Visual Abstract

Yadong Yu
Dec 1, 2020; 19:1997-2014
Research

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

Type I and III interferons induce expression of the “myxovirus resistance proteins” MxA in human cells and its ortholog Mx1 in murine cells. Human MxA forms cytoplasmic structures, whereas murine Mx1 forms nuclear bodies. Whereas both HuMxA and MuMx1 are antiviral toward influenza A virus (FLUAV) (an orthomyxovirus), only HuMxA is considered antiviral toward vesicular stomatitis virus (VSV) (a rhabdovirus). We previously reported that the cytoplasmic human GFP-MxA structures were phase-separated membraneless organelles (“biomolecular condensates”). In the present study, we investigated whether nuclear murine Mx1 structures might also represent phase-separated biomolecular condensates. The transient expression of murine GFP-Mx1 in human Huh7 hepatoma, human Mich-2H6 melanoma, and murine NIH 3T3 cells led to the appearance of Mx1 nuclear bodies. These GFP-MuMx1 nuclear bodies were rapidly disassembled by exposing cells to 1,6-hexanediol (5%, w/v), or to hypotonic buffer (40–50 mosm), consistent with properties of membraneless phase-separated condensates. Fluorescence recovery after photobleaching (FRAP) assays revealed that the GFP-MuMx1 nuclear bodies upon photobleaching showed a slow partial recovery (mobile fraction: ∼18%) suggestive of a gel-like consistency. Surprisingly, expression of GFP-MuMx1 in Huh7 cells also led to the appearance of GFP-MuMx1 in 20–30% of transfected cells in a novel cytoplasmic giantin-based intermediate filament meshwork and in cytoplasmic bodies. Remarkably, Huh7 cells with cytoplasmic murine GFP-MuMx1 filaments, but not those with only nuclear bodies, showed antiviral activity toward VSV. Thus, GFP-MuMx1 nuclear bodies comprised phase-separated condensates. Unexpectedly, GFP-MuMx1 in Huh7 cells also associated with cytoplasmic giantin-based intermediate filaments, and such cells showed antiviral activity toward VSV.

You might receive a Segmentation Violation when opening a database table in SAS. The SAS Log contains the error and traceback:

In SAS Life Science Analytics Framework 4.6, group membership removal fails with an exception if a user is set as assignee, a candidate, or a notification recipient in a user task for a Process Flow . The Process

In SAS Merchandise Financial Planning, custom time frame-based data versions do not aggregate correctly when referenced in worksheets with standard hierarchy levels. The data does not aggregate correctly from l

In SAS Customer Intelligence Studio,  when you add  Reply- node variable values in the Define Value dialog box, you might notice that two identically labeled data-grid variables are

When you log on to the SAS Risk Governance Framework and choose a solution, the web application might fail to load the solution content. When the problem occurs, you continue to see "Loading..." on the screen, an

Certain tables that are created in SAS Scalable Performance Data (SPD) Server might not be displayed correctly by SAS Federation Server Manager. Tables that have Latin5 characters in column names encounter this

This article has been withdrawn by the authors as part of this review overlapped with the contents of Pietrangelo A and Ridgway ND. 2018. Cellular and Molecular Life Sciences. 75; 3079-98.

AAA+ ATPases constitute a large family of proteins that are involved in a plethora of cellular processes including DNA disassembly, protein degradation and protein complex disassembly. They typically form a hexametric ring-shaped structure with six subunits in a (pseudo) 6-fold symmetry. In a subset of AAA+ ATPases that facilitate protein unfolding and degradation, six subunits cooperate to translocate protein substrates through a central pore in the ring. The number and type of nucleotides in an AAA+ ATPase hexamer is inherently linked to the mechanism that underlies cooperation among subunits and couples ATP hydrolysis with substrate translocation. We conducted a native MS study of a monodispersed form of PAN, an archaeal proteasome AAA+ ATPase, to determine the number of nucleotides bound to each hexamer of the WT protein. We utilized ADP and its analogs (TNP-ADP and mant-ADP), and a nonhydrolyzable ATP analog (AMP-PNP) to study nucleotide site occupancy within the PAN hexamer in ADP- and ATP-binding states, respectively. Throughout all experiments we used a Walker A mutant (PAN^K217A) that is impaired in nucleotide binding as an internal standard to mitigate the effects of residual solvation on mass measurement accuracy and to serve as a reference protein to control for nonspecific nucleotide binding. This approach led to the unambiguous finding that a WT PAN hexamer carried – from expression host – six tightly bound ADP molecules that could be exchanged for ADP and ATP analogs. Although the Walker A mutant did not bind ADP analogs, it did bind AMP-PNP, albeit at multiple stoichiometries. We observed variable levels of hexamer dissociation and an appearance of multimeric species with the over-charged molecular ion distributions across repeated experiments. We posit that these phenomena originated during ESI process at the final stages of ESI droplet evolution.

The development of the HUPO-PSI's (Proteomics Standards Initiative) standard data formats and MIAPE (Minimum Information About a Proteomics Experiment) guidelines should improve proteomics data sharing within the scientific community. Proteomics journals have encouraged the use of these standards and guidelines to improve the quality of experimental reporting and ease the evaluation and publication of manuscripts. However, there is an evident lack of bioinformatics tools specifically designed to create and edit standard file formats and reports, or embed them within proteomics workflows. In this article, we describe a new web-based software suite (The ProteoRed MIAPE web toolkit) that performs several complementary roles related to proteomic data standards. Firstly, it can verify the reports fulfill the minimum information requirements of the corresponding MIAPE modules, highlighting inconsistencies or missing information. Secondly, the toolkit can convert several XML-based data standards directly into human readable MIAPE reports stored within the ProteoRed MIAPE repository. Finally, it can also perform the reverse operation, allowing users to export from MIAPE reports into XML files for computational processing, data sharing or public database submission. The toolkit is thus the first application capable of automatically linking the PSI's MIAPE modules with the corresponding XML data exchange standards, enabling bidirectional conversions. This toolkit is freely available at http://www.proteored.org/MIAPE/.

Mass spectrometry-based glycoproteomics has gone through some incredible developments over the last few years. Technological advances in glycopeptide enrichment, fragmentation methods, and data analysis workflows have enabled the transition of glycoproteomics from a niche application, mainly focused on the characterization of isolated glycoproteins, to a mature technology capable of profiling thousands of intact glycopeptides at once. In addition to numerous biological discoveries catalyzed by the technology, we are also observing an increase in studies focusing on global protein glycosylation and the relationship between multiple glycosylation sites on the same protein. It has become apparent that just describing protein glycosylation in terms of micro- and macro-heterogeneity, respectively the variation and occupancy of glycans at a given site, is not sufficient to describe the observed interactions between sites. In this perspective we propose a new term, meta-heterogeneity, to describe a higher level of glycan regulation: the variation in glycosylation across multiple sites of a given protein. We provide literature examples of extensive meta-heterogeneity on relevant proteins such as antibodies, erythropoietin, myeloperoxidase and a number of serum and plasma proteins. Furthermore, we postulate on the possible biological reasons and causes behind the intriguing meta-heterogeneity observed in glycoproteins.

Nuclear Disarmament and the Protection of Cultural Heritage Research paper sysadmin 6 October 2017

States possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear-weapons doctrines and policies.

Summary

• Renewed risk assessments for nuclear weapons and policies are taking place around the world in light of nuclear modernization and the changing geostrategic environment that is making the use of nuclear weapons more likely. As such the humanitarian impacts of nuclear weapons and tests have received increased attention. However, the effect on cultural heritage has so far been neglected.
• The potential for armed conflict to destroy cultural heritage has been recognized in international law since 1954. There is significant evidence on the impact of nuclear weapons on cultural heritage including the consequences of their use in Hiroshima and Nagasaki and the effect of nuclear-testing programmes in places of cultural significance since 1945. States that possess nuclear weapons have increased liabilities and responsibilities to protect cultural heritage and cultural rights. The need to protect cultural heritage should strengthen the case for reducing and eliminating nuclear weapons.
• Failure to take into account the protection of heritage in the development of nuclear weapons policies – including disarmament, non-proliferation and arms-control negotiations – significantly undermines states’ existing commitments to protecting heritage threatened by conflict.
• Risk assessments of the impact of nuclear weapons on cultural heritage and important cultural artefacts – and methods of preventing such catastrophic damage – should be part of protecting cultural heritage in every country and the subject of informed public debate. A new body of knowledge on the full range of nuclear weapons impacts would introduce a fresh perspective to inform decision-makers, international organizations and the public in thinking about nuclear weapons policies and practices.
• Risk and resilience frameworks, which provide sets of solutions for risk assessments, would allow assessments of nuclear weapons threats to heritage and highlight vulnerabilities that need to be addressed. Such frameworks would provide a basis for policymakers to identify the world’s cultural heritage most at risk and help develop mitigation strategies to ensure that it is protected. In particular, states possessing nuclear weapons should be called upon to consider and publish the risks posed to cultural heritage, and their mitigation strategies, in their nuclear weapons doctrines and policies, as a contribution to transparency and confidence-building, and as a responsibility to the world’s shared heritage. International organizations, such as the UN Educational, Scientific, and Cultural Organization (UNESCO), have a role to play in bridging security perspectives with protecting cultural heritage.

Online Disinformation and Political Discourse: Applying a Human Rights Framework Research paper sysadmin 5 November 2019

Although some digital platforms now have an impact on more people’s lives than does any one state authority, the international community has been slow to hold to account these platforms’ activities by reference to human rights law.

This paper examines how human rights frameworks should guide digital technology.

Summary

• Online political campaigning techniques are distorting our democratic political processes. These techniques include the creation of disinformation and divisive content; exploiting digital platforms’ algorithms, and using bots, cyborgs and fake accounts to distribute this content; maximizing influence through harnessing emotional responses such as anger and disgust; and micro-targeting on the basis of collated personal data and sophisticated psychological profiling techniques. Some state authorities distort political debate by restricting, filtering, shutting down or censoring online networks.
• Such techniques have outpaced regulatory initiatives and, save in egregious cases such as shutdown of networks, there is no international consensus on how they should be tackled. Digital platforms, driven by their commercial impetus to encourage users to spend as long as possible on them and to attract advertisers, may provide an environment conducive to manipulative techniques.
• International human rights law, with its careful calibrations designed to protect individuals from abuse of power by authority, provides a normative framework that should underpin responses to online disinformation and distortion of political debate. Contrary to popular view, it does not entail that there should be no control of the online environment; rather, controls should balance the interests at stake appropriately.
• The rights to freedom of thought and opinion are critical to delimiting the appropriate boundary between legitimate influence and illegitimate manipulation. When digital platforms exploit decision-making biases in prioritizing bad news and divisive, emotion-arousing information, they may be breaching these rights. States and digital platforms should consider structural changes to digital platforms to ensure that methods of online political discourse respect personal agency and prevent the use of sophisticated manipulative techniques.
• The right to privacy includes a right to choose not to divulge your personal information, and a right to opt out of trading in and profiling on the basis of your personal data. Current practices in collecting, trading and using extensive personal data to ‘micro-target’ voters without their knowledge are not consistent with this right. Significant changes are needed.
• Data protection laws should be implemented robustly, and should not legitimate extensive harvesting of personal data on the basis of either notional ‘consent’ or the data handler’s commercial interests. The right to privacy should be embedded in technological design (such as by allowing the user to access all information held on them at the click of a button); and political parties should be transparent in their collection and use of personal data, and in their targeting of messages. Arguably, the value of personal data should be shared with the individuals from whom it derives.
• The rules on the boundaries of permissible content online should be set by states, and should be consistent with the right to freedom of expression. Digital platforms have had to rapidly develop policies on retention or removal of content, but those policies do not necessarily reflect the right to freedom of expression, and platforms are currently not well placed to take account of the public interest. Platforms should be far more transparent in their content regulation policies and decision-making, and should develop frameworks enabling efficient, fair, consistent internal complaints and content monitoring processes. Expertise on international human rights law should be integral to their systems.
• The right to participate in public affairs and to vote includes the right to engage in public debate. States and digital platforms should ensure an environment in which all can participate in debate online and are not discouraged from standing for election, from participating or from voting by online threats or abuse.

MLB Network's countdown of baseball's best players at each position continued with the third installment of the "Top 10 Right Now!" series, featuring the game's top left and center fielders.

American democracy in 2022: Trump, insurrection, and midterm elections 31 October 2022 — 2:00PM TO 3:00PM Anonymous (not verified) 7 October 2022 Online

How much has Donald Trump changed US politics and democracy, and will Trump and ‘Trumpism’ be more or less significant in the years ahead?

America’s democracy is divided, polarized and fragmenting. Inequality and internal division have a long history. But Trump’s lasting influence on the Republican party, and politics more broadly, continues to leave a mark. Repeated denials of President Joe Biden’s 2020 election win, wrapped in claims of electoral fraud, have eroded faith in the democratic institutions.

The memories of 6 January are still fresh, reminding all of the dangers posed by such actions. All told, America’s democracy has taken a beating in recent years.

To help make sense of the events over recent years and consequences for the coming mid-terms, Peter Baker and Susan Glasser (authors of The Divider: Trump in the White House 2017–2021) walk through in detail how the American politics of today has been arrived at.

Key questions discussed include:

• What has been learned from the January 6 Committee?

• Is there a likelihood of a similar event in the future?

• When and how will Trump lose his influence over the Republican party? 

• What are the broader ramifications of the Trump era?

• What did the events of 6 January mean for America’s relationships globally?

 As with all Chatham House member events, questions from members 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’

Private prison stocks soared Monday after President-elect Donald Trump announced immigration hardliner Tom Homan as the nation's next "border czar." GeoGroup jumped 4.5%, while CoreCivic increased 6.3%.

An American woman who was traveling in Hungary was killed in Budapest last week allegedly by a man she met on vacation.

The British parliament published an assisted-dying draft bill Tuesday that would give terminally ill adults with less than six months to live the legal right to end their lives with the help of medical professionals.

Alex Ovechkin calmly slid into the right circle and sniped a snapshot past a blinded Juuse Saros to lead the Washington Capitals to a 3-2 triumph over the Nashville Predators.

Linebacker Quinton Bell and Miami Dolphins defenders deleted drives and put the Los Angeles Rams offense in quicksand, holding them without a touchdown to propel a primetime victory and snap a three-game losing streak.

Gerry Faust, who won five Ohio high school football state titles before taking over as coach at Notre Dame in the early 1980s, has died, his family announced. He was 89.

A wallaby on the loose in Kentucky was caught on security camera during a nighttime visit to a Perry County family's front yard.

The National Toy Hall of Fame in Rochester, N.Y., announced this year's inductees: My Little Pony, Transformers and Phase 10.

A new study indicates what researchers describe as an ongoing "stubborn mistrust" in science among the American public as it relates to COVID-19 vaccines.

One of the most difficult problems with quantum computing relates to increasing the size of the quantum computer. Researchers globally are seeking to solve this “challenge of scale.” To bring […]

The post Recipe for Scaling: ARQUIN Framework for Simulating a Distributed Quantum Computing System appeared first on HPCwire.

President Joe Biden on Monday addressed a Veterans Day crowd at the national cemetery in Virginia where he revealed newly-expanded veteran benefits and urged Americans to "come together" and "keep faith."

Private prison stocks soared Monday after President-elect Donald Trump announced immigration hardliner Tom Homan as the nation's next "border czar." GeoGroup jumped 4.5%, while CoreCivic increased 6.3%.

Cameron Crowe, the writer and director behind "We Bought a Zoo," "Almost Famous" and "Jerry Maguire," has a new baby girl with girlfriend Anais Smith.

Netflix's hit docuseries "America's Sweethearts: Dallas Cowboys Cheerleaders" will return for a second season in 2025.

The Federal Aviation Administration has banned flights to-and-from Haiti for at least 30 days after JetBlue and Spirit Airlines planes were hit by gunfire Monday during attempts to land in Port-au-Prince.

Google is educating users about the lunar cycle with its latest interactive Doodle released Thursday.

Does your name suit your face? A study finds it is a kind of self-fulfilling prophecy.

One simple game is proving to be a surprising hero in the fight against PTSD.

What if AI could help connect you with the right medical care, exactly when you need it? Health systems entrepreneur, surgeon and TED Fellow Mohamed Aburawi explores how his digital health platform, Speetar, uses AI to bridge the healthcare gap in underserved regions, like his native Libya, by connecting patients with doctors who truly understand their needs.

When wildfires rage in California, incarcerated people are often on the front lines fighting the flames. TED Fellow Royal Ramey was one of them. He shares the story of how doing public service in prison inspired him to cofound the Forestry and Fire Recruitment Program, a nonprofit helping formerly incarcerated people become wildland firefighters — and find purpose along the way.

Bilingual individuals demonstrate different personality characteristics when speaking different languages. Marketers making media and language decisions when addressing multilingual markets should add this finding to their list of influencing factors.

The post Cultural Frame Switching: Different Language, Different Personality appeared first on Neuromarketing.