Zhaonan Wang and Yingpu Deng
Math. Comp. 93 (), 2921-2942.
Abstract, references and article information

15 July 2020

Simone Kurz
Dec 29, 2020; 0:RA120.002266v1-mcp.RA120.002266
Research

If the response variable is in the CLASS statement variable list before the class variables that also appear in the MODEL statement, and an OM-data-set is used, least squares means results for several of the statistical procedures are incorrect.

Roux-en-Y gastric bypass (RYGB) is one of the most commonly performed weight-loss procedures, but how severe obesity and RYGB affects circulating HDL-associated microRNAs (miRNAs) remains unclear. Here, we aim to investigate how HDL-associated miRNAs are regulated in severe obesity and how weight loss after RYGB surgery affects HDL-miRNAs. Plasma HDL were isolated from patients with severe obesity (n=53) before, 6 and 12 months after RYGB by immunoprecipitation using goat anti-human apoA-I microbeads. HDL were also isolated from 18 healthy participants. miRNAs were extracted from isolated HDL and levels of miR-24, miR-126, miR-222 and miR-223 were determined by TaqMan miRNA assays. We found that HDL-associated miR-126, miR-222 and miR-223 levels, but not miR-24 levels, were significantly higher in patients with severe obesity when compared with healthy controls. There were significant increases in HDL-associated miR-24, miR-222 and miR-223 at 12 months after RYGB. Additionally, cholesterol efflux capacity and paraoxonase (PON1) activity were increased and intracellular adhesion molecule-1 (ICAM-1) levels decreased. The increases in HDL-associated miR-24 and miR-223 were positively correlated with increase in cholesterol efflux capacity (r=0.326, P=0.027 and r=0.349, P=0.017 respectively). An inverse correlation was observed between HDL-associated miR-223 and ICAM-1 at baseline. Together, these findings show that HDL-associated miRNAs are differentially regulated in healthy versus patients with severe obesity and are altered after RYGB. These findings provide insights into how miRNAs are regulated in obesity before and after weight reduction, and may lead to the development of novel treatment strategies for obesity and related metabolic disorders.

Fabry disease is caused by deficient activity of α-galactosidase A, an enzyme that hydrolyzes the terminal α-galactosyl moieties from glycolipids and glycoproteins, and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb₃), globotriaosylsphingosine (lyso-Gb₃), and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb₃ isoforms (various fatty acids) and lyso-Gb₃ analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb₃ and lyso-Gb₃ levels in the heart, kidney, and dorsal root ganglion (DRG) were similar in the two strains. However, levels of the C20-fatty acid isoform of Gb₃ and particular lyso-Gb₃ analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared with Fabry-B6. By contrast, there was no difference in Gb₃ and lyso-Gb₃ isoforms/analogs in the kidneys and DRG between the two strains. Furthermore, using immunohistochemistry, we found that Gb₃ massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb₃ accumulation was not observed in nonpeptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of nonpeptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb₃ or lyso-Gb₃ may play major roles in the pathogenesis of Fabry disease, and that Gb₃ and lyso-Gb₃ are not responsible for the pathology in all tissues or cell types.

Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signaling networks, such as phosphorylation, methylation and ubiquitylation.

High performance liquid chromatography has been employed for decades to enhance detection sensitivity and quantification of complex analytes within biological mixtures. Among these analytes, glycans released from glycoproteins and glycolipids have been characterized as underivatized or fluorescently tagged derivatives by HPLC coupled to various detection methods. These approaches have proven extremely useful for profiling the structural diversity of glycoprotein and glycolipid glycosylation but require the availability of glycan standards and secondary orthogonal degradation strategies to validate structural assignments. A robust method for HPLC separation of glycans as their permethylated derivatives, coupled with in-line MSn fragmentation to assign structural features independent of standards, would significantly enhance the depth of knowledge obtainable from biological samples. Here, we report an optimized workflow for LC-MS analysis of permethylated glycans that includes sample preparation, mobile phase optimization, and MSn method development to resolve structural isomers on-the-fly. We report baseline separation and MSn fragmentation of isomeric N- and O-glycan structures, aided by supplementing mobile phases with Li+, which simplifies adduct heterogeneity and facilitates cross-ring fragmentation to obtain valuable monosaccharide linkage information. Our workflow has been adapted from standard proteomics-based workflows and, therefore, provides opportunities for laboratories with expertise in proteomics to acquire glycomic data with minimal deviation from existing buffer systems, chromatography media, and instrument configurations. Furthermore, our workflow does not require a mass spectrometer with high-resolution/accurate mass capabilities. The rapidly evolving appreciation of the biological significance of glycans for human health and disease requires the implementation of high-throughput methods to identify and quantify glycans harvested from sample sets of sufficient size to achieve appropriately powered statistical significance. The LC-MSn approach we report generates glycan isomeric separations, robust structural characterization, and is amenable to auto-sampling with associated throughput enhancements.

Russia's war on everybody 6 December 2022 — 5:00PM TO 6:00PM Anonymous (not verified) 14 October 2022 Chatham House and Online

Experts discuss the methods Moscow has employed to exert influence around the world over recent decades.

Russia’s assault on Ukraine has reminded the world about the threat it faces from Moscow. But that’s not the only war that Russia has been fighting and Ukraine is not the only target.

Long before February 2022, Russia was already engaged in semi-covert campaigns across Europe and around the world, using any means possible to expand its power and influence and leaving a trail of destruction along the way.

In his new book Russia’s War on Everybody, Chatham House associate fellow Keir Giles examines what this longer war means for us all. Instead of talking only to diplomats, politicians and generals, Giles has looked instead at the effect of Russia’s ambition on ordinary people.

Interviewing 40 eyewitnesses from four continents, he has tried to tell the stories the world doesn’t hear about the impact of Russia’s hostility on individuals and societies that may not even realize they are a target.

At this event, Giles introduces the book at Chatham House. He is joined by experts to talk about the human impact of Russia’s campaigns waged through leveraging corruption and cyber offensives respectively.

As with all members events, questions from the audience drive the conversation.

Read the transcript. 

America's abortion ban will hurt women everywhere The World Today mhiggins.drupal 9 August 2022

In the final part of a series on the impact of the Roe v Wade ruling, Nina van der Mark assesses the global impact of America’s reverse on reproductive rights.

In overturning the constitutional right to an abortion established by Roe v Wade, the Supreme Court of the United States placed the US alongside Poland, El Salvador and Nicaragua as countries that have restricted access to abortion in recent decades. While the Dobbs ruling is a domestic reversal, the US remains the largest funder of global health, family planning and reproductive health services. There is a lot at stake for women and girls around the world. 

Here are four potential global impacts to consider.

Millions of women will be at greater risk 

The Guttmacher Institute, a research and policy organization that aims to improve sexual and reproductive health worldwide, calculated that in 2021 American international family planning assistance saw an estimated 27.2 million women and couples receive contraceptive services, some 12 million pregnancies averted, four million unsafe abortions prevented and 19,000 maternal deaths avoided. These outcomes help to improve gender equity as well as increase women’s education and employment opportunities and boost economic growth. 

This happens despite US funding for international family planning being in decline over the past decade. It peaked during the Obama administration at $715 million in 2010 but since 2017 averaged about $607 million a year. Using US aid to directly fund abortions as a method of family planning is prohibited under the terms of the Helms Amendment of 1973.

In America, the Dobbs ruling has so far led 14 Republican-controlled states to enact anti-abortion legislation. This, in turn, has motivated pro-choice campaigners – on August 2, a referendum in the staunchly conservative state of Kansas returned a decisive vote to preserve abortion rights. That result gives hope to abortion-rights groups that the issue will cut across traditional political loyalties and bring swing voters to their cause in the mid-term congressional elections in November.  

That is important because Congress decides on the level of funding for America’s global health programmes, including family planning and reproductive health. The stakes are high. For instance, Kenya, Nigeria and Ethiopia, with a combined population of more than 370 million, are among the top 10 recipients of US Overseas Development Assistance, most of which goes to health programmes. Nigeria, for instance, received $794 million in such funding from America in 2019-2020. 

A sudden policy reversal affecting funding for reproductive health would lead to clinic closures, reduced access to help and shortages of essential family planning commodities. The result would be more unintended pregnancies, more unsafe abortions and a potential increase in maternal mortality. 

Women will have more unsafe abortions

The Helms Amendment, which prevents recipients of American aid directly funding abortion services, was passed by Congress in 1973 following the Roe v Wade decision. The Global Gag Rule, first enacted by Ronald Reagan in 1984, goes further, forbidding NGOs abroad in receipt of American aid from promoting or counselling abortion as a form of family planning, even when using their own funds. Since its introduction, Republican administrations have enforced the rule while Democratic administrations have rescinded it, as Biden did in January 2021.  

Restricting access to safe abortion services increases the number of unsafe abortions, whereas legalizing abortion services reduces them. During the Bush administration, the Global Gag Rule prompted a 12-per-cent increase in pregnancies in rural Ghana, which led to an additional 200,000 abortions. 

Another study found a substantial increase in abortions, a decline in contraceptive use and an increase in pregnancies in 26 countries in sub-Saharan Africa affected by the rule across three US administrations. It’s estimated that 77 per cent of abortions in the region are unsafe. In 2019 that translated into 6.2 million unsafe abortions.

The failure of America to consistently support safe abortion services contributes to the more than 35 million unsafe abortions that take place each year across 132 lower middle-income countries.  

Under the Trump administration, the Global Gag Rule was extended from family planning funding to cover all US global health assistance, increasing the level of US funding affected from around $600 million to $8.8 billion. Were a Republican administration to be elected in 2024 there is little doubt the rule would be reinstated, possibly in the most restrictive form that Trump enforced. 

Anti-abortion movements will double their efforts 

The repeal of Roe v Wade has not occurred in a silo, nor are its effects contained within the US.

News of the Dobbs ruling, which overturned Roe v Wade, prompted One of Us, a European anti-abortion platform, to mount an immediate, 20,000-strong anti-abortion demonstration in Spain, including leaders of the conservative Vox party.  On Twitter, Sara Larin, an anti-abortion activist from El Salvador, likened the Dobbs ruling to the abolition of slavery in the US, calling it ‘the beginning of the end for abortion [worldwide]’. 

Countries have based their legal protections for abortion access on Roe v Wade or cited it in their case law, which now opens them up to legal challenge domestically. A Christian anti-abortion group in Kenya is legally challenging a pro-choice ruling based on Roe v Wade. Such challenges may increase: anti-choice groups in Mexico and Peru cited the Dobbs ruling as an encouraging development. 

Many American Christian right-wing groups fund anti-abortion activities abroad. OpenDemocracy, an independent global media platform, recently reported that 28 Christian right-wing organizations spent more than $280 million internationally between 2007-2018 on anti-choice activities, targeting Europe primarily, followed by Africa and Asia.  

The American right is not afraid to take direct legal action abroad either. The European Center for Law and Justice, an offshoot of the Trump-backed American Center for Law and Justice, has made interventions in dozens of court cases on sexual and reproductive health and rights in the European Court, including in the case that overturned abortion rights in Poland.   

The European parliament in its most recent motion on the topic expressed concern about the potential for the Dobbs ruling to prompt a surge in the flow of money to anti-choice groups around the world.  

America’s global standing will take a hit 

The Dobbs ruling immediately attracted criticism from many world leaders.  ‘Watching the removal of a woman’s fundamental right to make decisions over their own body is incredibly upsetting,’ said Jacinda Ardern, the New Zealand prime minister. ‘To see that principle now lost in the United States feels like a loss for women everywhere.’  

President Emmanuel Macron of France tweeted: ‘I wish to express my solidarity with the women whose liberties are being undermined by the Supreme Court of the United States.’ 

The ruling is in conspicuous opposition to the Biden administration’s more progressive stance on sexual and reproductive health and rights and its advocacy abroad. It sends a clear message from the world’s most powerful democracy that these rights are not guaranteed. 

While many world leaders reacted to the Dobbs ruling with dismay, other senior figures from the conservative right welcomed it, including the Brazilian President Jair Bolsonaro’s son, Eduardo, and Javier Milei, a potential candidate in Argentina’s presidential election next year.  

In 2020, the Trump administration co-sponsored the ‘Geneva Consensus Declaration on Promoting Women’s Health and Strengthening the Family,’ declaring that there was ‘no international right to abortion.’ It was signed by more than 30 countries, including autocratic and right-wing governments in Brazil, Poland, Hungary and Saudi Arabia.  

The Biden administration withdrew from it – but its signatories are the governments who may yet take advantage of America’s self-inflicted erosion of authority on reproductive rights.  

The Dobbs ruling exposes the limitation of the American executive to act within the US legal system while opening up questions on American support of, and dedication to, fundamental rights.

Read the other two articles in this series: ‘Empowering women aids climate resilience’ and ‘Counting the cost of the abortion ban’

Turkey Is on the Road to a Severe Economic Crisis Expert comment sysadmin 12 July 2018

The deteriorating state of the economy is President Erdoğan’s Achilles’ heel and the biggest threat to his currently unrivalled leadership.

Fifteen days after Turkey’s parliamentary and presidential elections, Turkish President Recep Tayyip Erdoğan appointed a new government under radically enhanced executive powers granted by the constitution. He chose 16 loyalists and partisan figures to ensure that he remains front and centre in decision-making and policy formation.

Most notably, Erdoğan sacrificed the former deputy prime minister and ex-Merrill Lynch chief economist Mehmet Şimşek in favour of his inexperienced son-in-law Berat Albayrak as finance and treasury minister to manage the fragile economy. Whether he has the competence to placate jittery financial markets and foreign investors is debatable.

Erdoğan will prioritize short-term growth at all costs to the detriment of macroeconomic and financial stability. That entails foregoing interest rate hikes needed to contain runaway double-digit inflation and to support a plummeting lira that depreciated nearly 20 per cent this year. It also means loosening the purse strings, flooding the markets with cheap credit and sponsoring rampant construction and mega-infrastructure projects.

True to his promise, he has appropriated to himself, by presidential decree, the right to hire the central bank governor, deputies and monetary policy committee members for a four-year term. This completes the politicization of the once-respected and independent central bank and is in line with his unorthodox monetary views that higher interest rates equates with higher inflation.

Erdoğan associates progress with gleaming high-rise buildings, gargantuan infrastructure show-pieces and elevated growth rates. He is spiking the fuel to boost the speed of the sputtering mid-sized Audi-style Turkish economy to achieve superior Ferrari growth rates. As any mechanic knows, these tactics are unsustainable in the long term. Eventually, the engine will burn out.

He does not seem to appreciate that Turkey’s growth model requires an overhaul to join the league of rich economies. It is too reliant on consumer spending and government-sponsored infrastructure and construction projects funded by speculative financial flows rather than on sustained private investment and exports.

Net result: the corporate sector’s foreign-exchange liabilities have climbed to a record $328 billion as of the end of 2017. When netted against foreign-exchange assets, it is still a worrying $214 billion. Its US dollar and euro debt pile has more than doubled since 2008, 80 per cent of which is held by domestic banks. Given these acute balance-of-payments conditions, it is not farfetched that Turkey may impose capital controls in the short-to-medium term to restrict the outflow of foreign assets. At $50 billion, the current account deficit – defined as the sum of the trade balance and financial flows – is not even covered by the central bank’s net international reserves at nearly $45 billion.

Unsurprisingly, some major Turkish companies are negotiating with their bondholders to restructure their sizeable foreign loan obligations as lira devaluation increases the financial burden. Should a significant number of Turkish corporates default on their foreign obligations, this would reverberate across the Turkish economy, cause mass consumer panic, shake the confidence of international financial markets and potentially lead to a crisis within the Turkish financial system and to a deep and prolonged economic recession.

Revealingly, Erdoğan’s nationalist allies, the Nationalist Movement Party (MHP), refused to join his government. Perhaps Devlet Bahçeli, the MHP leader, learned the lessons of the 2001 financial crisis as a member of a three-party government. So he is opting to project influence from the outside, rather than risk being tainted with responsibility for an economic downturn.

Turkey’s president is doubling down on his singular approach to governance irrespective of the fallout. Notwithstanding his current political dominance, the deteriorating state of the economy is his Achilles’ heel and the biggest threat to his currently unrivalled leadership.

As Nissan on Thursday reported a roughly half-billion- dollar revenue drop in 2024, the Japanese automaker said it will cut 9,000 jobs and reduce manufacturing capacity by 20%.

How can manufacturers apply lessons learned from the dawn of the “Exascale Era” to Computer-Aided Engineering to achieve results like never before? Join Addison Snell, CEO, Intersect360 Research, Bill Mannel, VP, High Performance […]

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Customers now have access to Google’s homegrown hardware — its Axion CPU and latest Trillium TPU — in its Cloud service.  At the same time, Google gave customers a teaser […]

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