In plant–pathogen relations, disease symptoms arise from the interaction of the host and pathogen genomes. Host–pathogen functional gene interactions are well described, whereas little is known about how the pathogen genetic variation modulates both organisms’ transcriptomes. To model and generate hypotheses on a generalist pathogen control of gene expression regulation, we used the Arabidopsis thaliana–Botrytis cinerea pathosystem and the genetic diversity of a collection of 96 B. cinerea isolates. We performed expression-based genome-wide association (eGWA) for each of 23,947 measurable transcripts in Arabidopsis (host), and 9267 measurable transcripts in B. cinerea (pathogen). Unlike other eGWA studies, we detected a relative absence of locally acting expression quantitative trait loci (cis-eQTL), partly caused by structural variants and allelic heterogeneity hindering their identification. This study identified several distantly acting trans-eQTL linked to eQTL hotspots dispersed across Botrytis genome that altered only Botrytis transcripts, only Arabidopsis transcripts, or transcripts from both species. Gene membership in the trans-eQTL hotspots suggests links between gene expression regulation and both known and novel virulence mechanisms in this pathosystem. Genes annotated to these hotspots provide potential targets for blocking manipulation of the host response by this ubiquitous generalist necrotrophic pathogen.

The most fundamental genetic program of an annual plant defines when to grow and reproduce and when to remain dormant in the soil as a seed. With the right timing, plants can even live in hostile regions with only a few months of growth-favorable abundant rains and mild temperatures. To...

Microtubule-associated serine/threonine kinase like (MASTL), also known as Greatwall (Gwl) kinase, has an important role in the regulation of mitosis. By inhibiting protein phosphatase 2A (PP2A), it plays a crucial role in activating one of the most important mitotic kinases, known as cyclin-dependent kinase 1 (CDK1). MASTL has been seen to be upregulated in various types of cancers and is also involved in tumor recurrence. It is activated by CDK1 through phosphorylations in the activation/T-loop, but the complete mechanism of its activation is still unclear. Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation. Our results suggest that AKT increases CDK1-mediated phosphorylation and hence the activity of MASTL, which, in turn, promotes mitotic progression through PP2A inhibition. We also show that the oncogenic potential of AKT is augmented by MASTL activation, since AKT-mediated proliferation in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. In brief, we report that AKT plays an important role in the progression of mitosis in mammalian cells and that it does so through the phosphorylation and activation of MASTL.

The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2^B–/–). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids in vitro and in vivo. Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.

The objectives of the present study were to characterize GNE-947 for its phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitory activities, in vitro anti–cell migration activity in human umbilical vein endothelial cells (HUVECs), in vivo antineovascularization activity in laser-induced rat choroidal neovascular (CNV) eyes, pharmacokinetics in rabbit plasma and eyes, and ocular distribution using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) and autoradioluminography. Its PI3K and mTOR K_i were 0.0005 and 0.045 µM, respectively, and its HUVEC IC₅₀ was 0.093 µM. GNE-947 prevented neovascularization in the rat CNV model at 50 or 100 µg per eye with repeat dosing. After a single intravenous injection at 2.5 and 500 μg/kg in rabbits, its plasma terminal half-lives (t_1/2) were 9.11 and 9.59 hours, respectively. After a single intravitreal injection of a solution at 2.5 μg per eye in rabbits, its apparent t_1/2 values were 14.4, 16.3, and 23.2 hours in the plasma, vitreous humor, and aqueous humor, respectively. After a single intravitreal injection of a suspension at 33.5, 100, 200 μg per eye in rabbits, the t_1/2 were 29, 74, and 219 days in the plasma and 46, 143, and 191 days in the eyes, respectively. MALDI-IMS and autoradioluminography images show that GNE-947 did not homogenously distribute in the vitreous humor and aggregated at the injection sites after injection of the suspension, which was responsible for the long t_1/2 of the suspension because of the slow dissolution process. This hypothesis was supported by pharmacokinetic modeling analyses. In conclusion, the PI3K/mTOR inhibitor GNE-947 prevented neovascularization in a rat CNV model, with t_1/2 up to approximately 6 months after a single intravitreal injection of the suspension in rabbit eyes.

SIGNIFICANCE STATEMENT

GNE-947 is a potent phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor and exhibits anti–choroidal neovascular activity in rat eyes. The duration of GNE-947 in the rabbit eyes after intravitreal injection in a solution is short, with a half-life (t_1/2) of less than a day. However, the duration after intravitreal dose of a suspension is long, with t_1/2 up to 6 months due to low solubility and slow dissolution. These results indicate that intravitreal injection of a suspension for low-solubility drugs can be used to achieve long-term drug exposure.

Xiaofei Cao, Sergio Lilla, Zhenbo Cao, Marie Anne Pringle, Ojore B. V. Oka, Philip J. Robinson, Tomasz Szmaja, Marcel van Lith, Sara Zanivan, and Neil J. Bulleid

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfides. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is crucial for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER. These results provide compelling evidence for the crucial role of the cytosol in regulating ER redox homeostasis, ensuring correct protein folding and facilitating the degradation of misfolded ER proteins.

Autophagy captures intracellular components and delivers them to lysosomes for degradation and recycling. Conditional autophagy deficiency in adult mice causes liver damage, shortens life span to 3 mo due to neurodegeneration, and is lethal upon fasting. As autophagy deficiency causes p53 induction and cell death in neurons, we sought to test whether p53 mediates the lethal consequences of autophagy deficiency. Here, we conditionally deleted Trp53 (p53 hereafter) and/or the essential autophagy gene Atg7 throughout adult mice. Compared with Atg7^/ mice, the life span of Atg7^/p53^/ mice was extended due to delayed neurodegeneration and resistance to death upon fasting. Atg7 also suppressed apoptosis induced by p53 activator Nutlin-3, suggesting that autophagy inhibited p53 activation. To test whether increased oxidative stress in Atg7^/ mice was responsible for p53 activation, Atg7 was deleted in the presence or absence of the master regulator of antioxidant defense nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2^–/–Atg7^/ mice died rapidly due to small intestine damage, which was not rescued by p53 codeletion. Thus, Atg7 limits p53 activation and p53-mediated neurodegeneration. In turn, NRF2 mitigates lethal intestine degeneration upon autophagy loss. These findings illustrate the tissue-specific roles for autophagy and functional dependencies on the p53 and NRF2 stress response mechanisms.

Objective

We aimed to assess adherence to the Australian national guideline (COPD-X) against audited practice, and to document the outcomes of patients hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (COPD) at discharge and 28 days after.

Methods

A prospective clinical audit of COPD hospital admission from five tertiary care hospitals in five states of Australia was conducted. Post-discharge follow-up was conducted via telephone to assess for readmission and health status.

Results

There were 207 admissions for acute exacerbation (171 patients; mean 70.2 years old; 50.3% males). Readmission rates at 28 days were 25.4%, with one (0.6%) death during admission and eight (6.1%) post-discharge within 28 days. Concordance to the COPD-X guidance was variable; 22.7% performed spirometry, 81.1% had blood gases collected when forced expiratory volume in 1 s was <1 L, 99.5% had chest radiography performed, 95.1% were prescribed systemic corticosteroids and 95% were prescribed antibiotic therapy. There were 89.1% given oxygen therapy and 92.6% when arterial oxygen tension was <80 mmHg; 65.6% were given ventilatory assistance when pH was <7.35. Only 32.4% were referred to pulmonary rehabilitation but 76.8% had general practitioner follow-up arranged.

Conclusion

When compared against clinical practice guidelines, we found important gaps in management of patients admitted with COPD throughout tertiary care centres in Australia. Strategies to improve guideline uptake are needed to optimise care.

Vượt qua hai đối thủ nặng ký là Sydney và Melbourne, thành phố Brisbane thuộc bang Queensland gây bất ngờ khi ghi nhận tăng trưởng giá nhà đạt mốc kỷ lục tại thời điểm thị trường bất động sản Australia nói chung đang trong tình trạng ảm đạm.

Thị trường bất động sản Canberra, Australia gần đây sôi động hơn trước do sự có mặt của các nhà đầu tư và người mua nhà theo đuổi chiến lược rentvesting – vừa thuê nhà ở, vừa đầu tư khi nhận thấy khả năng sinh lời ở hai thị trường trọng điểm truyền thống là Sydney và Melbourne đang giảm sút.

Đây là những sản phẩm BĐS đặc biệt được tung ra thị trường trong bối cảnh dịch bệnh diễn biến phức tạp, nhiều công ty, doanh nghiệp cho phép nhân viên làm việc tại nhà và tự cách ly để tránh rủi ro lây nhiễm bệnh cho nhau.

Five Australian hospitals are set to receive the experimental coronavirus drug, remdesivir. Sydney's St Vincent hospital has been confirmed as one location, according to a report from The Guardian. More »

Last year, Google turned the mid-range phone market on its head by introducing the ludicrously-priced and well-specced Pixel 3a. A few other brands have followed suit since then, but none have been quite as exciting as the new iPhone SE. Now it truly seems like flagship inclusions at lower price points are here to stay - and it's about damn time. The trend of $1,500 - $2,000 becoming the norm for new phones over the last few years has been bad for buyers. A new middle ground has been long overdue and we welcome it. But is the resurrected iPhone SE actually a good phone to buy in 2020? More »

Apple dropped its brand new 13-inch MacBook Pro overnight, which is exciting because the dreaded butterfly keyboard is now finally dead. For real. In its place you'll find the newer Magic Keyboard which has previously been added to the 16-inch MacBook Pro and the MacBook Air. Today is a good day. If you're keen to get your paws on the new laptop, here's how much it will set you back in Australia. More »

Back in early March Apple announced that it would closing the majority of its physical stores worldwide. Roughly seven weeks later Australian Apple stores will be re-opening their doors around the country later this week. More »

Samsung just released the smaller version of its Galaxy Tab S6 tablet in Australia. Though it did appear in some online stores a little early, now it's official. Here's what its packing and how much it will cost in Australia. More »

Sennheiser has just released its second generation of its noise cancelling earbuds in Australia - the Sennheiser Momentum True Wireless 2. Here's what we know about them and how much they cost. Spoiler alert - they ain't cheap. More »

The cast of Community is reuniting for a virtual table read to raise money for coronavirus relief. Almost all of main cast will be back for the online event, including Donald Glover who left the show in season 5. It will also include a Q&A where fans can submit questions via social media. This is how you can watch it live. More »

Researchers at a Sydney university have discovered how some female bees have managed to reproduce despite never doing the deed with another. More »

The rate of new coronavirus cases is dropping in Australia, largely due to strict travel restrictions, but complacency could cause the virus to get out of hand

Australia recorded just 229 flu cases this April, compared with 18,705 last April, probably due to lockdown measures to stop the spread of the coronavirus

With Italy's gym clubs and training facilities having fallen silent because of the coronavirus pandemic, 28-year-old Italian gymnast Marco Lodadio, silver medallist in the 2019 men's world artistic gymnastics championships, turned his garden into a fitness studio.

Without the sophisticated facilities that high-performance athletes normally count on, Lodadio modified a structure for a swing to train on rings.

Lodadio, whose parents had a gym where he began training when he was nine, has been stuck in lockdown for almost two months and this week has finally gotten back to his usual rigourous training regime as Italy begins gradually lifting its strict restrictions.

… the opening round of the Davis Cup World Group on hard court … . Kyrgios led Australia to the Davis Cup semi-finals this year, while Zverev ….

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.

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Microsoft Corp. said on Friday it would create its first datacentre region in Italy under a $1.5 billion investment plan as the U.S. company expands its cloud computing services to more locations across the world.

The Australian government on Monday set aside A$300 million ($191 million) to jumpstart hydrogen projects with the help of low-cost financing as the country aims to build the industry by 2030, the country's energy minister said on Monday.

BP Plc has won Australian government backing for a feasibility study into producing hydrogen using wind and solar power to split water and converting the hydrogen to ammonia in Western Australia.

Tournament favourites Australia advanced into the semi-finals of the men's hockey World Cup on Monday after they beat Pakistan 2-1 in a pulsating match to finish top of Pool B.

Up to 30 new marine species discovered on research expedition into underwater canyons

Coronavirus: the symptoms Follow our live updates here

A kangaroo was spotted hopping through the empty streets of Adelaide amid the coronavirus lockdown.

Virgin Australia has gone into voluntary administration after failing to secure a government bailout due to impacts of the coronavirus pandemic.

Four police officers have died after being hit by a truck when they stopped to detain a speeding driver on an Australian motorway, officials said.

Memorial services will be held in Australia and New Zealand this week to mark Anzac Day.

Services around the world have been disrupted due to the coronavirus crisis

An Australian couple has discovered a novel way to meet up with neighbours and enjoy the good weather, despite the coronavirus lockdown.

"He pushed one of the police officers on the ground and I think he was about to lunge at another one of the police with the knife, that's what it looked like to me.

Italians were today enjoying the chance to exercise in parks for the first time in eight weeks as their country took its first significant steps out of its coronavirus lockdown.

A police officer accused of murdering former Aston Villa star Dalian Atkinson is set to go ahead in September, despite the current uncertainty about court timetables due to coronavirus.

The Queen has spoken to Australian Prime Minister Scott Morrison to discuss how the country is fighting coronavirus.

First there was crowded Bondi, then the deserted beaches, cordoned off with police tape. If you look closely, a whole nation can be read on the sand

A country reveals itself in a crisis. Americans are buying a record number of guns, in the UK Boris Johnson was reluctant to implement a full lockdown because he baulked at the idea of closing the pubs. In Australia, it is our beaches that are the metaphorical hills that we are metaphorically dying on.

Yeah, we want to beat this virus, but we also want to get a swim in.

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To mark 250 years since British explorers landed in Australia for the first time, authorities are planning to unveil new memorials at Captain James Cook's landing site in Botany Bay, while a replica Endeavour sailing vessel will circumnavigate Australia – when Covid-19 restrictions allow. But one Aboriginal elder, who grew up on the shores of Botany Bay and has spent years involved in the resurrection of his Indigenous Dharawal culture, explains why Aboriginal people will not be celebrating

• Paul Daley: Commemorating James Cook’s arrival, Australia should not omit his role in the suffering that followed

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Exclusive: Documents show department has stopped recommending assessment of ‘key threatening processes’ affecting native wildlife

The federal government has stopped listing major threats to species under national environment laws, and plans to address listed threats are often years out of date or have not been done at all.

Environment department documents released under freedom of information laws show the government has stopped assessing what are known as “key threatening processes”, which are major threats to the survival of native wildlife.

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Is it all moot because of the deadly virus infecting Australia and no I don’t mean the National party ahahaha

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A Derek Underwood-inspired England – assisted by the Oval’s resourceful spectators – beat the final-day flood, clock and Australian resistance to start my lifelong obsession with cricket

I was clearing out some old papers a while back when a small pink slip fell out. Even after 50 years I knew instantly what it was because it had been stuck to my bedroom wall when I was a teenager: indeed the old brown shadows of the tape were still there. It was the ticket for my first day’s Test cricket: the fifth Test against Australia at the Oval on 22 August 1968: Derek Underwood’s match and the game that started a lifelong obsession.

We joined my friend Matthew and his mother – two teenagers, what were we thinking of, taking our mothers? – and caught an early train from deepest Berkshire. London was a big, strange place where we rarely ventured and never as far south as SE11. We were square to the wicket and the players were so distant as to be indistinct, almost lost against the crowd.

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The app will ask for your name (or pseudonym), age range, postcode and phone number. Scott Morrison says the Australian government’s covid safe tracking app won’t be mandatory to download and install, but its uptake numbers could play a part in easing Covid-19 restrictions

• Authorities admit app is not working properly on iPhones
  
• How Australia’s Covidsafe compares to other countries’ contact tracing technology
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The Australian government has launched Covidsafe, an app that traces every person running the app who has been in contact with someone else using the app who has tested positive for coronavirus in the previous few weeks, in a bid to automate coronavirus contact tracing, and allow the easing of restrictions.

Here’s what we know about the app so far.

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Is Australia flattening the curve? We bring together all the latest Covid-19 confirmed cases, maps, stats and graphs from NSW, Victoria, Queensland, SA, WA, Tasmania, ACT and NT to get a broad picture of the Australian outbreak and track the impact of government response.

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Due to the difference in reporting times between states, territories and the federal government, it can be difficult to get a current picture of how many confirmed cases of coronavirus there are in Australia.

Here, we’ve brought together all the figures in one place, along with comparisons with other countries.

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Australian prime minister Scott Morrison has detailed a gradual opening up of society with the timing the stages to be determined by the states

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• Coronavirus Australia maps and cases: live numbers and statistics

Scott Morrison and the chief medical officer, Brendan Murphy, have laid out a three-step plan to reopen Australia after the coronavirus crisis. Morrison said he hoped step three could be achieved in July, but it would be up to each state and territory when they moved from one step to the next.

Below are some of the areas that will be opened up at each stage, according to the plan – and you can see the timeline for easing restrictions in each state here.

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Each Saturday we add 15 (or so) new songs to a Spotify playlist to soundtrack your physical distancing amid coronavirus – and help artists you love get paid

We’ve published a bunch of articles about how the coronavirus crisis has impacted the Australian arts industry. But there are small things you can do. It’s an imperfect solution, but streaming Australian music can help.

Each week, in partnership with Sounds Australia, Guardian Australia will add some 15 new songs to a playlist for you to put on repeat.

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