Following exposure to injury or infection, the body elicits a counteractive immune response which involves many different cell types and processes. Cytokines are substances secreted by cells which play a pivotal role in the regulation of this response. Professor Paige Lacy and colleagues in the Department of Medicine at the University of Alberta in Edmonton, Canada, have conducted extensive research into the exact mechanisms underpinning the regulation of cytokine release during the immune response with a particular focus on airway inflammatory disorders.

Cytokines and the Immune Response

Cytokines are intercellular messengers and purveyors of soluble regulatory signals which mediate the body’s response to injury due to pathogens, allergens and injury. Whilst cytokine release has been extensively studied, the precise mechanisms controlling this process are not yet fully understood, although it is acknowledged that the immune response is multifaceted and involves a complex system of different cell types, transport machinery and molecular pathways.

Over the past two decades, Professor Paige Lacy and her team in the Department of Medicine at the University of Alberta in Edmonton, Canada, have been investigating exactly how cytokines are synthesised, packaged, trafficked and released in response to external stimuli which cause cellular damage. Their work has identified many enzymes, membrane proteins, and receptors involved in these processes, and has revealed novel mechanisms of action in the regulation of the immune response in allergic airway inflammation and asthma.

Initially, Professor Lacy and colleagues reviewed published evidence to identify knowledge gaps relating to the mechanisms of cytokine release from immune cells. They explained that cytokine secretion by a range of cell types is a fundamental aspect of the immune response, and greatly influences the body’s reaction to stimuli.

Cytokine Secretion Pathways

Many different cells secrete cytokines, including epithelial cells, eosinophils, and macrophages. Epithelial cells are omnipresent, forming thin layers of lining tissue throughout the body, and are among the first cells to release cytokines in response to harmful signals. Epithelial cells work closely with the immune system by sending cues to initiate appropriate physiological reactions. Innate immune cells, such as macrophages and eosinophils, are naturally occurring cells which rapidly mobilise to the site of injury or infection, and can generate a wide range of cytokines. Collectively, these cells control pathogen invasion by recognising threats and producing toxic substances which kill harmful invaders, although the mechanisms relating to the movement of cytokines from epithelial cells prior to release remain to be fully determined.

Cytokines may be secreted via classical or non-classical pathways, which are defined depending upon the specific mode of action, and several pathways have been identified in specific immune cells. A major purpose of each pathway is to selectively regulate temporal cytokine release and to suitably terminate the response when necessary.

Most cytokine secretion, including from eosinophils, is via the classical pathway which is characterised by the packing and storage of cytokines in secretory granules within the cell prior to receptor-induced regulated release facilitated by membrane fusion. Alternatively, such as in macrophages, cytokines may be released immediately following synthesis which can ensue in a polarised manner. Furthermore, the process of cytokine secretion is customisable depending upon the required cell-specific immune function.

Eosinophils are highly granulated white blood cells which increase in abundance during an allergic response, and are capable of synthesising, storing, and secreting up to 35 different cytokines. Eosinophils have been observed in the airways of around half of asthma sufferers and may contribute to tissue damage. Cytokine secretion from eosinophils occurs predominantly via so-called piecemeal degranulation, where cytokines are recruited from larger storage granules and transported to the cell membrane in smaller vesicles, and degranulation may also occur via classical or compound exocytosis, as well as by lysis in dying cells.

Macrophages are derived from white blood cells predominantly found on mucosal surfaces including the airways and have a key role in wound healing and tissue repair. Cytokines within macrophages are continuously transported to the cell surface in preparation for release when these cells are activated.

Professor Lacy and her team summarised that the movement of cytokines through immune cells is dependent upon membrane-bound or cytoplasmic enzymes, proteins, trafficking molecules, and intracellular membrane receptors, which mediate transport, facilitate membrane fusion, and regulate secretion. Initiation of the secretion pathway occurs within minutes of encountering an agonist. However, the specific roles of certain enzymes and proteins and the importance of cellular structural rearrangements in cytokine release from innate immune cells had not yet been elucidated.

Determining Cytokine Secretion Mechanisms

Given the paucity of available information, Professor Lacy and colleagues attempted to determine which molecules regulate eosinophil degranulation within the context of airway inflammation. To do this, the team built upon an earlier study in which they discovered that asthma patients exhibited a higher expression and activity of a specific enzyme (Rab27a) within their eosinophils, and that this likely contributed to the physiological traits typically observed in asthma. Human and mouse eosinophils were isolated and subjected to various laboratory techniques to determine the presence, subcellular localisation, and polarisation of the selected molecule.

They found that the molecule selectively redistributed when the cells were stimulated with an agonist, which suggested that eosinophil cytokine release indeed occurred in a manner that was dependent on Rab27a. Further studies in eosinophils demonstrated a role for other intracellular enzymes and receptor proteins (Cdk5, VAMP-7). Professor Lacy and her team confirmed these findings by repeating the experiments in strains of mice which had been genetically modified to eliminate the proteins necessary for normal eosinophil function and observed that degranulation responses became defective. This research identified for the first time a direct role for specific regulatory molecules in inducing and controlling eosinophil degranulation in allergic inflammation and asthma.

Following these encouraging insights, Professor Lacy and her team endeavoured to further classify the proteins involved in the degranulation of eosinophils, since stimuli-induced activation of eosinophils is recognised as an exacerbating factor in the airway hyperresponsiveness associated with asthma. The researchers selected a vesicle-associated membrane protein (VAMP-7) which had previously been identified as an essential component of degranulation and confirmed that it was present in mouse eosinophils using fluorescence microscopy. Upon stimulation, isolated eosinophils translocate to gather at the edge of the cell, preparing for the release of granular contents.

Furthermore, genetically modified mice models lacking the chosen protein and mimicking allergic airway inflammation demonstrated a reduced incidence of degranulation and fewer cell-damaging products being released, suggesting a dysfunction in the eosinophil activation process, and confirming that eosinophil degranulation contributes to airway hyperresponsiveness. The fact that degranulation was not entirely abolished may be attributed to the small proportion of eosinophils that release their granular contents upon cell lysis, a recognised occurrence in allergic responses which depends on different signalling mechanisms. The researchers concluded that airway inflammation is at least partly mediated by degranulating eosinophils which can directly exacerbate the condition.

A Role for Cellular Structural Changes

To further investigate the mechanisms of cytokine secretion, Professor Lacy and colleagues proceeded to evaluate the intracellular storage sites of selected cytokines in eosinophils, and the pathways involved in their release. First, the team isolated human eosinophils from allergic or asthmatic participants and stimulated them to initiate cytokine trafficking. Fluorescence microscopy revealed altered eosinophil morphology and spatiotemporal increases in the levels of some cytokines following stimulation. Thereafter, the team deduced that membrane recycling pathways are likely employed by eosinophils to transport certain cytokines to the cell membrane for release, providing further insight into trafficking mechanisms within eosinophils.

This finding echoed that of earlier research conducted by Professor Lacy and her team investigating the mechanisms of cytokine secretion in macrophages, during which they reported that newly synthesised cytokines were also trafficked via a membrane recycling pathway. Delving further, the team continued to explore the mechanisms underlying the trafficking pathways and establish which mediators may be involved in the associated cellular structural changes. Using fluorescence microscopy techniques, dramatic alterations in the shape of cells were observed in the presence of a specific enzyme (Rac1), which was also associated with increased release of a selected cytokine and found to be vital for the final trafficking step prior to secretion within activated macrophages. Indeed, inhibition of the selected enzyme did not prevent cytokine synthesis in macrophages but did reduce transport and secretion, thus confirming, for the first time, its essential role in cytokine trafficking via the membrane recycling pathway.

Implications for Future Study

Understanding the various intercellular pathways involved in cytokine secretion is crucial for increasing our knowledge of cellular function in innate immunity and the associated ramifications for disease. Further studies surrounding the interrelationships of the regulatory pathways involved in the transport and secretion of cytokines and pro-inflammatory mediators may help to determine the underlying mechanisms unique to individual cell types. This is particularly prudent in the study of the mechanisms of cytokine release via non-classical pathways, since the theories surrounding this remain controversial.

More in-depth research to assess the secretion pathways of a wider range of cytokines and different cell types will undoubtedly prove highly beneficial in elucidating the underlying mechanisms of these phenomena. Using increasingly refined models of disease states has enabled Professor Lacy, her team, and collaborators to elicit the role of specific proteins in the degranulation of eosinophils in allergic inflammation using sophisticated gene targeting strategies. It is probable that complex multimodal mechanisms are involved in airway hyperresponsiveness involving synergistic product relationships, and experiments to decipher the contribution of individual components of eosinophil degranulation in asthmatic inflammation are warranted.

Perhaps most encouragingly, there is scope for exciting collaborations between scientific and clinical teams to apply the knowledge gained regarding the mechanisms of cytokine release in inflammatory disorders to the development of novel therapeutic targets.   

Chemotherapy, one of the mainstays of cancer treatment, can unfortunately act as a double-edged sword. While achieving the intended aim of killing cancerous cells, it also generates an accumulation of cell debris, which in turn, promotes tumour growth by stimulating inflammation in the tumour microenvironment. Dr Dipak Panigrahy and his colleagues from Harvard Medical School, USA, have conducted several studies in mice showing that targeting the tumour cell debris-mediated surge of proinflammatory and protumourigenic factors provides a strategy for enhancing the efficacy of chemotherapy.

The Double-Edged Sword of Chemotherapy

With advances in genomics and drug discovery, chemotherapy is the frontline treatment for cancer now more than ever before. However, accumulating evidence from various animal models of the disease suggests that rather than simply killing the cancerous cells, chemotherapy can also initiate the recurrence of cancerous tumours. Unfortunately, the mechanisms behind this double-edged sword are still poorly understood. Working to resolve important questions about this critical issue is Dr Dipak Panigrahy, along with his colleagues at Harvard Medical School, USA.

Apoptosis is the process of programmed cell death, and this may trigger escape from tumour dormancy by causing a cellular stress response linked to inflammation. Dr Panigrahy and his colleagues argue that increased levels of spontaneous apoptotic cell death in the tumours of cancer patients are associated with poor prognosis in several cancer types.

5-fluorouracil (5-FU) is a chemotherapeutic drug used to treat colorectal cancer. It reduces tumour mass by causing cell death, creating tumour cell debris in the form of apoptotic cells and cell fragments. Observing that apoptotic tumour cells can stimulate specialised cells known as macrophages and the production of proinflammatory cytokines, Dr Panigrahy and his colleagues proposed that 5-FU may be a source of tumour growth stimulation. In 2019, the Panigrahy laboratory published an important study that clearly demonstrated that 5-FU generates cellular debris that causes tumour cells and host macrophages to release a tumour factor known as osteopontin (OPN).

In clinical settings, OPN expression is linked to poor 5-year survival in many cancer types. OPN is a well-characterised factor that has been linked to cancer progression and angiogenesis, which is the growth of new blood vessels that tumours need to grow. Conventional chemotherapy may contribute to tumour progression and relapse via cell debris, suggesting that treating the tumour-promoting activity of cell debris is critical for the prevention of tumour recurrence.

In the 2019 study, Dr Panigrahy examined the cytotoxic activity of 5-FU in mice that were previously inoculated with colorectal cancer cells. As predicted, the researchers observed increased cell death in tumours that were treated with 5-FU compared with size-matched control tumours. Furthermore, the study confirmed that systemic 5-FU treatment and tumour cell debris increase OPN levels and that debris-stimulated tumour growth is mediated by enhanced tumour angiogenesis. The most important finding, however, was that pharmacologic and genetic ablation of OPN inhibited debris-stimulated tumour growth. Dr Panigrahy and his colleagues demonstrated that a combination of neutralising antibodies to inhibit OPN and continued treatment of 5-FU dramatically inhibited tumour growth.

Chemotherapy-generated Debris and Ovarian Cancer Resurgence

Epithelial ovarian cancer, a major cause of death in women worldwide, is characterised by a high tumour recurrence, which can occur in up to 70% of patients. To ascertain whether chemotherapy-generated debris is biologically relevant in ovarian cancer, via a similar mechanism initiated by 5-FU and mediated by OPN in colorectal cancer, Dr Panigrahy and his colleagues treated mouse and human cell lines with cytotoxic platinum- or taxane-based chemotherapeutic agents used for treating ovarian cancer. As a consequence of the treatment, the colleagues observed a surge of proinflammatory cytokines and bioactive lipid molecules known as eicosanoids, released by macrophages, in the tumour microenvironment. The findings of this study were published in 2019 in the prestigious journal, the Proceedings of the National Academy of Sciences (PNAS).

The research team also observed that the presence of debris alone without macrophages in the culture medium resulted in minimal to undetectable levels of cytokines, confirming that the release of lipid mediators and cytokines is macrophage-dependent. The PNAS study showed that the combined pharmacological inhibition of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the surge of both cytokines and lipid mediators by macrophages. These results confirmed that ovarian cancer patients may benefit from the suppression of eicosanoid and cytokine mediators, protecting the body from a therapy-induced debris-mediated cytotoxic and tumourigenic response.

Aspirin-triggered Mediators as Optimal Chemopreventive Agents

Many studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) aspirin is potent in counteracting the formation of tumours. Despite numerous reports confirming its beneficial properties in cancer prevention, the biochemical mechanisms behind this unique antitumour activity of aspirin compared with other NSAIDs remain poorly understood. Cyclooxygenase (COX)-1 and COX-2 are key targets of aspirin and are involved in the biosynthesis of proinflammatory lipids, such as prostaglandins. Dr Panigrahy and his colleagues published another study in 2019 showing that aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory mediators termed ‘aspirin-triggered specialised pro-resolving mediators’ (AT-SPMs), such as ‘aspirin-triggered resolvins’ (AT-RvDs) and ‘aspirin-triggered lipoxins’ (AT-LXs).

The research team demonstrated that treatment of mice with AT-RvDs or AT-LXs inhibited primary tumour growth by enhancing macrophage removal of tumour cell debris and inhibiting the production of macrophage-secreted proinflammatory cytokines. Following the publication of the 2019 study, AT-SPMs, including resolvins, have been considered in clinical studies for their tumour-preventing activity. Dr Panigrahy and his colleagues have shown that, given the risks associated with chronic low-dose aspirin intake, mediators such as aspirin-triggered resolvins and other AT-SPMs may be a more desirable therapeutic option, since they display more potent antitumour activity and are devoid of aspirin-related toxicity.

Resolvins Enhance Cancer Therapy by Clearing Cell Debris

As demonstrated in many studies by the Panigrahy team, dead and dying tumour cells greatly affect the tumour microenvironment. This leaves the medical profession with a dilemma between treating tumours with chemotherapy and minimising the effects of debris-induced tumour progression. Resolving this dilemma is paramount to preventing tumour recurrence after therapy.

In a study published in 2017, Dr Panigrahy and his colleagues demonstrated that apoptotic debris stimulates tumour growth through the action of phosphatidylserine (PS), a modified amino acid that is present on the surface of apoptotic cells. The study showed that blocking PS in the debris with a recombinant protein or an anti-PS neutralising antibody significantly inhibited debris-stimulated tumour growth in a dose-dependent manner.

The 2017 study adds further evidence in support of using specialised pro-resolving mediators, such as resolvins, to clear apoptotic debris. The novel approach alongside chemotherapy would greatly prevent tumour recurrence and enhance the benefits of cancer therapy. The observations were supported by the results of a 2019 study in which Dr Panigrahy and his colleagues demonstrated that the resolution of inflammation via resolvins, before surgery, inhibited the formation of new tumour growth, inducing robust anticancer T cell immunity in mice affected by Lewis lung carcinoma.

Resolution of Inflammation Halts Liver Cancer Progression

Building on the observations published in previous years, Dr Panigrahy and his colleagues recently published a new study on the effects of inflammation on the changes to the tumour microenvironment triggered by cytokine and eicosanoid storms during hepatocellular carcinoma (HCC). Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus fungi, may play a causative role in 4.6 to 28.2% of all HCC cases worldwide. Aflatoxin-induced HCC is most prevalent in developing countries due to the regular consumption of food contaminated with aflatoxins.

HCC is associated with excessive production of proinflammatory cytokines, including TNF-α and IL-6, which lead to apoptotic cell death in multiple cell types. AFB1 can also negatively impact macrophages by impairing their ability to remove cell debris. By causing excessive production of oxidative stress, proinflammatory cytokines start a cascade that leads to DNA damage and new tumour growth, correlating with poor patient survival. Dr Panigrahy and his colleagues demonstrated that tumour cells killed by AFB1 stimulate primary HCC growth when co-injected in mice with a nontumourigenic inoculum of tumour cells and that the malignant growth is dependent on a macrophage-derived eicosanoid and cytokine storm that also involves mediators that promote the formation of new blood vessels.

Dr Panigrahy and colleagues demonstrated that dual COX-2/sEH inhibitors can be administered during and immediately after periods of high exposure to aflatoxins, resulting in a physiological switch from a pattern of inflammation to the resolution of inflammation. By targeting the debris-mediated eicosanoid and cytokine storm, via clearance of tumour cell debris, dual COX-2/sEH inhibition may provide an effective strategy for the prevention of AFB1-induced hepatocellular carcinoma.

When Earth’s magnetic field is struck by violent geomagnetic storms, narrow streams of fast-moving ions can form, which pose serious threats to vital satellite systems. Through her research, Dr Amy Keesee at the University of New Hampshire is shedding new light on how these streams originate, by picking up the energetic neutral atoms they occasionally generate. Her team’s work has proved that these atoms can be used to build reliable temperature maps of the magnetosphere – the region around Earth dominated by the planet’s magnetic field. Such temperature maps can help us to better predict when satellite systems may be under threat.

Earth’s Protective Shield

The magnetic field which surrounds our planet provides a vital barrier against the streams of energetic ions which constantly hurtle towards us. Under the laws of electromagnetism, the paths of these charged particles are deflected by magnetic field lines, so that when they interact with Earth’s magnetosphere, particles that were previously on a collision course with Earth are repelled into space, protecting the planet’s surface from dangerous radiation.

Most of the time, these particles come in the form of electrons, protons, and helium nuclei originating in the Sun’s upper atmosphere, which permeate the solar system in a steady stream named the solar wind. In more extreme cases, particles can be ejected through violent eruptions of plasma on the Sun’s surface, named coronal mass ejections.

Triggering Storms

These dramatic events send energetic blobs of plasma out into space, which carry significant magnetic fields of their own. As they clash with Earth’s magnetosphere, the magnetic forces induced by these blobs can generate shockwaves which reverberate throughout the entire system, in events named geomagnetic storms.

In turn, these shockwaves can generate violent and unpredictable movements in the ionosphere: a region in Earth’s upper atmosphere that is mostly unshielded from the Sun’s radiation. Here, atoms have been stripped of their outer electrons, leaving behind positively-charged atomic nuclei whose motions are directly influenced by surrounding magnetic fields. As these particles interact with the reverberating magnetosphere, the energy they gain can allow them to penetrate far deeper into Earth’s atmosphere.

This phenomenon can have destructive consequences for the satellite systems we now rely on for many vital applications: including communication, navigation, financial transactions, and national security. During geomagnetic storms, energetic ions and electrons can more readily cross paths with these orbiting satellites – damaging and potentially even destroying their electronics if they are still powered on. This makes it particularly crucial for researchers to understand the coupled dynamics that play out in the magnetosphere and ionosphere when geomagnetic storms strike.

Heated Ion Slingshots

Dr Amy Keesee and her colleagues at the University of New Hampshire explore one particularly important aspect of this process, which stems from the unique geometry of Earth’s magnetic field on its night-time side. While the field lines facing the Sun are continually compressed by the solar wind, those on the opposite side form an elongated ‘magnetotail’ – which points away from the Sun, and extends far out into interplanetary space.

As the energy deposited during a geomagnetic storm reverberates around the magnetosphere, it will eventually be dumped in the magnetotail. This causes the tail’s elongated magnetic field lines to act like a slingshot – capturing particles within small sections of the magnetosphere, heating them up, and sending them hurtling towards Earth.

These channels of fast-moving ions are a major part of the threat faced by orbiting satellites during geomagnetic storms, but so far, they have proven notoriously difficult to study. The problem is that these channels don’t emit secondary particles of their own – like how a star can be analysed by the photons it emits, for example.

Ultimately, the only way to study them is to place observational instruments directly in their path. This is particularly challenging, since the events are both unpredictable and short-lived, making it increasingly difficult for researchers to observe them directly. So far, these challenges have prevented researchers from making accurate predictions of when and where heated channels of ions will arise; and subsequently, how satellite systems can be better protected from them.

Searching for Energetic Neutral Atoms

Dr Keesee and her colleagues have been developing a way around this barrier, which could make the process far easier to study. Their approach is based on searching for particles named energetic neutral atoms (ENAs) – which only emerge in rare circumstances, but may offer vital clues as to what is happening in the magnetotail during geomagnetic storms.

ENAs are generated when fast-moving atomic nuclei steal orbiting electrons from the neutral atoms they interact with, while barely losing any of their original energy. As ordinary atoms, the paths taken by these new particles are no longer influenced by the shape of Earth’s magnetic field, leaving them free to travel unabated towards the planet’s surface.

By detecting the ENAs that make it to the inner magnetosphere, some researchers have proposed that the particles could be used to study localised bursts of charged particles in the magnetotail. So far, however, it has remained unclear whether this link can really be made.

For example, while ENAs have been observed at around the same time as geomagnetic storms in the past, similar observations have also been made without any concurrent evidence of energy being injected into the magnetosphere – placing doubt on whether ENAs could really be used to study the magnetosphere’s deeply complex dynamics.

Measurements with TWINS

To shed new light on the problem, Dr Keesee’s team analysed the ENA observations made by NASA’s Two Wide-Angle Imaging Neutral-Atom Spectrometers (TWINS) mission, which ran from 2008 until 2020. On top of this, they aimed to recreate narrow streams of ions within simulations of real geomagnetic storms – incorporating the coupled interactions between charged particles and moving magnetic fields.

In one recent study, the team used their simulations to create a temperature map of the magnetosphere, in which higher ion temperatures are associated with local-scale accelerations within the magnetotail. ‘We used a novel technique to observe these ions by calculating ion temperature maps of the magnetosphere using data from energetic neutral atom imagers,’ says Dr Keesee.

As they had hoped, the maps produced by their simulations largely agreed with the temperature maps generated by TWINS through its ENA measurements. This was a particularly welcome surprise – providing robust evidence that ENAs are indeed a reliable indicator of where ions are being heated and accelerated.

The researchers did find that the ion channels observed by TWINS were hotter than those that appeared in their simulations. All the same, they hope that these differences could be ironed out through further improvements to their simulation techniques, which consider the many different factors involved in the accelerations in greater detail.

Mapping the Magnetosphere

In an additional study, Dr Keesee and her colleagues combined ENA observations from TWINS with direct observations of energetic streams of ions made by orbiting satellites. They also included ground-based measurements of Earth’s magnetic field, and observations of the aurora: the famous light display commonly seen in Earth’s polar regions, where ions can penetrate far enough through the magnetosphere to interact with the atmosphere.

While this phenomenon usually occurs since Earth’s magnetic field lines dip below its surface above its poles, leaving the atmosphere exposed to outer space, the disruption unleashed by geomagnetic storms can make the aurora visible at lower latitudes.

With these combined measurements, the researchers examined the changes that unfolded within the ionosphere and magnetotail during a real geomagnetic storm, triggered by a coronal mass ejection in 2012. They discovered that the ENAs picked up by TWINS both prior to and during the storm were closely associated with streams of charged particles being heated and accelerated in the magnetotail – but only after a reconfiguration of the Earth’s magnetic field were enhancements picked up by the magnetic field and aurora-measuring instruments.

Early Warning Systems

The team’s results are already incredibly promising – proving definitively that the ENA measurements provided by the TWINS mission could realistically be used to create temperature maps of the magnetotail. Crucially, they also show that the same instrument could be used to examine how local-scale temperatures in the magnetotail vary over time, without any need to send spacecraft to monitor its unpredictable dynamics directly.

These maps could be particularly crucial when geomagnetic storms are imminent. If coupled with observations of coronal mass ejections on the Sun, they could provide a more accurate weather forecast for the magnetosphere – allowing researchers to better predict when bursts of energetic ions are more likely to penetrate closer to Earth’s surface.

In turn, the techniques developed by the team could provide more effective early warning systems for satellite systems. By paying close attention to these warnings, satellite operators could assess when their instruments may be vulnerable to incoming streams of ions – signalling an urgent need to power their systems down.

Although this would incur financial and operational costs in the short term, it could also save satellites from potentially irreparable damage – allowing them to remain fully operational during future solar storms.

In her current research, Dr Keesee is working with colleagues that are designing a new generation of imaging instruments. If achieved, these designs could ultimately produce maps of the magnetotail’s constantly varying temperature in unprecedented detail, based on ENA measurements alone.

Recent studies suggest that South Africa’s youth are less engaged in formal politics than earlier generations. Professor Elirea Bornman and her students at University of South Africa have recently investigated the opinions of youth on democratic institutions and the state of democracy in post-Apartheid South Africa. Their findings suggest that the apparent political disengagement and withdrawal from voting among young people is not necessarily associated with apathy or a lack of political opinions, but can reflect their lack of confidence in political processes and older generations of leaders.

Politics in Post-Apartheid South Africa 

The disengagement of youth in politics is a major issue facing democracies worldwide. When young people are not engaged with political processes, this means that they have no influence in important decisions that affect their daily lives. By including the voices of youth and responding to their needs, countries across the globe can build more equitable, stable and peaceful societies.

The involvement of young people in African politics is more controversial than that of youth in other parts of the world. Over the past few decades, African youth have been associated with very different political events, such as the ‘Arab spring’ in North Africa, where youth were at the forefront of political change, and – on the other hand –  the suppression of youth during the 1970s Red Terror in Ethiopia. In addition, African culture highly values age as a cultural symbol. Thus, it often only views young people as citizens of the future.

Because of its unique history, the political situation in South Africa is particularly complex. During apartheid, voting rights were restricted to white people only. These rights were extended to all citizens in 1994, enabling newer generations to vote irrespective of their ethnic or racial background.

Investigating Political Opinions

People born in South Africa after 1994 are often referred to as the ‘Born Frees’, as they have grown up in a society where equal rights to vote and to participate in society are guaranteed. Professor Elirea Bornman and her students wanted to understand how ‘Born Frees’ view their role in South African politics, as well as to gain insight into their opinions about elections, political parties, and party membership.

Recently, analysts suggested that many young people who do not vote might be voicing their opinions in other ways, such as on social media or through political protests. To determine whether this is the case, the researchers gathered the opinions of South African youth residing in the Pretoria area, by conducting six focus groups conducted between 2014 and 2018.

The participants were between 18 and 34 years old. As past studies suggested that white people in South Africa are sometimes hesitant to voice their opinions in the presence of other cultural groups, the researchers conducted separate focus groups for white and black participants.

Reasons for Voting

During the focus groups, the young people voiced a wide range of opinions. Overall, the findings gathered by the team suggest that South African youth form a very diverse group, as different participants had very different views on politics, voting, and political processes.

While some participants reported that they regularly voted, others said that they had no intention of participating in elections. The researchers tried to understand the reasons behind these differences and what encouraged South African youth to vote or to abstain from voting.

‘Some participants viewed voting as an expression of their love and dedication to the country,’ says Professor Bornman. Many saw it as a rite of passage into adulthood, through which they could influence decision-making and bring about change. Others, particularly some of the black participants, viewed voting as a responsibility, feeling that they should take full advantage of the rights that were unjustly denied to their ancestors.

Reasons for Not Voting

While some of the participants were politically active and deeply valued the democratic process, others said that they had no interest in voting or participating in political conversations. This lack of interest, however, did not always appear to be associated with ignorance or with what theorists have described as ‘political apathy’.

Instead, many people who did not vote expressed a general lack of confidence in the older generation of leaders and existing political parties, as they believed that these leaders were too old and did not reflect the needs of younger generations. For instance, some pointed out that current politicians did not understand problems of the modern era and did not communicate using contemporary technological tools, such as social media and the internet.

Others also believed that voting did not bring any real change, as the ANC party, the most supported party in South Africa, would likely win irrespective of their vote. Government corruption and poor performance were also two major reasons why some participants preferred not to vote.

‘In their case, withdrawal from elections cannot be regarded as political apathy, but represents a conscious act of opposition and an alternative form of political participation,’ says Professor Bornman. ‘However, whether they intended to participate in elections or not, most of the participants expressed dissatisfaction with the current political leadership in the country.’

Interestingly, regardless of whether they voted or not, most participants appeared dissatisfied with the current government in South Africa, as they felt that it did not prioritise the interests of the country and its citizens. As one of the participants put it: ‘I really think the ANC has been in power too long and we need some sort of a change. The politics are becoming… stagnated… the fat cats are getting fatter.’

Another participant added: ‘I feel like they should really start realising our education, our children, our healthcare, our poverty, jobs… they really, really have to start doing something about that, which I don’t feel our government does.’

Preventing Alienation

Overall, the recent study carried out by Professor Bornman and her team shows that South African youth range from young people who are engaged in politics to those who are largely disengaged. However, their findings suggest that those who do not actively participate in politics do not always desist due to apathy. Instead, some are untrusting of existing politicians and parties.

‘Our findings are important not only to achieve a better understanding of youth in post-apartheid South Africa, but also to get a glimpse of the disillusionment and frustration of youth in Africa where they no longer share the revolutionary ideals of their political leaders,’ says Professor Bornman. ‘They have also become tired of gerontocratic African leaders. Instead, the Arab Spring as well as the influence of the media – and social media in particular – have raised awareness among African youth of what good and accountable democratic governance entails.’

In the future, Professor Bornman’s study could encourage South African leaders and political parties to devise alternative communication strategies and initiatives that address the doubts and concerns of younger generations. Such initiatives could ultimately bring youth back into the political dialogue, ensuring that their voice is heard during important decision-making processes.

‘Youth alienation could, in the end, have far-reaching negative implications for the stabilisation of democracy in South Africa, but also in other post-colonial societies,’ says Professor Bornman. ‘In order to consolidate democracy and to prevent destabilising youth uprisings, political leaders should govern in transparent and accountable ways. The youth should furthermore not be perceived as citizens of the future. Their voice in the current political situation should be taken seriously.’

A key step towards a carbon-neutral future could be reached through dispersed power grids, featuring networks of local-scale renewable energy and battery storage plants. To prevent these power grids from damaging themselves and their surroundings when electrical faults arise, they must be integrated with ‘circuit breakers’, which temporarily interrupt the current flowing through them. However, currently available circuit breakers cannot handle the medium-voltage direct currents best suited for these grids. Through an innovative new circuit breaker design, Steve Schmalz and his colleagues at Eaton Corporation, the Illinois Institute of Technology (IIT), Virginia Tech and the National Energy Technology Laboratory (NETL), hope that this challenge will soon be overcome.

AC vs DC

Currents in electrical circuits can flow in two distinct ways: either periodically changing direction in alternating current (AC), or maintaining a constant direction in direct current (DC). Each of these types has its own advantages. Owing to its high efficiency and low maintenance costs, AC has dominated the US power grid for over a century. However, through the latest advances in semiconductor electronics, DC is now becoming increasingly popular.

With its ability to transmit large amounts of power with very little energy loss, DC is now the current of choice in a wide array of applications, which vary depending on voltage. While low-voltage DC is commonly used in consumer electronics, LED lighting and electric vehicles, high-voltage DC can reliably transmit power across large distances – making it key to the performance of undersea and underground cables.

While the technology required to implement DC at low and high voltages is now maturing, there remains a gap in the middle, spanning voltages ranging from 1 to 100 kilovolts. Such ‘medium-voltage DC’ is still in the early stages of technological development.

Dispersed Power Grids

Steve Schmalz and his colleagues at Eaton Corporation, alongside partners at IIT, Virginia Tech and NETL, recognise two key advantages of medium-voltage DC: it is both the most practical voltage range for converting AC into DC, and is well suited to transmitting power across local-scale regions. Because of these advantages, progress in medium-voltage DC technology could bring immense benefits to the development of dispersed power grids. Rather than being generated on industrial scales in single locations, such as coal or nuclear power plants, energy in these grids is produced, stored and distributed on local scales.

In a dispersed power grid, the excess energy produced by networks of smaller renewable energy plants, including wind and solar farms, can easily be stored in local battery facilities, and then released when required. For example, a solar farm may produce more energy than demand requires during the day – and so this excess can be used to charge a battery. This energy can then be used to power homes and businesses after sunset, when no solar power is being generated.

On top of this, the use of medium-voltage DC would mean that these new systems could easily plug into existing AC power grids, without major changes to infrastructure. ‘For example, a medium-voltage DC system could serve as a bi-directional link between separate AC grids that are unsynchronised and could otherwise not be connected without massive reconfiguration or replanning,’ explains Schmalz. ‘This could provide added grid resilience allowing one AC grid with excess capacity to share with an adjacent grid that is being overtaxed. Depending on the geography, retrofit medium-voltage power converters between the AC and DC systems could control the power flow between grids with less added infrastructure, and minimizing the need to clear rights-of-way for completely new AC power lines.’

Altogether, the efficiency and flexibility offered by dispersed, small-scale power grids could make them central to the widespread rollout of renewable energy. As such, dispersed power grids could be essential in drastically reducing greenhouse gas emissions. However, before this can be achieved, new innovations in the technology required to support medium-voltage DC will be essential.

Interrupting Faulty Circuits

Currently, one of the biggest roadblocks in this development is the need for an essential safety component, named a ‘circuit breaker’. These devices come in a wide array of designs, but all operate by the same general principles. During electrical faults, which can produce damaging or even dangerous surges in current, powered sensing devices detect any excess flows of current by picking up the heating or magnetic effects they generate.

Once the fault is detected, the device opens a switch to break the circuit, temporarily interrupting the path of its flowing current, thus stopping the surge. In mechanical circuit breakers, this involves using transducers in response to the excess current to trigger switch mechanisms such as springs or levers – physically separating two contacts in the circuit in a controlled way. This separation generates an arc of electricity where the current jumps between the contacts, which must be cooled, contained, and extinguished as quickly as possible.

The main advantage of mechanical circuit breakers is that they allow currents to flow with very little conduction loss in normal circumstances. However, since their contact separation mechanisms can take a long time to trigger, the level of safety they offer can be limited. In addition, the emergence of an arc can damage the device, limiting its operational lifetime. More fundamentally, quenching an arc between parting contacts is more difficult to accomplish in DC, as the current does not periodically reach zero like in AC, allowing the arc to extinguish. So far, these drawbacks have meant the use of mechanical circuit breakers has largely been limited to AC and low-voltage DC systems. These challenges make upscaling to medium-voltage DC more difficult.

Alternatively, solid-state circuit breakers involve the use of semiconductor-based transistors, which interrupt flowing currents within the semiconductor material itself. These switches don’t generate arcs, and can be switched to block current far more quickly when electrical faults arise. This makes them ideal for applications where circuit breakers are placed close to the equipment being protected, such as battery packs in electric vehicles.

However, solid-state circuit breakers also induce high energy losses. This means that much of the current flowing through them is lost as heat – creating the need for separate cooling systems. Currently, it would be incredibly difficult to scale this setup to medium-voltage levels, without sacrificing their cost and efficiency.

Hybrid Circuit Breakers

One further design, named a ‘hybrid’ circuit breaker combines the advantages of mechanical and solid-state circuit breakers – rapidly interrupting circuits when faults arise, while keeping power losses comparatively low.

Hybrid circuit breakers can have different configurations, but each one employs four basic functional elements: a mechanical switch, at least one semiconductor-based switch which ultimately interrupts the current flow, a means of transferring or ‘commutating’ current flow from the mechanical switch to the semiconductor interrupter, and a system of surge arrestors that limit the peak voltage and dissipate any excess electrical energy as heat.

When a fault occurs, the commutator transfers the current to the semiconductor switch. The mechanical switch then opens, but only once the current has been completely diverted – preventing an arc from forming. Afterwards, the semiconductor is turned off, and any remaining current is dissipated by the surge arresters.

Roadblocks to Commercial Rollout

In principle, this combination of circuit breaking mechanisms makes hybrid circuit breakers ideal for integrating with medium-voltage DC systems. However, there are still challenges to overcome. While existing hybrid circuit breaker designs provide lower energy losses than solid-state circuit breakers, they don’t typically provide the same rapid response times because they are limited by the speed of the mechanical switches. Meanwhile, the method of commutation may compromise the overall efficiency that the hybrid circuit breaker can truly achieve.

Prototypes for medium-voltage DC circuit breakers are now in development by several research teams around the world, and are now capable of handling voltages ranging from 7 to 12 kilovolts. However, these challenges mean that they have only been demonstrated in lab settings and aren’t yet considered commercially-viable products.

Designing an Improved Hybrid Topology

Through their research, Schmalz and his colleagues have made promising steps towards overcoming this barrier, through the development of a modular, scalable device, specifically designed for interrupting medium-voltage DC current, with key improvements to the essential hybrid breaker elements.

Some previous hybrid designs employ methods to transfer current from the mechanical switch to the semiconductor interrupter. Such designs require the insertion of another semiconductor in the conduction path with the mechanical switch, which compromises overall efficiency. In the team’s new design, current flows only through a closed mechanical switch under normal circumstances, minimising energy loss. This switch is connected in parallel to a second conduction path, containing a novel power electronic circuit that can carefully track the current flowing through it, and subsequently inject current in the opposite direction.

When a fault occurs, this injector transfers the current from the mechanical switch to its own conduction path – which also contains the semiconductor interrupting switch. When the current passing through the mechanical switch reaches zero, it opens with no arcing or damage to the contacts.

Other key improvements in the design reside in the mechanical switch, which employs contacts enclosed in a vacuum and a Thomson coil-based actuator capable of forcing the contacts open 20 times faster than traditional mechanisms. The vacuum provides higher-voltage insulating properties at shorter contact separation distances. These traits combine to dramatically improve the response time to be comparable to that of pure solid-state circuit breakers, because the semiconductor interrupting switch can be switched off soon after the contacts part, completing the fault interruption process.

Another key advantage of this design is that the semiconductor interrupting switch is completely modular – meaning any number of them could be connected in series to scale to higher voltage systems. In turn, this means that the surging current can be shared between as many interrupters as required.

Such an easily scalable setup allowed Schmalz’s team to optimise their system over a wide range of voltages. In their setup, they used their hybrid circuit breaker to handle up to 6 kilovolts. Compared with previous designs, this setup offered both comparatively fast response times, improved efficiency and far higher power density. This allowed it to be compacted into far smaller volumes, removing any need for bulky and expensive cooling apparatus.

Bringing Medium-Voltage DC to Maturity

Schmalz and his colleagues hope that their novel hybrid circuit breaker design could help to overcome many of the challenges currently faced by medium-voltage DC technology. By integrating their device into power grids, operators could confidently safeguard their systems against damage when electrical faults arise.

If the device becomes commercially available in the near future, it will enable easier integration of renewable energy and battery storage into existing power grids, in addition to more efficient powering of native DC loads that connect to power grids, such as railways and data centres. By implementing dispersed power grids, capable of generating and delivering energy on local scales, Schmalz and his colleagues hope that an important step towards a carbon-neutral future may finally be achieved.

Within the wider worlds of engineering, manufacturing and construction, there is a growing demand for accurate computer modelling of large-scale projects. Through the use of artificial intelligence, engineers can more accurately predict and improve various aspects of construction work, from calculating the total cost of a project, to optimising the quality of concrete. Dr Ming Lu and his team at the University of Alberta are developing such artificial intelligence systems, towards ultimately overhauling how we plan large-scale engineering work.

Computational Solutions to Engineering Problems

Throughout history, engineers have relied on a combination of skill and experience, passed down from generation to generation, in order to improve upon their designs and methods over time. However, there are drawbacks to this method of gathering information. It can take a long time to train competent engineers, meaning they are often in short supply. Furthermore, some engineering jobs can be time consuming and require a lot of data processing. In essence, many aspects of the profession need to be optimised, so that engineering projects can be completed as efficiently as possible.

Towards this aim, Dr Ming Lu and his colleagues have been researching how we can implement exciting new artificial intelligence (AI) systems into the various fields of engineering. By harnessing the power of AI, he hopes that many large-scale engineering projects can be completed more efficiently and with less subjective input.

Optimising Concrete

For thousands of years, humans have been using lime to create cement, leading to the material that forms a cornerstone of our society: concrete. Increasing in popularity since the Industrial Revolution, this material has been widely used and thus closely studied. This means that there is a huge bank of knowledge on the properties of the material, which modern engineers must appreciate to achieve the best results.

One such property is referred to as the ‘slump’ of concrete, which describes the consistency of fresh concrete before it hardens. This property is essential to understand when working with concrete, as it can affect the way that the material sets, and thus the quality of the final product. As such, it would be useful if engineers could design a system that accurately predicts the outcome when producing concrete using different methods and ingredients.

Previous studies have used artificial neural networks to model the quality of different concrete mixtures and predict the outcome of specific mixing processes. While these neural networks have proven to be effective, many researchers believe that they are too complicated to fully understand and implement effectively. Thus, researchers have been attempting to develop other systems, which are easier to implement while still achieving the same standard of results.

Dr Lu and his team propose a different method of modelling this phenomenon, using what is known as a ‘model tree algorithm’. This method, which works by classifying data and sorting it into categories to better understand it, has been previously shown to be effective for this sort of work. Thus, the team began to compile data and work towards producing a system that would achieve this goal.

Through their work, the team developed a system that can analyse existing data in order to gain better understanding of the factors affecting the slump of the concrete. They then used their system to attain estimates about theoretical mixtures based on a number of possible variables. This is a major breakthrough, as it could allow engineers to better understand how concrete can be produced in an optimal way for a specific purpose, before any resources are consumed. This approach would help to make the construction industry far less wasteful – in terms of raw materials, money and time.

Cost Estimation of Steel Fabrication

Any type of construction project is going to incur large costs due to numerous factors, including the labour required. Often these costs will be calculated by first estimating the number of ‘labour-hours’ that each team will require to complete their tasks, which can be used to give a rough estimate of the total labour costs involved. However, during the planning stages of a construction project, it can be almost impossible to achieve accurate estimates, which can cause cash-flow problems down the line.

Therefore, many engineers turn to computational management systems, which can more precisely predict the labour-hour requirements for construction work, leading to more accurate cost estimations.

In a recent research project, Dr Lu and his colleagues developed a model that can accurately predict the labour costs involved in large-scale construction projects. In this case, the team used a steel fabrication project as a case study. The process of making steel, which itself is widely used in construction, has many crucial steps, each of which can have their own associated costs. Thus, it was a perfect example to test the team’s new model.

Utilising a similar process to that employed to solve the concrete problem, Dr Lu and his team implemented an AI that was able to provide reasonable estimates for the time, and therefore costs, involved in various steelmaking projects. This tool could be invaluable for assisting with the decision-making process when it comes to planning large-scale work in the future.

Calculating the Cost of Prefabricated Components

Dr Lu and his team then decided to extend the limits of their computational work and branch out into other fields of cost prediction. This time, the study wasn’t focused on the fabrication of steel, but the prefabrication of parts for construction, such as precast concrete components or prefabricated piping spools.

With a huge number of different designs, materials and components available, engineers have more choice than ever when it comes to purchasing and using pre-made parts. This can help to significantly reduce the work required, and allows engineers to use a wider array of different components within their projects.

However, pre-made parts can sometimes be expensive, so it is important for engineers to understand whether it is more cost-effective to buy such parts or to build them from scratch. In addition, engineers need to predict the time and cost required for making various structural components.

This can once again be achieved through carefully designed models, which can use existing data to establish accurate cost scaling and come up with optimal plans. Dr Lu’s team has been using data from the manufacturing of pipe spools and wall panels, in order to produce a precise and adaptable model.

Once again, the team was successful in delving into established mathematical theories and designing a system that could produce a reasonable prediction of the uncertainties in the costs involved in these processes by analysing existing data on the subject. This tool could provide a suitable way for engineers to plan their work within budget, to the greatest efficiency and cost-effectiveness.

Creating an Explainable AI System

As Dr Lu has demonstrated, well-designed AI systems can allow engineers to greatly cut down on the time they need to spend making calculations. As such, these systems help us to achieve large-scale engineering projects more efficiently.

However, while these AI systems are incredible, their complexity can lead to issues in usability. If an engineer cannot understand how an AI system calculates its results, it is difficult to evaluate how effectively it is working.

The solution is an additional branch of computer management system design, known as ‘explainable AI’. This revolves around the design and implementation of a second model, which can help to articulate the logic used by an AI system, while still allowing it to work effectively. In short, this allows the end user to understand the mechanisms that the system used to reach its results, evaluate its effectiveness and gain additional insight into the problem being solved.

Working alongside a structural steel fabricator, Dr Lu and his colleagues set out to develop a system that would not only predict the labour-hour requirement involved in steel fabrication, but would also do so in a way that can be interpreted by professionals working at the company.

‘Model explainability matters as much as prediction accuracy in engineering applications,’ says Dr Lu. ‘We wished to turn the model tree algorithm into an explainable AI, so as to reveal which inputs play what roles in predicting outputs, along with the uncertainties associated with the predicted outputs.’

When it comes to understanding how to work with certain materials, such as steel, it is hard to do better than real on-the-job experience. The AI system designed by Dr Lu’s team was not supposed to replace this know-how, but rather lend analytical decision support to complement this know-how. To ensure that these predictions were accurate, the team designed their system so that users, both inexperienced and experienced, can understand how the AI system reaches its conclusions.

Transforming the Field of Engineering

Through the inventive use of AI, Dr Lu and his colleagues have demonstrated how we can better cope with the complexities and variations in connection with construction and fabrication processes, providing construction engineers and managers with much needed decision support by making the most of the available data. The team’s systems not only make accurate predictions, but also allow users to understand how they reach their conclusions. Efforts like this may ultimately change the world of engineering, providing future generations of engineers with the tools they need to build as effectively as possible.