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

In conversation with Julien Harneis, UN Assistant Secretary-General 18 November 2024 — 2:30PM TO 3:30PM Anonymous (not verified) 11 November 2024 Chatham House and Online

In this discussion, Julien Harneis will give critical insights into the UN’s humanitarian response in Yemen and the importance of maintaining independent humanitarian assistance.

According to the United Nations, Yemen has faced the world’s worst humanitarian crisis in the last decade, with over 20 million people in need of assistance. Years of ongoing conflict have devastated infrastructure, displaced millions, and caused widespread food insecurity and health emergencies. Access to essential services remains a daily struggle, and the escalating economic collapse has left vulnerable communities facing critical shortages in food, water, and medical supplies.

However, humanitarian actors are continually facing challenges in delivering aid to Yemen due to security threats and supply chain barriers, highlighting the urgent need for coordinated and sustainable international assistance.

UN Assistant Secretary-General and Humanitarian Coordinator for Yemen, Julien Harneis, will provide an account of the humanitarian mission and evolving strategies in Yemen, the impact of regional conflicts in the delivery of aid and discuss other key questions including:

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

James E. Balmer
Nov 1, 2002; 43:1773-1808
Reviews

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

K Schoonjans
May 1, 1996; 37:907-925
Reviews

IJ Goldberg
Apr 1, 1996; 37:693-707
Reviews

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

Strengthening Our Commitment to the Next Generation News Release NCapeling 9 November 2020

Panel of Young Advisers and Queen Elizabeth II Academy Ambassadors underscore our drive to reach, engage and inspire young people to change their world.

Supporting Next Generation of Leaders in Sustainability News Release NCapeling 28 January 2021

A new programme offering paid internships for young people who are passionate about social, economic, and environmental sustainability has been launched.

Why the next generation is key to protecting human rights Expert comment LToremark 23 June 2021

Strengthening youth participation in public affairs is essential to building inclusive and democratic societies that respect human rights.

Young people have always been drivers of social and economic reform, and today’s global youth population is more numerous and interconnected than ever before. While they have been at the forefront of civic rights movements in recent years, young people are largely excluded from discussions around human rights norms and how to monitor their protection and defence.

Young people are consistently underrepresented in intergovernmental mechanisms and national dialogues, which not only squanders their potential to contribute to effective solutions but also risks disengagement and disillusionment with multilateralism more broadly, at a time when many are already warning of the fraying of the international liberal order. Although there are actors and initiatives working to lift barriers to youth participation in governance – such as the UN Secretary-General’s Envoy on Youth, Jayathma Wickramanayake, or the UN 2016 Not Too Young To Run campaign – these efforts tend to fall short in effecting real change and rarely translate into institutionalized procedures.

While ‘the youth’ is a heterogenous group, comprising different ages, ethnicities, national identities and interests, their participation in realizing human rights is essential to addressing the current challenges and possibilities of human rights for future generations. This will help foster more effective solutions to rights-related challenges, re-build trust in the international human rights framework among younger demographics and broaden and deepen commitments to human rights across generations.

Human rights policies and the online environment

Young people tend to be more technologically literate than their predecessors and also represent the majority of internet users and social media consumers in many countries. They can therefore play a key role in innovating and imagining rights-based solutions to emerging problems for the human rights framework, such as illegitimate collection of data by governments and companies, microtargeting by online platforms, and the sharing of harmful content online. In many cases, international human rights practices have failed to keep pace with these changes and the challenges they bring.

Younger demographics may also approach these novel human rights issues from different starting points. For example, a UK study found that 30 per cent of 18-24 year-olds were ‘unconcerned’ about data privacy compared with only 12 per cent of those aged 55-64, and it has been shown that younger people tend to be more discerning of fake news compared to older generations. There may be a need for human rights institutions and practitioners to acknowledge and bridge these gaps in perspective and understanding to ensure long-term support for proposed solutions.

International cooperation for human rights protection

It has been suggested that young people have reaped the benefits of previous human rights-based policy reforms and have a strong sense of what rights they are entitled to and why these need to be protected through an international framework. Young people are also generally more supportive of multilateralism compared to their older counterparts, as demonstrated by a 2020 survey by Pew Research Center on global attitudes, which showed that 72 per cent of respondents aged 18-29 stated they have a favourable view of the UN, compared with 58 per cent of respondents aged 50 and older.

At a recent Chatham House workshop, young participants from countries as diverse as Lebanon, Kenya and the United States expressed concern that growing hostility towards globalization threatens to undo progress in human rights standards and multilateralism more broadly, progress that they have seen and benefitted from. The rise of nationalist and populist parties has also seen countries shift their attention inwards, as evidenced by former president Trump’s decision to withdraw the US from the Paris Agreement on climate change, and threats by Brazil’s president, Jair Bolsonaro, to follow suit.

Engaging more actively with younger individuals on global human rights reform will help ensure the long-term relevance of multilateral cooperation as well as domestic buy-in of human rights commitments.

Awareness of the interconnectivity of global problems

Young people’s proficiency on online platforms has enabled greater coordination and knowledge sharing without geographical constraints, allowing young activists – like Greta Thunberg – to inspire global movements and foster online discussions about intersectional solutions to modern-day challenges.

This intersectional and transnational lens will be a vital component of building solutions to politically or historically complex issues and can be leveraged to foster better understanding of competing human rights claims relating to issues such as land re-distribution in South Africa or limitations on freedom of movement during the COVID-19 pandemic. These democratic forums and platforms will ultimately help build a global community committed to and engaged with human rights.

Capturing the next generation’s potential

With these concerns and areas of potential in mind, how can human rights institutions and mechanisms create more meaningful avenues for youth input? 

Recent Chatham House research has suggested that multilateral institutions’ efforts to engage youth has often taken the form of ‘superficial listening’, for example inviting a high-profile youth actor to a one-off event or appointing youth delegates who are not able to participate in formal discussions or mainstream governance forums. While encouraging youth participation in meetings focused on human rights can lead to positive change, tokenism can discourage future engagement and dilute the effectiveness of the forums in question.

Capitalizing on the potential of the next generation can be achieved through integrating youth councils and advisers into national and international human rights policy processes, as well as human rights institutions. A few replicable models are already operational, such as the Y7 and the Y20 delegations – the official youth engagement groups for the G7 and G20 – that advance evidence-based proposals to world leaders ahead of the G7 and G20 summits.

At the domestic level, grassroots youth-led movements can help bridge the gap between local constituencies and international policymakers, with youth activists on the ground helping to implement human rights standards and fighting against the spread of misinformation. Strong local networks and civic spaces are essential for pushing back against human rights abuses, and youth activists should be mobilized to connect the efforts of domestic and international bodies to the real issues on the ground; for example, canvassing grassroots youth networks on domestic and traditional customs before implementing development agendas around women’s rights.

As well as providing insertion points for youth policy actors, human rights institutions must communicate their goals more effectively to younger generations and promote intergenerational and inclusive dialogue, for example by holding virtual consultations that  give access to individuals from different backgrounds. Similarly, they should ask young people about their priorities for human rights reform using regular and accessible surveys or by sharing information on online platforms regularly used by this demographic. This will ensure lasting buy-in from the next generation, essential for the relevance and sustainability of the human rights framework in the years to come.

This piece draws upon insights gathered at a workshop hosted by Chatham House in March 2021, which brought together the Institute’s networks of next generation groups including representatives of the QEII Academy Ambassadors, the Panel of Young Advisers, and the Common Futures Conversations community, as well as young members from the South African Institute of International Affairs.

Zika virus (ZIKV) is a neurotropic flavivirus that causes several diseases including birth defects such as microcephaly. Intrinsic immunity is known to be a frontline defense against viruses through host anti-viral restriction factors. Limited knowledge is available on intrinsic immunity against ZIKV in brains. Amyloid precursor protein (APP) is predominantly expressed in brains and implicated in the pathogenesis of Alzheimer's diseases. We have found that ZIKV interacts with APP, and viral infection increases APP expression via enhancing protein stability. Moreover, we identified the viral peptide, HGSQHSGMIVNDTGHETDENRAKVEITPNSPRAEATLGGFGSLGL, which is capable of en-hancing APP expression. We observed that aging brain tissues with APP had protective effects on ZIKV infection by reducing the availability of the viruses. Also, knockdown of APP expression or blocking ZIKV-APP interactions enhanced ZIKV replication in human neural progenitor/stem cells. Finally, intracranial infection of ZIKV in APP-null neonatal mice resulted in higher mortality and viral yields. Taken together, these findings suggest that APP is a restriction factor that protects against ZIKV by serving as a decoy receptor, and plays a protective role in ZIKV-mediated brain injuries.

CARM1 is a protein arginine methyltransferase (PRMT) that acts as a coactivator in a number of transcriptional programs. CARM1 orchestrates this coactivator activity in part by depositing the H3R17me2a histone mark in the vicinity of gene promoters that it regulates. However, the gross levels of H3R17me2a in CARM1 KO mice did not significantly decrease, indicating that other PRMT(s) may compensate for this loss. We thus performed a screen of type I PRMTs, which revealed that PRMT6 can also deposit the H3R17me2a mark in vitro. CARM1 knockout mice are perinatally lethal and display a reduced fetal size, whereas PRMT6 null mice are viable, which permits the generation of double knockouts. Embryos that are null for both CARM1 and PRMT6 are noticeably smaller than CARM1 null embryos, providing in vivo evidence of redundancy. Mouse embryonic fibroblasts (MEFs) from the double knockout embryos display an absence of the H3R17me2a mark during mitosis and increased signs of DNA damage. Moreover, using the combination of CARM1 and PRMT6 inhibitors suppresses the cell proliferation of WT MEFs, suggesting a synergistic effect between CARM1 and PRMT6 inhibitions. These studies provide direct evidence that PRMT6 also deposits the H3R17me2a mark and acts redundantly with CARM1.

Stop codon read-through (SCR) is a process of continuation of translation beyond a stop codon. This phenomenon, which occurs only in certain mRNAs under specific conditions, leads to a longer isoform with properties different from that of the canonical isoform. MTCH2, which encodes a mitochondrial protein that regulates mitochondrial metabolism, was selected as a potential read-through candidate based on evolutionary conservation observed in the proximal region of its 3' UTR. Here, we demonstrate translational read-through across two evolutionarily conserved, in-frame stop codons of MTCH2 using luminescence- and fluorescence-based assays, and by analyzing ribosome-profiling and mass spectrometry (MS) data. This phenomenon generates two isoforms, MTCH2x and MTCH2xx (single- and double-SCR products, respectively), in addition to the canonical isoform MTCH2, from the same mRNA. Our experiments revealed that a cis-acting 12-nucleotide sequence in the proximal 3' UTR of MTCH2 is the necessary signal for SCR. Functional characterization showed that MTCH2 and MTCH2x were localized to mitochondria with a long t1/2 (>36 h). However, MTCH2xx was found predominantly in the cytoplasm. This mislocalization and its unique C terminus led to increased degradation, as shown by greatly reduced t1/2 (<1 h). MTCH2 read-through–deficient cells, generated using CRISPR-Cas9, showed increased MTCH2 expression and, consistent with this, decreased mitochondrial membrane potential. Thus, double-SCR of MTCH2 regulates its own expression levels contributing toward the maintenance of normal mitochondrial membrane potential.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 μg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 μg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo. Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

The molecular mechanisms of reduced frataxin (FXN) expression in Friedreich's ataxia (FRDA) are linked to epigenetic modification of the FXN locus caused by the disease-associated GAA expansion. Here, we identify that SUV4-20 histone methyltransferases, specifically SUV4-20 H1, play an important role in the regulation of FXN expression and represent a novel therapeutic target. Using a human FXN–GAA–Luciferase repeat expansion genomic DNA reporter model of FRDA, we screened the Structural Genomics Consortium epigenetic probe collection. We found that pharmacological inhibition of the SUV4-20 methyltransferases by the tool compound A-196 increased the expression of FXN by ∼1.5-fold in the reporter cell line. In several FRDA cell lines and patient-derived primary peripheral blood mononuclear cells, A-196 increased FXN expression by up to 2-fold, an effect not seen in WT cells. SUV4-20 inhibition was accompanied by a reduction in H4K20me2 and H4K20me3 and an increase in H4K20me1, but only modest (1.4–7.8%) perturbation in genome-wide expression was observed. Finally, based on the structural activity relationship and crystal structure of A-196, novel small molecule A-196 analogs were synthesized and shown to give a 20-fold increase in potency for increasing FXN expression. Overall, our results suggest that histone methylation is important in the regulation of FXN expression and highlight SUV4-20 H1 as a potential novel therapeutic target for FRDA.

Expert

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

DNA polymerases are today used throughout scientific research, biotechnology, and medicine, in part for their ability to interact with unnatural forms of DNA created by synthetic biologists. Here especially, natural DNA polymerases often do not have the “performance specifications” needed for transformative technologies. This creates a need for science-guided rational (or semi-rational) engineering to identify variants that replicate unnatural base pairs (UBPs), unnatural backbones, tags, or other evolutionarily novel features of unnatural DNA. In this review, we provide a brief overview of the chemistry and properties of replicative DNA polymerases and their evolved variants, focusing on the Klenow fragment of Taq DNA polymerase (Klentaq). We describe comparative structural, enzymatic, and molecular dynamics studies of WT and Klentaq variants, complexed with natural or noncanonical substrates. Combining these methods provides insight into how specific amino acid substitutions distant from the active site in a Klentaq DNA polymerase variant (ZP Klentaq) contribute to its ability to replicate UBPs with improved efficiency compared with Klentaq. This approach can therefore serve to guide any future rational engineering of replicative DNA polymerases.

V. G. Lysov
Trans. Moscow Math. Soc. 83 (), 291-304.
Abstract, references and article information

H. G. Kazaryan and V. N. Margaryan
Trans. Moscow Math. Soc. 83 (), 151-181.
Abstract, references and article information

Gurmeet K. Bakshi, Jyoti Garg and Gabriela Olteanu
Math. Comp. 93 (), 3027-3058.
Abstract, references and article information

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

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

Yinji Li, Zhiwei Wang and Xiangyu Zhou
Trans. Amer. Math. Soc. 377 (), 5947-5992.
Abstract, references and article information

Dylan Langharst and Dongmeng Xi
Proc. Amer. Math. Soc. 152 (), 5299-5311.
Abstract, references and article information

Yongqiang Liu, Laurentiu Maxim and Botong Wang
Proc. Amer. Math. Soc. 152 (), 5279-5288.
Abstract, references and article information

N. Lebedeva and A. Petrunin
St. Petersburg Math. J. 35 (), 473-476.
Abstract, references and article information

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

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

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

Investigations of bacterial resistance strategies can aid in the development of new antimicrobial drugs as a countermeasure to the increasing worldwide prevalence of bacterial antibiotic resistance. One such strategy involves the TipA class of transcription factors, which constitute minimal autoregulated multidrug resistance (MDR) systems against diverse antibiotics. However, we have insufficient information regarding how antibiotic binding induces transcriptional activation to design molecules that could interfere with this process. To learn more, we determined the crystal structure of SkgA from Caulobacter crescentus as a representative TipA protein. We identified an unexpected spatial orientation and location of the antibiotic-binding TipAS effector domain in the apo state. We observed that the α6–α7 region of the TipAS domain, which is canonically responsible for forming the lid of antibiotic-binding cleft to tightly enclose the bound antibiotic, is involved in the dimeric interface and stabilized via interaction with the DNA-binding domain in the apo state. Further structural and biochemical analyses demonstrated that the unliganded TipAS domain sterically hinders promoter DNA binding but undergoes a remarkable conformational shift upon antibiotic binding to release this autoinhibition via a switch of its α6–α7 region. Hence, the promoters for MDR genes including tipA and RNA polymerases become available for transcription, enabling efficient antibiotic resistance. These insights into the molecular mechanism of activation of TipA proteins advance our understanding of TipA proteins, as well as bacterial MDR systems, and may provide important clues to block bacterial resistance.

Climate migration: Ways ahead from the next generation The World Today rsoppelsa.drupal 25 May 2022

Ella Dennis and Mike Higgins talk to young activists seeking solutions as global warming wreaks havoc in sub-Saharan Africa

Africa has the lowest carbon emissions per capita yet the highest rate of temperature increase in the world. Rising levels of desertification, drought and flooding are already forcing millions of Africans to relocate to find more stable livelihoods. 

The continent’s youth will bear the brunt of this climate migration problem. It is estimated that by 2050, Africa will be home to 86 million internal climate migrants.

How is climate migration already affecting sub-Saharan Africa and what frameworks could tackle it? To begin to answer those questions, five young activists from across the region, who are members of Chatham House’s Common Futures Conversations, took part in a panel discussion at the world’s first youth-led Conference on Climate Migration, convened in April by the Alliance for Citizen Engagement, a nonpartisan think tank based in the US. 

The conversation and follow-up discussions focused on a common problem – climate migration brings people into conflict and puts pressure on infrastructure. 

In Kenya, droughts have left 3.5 million people hungry and the chronic flooding of several lakes in the Rift Valley has displaced hundreds of thousands, said Gerald Muchiri, 29, a social scientist from Kenya. One result has been outbreaks of violence between pastoralists such as the Orma people and the farmers of the Pokomo community, said Laura Mukhwana, 33, a PhD student in Kenya. She believes this violence is likely to worsen. ‘Inter-group conflicts will pose even larger security concerns for surrounding communities as climate migration intensifies,’ she said.

Suleman Nuhu, 24, a farmer and veterinary student from Nigeria, said farmer-herder conflicts were his country’s most significant climate-migration issue. The movement of nomadic tribes from the north had affected him personally: ‘Nomads have trespassed on [my family’s] farms many times while moving with their livestock, destroying our crops.’ 

Changes in climate also force people to move from rural to urban areas. Nigeria, for instance, struggles with the so-called ‘Lagos problem’, said Temiloluwa Lawal, 25, a lawyer and researcher from Nigeria. An estimated 22 million people, a number that is rising fast, are crammed into a city smaller than Greater London. While not on the same scale, Zimbabwe experiences comparable challenges, said Tinotenda Dube, 29, a Zimbabwean finance director. Thanks to drought, unemployed rural migrants arriving in cities ‘put excessive pressure on service delivery against a low tax base,’ he said. ‘People, including close family members of mine, are crowded in dilapidated homes because they cannot afford to pay rent for decent housing.’ 

But there is hope, say the activists. Dube believes that affordable housing is an ‘integral component of [tackling] the climate migration crisis’. 

In Zimbabwe, he has developed a low-cost home finance model that, he said, has helped more than 250 low-income households find good-quality accommodation. Alongside this initiative, Dube has co-founded a property and construction company, Solinfra Zimbabwe Private Ltd, to provide low-cost housing. 

Muchiri is taking action in Kenya, founding an NGO called Social Assistance Welfare to tackle public health issues, he said: ‘As climate migration becomes more intense, I expect preventable health issues to increase throughout the region, and thus see Social Assistance Welfare as an important mitigation.’

In Nigeria, Nuhu noted that to help reduce conflict between farmers and herders social-media campaigns are encouraging pastoralists to move from nomadic livestock farming to more efficient intensive systems, using ranching and grazing reserves. ‘As for food security problems, the best mitigation is to reduce reliance on rain-fed agriculture through irrigation schemes,’ he said. 

All five agreed that, in their experience, the youth of sub-Saharan Africa could be better informed about climate migration. But they took encouragement from the fact the young are passionate about tackling issues arising from the broader climate crisis. 

In Kenya, Mukhwana pointed to successful youth projects around agro-forestry and tree-planting. She added that there is ‘a growing movement of urban youth who are advocating for climate justice, such as the Kenyan Youth Environmental Network and Fridays for the Future Kenya’. It was pleasing too, she said, that when the Kenyan government revised its contributions to the Paris Climate Accords it staged a week-long youth conference to include their opinions.

‘Overall, I am quite hopeful about how the youth are mobilizing themselves in Kenya,’ she added.

Find out more about Chatham House’s Common Futures Conversations
 

Visual Abstract

Madison T Wright
Nov 18, 2020; 0:RA120.002168v1-mcp.RA120.002168
Research

Mingkun Yang
Nov 24, 2020; 0:RA120.002144v1-mcp.RA120.002144
Research

Qin Zhang
Nov 17, 2020; 0:RA120.002325v1-mcp.RA120.002325
Research

Kailun Fang
Nov 30, 2020; 0:RA120.002081v1-mcp.RA120.002081
Research

Congcong Lu
Nov 17, 2020; 0:R120.002257v1-mcp.R120.002257
Review

Gle1 is a conserved, essential regulator of DEAD-box RNA helicases, with critical roles defined in mRNA export, translation initiation, translation termination, and stress granule formation. Mechanisms that specify which, where, and when DDXs are targeted by Gle1 are critical to understand. In addition to roles for stress-induced phosphorylation and inositol hexakisphosphate binding in specifying Gle1 function, Gle1 oligomerizes via its N-terminal domain in a phosphorylation-dependent manner. However, a thorough analysis of the role for Gle1 self-association is lacking. Here, we find that Gle1 self-association is driven by two distinct regions: a coiled-coil domain and a novel 10-amino acid aggregation-prone region, both of which are necessary for proper Gle1 oligomerization. By exogenous expression in HeLa cells, we tested the function of a series of mutations that impact the oligomerization domains of the Gle1A and Gle1B isoforms. Gle1 oligomerization is necessary for many, but not all aspects of Gle1A and Gle1B function, and the requirements for each interaction domain differ. Whereas the coiled-coil domain and aggregation-prone region additively contribute to competent mRNA export and stress granule formation, both self-association domains are independently required for regulation of translation under cellular stress. In contrast, Gle1 self-association is dispensable for phosphorylation and nonstressed translation initiation. Collectively, we reveal self-association functions as an additional mode of Gle1 regulation to ensure proper mRNA export and translation. This work also provides further insight into the mechanisms underlying human gle1 disease mutants found in prenatally lethal forms of arthrogryposis.

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

Priyanka Tripathi
Dec 30, 2020; 0:jlr.RA120001190v1-jlr.RA120001190
Research Articles

Stephanie E. Hood
Dec 1, 2020; 61:1720-1732
Research Articles

Melissa Gómez
Dec 1, 2020; 61:1658-1674
Research Articles

Jiayan Guo
Dec 1, 2020; 61:1764-1775
Research Articles