Balamuthia mandrillaris is an under-reported, pathogenic free-living amoeba that causes Balamuthia amoebic encephalitis (BAE) and cutaneous skin infections. Although cutaneous infections are not typically lethal, BAE with or without cutaneous involvement is usually fatal. This is due to the lack of drugs that are both efficacious and can cross the blood-brain barrier. We aimed to discover new leads for drug discovery by screening the open-source Medicines for Malaria Venture (MMV) Malaria Box and MMV Pathogen Box, with 800 compounds total. From an initial single point screen at 1 and 10 μM, we identified 54 hits that significantly inhibited the growth of B. mandrillaris in vitro. Hits were reconfirmed in quantitative dose-response assays and 23 compounds (42.6%) were confirmed with activity greater than miltefosine, the current standard of care.

Pseudomonas aeruginosa exploits intrinsic and acquired resistance mechanisms to resist almost every antibiotic used in chemotherapy. Antimicrobial resistance in P. aeruginosa isolates recovered from cystic fibrosis (CF) patients is further enhanced by the occurrence of hypermutator strains, a hallmark of chronic infections in CF patients. However, the within-patient genetic diversity of P. aeruginosa populations related to antibiotic resistance remains unexplored. Here, we show the evolution of the mutational resistome profile of a P. aeruginosa hypermutator lineage by performing longitudinal and transversal analyses of isolates collected from a CF patient throughout 20 years of chronic infection. Our results show the accumulation of thousands of mutations, with an overall evolutionary history characterized by purifying selection. However, mutations in antibiotic resistance genes appear to have been positively selected, driven by antibiotic treatment. Antibiotic resistance increased as infection progressed toward the establishment of a population constituted by genotypically diversified coexisting sublineages, all of which converged to multidrug resistance. These sublineages emerged by parallel evolution through distinct evolutionary pathways, which affected genes of the same functional categories. Interestingly, ampC and ftsI, encoding the β-lactamase and penicillin-binding protein 3, respectively, were found to be among the most frequently mutated genes. In fact, both genes were targeted by multiple independent mutational events, which led to a wide diversity of coexisting alleles underlying β-lactam resistance. Our findings indicate that hypermutators, apart from boosting antibiotic resistance evolution by simultaneously targeting several genes, favor the emergence of adaptive innovative alleles by clustering beneficial/compensatory mutations in the same gene, hence expanding P. aeruginosa strategies for persistence.

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.

Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment options targeting coronary artery diseases. Recent studies with the state-of-the-art technologies have identified novel origins of, as well as new, cellular and molecular mechanisms underlying the formation of coronary vessels in the postnatal heart, including collateral artery formation, endocardial-to-endothelial differentiation and mesenchymal-to-endothelial transition. These new mechanisms of coronary vessel formation and regeneration open up new possibilities targeting neovascularization for promoting cardiac repair and regeneration. Here, we highlight some recent studies on cellular mechanisms of coronary vessel formation, and discuss the potential impact and significance of the findings on basic research and clinical application for treating ischemic heart disease.

Cell death is an invariant feature throughout our life span, starting with extensive scheduled cell death during morphogenesis and continuing with death under homeostasis in adult tissues. Additionally, cells become victims of accidental, unscheduled death following injury and infection. Cell death in each of these occasions triggers specific and specialized responses in the living cells that surround them or are attracted to the dying/dead cells. These responses sculpt tissues during morphogenesis, replenish lost cells in homeostasis to maintain tissue/system function, and repair damaged tissues after injury. Wherein lies the information that sets in motion the cascade of effector responses culminating in remodeling, renewal, or repair? Here, we attempt to provide a framework for thinking about cell death in terms of the specific effector responses that accompanies various modalities of cell death. We also propose an integrated threefold "cell death code" consisting of information intrinsic to the dying/dead cell, the surroundings of the dying cell, and the identity of the responder.

To date, more than 200 monogenic, often devastating, skin diseases have been described. Because of unmet medical needs, development of long-lasting and curative therapies has been consistently attempted, with the aim of correcting the underlying molecular defect. In this review, we will specifically address the few combined cell and gene therapy strategies that made it to the clinics. Based on these studies, what can be envisioned for the future is a patient-oriented strategy, built on the specific features of the individual in need. Most likely, a combination of different strategies, approaches, and advanced therapies will be required to reach the finish line at the end of the long and winding road hampering the achievement of definitive treatments for genodermatoses.

Maintenance of the proteome, ensuring the proper locations, proper conformations, appropriate concentrations, etc., is essential to preserve the health of an organism in the face of environmental insults, infectious diseases, and the challenges associated with aging. Maintaining the proteome is even more difficult in the background of inherited mutations that render a given protein and others handled by the same proteostasis machinery misfolding prone and/or aggregation prone. Maintenance of the proteome or maintaining proteostasis requires the orchestration of protein synthesis, folding, trafficking, and degradation by way of highly conserved, interacting, and competitive proteostasis pathways. Each subcellular compartment has a unique proteostasis network compromising common and specialized proteostasis maintenance pathways. Stress-responsive signaling pathways detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors and respond by generating an active transcription factor. Subsequent transcriptional programs up-regulate proteostasis network capacity (i.e., ability to fold and degrade proteins in that compartment). Stress-responsive signaling pathways can also be linked by way of signaling cascades to nontranscriptional means to reestablish proteostasis (e.g., by translational attenuation). Proteostasis is also strongly influenced by the inherent kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins, and these sequence-based attributes in combination with proteostasis network capacity together influence proteostasis. In this review, we will focus on the growing body of evidence that proteostasis deficits leading to human pathology can be reversed by pharmacologic adaptation of proteostasis network capacity through stress-responsive signaling pathway activation. The power of this approach will be exemplified by focusing on the ATF6 arm of the unfolded protein response stress responsive-signaling pathway that regulates proteostasis network capacity of the secretory pathway.

Background:

New technologies are being developed for early detection of multiple types of cancer simultaneously. To quantify the potential benefit, we estimated reductions in absolute cancer–related deaths that could occur if cancers diagnosed after metastasis (stage IV) were instead diagnosed at earlier stages.

Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.

BACKGROUND AND PURPOSE:

Conventional nonadhesive liquid embolic agents currently are the criterion standard for endovascular embolization of cerebral AVMs. However, inadequate distal penetration into the nidus and unstable proximal plug formation are the major limitations of this approach and of the currently available embolic materials. The aim of this study was to evaluate the hypothetic efficacy of combining liquid embolic agents with different properties and viscosities for use in endovascular embolization of cerebral AVMs.

SUMMARY:

Polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) are recently described CNS tumors. Classically, PLNTYs are epileptogenic and are a subtype of a heterogeneous group of low-grade neuroepithelial tumors that cause refractory epilepsy, such as angiocentric gliomas, oligodendrogliomas, gangliogliomas, and pleomorphic xanthoastrocytomas. Although they are a relatively new entity, a number of imaging and histologic characteristics of PLNTYs are already known. We present the imaging and pathologic findings of such a tumor as well as the surgical approach and clinical management.

शनिवार को दोपहर बाद उत्तराखंड के पहाड़ी इलाकों में मौसम बदल गया। वहीं अधिकतर मैदानी इलाकों में बादल छाए रहे।

Publisher Warner Bros. Interactive Entertainment and developer NetherRealms Studios have announced a new expansion for Mortal Kombat 11 called Aftermath. It will release on May 26.

The Mortal Kombat 11: Aftermath expansion adds a new cinematic story, three characters and three new skins for $39.99. The three new characters are Fujin, Sheeva, and RoboCop).

A $59.99 Mortal Kombat: Aftermath Kollection has also been announced. It includes the base game, Kombat Pack DLC and the Aftermath expansion. 

View the announcement trailer for the expansion and RoboCop reveal trailer below:

Here is an overview of the expansion:

Mortal Kombat 11: Aftermath is a new expansion for the hit videogame, Mortal Kombat 11, the best-selling title in franchise history that was named Fighting Game of the Year at the 2019 D.I.C.E. Awards. Developed by award-winning NetherRealm Studios, Mortal Kombat 11: Aftermath expands the critically acclaimed story campaign with an all-new, cinematic narrative centered around trust and deceit, while also adding new playable characters in returning Mortal Kombat fighters, Fujin and Sheeva, and guest character, RoboCop, who is making his series debut.

Key Features:

• Franchise-First Story Expansion – The critically acclaimed story campaign continues with an all-new cinematic narrative that picks up directly where Mortal Kombat 11 left off. Fire God Liu Kang, the new keeper of time and protector of Earthrealm, must now enlist the help of unlikely allies and familiar foes to forge a new history as the fate of two worlds hang in the balance.
• Exciting New Characters Join the Roster – New playable characters join the fight with the triumphant return of Fujin, the God of Wind who serves as Earthrealm’s protector alongside his brother Raiden, and Sheeva, the fourarmed, half-human and half-dragon queen of the ancient Shokan race. RoboCop, the iconic, highly advanced cybernetic police officer, makes his first appearance in the franchise, continuing the pedigree of popular Mortal Kombat guest fighters. RoboCop in Mortal Kombat 11: Aftermath features the voice and likeness of actor Peter Weller, who portrayed the popular character in both the original RoboCop (1987) film and RoboCop 2 (1990) sequel. Mortal Kombat 11: Aftermath will also include three new character skin packs to be released over time.
• Fan-Favorite Stages, Stage Fatalities & Friendships Return – In conjunction with the Mortal Kombat 11: Aftermath release, all Mortal Kombat 11 owners will have access to a free content update featuring new Stages, including the return of the Klassic Dead Pool and Soul Chamber arenas; Stage Fatalities, the fan-favorite finishing moves that use the environment to destroy opponents; and the popular Friendships feature, allowing players to take down their adversaries with a hint of kindness.
• New Players Can Join the Fight with Mortal Kombat 11: Aftermath Kollection – Offers the perfect opportunity for new players to join the fight, featuring all characters, story content, game modes and pre-order bonuses in one ultimate package. This compilation includes Mortal Kombat 11 along with all content from Mortal Kombat 11: Aftermath and the previously released Mortal Kombat 11 Kombat Pack, containing six playable characters—Shang Tsung, Nightwolf, Sindel, Terminator T-800, The Joker and Spawn – plus 25 additional character skins. The Mortal Kombat 11: Aftermath Kollection can be pre-ordered for $59.99 (SRP) with digital pre-orders offering immediate access to Mortal Kombat 11 and the Kombat Pack upon purchase. The physical version will be available this June in the Americas only.
• Upgrade Options for Current Mortal Kombat 11 Owners – Those who have already purchased Mortal Kombat 11 can pre-order the Mortal Kombat 11 Aftermath expansion for $39.99 (SRP) or the Mortal Kombat 11: Aftermath + Kombat Pack Bundle for $49.99 (SRP).
• Pre-order for Exclusive Content – All preorders* receive the Eternal Klash Skin Pack at launch, featuring three new character skin variants – “Unbound Rage” Scorpion inspired by Mortal Kombat (2011), “Son of Arctika” Sub-Zero inspired by Mortal Kombat: Deception and “Kori Power” Frost, a Klassic version of the Lin Kuie warrior.
• Best-In-Class, Brutal Kombat – Mortal Kombat 11 is the latest installment in the critically acclaimed franchise, providing a deeper and more personalized experience than ever before. The best-selling title is packed to the brim with multiple features and modes for all players, including the Story mode, Custom Character Variation System, Towers of Time, Kombat League, The Krypt and the signature roster returning and franchise-first fighters, all equipped with powerful Krushing Blows and unique Fatalities that display devastatingly brutal cinematic visuals.

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/443404/mortal-kombat-11-aftermath-expansion-announced-adds-3-new-characters-and-new-story/

A centenarian who tested positive for COVID-19 has become the oldest local resident to die from the virus. The woman in her 100s was a resident of a long-term care or retirement home. She died on Thursday, the Windsor-Essex County Health Unit reported during its end-of-week epidemic data summary on Friday. “I would like to […]

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

This week, hide behind the sofa from mind-altering plants, listen and learn from technologies past and find out how the world is underpinned by numbers

Pandemics of the past can teach us about the current one, says John Troyer, who studies how we use technology to alter the experience of death

Why? Because that’s our reality here in the year 2020.

Strange as it may sound, Animal Crossing: New Horizons feels like where Breath of the Wild should have ended up gameplay-wise.

It does make several enormous assumptions about the future that now seem perilously flaky.

Campaigns and consultants have spent the last four years worrying about the Trump campaign’s digital operation. Even before COVID-19 upended the election and forced candidates online, the Trump campaign was geofencing campaign rallies, micro-targeting digital ads, and amplifying deepfake videos.

And now, as both the crisis and the general election enter their third month, panic is beginning to set in about the startling digital gap between the two parties, amplified by the recent Trump campaign announcement of both a new app experience and the start of a $10 million digital push against Joe Biden. 

President Trump’s campaign manager has called what he’s built a “juggernaut” and is likening his digital infrastructure to a Death Star. In reality, what he's built is a trap.  

Read more at The Daily Beast.

Watford chairman Scott Duxbury has questioned whether the Premier League should return amid the coronavirus pandemic.

The first US woman to spacewalk flew on three shuttle missions and says nothing beats space flight – but her proudest achievement is helping to repair the Hubble Space Telescope

China’s Yutu-2 rover has used radar to peer 40 metres under the surface of the far side of the moon and revealed how past impacts have shaped its geology

The question of how the brain gives rise to subjective experience is the hardest of all. Mathematicians think they can help, but their first attempts have thrown up some eye-popping conclusions

Experts representing a diversity of views on autonomous weapons systems collaborate on a realistic policy roadmap

If Stephen King keeps writing ‘em, we’ll keep seeing ‘em.

Shenmue III is still accepting backers. Fallout 76 is still something we don't understand. And Utawarerumono is still unpronounceable.

Keep up to date with all the latest coronavirus news from Glasgow, Scotland and beyond - LIVE

People who attended religious services at least once a week were significantly less likely to die from 'deaths of despair,' including deaths related to suicide, drug overdose, and alcohol poisoning, according to new research.

With New York’s glitziest fashion event in lockdown, people rose to the occasion on social media

• Coronavirus latest: at a glance

The annual Met Gala would have taken place in New York last week, had it not been postponed indefinitely in March owing to the pandemic. The theme would have been About Time: Fashion and Duration, or “time itself”, according to Andrew Bolton, the curator of the Metropolitan Museum of Art’s partner exhibition, which is ironic now that a morning can feel like a month, and a week can feel like a minute.

Ordinarily, it is one of my favourite celebrity bashes, sitting happily in the middle of a ridiculous/gorgeous Venn diagram, showing off high fashion so high that the people who point at Picassos and say “my five-year-old could have done that” will inevitably comment that “you couldn’t wear that down the shops”, as if the point of a ballgown in the shape of a chandelier were to make the trip to Tesco a bit more lively. (Having said that, you could definitely have used it to carry a few extra bags home.)

Hollywood loves a good comeback, and post-coronavirus will be no exception, writes costume designer Kristin M Burke

Many events have killed the film industry: the 1918 influenza epidemic, the second world war, the invention of television, the invention of VCRs, the invention of the internet, 9-11, strike after strike after strike. And yet, like a phoenix, it rises, every time stronger than before. The appetite for its product is insatiable especially in times of political trouble and uncertainty about the future. People want to escape. They want to be entertained.

The way we make movies most certainly must change. In the best of circumstances, we are a crew of 75 people jammed into a room with very little ventilation, holding our breath until we hear “CUT”. We are in close contact with one another all day long. We never really thought about it before. All of that is about to change. Film sets usually function as big families, and moving forward, that family unit will take on a stronger, protective meaning. This is how we self-regulate in the post-pandemic era.

Moonlight’s Ashton Sanders gives a compelling lead performance as a young man trying to escape his father’s shadow

It’s an unusually stacked week for new films on Netflix (one they might regret when pre-pandemic content starts to dry up) with a teen comedy, a B-thriller and a romantic documentary all launching before the weekend, a feast for viewers at home but a glut that could overshadow one of their finer offerings quietly releasing alongside. All Day and a Night, a tough-minded drama from Black Panther co-writer Joe Robert Cole, might not be quite worthy enough for their awards slate (although it’s a damn sight more compelling than The Two Popes …) but it’s a step up from what one might expect of an unhyped May movie from the streamer. Think of it as a classier boutique release, deserving of a higher shelf placement.

Related: The Half of It review – charming Netflix teen comedy takes on Cyrano

Complacency is not a word in Kelsey Wog’s vocabulary. Every season, the fourth-year Bisons swimmer finds a way to take her game to the next level and break records along the ...

The U.S. Centers for Disease Control and Prevention (CDC) on Friday reported 1,248,040 cases of the new coronavirus, an increase of 28,974 cases from its previous count, and said that the number of deaths had risen by 2,180 to 75,477.

The number of deaths from the coronavirus in Mexico's best-known border city, Tijuana, has soared and the COVID-19 mortality rate is twice the national average, the health ministry says, after medical staff quickly fell ill as the outbreak rampaged through hospital wards.

New Delhi, May 08: From Gilgit to Guwahati, Doordarshan and All India Radio have started forecasting the weather from across the territory of India. These Weather reports cover every small detail from every nook and corner of the country while highlighting

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

Despite data pouring in from many countries, estimates of how many of those infected with covid-19 die still vary widely

With all the unknowns about covid-19, any numbers you hear about death tolls or how long restrictions will last should be taken not just with a pinch of salt but with a sack of it

Taking deep breaths and forcing a cough can help clear mucus, but these techniques are unlikely to prevent or treat coronavirus infections – here’s why

The 36th edition of the European Athletics Indoor Championships is scheduled to take place from March 5 to 7 next year in Torun, Poland.