Video is beginning to fulfill its promise as a transformational technology. Beyond merely cutting communications costs, video is starting to change the way companies do business, and is rapidly being accepted as a "need to have" rather than a "nice to have."

Cisco CEO John Chambers predicts video traffic on the internet will increase six fold by 2012. Here is a link to Cisco's August 5 earnings call where he makes that prediction.

A classic example of the power of video is that of electronics manufacturer NEC. They have a network of nearly 500 dealers across the United States that sell their products. They saved more than $250,000 annually in training costs by delivering product training with video webcasting rather than sending trainers to the dealers or bringing the dealers to the trainers.

They also dramatically reduced the time it takes to train the entire network on new products. Click here to watch a video case study.

A newer example shows how video can literally transform the way a company does business. A major sneaker company manufacturers its products in China. Each time they re-tooled to manufacture a new sneaker, executives would have to fly to China to ensure the tooling was correct and the sneakers were meeting specifications before they began mass production.

They began to use high definition cameras at the plant in China to webcast video of the sneakers to allow executives to make their inspection virtually. Sure, they save money on travel to China. But more importantly, there was a practical limit to the amount of people who could go to China to see the actual design come off the assembly line. The video process allows them to solicit input from a much broader segment of the company, and even get input from retailers while there is still time to respond to suggestions.

The end result is that they can bring their products to market faster than their competition, which creates a significant competitive advantage. Click here to see the video discussion.

I am particularly pleased to see clear evidence of unmistakable, game-changing ROI.

Here is a link to a recent post by Roger Courville on his "The Virtual Presenter" blog. It reads

A VFAQ (VERY frequently asked question) I get is “what’s the difference between web conferencing, webinars, and webcasts?”

The short answer, these days, is “not very much and a whole bunch.”

Seriously, the lines have blurred from the days that “webcasting” was akin to broadcasting (using streaming media) with virtually no interactivity, whereas web conferencing was (and remains) live, totally realtime (you don’t want any delay when you’re talking on a phone conference, right? In many use cases, you don’t on the web either).

Webinar is simply a portmanteau of web seminar – arguably a use case rather than a technology. That is brief, but it’s as deep as I’m going as I introduce IVT and their enterprise video communications.

I recently had the pleasure of speaking with Mitch, Hugh, Jim, and Ryan, all at the same time. In addition to the knowledge and passion and history (Hugh’s a fellow ex-Microsoftie with some common connections), what I’m most enthused by is their clarity of mission.

Hello software

First, IVT’s a software company. You can host the software, but for reasons I’ll not get into, you want to take advantage of the fact that they host the software for you. What’s interesting here isn’t a “right or wrong,” it’s a commitment to a business model. Many (if not most) companies who have solutions for webcasting also provide professional production/event management services. IVT is committed to their robust partner community who deliver value-added services atop the IVT platform. Again, this isn’t a right or wrong, but you have to appreciate focus.

Hello production tools

It’s hard to tell you how important the backend of a product is. It’s what economists call an “experience good” …you have to have been there to get it and appreciate it. As it just so happens I spent many years running organizations in the production business, let me say the two words that will bring any accountants to their needs and get the producers all excited: labor and labor. Labor is expensive. Technology, especially over time, often gets less expensive. If you’ve ever produced an event, let alone a bunch of them, you know that the project management time can create a big sucking sound in your budget. This is where producers get excited… not only will they find the flexibility on the back end of IVT’s platform a joy when meeting numerous and disparate client/stakeholder needs, but it’ll save them time.

Hello customization

Okay, so many different solutions offer degrees of customization, but far fewer have down-to-the-pixel capabilities. When clients demand that, you’ve got to deliver. Further, there’s customization of user experiences, such as different tools you might make available to a presenter versus what the marketing department sees when they need to pull down a report. And then there are web services for the data integration geeks (I say that with love, mind you).

Hello remote presenters – but wait, there’s more

A point of differentiation here is multiple presenters, each with different camera types. One can have a webcam in Sydney, one can be standing in front of a hi-def broadcast camera at a conference in a New York hotel…you get the idea. Need to switch back and forth like a television newscast? Can do.

As is my style, my goal isn’t a vendor-by-vendor shootout, to talk about price, or make a recommendation. I’m excited and privileged to be independent, talk to great people with their own angle on the market, and share with you my own spin on it. It sounds like IVT has a solution if you need to reasonably reach 100 people and the horsepower to reach 20K if you need. If you need flexibility and reach and a commitment to knowing their core biz, IVT (or one of their partners) might be someone to add to your must-investigate list.

As the article appeared in TechCrunch...

IVT, a company that produces enterprise-friendly webcasting software, has raised $5.5 million in Series B funding from Syncom Venture Partners with Barshop Ventures, Monitor Ventures and Tudor Ventures participating in the investment round. IVT raised $3 million in Series A funding in 2006.
IVT’s SaaS offering not only helps power webcasts, but also converts multimedia files, such as slideshows, into viewable videos for the web. IVT also offers a YouTube-like hosting and social media site for companies to disseminate videos and webcasts. And the startup has a number of prominent companies that use its webcasting software including Oracle, Dow Chemical, IBM and NEC.

The following article, Will These Deranged Celebrities Who Promised To End Their Lives Or Flee The Country If Trump Wins Actually Follow Through?, was first published on Conservative Firing Line.

(Natural News) Similar to what happened in 2016, a host of celebrities and influencers made wild claims that they would leave the country or even end their lives if Donald Trump won another term in the White House. Will any of them actually follow through? Take Rob Reiner, for instance. He promised to “set himself on …

Continue reading Will These Deranged Celebrities Who Promised To End Their Lives Or Flee The Country If Trump Wins Actually Follow Through? ...

Video: Merlin Mann - "Time & Attention Talk (improvised)"

Audio (mp3): "Merlin Mann - 'Rutgers Time & Attention Talk'"

This is a talk I did at Rutgers earlier this month. I kinda like it, but for a weird reason. Something something, perfect storm of technology Ragnarok, and yadda yadda, I had to start the talk 20 minutes late with no slides. Nothing.

So, I riffed.

And, I ended up talking about a lot of the new stuff you can expect to see in the Inbox Zero book—work culture, managing expectations, the 3 deadly qualities of email, and one surprising reason email's not as much fun as Project Runway.

Some people liked it. I think. I liked it. I hope you do, too.

Here's the slides I would have shown. ;-)

Many thanks, again, to my great pal, Dr. Donald Schaffner, for bringing me in for this visit. I had a great time and met some fantastic, passionate people. Much appreciated.

update 2010-04-27_13-50-00

Apologies—my friends at Rutgers (inexplicably) have placed this video under lock and key. Fortunately, I have a lock-picker called Firefox. Samizdat video available soon...

update 2010-04-27_14-42-24

Yay, fixed! Many thanks to my hero, Jesse Schibilia.

Bafana Bafana coach Hugo Broos has welcomed the number of young players who are given a chance and backed in the premier division, but has warned that to build on their progress, agents must prioritise players' development over their personal enrichment.

Evidence Makgopa wore a sheepish smile when Bafana Bafana coach Hugo Broos showered him with praise before literally patting the forward on the back, making him blush at Dobsonville Stadium.

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities.

Dilated cardiomyopathy (DCM) is associated with mutations in cardiomyocyte sarcomeric proteins, including α-tropomyosin. In conjunction with troponin, tropomyosin shifts to regulate actomyosin interactions. Tropomyosin molecules overlap via tropomyosin–tropomyosin head-to-tail associations, forming a continuous strand along the thin filament. These associations are critical for propagation of tropomyosin's reconfiguration along the thin filament and key for the cooperative switching between heart muscle contraction and relaxation. Here, we tested perturbations in tropomyosin structure, biochemistry, and function caused by the DCM-linked mutation, M8R, which is located at the overlap junction. Localized and nonlocalized structural effects of the mutation were found in tropomyosin that ultimately perturb its thin filament regulatory function. Comparison of mutant and WT α-tropomyosin was carried out using in vitro motility assays, CD, actin co-sedimentation, and molecular dynamics simulations. Regulated thin filament velocity measurements showed that the presence of M8R tropomyosin decreased calcium sensitivity and thin filament cooperativity. The co-sedimentation of actin and tropomyosin showed weakening of actin-mutant tropomyosin binding. The binding of troponin T's N terminus to the actin-mutant tropomyosin complex was also weakened. CD and molecular dynamics indicate that the M8R mutation disrupts the four-helix bundle at the head-to-tail junction, leading to weaker tropomyosin–tropomyosin binding and weaker tropomyosin–actin binding. Molecular dynamics revealed that altered end-to-end bond formation has effects extending toward the central region of the tropomyosin molecule, which alter the azimuthal position of tropomyosin, likely disrupting the mutant thin filament response to calcium. These results demonstrate that mutation-induced alterations in tropomyosin–thin filament interactions underlie the altered regulatory phenotype and ultimately the pathogenesis of DCM.

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

Heterotrimeric G-proteins are signaling switches broadly divided into four families based on the sequence and functional similarity of their Gα subunits: Gs, Gi/o, Gq/11, and G12/13. Artificial mutations that activate Gα subunits of each of these families have long been known to induce oncogenic transformation in experimental systems. With the advent of next-generation sequencing, activating hotspot mutations in Gs, Gi/o, or Gq/11 proteins have also been identified in patient tumor samples. In contrast, patient tumor-associated G12/13 mutations characterized to date lead to inactivation rather than activation. By using bioinformatic pathway analysis and signaling assays, here we identified cancer-associated hotspot mutations in Arg-200 of Gα13 (encoded by GNA13) as potent activators of oncogenic signaling. First, we found that components of a G12/13-dependent signaling cascade that culminates in activation of the Hippo pathway effectors YAP and TAZ is frequently altered in bladder cancer. Up-regulation of this signaling cascade correlates with increased YAP/TAZ activation transcriptional signatures in this cancer type. Among the G12/13 pathway alterations were mutations in Arg-200 of Gα13, which we validated to promote YAP/TAZ-dependent (TEAD) and MRTF-A/B-dependent (SRE.L) transcriptional activity. We further showed that this mechanism relies on the same RhoGEF-RhoGTPase cascade components that are up-regulated in bladder cancers. Moreover, Gα13 Arg-200 mutants induced oncogenic transformation in vitro as determined by focus formation assays. In summary, our findings on Gα13 mutants establish that naturally occurring hotspot mutations in Gα subunits of any of the four families of heterotrimeric G-proteins are putative cancer drivers.

The inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IP3Rs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IP3R function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized. Moreover, many of these diseases occur as the result of autosomal dominant inheritance, suggesting that WT and mutant subunits associate in heterotetrameric channels. How the in-corporation of different numbers of mutant subunits within the tetrameric channels affects its activities and results in different disease phenotypes is also unclear. In this report, we investigated representative disease-associated missense mutations to determine their effects on IP3R channel activity. Additionally, we designed concatenated IP3R constructs to create tetrameric channels with a predefined subunit composition to explore the functionality of heteromeric channels. Using calcium imaging techniques to assess IP3R channel function, we observed that all the mutations studied resulted in severely attenuated Ca2+ release when expressed as homotetramers. However, some heterotetramers retained varied degrees of function dependent on the composition of the tetramer. Our findings suggest that the effect of mutations depends on the location of the mutation in the IP3R structure, as well as on the stoichiometry of mutant subunits assembled within the tetrameric channel. These studies provide insight into the pathogenesis and penetrance of these devastating human diseases.

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

Mark Carney to chair Chatham House senior advisers News release NCapeling 17 May 2022

Former Bank of England Governor Mark Carney will succeed Sir John Major as chair of Chatham House’s Panel of Senior Advisers.

Chatham House is pleased to announce Mark Carney will succeed Sir John Major as chair of the institute’s Panel of Senior Advisers.

Chatham House senior advisers bring deep, first-hand experience of the policy and business worlds and use their experience, knowledge and networks to advise the institute’s research agenda and disseminate its policy ideas.

Mark Carney is currently United Nations (UN) Special Envoy on Climate Action and Finance, UK prime minister Boris Johnson’s special finance adviser on COP26, as well as vice chairman and head of transition investing at Brookfield Asset Management.

He served as Governor of the Bank of England between 2013 and 2020 and as Governor of the Bank of Canada between 2008 and 2013.

Robin Niblett, director and chief executive of Chatham House says: ‘We are delighted to benefit from Mark Carney’s wealth of experience at the highest levels of decision-making on international financial policy, crisis management, and sustainability.

‘His personal commitment to leveraging economic and finance policies to combat climate change aligns with a central plank of the institute’s mission to help governments and societies build a sustainable future.

‘I also want to thank Sir John Major for his invaluable advice and support through such a pivotal time in the institute’s history; we are delighted that he will retain an affiliation as a President Emeritus of Chatham House.’

Sir Nigel Sheinwald, chair of Chatham House, says: ‘Mark Carney is perfectly placed to lead the institute’s Panel of Senior Advisers and help ensure our research is focused on improving international relations in practical ways.

‘His experience and expertise will be of great value as the institute undertakes a leadership transition and welcomes Bronwen Maddox as its new director in the autumn.

‘The Chatham House council greatly appreciates Mark Carney’s engagement in our future success, as we do Sir John’s commitment to the institute these past thirteen years.’

Mark Carney says: ‘I have long respected Chatham House as one of the world’s leading independent institutes on international policy and am honoured to take up the reins from Sir John Major of chairing its eminent Panel of Senior Advisers. Alongside other members of the panel, I look forward to contributing to the relevance and impact of Chatham House’s important work.’

In addition to having been Governor of the Bank of England and the Bank of Canada, Mark Carney also chaired the Financial Stability Board from 2011 to 2018 and, in 2015, established the Task Force on Climate Related Financial Disclosures.

In 2021, he launched the Glasgow Financial Alliance for Net Zero, to unite net-zero financial sector-specific alliances from across the world into one industry-wide strategic alliance.

Chatham House established the Panel of Senior Advisers in 2009, under Sir John’s Major’s chairmanship, to support the institute in achieving its mission to build a sustainably secure, prosperous and just world.

Individually and collectively, members of the panel support the institute in achieving its mission by advising on new topics for debate, offering input to the institute’s research, contributing to its private and public meetings, and disseminating the institute’s ideas across their networks.

The panel does not have governance responsibilities, which reside fully with the Chatham House council.

Independent Thinking: US midterms surprise, COP27 begins Audio NCapeling 11 November 2022

The fourth episode of our new podcast analyses early results from the US midterm elections and brings the latest insights from a crucial COP27.

The US midterm elections threw up some surprising results with the anticipated Republican ‘red wave’ failing to materialize. Meanwhile at COP27 in Egypt, world leaders met in the first week of the summit. What did their presence achieve?

To find out, returning to the podcast this week with Bronwen Maddox are Leslie Vinjamuri, director of the Chatham House US and Americas programme who was in Atlanta Georgia for the midterms, and Anna Aberg, research associate in the Environment and Society programme who is on the ground at COP27.

Joining them are Peter Trubowitz, professor of international relations and director of the Phelan US Centre at the London School of Economics and Antony Froggart, deputy director and senior research fellow in the Environment and Society programme.

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

Synapse loss is associated with motor and cognitive decline in multiple neurodegenerative disorders, and the cellular redistribution of tau is related to synaptic impairment in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Here, we examined the cellular distribution of tau protein species in human tau overexpressing line 66 mice, a transgenic mouse model akin to genetic variants of frontotemporal dementia. Line 66 mice express intracellular tau aggregates in multiple brain regions and exhibit sensorimotor and motor learning deficiencies. Using a series of anti-tau antibodies, we observed, histologically, that nonphosphorylated transgenic human tau is enriched in synapses, whereas phosphorylated tau accumulates predominantly in cell bodies and axons. Subcellular fractionation confirmed that human tau is highly enriched in insoluble cytosolic and synaptosomal fractions, whereas endogenous mouse tau is virtually absent from synapses. Cytosolic tau was resistant to solubilization with urea and Triton X-100, indicating the formation of larger tau aggregates. By contrast, synaptic tau was partially soluble after Triton X-100 treatment and most likely represents aggregates of smaller size. MS corroborated that synaptosomal tau is nonphosphorylated. Tau enriched in the synapse of line 66 mice, therefore, appears to be in an oligomeric and nonphosphorylated state, and one that could have a direct impact on cognitive function.

Lord Hammond Joins Panel of Senior Advisers News Release NCapeling 10 December 2020

Chatham House is pleased to announce that Lord Hammond of Runnymede is joining our Panel of Senior Advisers.

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

Expert

Environmental Change and Emerging Diseases 28 October 2020 — 3:00PM TO 4:00PM Anonymous (not verified) 13 October 2020 Online

Understanding how environmental changes are directly and indirectly affecting the emergence and spread of disease has assumed global importance.

There is growing awareness that deforestation and land-use conversion, urbanization, human migration, international commerce, and climate change are having significant impacts on human health, but their impact on increasing infectious disease risks has only become more evident with the coronavirus pandemic.

With climate change, and environmental change more generally, disrupting ecologies, and people interacting with wildlife in new ways, it creates the conditions for new diseases to emerge: a better understanding of the health dimensions of environmental change will be critical to managing pandemic risks in future. 

Our event will examine the relationship between environmental change and disease, how these linkages have manifested in historical outbreaks and in the coronavirus pandemic, and the role of environmental policies in minimizing the risk of future emerging diseases.  What can be done to ensure equitable action? What can we learn from our responses to previous pandemics? And will the growing recognition of the diverse risks arising from climate change motivate more climate action?

This event will launch the Energy, Environment and Resources (EER) Programme’s Environment and Society Discussion Series. This series aims to provide a platform to promote interdisciplinary knowledge sharing and policy dialogue to mitigate and adapt to the impacts that climate change, biodiversity loss and natural resource depletion are having on people and communities globally, and on geopolitics, security and international development.

Sign up to find out about more events in this series here. 

David M. Williams and Qingguo Hong
Math. Comp. 93 (), 2587-2609.
Abstract, references and article information

Jong In Han and Sijong Kwak
Trans. Amer. Math. Soc. 377 (), 5561-5581.
Abstract, references and article information

The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.

Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases.

Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.

Infiltration of peripheral immune cells after blood-brain barrier dysfunction causes severe inflammation after a stroke. Although the endothelial glycocalyx, a network of membrane-bound glycoproteins and proteoglycans that covers the lumen of endothelial cells, functions as a barrier to circulating cells, the relationship between stroke severity and glycocalyx dysfunction remains unclear. In this study, glycosaminoglycans, a component of the endothelial glycocalyx, were studied in the context of ischemic stroke using a photochemically induced thrombosis mouse model. Decreased levels of heparan sulfate and chondroitin sulfate and increased activity of hyaluronidase 1 and heparanase (HPSE) were observed in ischemic brain tissues. HPSE expression in cerebral vessels increased after stroke onset and infarct volume greatly decreased after co-administration of N-acetylcysteine + glycosaminoglycan oligosaccharides as compared with N-acetylcysteine administration alone. These results suggest that the endothelial glycocalyx was injured after the onset of stroke. Interestingly, scission activity of proHPSE produced by immortalized endothelial cells and HEK293 cells transfected with hHPSE1 cDNA were activated by acrolein (ACR) exposure. We identified the ACR-modified amino acid residues of proHPSE using nano LC–MS/MS, suggesting that ACR modification of Lys139 (6-kDa linker), Lys107, and Lys161, located in the immediate vicinity of the 6-kDa linker, at least in part is attributed to the activation of proHPSE. Because proHPSE, but not HPSE, localizes outside cells by binding with heparan sulfate proteoglycans, ACR-modified proHPSE represents a promising target to protect the endothelial glycocalyx.

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired U2AF2 mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical AdML polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired U2AF2 mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.

Chorismate mutase (CM), an essential enzyme at the branch-point of the shikimate pathway, is required for the biosynthesis of phenylalanine and tyrosine in bacteria, archaea, plants, and fungi. MtCM, the CM from Mycobacterium tuberculosis, has less than 1% of the catalytic efficiency of a typical natural CM and requires complex formation with 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase for high activity. To explore the full potential of MtCM for catalyzing its native reaction, we applied diverse iterative cycles of mutagenesis and selection, thereby raising kcat/Km 270-fold to 5 × 105 m−1s−1, which is even higher than for the complex. Moreover, the evolutionarily optimized autonomous MtCM, which had 11 of its 90 amino acids exchanged, was stabilized compared with its progenitor, as indicated by a 9 °C increase in melting temperature. The 1.5 Å crystal structure of the top-evolved MtCM variant reveals the molecular underpinnings of this activity boost. Some acquired residues (e.g. Pro52 and Asp55) are conserved in naturally efficient CMs, but most of them lie beyond the active site. Our evolutionary trajectories reached a plateau at the level of the best natural enzymes, suggesting that we have exhausted the potential of MtCM. Taken together, these findings show that the scaffold of MtCM, which naturally evolved for mediocrity to enable inter-enzyme allosteric regulation of the shikimate pathway, is inherently capable of high activity.

Zinc is a critical element for insulin storage in the secretory granules of pancreatic beta cells. The islet-specific zinc transporter ZnT8 mediates granular sequestration of zinc ions. A genetic variant of human ZnT8 arising from a single nonsynonymous nucleotide change contributes to increased susceptibility to type-2 diabetes (T2D), but it remains unclear how the high risk variant (Arg-325), which is also a higher frequency (>50%) allele, is correlated with zinc transport activity. Here, we compared the activity of Arg-325 with that of a low risk ZnT8 variant (Trp-325). The Arg-325 variant was found to be more active than the Trp-325 form following induced expression in HEK293 cells. We further examined the functional consequences of changing lipid conditions to mimic the impact of lipid remodeling on ZnT8 activity during insulin granule biogenesis. Purified ZnT8 variants in proteoliposomes exhibited more than 4-fold functional tunability by the anionic phospholipids, lysophosphatidylcholine and cholesterol. Over a broad range of permissive lipid compositions, the Arg-325 variant consistently exhibited accelerated zinc transport kinetics versus the Trp-form. In agreement with the human genetic finding that rare loss-of-function mutations in ZnT8 are associated with reduced T2D risk, our results suggested that the common high risk Arg-325 variant is hyperactive, and thus may be targeted for inhibition to reduce T2D risk in the general populations.

Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.

Review: the rise of Africa’s superwomen The World Today mhiggins.drupal 1 August 2022

From foster care in England to colonialism’s legacy in Zimbabwe, this set of essays on race, feminism and identity is searingly honest, says Masiyaleti Mbewe.

Black and Female
Tsitsi Dangarembga, Faber, £9.99

The 1988 novel Nervous Conditions by the Zimbabwean author Tsitsi Dangarembga is considered one of Africa’s finest literary exports. It won the Commonwealth Writers’ Prize and alongside The Book of Not (2006) and This Mournable Body (2018), shortlisted for the 2020 Booker Prize, forms a trilogy of semi-autobiographical novels that grapple with the gendered colonial oppression of young black girls and women from Southern Rhodesia through to Zimbabwe. 

In Black and Female, Dangarembga continues the interrogation of these intersections in an unflinchingly honest and personal, if occasionally dense, collection of essays. Along the way, she examines the sheer magnitude of colonialism’s effects on African people, and how they ripple through her early childhood in England and her formative years as a writer, filmmaker and feminist activist in post-independence Zimbabwe.

‘Writing While Black and Female’

In 1961 Dangarembga’s parents relocated from Southern Rhodesia to the UK. While they worked and studied in London, they put their two-year-old daughter, her older brother and, later, her younger sister into private foster care in Dover, Kent (as many Africans did – a fact that was new to me). The first essay, ‘Writing While Black and Female’, takes a painful look at the four years she spent with her foster parents, Mummy-Gran and Daddy Henry. 

Blackness, she learned in those years, was a consequence of her non-whiteness. So Dangarembga writes of the momentary elation she felt when a stranger addressed her as a ‘lovely little piccaninny’, giving her ‘a category I could wield against the void of no longer being’. To cope with this sort of racialization and her abandonment, the young Dangarembga turned to disassociation and self-harm. 

As she writes: ‘Blackness is a condition imposed on me, rather than being an experienced identity.’ Instead of ‘black’ people, therefore, Dangarembga prefers the term ‘highly melanated people’. It is a resonant phrase, highlighting the inherently ridiculous nature of racism.

Dangarembga’s ‘Africanness’ shifts into focus upon her return to Rhodesia in 1965. At first, other children refused to play with her and her siblings, calling them ‘varungu’ (white people). As she describes it: ‘The dance of my identities … became frenetic’. 

In ‘Black, Female and the Superwoman Black Feminist’, the second essay, Dangarembga is adamant about the urgent necessity of a black feminist practice that is centred on action to provide real, material change. Along the way, she makes a distinction – a slightly uneasy one to my mind – between the patriarchy that western colonization imposed, based on private ownership, and the patriarchy of pre-colonial African society with its foundations in kinship that devolved power to an extent.

‘Hence women could and did become rulers and warriors, and royal spirit mediums called mhondoro,’ Dangarembga writes approvingly. She is making a nuanced point; but the idea of a more accommodating sort of patriarchy jars a little nonetheless.

While independence may have arrived for Zimbabwe more than 40 years ago, Dangarembga argues strongly that the subjugation of women and feminists at the hands of the ruling Zanu-PF government continues as an extension of colonial rule. Indeed, beyond Zimbabwe, black feminists remain ‘a small, often embattled group’ across Africa, believes Dangarembga. 

As a young black feminist who is part of this ‘small, embattled group’, I should say we have been able to foster large communities digitally and otherwise to work around the hostility we are often faced with. Despite internet shutdowns and restrictions, we resist – an act Dangarembga encourages.  

Resistance, she says, starts with establishing community despite these difficulties. At the nucleus of Dangarembga’s argument is the ‘superwoman’ of the essay’s title, the African woman who doesn’t require external factors to be inspired to action but who continuously draws on what Dangarembga calls ‘internal agency’ that derives from ‘an unrelenting fight for survival and dignity’.

Pointedly, she criticizes global feminism’s greater focus on optics than activism in the practical sense. One only has to observe the performative allyship and ‘Instagram activism’ rampant on the internet today to see her point.
 

The complexities of decolonization

In the final essay, ‘Decolonization as Revolutionary Imagining’, Dangarembga turns her gaze upon the ‘highly stratified’ European societies that outsourced their violent inequality to their empires and ‘the work of decolonization’. However, decolonial discourse is complex, and it is here that the writing occasionally gets bogged down. Fewer recommendations with more elaboration perhaps would have helped.

She herself acknowledges the difficulties of decolonization. Centuries of the Enlightenment and its logic of ‘racism, slavery, genocide and colonization’ are hard to uproot ‘whatever one’s melanin concentration’, she writes.

Nevertheless, Dangarembga concludes with the radical determination to dismantle that is evident throughout this searing yet hopeful collection: ‘The trajectory of current and future generations depends on that uprooting.’

Culture notes: Europe's broken promises to Africa The World Today mhiggins.drupal 1 August 2022

Europe’s ‘gas grab’ in Africa is just the latest abuse of its relationship with the continent, says Catherine Fieschi.

When Emmanuel Macron made one of his first visits to Africa as France’s recently elected young president in 2017, his speech at Ouagadougou University in Burkina Faso was designed to set the tone for a new relationship between his country and African countries. 

‘There no longer is a French policy for Africa,’ he said.

This was a signal away from ‘la Françafrique’, with its post-colonial accents and the propping up of regimes friendly to France, to something that was more strategic, equitable and transparent – more partnership and less tutelage. 

And Europe seemed to be following suit. In March 2020 the European Union and Africa decided that they would redefine their relationship. The European Commission unveiled its vision for a ‘comprehensive strategy with Africa’. The roadmap would give Africa significantly more say over the nature and extent of the relationship, more choice and more political agency.

But what, today, is left of these aspirations? Despite repeated statements, Europe seems to be saying one thing and doing another. 

Earlier this year, after the long-awaited 6th annual EU-African Union summit in Brussels, South African president Cyril Ramaphosa was frank when he summed up the gap between stated ambitions and the current relationship. The pandemic-weary Global South had reason to be wary. Ramaphosa laid out missed opportunities, disappointment and the low expectations that act as self-fulfilling prophecies. 

Europe’s changing focus in Africa 

From the apparent high point of the Ouagadougou speech, Macron has now turned to the Organization Internationale de la Francophonie (OIF) in Africa for geopolitical purposes. His primary aim is to combat the rise of Islamist militants and terrorism in the Sahel as well as to tackle the growing influence of China and Russia in the region. 

Russian inroads – via the security firm Wagner in Mali, for instance – have given France further cause to use the OIF to counter destabilization activities. Both the United Kingdom and France train African military in the Sahel, but now, with the end of France’s anti-insurgent Operation Barkhane in Mali, the subsequent withdrawal of French troops and the increasingly established presence of the Wagner group, the security situation in the region is expected to deteriorate dramatically and become increasingly impermeable to European interests and forces.

As for development aid, Britain’s Integrated Review of Security, Defence, Development and Foreign Policy makes no bones about the fact that Asia is now a priority over Africa.

The relationship between Africa and Britain is being transformed as a result, most obviously through the cuts in development aid, with African aid cut by 66 per cent in 2021. But the nature of the relationship, which has become both more conditional and more transactional, has also changed. 

The UK is emphasizing human rights and ‘free societies’, but also pushing for free market principles rather than the kind of state involvement that some African countries often prefer as a road to accelerated and more autonomous development. 

The future of energy exports and COP27

The issue of energy exports points to what will most likely trigger the greatest disappointment in the next few years – climate and climate finance. 

Green energy deals, like the $8.5 billion COP26 package from the EU, United States and UK to South Africa, look far more problematic now in the light of Europe’s African gas-grab. Indeed, Europe is importing as much African gas as it can after the invasion of Ukraine by Russia reduced supplies. Yet African countries are still being told to curb their own use of ‘dirty’ energy. 

As an illustration, Nigeria holds 3 per cent of the world’s gas reserves, but has barely tapped them, while 40 per cent of its output is exported to Europe. In April, Italy closed deals to buy gas from Angola and the Republic of Congo, while Germany did the same with Senegal.
 

At COP15 in Copenhagen in 2009, developed countries pledged an annual $100 billion in climate finance to developing countries for both adaptation and mitigation. But pledges have never really materialized. The aid agency Oxfam estimates that only about a third of the money has been delivered. Climate finance was again the main focus of COP26 – and dismissed by Greta Thunberg as more ‘blah, blah, blah’.

This series of repeated resets, pledges and disappointments tells a story – indeed, several stories. First and foremost, it is one of arrogance and betrayal. That much is obvious. But it is also a story about stories – about how the narratives elaborated by various European countries and leaders never amount to more than a sum of transactions. 

Climate change places Europe, and other rich nations, at a crossroads in its relationship with Africa: the former holds the wealth, but also some of the keys and threats to the transition. COP27, to be held in Egypt in November, will be the next chapter in the story. 

Visual Abstract

Jessica Y. Franco
Dec 1, 2020; 19:1936-1951
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Ji Eun Kim
Dec 20, 2020; 0:RA120.002159v1-mcp.RA120.002159
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Qin Zhang
Nov 17, 2020; 0:RA120.002325v1-mcp.RA120.002325
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