Elisa Vidal
Dec 1, 2020; 61:1733-1746
Research Articles

Yueming Hu
Dec 11, 2020; 0:jlr.RA120000919v1-jlr.RA120000919
Research Articles

For data that is being loaded from a SAS Stored Process Server, an insertion process might fail to a MySQL database with a warning, as well as an error message that says "During insert: Incorrect datetime value…"

Photoreceptors have high energy-demands and a high density of mitochondria that produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) of fuel substrates. Although glucose is the major fuel for central nervous system (CNS) brain neurons, in photoreceptors (also CNS), most glucose is not metabolized through OXPHOS but is instead metabolized into lactate by aerobic glycolysis. The major fuel sources for photoreceptor mitochondria remained unclear for almost six decades. Similar to other tissues (like heart and skeletal muscle) with high metabolic rates, photoreceptors were recently found to metabolize fatty acids (palmitate) through OXPHOS. Disruption of lipid entry into photoreceptors leads to extracellular lipid accumulation, suppressed glucose transporter expression, and a duel lipid/glucose fuel shortage. Modulation of lipid metabolism helps restore photoreceptor function. However, further elucidation of the types of lipids used as retinal energy sources, the metabolic interaction with other fuel pathways, as well as the crosstalk among retinal cells to provide energy to photoreceptors is not yet known. In this review, we will focus on the current understanding of photoreceptor energy demand and sources, and potential future investigations of photoreceptor metabolism.

Genetic variants that increase the risk of fatty liver disease (FLD) and cirrhosis have recently been identified in the proximity of membrane bound O-acyltransferase domain-containing 7 (MBOAT7).  To elucidate the link between these variants and FLD we characterized Mboat7 liver-specific knock-out mice (Mboat7-LSKO).  Chow-fed Mboat7-LSKO mice developed fatty livers and associated liver injury.  Lipidomic analysis of liver using mass spectrometry revealed a pronounced reduction in 20-carbon polyunsaturated fatty acid content in phosphatidylinositols (PIs), but not in other phospholipids. The change in fatty acid composition of PIs in these mice was associated with a marked increase in de novo lipogenesis due to activation of SREBP-1c, a transcription factor that coordinates the activation of genes encoding enzymes in the fatty acid biosynthesis pathway. Hepatic removal of both SREBP cleavage activating protein (Scap) and Mboat7 normalized hepatic triglycerides relative to Scap only hepatic knock-out showing increased SREBP-1c processing is required for Mboat7 induced steatosis.  This study reveals a clear relationship between PI fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.

Apolipoproteins C-I, C-II and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer’s disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1. delineate apoC-I, C-II and C-III isoform profiles in CSF and plasma in a cohort of non-demented older individuals (n = 61), and 2. examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared to matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two non-sialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF, and apoC-II in plasma and CSF, was observed in individuals carrying at least one apoE E4 allele. Increased apoC-I and apoC-II truncations were  associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of E4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE E4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer’s disease pathology with apoCs processing and function in the brain.

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1^fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1^fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1^fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.

Among the virulence factors in Neisseria infections, a major inducer of inflammatory cytokines is the lipooligosaccharide (LOS). The activation of NF-B via extracellular binding of LOS or lipopolysaccharide (LPS) to the toll-like receptor 4 and its coreceptor, MD-2, results in production of pro-inflammatory cytokines that initiate adaptive immune responses. LOS can also be absorbed by cells and activate intracellular inflammasomes, causing the release of inflammatory cytokines and pyroptosis. Studies of LOS and LPS have shown that their inflammatory potential is highly dependent on lipid A phosphorylation and acylation, but little is known on the location and pattern of these posttranslational modifications. Herein, we report on the localization of phosphoryl groups on phosphorylated meningococcal lipid A, which has two to three phosphate and zero to two phosphoethanolamine substituents. Intact LOS with symmetrical hexa-acylated and asymmetrical penta-acylated lipid A moieties was subjected to high-resolution ion mobility spectrometry MALDI-TOF MS. LOS molecular ions readily underwent in-source decay to give fragments of the oligosaccharide and lipid A formed by cleavage of the ketosidic linkage, which enabled performing MS/MS (pseudo-MS³). The resulting spectra revealed several patterns of phosphoryl substitution on lipid A, with certain species predominating. The extent of phosphoryl substitution, particularly phosphoethanolaminylation, on the 4'-hydroxyl was greater than that on the 1-hydroxyl. The heretofore unrecognized phosphorylation patterns of lipid A of meningococcal LOS that we detected are likely determinants of both pathogenicity and the ability of the bacteria to evade the innate immune system.

Spatial changes of FAs in the retina in response to different dietary n-3 formulations have never been explored, although a diet rich in EPA and DHA is recommended to protect the retina against the effects of aging. In this study, Wistar rats were fed for 8 weeks with balanced diet including either EPA-containing phospholipids (PLs), EPA-containing TGs, DHA-containing PLs, or DHA-containing TGs. Qualitative changes in FA composition of plasma, erythrocytes, and retina were evaluated by gas chromatography-flame ionization detector. Following the different dietary intakes, changes to the quantity and spatial organization of PC and PE species in retina were determined by LC coupled to MS/MS and MALDI coupled to MS imaging. The omega-3 content in the lipids of plasma and erythrocytes suggests that PLs as well as TGs are good omega-3 carriers for retina. However, a significant increase in DHA content in retina was observed, especially molecular species as di-DHA-containing PC and PE, as well as an increase in very long chain PUFAs (more than 28 carbons) following PL-EPA and TG-DHA diets only. All supplemented diets triggered spatial organization changes of DHA in the photoreceptor layer around the optic nerve. Taken together, these findings suggest that dietary omega-3 supplementation can modify the content of FAs in the rat retina.

Maikel Franco followed the endless and often mind-numbing speculation the past few months from the Dominican Republic. Franco knows that Manny Machado could show up at Spectrum Field at any moment. The Phillies entertained him at Citizens Bank Park just before Christmas. They have made him at least one contract offer. If the Phillies sign him, Franco also knows he could be traded.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

The next five weeks will see lots of shuffling on Major League rosters. Here are the most intriguing positional battles on each of the 30 MLB clubs.

Ramaphosa Has Won the Battle. But Can He Win the War? Expert comment sysadmin 21 December 2017

Cyril Ramaphosa is taking charge of South Africa’s ruling party, the ANC, at its weakest point in post-apartheid history. Expectations couldn’t be higher.

Ramaphosa ran for the leadership of the ANC on a platform of party renewal, economic recovery, and building the capacity of the state. But Jacob Zuma remains the President of South Africa and, under the constitution, can stay in office until elections in 2019. Therefore, meeting expectations on economic recovery will depend on Ramaphosa taking the presidency – and he has a number of political battles to face before that becomes reality.

To begin with, Ramaphosa and his supporters did not win a total victory at the elective conference. The presidency was only one position in the senior cadre – the co-called ‘top six’ – that was elected. This body is now split evenly between Ramaphosa and his allies, and those that supported his opponent Dr Nkosazana Dlamini-Zuma - Jacob Zuma’s preferred successor. This creates two centres of power in the ANC, limiting what Ramaphosa will be able to achieve from within the party.

Although there is significant pressure from the electorate to remove Zuma from national office, actually doing so will be difficult. Zuma’s predecessor Thabo Mbeki was removed from the national presidency before his term was up when the National Executive Committee (NEC) of the party recalled him from office following Zuma’s assumption of party leadership. But this option may not be available to Ramaphosa. The split within the ‘top six’ and new NEC will make it difficult to present an ultimatum to Zuma. His loyalists will not want a witch hunt within the party.

Corruption and elitism within the party

Much of the tension centres on questions of corruption, the dominant political issue in South Africa at the moment. In the build up to the elective conference Gwede Mantashe - now national chairperson - admitted that “The biggest challenge from where we’re sitting is the image and the reputation of the ANC. The ANC is seen as equal to corruption and looting.” Ramaphosa made anti-corruption initiatives a centrepiece of his campaign, including the establishment of a judicial commission and rapid action to investigate and prosecute the guilty.

But the split within the party may undermine the credibility of these promises. Ramaphosa’s problem is that some of the new ‘top six’ - including Deputy President David Mabuza, and Secretary General Ace Magashule – would be high on the list of those the electorate want to see investigated. Party resistance may restrict the extent to which Ramaphosa can demonstrate a comprehensive break from the past.

Corruption within the party goes far deeper than the headline cases of ‘state capture’ and expropriation. At a branch level, access to political power has become the primary means of access to economic resource. It is a process of selective patronage that differentiates between those who are ‘in’ from those who aren’t. At its broadest, this type of corruption has created a mistrust of the ANC and the new economic elite that the party has created around it – including Ramaphosa himself.

Having lost out to Mbeki in the fight to succeed Mandela despite being the favourite for the job, Ramaphosa spearheaded the ANC’s deployment of cadres in business. He has become one of the country’s richest men, and a highly sought after board member by South Africa’s largest companies across mining, telecoms, and logistics.

One of his biggest challenges will be to remove the perception of elitism as his senior position within the party and economy has given rise to mistrust from a grass roots level. The political tussle at the conference was also largely driven by a small number of the party elite being able to control large groups of delegate votes. The nature of political competition within the party is symptomatic of the ANCs electoral dominance in the early days of the nation’s democracy. But this support is now far less certain, and the party cannot afford to become complacent.

Resetting the relationship with business

Ramaphosa’s business dealings may mean he has to walk a fine line in censuring his colleagues for making money from politics. But it may also be a significant opportunity for the party to reset its relationship with the private sector. Under Mbeki, relations between the ANC and business were distant, but characterized by recognition of mutual dependence.

Under Zuma this relationship deteriorated, and the President demonstrated he was willing to make decisions to boost his political power irrespective of economic consequences. Ramaphosa could, for the first time, truly align the interests of business and government, without abandoning his transformative policy agenda.

At an ANC regional economic colloquium in Johannesburg in November Ramaphosa outlined his ten-point economic plan. It would deliver the party’s adopted mantra of ‘radical economic transformation’, but through broadly neo-liberal policies on private business development and state-owned enterprise reform to allow private capital to co-invest.

He took the ethos and principles of the Freedom Charter – the 1955 statement of core ANC principles – and applied them to a modernising economy. Talk of a ‘new deal’, productive partnerships in the mining sector, and an emphasis on job creation in manufacturing will woo investors. The rand surged upon his election.

But Ramaphosa will not be able to deliver on the economic demands of the country until he is in the office of the presidency - and Zuma still holds many of the cards. Ramaphosa can promise his followers potential power and government positions in future, but Zuma can still offer them now.

Removing Zuma will require skilful internal party politicking, and Ramaphosa will need to limit the fallout – he cannot afford to further damage the credibility of the party before it faces the electorate in 2019. He has won the battle, but the outcome of the war is far from certain.

Angola Forum 2018: 30th Anniversary of the Battle of Cuito Cuanavale 23 March 2018 — 10:00AM TO 2:30PM Anonymous (not verified) 8 March 2018 Chatham House, London

Reflections on Southern Africa’s Turning Point

23 March 2018 marks the 30th anniversary of the final assault of what became known as the Battle of Cuito Cuanavale.

The confrontation between the Angolan army, supported by Cuba and the Soviet Union, and the armed opposition UNITA, supported by the South African Defence Force, is the largest land battle to have taken place in Africa since World War Two.

The battle was a watershed in Angolan and southern African history, but its significance continues to be contested. Today, although the battlefield has a monument and museum, it remains one of the most landmine-contaminated parts of Angola and this hinders development plans for international tourism.

This event brings together veterans and experts to contribute towards developing a deeper understanding of the battle. Discussions will further focus on the significance of the wider events around the battle, its regional implications, as well as the legacy of the battlefield.

The battle for truth: The BBC's role at 100 22 November 2022 — 6:30PM TO 7:30PM Anonymous (not verified) 13 October 2022 Chatham House and Online

Tim Davie, director general of the BBC, and others discuss how the BBC shapes, and is shaped by, the world today.

This year, the BBC turns 100 and the World Service 90 in a world facing crises of increasing scale and frequency and in an age of disinformation, democratic disruption and a growing assault on truth and free reporting worldwide. What does this mean for Britain’s foremost news provider at home and across the globe?

This conversation considers:

• How does the BBC navigate a drastically changing media landscape?

• What does the BBC represent in the UK and to the world?

• What ‘soft power’ does the BBC have and how does it use it best?

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

Read the transcript. 

Mattel has apologized after inadvertently directing customers of its new line of Wicked dolls to a pornographic website, stating it is taking action to remove the misprinted toys' packaging.

SpaceX has reportedly struck a deal with LG Energy Solution Ltd. to supply cylindrical lithium-ion batteries for Elon Musk's Starship rocket, expected to launch early next year, according to industry sources.

Mattel has apologized after inadvertently directing customers of its new line of Wicked dolls to a pornographic website, stating it is taking action to remove the misprinted toys' packaging.

A boom in AI has created a problem for the organizers of the NeurIPS conference, which is considered an essential machine-learning research conference. The sheer number of registrations has overwhelmed […]

The post Lottery to Determine Major AI Conference Attendees Amid Registration Boom appeared first on HPCwire.

SpaceX has reportedly struck a deal with LG Energy Solution Ltd. to supply cylindrical lithium-ion batteries for Elon Musk's Starship rocket, expected to launch early next year, according to industry sources.

Film star Chris Pratt and his wife, author Katherine Schwarzenegger, have announced the birth of their third child.

A man drove a vehicle into a crowd at a sports center in Zhuhai, China, killing 35 people and injuring 43 others, police said.

The wreckage of the U.S. destroyer USS Edsall, sunk by Japanese forces more than 80 years ago during World War II, has been found at the bottom of the Indian Ocean, according to the U.S. Navy.

The Biden administration has sanctioned the West Darfur commander of the Rapid Support Forces on accusations that troops under his control have been responsible for violence targeting civilians.

NASA is inviting pubic participation in some virtual activities to watch the SpaceX space station resupply mission scheduled for a Monday night liftoff from NASA's Kennedy Space Center in Florida.

In this ode to improvisation, musician and comedian Reggie Watts beatboxes, raps, loops his own rhythms and reflects upon the everyday power of turning the mundane into magic. After all, he says, we're all just making it up as we go along.

TED Fellow and chemosensory researcher Paule Joseph unveils the hidden power of a sense that's too often overlooked: smell. She delves into the science behind smell — from how it evokes memory and emotion to its potential for early disease detection — and advocates for the creation of a baseline test for taste and smell that could open the door to more comprehensive health care.

Who says neuroscience can’t be fun? The toy giant Mattel makes Mindflex, a toy that lets players control a ping pong ball with their brain waves. I wrote about the toy way back in 2009, and was surprised to find it was still selling. It seemed like a gimmick when introduced, and I didn’t expect […]

The post Mattel Mindflex Game: Brain-controlled Neuro-Toy appeared first on Neuromarketing.

Attendance and login records show that Ohio's Electronic Classroom of Tomorrow was paid for 9,000 students more than it should have been, according to a state audit.

School boards play a critical role in steering the progress of the nation’s schools, but the relationship between school boards and school district leaders could be better.

Most school boards don’t look the students they serve, but new research suggests that must change.

Kentucky Attorney General Daniel Cameron has joined a private school in a lawsuit against Gov. Andy Beshear, arguing that a school closure order not only violated state law but also the First Amendment.

Cursive writing is experiencing a resurgence of sorts in North Carolina elementary schools thanks to a state law that was passed in 2013.

Kentucky Attorney General Daniel Cameron has joined a private school in a lawsuit against Gov. Andy Beshear, arguing that a school closure order not only violated state law but also the First Amendment.

Data suggest low-income communities are hit much harder than affluent ones, writes researcher Heather C. Hill.

Looking for new ways to combat kids who bully, some communities are threatening to fine parents with no evidence that the approach is effective.

Wisconsin is one of a handful of states where how much schools will get this fall is still being debated in the state capitol.

The Arkansas Department of Education will now provide on-site help for schools and districts in the state that are experiencing cybersecurity incidents.

Lawsuits are percolating nationwide as state officials, parents, teachers, and others clash over how and whether school buildings should reopen amid the continuing pandemic.

30-year-old was acquired in a trade for Timothy Liljegren, was pointless in seven games with San Jose this season

The state's highest court ruled that Washington's charter school law is mostly constitutional, and that charter schools can continue to receive public money.

A West Virginia official turns up the heat on financial disclosure for the state’s beleaguered schools, and ruffles feathers in the process.

Pope Francis will add his voice to the fight against hunger and malnutrition by addressing the Second International [...]

FAO Director-General José Graziano da Silva will be away from Rome during the next few weeks. During this period he will be involved in a range of [...]