Recent studies have strived to find an association between rapid antidepressant effects and a specific subset of pharmacological targets and molecular pathways. Here, we propose a broader hypothesis of encoding, consolidation, and renormalization in depression (ENCORE-D), which suggests that, fundamentally, rapid and sustained antidepressant effects rely on intrinsic homeostatic mechanisms evoked as a response to the acute pharmacological or physiologic effects triggered by the treatment. We review evidence that supports the notion that various treatments with a rapid onset of action, such as ketamine, electroconvulsive therapy, and sleep deprivation, share the ability to acutely excite cortical networks, which increases synaptic potentiation, alters patterns of functional connectivity, and ameliorates depressive symptoms. We proceed to examine how the initial effects are short-lived and, as such, require both consolidation during wake and maintenance throughout sleep to remain sustained. Here, we incorporate elements from the synaptic homeostasis hypothesis and theorize that the fundamental mechanisms of synaptic plasticity and sleep, particularly the homeostatic emergence of slow-wave electroencephalogram activity and the renormalization of synaptic strength, are at the center of sustained antidepressant effects. We conclude by discussing the various implications of the ENCORE-D hypothesis and offer several considerations for future experimental and clinical research.

Background and objectives

Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion–transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl–CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.

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.

Venous thromboembolism (VTE), as a term that encompasses pulmonary embolism (PE) and deep vein thrombosis (DVT), is one of the leading causes of maternal morbidity and mortality [1], especially in developed countries, where PE takes second place after complications of hypertensive disorders [2]. When compared to non-pregnant women of similar age, pregnant women have an approximately four to five times higher risk of VTE [3], with an incidence of 1 in 1000 pregnancies [4]. Approximately 20–25% of VTE cases are caused by PE and 75–80% of cases are caused by DVT [5]. About 60% of DVT occurs antepartum, with the highest risk of antepartum pregnancy-associated VTE being in the third trimester.However, about 60% of PE occurs postpartum [3].

Purpose:

Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus. As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

Enterococcus faecium strains are commonly resistant to vancomycin and β-lactams. In addition, E. faecium often causes biofilm-associated infections and these infections are difficult to treat. In this context, we investigated the activity of dosing regimens using daptomycin (DAP) (8, 10, 12, and 14 mg/kg of body weight/day) alone and in combination with ceftaroline (CPT), ampicillin (AMP), ertapenem (ERT), and rifampin (RIF) against 2 clinical strains of biofilm-producing vancomycin-resistant Enterococcus faecium (VREfm), namely, strains S447 and HOU503, in an in vitro biofilm model. HOU503 harbors common LiaS and LiaR substitutions, whereas S447 lacks mutations associated with the LiaFSR pathway. MIC results demonstrated that both strains were susceptible to DAP and resistant to CPT, AMP, ERT, and RIF. The 168-h pharmacokinetic/pharmacodynamic (PK/PD) CDC biofilm reactor models (simulating human antibiotic exposures) were used with titanium and polyurethane coupons to evaluate the efficacy of antibiotic combinations. DAP 12 and 14 achieved bactericidal activity against S447 but lacked such effect against HOU503. Addition of ERT and RIF enhanced DAP activity, allowing DAP 8 and 10 plus ERT or RIF to produce bactericidal activity against both strains at 168 h. While DAP 8 and 10 plus CPT improved killing, they did not reach bactericidal reduction against S447. Combination of AMP, CPT, ERT, or RIF resulted in enhanced and bactericidal activity for DAP against HOU503 at 168 h. Our data provide further support for the use of combinations of DAP with AMP, ERT, CPT, and RIF in infections caused by biofilm producing VREfm. Further research involving DAP combinations against biofilm-producing enterococci is warranted.

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.

Windsor’s tech community came together Friday to share all the ways they are making the most of the COVID-19 pandemic. During an online event, leaders of seven local tech companies explained how they are dealing with, and capitalizing on the current pandemic. From the ability to scan facial temperatures, checking your blood for COVID-19 immunity, […]

We have to capture carbon dioxide to slow climate change, but instead of simply burying it we could first use it to extract useful metals from old electrical equipment

In the wake of Covid-19, We Are One: A Global Film Festival is taking the experience online. But cinema is a bigger encounter

Every year, at Cannes (and other festivals) there’s a plaintive argument about what Cannes (or other festivals) are really all “about”. Some Savonarola-type person will dash the glass of rosé out of your hand, throw your canape into the Med and tell you Cannes is not about red-carpet narcissism, not about stars preening in the flashbulb glare of celeb-worship, not about L’Oréal sponsorship, not about getting drunk at a million late-night parties. It’s about the movies, about cinema itself.

Of course. And that’s what the new Covid-19-related We Are One: A Global Film Festival appears to offer: the 10-day online festival, beginning 29 May, curated by Jane Rosenthal of the Tribeca film festival, featuring arthouse films (though not the big-ticket Hollywood items) from Cannes, Venice, Berlin and many more, streaming for free in return for an optional donation to the World Health Organization’s Covid-19 fund. So there you have it. A festival with all the frills and extras and flummeries stripped away. Just you, in your bedroom, with your laptop, communing with cinema. Isn’t that what it’s all about?

An analysis of the fossilized teeth of Deinonychus antirrhopus, a species of wolf-sized dromaeosaurid dinosaur that lived between 115 and 108 million years ago (Cretaceous period) in what is now the United States, adds to the growing evidence that this and other raptors were not complex social hunters by modern mammalian standards. The image of [...]

What film critics have to say about this week's new releases.

Stuck With U also saw Ariana confirm she's got a new beau.

Researchers have found that flies sleep more when they can't fly, possibly because sleeping helps them adapt to a challenging new situation.

The following is a brief roundup of the latest scientific studies on the novel coronavirus and efforts to find treatments and vaccines for COVID-19, the illness caused by the virus.

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UPDATE: War veteran, 99, hits £9 million for NHS as Matt Hancock calls him an 'inspiration'

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Follow our live Covid-19 updates HERE Coronavirus: The symptoms

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The Duke of Cambridge and his stepmother the Duchess of Cornwall have both written to Captain Tom Moore, 99, to congratulate him on smashing his NHS fundraising target.

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NHS staff and Carrie Symonds are among those who have thanked "inspirational" war veteran Captain Tom Moore during the weekly clap for carers.

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A motorcyclist has died after a crash on a busy road in north-east London.

War veteran Captain Tom Moore has now raised more than £20 million to help the NHS during the coronavirus crisis - twenty thousand times his initial target.

National treasure Captain Tom Moore, 99, will help open the newest NHS Nightingale hospital as a "guest of honour."

He has raised more than £25 million

The Duke of Sussex has said he's "incredibly proud" of the British public as the country rallies together to tackle the coronavirus crisis.

Captain Tom Moore and Michael Ball are on course to score a number one single for their cover of You'll Never Walk Alone.

New field hospital in Harrogate to provide 500 extra beds for Covid-19 patients

Fundraising hero Captain Tom Moore praised the NHS for doing a "magnificent job" as he opened Yorkshire's new Nightingale hospital via video link today.

War veteran Captain Tom Moore, who has raised £28 million for the NHS by walking lengths of his garden, has been sent tens of thousands of cards ahead of his 100th birthday.

War veteran Captain Tom Moore, who has raised £28 million for the NHS by walking lengths of his garden, has been given a Pride of Britain award.

War veteran Captain Tom Moore, who has raised millions for the NHS by walking lengths of his garden, has thanked The Weeknd for his "kind gesture" after the singer urged his fans to support the 99-year-old's single.

The Royal Navy is investigating reports that a nuclear submarine crew held a party after returning to their UK base while the rest of the country was under coronavirus lockdown.

These stunning images show some of the mesmerising sights captured by the Hubble Telescope during its 30 years of observing space.

All mail sent this week in the UK will be stamped with a special postmark to celebrate the 100th birthday of NHS fundraiser Captain Tom Moore.

A school in Bedfordshire has been flooded with thousands of cards from well wishers across the globe for Captain Tom Moore's upcoming 100th birthday.

Biggin Hill Heritage Hangar said it would instead fly The Spirit of Kent on a circuit around the Biggin Hill airfield at 8pm on Thursday, to coincide with the nation's weekly "Clap for our Carers" event.

Captain Tom Moore has sent a message to the nation saying he is "completely overwhelmed" by the love he has received ahead of his 100th birthday.

Captain Tom Moore has been appointed as an honorary colonel to mark his 100th birthday after raising almost £30 million for the NHS by walking laps of his garden.

Boris Johnson has hailed Captain Tom Moore a "point of light" in the lives of the nation as he led tributes to the war veteran on his 100th birthday.

The nine-year-old was inspired by hero fundraiser Captain Tom Moore's £30 million fundraiser