The Maestro Project: A Patient Navigator for the Transition of Care for Youth With Type 1 Diabetes
Norma Van Walleghem
Feb 1, 2011; 24:9-13
From Research to Practice/Transitions in Young Adults with Type 1 Diabetes
Norma Van Walleghem
Feb 1, 2011; 24:9-13
From Research to Practice/Transitions in Young Adults with Type 1 Diabetes
What are the opportunities and challenges of collecting consumer insights in developing countries—and how can the challenges be overcome?
Can Impossible Foods change the way meat is produced on a large enough scale to make a serious inroad in the battle against climate change?
Up-and-coming recording artiste Kaay Jones says she did not know she was becoming part of a transformational music project that would connect her to a wide cross section of talent in the Caribbean. Jones carries Jamaica's flag in a unified...
Hours after he was released from police lock-up last week, dancehall artiste Dexta Daps dropped some new music on his eager fans. The track, Breaking News, explores an all-too-familiar domestic violence storyline, but incorporates a controversial...
Up-and-coming entertainer Shav-A says the COVID-19 pandemic made her reflect on her life. "I needed a reset. With all this downtime, I have realised that I needed to stop and rethink a lot of things that are going on in my life, and it also...
Last month, Prime Minister Andrew Holness announced the establishment of an Economic Recovery Task Force, chaired by Finance Minister Dr Nigel Clarke. The multisectoral task force, which is mandated to oversee Jamaica's economic recovery from...
A Manchester mother is pleading with the authorities to provide her with the results of COVID-19 tests done on her and her week-old baby. The woman claims that she has been in isolation in hospital since April 27, a day after she gave birth to...
Deborah Fearon is a bar owner who also has a small chicken business. She depends on both for a living. Before the COVID-19 outbreak she was doing well, and had plans of completing her house this year. However, she has been hit hard by the economic...
Despite being placed under strict restrictions and COVID-19 curfew measures, shoppers, commuters, motorists, and vendors in Montego Bay got a feel of Christmas on Wednesday, when they were showered with items as part of the COVID-19 giveaway by an...
Management professors Adam Galinksy and Paul Ingram, together with Jonathan Laor ’21, CEO of Applicaster, advise on leadership during a crisis.
Earthquake: 2020-05-06 21:54HKT M6.7 [7.0S, 130.0E] in Tanimbar Islands Region, Indonesia http://openstreetmap.org/?mlat=-7&mlon=130.
Gary Lichtenstein Editions has partnered with Urban Pathways to increase awareness and safety in the homeless community.
Retail giants like Yoox Net-a-Porter Group and Brooks Brothers quickly pivoted to offer life-saving services.
The SBDC offers resources and guidance to Harlem’s small businesses amidst the COVID-19 crisis.
6 April 2018
Agantaranansa Juanda speaks to Jason Naselli about the promises the government has made and the steps that still need to be taken for the country to deliver justice for past violations of human rights.It does and it does not; it really depends on the context. Indonesia looks good among its neighbours in Southeast Asia in terms of protection of civil and political rights, and to some extent economic, social and cultural rights, although room for improvements exists.
But one of the promises of the current president, Joko Widodo, during his 2014 campaign was about international criminal justice, which involves rights for many victims of past cases of human rights abuses in Indonesia. In that sense, it does not protect these rights, including the rights to justice, truth, reparations or guarantees of non-recurrence.
For example, in the case of the conflict over independence for East Timor in 1999, there were many gross violations of human rights. However, there has never been any sort of effective judicial process to address gross violations of human rights, and crimes against humanity in particular.
In 1965–66, during the government’s violent anti-communist operations, 500,000 people or more were killed. Indonesia’s National Commission on Human Rights was tasked with conducting an investigation into this period within its limited mandate, but it led to nothing; there have never been any prosecutions relating to these crimes.
The election promise of the current president was to deal with a number of these past human rights cases, and this promise has not been met at all. His opponent in 2014, Prabowo Subianto, was a former military general involved in alleged past human rights abuses, so it was politically expedient to make such a promise. But it has not been pursued in office.
Some human rights activists suggested that the establishment of the Human Rights Court took place under international pressure following the independence of East Timor. To avoid international scrutiny, for example the creation of an ad hoc international tribunal, the government established this court.
Based on the report of the International Commission of Inquiry on East Timor in 2000, it was indeed recommended that an international human rights tribunal be set up. Indonesian government rejected the proposal with strong assurances that it would provide justice for atrocities committed by its nationals. So it is fair for some to see the establishment of Indonesia’s Human Rights Court as a political move by the government at that time, in order to avoid scrutiny by the international community.
When it comes to performance, the Human Rights Court actually investigated and prosecuted cases relating to atrocities in East Timor. There were around 100 suspects identified, and 18 were put on trial. Out of these 18, only one trial, of Eurico Guterres, ended in a conviction for crimes against humanity. However, the Indonesian Supreme Court cleared Guterres of all charges in 2008. So the Human Rights Court did take steps, but the net result amounted to essentially nothing. Impunity remains.
So it has not lived up to its mandate, but there is another factor, which is that the founding law of the Human Rights Court does not accommodate international standards of criminal justice. It only covers two of the four categories of crime as outlined in the Rome Statute – crimes against humanity and genocide. It also does not provide adequate protection for victims and witnesses. So there are issues not only with the performance of the Human Rights Court but also with the legislation establishing it.
The main opposition came from the military, because they were afraid of being targeted by the ICC. There was also a lot of discussion about Indonesia’s ‘sovereign right to prosecute’.
But what those opposing failed to understand is that the ICC is bound by temporal and territorial boundaries, meaning that it will not intervene if the state in question is able and willing to prosecute. So I think accession to the Rome Statute has not taken place because of this misunderstanding.
I think another factor since this was initially raised is there is a focus on other issues. Indonesia is an emerging country economically; there is a focus on building infrastructure. So many in government feel like they are done with the past. But for the millions of victims of past crimes and their families, the past is not done.
So it’s very important at this point in the country’s history to revisit the commitment to international criminal justice to be able to contribute to sustainable peace and development.
The establishment of the Human Rights Court was an important starting point, but clearly there has to be significant reform, both in terms of the substantive law underpinning it and its procedures.
Clearly the domestic laws need to be reformed, but also, an effort needs to be made to improve the courts capacity in terms of manpower and logistical support. This is why the government needs to restart the discussion about becoming a party to the Rome Statute. Through the outreach programme of the ICC, this would give the Human Rights Court the capacity, in terms of manpower and logistical support, to tackle past human rights violations in Indonesia, which the Human Rights Court is currently lacking.
Only if these two steps are taken – reforming the domestic Human Rights Court and restarting discussion about becoming a party to the Rome Statute – will the Indonesian government be able to say it has made progress on international criminal justice.
The Indonesian government is actually running for a seat on the UN Security Council for the period of 2019–20. So I think it is an urgent discussion that the Indonesian government needs to have before it makes another pledge to contribute to the maintenance of international peace and security. It is difficult to have sustainable peace without justice.
Conference
Chatham House, London
Ever-increasing consumer, investor and employee awareness continues to drive the business case for responsible behaviour, and recent events have highlighted the growing need for corporate accountability and transparency from C-suite behaviour to global supply chain management. But what exactly are these expectations across different sectors, as the acceleration of the digital age continues to present new risks, opportunities and concerns? How can the right behaviours be encouraged?
Furthermore, ongoing political transitions and regulatory stances over the last two years have shone a light on companies’ potential and realized impact on society. With trust in political institutions low, many are calling upon businesses not only to reflect their values but to actively bridge the governance gap on issues such as equality, sustainability and human rights, in their own business operations and beyond. But what role should business be adopting, and what are the consequences of this trend? What are the perceived trade-offs?
The past year has seen examples of technology leaders being held to account for the mishandling of data, global corporations taking a proactive stance on contentious political issues and executive behaviour directly impacting share price. It is critical that policy-makers and business leaders re-evaluate their priorities, practices and principles as technology and politics continue to reshape the landscape.
The third annual Chatham House Responsible Business conference will explore key questions, including:
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To enable as open a debate as possible, this conference will be held under the Chatham House Rule.
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Welcome and chair's opening remarks
Dr Robin Niblett, Director, Chatham House
Keynote address
Simon Thompson, Chairman, Rio Tinto
Questions and discussion
This opening session will examine the status of corporate leadership in responsible business, evolving policy environments and stakeholder expectations, and how they continue to shape roles and responsibilities.
Chair
Tamzin Booth, European Business Editor, The Economist
Speakers
Helena Morrissey, Head of Personal Investing, Legal & General Investment Management, and Founder of the 30% Club
Ioannis Ioannou, Associate Professor of Strategy and Entrepreneurship, London Business School
Phil Bloomer, Executive Director, Business & Human Rights Resource Centre
Sue Garrard, EVP Sustainable Business and Communications, Unilever (2014-18)
Questions and discussion
1115-1145 Refreshments
This session will address regulatory frameworks and economic incentives governing responsible business conduct, as well as human rights and business operations across global supply chains.
Chair
Bennett Freeman, Deputy Assistant Secretary for Democracy, Human Rights and Labor, US Department of State (1999–2001)
Speakers
Gillian Caldwell, CEO, Global Witness
Madelaine Tuininga, Head of Unit, DG Trade, European Commission
Sharan Burrow, General Secretary, International Trade Union Confederation
Guus Houttuin, Trade Adviser, European External Action Service, and Chair, the OECD Multi-stakeholder Steering Group
Questions and discussion
1300-1400 Lunch
This session will examine the risks and opportunities presented by digitization and other technological developments for responsible business practices.
Chair
John Thornhill, Innovation Editor, Financial Times
Speakers
Nuala O’Connor, President and CEO of the Center for Democracy and Technology
Simon McDougall, Executive Director, Technology Policy and Innovation, Information Commissioner’s Office
Rebecca MacKinnon, Director, Ranking Digital Rights, New America
Sarah Drinkwater, Director, Tech and Society Solutions Lab, Omidyar Network
Questions and discussion
1515-1545 Afternoon refreshments
This closing session will explore the role of corporate governance in setting standards and leading responsible business practices, including diversity and inclusion as well as C-suite accountability and transparency.
Chair
Aris Vrettos, Director of Open Programmes and International Markets, Cambridge Institute for Sustainability Leadership
Speakers
Catherine Howarth, CEO, ShareAction
Jane Ellis, Director, GoodCorporation
Mo Ibrahim, Founder, Mo Ibrahim Foundation
Alison Cottrell, CEO, Banking Standards Board
Questions and discussion
1700 Close of conference and drinks reception
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Research Event
Graduate Institute | Chemin Eugène-Rigot 2 | 1202 Geneva | Switzerland
Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House
Ezequiel Heffes, Thematic Legal Adviser, Geneva Call
Sigrid Redse Johansen, Judge Advocate General, The Norwegian Armed Forces
Chair: Elizabeth Wilmshurst, Distinguished Fellow, Chatham House
Further speakers to be announced.
PLEASE NOTE THIS EVENT IS BEING HELD IN GENEVA.
There have been large numbers of civilian deaths in the armed conflicts in Yemen and Syria. Is international humanitarian law being ignored?
This meeting coincides with the launch of a Chatham House research paper on the incidental harm side of the proportionality assessment which belligerents are legally required to make. The panel at the meeting will consider the types of harm that fall within the scope of proportionality assessments, what constitutes ‘excessive’ harm and measures that belligerents can take to give effect to the rule on proportionality.
This event will be followed by a reception.
Research Event
Chatham House, London
Emanuela-Chiara Gillard, Associate Fellow, International Law Programme, Chatham House
Ezequiel Heffes, Thematic Legal Adviser, Geneva Call
Sigrid Redse Johansen, Judge Advocate General, Norwegian Armed Forces
Andrew Murdoch, Legal Director, UK Foreign & Commonwealth Office
Chair: Elizabeth Wilmshurst, Distinguished Fellow, International Law Programme, Chatham House
There have been large numbers of civilian deaths in the armed conflicts in Yemen and Syria. Is international humanitarian law being ignored?
This meeting marks the London launch of a Chatham House research paper on the incidental harm side of the proportionality assessment which belligerents are legally required to make. The panel at the meeting will consider the types of harm that fall within the scope of proportionality assessments, what constitutes ‘excessive’ harm and measures that belligerents can take to give effect to the rule on proportionality.
This event will be followed by a reception.
10 December 2018
Clarification of international humanitarian law is important in ensuring compliance with the rule of proportionality, but a culture of compliance within armed forces and groups is also crucial.
Research Event
Chatham House | 10 St James's Square | London | SW1Y 4LE
Koji Tsuruoka, Ambassador of Japan to the United Kingdom
Ben Saul, Associate Fellow, International Law Programme, Chatham House; Challis Chair of International Law, Australian National University
Lee Chen Chen, Director, Singapore Institute of International Affairs
Aniruddha Rajput, Member, UN International Law Commission; Consultant, Withersworldwide
The rapid growth in the Asia-Pacific’s economic and political power has significant implications for global governance. Asia-Pacific countries such as Japan, India and China – and regional bodies such as ASEAN – are increasingly informing, influencing and seeking to shape international standards and norms.
This conference will bring together international law and policy experts to explore the political and legal dynamics affecting economic relations, security challenges and maritime governance in the region.
Given security and prosperity challenges within the region as well as the increasingly complex environment for global governance, to what extent is international law operating as a tool of cooperation in the Asia-Pacific? In which areas is it a source of friction?
And what are the broader implications for global governance including the development of international law?
27 June 2019
Siege warfare has been employed throughout the ages and remains dramatically relevant today. Questions of the compatibility of this practice with international humanitarian law (IHL) arise when besieged areas contain civilians as well as enemy forces. This briefing addresses those rules of IHL that are particularly relevant to sieges.
Summary
Research Event
Chatham House | 10 St James's Square | London | SW1Y 4LE
Susie Alegre, Barrister and Associate Tenant, Doughty Street Chambers
Evelyn Aswad, Professor of Law and the Herman G. Kaiser Chair in International Law, University of Oklahoma
Barbora Bukovská, Senior Director for Law and Policy, Article 19
Kate Jones, Director, Diplomatic Studies Programme, University of Oxford
Chair: Harriet Moynihan, Associate Fellow, International Law Programme, Chatham House
1 November 2019
The 'Security and Prosperity in Asia' conference looked at the impact of international law in the Asia-Pacific with a focus on regional economic and security issues such as the South China Sea disputes.
About the Conference
At a time of geopolitical uncertainty and with multilateralism under pressure, this conference brought together diverse actors to explore the evolving role of international law on critical security and economic issues in the Asia-Pacific. From trade agreements to deep-sea mining, cyberwarfare to territorial disputes, the breadth of the discussion illustrated the growing reach of international law in the region.
Hosted by the International Law Programme and the Asia-Pacific Programme at Chatham House on 27 March 2019, the conference focused on three themes: trade and investment, maritime security and governance, and emerging security challenges. What trends are emerging in terms of engagement with international law in the region, and how can international standards play a greater role in encouraging collaboration and reducing tensions? And, with the eastward shift in geopolitical power, how will Asia-Pacific states shape the future of international law?
6 November 2019
Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law. This paper examines how human rights frameworks should guide digital technology.
Summary
3 December 2019
A new Chatham House paper examines the prospects of countries reaching agreement on issues of sovereignty and non-intervention in cyberspace in the face of persistent, low-level, state-to-state cyber attacks.In discussions to date about how international law applies in cyberspace, commentators have tended to focus their attention on how the rules on the use of force, or the law of armed conflict, apply to cyber activities conducted by states that give rise to physical damage, injury or death.
But in practice, the vast majority of state cyberattacks fall below this threshold. Far more common are persistent, low-level attacks that may leave no physical trace but that are capable of doing significant damage to a state’s ability to control its systems, often at serious economic cost.
Such cyber incursions might include network disruptions in the operation of another government’s websites; tampering with electoral infrastructure to change or undermine the result; or using cyber means to destabilize another state’s financial sector.
For these kinds of cyber operation, the principle of sovereignty, and the principle of non-intervention in another state’s internal affairs, are the starting point.
A UN Group of Government Experts (GGE) agreed in 2013 and 2015 that the principles in the UN Charter, including sovereignty and the prohibition on intervention in another state’s affairs, apply to states’ activities in cyberspace. The 2015 GGE also recommended eleven (non-binding) norms of responsible state behaviour in cyberspace.
However, states have not yet reached agreement on how to apply these principles. Until recently, there has also been very little knowledge of what states actually do in cyberspace, as they usually conduct cyber operations covertly and have been reluctant to put their views on record.
A new Chatham House research paper analyses the application of the principles of sovereignty and non-intervention to state cyberattacks that fall below the principle of use of force. As well as analysing the application of the law in this area, the paper also makes recommendations to governments on how they might best make progress in reaching agreement in this area.
As the research paper makes clear, there is currently some debate, principally between countries in the West, about the extent to which sovereignty is a legally binding rule in the context of cyberspace and, if so, how it and the principle of non-intervention might apply in practice.
In the last few years, certain states have put on record how they consider international law to apply to states’ activities in cyberspace, namely the UK, Australia, France and the Netherlands. While there may be some differences in their approaches, which are discussed in the paper, there also remains important common ground: namely, that existing international law already provides a solid framework for regulating states’ cyber activities, as it regulates every other domain of state-to-state activity.
There is also an emerging trend for states to work together when attributing cyberattacks to hostile states, enabling them to call out malign cyber activity when it violates international law. (See, for example, the joint statements made in relation to the NotPetya cyber attack and malicious cyber activity attributed to the Russian government).
However, other countries have questioned whether existing international law as it stands is capable of regulating states’ cyber interactions and have called for ‘new legal instruments’ in this area.
This includes a proposal by the Shanghai Cooperation Organization (led by Russia and China) for an International Code of Conduct on Information Security, a draft of which was submitted to the UN in 2011 and 2015, without success. The UN has also formed a new Open-Ended Working Group (OEWG) under a resolution proposed by Russia to consider how international law applies to states’ activities in cyberspace.
The resolution establishing the OEWG, which began work earlier this year, includes the possibility of the group ‘introducing changes to the rules, norms and principles of responsible behaviour of States’ agreed in the 2013 and 2015 GGE reports. In the OEWG discussions at the UN in September, several countries claimed that a new legal instrument was needed to fill the ‘legal vacuum’ (Cuba) or ‘the gap of ungoverned areas’ (Indonesia).
It would be concerning if the hard-won consensus on the application of international law to cyberspace that has been reached at past GGEs started to unravel. In contrast to 2013 and 2015, the 2017 meeting failed to reach an agreement.
On 9 December, a renewed GGE will meet in New York, but the existence of the OEWG exploring the same issues in a separate process reflects the fact that cyber norms have become an area of geopolitical rivalry.
Aside from the application of international law, states are also adopting divergent approaches to the domestic regulation of cyberspace within their own territory. The emerging trend towards a ‘splinternet’ – i.e. between states that believe the internet should be global and open on the hand, and those that favour a ‘sovereignty and control’ model on the other – is also likely to make discussions at the GGE more challenging.
Distinct from the international law concept of sovereignty is the notion of ‘cybersovereignty’, a term coined by China to describe the wide-ranging powers it assumes under domestic law to regulate its citizens’ access to the internet and personal data within its territory. This approach is catching on (as reflected in Russia’s recently enacted ‘Sovereign Internet Law’), with other authoritarian states likely to follow suit.
In parallel with regional and UN discussions on how international law applies, a number of initiatives by non-state actors have also sought to establish voluntary principles about responsible state behaviour in cyberspace.
The Global Commission on the Stability of Cyberspace, a multi-stakeholder body that has proposed principles, norms and recommendations to guide responsible behaviour by all parties in cyberspace, recently published its final report. The Cybersecurity Tech Accord aims to promote collaboration between tech companies on stability and resilience in cyberspace. President Macron’s ‘Paris Call for Trust and Security in Cyberspace’ has to date received the backing of 67 states, 139 international and civil society organizations, and 358 private-sector organizations.
It remains to be seen in the long term whether the parallel processes at the UN will work constructively together or be competitive. But notwithstanding the challenging geopolitical backdrop, the UN GGE meeting next week at the least offers states the opportunity to consolidate and build on the results of past meetings; to increase knowledge and discussion about how international law might apply; and to encourage more states to put their own views of these issues on the record.
The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.
β-Glucocerebrosidase (GBA) hydrolyzes glucosylceramide (GlcCer) to generate ceramide. Previously, we demonstrated that lysosomal GBA1 and nonlysosomal GBA2 possess not only GlcCer hydrolase activity, but also transglucosylation activity to transfer the glucose residue from GlcCer to cholesterol to form β-cholesterylglucoside (β-GlcChol) in vitro. β-GlcChol is a member of sterylglycosides present in diverse species. How GBA1 and GBA2 mediate β-GlcChol metabolism in the brain is unknown. Here, we purified and characterized sterylglycosides from rodent and fish brains. Although glucose is thought to be the sole carbohydrate component of sterylglycosides in vertebrates, structural analysis of rat brain sterylglycosides revealed the presence of galactosylated cholesterol (β-GalChol), in addition to β-GlcChol. Analyses of brain tissues from GBA2-deficient mice and GBA1- and/or GBA2-deficient Japanese rice fish (Oryzias latipes) revealed that GBA1 and GBA2 are responsible for β-GlcChol degradation and formation, respectively, and that both GBA1 and GBA2 are responsible for β-GalChol formation. Liquid chromatography–tandem MS revealed that β-GlcChol and β-GalChol are present throughout development from embryo to adult in the mouse brain. We found that β-GalChol expression depends on galactosylceramide (GalCer), and developmental onset of β-GalChol biosynthesis appeared to be during myelination. We also found that β-GlcChol and β-GalChol are secreted from neurons and glial cells in association with exosomes. In vitro enzyme assays confirmed that GBA1 and GBA2 have transgalactosylation activity to transfer the galactose residue from GalCer to cholesterol to form β-GalChol. This is the first report of the existence of β-GalChol in vertebrates and how β-GlcChol and β-GalChol are formed in the brain.
Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.
Haploinsufficiency of Meis homeobox 2 (MEIS2), encoding a transcriptional regulator, is associated with human cleft palate, and Meis2 inactivation leads to abnormal palate development in mice, implicating MEIS2 functions in palate development. However, its functional mechanisms remain unknown. Here we observed widespread MEIS2 expression in the developing palate in mice. Wnt1Cre-mediated Meis2 inactivation in cranial neural crest cells led to a secondary palate cleft. Importantly, about half of the Wnt1Cre;Meis2f/f mice exhibited a submucous cleft, providing a model for studying palatal bone formation and patterning. Consistent with complete absence of palatal bones, the results from integrative analyses of MEIS2 by ChIP sequencing, RNA-Seq, and an assay for transposase-accessible chromatin sequencing identified key osteogenic genes regulated directly by MEIS2, indicating that it plays a fundamental role in palatal osteogenesis. De novo motif analysis uncovered that the MEIS2-bound regions are highly enriched in binding motifs for several key osteogenic transcription factors, particularly short stature homeobox 2 (SHOX2). Comparative ChIP sequencing analyses revealed genome-wide co-occupancy of MEIS2 and SHOX2 in addition to their colocalization in the developing palate and physical interaction, suggesting that SHOX2 and MEIS2 functionally interact. However, although SHOX2 was required for proper palatal bone formation and was a direct downstream target of MEIS2, Shox2 overexpression failed to rescue the palatal bone defects in a Meis2-mutant background. These results, together with the fact that Meis2 expression is associated with high osteogenic potential and required for chromatin accessibility of osteogenic genes, support a vital function of MEIS2 in setting up a ground state for palatal osteogenesis.
The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.
Sperm head shaping is a key event in spermiogenesis and is tightly controlled via the acrosome–manchette network. Linker of nucleoskeleton and cytoskeleton (LINC) complexes consist of Sad1 and UNC84 domain–containing (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain proteins and form conserved nuclear envelope bridges implicated in transducing mechanical forces from the manchette to sculpt sperm nuclei into a hook-like shape. However, the role of LINC complexes in sperm head shaping is still poorly understood. Here we assessed the role of SUN3, a testis-specific LINC component harboring a conserved SUN domain, in spermiogenesis. We show that CRISPR/Cas9-generated Sun3 knockout male mice are infertile, displaying drastically reduced sperm counts and a globozoospermia-like phenotype, including a missing, mislocalized, or fragmented acrosome, as well as multiple defects in sperm flagella. Further examination revealed that the sperm head abnormalities are apparent at step 9 and that the sperm nuclei fail to elongate because of the absence of manchette microtubules and perinuclear rings. These observations indicate that Sun3 deletion likely impairs the ability of the LINC complex to transduce the cytoskeletal force to the nuclear envelope, required for sperm head elongation. We also found that SUN3 interacts with SUN4 in mouse testes and that the level of SUN4 proteins is drastically reduced in Sun3-null mice. Altogether, our results indicate that SUN3 is essential for sperm head shaping and male fertility, providing molecular clues regarding the underlying pathology of the globozoospermia-like phenotype.
We are pleased to announce a major new release with more than 150 new features and improvements!
WYSIWYG Web Builder 7.5 is a major update with more than 50 new features and improvements (compared to version 7.2.1). Our christmas gift to you!
We are pleased to announce a major new release with more than 150 new features and improvements!
WYSIWYG Web Builder 8.5 is a major update with more than 50 new features and improvements (compared to version 8.2.1).
We are pleased to announce a major new release with more than 150 new features and improvements!
WYSIWYG Web Builder 9.1 fixes known problems, adds new features and includes other improvements.