next generation. Featuring an entirely-new cast of characters and taking place in the brand new and beautifully-realized setting of Yokohama, players can jump right into the drama, action, and hilarity that Yakuza is known for.

Character Introductions

• Ichiban Kasuga (voiced by Kazuhiro Nakaya) – Of the Arakawa Family, a Tojo Clan subsidiary. A low-ranking member of a low-ranking family, Kasuga is asked by his patriarch and father-figure, Masumi Arakawa, to turn himself in for a murder committed by the family captain, Jo Sawashiro. He is released after serving 18 years in prison, only to discover that the Tojo Clan has been eradicated from Kamurocho and in its place is the Omi Alliance of Kansai—and that Masumi Arakawa may be behind all of it. Seeking the truth, he heads to meet with his former patriarch.

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/443429/yakuza-like-a-dragon-is-a-launch-title-for-xbox-series-x/

Yell at yer friends in 1-4 player co-op while working under time pressure to serve up meals to an unforgiving god in Overc—er sorry, Cannibal Cuisine. It’s certainly got a familiar vibe to it, so if you liked the frantic food prep of that other friendship-ender perhaps you’ll like doing it with a new secret […]

Pigeons feathers are remarkably complex and understanding how they work has led to the first robot that flies like a pigeon, dubbed PigeonBot

Soft finger-like gripper robots have been engineered to sweat when hot and are able to cool down almost three times more efficiently than humans

A sci-fi collection explores extreme corporate futures, such as a Tinder-run city where you can swipe left or right for everything from sex to teachers

A robot can recreate the mechanism plants use to transport water to bend itself towards the sun and open its leaves like a real plant

Fabric with tiny vibrating motors elicits sensations associated with clouds, water and rocks on the skin and has been made into a dress that could improve emotions

These findings suggest that scientists may need to broaden their definition of what a life-supporting planet might look like.

Scientists are speculating as to how the two creatures managed to become preserved in such an unusual way.

Because Amazon movie purchases are really just long-term rentals that can disappear from your library at any time.

Up until now mask-wearing had only been an unenforced suggestion by the company.

Only the best images are used to create a mosaic of the entire planet, resulting in a super-crisp, high-definition view.

On Tuesday the president took his first trip since the coronavirus grounded the country, to a Honeywell factory in battleground state Arizona. This particular Honeywell factory produces N95 masks. Pictures of the trip immediately surfaced on the internet, and they showed a president sporting his usual mango-tinted, ever-tan skin, his usual topiary-structured hair tinted a baffling yellowish, and a pair of clear safety goggles.

But what was missing? What we did not see on the president’s face was a mask. While the rest of us cover our faces as recommended by the CDC, the president does not. In fact, we have never seen a mask on the president, despite the president’s love of masking himself when it comes to his tax returns, his sexual assault allegations, and his financial dealings.   

On Wednesday, when pressed on his decision not to wear a mask at a mask factory, the president responded with the very fishy, “I had a mask on for a period of time, I had it on back, backstage. But they said you didn’t need it, so, I didn’t need it. And by the way, if you noticed, nobody else had it on that was in the group.” Okay. Whatever you say. 

Read more at The Daily Beast.

How can we get a picture of the whole Milky Way if we are inside it? Good sleuthing is needed to combine all the clues, writes Chanda Prescod-Weinstein

Our images of deep space are spectacular, but don’t reflect what our eyes would see. Here's what their stunning true colours reveal about the cosmos

A new computational method allows robotic characters to perform fast motions without excessive vibrations

शॉर्ट वीडियो एप लाईकी ज्वाइन करने का मतबल लाईकी के लाखों यूजर्स को रियल टाइम में कोरोना के संक्रमण के बारे में जानकारी देना और रोकधाम के उपाय को बताना है।

Chris drowns in potions. Anna Marie hits one hundred. Alice shops with e’s. And Manny plays some 360 games now that he finally has an...

Chris has to finish writing this summary so he can start building his new PC. So….the folks talk about E3 and some stuff and amiibos...

Manny teaches us 20 girls Chinese. Anna Marie plays through the best games of the past decade. Chris plays more WoW, and…oh…what’s that? Clicker Heroes...

Alice delivers missiles and then takes a shower. Anna Marie crosses her exes and upgrades her goggles. Chris kickstarts all the games and laments over...

While Chris and Anna practice their skinship this weekend, Robert, aka “lolwhoops”, joins to talk about his digi-obsession. Alice once again disappoints in the area...

Big show this week as we go over our PAX experience. We’ve also got our Extra Life plans, legion impressions, and Persona 5 jealousy. Now...

E3 is just around the corner, so everyone’s working on their backlogs before the new stuff gets announced. There are predictions, Pokémon, and vague Fallout...

Anna Marie puts shirts on. Chris enters mania. Kelley needs a loot box. And you, dear listener, what are you playing? Oh yeah, that car is totally the Ghostbusters car.

Never has one man in inexpensive rumpled suits been so loved by the style set - but Sanders’ clothes signal an authenticity other politicians can only dream of

Of all the things we’ll miss about Bernie Sanders, now that he has dropped out of the Democratic race, his style should be the least of it. Not only because his politics are so right on – this is the man who believes in free education and Medicare for all and who has had many Americans, who until recently felt disenfranchised by mainstream politics, feeling activated by it. But also because his clothes are so seemingly unremarkable.

He wears crumpled suits that look borrowed from a slightly larger man and creased shirts with straight-lace striped ties. The inconspicuousness of his geography teacher shoes are matched only by his inoffensive navy round-neck jumpers.

In another blistering attack on Donald Trump, the actor says the New York governor is doing what a president should do

Robert De Niro has said he would be keen to play New York state governor Andrew Cuomo in a future movie about the coronavirus epidemic, as the actor made another blistering attack on Donald Trump.

Appearing on The Late Show with Stephen Colbert, De Niro expressed his admiration for Cuomo, saying: “He’s doing what a president should do.” He added: “I could see [a President Cuomo]. I am for Biden, and want everything to go well for Biden, but at least we have a person who is very capable, a very capable backup, if you will … he’s doing a great job, he’s doing what any president should do.”

Giant elliptical galaxies are not as likely as previously thought to be cradles of complex life, according to a paper published in the Monthly Notices of the Royal Astronomical Society. In 2015, University of Durham astronomer Pratika Dayal and colleagues concluded that large elliptical galaxies have up to 10,000 times more habitable planets than the [...]

More men die of covid-19 than women. Reasons for this may include differences in smoking, general health, immune defences, hormones and even hygiene

Even if we find drugs that are effective against the coronavirus, that doesn't necessarily mean they will change the wider situation and help end lockdowns

Covid-19 contact tracers are part healthcare worker, part detective and part call centre operative. But what is the job really like? New Scientist spoke to one in Ireland to find out

A number of studies have found a link between air pollution and increased covid-19 deaths, but it isn't clear why. Both attack the lungs, but it could just be that more people live in polluted areas

The latest coronavirus news updated every day including coronavirus cases, the latest news, features and interviews from New Scientist and essential information about the covid-19 pandemic

UFC 249 fight card isn't full of stars, due to the coronavirus enforced restrictions, but is expected to be a much-watched affair, however not in the arena.

Chief junior national coach Sanjay Mishra tells his wards to try and control the negative thoughts which would also help them deal with tough match situations.