(Oct. 17) When Vice President Kamala Harris repeated on Oct. 15 that she thinks the idea of racial “reparations” should be studied further, she evinced a radicalism she just can’t […]

The post Harris is open to ‘reparations.’ It’s ore proof she’s a radical. appeared first on Quin Hillyer.

The world lost an incredible talent with the death of Tomie dePaola. 

A few tips for ensuring that students—particularly those with disabilities and English learners—and their families get the year off to a good start.

See the full guide Preparing Young Children for School Practice Guide › Recent research has identified practices that have the potential to prepare young children to benefit from the learning opportunities they will encounter in school.

The Gauteng education department has postponed the appointment of new office-based staff as well as teachers who applied to be promoted as heads of department, deputy principals and principals until April because of budget constraints.

AI is everywhere—we’re in a middle of a technology shift that’s as big as (and possibly bigger than) the arrival of the web in the 1990s. Even though ChatGPT appeared almost two years ago, we still feel unprepared: we read that AI will change every job, but we don’t know what that means or how […]

IDC released its Worldwide Quarterly Server Tracker on September 2, 2009, which reports that "factory revenue in the worldwide server market declined 30.1% year over year to $9.8 billion in the second quarter of 2009 (2Q09)."

According to IDC, this is the lowest quarterly server revenue since they began tracking this market in 1996.

The obvious implication is that the economy has been awful and companies have been avoiding / deferring IT spend. But beyond that it seems that virtualization has both benefited from and contributed to this decline.

With a single server now able to run multiple workloads, it seems inevitable that the server footprint is destined to continue getting smaller within the corporate data center. But the benefits of virtualization do not stop with simply running more apps on one machine; the whole datacenter becomes more agile, more flexible to deal with unexpected changes in workload.

The ability to get more from fewer boxes is certainly a contributing factor to less boxes being bought. And tight budgets in the 2009 economy have certainly contributed to IT managers seeking out less costly options.

It will be interesting to see how the server market rebounds.

Andy Patrizio in his InternetNews.com blog quotes Rahul Agarwal, co-founder of Infiniti Research. Within the dismal sales figures, Agarwal notes that both Gartner and IDC report that unit costs are going up for server sales. Agarwal believes that this is due to sellers trying to widen margins by selling more feature-rich machines:

Our view is that to offset this volume pressure, hardware vendors will be
forced to improve unit margins by building in virtualization capability, memory
and I/O interfaces in the hardware.

The server market of tomorrow will be a value game and not a volume game.

In a surprise move that broke in the early hours of Tuesday morning, President-elect Donald Trump has reportedly picked South Dakota Gov. Kristi Noem as his nominee to head the […]

The post Trump Makes His Pick for Secretary of the Department of Homeland Security Secretary: Report appeared first on The Western Journal.

CNN reportedly will be making more cuts in the near future, including to its highly paid on-air personalities, following poor election ratings. The New York Post reported that Fox News […]

The post On-Air Talent Will Not Be Spared as CNN Prepares Mass Layoffs in Wake of Election: Report appeared first on The Western Journal.

Xi Jinping prepares the Communist party for new reality Expert comment NCapeling 20 October 2022

Political report reflects a worsened economic and diplomatic position as Xi knows his unprecedented third term as leader will be judged on results.

In stark contrast to the aura of triumphant glory that greeted Xi Jinping at the last National Congress of the Chinese Communist Party in 2017, this week’s convocation opened with an air of sobriety.

Amid a domestic economic downturn and a return to enmity with Western liberal democracies, Xi offered his own recipe for party legitimacy and the country’s economic survival in the lengthy executive summary of his political report to the CCP congress. The prime keyword was security, with some 73 mentions, underscored with a message of self-reliance.

The periodic report acts as a summary of the party’s achievements and of its future plans, with both expressed as the lowest common denominator of consensus between competing voices in the CCP. It thus typically sheds some light on relationships among senior party members and insights into the political fortunes of important intraparty groups.

Most portions of the new report combined Xi’s personal preferences with concessions to the reality of what is necessary for China’s economic survival. Both ends point to an urgent prioritization of economic and political self-reliance for Xi’s third term as party general secretary.

Holistic concept of security

On the domestic front, much emphasis was given to enhancing national security and promoting equitable growth.

Since even before COVID-19, Xi has advocated a holistic conceptualization of security that includes food, the internet, energy and manpower. Reflecting Beijing’s deep anxieties about high-tech development and its frustrations with dependence on overseas suppliers vulnerable to the vagaries of geopolitical tensions, the political report noted the need for China’s supply chains to become more “self-determined and self-controlled.”

Xi, though, went further to stress the importance of improving scientific education and grooming and attracting the necessary talent to accelerate China’s quest to achieve breakthroughs in semiconductor production and overcome development choke points created by Western technological monopolies.

As China has traditionally relied on connectivity with the rest of the world to support innovation and attract talent, a turn toward autarky is not a viable option, given Xi’s technological priorities. Yet the renewed mention of his ‘dual circulation’ strategy in the report signals that Beijing is indeed turning to domestic consumption and homegrown technological prowess as the means to provide the rising wealth that the Chinese people have come to expect from the Communist Party.

Worsening Sino-US relations and tightening access to overseas markets for Chinese companies have prompted party leaders not only to reconsider the country’s sources of economic growth but have also forced them to reconfigure their approach to foreign affairs.

Judging by his report summary, Xi has completely abandoned the ‘new type of great power relations’ concept used repeatedly in the last two editions of his congressional update to refer to his preferred approach to relations with the US-led West.

The omission shows that Beijing has concluded that its fraught relationship with advanced developed nations is here to stay, with little prospect of improvement soon. To this end, China needs to prepare for the worst of decoupling and become more self-reliant in terms of markets and technologies.

In place of the discarded concept, Xi stressed that China should further develop its ties with the global South through the Global Development Initiative and the Global Security Initiative he announced earlier this year. These efforts aim to reshape the global governance agenda in multilateral forums and to project Beijing’s influence on the developing world.

Meanwhile, the party’s latest official rhetoric about the Belt and Road Initiative shows it is no longer a one-size-fits-all slogan but on its way to becoming a genuine tool of trade and investment promotion with China’s near neighbors but with provincial governments taking the lead rather than Beijing.

With the central government grappling with the country’s domestic economic woes, its spending spree on development assistance has had to come to an end. The new political report clearly signals this change.

A modern socialist society is still the aim

The current economic downturn and dangerous geopolitical tensions have not dented the CCP’s ambitions to build a modern socialist society by 2035 and thus join the world’s club of upper middle-income countries, but this is easier said than done.

The G20 will survive but needs major repair Expert comment NCapeling 15 November 2022

Russia’s attack on Ukraine is the biggest challenge to the existence of the G20 since its foundation.

The leader-level version of the G20 was founded in 2008 to coordinate the international response to the global financial crisis across advanced and major emerging economies.

At the outset it was judged a great success. The 2009 London Summit demonstrated a high degree of unity among the world’s largest economies on a comprehensive action plan to tackle the crisis.

The group’s subsequent performance has disappointed. Particularly during the pandemic and the Donald Trump presidency in the US, the group made only a limited additional contribution to policies which national governments were pursuing in any case.

Nonetheless, its members continued to see it as an essential forum without which it would be even harder to tackle a growing list of global economic challenges. This faith was partly repaid when, following the election of the Joe Biden administration in the US, agreement was reached on the $650 billion special drawing rights (SDR) general allocation by the International Monetary Fund (IMF) in summer 2021.

Impact of the war in Ukraine

Following Russia’s attack on Ukraine earlier this year, leading western members of the group called for Russia to be suspended from the G20 as Russia’s action ran directly against the key principles of the rules-based international system on which the G20 was founded.

Western countries also walked out of meetings of the G20 Finance Ministers’ and International Monetary and Financial Committee this spring rather than sit at the same table as Russian representatives.

This contrasted with 2014 when Russia was suspended indefinitely from the G7 for its takeover of Crimea but no action was taken against it in the G20.

However, China and India, supported by several other emerging economies declined to suspend Russia, creating a standoff which could have resulted in a rapid collapse of the G20, particularly as its informal structure means that, in contrast to the international financial institutions (IFIs), there are no legal principles or procedures to determine how to address such a situation.

It appears the West has now concluded (rightly) that the G20 is too important as a forum for working with China and the other major emerging economies to be allowed to disappear.

This is likely to be because there are no straightforward alternatives. The G7 is too narrow to fill the role and China is now highly unlikely to attend a future G7 Summit as a guest. The boards of the IFIs are not equipped to coordinate across institutions, which is a vital role of the G20, and the United Nations (UN) system does not offer the scope, speed, leader-level engagement, or flexibility of the G20.

Moreover, as evidenced by the chair’s summary of the third G20 Finance Ministers’ and Central Bank Governors’ meeting in July, once the group gets past the dispute over how to handle Russia, there is a worthwhile agenda of issues which can be agreed on.

As the 2022 president of the G20, Indonesia has been determined to produce a final communique for the leaders’ summit and it looks increasingly like this will be achieved, even though it was impossible to agree concluding statements for some earlier G20 ministerial meetings.

The key will be to deal with the differences over Ukraine between the West and emerging economies with a short opening paragraph reflecting both views. This would then be followed by a consensus text on all the areas where the two groups do agree.

Russia is unlikely to play a disruptive role as preserving its membership of the group will be its key objective, and it will not want to undermine support among other emerging economies by blocking issues that all agree on.

However, even with a final communique achieved, returning to a fully functioning agenda setting, coordination, and decision-making role for G20 will be very challenging, particularly while the war in Ukraine continues.

Tackling sovereign debt distress should be a top priority

There are critically important issues on which G20 action is urgently needed. Top of the list is the acute problem of sovereign debt distress. Some 60 per cent of low-income countries are now judged to be in debt distress or at high risk of debt distress.

But the existing G20 approach for tackling debt distress in low-income countries, the ‘Common Framework’, is progressing far too slowly, and there is no agreed mechanism for handling the growing list of emerging economies in debt distress.

Without tackling debt distress, it is extremely hard to see how it will be possible to generate the vast flow of private sector climate finance necessary to help the developing world progress to net zero.

And yet the G20 is one of the few forums in which a high-level approach to debt distress can be defined because China – along with the IFIs and the western-based private sector – is a key player in any solution.

Urgent repairs needed

However, there is a critical lack of trust among G20 participants which, although in part a reflection of the disagreements over handling Russia, is also about longer-term factors such as the growing geopolitical tensions between China and the US on trade and investment in high tech.

An example of how this has played out was the action China and India took at the Rome G20 Summit in 2021 in blocking Italy’s efforts to establish a new ministerial task force designed to address the threat of future pandemics – a subject which all G20 countries agree is important.

Jennifer L. Macdonald
May 1, 2005; 46:1061-1067
Methods

JL Dixon
Feb 1, 1993; 34:167-179
Reviews

Robert W. Mahley
Jan 1, 1999; 40:1-16
Reviews

William R. Morrison
Oct 1, 1964; 5:600-608
Articles

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

Shoham Letzter
Trans. Amer. Math. Soc. 377 (), 5583-5615.
Abstract, references and article information

Christian Weiss
Theor. Probability and Math. Statist. 111 (), 199-209.
Abstract, references and article information

The Math Community Educational Outreach (Math CEO) program at the University of California, Irvine (UCI) will receive the 2025 AMS Award for an Exemplary Program or Achievement in a Mathematics Department.

Founded in 2014, UCI’s Math CEO is an after-school math enrichment program aimed at increasing the number of talented students in STEM from diverse backgrounds by fostering mathematical exploration, mentor development, and community engagement.

From the citation

The University of California, Irvine (UCI) Math CEO program is recognized for its exceptional contributions to the mathematics community and society at large. Established in 2014 by professors Alessandra Pantano and Li-Sheng Tseng, Math CEO targets students from Title I middle schools, providing them with a high-quality after-school math enrichment program. This program brings middle-school students to the UCI campus to work in small groups with undergraduate mentors, many of whom are also from historically marginalized groups, to engage in challenging mathematical tasks and encourage exploration. 

From September 2019 to June 2024, Math CEO engaged a total of 1,221 youth, with 48.6% identifying as female. The ethnic background of the participants was predominantly Latinx (93.5%), with smaller representations of Asian, white, and multiethnic students. In the same five-year period, Math CEO engaged 553 undergraduate mentors, 62.2% of whom were female. The mentors’ ethnic backgrounds were diverse, with significant representation of Asian (52%) and Latinx (30%) students. The undergraduate mentors, many of whom pursue careers in education, receive training in culturally responsive teaching practices and equity in education, significantly impacting their professional development. In a post-survey, 52.3% of the undergraduate mentors expressed interest in teaching or working in education and 45.9% were likely to pursue professions working with children or families.

Recognizing the central role of families in supporting Latinx youth, Math CEO involves parents through bilingual workshops that enhance community awareness of college pathways and financial opportunities. 

Math CEO has been the foundation for numerous research projects in mathematics education, supported by NSF grants, leading to publications and program growth. The program’s success is evident in its expansion to high schools and other regions in Southern California, including a new branch at California State University, Dominguez Hills. Math CEO continues to make a substantial impact on underserved youth, demonstrating a model of systemic, reproducible change that can be implemented by others.

Response of Alessandra Pantano, UCI Math CEO

I am deeply honored to receive the AMS Award for an Exemplary Program in a Mathematics Department on behalf of the UCI Math CEO team. This wonderful award recognizes the work of many colleagues, graduate students, and undergraduate students in developing and delivering the UCI Math Community Educational Outreach (Math CEO) program. For over a decade, Math CEO has provided creative and culturally responsive math enrichment opportunities for hundreds of underprivileged middle-school students, many of which have since “graduated” to high school or even college. Leading this exceptional and dedicated team of volunteers has been the highest pride of my professional life. A special thanks to my partners-in-crime, Prof. Li-Sheng Tseng, codirector of Math CEO, and former graduate student Andres Forero Cuervo, academic coordinator for Math CEO: We could have never done this without you. I look forward to pushing this activity forward and continuing to dedicate my energy to help kids in our county find the way to express their potential – in math and in life! A big thanks to the colleagues who nominated us and to the AMS for recognizing our efforts.  

History of the program

The UC Irvine Math Community Educational Outreach (Math CEO) program was founded in 2014 by math faculty Alessandra Pantano and Li-Sheng Tseng in collaboration with Santa Ana Unified math teacher Jasmina Matasovic. The founders shared a belief that low standardized test scores in underserved communities do not reflect students’ interest and potential to succeed in STEM. Math CEO runs free, weekly, after-school math enrichment sessions, welcoming all youth regardless of math achievement. Starting with only 25 students from one middle school, the program has grown and engaged nearly two thousand students in all, from multiple school districts in Southern California.

About the award

The annual AMS Award for an Exemplary Program or Achievement in a Mathematics Department was established in 2004 and first given in 2006. This award recognizes a department which has distinguished itself by undertaking an unusual or particularly effective program of value to the mathematics community, internally or in relation to the rest of society. Departments of mathematical sciences in North America that offer at least a bachelor’s degree in mathematical sciences are eligible. The award amount is currently $5,000. The award will be presented at the 2025 Joint Mathematics Meetings in Seattle.

Learn more about the award and previous recipients.

Contact: AMS Communications.

*****

The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs.
 

CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational switch in the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol-sensing mechanism; however, its relevance for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81–cholesterol association but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol-unbound) or closed (cholesterol-bound) conformation. The open mutant of CD81 exhibited reduced HCV receptor activity, whereas the closed mutant enhanced activity. These data are consistent with cholesterol sensing switching CD81 between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81–partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry, and CD81's function as a molecular scaffold; these insights are relevant to CD81's varied roles in both health and disease.

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

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

Yi Liu
Dec 1, 2020; 19:1968-1985
Research

Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid (GC)-induced liver damage model of mice, found that GC stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that GC stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.

Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of key proteins involved in ERAD increased cell death under both basal conditions and in response to proinflammatory cytokines, a situation frequently found in NAFLD. Decreased viability of ERAD-deficient HepG2 cells was traced to impaired mitochondrial functions including reduced ATP production, enhanced reactive oxygen species (ROS) accumulation, and increased mitochondrial outer membrane permeability. Transcriptome profiling revealed widespread down-regulation of genes underpinning mitochondrial functions, and up-regulation of genes associated with tumor growth and aggression. These results highlight a critical role for ERAD in maintaining mitochondrial functional and structural integrity and raise the possibility of improving cellular and organismal mitochondrial function via enhancing cellular ERAD capacity.

Thibaut Bourgeois
Dec 11, 2020; 0:jlr.RA120000737v1-jlr.RA120000737
Research Articles

Abudukadier Abulizi
Dec 1, 2020; 61:1565-1576
Research Articles

Stacey N Keenan
Dec 17, 2020; 0:jlr.RA120001126v1-jlr.RA120001126
Research Articles

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.

Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these organs, LPCAT3 critically supports cell membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3’s role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approx. 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid [AA]) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr-/-) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.

Perilipin (PLIN) 5 is a lipid droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155, S161 and S163 of recombinant PLIN5 by PKA in vitro and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation compared with cells expressing wildtype PLIN5. These differences in lipid metabolism were not associated with differences in the cellular distribution of PLIN5. Rather, FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase (ATGL) at the lipid droplet, but not with the co-activator of ATGL, α-β hydrolase domain-containing 5 (ABHD5). Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis when compared to mice with wildtype PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism, such as fatty acid oxidation, de novo lipogenesis and triglyceride secretion. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of CVDs, and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affects atherosclerosis progression in the atheroprone LDLR-deficient mice. Compared with control-fed Ldlr^–/– mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr^–/–/Bco1^–/– mice despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp^–/–) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp^–/– mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp^–/– mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKC activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp^–/– mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKC activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp^–/– mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKC activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp^–/– mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp^–/– mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp^–/– mice.

Mallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-B activation. However, the precise mechanism that links protein aggregation to NF-B-activation and inflammatory response remains unclear. Herein we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin (NMPP), protoporphyrin IX (PPIX), or Zinc-protoporphyrin IX (ZnPP)) elicited an IBα-loss with consequent NF-B activation. Four known mechanisms of IBα-loss i.e. the canonical ubiquitin-dependent proteasomal degradation (UPD), autophagic-lysosomal degradation, calpain degradation and translational inhibition, were all probed and excluded. Immunofluorescence analyses of ZnPP-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IBα-loss was due to its sequestration along with IBβ into insoluble aggregates, thereby releasing NF-B. Through affinity pulldown, proximity biotinylation by antibody recognition, and other proteomic analyses, we verified that NF-B subunit p65, which stably interacts with IBα under normal conditions, no longer binds to it upon ZnPP-treatment. Additionally, we identified 10 proteins that interact with IBα under baseline conditions, aggregate upon ZnPP-treatment, and maintain the interaction with IBα after ZnPP-treatment, either by cosequestering into insoluble aggregates or through a different mechanism. Of these 10 proteins, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as mediators of IBα-nuclear import. The concurrent aggregation of IBα, NUP153, and RanBP2 upon ZnPP-treatment, synergistically precluded the nuclear entry of IBα and its consequent binding and termination of NF-B activation. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thus identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.

Withdrawn by Author.

We developed a simple and rapid method to enrich protein N-terminal peptides, in which the protease TrypN is first employed to generate protein N-terminal peptides without Lys or Arg and internal peptides with two positive charges at their N-termini, and then the N-terminal peptides with or without N-acetylation are separated from the internal peptides by strong cation exchange chromatography according to a retention model based on the charge/orientation of peptides. This approach was applied to 20 μg of human HEK293T cell lysate proteins to profile the N-terminal proteome. On average, 1,550 acetylated and 200 unmodified protein N-terminal peptides were successfully identified in a single LC/MS/MS run with less than 3% contamination with internal peptides, even when we accepted only canonical protein N-termini registered in the Swiss-Prot database. Since this method involves only two steps, protein digestion and chromatographic separation, without the need for tedious chemical reactions, it should be useful for comprehensive profiling of protein N-termini, including proteoforms with neo-N-termini.

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.

In nucleotide excision repair, bulky DNA lesions such as UV-induced cyclobutane pyrimidine dimers are removed from the genome by concerted dual incisions bracketing the lesion, followed by gap filling and ligation. So far, two dual-incision patterns have been discovered: the prokaryotic type, which removes the damage in 11–13-nucleotide-long oligomers, and the eukaryotic type, which removes the damage in 24–32-nucleotide-long oligomers. However, a recent study reported that the UvrC protein of Mycobacterium tuberculosis removes damage in a manner analogous to yeast and humans in a 25-mer oligonucleotide arising from incisions at 15 nt from the 3´ end and 9 nt from the 5´ end flanking the damage. To test this model, we used the in vivo excision assay and the excision repair sequencing genome-wide repair mapping method developed in our laboratory to determine the repair pattern and genome-wide repair map of Mycobacterium smegmatis. We find that M. smegmatis, which possesses homologs of the Escherichia coli uvrA, uvrB, and uvrC genes, removes cyclobutane pyrimidine dimers from the genome in a manner identical to the prokaryotic pattern by incising 7 nt 5´ and 3 or 4 nt 3´ to the photoproduct, and performs transcription-coupled repair in a manner similar to E. coli.

Homologous recombination (HR) repairs DNA double-strand breaks using intact homologous sequences as template DNA. Broken DNA and intact homologous sequences form joint molecules (JMs), including Holliday junctions (HJs), as HR intermediates. HJs are resolved to form crossover and noncrossover products. A mismatch repair factor, MLH3 endonuclease, produces the majority of crossovers during meiotic HR, but it remains elusive whether mismatch repair factors promote HR in nonmeiotic cells. We disrupted genes encoding the MLH3 and PMS2 endonucleases in the human B cell line, TK6, generating null MLH3−/− and PMS2−/− mutant cells. We also inserted point mutations into the endonuclease motif of MLH3 and PMS2 genes, generating endonuclease death MLH3DN/DN and PMS2EK/EK cells. MLH3−/− and MLH3DN/DN cells showed a very similar phenotype, a 2.5-fold decrease in the frequency of heteroallelic HR-dependent repair of restriction enzyme–induced double-strand breaks. PMS2−/− and PMS2EK/EK cells showed a phenotype very similar to that of the MLH3 mutants. These data indicate that MLH3 and PMS2 promote HR as an endonuclease. The MLH3DN/DN and PMS2EK/EK mutations had an additive effect on the heteroallelic HR. MLH3DN/DN/PMS2EK/EK cells showed normal kinetics of γ-irradiation–induced Rad51 foci but a significant delay in the resolution of Rad51 foci and a 3-fold decrease in the number of cisplatin-induced sister chromatid exchanges. The ectopic expression of the Gen1 HJ re-solvase partially reversed the defective heteroallelic HR of MLH3DN/DN/PMS2EK/EK cells. Taken together, we propose that MLH3 and PMS2 promote HR as endonucleases, most likely by processing JMs in mammalian somatic cells.

Mugabe’s Departure Ushers in a Heady New Era for Zimbabwe Expert comment sysadmin 23 November 2017

The country is experiencing an almost unprecedented convergence, with traditional political, economic and social fault lines bridged as Zimbabweans make common cause for change.

The ecstatic scenes said it all – Zimbabweans around the world are celebrating the resignation of Robert Mugabe as president. In January 1980, hundreds of thousands of Zimbabweans thronged Zimbabwe Grounds stadium in Highfields township, Harare, to welcome Mugabe back from exile. In March 1980, with reggae icon Bob Marley and Britain’s Prince Charles in attendance, thousands filled Rufaro Stadium to witness the handover from Rhodesia to the new nation of Zimbabwe. Thirty-seven years later, the largest crowds Harare has ever witnessed flooded the streets once again; not to welcome Mugabe in, but to see him out. One simple, taut phrase summed up the day’s events: ‘This is our second independence day.’

How did it come to this?

History has been put on fast-forward, and left Zimbabwe – and the world – shaken. Just two weeks ago, it seemed to be the height of folly to think that Mugabe would leave office on any but his own terms. Emmerson Mnangagwa had been sacked as vice president, and his followers had been purged. Grace Mugabe, with ringing endorsements from the women’s and youth leagues, looked set to be elevated to the vice presidency at the ZANU-PF congress in less than a month’s time.

Mugabe was expected to stay until the 2018 elections, after which he would hand over the presidency to his wife. It was the prospect of Grace Mugabe becoming Zimbabwe’s next president which brought in the military. Aware that they had three weeks or less to prevent a dynastic succession and a looming purge of the military itself, Zimbabwe’s military chose, not the audacity of hope, but the hope of audacity, and launched Operation Restore Legacy to stop the rot.

What has happened in Zimbabwe is not a people’s revolution in the traditional sense. The Bourbons in France, the Romanov dynasty in Russia, the Shah of Iran, and the autocrats of north Africa’s Arab Spring were all felled by continuous street protests which ultimately received the support of the military.

In Zimbabwe it has been the military who have been the drivers of revolutionary change. What has happened is that an internal party-factional power struggle has inadvertently led to a military-guided popular revolution and the ousting of the Mugabes. Zimbabwe’s military, often seen as the guardians of the state, became instead the guardians of the people. They are seen, for now at least, as liberators, and national heroes. This has been a very Zimbabwean revolution.

So what next?

These are heady days. Zimbabwe is experiencing an almost unprecedented national convergence, with traditional political, economic and social fault lines bridged as Zimbabweans make common cause for change. It is not quite a ‘Zimbabwe Spring’, but it is perhaps a ‘Zimbabwe Sunrise’.

Parliament, which on Tuesday had met to impeach Robert Mugabe, is now installing, through constitutional procedures, Emmerson Mnangagwa as president, who will be given the mandate to form an interim government. Mnangagwa will be further ratified at the ZANU-PF Congress in December where he will be named and acclaimed as ZANU-PF’s candidate for the next general elections, which constitutionally are due by mid-2018 (although it is unclear whether this will indeed be the case).

Mnangagwa has a full in-tray. He needs to form a government quickly and has to balance the need for inclusivity and consultation, with the undoubted pressure to reward his followers. With Zimbabwe’s economy nearing paralysis, Zimbabwe’s new president will be under pressure to deliver. Although many are nervous about his history as Mugabe’s ally and his reputation for toughness, Mnangagwa is also an astute political survivor, and has been pro-business and supportive of Zimbabwe’s ongoing re-engagement with the global community.

Zimbabwe has become a cashless society not by design, but by default; with formal unemployment at 80 per cent and with a largely informalized economy in which much of Zimbabwe’s citizenry have been reduced to penury and classic short-termism, there is plenty for Zimbabwe’s next president to think about. Activists wonder whether he will try to introduce systemic change, or merely go through the motions. He may well face a binary choice between government or governance.

And yet there are also positives. Zimbabwe’s institutions have proven to be resilient, and there is still a reservoir of dedicated and competent professionals in both public and private sectors. Although still laggardly, Zimbabwe had begun to progress in ‘ease of doing business’ indices. There is a large diaspora who have continued to engage with Zimbabwe; and Zimbabwe’s recent ‘Look East’ and de facto ‘Look West’ re-engagement policies can be built upon.

Many are urging caution and saying that Zimbabwe needs a second, truly democratic revolution. Perhaps. But right now, Mnangagwa should be given a chance. Farai, a friend of mine in Harare, said this: ‘Yes we know this euphoria may be short-lived. But even if it turns out that we were only happy for a day, let’s make it a brilliant day. Rega tifare nhasi (Let us be happy today).’

A version of this article was first published by the Guardian.

To date, the imaging and diagnosis of hepatocellular carcinoma (HCC) rely on CT/MRI, which have well-known limitations. Glypican-3 (GPC3) is a cell surface receptor highly expressed by HCC but not by normal or cirrhotic liver tissue. Here we report initial clinical results of GPC3-targeted PET imaging with [⁶⁸Ga]Ga-DOTA-RYZ-GPC3 (RAYZ-8009), a peptide-based GPC3 ligand in patients with known or suspected HCC. Methods: [⁶⁸Ga]Ga-RAYZ-8009 was obtained after labeling the peptide precursor with ⁶⁸Ga from a ⁶⁸Ge/⁶⁸Ga generator and heating at 90°C for 10 min followed by sterile filtration. After administration of [⁶⁸Ga]Ga-RAYZ-8009, a dynamic or static PET/CT scan was acquired between 45 min and 4 h after administration. Radiotracer uptake was measured by SUVs for the following tissues: suspected or actual HCC or hepatoblastoma lesions, non–tumor-bearing liver, renal cortex, blood pool in the left ventricle, and gastric fundus. Additionally, tumor–to–healthy-liver ratios (TLRs) were calculated. Results: Twenty-four patients (5 patients in the dynamic protocol; 19 patients in the static protocol) were scanned. No adverse events occurred. Two patients had no lesion detected and did not have HCC during follow-up. In total, 50 lesions were detected and analyzed. The mean SUV_max of these lesions was 19.6 (range, 2.7–95.3), and the mean SUV_mean was 10.1 (range, 1.0–49.2) at approximately 60 min after administration. Uptake in non–tumor-bearing liver and blood pool rapidly decreased over time and became negligible 45 min after administration (mean SUV_mean, <1.6), with a continuous decline to 4 h after administration (mean SUV_mean, 1.0). The opposite was observed for HCC lesions, for which SUVs and TLRs continuously increased for up to 4 h after administration. In individual lesion analysis, TLR was the highest between 60 and 120 min after administration. Uptake in the gastric fundus gradually increased for up to 45 min (to an SUV_max of 31.3) and decreased gradually afterward. Conclusion: [⁶⁸Ga]Ga-RAYZ-8009 is safe and allows for high-contrast imaging of GPC3-positive HCC, with rapid clearance from most normal organs. Thereby, [⁶⁸Ga]Ga-RAYZ-8009 is promising for HCC diagnosis and staging. Further research is warranted.

President-elect Donald Trump announced Tuesday that Elon Musk and Vivek Ramaswamy will lead his administration's new Department of Government Efficiency, or DOGE, to end "government waste" and "slash excess regulations."

It will cost $55.7 million to repair Tropicana Field, home to the MLB Tampa Bay Rays, in time for the 2026 home opener, St. Petersburg., Fla., city officials said Tuesday.

President-elect Donald Trump has chosen former Republican Rep. Lee Zeldin of New York to run the Environmental Protection Agency.