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Telomeres are specific nucleoprotein structures that are located at the ends of linear eukaryotic chromosomes and play crucial roles in genomic stability. Telomere DNA consists of simple repeats of a short G-rich sequence: TTAGGG in mammals and TTTAGGG in most plants. In recent years, the mammalian telomeric G-rich repeats have been shown to form G-quadruplex (G4) structures, which are crucial for modulating telomere functions. Surprisingly, even though plant telomeres are essential for plant growth, development, and environmental adaptions, only few reports exist on plant telomeric G4 DNA (pTG4). Here, using bulk and single-molecule assays, including CD spectroscopy, and single-molecule FRET approaches, we comprehensively characterized the structure and dynamics of a typical plant telomeric sequence, d[GGG(TTTAGGG)3]. We found that this sequence can fold into mixed G4s in potassium, including parallel and antiparallel structures. We also directly detected intermediate dynamic transitions, including G-hairpin, parallel G-triplex, and antiparallel G-triplex structures. Moreover, we observed that pTG4 is unfolded by the AtRecQ2 helicase but not by AtRecQ3. The results of our work shed light on our understanding about the existence, topological structures, stability, intermediates, unwinding, and functions of pTG4.

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Structural basis of specific inhibition of extracellular activation of pro- or latent myostatin by the monoclonal antibody SRK-015 [Molecular Biophysics]

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Published On :: 2020-04-17T00:06:05-07:00

Myostatin (or growth/differentiation factor 8 (GDF8)) is a member of the transforming growth factor β superfamily of growth factors and negatively regulates skeletal muscle growth. Its dysregulation is implicated in muscle wasting diseases. SRK-015 is a clinical-stage mAb that prevents extracellular proteolytic activation of pro- and latent myostatin. Here we used integrated structural and biochemical approaches to elucidate the molecular mechanism of antibody-mediated neutralization of pro-myostatin activation. The crystal structure of pro-myostatin in complex with 29H4-16 Fab, a high-affinity variant of SRK-015, at 2.79 Å resolution revealed that the antibody binds to a conformational epitope in the arm region of the prodomain distant from the proteolytic cleavage sites. This epitope is highly sequence-divergent, having only limited similarity to other closely related members of the transforming growth factor β superfamily. Hydrogen/deuterium exchange MS experiments indicated that antibody binding induces conformational changes in pro- and latent myostatin that span the arm region, the loops contiguous to the protease cleavage sites, and the latency-associated structural elements. Moreover, negative-stain EM with full-length antibodies disclosed a stable, ring-like antigen–antibody structure in which the two Fab arms of a single antibody occupy the two arm regions of the prodomain in the pro- and latent myostatin homodimers, suggesting a 1:1 (antibody:myostatin homodimer) binding stoichiometry. These results suggest that SRK-015 binding stabilizes the latent conformation and limits the accessibility of protease cleavage sites within the prodomain. These findings shed light on approaches that specifically block the extracellular activation of growth factors by targeting their precursor forms.

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Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction]

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Published On :: 2020-05-01T00:06:09-07:00

Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity.

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Delineating an extracellular redox-sensitive module in T-type Ca2+ channels [Membrane Biology]

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Published On :: 2020-05-01T00:06:09-07:00

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

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Crystallographic and kinetic analyses of the FdsBG subcomplex of the cytosolic formate dehydrogenase FdsABG from Cupriavidus necator [Molecular Biophysics]

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Published On :: 2020-05-08T03:41:14-07:00

Formate oxidation to carbon dioxide is a key reaction in one-carbon compound metabolism, and its reverse reaction represents the first step in carbon assimilation in the acetogenic and methanogenic branches of many anaerobic organisms. The molybdenum-containing dehydrogenase FdsABG is a soluble NAD+-dependent formate dehydrogenase and a member of the NADH dehydrogenase superfamily. Here, we present the first structure of the FdsBG subcomplex of the cytosolic FdsABG formate dehydrogenase from the hydrogen-oxidizing bacterium Cupriavidus necator H16 both with and without bound NADH. The structures revealed that the two iron-sulfur clusters, Fe4S4 in FdsB and Fe2S2 in FdsG, are closer to the FMN than they are in other NADH dehydrogenases. Rapid kinetic studies and EPR measurements of rapid freeze-quenched samples of the NADH reduction of FdsBG identified a neutral flavin semiquinone, FMNH•, not previously observed to participate in NADH-mediated reduction of the FdsABG holoenzyme. We found that this semiquinone forms through the transfer of one electron from the fully reduced FMNH−, initially formed via NADH-mediated reduction, to the Fe2S2 cluster. This Fe2S2 cluster is not part of the on-path chain of iron-sulfur clusters connecting the FMN of FdsB with the active-site molybdenum center of FdsA. According to the NADH-bound structure, the nicotinamide ring stacks onto the re-face of the FMN. However, NADH binding significantly reduced the electron density for the isoalloxazine ring of FMN and induced a conformational change in residues of the FMN-binding pocket that display peptide-bond flipping upon NAD+ binding in proper NADH dehydrogenases.

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Exploring the Looming Water Crisis

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Published On :: Tue, 26 Nov 2019 16:12:28 +0000

28 November 2019

Gitika Bhardwaj

Editor, Communications & Publishing, Chatham House

Loïc Fauchon

President, World Water Council

Loïc Fauchon, president of the World Water Council, speaks to Gitika Bhardwaj about the causes of water scarcity around the world and how best to implement sustainable solutions.

GettyImages-686773184.jpg

Dry sand and a narrow body of water near the Theewaterskloof Dam in South Africa which has had less than 20 per cent of its normal water capacity during recent water shortages. This dam, about 108km from Cape Town, is the main water source for residents of the city. Photo: Getty Images.

One-quarter of humanity faces a looming water crisis, including the prospect of running out of water, which may seem inconceivable when 70 per cent of the Earth’s surface is water. Nevertheless up to 80 per cent of available surface and groundwater is being used every year and water demand globally is projected to increase by 55 per cent by 2050. Why is the world facing a crisis of water scarcity and what is driving the increasing demand for water?

The first reason that is causing water stress around the world is the growing human population at the same time as the water supply has remained the same. Given that there are almost one billion more inhabitants on Earth every 15-20 years, this has led to a progressive deficit in the global water supply.

The second reason is due to the uneven concentration of the global population. There is not a clear link between the presence of the population in some regions and the presence of water, in other words, water is not where we want it to be every time.

For example, there is, what we call, a ‘triangle of thirst’ from southern Spain, to Pakistan, to the Horn of Africa and back again. In this triangle, you have around two billion people in a very water-scarce region.

Comparatively, if you go to Russia or Canada, they have more water than they need in terms of the size of their population. So this is another crucial reason we are facing a crisis of water scarcity in some regions of the world – but not everywhere.

Climate [change] will be the fruit on the cake. Currently we have global population growth and then later we will have climate change affecting water availability. But at this very moment, however, the problem for water suppliers and for political leaders is the demographic crisis we are facing – not the climate.

Water use has grown at more than twice the rate of the human population over the last century in part due to industries, such as agriculture, which account for 70 per cent of global freshwater use.

Given that food production will need to grow by up to 70 per cent by 2035 to feed the growing human population, how do we balance the use of water with the need to provide food?

There are some solutions. The first is that we need to improve water efficiency in the agricultural sector. We need to have all around the world, but mostly in developing countries, a better capacity to increase the water efficiency of agriculture without increasing the use of industrial chemical products and to move, step-by-step, to an economical system of organic farming. It will take time – it will not be done in one or even five years but more likely over a generation – but it is the best way.

Secondly, which could be a faster solution, is that we have to reduce all kind of food waste which represents around 30-40 per cent of all agricultural production. Agriculture is a large sector involving the growing of crops but also livestock. There’s not only waste in terms of consumption but also during the production line, for example, during the transportation of food products. So there is this, sort of, waste cycle which is very important to consider. If you are able to reduce the water waste during the production line by 30-40 per cent, then you use less water, obviously.

The third solution is to be able to, step-by-step, change our consumption patterns. Use less meat, all kinds of agricultural products which need a lot of water etc. I think we will be obliged to do this over the next couple of decades, and we will probably have low animal protein diets in the future, which will mean we have to think of different ways to be able to provide food to the increasing global population.

There are other industries that are water-intensive that also need to be looked at in terms of their water waste such as the clothing and automobile industries. One piece of paper, for example, takes about 100 litres of water to produce while one litre of milk takes about 1,000 litres of water. Another example is that one cup of coffee takes 150 litres of water – just one cup of coffee – that’s because there is not only the water you are drinking but the water needed to prepare the coffee beans and the water used in the materials that make the coffee cup and so on.

So everything consumes water and that’s why humans will be obliged to consume less water over the coming years.

More than one in three people globally do not have access to safe drinking water and more than 4 billion people lack adequate sanitation. How can waste water be more efficiently used and do you think global goals to provide everyone with safe and clean drinking water are still realistic?

In French, we use a phrase, parent pauvre, which means poor relative. Most of the decisions concerning access to water are not acceptable in the long term. That’s why we at the World Water Council are pushing for the financing of water and sanitation goals [concurrently].

For example, if you have a programme for a city to increase access to water for its citizens, they also need a sanitation programme. If we don’t do that, the mismatch that currently exists between water and sanitation will remain.

There’s also another important solution which political leaders will be obliged to invest more in which is having more water coming from water reuse. If you produce water from water reuse processes then it means that it will likely have undergone sanitation treatment already which is a win-win solution [for providing safe and clean drinking water].

It’s all moving slowly but I’m optimistic concerning the increasing consciousness of people regarding water pollution – for example the pollution of our rivers, seas and oceans – and I think we will move faster in the sanitation area than in the water access area over the next decade.

Personally, I do not think that global goals to provide everyone with safe and clean drinking water [are the best solution]. I am more in favour of national and local commitments rather than global commitments. National and local efforts are stronger then [the rhetoric] around global goals where there is no authority to oversee the progress they are making. Only the population of a country or of a city can see if their leaders have done their job regarding providing access to safe and clean water.

People queue up to collect water from taps fed by a spring in Newlands in 15 May 2017 in Cape Town, South Africa. South Africa's Western Cape region declared a drought disaster on 22 May 2017 as the province battled its worst water shortages for more than 112 years. Photo: Getty Images.

With the depletion of global water supplies, how can governments avoid the politicization of water, as seen in cases such as the Nile River Basin and across the Middle East, to avoid conflicts over water?

This is a complicated issue because politicians will always do politics so it will always be difficult to avoid attempts to politicize situations. But the key is dialogue, dialogue and dialogue. That is the only way to solve water conflicts as well as better management of water because, in some regions, some of these conflicts are arising from the mismanagement of water supplies – not because of water scarcity.

If you look at Egypt and the US, people are consuming around 800 litres [of water] per day whereas in Europe people are consuming around 200 litres per day. But why is [water consumption] in Egypt, rather than Europe, the same as in the US? Because they have considerable water losses in industries such as agriculture.

In addition, in the main cities like Cairo, there is not an adequate range of water networks, so, if in the future those living in Cairo are able to consume less water, they will need less water coming from the Nile River which will make politicization of water by politicians less likely.

In the future, social unrest from water shortages is likely, however, I do not think it will ever lead to wars.

Countries across the Middle East have invested in modern techniques, such as desalination plants, as an answer to water scarcity, but this can have a negative impact, notably on marine life. In contrast, some of the more ancient techniques, like rainwater harvesting, are being repurposed in cities around the world today. What is your view on these practices and what other solutions are available?

There are a lot of solutions and desalination is among them. Currently probably 100 countries in the world are using, or preparing to use, desalination as a solution so it surely is an important solution. But at the same time, reused water is developing fast and is a much cheaper option than desalination.

Nevertheless, the price of desalination has been decreasing over the past 20 years and is now less than $1 a cubic metre, whereas 15 years ago, it was $10 a cubic metre.

Some of the negative impacts of desalination exist when you are separating the water from the salt, which can lead to disasters, for example, what has happened in the Persian Gulf. When Kuwait, Saudi Arabia, Bahrain and Qatar first used desalination treatments, the temperature of the sea was around 30°C, whereas today, it can be up to 40°C. This increasing sea temperature as a result of the desalination plants has contributed to changes in biodiversity. For example, we are seeing fish disappearing and even the growing population of giant jellyfish – which some desalination plants in Saudi Arabia are dealing with by using shredders which is another type of disaster.

Furthermore, in some regions, we need to keep in mind that desalination is not only along the coast but it’s also in the middle of the land too. For example, in the Sahara region, like in Algeria or Morocco, the water coming from the ground is salted so you need to have desalination plants inland and not on the coast. But where they keep the salt inland, that salt mixes with the rain and enters the ground, thereby destroying some of the biodiversity there too. So it must be used prudently.

Rainwater harvesting is a technique from centuries ago and I am a great supporter of it as a solution to water scarcity in India, particularly in Rajasthan, and I think it could also be part of the solutions in some places across Africa.

That’s why I believe there needs to be an exchange of solutions because something which is successful here could be successful somewhere else. In this way, we need to be able to show a Senegalese farmer a solution which has been implemented elsewhere, such as in India, and show him this can work for you too – it’s sort of like when the Japanese built the Toyota by looking at the British Land Rover.

With billions of people threatened by the global water crisis, increased water stress could lead to more ‘Day Zeroes’, a term used in 2018 as Cape Town in South Africa came dangerously close to running out of water. In your view, what will happen if the world doesn’t adequately address the global crisis of water scarcity?

The increasing absence of water would mean not only the migration of humans to more water-abundant regions but also the absence of socioeconomic growth of any kind in some places because water scarcity will pose a risk to businesses who will be forced to move to new areas – from small businesses like a hairdresser to factories that are unable to produce any goods or provide any services. So not tackling the water crisis means not being able to tackle our own capacity to prosper by not protecting the environment we depend on.

In Cape Town, there was a lack of rain in the city which contributed to the water crisis there but there was also a lack of water management. They knew they could have a lack of rain, and when you have a lack of rain, you have the obligation to prepare a reservoir of water for the year to the next year and so on but that did not happen.

There is a French poem from Jean de La Fontaine about a grasshopper and an ant. The grasshopper just spends his time in the summer enjoying life but the ant keeps working hard throughout the summer to save all of his supplies for the winter. In this way, we need to be like the ant, preparing water supplies for today and for tomorrow.

In the case of Cape Town, there was also another element, which was that the water supplies were being used by the central government as a tool to isolate the regional governor there who was part of the opposition. So the lack of water management was almost used as a political tool as we discussed earlier.

Some say that the water scarcity we are seeing is because of climate change. Yes it is but there is also a lack of water management by humans. If you look at the people living throughout the centuries all the way to antiquity, you see that people around the world prepared reservoirs of water to keep water from the winter to the summer, from the one year to the next, whereas today, we are seeing bad water management. So, in this way, I believe climate change should not be the scapegoat of human error.

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Climate Change, Energy Transition, and the Extractive Industries Transparency Initiative (EITI)

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Published On :: Thu, 05 Dec 2019 15:45:01 +0000

Invitation Only Research Event

17 January 2020 - 9:30am to 5:00pm

Chatham House | 10 St James's Square | London | SW1Y 4LE

Climate change and energy transition are re-shaping the extractive sectors, and the opportunities and risks they present for governments, companies and civil society. As the central governance standard in the extractives sector, the EITI has a critical role in supporting transparency in producer countries.

This workshop will bring together experts from the energy and extractives sectors, governance and transparency, and climate risk and financial disclosure initiatives to discuss the role of governance and transparency through the transition. It will consider the appropriate role for the EITI and potential entry points for policy and practice, and the potential for coordination with related transparency and disclosure initiatives.

Please note attendance is by invitation only.

Department/project

Energy, Environment and Resources Programme

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Lipid rafts and pathogens: the art of deception and exploitation [Thematic Reviews]

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Published On :: 2020-05-01T00:05:27-07:00

Lipid rafts, solid regions of the plasma membrane enriched in cholesterol and glycosphingolipids, are essential parts of a cell. Functionally, lipid rafts present a platform that facilitates interaction of cells with the outside world. However, the unique properties of lipid rafts required to fulfill this function at the same time make them susceptible to exploitation by pathogens. Many steps of pathogen interaction with host cells, and sometimes all steps within the entire lifecycle of various pathogens, rely on host lipid rafts. Such steps as binding of pathogens to the host cells, invasion of intracellular parasites into the cell, the intracellular dwelling of parasites, microbial assembly and exit from the host cell, and microbe transfer from one cell to another all involve lipid rafts. Interaction also includes modification of lipid rafts in host cells, inflicted by pathogens from both inside and outside the cell, through contact or remotely, to advance pathogen replication, to utilize cellular resources, and/or to mitigate immune response. Here, we provide a systematic overview of how and why pathogens interact with and exploit host lipid rafts, as well as the consequences of this interaction for the host, locally and systemically, and for the microbe. We also raise the possibility of modulation of lipid rafts as a therapeutic approach against a variety of infectious agents.

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GPIHBP1, a partner protein for lipoprotein lipase, is expressed only in capillary endothelial cells [Images In Lipid Research]

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Published On :: 2020-05-01T00:05:27-07:00

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Assad’s extortion fails to ease Syria’s financial crisis

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Published On :: Mon, 24 Feb 2020 14:55:32 +0000

Source

Arab News

URL

https://www.arabnews.com/node/1625786

Release date

10 February 2020

Expert

Haid Haid

In the news type

Op-ed

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What's next for India's Muslims?

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Published On :: Fri, 06 Mar 2020 16:32:27 +0000

Source

The Independent

URL

https://www.independent.co.uk/voices/india-modi-muslims-delhi-riots-hindu-violen...

Release date

04 March 2020

Expert

Dr Gareth Price

In the news type

Op-ed

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Long noncoding RNA pncRNA-D reduces cyclin D1 gene expression and arrests cell cycle through RNA m6A modification [RNA]

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Published On :: 2020-04-24T06:08:45-07:00

pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression.

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RNA helicase-regulated processing of the Synechocystis rimO-crhR operon results in differential cistron expression and accumulation of two sRNAs [Gene Regulation]

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Published On :: 2020-05-08T03:41:14-07:00

The arrangement of functionally-related genes in operons is a fundamental element of how genetic information is organized in prokaryotes. This organization ensures coordinated gene expression by co-transcription. Often, however, alternative genetic responses to specific stress conditions demand the discoordination of operon expression. During cold temperature stress, accumulation of the gene encoding the sole Asp–Glu–Ala–Asp (DEAD)-box RNA helicase in Synechocystis sp. PCC 6803, crhR (slr0083), increases 15-fold. Here, we show that crhR is expressed from a dicistronic operon with the methylthiotransferase rimO/miaB (slr0082) gene, followed by rapid processing of the operon transcript into two monocistronic mRNAs. This cleavage event is required for and results in destabilization of the rimO transcript. Results from secondary structure modeling and analysis of RNase E cleavage of the rimO–crhR transcript in vitro suggested that CrhR plays a role in enhancing the rate of the processing in an auto-regulatory manner. Moreover, two putative small RNAs are generated from additional processing, degradation, or both of the rimO transcript. These results suggest a role for the bacterial RNA helicase CrhR in RNase E-dependent mRNA processing in Synechocystis and expand the known range of organisms possessing small RNAs derived from processing of mRNA transcripts.

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