Vitali Matyash
May 1, 2008; 49:1137-1146
Methods

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

DL Brasaemle
Nov 1, 1997; 38:2249-2263
Articles

Dawn L. Brasaemle
Dec 1, 2007; 48:2547-2559
Thematic Reviews

Linda J. Pike
Apr 1, 2003; 44:655-667
Thematic Reviews

G Lepage
Jan 1, 1986; 27:114-120
Articles

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

JE Hixson
Mar 1, 1990; 31:545-548
Articles

Expert

Expert

Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.

Defining discontinuous antigenic epitopes remains a substantial challenge, as exemplified by the case of lipid transfer polyproteins, which are common pollen allergens. Hydrogen/deuterium exchange monitored by NMR can be used to map epitopes onto folded protein surfaces, but only if the complex rapidly dissociates. Modifying the standard NMR-exchange measurement to detect substoichiometric complexes overcomes this time scale limitation and provides new insights into recognition of lipid transfer polyprotein by antibodies. In the future, this new and exciting development should see broad application to a range of tight macromolecular interactions.

Myosins generate force and motion by precisely coordinating their mechanical and chemical cycles, but the nature and timing of this coordination remains controversial. We utilized a FRET approach to examine the kinetics of structural changes in the force-generating lever arm in myosin V. We directly compared the FRET results with single-molecule mechanical events examined by optical trapping. We introduced a mutation (S217A) in the conserved switch I region of the active site to examine how myosin couples structural changes in the actin- and nucleotide-binding regions with force generation. Specifically, S217A enhanced the maximum rate of lever arm priming (recovery stroke) while slowing ATP hydrolysis, demonstrating that it uncouples these two steps. We determined that the mutation dramatically slows both actin-induced rotation of the lever arm (power stroke) and phosphate release (≥10-fold), whereas our simulations suggest that the maximum rate of both steps is unchanged by the mutation. Time-resolved FRET revealed that the structure of the pre– and post–power stroke conformations and mole fractions of these conformations were not altered by the mutation. Optical trapping results demonstrated that S217A does not dramatically alter unitary displacements or slow the working stroke rate constant, consistent with the mutation disrupting an actin-induced conformational change prior to the power stroke. We propose that communication between the actin- and nucleotide-binding regions of myosin assures a proper actin-binding interface and active site have formed before producing a power stroke. Variability in this coupling is likely crucial for mediating motor-based functions such as muscle contraction and intracellular transport.

Minerals and Metals for a Low-Carbon Future: Implications for Developing Countries 30 October 2017 — 5:00PM TO 8:00PM Anonymous (not verified) 13 October 2017 Chatham House, London

This roundtable will explore two sides of minerals and metals for a low-carbon future - the growing demand for metals required for low-carbon technology and the technological and policy innovations that will be required to manage the carbon footprint of the mining sector and its wider energy and industrial linkages. Based around a presentation and scenarios developed by the World Bank, this roundtable discussion will assess which strategic metals will likely rise in demand in order to deliver a low-carbon future, before exploring the possible implications for resource-rich developing countries. In particular, what does a growing demand of minerals for a clean energy future mean for governments and industry, and how might developing countries benefit from this trend? What impact might growth of the mining sector have on a sustainable and climate-smart development? Can renewable energy and other clean tech innovations in the mining industry help reduce the carbon footprint of the sector and related industries, and under what circumstances? And how fit-for-purpose are current donor approaches to the mining sector in an increasingly carbon-constrained world?

Attendance at this event is by invitation only.

Fossil Fuels Expert Roundtable: How Solar is Shaping the Energy Transition 1 June 2018 — 9:00AM TO 10:30AM Anonymous (not verified) 22 May 2018 Chatham House, London

As global temperatures rise and extreme weather events multiply, doubts over the reality and imminence of climate change have dissipated. Despite this, there is a clear lack of urgency by governments to the approaching crisis. At this event, Prem Shankar Jha will set out what he believes are the three main causes for this inaction.

Furthermore, he will argue that catastrophic climate change is imminent, but even if it weren’t, the risk is too great to ignore. Only a complete shift from fossil fuels by 2070 at the latest would provide reasonable certainty of avoiding irreversible consequences. This transition is not only possible but the technologies to enable it were harnessed four to nine decades ago – and all of them draw their primary energy from the sun. These technologies are already capable of delivering electricity, transport fuels, and petrochemicals at prices that are competitive with the current delivered cost of electricity in the US and Western Europe. So what is holding up the energy shift?

Attendance at this event is by invitation only.

Duterte’s Victory Is Cry for Help From Those Left Behind in Philippines Expert comment sysadmin 12 May 2016

But large support for mainstream parties and a mature democratic system should keep the country from slipping back towards authoritarianism.

The victory of political outsider Rodrigo Duterte in the 2016 Philippines’ elections is proof that a significant minority of the country’s population feels left behind by its recent economic success and estranged from its political elite. However the results of the elections as a whole suggest that most voters opted for a continuation of the current government’s policies.

Duterte looks almost certain to be inaugurated as the next president of the Philippines on 30 June. The country’s presidential voting system – a single round, first-past-the-post election – delivered victory to a populist outsider with 39 per cent support. Two candidates advocating a continuation of the current government’s policies − the Liberal Party’s Mar Roxas and independent Grace Poe − polled a combined 45 per cent. The long-standing factionalism within Philippines elite politics split the ‘anti-Duterte’ vote.

Changing the conversation

The contrast between Duterte and Roxas could hardly be greater. Mar Roxas is the grandson of the first president of an independent Philippines, a graduate of Wharton Business School and a former investment banker in the US. Rodrigo Duterte is a political outsider with an electoral base geographically almost as far from Manila as is possible to get in the Philippines: the city of Davao on the island of Mindanao.

The story of Duterte’s victory is the story of how ‘Duterte managed to change the national conversation from poverty towards crime and corruption,’ says Marites Vitug, editor-at-large of one of the Philippines’ most popular online news sites, Rappler. In January, Duterte was running fourth in opinion polls but a strategy that positioned him as the only opponent to the Manila elite gave him victory. This is the first time a provincial official has made it to the top job.

The headline figures tell us that the Philippines’ economy has done very well under President Benigno Aquino. Between 2010 and 2014, growth averaged 6.3 per cent per year. That fell to a still-impressive 5.8 per cent last year but is expected to pick up this year and next, according to the Asian Development Bank. Growth in agriculture, however, is significantly slower and rural areas feel left behind. While economic growth is benefiting the majority, inequality is worsening and resentment rising in poor villages. The contrast between the metropolitan sophistication of the Makati district in Manila and life in faraway provinces such as Duterte’s Mindanao is widening.

Ironically the Philippines’ economic success is a part of the explanation for the defeat of the ‘mainstream’ presidential candidates. Crime and corruption may have become more important issues simply because more voters have become better off and therefore more likely to be concerned about crime and corruption than before. It’s also undeniable that Duterte has a record for getting things done. Human rights groups rightly criticize his (at best) tolerance of the extra-judicial killing of alleged criminals but his repeated re-election as mayor demonstrates that many citizens are prepared to accept that in exchange for improved personal security. A surprising number of Manila residents have actually moved to Davao because of its better quality of life.

Traditional power bases

However, the results as a whole suggest a narrow majority in favour of current policies. In the vice-presidential race, the Liberal Party candidate Leni Robredo is narrowly ahead of Ferdinand ‘Bongbong’ Marcos, the son of the eponymous former president. Like Duterte she is regarded as a successful mayor of a well-run city, Albay. Duterte’s running mate Alan Cayetano received just 14 per cent of the vote.

In the senate election, Liberals won five of the 12 seats being contested, with a party- backed independent winning a sixth. The opposition, even with boxing champion and national idol Manny Pacquiao running for the United Nationalist Alliance, won four.

Taken as a whole, the results show the enduring nature of traditional Philippines power bases. The country’s many islands and distinct linguistic and cultural regions are virtual fiefs in which families and big bosses can wield almost total power through control of local authorities, businesses, the courts and security forces.

Threat to democracy?

It’s easy to forget that the election of Ferdinand Marcos in 1965 was originally welcomed as a challenge to the traditional elites of Philippine politics. The same accolades are currently greeting Duterte. Could they presage a return to the Philippines’ bad old days?

This seems less likely. Philippine democracy has matured considerably since Marcos declared martial law in 1972. There is a substantial, and vocal, middle class with experience of mobilizing against ‘bad’ presidents. There will also be pressures from international investors and the Philippines’ treaty ally, the United States, for better governance.

The Philippines will chair the Association of Southeast Asian Nations next year. That will put Duterte in the international spotlight as host of several international meetings – including the East Asia Summit attended by, among others, the presidents of China, Russia and the US. Since his victory Duterte has promised to act with decorum in office and declared that his election campaign antics were just a ploy to attract attention. Some leaders in Southeast Asia will use his victory to buttress their arguments against allowing their people to freely vote. It’s up to Duterte to decide whether he wants to be an advertisement for – or an argument against – democracy.

To comment on this article, please contact Chatham House Feedback

Katherine Baker, Lehel Banjai and Mariya Ptashnyk
Math. Comp. 93 (), 2711-2743.
Abstract, references and article information

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

Lorin Crawford explains how he uses math to analyze interactions between genes. Your DNA (the biological instruction manual in all of your cells) contains a mind-boggling amount of information represented in roughly 20,000 genes that encode proteins, plus a similar number of genes with other functions. As the cost of analyzing an individual's DNA has plummeted, it has become possible to search the entire human genome for genetic variants that are associated with traits such as height or susceptibility to certain diseases. Sometimes, one gene has a straightforward impact on the trait. But in many cases, the effect of one gene variant depends on which variants of other genes are present, a phenomenon called "epistasis." Studying such interactions involves huge datasets encompassing the DNA of hundreds of thousands of people. Mathematically, that requires time-intensive calculations with massive matrices and a good working knowledge of statistics.

Rodney Kizito from U.S. Department of Energy discusses solar energy, mathematics, and microgrids. When you flip a switch to turn on a light, where does that energy come from? In a traditional power grid, electricity is generated at large power plants and then transmitted long distances. But now, individual homes and businesses with solar panels can generate some or all of their own power and even send energy into the rest of the grid. Modifying the grid so that power can flow in both directions depends on mathematics. With linear programming and operations research, engineers design efficient and reliable systems that account for constraints like the electricity demand at each location, the costs of solar installation and distribution, and the energy produced under different weather conditions. Similar mathematics helps create "microgrids" — small, local systems that can operate independent of the main grid.

Guido De Philippis, Nicola Fusco and Massimiliano Morini
Trans. Amer. Math. Soc. 377 (), 5787-5835.
Abstract, references and article information

Ming-Lun Hsieh and Shunsuke Yamana
Trans. Amer. Math. Soc. 377 (), 5617-5672.
Abstract, references and article information

Christoforos Neofytidis
Trans. Amer. Math. Soc. 377 (), 5289-5321.
Abstract, references and article information

Simone Cecchini and Rudolf Zeidler
Trans. Amer. Math. Soc. 377 (), 5271-5288.
Abstract, references and article information

dannyhennesy posted a photo:

On the Capital planet the rebellious droids had followed maily the Bat-Bot, but as time progressed his circuits had gone all mushy at 780 years or so without maintenance…

Several splinter groups all with their local bot leaders emerged such as the Che-bot, the traffic-light-robot and the Butt-bot, but none of these collected enough sentient circuits to call themselves a popular (or Animata) mass movement!

That was until a cyborg came along, one known as Jones, a long time prisoner and terrorist, his easy solutions to every problem rang well in the masses' auditory circuits!!!

His slogans and simple rhetoric were simple enough for the simple traffic-light to comprehend and cheer!

His language was full of hate towards the organics and especially the humans who were the most common races among the ruling class of the federation!!!

Despite being a “Fleshie” himself his message collected the angry enslaved
bot community by only weeks all rebellious robots except for a few fringe loonies had forgotten the old leaders…

One morning at Jones gave the signal…

All over the capital planet hordes and swarms of any form of mechanical sentient beings attacked first the police stations, then the Company boards running the planet and the federation as well as their starfleet…

Many died, especially the low level police and army! Many mechanicals died too, but their ranks were soon filled by Mutant fleshie allies of the lower levels who hated the Federation feudal society and upper classes as much as their technological allies…

The Federation state apparatus and ruling class, most of their fleet army fled when they knew the game was up, they activated the emergency escape plan and whole city blocks with important factories, administrational units, valuable assets and so on separated from the capital by hidden rocket engines and homed in their course to Mars…

On Mars the federation regrouped and formed their new society…

On the Capital planet, the robots proclaimed the first Techno-republic of the advanced inorganic civilization, the low level fleshies left behind, became slaves and their mutant allies got to rule their own minute chiefdoms as protectorates under the Techno-republic…

Jones was now the undisputed ruler of the capital planet, but the victory was a pyrros one since, all important buildings, all of value was now one Mars!

But as Jones put it:

Our proud race the Techno-species didn’t need the Fleshies administration, their infrastructure, their spaceships…

We shall start from scratch, with a new administration, a new order, every droid shall work at 4x speed than they did during human oppression since now we are free and the fleshies shall work twice as hard than the Techno-Race, until we have breed enough new fleshies so they can do all work!

Our future is bright and shiny like glistering shiny metal!

The snapshot seen here is from the first police station attacked in sector 45-34v-ss-g the first one to fall according to official techno-history!

———————————————/
Designers note:

I am sad to say that this is the last episode in this years-spanning space series… At least for a while, I will still post LEGO hobby stuff here but without a storyline, perhaps small designs and builds… and occasionally a story when I feel like it!!!

I would like to thank all who had been in this journey of our heros, but it has taken far to much time and effort and since the state of the world is as it is, I am spiraling down in another depression, I must stop it before I reach the abyss, so I have remove some stress out of my equation… I ended it in a cliffhanger so I can easily restart it when my mental health improves… I hope that won’t be forever???

I would love if someone used my characters or ideas, please send me a link if you do, I would love to read it or look at it!!!

But there will be more Lego, just in different format without long stories, I need to focus more on my art and to be honest that is the only time the mental pain eases, when I create!!!


Peace and Noise!

MushroomBrain a FOL

Anne-Miek Bibbe posted a photo:

JOEPIE: I'm almost there! I wish Uncle Jeroen was here, I'm a little, really just a little bit afraid of the dark.
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JOEPIE: Ik ben bijna bij Peter! Ik wou dat oom Jeroen hier was, ik ben een beetje, echt maar een héél klein beetje bang in het donker.

Cheng Chu
Proc. Amer. Math. Soc. 152 (), 5289-5297.
Abstract, references and article information

PROMOTED RACING, CHAPELTON MAROONS RENEW RIVALRY IN JPL - A16 FUNCAANDUN SET FOR FIFTH STRAIGHT WIN - A21

An out-of-body experience is the inspiration behind Benzly Hype's latest album Star Its The 7th Year. Released on November 7, the entertainer said the project was done to bring back joy in music and will leave its listeners in an upbeat mood....

As I walked into the embalming room at Jones Funeral Home and Supplies in Kingston on Sunday, I immediately felt the weight of the room. The air was thick with the scent of various chemicals used in the trade permeating the space. Tools such as...

Health Minister Dr Christopher Tufton is warning about the possible dangers to the health of students caused by vaping. "We have seen cases where students have been rushed to the A...

PORT-AU-PRINCE, Haiti (AP) — Haiti's main airport remained closed on Tuesday, a day after violence erupted as the country swore in its new prime minister in a politically tumultuous transition.

Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit.

RNase J enzymes are metallohydrolases that are involved in RNA maturation and RNA recycling, govern gene expression in bacteria, and catalyze both exonuclease and endonuclease activity. The catalytic activity of RNase J is regulated by multiple mechanisms which include oligomerization, conformational changes to aid substrate recognition, and the metal cofactor at the active site. However, little is known of how RNase J paralogs differ in expression and activity. Here we describe structural and biochemical features of two Staphylococcus epidermidis RNase J paralogs, RNase J1 and RNase J2. RNase J1 is a homodimer with exonuclease activity aided by two metal cofactors at the active site. RNase J2, on the other hand, has endonuclease activity and one metal ion at the active site and is predominantly a monomer. We note that the expression levels of these enzymes vary across Staphylococcal strains. Together, these observations suggest that multiple interacting RNase J paralogs could provide a strategy for functional improvisation utilizing differences in intracellular concentration, quaternary structure, and distinct active site architecture despite overall structural similarity.

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Identification of antibody-binding epitopes is crucial to understand immunological mechanisms. It is of particular interest for allergenic proteins with high cross-reactivity as observed in the lipid transfer protein (LTP) syndrome, which is characterized by severe allergic reactions. Art v 3, a pollen LTP from mugwort, is frequently involved in this cross-reactivity, but no antibody-binding epitopes have been determined so far. To reveal human IgE-binding regions of Art v 3, we produced three murine high-affinity mAbs, which showed 70–90% coverage of the allergenic epitopes from mugwort pollen–allergic patients. As reliable methods to determine structural epitopes with tightly interacting intact antibodies under native conditions are lacking, we developed a straightforward NMR approach termed hydrogen/deuterium exchange memory (HDXMEM). It relies on the slow exchange between the invisible antigen-mAb complex and the free 15N-labeled antigen whose 1H-15N correlations are detected. Due to a memory effect, changes of NH protection during antibody binding are measured. Differences in H/D exchange rates and analyses of mAb reactivity to homologous LTPs revealed three structural epitopes: two partially cross-reactive regions around α-helices 2 and 4 as well as a novel Art v 3–specific epitope at the C terminus. Protein variants with exchanged epitope residues confirmed the antibody-binding sites and revealed strongly reduced IgE reactivity. Using the novel HDXMEM for NMR epitope mapping allowed identification of the first structural epitopes of an allergenic pollen LTP. This knowledge enables improved cross-reactivity prediction for patients suffering from LTP allergy and facilitates design of therapeutics.

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.

The life cycle of malaria parasites in both their mammalian host and mosquito vector consists of multiple developmental stages that ensure proper replication and progeny survival. The transition between these stages is fueled by nutrients scavenged from the host and fed into specialized metabolic pathways of the parasite. One such pathway is used by Plasmodium falciparum, which causes the most severe form of human malaria, to synthesize its major phospholipids, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine. Much is known about the enzymes involved in the synthesis of these phospholipids, and recent advances in genetic engineering, single-cell RNA-Seq analyses, and drug screening have provided new perspectives on the importance of some of these enzymes in parasite development and sexual differentiation and have identified targets for the development of new antimalarial drugs. This Minireview focuses on two phospholipid biosynthesis enzymes of P. falciparum that catalyze phosphoethanolamine transmethylation (PfPMT) and phosphatidylserine decarboxylation (PfPSD) during the blood stages of the parasite. We also discuss our current understanding of the biochemical, structural, and biological functions of these enzymes and highlight efforts to use them as antimalarial drug targets.

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.

24 July 2020

14 September 2020

The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin–proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methylglutaryl CoA reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

Africa Aware: Relations between Ethiopia and Sudan Audio bhorton.drupal 9 April 2022

This episode of Africa Aware examines the relationship between Ethiopia and Sudan.

Ahmed Soliman provides an overview of the Africa Programme’s work on cross-border conflict as part of the XCEPT project.

First, we speak to Kholood Khair on the steady deterioration in relations between Sudan and Ethiopia. Then Abel Abate Demissie discusses how recent political developments in Ethiopia and Sudan have impacted relations between the two countries.

This podcast was produced with support from the Cross-Border Conflict Evidence, Policy and Trends (XCEPT) project, funded by UK Aid from the UK government. The views expressed do not necessarily reflect the UK government’s official policies.

It is also part of a series of outputs on Ethiopia’s political transition.

Priorities for implementing Ethiopia's national dialogue 11 May 2022 — 1:00PM TO 3:00PM Anonymous (not verified) 3 May 2022 Online

Experts discuss challenges and priorities in shaping an inclusive and effective national dialogue in Ethiopia.

Ethiopia is grappling with numerous contentious national issues – not least persistent conflict in several parts of the country – which underscore the need for large-scale dialogue and reconciliation efforts to address the country’s deep-rooted societal and political divisions. Ethiopia’s newly established National Dialogue Commission – whose 11 commissioners were appointed in February 2022 – has begun a four-phased process of preparations for a dialogue, with its initial stage focused on stakeholder engagement and local knowledge mobilization.

There are major challenges, however, in ensuring inclusivity amidst ongoing conflict and questions on how a country-wide process will sit alongside local dialogue initiatives and wider mediation and peacebuilding efforts. Linking the process to constitutional bodies will also be an important priority to ensure dialogue outcomes are effectively implemented.

At this public event, panellists will exchange perspectives on how to shape an effective national dialogue in Ethiopia, including priorities for building a credible National Dialogue Commission and the roles and responsibilities of other national, regional and local-level actors. They will also discuss key implementation mechanisms and long-term priorities for trust-building and cultivating a conducive environment for inclusive dialogue.

This webinar is part of a series of events and outputs on Ethiopia’s political transition.

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