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.

Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa, ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.

Of four genotypes of Encephalitozoon cuniculi, E. cuniculi genotype II is considered to represent a parasite that occurs in many host species in a latent asymptomatic form, whereas E. cuniculi genotype III seems to be more aggressive, and infections caused by this strain can lead to the death of even immunocompetent hosts. Although albendazole has been considered suitable for treatment of Encephalitozoon species, its failure in control of E. cuniculi genotype III infection has been reported. This study determined the effect of a 100x recommended daily dose of albendazole on an Encephalitozoon cuniculi genotype III course of infection in immunocompetent and immunodeficient mice and compared the results with those from experiments performed with a lower dose of albendazole and E. cuniculi genotype II. The administration of the regular dose of abendazole during the acute phase of infection reduced the number of affected organs in all strains of mice and absolute counts of spores in screened organs. However, the effect on genotype III was minor. Surprisingly, no substantial effect was recorded after the use of a 100x dose of albendazole, with larger reductions seen only in the number of affected organs and absolute counts of spores in all strains of mice, implying variations in albendazole resistance between these Encephalitozoon cuniculi genotypes. These results imply that differences in the course of infection and the response to treatment depend not only on the immunological status of the host but also on the genotype causing the infection. Understanding how microsporidia survive in hosts despite targeted antimicrosporidial treatment could significantly contribute to research related to human health.

There is an ongoing need for safe and effective anti-bedbug compounds. Here, we tested the toxicity of three antimicrobial agents against bedbugs when administered orally. We reveal that doxycycline has direct insecticidal activity at 250 μg/ml (0.025%) that is particularly strong against immature bedbugs and appears to be independent of antimicrobial activity. Future studies to determine the mechanisms behind this property could be useful for the development of orally active insecticides or anti-bedbug therapeutics.

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.

Choosing good location, prestigious investor, reasonable price; considering legal issues and focusing on infrastructure are the secrets for investors to gain high profit from investing in land.

After lots and lots of #hype in the form of a livestream digital painting reveal that was the precursor to a proper trailer which was also just a precursor to what we were assured would be a first look at actual gameplay, folks were a bit let down by the not very gameplay-looking new video for […]

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

CORONAVIRUS has forced people to re-evaluate their finances as income takes a hit and budgets are stretched. One of the first port of calls for change has been direct debits and new research reveals that some people may find themselves with more cash available once this all ends.

Consultancy firm Certified Artificial, which is offering to certify AI companies, has demonstrated its prowess by rating the expertise of Elon Musk and Henry Kissinger

The OpenAI project demonstrated "emergent behavior" by the AI players, including surfing

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While Jackbox clearly owes a great deal of its current popularity to the shelter-in-place policies, they've also been honing their craft for years. It's worth looking at what makes them work.

The notoriously independent-minded federal judge who once said he was disgusted by the conduct of Michael Flynn could block the administration's bid to drop criminal charges against the former adviser to President Donald Trump, legal experts said.

A dialogue on sex, consent, ownership over bodies must be introduced from a young age so that it becomes part of a dominant narrative, say experts.

Neil Ferguson, whose modelling has informed the UK's coronavirus strategy, says that the need for intensive care beds will come close to, but not exceed, national capacity

The peak of the UK coronavirus epidemic now looks likely to arrive within the next month, according to analysis by the government’s science advisers

A device that carries hot water down a tube into the gut may help manage diabetes by killing overgrown gut cells that release hormones key to metabolising food

Whether you are at home alone or juggling work and family, those working in mental health share their advice on how to cope with 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.

Marin Cilic has experienced many great moments on court in recent years, but the 18-time tour-level titlist announced that he will enjoy a milestone moment off the court in 2020. Speaking to his 170,000 followers on Twitter, the Croat shared the news that he will become a father next year. The news comes just 18 months after Cilic married Kristina Milkovic in Dubrovnik. Cilic’s announcement was accompanied by a photo of the 31-year-old shopping for a pushchair. New ride ?? ?? Excited to share with you all that #teamCilic will be growing. New member joining us in 2020 ???????? pic.twitter.com/m0Qxn6AdQB — Marin Cilic (@cilic_marin) 7 October 2019 Cilic will compete at next week’s VTB Kremlin Cup in Moscow, where he will be aiming to achieve his 500th tour-level victory. If Cilic achieves the feat, he would become the 10th active player on the ATP Tour to reach that mark..

They say the hornet “hype" reminds them of the “killer bees” scare of the 1970s

Shopping for face masks? We consulted medical experts on how to shop for face masks and rounded up those adhering to the CDC's guidelines.

TD also said it will have about $600 million of set-asides tied to U.S. credit cards

Economic reconstruction is a chance to speed up decarbonisation, and the pandemic has shown a different kind of politics is possible

We’re already being swamped with ideas about “reforms” needed to recover from the pandemic crisis. But the word reform is like gift wrap – a handy cover for any offering, thought-through or otherwise.

Perhaps we should ditch the word entirely, and with it the forest of feelpinions about what governments “must” do to advance an author’s previously-held ideological positioning in the post-corona world.

On a ship frozen in the Arctic, scientists have spent all winter to shed light on exactly how the world is changing

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.

Rookie phenom Connor Bedard is the headliner of a workmanlike forward group that's looking to come of age with the Regina Pats.

The U.S. economy likely lost a staggering 22 million jobs in April, in what would be the steepest plunge in payrolls since the Great Depression and the starkest sign yet of how the novel coronavirus pandemic is battering the world's biggest economy.

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

Boris Johnson's frightening experience of suffering from coronavirus may still leave a lasting impression, a leading psychiatrist has said.

Coronavirus: the symptoms

Increased social isolation, health anxiety and stress over an economic downturn are all factors that could spark a protracted crisis, the group said.

Follow our live coronavirus updates here Coronavirus: the symptoms

Twitter is down for a large number of users leaving them unable to load posts.

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A couple who were living their dream of sailing across the Atlantic have shared their "shock" of returning to land and hearing the news about the global coronavirus pandemic.

The UK is set for more warm weather over the weekend while temperatures soared to more than 24C on Thursday.

Donald Trump has told a coronavirus press conference that the idea of injecting Covid-19 patients with disinfectant "sounds interesting to me".

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Businesses are giving schoolchildren virtual work experience placements to prevent them from missing out on opportunities during the crisis.

More deadly pandemics are likely to follow the coronavirus outbreak in future unless nature is protected, experts have warned.

Experts have said it is too early to reopen schools in the UK as it is still unclear how coronavirus spreads among children.