Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.

13 August 2020

Visual Abstract

Visual Abstract

The Wnt/β-catenin pathway is one of the major pathways that regulates embryonic development, adult homeostasis, and stem cell self-renewal. In this pathway, transcription factors T-cell factor and lymphoid enhancer factor (TCF/LEF) serve as a key switch to repress or activate Wnt target gene transcription by recruiting repressor molecules or interacting with the β-catenin effector, respectively. It has become evident that the protein stability of the TCF/LEF family members may play a critical role in controlling the activity of the Wnt/β-catenin signaling pathway. However, factors that regulate the stability of TCF/LEFs remain largely unknown. Here, we report that pVHL binding protein 1 (VBP1) regulates the Wnt/β-catenin signaling pathway by controlling the stability of TCF/LEFs. Surprisingly, we found that either overexpression or knockdown of VBP1 decreased Wnt/β-catenin signaling activity in both cultured cells and zebrafish embryos. Mechanistically, VBP1 directly binds to all four TCF/LEF family members and von Hippel-Lindau tumor-suppressor protein (pVHL). Either overexpression or knockdown of VBP1 increases the association between TCF/LEFs and pVHL and then decreases the protein levels of TCF/LEFs via proteasomal degradation. Together, our results provide mechanistic insights into the roles of VBP1 in controlling TCF/LEFs protein stability and regulating Wnt/β-catenin signaling pathway activity.

Aloïs Dusuel
Dec 9, 2020; 0:jlr.RA120000704v1-jlr.RA120000704
Research Articles

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.

After ejaculation, mammalian spermatozoa must undergo a process known as capacitation in order to successfully fertilize the oocyte. Several post-translational modifications occur during capacitation, including sialylation, which despite being limited to a few proteins, seems to be essential for proper sperm-oocyte interaction. Regardless of its importance, to date, no single study has ever identified nor quantified which glycoproteins bearing terminal sialic acid (Sia) are altered during capacitation. Here we characterize sialylation during mouse sperm capacitation. Using tandem MS coupled with liquid chromatography (LC–MS/MS), we found 142 nonreductant peptides, with 9 of them showing potential modifications on their sialylated oligosaccharides during capacitation. As such, N-linked sialoglycopeptides from C4b-binding protein, endothelial lipase (EL), serine proteases 39 and 52, testis-expressed protein 101 and zonadhesin were reduced following capacitation. In contrast, mitochondrial aconitate hydratase (aconitase; ACO2), a TCA cycle enzyme, was the only protein to show an increase in Sia content during capacitation. Interestingly, although the loss of Sia within EL (N62) was accompanied by a reduction in its phospholipase A₁ activity, a decrease in the activity of ACO2 (i.e. stereospecific isomerization of citrate to isocitrate) occurred when sialylation increased (N612). The latter was confirmed by N612D recombinant protein tagged with both His and GFP. The replacement of Sia for the negatively charged Aspartic acid in the N612D mutant caused complete loss of aconitase activity compared with the WT. Computer modeling show that N612 sits atop the catalytic site of ACO2. The introduction of Sia causes a large conformational change in the alpha helix, essentially, distorting the active site, leading to complete loss of function. These findings suggest that the switch from oxidative phosphorylation, over to glycolysis that occurs during capacitation may come about through sialylation of ACO2.

Homologous recombination (HR) repairs DNA double-strand breaks using intact homologous sequences as template DNA. Broken DNA and intact homologous sequences form joint molecules (JMs), including Holliday junctions (HJs), as HR intermediates. HJs are resolved to form crossover and noncrossover products. A mismatch repair factor, MLH3 endonuclease, produces the majority of crossovers during meiotic HR, but it remains elusive whether mismatch repair factors promote HR in nonmeiotic cells. We disrupted genes encoding the MLH3 and PMS2 endonucleases in the human B cell line, TK6, generating null MLH3−/− and PMS2−/− mutant cells. We also inserted point mutations into the endonuclease motif of MLH3 and PMS2 genes, generating endonuclease death MLH3DN/DN and PMS2EK/EK cells. MLH3−/− and MLH3DN/DN cells showed a very similar phenotype, a 2.5-fold decrease in the frequency of heteroallelic HR-dependent repair of restriction enzyme–induced double-strand breaks. PMS2−/− and PMS2EK/EK cells showed a phenotype very similar to that of the MLH3 mutants. These data indicate that MLH3 and PMS2 promote HR as an endonuclease. The MLH3DN/DN and PMS2EK/EK mutations had an additive effect on the heteroallelic HR. MLH3DN/DN/PMS2EK/EK cells showed normal kinetics of γ-irradiation–induced Rad51 foci but a significant delay in the resolution of Rad51 foci and a 3-fold decrease in the number of cisplatin-induced sister chromatid exchanges. The ectopic expression of the Gen1 HJ re-solvase partially reversed the defective heteroallelic HR of MLH3DN/DN/PMS2EK/EK cells. Taken together, we propose that MLH3 and PMS2 promote HR as endonucleases, most likely by processing JMs in mammalian somatic cells.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

The countdown to pitchers and catchers reporting is down to single digits for all 30 MLB clubs, but as exciting as it is to see the return of Major League stars, it's also a time to dream about the next wave of baseball talent.

Spring Training is imminent, Opening Day is within sight and the big league season isn't complete for fans without a subscription to MLB.TV. The most comprehensive streaming service in professional sports is now available for the 2019 season.

All 30 Major League teams will wear special "MLB 150" patches on their uniforms for the entire 2019 season in honor of the 150th anniversary of the 1869 Cincinnati Red Stockings, the first openly all-salaried professional baseball team.

Shohei Ohtani remains a must-watch player for Angels fans in 2019, and his recovery from Tommy John surgery will be worth monitoring throughout the season as he prepares to pitch again in '20.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

South Africa’s ANC party policy conference 2022: Outcomes and prospects 10 August 2022 — 1:00PM TO 2:00PM Anonymous (not verified) 4 August 2022 Online

Paul Mashatile, Treasurer-General of the African National Congress (ANC), discusses the outcomes of the 6th ANC Policy Conference 2022.

The African National Congress (ANC) recently concluded its 6th National Policy Conference in Johannesburg, in the year that the ANC has declared ‘The Year of Unity and Renewal to Defend and Advance South Africa’s Democratic Gains’. The conference was a precursor to the party’s 55th National Elective Conference to be held in December.

The conference has come less than a year after municipal polls in which the ANC garnered less than 50 per cent of votes, its lowest since 1994. Many believe internal factionalism is impeding party reform and hampering its ability to address unemployment and entrenched inequality.

At this webinar, Paul Mashatile, Treasurer-General of the ANC, will discuss the outcomes of the ANC Policy Conference 2022, including measures to accelerate inclusive growth, job creation and a just energy transition.

This event will also be broadcast live on the Chatham House Africa Programme’s Facebook page.

Ten conflicts to watch in 2023 11 January 2023 — 6:00PM TO 7:00PM Anonymous (not verified) 8 December 2022 Chatham House and Online

This event examines the most dangerous wars and crises through the lens of the International Crisis Group’s flagship annual report ‘10 Conflicts to watch in 2023’.

Each year, International Crisis Group compiles a list of the ten conflicts to watch that examines key conflicts across the globe. Please join us for this event at which Dr Comfort Ero, International Crisis Group president and CEO, discusses today’s and tomorrow’s most impactful wars and crises.

Key questions to consider include:

• What far-reaching repercussions and knock-on effects of Russia’s war on Ukraine will have for Europe and the rest of the world?

• Which crises beyond Ukraine warrant collective attention in the year ahead?

• How do rising tensions among major powers impact multilateral efforts to resolve these conflicts, impede progress on global challenges and impact institutions working on crisis prevention?

As with all members events, questions from the audience drive the conversation.

Read the transcript. 

Can rhetoric match reality? Britain’s international development future 27 April 2023 — 9:00AM TO 10:00AM Anonymous (not verified) 12 April 2023 Chatham House and Online

In conversation with Andrew Mitchell, minister of state, UK Foreign, Commonwealth and Development Office. 

Last month’s updated Integrated Review positioned international development as a key pillar of British foreign policy which sets out the importance of the UK’s efforts to shape the ‘global strategic environment’.

Focusing heavily on Africa and the Indo-Pacific, international development will be central to the ambition of a ‘Global Britain’.

The Integrated Review outlines seven priority areas to revitalize the drive to meet the Global Goals, with a climate security strategy at its heart, while seeking to go beyond official development assistance (ODA).

However, there are major challenges ahead. Since 2021, the UK’s ODA has been cut from 0.7 per cent to 0.5 per cent gross national income (GNI). Some are concerned that since being subsumed by the UK Foreign Office, the UK Foreign, Commonwealth and Development Office has diluted the effectiveness of UK international development. Then there is the question of the strength of British public support for development assistance at a time of domestic economic hardship.

Can rhetoric match reality?

This event tackles questions including:

• What does the UK’s vision for international development mean in practice?
• Will aid and development help push Britain’s influence around the world?
• Can policymakers and politicians garner domestic support for international aid in times of economic uncertainty, and if so, how?
• Can the UK rebuild its reputation in the world while it doesn’t meet its 0.7 per cent GNI target?

This event will be balloted for in-person attendance. Register your interest to join and a confirmation email will be sent to you on Tuesday 25 May at 12:00 BST to confirm your place at the event.

As with all member events, questions from the audience drive the conversation.

A coffee reception will immediately follow this event.

Issues to watch in 2023 The World Today mhiggins.drupal 29 November 2022

From nuclear proliferation to African debt, here are the issues six of our expert contributors expect to make the news in the year ahead.

Europe’s energy outlook

Mike Bradshaw, Professor of Global Energy, Warwick Business School

There is cautious optimism that Europe will endure this winter without an energy crisis. Gas prices have fallen, storage is 95 per cent full, and the autumn was mild. High summer gas prices cut industrial demand but domestic heating demand will be critical over the winter. Already, France’s problematic nuclear fleet and lower hydroelectric output mean Europe is using more gas to generate power. 

Russian pipeline gas supply to southern Europe has fallen by 55 per cent. While Asian demand has fallen, Europe has still paid record prices to secure additional liquefied natural gas (LNG), largely from America but also Russia. European demand for LNG this winter will push prices up, and these will rise even higher if China relaxes its Zero-Covid policy and demand recovers. However, with luck, Europe will avoid power cuts in early 2023. The problem is next winter. With less Russian pipeline gas and a tight LNG market, 90 per cent winter gas storage levels will be much harder to achieve. 

NATO’s resurgence

Alice Billon-Galland, Research Fellow, Europe Programme, Chatham House and one of 14 NATO Young Leaders

In response to Russia’s invasion of Ukraine, NATO adopted a new strategic concept. Member states will reinforce NATO battlegroups and bolster higher readiness forces from 40,000 troops to more than 300,000, while striving to avoid escalation with Russia. Turkey’s attempts to block Sweden and Finland’s NATO membership will preoccupy Jens Stoltenberg, the Secretary-General, until he leaves his post next autumn.

Expect arguments on defence spending in the run-up to the July summit in Vilnius. Although only nine of its 30 members are expected to meet the 2 per cent spending target, the debate is moving towards 3 per cent, in part to reduce dependency on American assets and hedge against the uncertainty of the 2024 US presidential election. Infrastructure vulnerabilities, such as the Nord Stream pipeline sabotage in the Baltic, will also be a focus. Otherwise, NATO ’s eyes will be on China: from its relations with Russia to the threat of cyberattacks.

Universal health reforms

Robert Yates, Executive Director, Centre for Universal Health, Chatham House

In response to the perma-crisis experienced by many populations this past year, some leaders are launching or extending universal health reforms. New left-wing leaders in Chile, Colombia and Brazil have promised to rebuild their publicly financed universal health systems. In Brazil, newly elected president Lula da Silva has pledged to increase public health spending and improve access to medicines. It is hoped Malaysia’s new coalition will carry forward its predecessor’s pledge to raise health spending to 5 per cent of GDP by 2027 to provide a universal package of free health services.

In September, world leaders will discuss universal health coverage at the UN General Assembly. There, Chatham House will publish its Commission for Universal Health report, identifying countries in which crises may trigger new national health programmes. Might this be when a US presidential candidate announces a platform to create a publicly financed health system?

Weapons of mass destruction

Patricia Lewis, Director of the International Security Programme, Chatham House

Since its illegal invasion of Ukraine, Russia has attacked civil nuclear power stations, falsely accused Ukraine of possessing bioweapons and radiological bombs, and threatened to use nuclear weapons. In contrast, NATO has instead demonstrated that deterrence can be highly effective with conventional weaponry. In the coming year, the Kremlin’s nuclear brinkmanship will still be a focus. Washington will try to restart bilateral nuclear negotiations with Moscow and similarly try to engage Beijing.

Following the failure of the nuclear Non-Proliferation Treaty Review Conference to reach consensus in August, the next review cycle will start by looking at strengthening the process. Iran’s nuclear capabilities remain a concern, and North Korea’s nuclear weapons programme is a growing threat. So, we are left with a question: will 2023 be the year of  nuclear conflict or the year when states get busy again on non-proliferation and disarmament?  

Africa’s mounting debt

Joseph Asunka, Chief Executive Officer, Afrobarometer

Inflation is at historic highs in several African economies. Meanwhile, many African countries including Nigeria, Zimbabwe and Democratic Republic of Congo will hold  elections in 2023, driving up public spending, increasing inflationary pressures and exacerbating poverty. According to Afrobarometer data, the proportion of Africans experiencing high levels of poverty has increased from 19 per cent in 2014/2015 to  26 per cent in 2021/2022.

Worse still, many of those countries holding elections are either, like Zimbabwe, in debt distress – that is unable to honour their obligations to creditors – or at high risk of debt distress, like Nigeria. This makes the elections in Zimbabwe and Nigeria critical. The expiration of the World Bank/IMF-backed debt service suspension initiative in 2021 has only amplified this risk. What are viable policy options to tackle this dire economic predicament? A debt service moratorium, debt cancellation and serious attention to fiscal discipline.

Feminist foreign policy

Daniela Philipson García, Co-founder of Internacional Feminista, and a PhD candidate, Monash University

Feminist Foreign Policy (FFP) is under threat. The war in Ukraine led to strengthened military budgets and alliances at odds with FFP’s human security and peace-centred approaches. Sweden’s new right-wing government reversed its FFP. In Mexico, the first Global South country to adopt an FFP, Congress has voted to expand the military’s role to curb cartel-related violence, in contradiction of its FFP. The second anniversary of the US withdrawal from Afghanistan will be a moment to assess how foreign policy, diplomacy and women’s and girls’ rights have been affected globally. 

There is hope. Germany, whose coalition government adopted an FFP in 2021, is to publish more guidelines in the spring. The governments of Colombia and Chile have announced their own FFPs. Colombia’s first National Action Plan on Women, Peace and Security, to be announced at the UN General Assembly in September, is expected to set a standard for a region submerged in violence. 

C-X-C motif chemokine receptor 4 (CXCR4)–directed imaging has gained clinical interest in aiding clinical diagnostics in primary aldosteronism (PA). We retrospectively evaluated the feasibility of CXCR4-directed scintigraphy using the novel CXCR-4 ligand [^99mTc]Tc-pentixatec in patients with PA. Methods: Six patients (mean age ± SD, 49 ± 15 y) underwent CXCR4-directed scintigraphy (including planar imaging and SPECT/CT) 30, 120, and 240 min after injection of 435 ± 50 MBq of [^99mTc]Tc-pentixatec. Adrenal CXCR4 expression was analyzed by calculating lesion-to-contralateral ratios (LCRs). Imaging results were correlated to clinical information. Histopathology and clinical follow-up served as the standard of reference. Results: Three subjects showed lateralization of adrenal tracer accumulation, with a mean maximum lesion-to-contralateral ratio of 1.65 (range, 1.52–1.70), which correlated with morphologic findings on CT. One individual underwent adrenalectomy and presented with complete biochemical and clinical remission at follow-up. Histopathologic workup confirmed unilateral aldosterone-producing adenoma. Conclusion: [^99mTc]Tc-pentixatec scintigraphy with SPECT in patients with PA is feasible and might offer a valuable alternative to CXCR4-directed imaging with [⁶⁸Ga]Ga-pentixafor PET.

Planet Fitness is seeking to further grow its number of locations in a second bid for the Blink Fitness chain of workout facilities, according to new reports.

Costco voluntarily recalled 79,200 pounds of two types of its store-brand butter over the past month because their labels may not have said the products contain milk.

A hologram of a sex worker who was murdered in Amsterdam more than a decade ago could help solve the cold case, investigators hope.

A British daredevil was intentionally dragged behind his motorcycle at a speed of 159.52 mph to break a Guinness World Record.

Police in a small South Carolina town are warning residents to keep their doors and windows locked after 43 monkeys escaped from a research facility.

A black bear with a sweet tooth visited the front porch of a Connecticut home to raid a bowl of Halloween candy and steal a pumpkin.

The 2024 Egg Fair in Mexico broke a Guinness World Record when more than 2,000 young people participated in a race while balancing eggs on spoons.

Mysterious black balls that washed up on Sydney, Australia, beaches were initially suspected to be tar balls but turned out to be miniature "fatbergs" containing human feces.

An emperor penguin is being cared for by wildlife experts after becoming the first member of its species to make the 2,200-mile trek from Antarctica to Australia.

A British YouTube star and professional wrestling superfan showed off his knowledge by breaking the Guinness World Record for the most WWE wrestlers identified by their entrance music in one minute.

A baby goat stranded on a Hawaii cliff was rescued by members of the public after four days.

A wallaby on the loose in Kentucky was caught on security camera during a nighttime visit to a Perry County family's front yard.

The U.S. Space Force will take over satellite communications billets, funding and mission responsibility from the U.S. Army and Navy, the Department of Defense announced Wednesday.

A Missouri thrift store is unraveling the mystery of a cache of World War II love letters found in a donation bin.

Costco voluntarily recalled 79,200 pounds of two types of its store-brand butter over the past month because their labels may not have said the products contain milk.

A Rhode Island man with a passion for caffeine earned a Guinness World Record for his collection of 1,019 energy drink cans.

A new HBO Max teaser offers a glimpse of the upcoming shows viewers can look forward to in the next year.

Paramount Pictures is teasing "Mission: Impossible -- The Final Reckoning," starring Tom Cruise.

MTV's Europe Music Awards included a heartfelt tribute to late musician Liam Payne.

"Alien: Earth," "Andor" Season 2, "The Bear" Season 4, "Daredevil: Born Again" and other Disney+ and Hulu series will premiere in 2025.

Hulu released the trailer for "Nutcrackers" Tuesday. The Ben Stiller holiday comedy premieres Nov. 29.

President-elect Donald Trump announced his choice Tuesday for CIA Director, tapping his former intelligence chief John Ratcliffe, who he called a "warrior of truth."

The U.S. military conducted retaliatory airstrikes Tuesday in Syria, targeting facilities of Iran-backed militias following rockets launched at U.S. forces in the Middle Eastern country.

SpaceX launched 23 Starlink satellites from Cape Canaveral Space Force Center on Wednesday to match its own record of launches in one year.