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The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation]

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.




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It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly [RNA]

The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.




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New notification arrangements on Secondary One discretionary places and distribution of school choice documents for Central Allocation




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'Terrible twos' not inevitable: With engaged parenting, happy babies can become happy toddlers

(University of Cambridge) Parents should not feel pressured to make their young children undertake structured learning or achieve specific tasks, particularly during lockdown. A new study of children under the age of two has found that parents who take a more flexible approach to their child's learning can - for children who were easy babies - minimise behavioural problems during toddlerhood.




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Timing of immune response to COVID-19 may contribute to disease severity

(Keck School of Medicine of USC) A new USC study suggests that temporarily suppressing the body's immune system during the early stages of COVID-19 could help a patient avoid severe symptoms. That's because the research shows that an interaction between the body's two main lines of defense may be causing the immune system to go into overdrive in some patients.




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Effects of recommender systems in e-commerce vary by product attributes and review ratings

(Carnegie Mellon University) A new study sought to determine how the impact of recommender systems (also called recommenders) is affected by factors such as product type, attributes, and other sources of information about products on retailers' websites. The study found that recommenders increased the number of consumer views of product pages as well as the number of products consumers consider, but that the increase was moderated by product attributes and review ratings.




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Arctic Edmontosaurus lives again -- a new look at the 'caribou of the Cretaceous'

(Perot Museum of Nature and Science) Published in PLOS ONE today, a study by an international team from the Perot Museum of Nature and Science in Dallas and Hokkaido University in Japan further explores the proliferation of the most commonly occurring duck-billed dinosaur of the ancient Arctic as the genus Edmontosaurus. The findings reinforce that the hadrosaurs -- dubbed 'caribou of the Cretaceous' -- had a geographical distribution of approximately 60 degrees of latitude, spanning the North American West from Alaska to Colorado.




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JCF distribute PSOJ COVID-19 food packages

Members of the Jamaica Constabulary Force on Thursday, distributed more than 300 food packages to individuals and families impacted by COVID-19 in St. James, under the Private Sector Organisation of Jamaica (PSOJ)-led COVID-19 Response Fund...




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Cybersecurity in the Commonwealth: Building the Foundations of Effective National Responses in the Caribbean

Invitation Only Research Event

8 March 2019 - 9:00am to 5:30pm

Bridgetown, Barbados

Event participants

Joyce Hakmeh, Cyber Research Fellow, International Security Department, Chatham House

This workshop is the second in a series in the 'Implementing the Commonwealth Cybersecurity Agenda' project. The workshop aims to provide a multi-stakeholder pan-Commonwealth platform to discuss how to take the implementation of the 'Commonwealth Cyber Declaration' forward with a focus on the second pillar of the declaration – building the foundations of an effective national cybersecurity response with eight action points. 

As such, the workshop gathers different project implementers under the UK Foreign and Commonwealth Office’s Cyber Programme, in addition to other key relevant stakeholders from the global level, to explore ongoing initiatives which aim to deliver one or more of pillar two’s action points.

The workshop addresses issues from a global perspective and a Commonwealth perspective and will include presentations from selected partners from different Commonwealth countries.

Calum Inverarity

Research Analyst and Coordinator, International Security Department
+44 (0) 207 957 5751




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Radiation dosimetry and biodistribution of 68Ga-FAPI-46 PET imaging in cancer patients

Background: Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy as they can constitute as much as 90% of tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP-inhibitor PET tracer, 68Ga-FAPI-04, has been previously shown to yield high tumor-to-background ratios (TBR) in patients with various cancers. Recent developments towards an improved compound for therapeutic application have identified FAPI-46 as a promising agent due to a longer tumor retention time in comparison with FAPI-04. Here we present a PET biodistribution and radiation dosimetry study of 68Ga-FAPI-46 in cancer patients. Methods: Six patients with different cancers underwent serial 68Ga-FAPI-46 PET/CT scans at three time points following radiotracer injection: 10 minutes, 1 hour, and 3 hours. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and body remainder. OLINDA/EXM v.1.1 software was used to fit and integrate the kinetic organ activity data to yield total body and organ time-integrated activity coefficients/residence times and finally organ absorbed doses. Standardized uptake values (SUV) and TBR were generated from the contoured tumor and source organ volumes. Spherical volumes in muscle and blood pool were also obtained for TBR (Tumor SUVmax / Organ SUVmean). Results: At all timepoints, the highest organ SUVmax was observed in the liver. Tumor and organ mean SUVs decreased whereas TBRs in all organs but the uterus increased with time. The highest TBRs at 3 hours were observed with the bone marrow (31.1), muscle (22.8), heart (19.1), and spleen (19.0). Organs with the highest effective doses were the bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04mSv/MBq). The average effective total body dose was 7.80E-03 mSv/MBq. Thus for administration of 200 MBq 68Ga-FAPI-46 the effective total body dose is 1.56 mSv ± 0.26 mSv, in addition to approximately 3.7 mSv from one low-dose CT scan done for attenuation correction. Conclusion: 68Ga-FAPI-46 PET/CT has a favorable dosimetry profile with an estimated whole body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of 68Ga-FAPI-46 (1.56± 0.26 mSv from the PET tracer and 3.7 mSv from one low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.




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Imaging the Distribution of Gastrin Releasing Peptide Receptors in Cancer

Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncological applications. Such approaches have increased significantly over the past decade. Peptides such as gastrin-releasing peptide receptors (GRPR) targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. GRPR, part of the bombesin (BBN) family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.




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Biokinetics of Radiolabeled Monoclonal Antibody BC8: Differences in Biodistribution and Dosimetry among Hematologic Malignancies.

We reviewed 111In-DOTA-anti-CD45 antibody (BC8) imaging and bone marrow biopsy measurements to ascertain biodistribution and biokinetics of the radiolabeled antibody and to investigate differences based on type of hematologic malignancy. Methods: Serial whole-body scintigraphic images (4 time-points) were obtained after infusion of the 111In-DOTA-BC8 (176-406 MBq) in 52 adult patients with hematologic malignancies (lymphoma, multiple myeloma, acute myeloid leukemia and myelodysplastic syndrome). Counts were obtained for the regions of interest for spleen, liver, kidneys, testicles (in males), and two marrow sites (acetabulum and sacrum) and correction for attenuation and background was made. Bone marrow biopsies were obtained 14-24 hours post-infusion and percent of administered activity was determined. Radiation absorbed doses were calculated. Results: Initial uptake in liver averaged 32% ± 8.4% (S.D.) of administered activity (52 patients), which cleared monoexponentially with biological half-time of 293 ± 157 hours (33 patients) or did not clear (19 patients). Initial uptake in spleen averaged 22% ± 12% and cleared with a biological half-time 271 ± 185 hours (36 patients) or longer (6 patients). Initial uptake in kidney averaged 2.4% ± 2.0% and cleared with a biological half-time of 243 ± 144 hours (27 patients) or longer (9 patients). Initial uptake in red marrow averaged 23% ± 11% and cleared with half-times of 215 ± 107 hours (43 patients) or longer (5 patients). Whole-body retention half-times averaged 198 ± 75 hours. Splenic uptake was higher in the AML/MDS group when compared to the lymphoma group (p ≤ 0.05) and to the multiple myeloma group (p ≤ 0.10). Liver represented the dose-limiting organ. For liver uptake, no significant differences were observed between the three malignancy groups. Average calculated radiation absorbed doses per unit administered activity for a therapy infusions of 90Y-DOTA-BC8 were for red marrow: 470 ± 260 cGy/MBq, liver 1100 ± 330 cGy/MBq, spleen 4120 ± 1950 cGy/MBq, total body 7520 ± 20 cGy/MBq, osteogenic cells 290 ± 200 cGy/MBq, and kidneys 240 ± 200 cGy/MBqR. Conclusion: 111In-DOTA-BC8 had long retention time in liver, spleen, kidneys, and red marrow, and the highest absorbed doses were calculated for spleen and liver. Few differences were observed by malignancy type. The exception was greater splenic uptake among leukemia/MDS group when compared to lymphoma and multiple myeloma groups.




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Biodistribution of a CD3/EpCAM bispecific T-cell engager is driven by the CD3 arm

BiTE® (Bispecific T-cell engager) molecules are designed to engage and activate cytotoxic T-cells to kill tumor cells. Little is known about their biodistribution in immunocompetent settings. To explore their pharmacokinetics and the role of the immune cells, BiTE molecules were radiolabeled with positron emission tomography (PET) isotope zirconium-89 (89Zr) and studied in immunocompetent and immunodeficient mouse models. PET images and ex-vivo biodistribution in immunocompetent mice with 89Zr-muS110, targeting mouse CD3 (Kd = 2.9 nM) and mouse EpCAM (Kd = 21 nM), and 89Zr-hyS110, targeting only mouse CD3 (Kd = 2.9 nM), showed uptake in tumor, spleen and other lymphoid organs, while the human-specific control BiTE 89Zr-AMG 110 showed similar tumor uptake but lacked spleen uptake. 89Zr-muS110 spleen uptake was lower in immunodeficient than in immunocompetent mice. After repeated administration of non-radiolabeled muS110 to immunocompetent mice 89Zr-muS110 uptake in spleen, and other lymphoid tissues, decreased and was comparable to uptake in immunodeficient mice, indicating saturation of CD3 binding sites. Autoradiography and immunohistochemistry demonstrated colocalization of 89Zr-muS110 and 89Zr-hyS110 with CD3-positive T-cells in the tumor and spleen but not with EpCAM expression. Also, uptake in the duodenum correlated with a high incidence of T-cells. This study shows that in immunocompetent mice the BiTE 89Zr-muS110 distribution is predominantly based on its high affinity CD3 binding arm. Significance: 89Zr-muS110 biodistribution is mainly dependent on the T-cell targeting arm with limited contribution of its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs as results might have implications for their respective drug development and clinical translation.




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Sphingolipids distribution at mitochondria-associated membranes (MAM) upon induction of apoptosis.

Vincent Mignard
Apr 29, 2020; 0:jlr.RA120000628v1-jlr.RA120000628
Research Articles




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Episode 15 - The Internet of ill Advised Man Buns (IoIAMB) Google I/O and terrible film adaptations

Host Matt Egan is joined by producer Chris to talk about the raft of announcements coming out of the Google I/O developer conference this week, including Android N, Google assistant and Allo. Techworld.com editor Charlotte Jee joins in to discuss driverless cars (17:00) following the Queen's speech this week. Finally, acting editor at Macworld.co.uk David Price talks about terrible film adaptations of video games, from Angry Birds to World of Warcraft (29:00). Don't forget to like, share and tell your friends!  


See acast.com/privacy for privacy and opt-out information.




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Episode 17 - The Internet of Not Terrible Windows Phones (IoNTWP) - VR games & phones at gigs

This week host Matt Egan is joined by PC Advisor staff writer Chris Minasians to chat about the AMD Radeon RX 480 graphics card and what this could mean for the future of virtual reality games. Fellow staff writer at PC Advisor Henry Burrell jumps in to talk about the "not terrible" Windows 10 phone as he starts using the Microsoft Lumia 950 and can't see what everyone's beef with it is (13:00). Finally Ashleigh Allsopp, engagement editor at Macworld UK chats about using your technology at concerts (24:30).  


See acast.com/privacy for privacy and opt-out information.




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Phosphatidylinositol Metabolism, Phospholipases, Lipidomics, and Cancer:In Memoriam of Michael J. O. Wakelam (1955-2020) [Tribute]




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Sphingolipids distribution at mitochondria-associated membranes (MAM) upon induction of apoptosis. [Research Articles]

The levels and composition of sphingolipids and related metabolites are altered in aging and common disorders such as diabetes and cancers, as well as in neurodegenerative, cardiovascular, and respiratory diseases. Changes in sphingolipids have been implicated as being an essential step in mitochondria-driven cell death. However, little is known about the precise sphingolipid composition and modulation in mitochondria or related organelles. Here, we used LC–MS/MS to analyze the presence of key components of the ceramide metabolic pathway in vivo and in vitro in purified endoplasmic reticulum (ER), mitochondria-associated membranes (MAM), and mitochondria. Specifically, we analyzed the sphingolipids in the three pathways that generate ceramide: sphinganine in the de novo ceramide pathway, sphingomyelin in the breakdown pathway, and sphingosine in the salvage pathway. We observed sphingolipid profiles in mouse liver, mouse brain, and a human glioma cell line (U251). We analyzed the quantitative and qualitative changes of these sphingolipids during staurosporine (STS)-induced apoptosis in U251 cells. Ceramide, especially C16-ceramide, levels increased during early apoptosis possibly through a conversion from mitochondrial sphinganine and sphingomyelin, but sphingosine and lactosyl- and glucosyl-ceramide levels were unaffected. We also found that ceramide generation is enhanced in mitochondria when sphingomyelin levels are decreased in the MAM. This decrease was associated with an increase in acid sphingomyelinase (ASM) activity in MAM. We conclude that meaningful sphingolipid modifications occur in MAM, the mitochondria, and ER during the early phases of apoptosis.




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Justice for the Rohingya: Lessons from the Khmer Rouge Tribunal

8 April 2020

Sandra Smits

Programme Manager, Asia-Pacific Programme
The Cambodian case study illustrates the challenges of ensuring justice and accountability for the Rohingya in Myanmar.

2020-04-08-Rohingya.jpg

Coast guards escort Rohingya refugees following a boat capsizing accident in Teknaf on 11 February 2020. Photo: Getty Images.

International criminal justice provides a stark reminder that state sovereignty is not an absolute, and that the world’s most heinous crimes should be prosecuted at an international level, particularly where domestic systems lack the capacity or will to hold perpetrators to account. 

The post-Cold War period witnessed a dramatic rise in the number of international tribunals with jurisdiction over war crimes and serious human rights abuses in countries including Cambodia, East Timor, Rwanda, Liberia, Sierra Leone and Yugoslavia. With these processes approaching, or having reached the end of their dockets, many have called for the creation of new tribunals to address more recent conflicts, including the army crackdown in Myanmar in 2017 that resulted in evidence of crimes against humanity against the Rohingya

In January this year, the International Court of Justice (ICJ) imposed emergency provisional measures on Myanmar, instructing it to prevent genocidal violence against its Rohingya minority. But a final judgement is expected to take years and the ICJ has no way of enforcing these interim measures. Myanmar has already responded defiantly to international criticism

Model for justice

Myanmar is not the first country to face scrutiny for such crimes in Southeast Asia. The Extraordinary Chambers in the Courts of Cambodia (ECCC), more commonly known as the Khmer Rouge Tribunal was established in 1997 to prosecute Khmer Rouge leaders for alleged violations of international law and serious crimes perpetrated during the Cambodian genocide. This provides an opportunity to consider whether the Tribunal can act as a ‘hybrid’ model for justice in the region. 

The first lesson that can be taken from the Cambodian context is that the state must have the political will and commitment to pursue accountability. It was indeed the Cambodian government itself, who requested international assistance from the United Nations (UN), to organize a process for holding trials. The initial recommendation of the UN-commissioned Group of Experts was for the trial to be held under UN control, in light of misgivings about Cambodia’s judicial system. Prime Minister Hun Sen rejected this assessment and in prolonged negotiations, continued to spearhead the need for domestic involvement (arguably, in order to circumscribe the search for justice). This eventually resulted in the creation of a hybrid body consisting of parallel international and Cambodian judges and prosecutors with supermajority decision-making rules.   

It is worth noting that the Hun Sen government initially chose to do business with former Khmer Rouge leaders, until it became more advantageous to embrace a policy of putting them on trial. It is possible to infer from this that there will be no impetus for action in Myanmar until it is domestically advantageous to do so. At present, this appetite is clearly lacking, demonstrated by de-facto leader Aung San Suu Kyi shying away from accountability and instead defending the government’s actions before the ICJ.

One unique aspect of the Khmer Rouge Tribunal has been the vast participation by the Cambodian people in witnessing the trials as well as widespread support for the tribunal. This speaks to the pent-up demand in Cambodia for accountability and the importance of local participation. While international moral pressure is clear, external actors cannot simply impose justice for the Rohingya when there is no domestic incentive or support to pursue this. The reality is that the anti-Rohingya campaign has galvanized popular support from the country’s Buddhist majority. What is more, the Rohingya are not even seen as part of Myanmar so there is an additional level of disenfranchisement.

Secondly, the Cambodian Tribunal illustrates the need for safeguards against local political interference. The ECCC was designed as national court with international participation. There was an agreement to act in accordance with international standards of independence and impartiality, but no safeguards in place against serious deficiencies in the Cambodian judicial system. Close alliances between judges and the ruling Cambodian People’s Party, as well as high levels of corruption meant the tribunal effectively gave Hun Sen’s government veto power over the court at key junctures. Despite the guise of a hybrid structure, the Cambodian government ultimately retained the ability to block further prosecutions and prevent witnesses from being called. 

In Myanmar, political interference could be a concern, but given there is no popular support for justice and accountability for crimes committed against the Rohingya, the prospects of a domestic or hybrid process remain unlikely. However, there are still international options. The investigation by the International Criminal Court (ICC) into crimes that may have taken place on the Myanmar–Bangladesh border represents a potential route for justice and accountability. The UN Human Rights Council has also recently established the Independent Investigative Mechanism for Myanmar (IIMM), mandated to collect and preserve evidence, as well as to prepare files for future cases before criminal courts.

Finally, the Cambodian case illustrates the culture of impunity in the region. The ECCC was conceived partly as a showcase for international standards of justice, which would have a ‘contagion effect’ upon the wider Cambodian and regional justice systems. 

Cambodia was notorious for incidents in which well-connected and powerful people flouted the law. This culture of impunity was rooted in the failure of the government to arrest, try and punish the Khmer Rouge leadership. The Tribunal, in holding perpetrators of the worst crimes to account, sought to send a clear signal that lesser violations would not be tolerated in the same way. Arguably, it did not achieve this in practice as Cambodia still has a highly politicized judicial system with high levels of corruption and clear limits to judicial independence

What this illustrates is that the first step towards accountability is strengthening domestic institutions. The United Nation’s Special Rapporteur on the situation of human rights in Myanmar has urged domestic authorities to embrace democracy and human rights, highlighting the need to reform the judicial system in order to ensure judicial independence, remove systemic barriers to accountability and build judicial and investigatory capacity in accordance with international standards. Based on this assessment, it is clear that domestic institutions are currently insufficiently independent to pursue accountability.

The ECCC, despite its shortcomings, does stand as proof that crimes against humanity will not go completely unpunished. However, a process does not necessarily equal justice. The region is littered with justice processes that never went anywhere: Indonesia, Nepal, and Sri Lanka. International recourse is also challenging in a region with low ratification of the ICC, and the absence of regional mechanisms like the Inter-American Court of Human Rights, the European Court of Human Rights, and the African Court on Human and Peoples’ Rights (although their remit is not mass atrocity prosecutions). 

The Cambodian case study illustrates the challenges of ensuring justice and accountability within the region. The end of impunity is critical to ensure peaceful societies, but a purely legalistic approach will fail unless it is supported by wider measures and safeguards. It is these challenges, that undermine the prospects for ensuring justice for the Rohingya within Myanmar.




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Iraq Tribunal: US Pulling Out

1 May 2008 , Number 3

Rowdy sessions of the Iraq High Tribunal attracted sensational daily news coverage while Saddam Hussein was being tried. However, following his grim execution in December 2006, coverage all but evaporated. The foreign press and most western monitors packed their bags and left, and television reporting in Iraq dwindled. Now even the United States Department of Justice, which initially provided key financial and political support, is quietly withdrawing its advisers. So what is happening at the Tribunal and why are the Americans pulling out?

Sonya Sceats

Associate Fellow, International Law Programme




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In Memoriam: Lina M. Obeid (1957-2019) [Tribute]




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Problem Notes for SAS®9 - 65868: Saving a report distribution in SAS Visual Analytics Designer fails with "The name is invalid"

When you attempt to save a report distribution in SAS Visual Analytics Designer, you might see the error shown in the following display:  imgalt="" src="{fusion_65868_1_distributionerror.png}" />



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The heme-regulatory motifs of heme oxygenase-2 contribute to the transfer of heme to the catalytic site for degradation [Protein Structure and Folding]

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.




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Iraq Tribunal: US Pulling Out

1 May 2008 , Number 3

Rowdy sessions of the Iraq High Tribunal attracted sensational daily news coverage while Saddam Hussein was being tried. However, following his grim execution in December 2006, coverage all but evaporated. The foreign press and most western monitors packed their bags and left, and television reporting in Iraq dwindled. Now even the United States Department of Justice, which initially provided key financial and political support, is quietly withdrawing its advisers. So what is happening at the Tribunal and why are the Americans pulling out?

Sonya Sceats

Associate Fellow, International Law Programme




rib

Justice for the Rohingya: Lessons from the Khmer Rouge Tribunal

8 April 2020

Sandra Smits

Programme Manager, Asia-Pacific Programme
The Cambodian case study illustrates the challenges of ensuring justice and accountability for the Rohingya in Myanmar.

2020-04-08-Rohingya.jpg

Coast guards escort Rohingya refugees following a boat capsizing accident in Teknaf on 11 February 2020. Photo: Getty Images.

International criminal justice provides a stark reminder that state sovereignty is not an absolute, and that the world’s most heinous crimes should be prosecuted at an international level, particularly where domestic systems lack the capacity or will to hold perpetrators to account. 

The post-Cold War period witnessed a dramatic rise in the number of international tribunals with jurisdiction over war crimes and serious human rights abuses in countries including Cambodia, East Timor, Rwanda, Liberia, Sierra Leone and Yugoslavia. With these processes approaching, or having reached the end of their dockets, many have called for the creation of new tribunals to address more recent conflicts, including the army crackdown in Myanmar in 2017 that resulted in evidence of crimes against humanity against the Rohingya

In January this year, the International Court of Justice (ICJ) imposed emergency provisional measures on Myanmar, instructing it to prevent genocidal violence against its Rohingya minority. But a final judgement is expected to take years and the ICJ has no way of enforcing these interim measures. Myanmar has already responded defiantly to international criticism

Model for justice

Myanmar is not the first country to face scrutiny for such crimes in Southeast Asia. The Extraordinary Chambers in the Courts of Cambodia (ECCC), more commonly known as the Khmer Rouge Tribunal was established in 1997 to prosecute Khmer Rouge leaders for alleged violations of international law and serious crimes perpetrated during the Cambodian genocide. This provides an opportunity to consider whether the Tribunal can act as a ‘hybrid’ model for justice in the region. 

The first lesson that can be taken from the Cambodian context is that the state must have the political will and commitment to pursue accountability. It was indeed the Cambodian government itself, who requested international assistance from the United Nations (UN), to organize a process for holding trials. The initial recommendation of the UN-commissioned Group of Experts was for the trial to be held under UN control, in light of misgivings about Cambodia’s judicial system. Prime Minister Hun Sen rejected this assessment and in prolonged negotiations, continued to spearhead the need for domestic involvement (arguably, in order to circumscribe the search for justice). This eventually resulted in the creation of a hybrid body consisting of parallel international and Cambodian judges and prosecutors with supermajority decision-making rules.   

It is worth noting that the Hun Sen government initially chose to do business with former Khmer Rouge leaders, until it became more advantageous to embrace a policy of putting them on trial. It is possible to infer from this that there will be no impetus for action in Myanmar until it is domestically advantageous to do so. At present, this appetite is clearly lacking, demonstrated by de-facto leader Aung San Suu Kyi shying away from accountability and instead defending the government’s actions before the ICJ.

One unique aspect of the Khmer Rouge Tribunal has been the vast participation by the Cambodian people in witnessing the trials as well as widespread support for the tribunal. This speaks to the pent-up demand in Cambodia for accountability and the importance of local participation. While international moral pressure is clear, external actors cannot simply impose justice for the Rohingya when there is no domestic incentive or support to pursue this. The reality is that the anti-Rohingya campaign has galvanized popular support from the country’s Buddhist majority. What is more, the Rohingya are not even seen as part of Myanmar so there is an additional level of disenfranchisement.

Secondly, the Cambodian Tribunal illustrates the need for safeguards against local political interference. The ECCC was designed as national court with international participation. There was an agreement to act in accordance with international standards of independence and impartiality, but no safeguards in place against serious deficiencies in the Cambodian judicial system. Close alliances between judges and the ruling Cambodian People’s Party, as well as high levels of corruption meant the tribunal effectively gave Hun Sen’s government veto power over the court at key junctures. Despite the guise of a hybrid structure, the Cambodian government ultimately retained the ability to block further prosecutions and prevent witnesses from being called. 

In Myanmar, political interference could be a concern, but given there is no popular support for justice and accountability for crimes committed against the Rohingya, the prospects of a domestic or hybrid process remain unlikely. However, there are still international options. The investigation by the International Criminal Court (ICC) into crimes that may have taken place on the Myanmar–Bangladesh border represents a potential route for justice and accountability. The UN Human Rights Council has also recently established the Independent Investigative Mechanism for Myanmar (IIMM), mandated to collect and preserve evidence, as well as to prepare files for future cases before criminal courts.

Finally, the Cambodian case illustrates the culture of impunity in the region. The ECCC was conceived partly as a showcase for international standards of justice, which would have a ‘contagion effect’ upon the wider Cambodian and regional justice systems. 

Cambodia was notorious for incidents in which well-connected and powerful people flouted the law. This culture of impunity was rooted in the failure of the government to arrest, try and punish the Khmer Rouge leadership. The Tribunal, in holding perpetrators of the worst crimes to account, sought to send a clear signal that lesser violations would not be tolerated in the same way. Arguably, it did not achieve this in practice as Cambodia still has a highly politicized judicial system with high levels of corruption and clear limits to judicial independence

What this illustrates is that the first step towards accountability is strengthening domestic institutions. The United Nation’s Special Rapporteur on the situation of human rights in Myanmar has urged domestic authorities to embrace democracy and human rights, highlighting the need to reform the judicial system in order to ensure judicial independence, remove systemic barriers to accountability and build judicial and investigatory capacity in accordance with international standards. Based on this assessment, it is clear that domestic institutions are currently insufficiently independent to pursue accountability.

The ECCC, despite its shortcomings, does stand as proof that crimes against humanity will not go completely unpunished. However, a process does not necessarily equal justice. The region is littered with justice processes that never went anywhere: Indonesia, Nepal, and Sri Lanka. International recourse is also challenging in a region with low ratification of the ICC, and the absence of regional mechanisms like the Inter-American Court of Human Rights, the European Court of Human Rights, and the African Court on Human and Peoples’ Rights (although their remit is not mass atrocity prosecutions). 

The Cambodian case study illustrates the challenges of ensuring justice and accountability within the region. The end of impunity is critical to ensure peaceful societies, but a purely legalistic approach will fail unless it is supported by wider measures and safeguards. It is these challenges, that undermine the prospects for ensuring justice for the Rohingya within Myanmar.




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Actor Boy Awards pays tribute to those we lost - Event goes online Saturday

Choreographer and designer Barry Moncrieffe; actress Lois Kelly Miller; New York-based broadcaster Gil Bailey; and actor and teacher Carl Samuels will all be remembered with a special tribute at Saturday’s staging of the annual Actor Boy Awards....




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Collab shows we are one Caribbean - ‘We Got This’ presents a united regional front against COVID-19

WHAT STARTED as an idea of two Barbadians – Ian Webster and Cheyne Jones – transformed into We Got This, a song which proved enough to stir the collective imagination of 25 recording artistes from 14 countries across the region, disseminating the...




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COVID-19 crippling Caribbean football – McNab

FORMER NATIONAL footballer Aldrick ‘Allie’ McNab is concerned about the effect of the COVID-19 pandemic on the Caribbean’s football development. The coronavirus has caused the postponement, suspension, and cancellation of a number of sporting...




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Late Lattimore described as ‘crowd-pleaser’

Former national footballer Arthur Lattimore passed away after a long battle with throat cancer. Lattimore, who represented Jamaica’s football team through­out the 1970s, died at his home in Florida, leaving behind five children, grandchildren, and...




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Should doctors prescribe acupuncture for pain?

Our latest debate asks, should doctors recommend acupuncture for pain? Asbjørn Hróbjartsson from the Center for Evidence-based Medicine at University of Southern Denmark argues no - evidence show's it's no worse than placebo. Mike Cummings, medical director of the British Medical Acupuncture Society argues yes - that there is evidence of efficacy,...




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Social prescribing

Non-medical interventions are increasingly being proposed to address wider determinants of health and to help patients improve health behaviours and better manage their conditions - this is known as social prescribing. In England, the NHS Long Term Plan states that nearly one million people will qualify for referral to social prescribing schemes...




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Talk Evidence - aggravating acronyms, a time to prescribe, and screening (again)

Talk Evidence is back, with your monthly take on the world of EBM with Duncan Jarvies and GPs Carl Heneghan (also director for the Centre of Evidence Based Medicine at the University of Oxford) and Helen Macdonald (also The BMJ's UK research Editor). This month Helen talks about the messy business of colon cancer screening - which modality is...




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Hickling hailed for sterling contribution to mental health

The Senate on Friday paid tribute to distinguished consultant psychiatrist, Frederick Hickling, for his tremendous contribution to persons with intellectual disabilities. Hickling died on Thursday. Senator Dr Saphire Longmore remembered Professor...




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World Bank predicts sharpest decline of remittances to Caribbean

WASHINGTON, CMC – The World Bank has predicted the sharpest decline of remittances to Latin America and the Caribbean, saying that global remittances on a whole are projected to fall by about 20 percent in 2020 due to the economic crisis...




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Tribute to Prof Fred Hickling

THE EDITOR, Madam: Words cannot describe my feeling of loss on hearing that prominent psychiatrist Professor Fred Hickling has died. Professor Hickling was one of Jamaica’s treasures through his work in the field of community mental health. His...




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How the New Indonesia-EU FLEGT Licence Can Contribute to the Sustainable Development Agenda

15 November 2016

Alison Hoare

Senior Research Fellow, Energy, Environment and Resources Programme
The FLEGT timber licence marks a breakthrough in the battle against illegal logging and has the potential to help towards achieving the SDGs in the forest sector and beyond.

2016-11-15-Indonesia-logging.jpg

Collected logs along a river in West Kalimantan province, Indonesia. Photo by Getty Images.

Today Indonesia begins issuing the first ever FLEGT licenses for timber exports bound for the EU market. A major step in the battle against illegal logging and trade in illegal timber, these licenses are issued under a national system to verify the legality of all timber and timber products. A commitment to licensing its timber exports to Europe was made in the country’s Voluntary Partnership Agreement (VPA) with the EU, although the licensing system applies to all exports and to the domestic market. The scale of this achievement can not be underestimated given the size of the country and of its forest sector – there are hundreds of thousands of forest enterprises ranging from large-scale concession holders and processing industries, to smallholders and micro-scale loggers, saw-millers and manufacturers.

It is also remarkable given the state of Indonesia’s forest sector at the turn of the century. Looking back to 2000, rule of law was all but absent and corruption was rife - with the allocation of concessions and timber industries closely tied with the country’s ruling elite. Widespread logging contributed to the high rates of deforestation seen at the turn of the century, which stood at over one per cent per year.

In 2016, the forest sector is vastly different – there are much higher levels of accountability and legal compliance, the result of the considerable effort and resources that have been put into enforcement and anti-corruption efforts. The sector is also much more open, reflected both in the significant improvements in the availability of forest data and legislation as well as the increased space that has been made available to civil society to participate both in policy processes and in monitoring of the sector.

These improvements are the result in large part of the reform processes that have been enabled and supported by the VPA process, for which negotiations began in 2007. However, the process is far from complete and the issuance of FLEGT licences is best viewed as a marking point in an ongoing trajectory towards establishing a legal and sustainable sector.

If we take 2000 as the starting point of this trajectory, with FLEGT licensing as the midway point, this brings us to just beyond 2030, the target date for the UN’s global agenda for sustainable development of which the Sustainable Development Goals (SDG) are an integral part. The SDGs provide a broader framework for considering what further progress is needed in the coming years both to improve legality and to ensure that the forest sector makes a positive contribution towards achieving widespread sustainable development in Indonesia.

There are a number of factors that risk the achievement of these aims. Key challenges that remain in the country’s forest sector include the high levels of informality in the small-scale sector, corruption, limited transparency and pressure on forests from other sectors (as highlighted in the report 'Illegal Logging and Related Trade. The Response in Indonesia').

As noted, there are hundreds of thousands of forest enterprises in the country, many of which – particularly small-scale businesses – operate informally. Further concerted efforts are needed to ensure that these enterprises are not excluded from the formal market, but are able to contribute to a thriving economy – for example, through continued support for certification, as well as much greater investment in the provision of extension services and further reforms to establish a policy framework that facilitates the growth of small businesses (see 'Improving Legality Among Small-Scale Forest Enterprises'). This will make an important contribution to the achievement of SDG 8, to enable ‘decent work and economic growth’, this including the target [8.3] to encourage the growth of small enterprises.

Both corruption and limited transparency also need to be addressed if widespread legality and sustainability are to be achieved in the forest sector. Transparency has improved greatly in the forest sector, with significant improvements to the availability of information and the establishment of independent monitoring by civil society. However, further progress is needed to improve the accessibility of information, not least to ensure that NGOs are able to fulfil this monitoring role. In relation to corruption, the anti-corruption agency has made good progress, but it remains under threat and needs to be strengthened. Improving governance is a priority under the SDGs, Goal 16 (peace, justice and strong institutions) including targets to reduce corruption, develop transparent institutions and ensure public access to information.  

The progress made in these areas also needs to be replicated outside the forest sector. A major threat to Indonesia’s forests comes from conversion to other land-uses, in particular agricultural plantations. Effective land-use planning, including transparent and participatory decision-making, is needed if the sustainable management and efficient use of natural resources is to be achieved and deforestation slowed – as set out under SDG 12 (responsible consumption and production) and SDG 15 (life on land).

An important means to drive progress is to ensure close monitoring of progress as well as the evaluation of the measures being adopted. A framework for monitoring the impact of FLEGT licences, as well as the related measures being implemented under the VPA, is under development. This will need to link up to national efforts to monitor progress towards the SDGs – both to contribute towards the monitoring of these goals and to facilitate communication of the progress and lessons being learnt in the forest sector.

To comment on this article, please contact Chatham House Feedback




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First-in-Humans Imaging with 89Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1–2, 6–8, 24, 48, and 96–144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results: 89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time–activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24–48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C–positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion: 89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell–rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.




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Starbucks operator Caribbean Coffee floats US$30m bond

Caribbean Coffee Traders Limited, CCTL, is moving ahead with plans for a US$30-million bond placement, the proceeds from which it will likely use to expand the Starbucks chain it operates in three regional markets. The initial franchise agreement...




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Government recognises contribution of EU workers to the NHS, says health minister




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Impact of 1,N6-ethenoadenosine, a damaged ribonucleotide in DNA, on translesion synthesis and repair [Enzymology]

Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.




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2009 E Pluribus Unum Awards

Award winners for the inaugural year of the E Pluribus Unum Prizes program were honored at a reception at the Library of Congress in Washington, DC in 2009.




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2010 E Pluribus Unum Prizes: Honoring Exceptional Immigrant Integration Initiatives

Award winners were honored at the second annual awards ceremony in Washington, DC, on May 18, 2010.




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2010 E Pluribus Unum Prizes: Honoring Exceptional Immigrant Integration Initiatives

Winners of the 2nd annual E Pluribus Unum Prizes awarded to exceptional immigrant integration initiatives by MPI's National Center on Immigrant Integration Policy are the Illinois New Americans Integration Initiative; the Latino Community Credit Union in Durham, NC; Tacoma Community House in Tacoma, WA; and Upwardly Global in San Francisco, CA. McDonald's Corp. of Oak Brook, IL, received the sole honorable mention. The Prizes seek to reward exemplary efforts that uphold and update the ideal of "out of many, one" and inspire others to take on the important work of helping immigrants and their children join the mainstream of U.S. society as well as build stronger ties between immigrants and the native-born. Award winners were honored at the second annual awards ceremony in Washington, DC, on May 18, 2010. Watch highlights of the ceremony here.




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E Pluribus Unum Prizes Panel Discussions and Awards Ceremony

This awards ceremony, honoring the 2011 recipients of the E Pluribus Unum Prizes — a national awards program for exceptional immigrant integration initiatives — featured panel discussions with the awardees and federal officials and remarks by White House Director of Intergovernmental Affairs Cecilia Muñoz and Assistant Secretary of Education Brenda Dann-Messier.




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E Pluribus Unum Prizes Panel Discussions and Awards Ceremony

This awards ceremony, honoring the 2011 recipients of the E Pluribus Unum Prizes -- a national awards program for exceptional immigrant integration initiatives -- featured panel discussions with the awardees and federal officials and remarks by White House Director of Intergovernmental Affairs Cecilia Muñoz and Assistant Secretary of Education Brenda Dann-Messier.




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2012 E Pluribus Unum Prizes

The winners of the Migration Policy Institute's 2012 E Pluribus Unum Prizes, honoring exceptional immigrant integration initiatives in the United States, discussed their work during a plenary luncheon on September 24, 2012 at the National Immigrant Integration Conference held in Baltimore, MD.




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2012 E Pluribus Unum Prizes

The winners of the Migration Policy Institute's 2012 E Pluribus Unum Prizes--ACCESS (the Arab Community Center for Economic and Social Services), Building Skills Partnership, Californians Together, and Citi Community Development--discussed their immigrant integration initiatives at the National Immigrant Integration Conference.




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2013 E Pluribus Unum Prizes Awards Ceremony

This awards ceremony honored the 2013 winners of the E Pluribus Unum Prizes, which provides $50,000 prizes to exceptional U.S. immigrant integration initiatives. The awardees took part in a panel discussion with White House and state officials, followed by remarks from Congressman Luis Gutierrez and U.S. Senator Amy Klobuchar.




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With Engaged Parenting, "Terrible Twos" Are Not Inevitable

Source:

Parents should not feel pressured to make their young children undertake structured learning or achieve specific tasks, particularly during lockdown. A new study of children under the age of two has found that parents who take a flexible approach to their child's learning can minimize behavioral problems during toddlerhood.






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Metabolic Implications of Body Fat Distribution

Per Björntorp
Dec 1, 1991; 14:1132-1143
Diet and Diabetes