Sonu Shrestha Baral, Molly E. Lieux, and Patrick J. DiMario

Different stem cells or progenitor cells display variable threshold requirements for functional ribosomes. This is particularly true for several human ribosomopathies in which select embryonic neural crest cells or adult bone marrow stem cells, but not others, show lethality due to failures in ribosome biogenesis or function (now known as nucleolar stress). To determine if various Drosophila neuroblasts display differential sensitivities to nucleolar stress, we used CRISPR-Cas9 to disrupt the Nopp140 gene that encodes two splice variant ribosome biogenesis factors (RBFs). Disruption of Nopp140 induced nucleolar stress that arrested larvae in the second instar stage. While the majority of larval neuroblasts arrested development, the mushroom body (MB) neuroblasts continued to proliferate as shown by their maintenance of deadpan, a neuroblast-specific transcription factor, and by their continued EdU incorporation. MB neuroblasts in wild-type larvae appeared to contain more fibrillarin and Nopp140 in their nucleoli as compared to other neuroblasts, indicating that MB neuroblasts stockpile RBFs as they proliferate in late embryogenesis while other neuroblasts normally enter quiescence. A greater abundance of Nopp140 encoded by maternal transcripts in Nopp140-/- MB neuroblasts of 1­­­–2-day-old larvae likely rendered these cells more resilient to nucleolar stress.

This article has an associated First Person interview with the first author of the paper.

Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

For years, clinical and basic researchers have been aware of the presence of PTEN in the nucleus in cell culture, animal models, and both healthy and diseased human tissues. Despite the early recognition of nuclear PTEN, the understanding of the mechanisms of its nuclear localization, function in the nucleus, and importance in biology and human disease has been lacking. Over the last decade, emerging concepts for the complex involvement of nuclear PTEN in a variety of processes, including genome maintenance and DNA repair, cell-cycle control, gene expression, and DNA replication, are illuminating what could prove to be the key path toward a full understanding of PTEN function in health and disease. Dysregulation of nuclear PTEN is now considered an important aspect of the etiology of many pathologic conditions, prompting reconsideration of the therapeutic approaches aimed at countering the consequences of PTEN deficiency. This new knowledge is fueling the development of innovative therapeutic modalities for a broad spectrum of human conditions, from cancer and metabolic diseases, to neurological disorders and autism.

Within months researchers will attempt to create a ball of plasma hotter than the sun inside the Joint European Torus, a doughnut-shaped machine in south-east England

Ironbark is one of 2020’s anticipated movies. Benedict Cumberbatch plays the MI6 handler of a Russian spy who may have helped prevent nuclear war

Businesses, individuals with land, and local governments are competing to host an underground nuclear waste facility in the UK, and receive a yearly £2.5 million incentive

Safety fears derail plan to import reactors.

Workers at ‘most toxic place in America’ are terrified to return to a site where there has been very little protection from the outbreak

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For more than a month, coronavirus has brought cleanup of a 586-square-mile decommissioned nuclear production complex in south-eastern Washington state to a near standstill.

Most of the more than 11,000 employees at the Hanford site were sent home in late March, with only essential workers remaining to make sure the “most toxic place in America” stays safe and secure.

Nuclear Regulatory Commission keen to allow material to be disposed of by ‘land burial’ – with potentially damaging effects

The federal agency providing oversight of the commercial nuclear sector is attempting to push through a rule change critics say could allow dangerous amounts of radioactive material to be disposed of in places like municipal landfills, with potentially serious consequences to human health and the environment.

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Three new wildfires have broken out in the radiation-contaminated evacuation zone around the wrecked Chernobyl nuclear power plant in Ukraine.

I’m no stranger to forced isolation. For the better part of my 20s, I served as a nuclear submarine officer running secret missions for the United States Navy. I deployed across the vast Pacific Ocean with a hundred other sailors on the USS Connecticut, a Seawolf-class ship engineered in the bygone Cold War era to be one of the fastest, quietest, and deepest-diving submersibles ever constructed. The advanced reactor was loaded with decades of enriched uranium fuel that made steam for propulsion and electrical power so we could disappear under the waves indefinitely without returning to port. My longest stint was for two months, when I traveled under the polar ice cap to the North Pole with a team of scientists studying the Arctic environment and testing high frequency sonar and acoustic communications for under-ice operations. During deployments, critical-life events occur without you: holidays with loved ones, the birth of a child, or in my case, the New York Giants 2011-2012 playoff run to beat Tom Brady’s Patriots in the Super Bowl for the second time. On the bright side, being cut off from the outside world was a great first job for an introvert.

It’s been a month since COVID-19 involuntarily drafted me into another period of isolation far away from home. I’m in Turkey, where a two-week trip with my partner to meet her family has been extended indefinitely. There were no reported cases here and only a few in California in early March when we left San Francisco, where I run a business design studio. I had a lot of anticipation about Turkey because I’d never been here. Now I’m sheltering in a coastal town outside of Izmir with my partner, her parents, their seven cats, and a new puppy.

Shuttered in a house on foreign soil where I don’t speak the language, I have found myself snapping back into submarine deployment mode. Each day I dutifully monitor online dashboards of data and report the status of the spread at the breakfast table to no one in particular. I stay in touch with friends and family all over the world who tell me they’re going stir crazy and their homes are getting claustrophobic. But if there is one thing my experience as a submarine officer taught me, it’s that you get comfortable being uncomfortable.

My training began with psychological testing, although it may not be what you think. Evaluating mental readiness for underwater isolation isn’t conducted in a laboratory by clipboard-toting, spectacled scientists. The process to select officers was created by Admiral Hyman Rickover—the engineering visionary and noted madman who put the first nuclear reactor in a submarine—to assess both technical acumen and composure under stress. For three decades as the director of the Navy’s nuclear propulsion program, Rickover tediously interviewed every officer, and the recruiting folklore is a true HR nightmare: locking candidates in closets for hours, asking obtuse questions such as “Do something to make me mad,” and sawing down chair legs to literally keep one off balance.

Rickover retired from the Navy as its longest-serving officer and his successors carried on the tradition of screening each officer candidate, but with a slightly more dignified approach. Rickover’s ghost, though, seemed to preside over my interview process when I applied to be a submariner as a junior at the U.S. Naval Academy in Annapolis, Maryland. I was warned by other midshipmen that I would fail on the spot if I initiated a handshake. So, dressed in my formal navy blue uniform and doing my best to avoid tripping into accidental human contact, I rigidly marched into the Admiral’s office, staring straight ahead while barking my resume. When I took a seat on the unaltered and perfectly level chair in front of his desk, the Admiral asked me bluntly why I took so many philosophy classes and if I thought I could handle the technical rigors of nuclear power school. My response was a rote quip from John Paul Jones’ “Qualifications of a Naval Officer.” “Admiral, an officer should be a gentleman of liberal education, refined manners, punctilious courtesy, and the nicest sense of personal honor.” My future boss looked at me, shook his head like he thought I’d be a handful, and told me I got the job.

Confinement opened something up in my psyche and I gave myself permission to let go of my anxieties.

Nuclear power training is an academic kick in the face every day for over a year. The curriculum is highly technical and the pedagogy resembles a cyborg assembly-line without even a hint of the Socratic method. Our grades were conspicuously posted on the classroom wall and a line was drawn between those who passed and those who failed. I was below the line enough to earn the distinguished dishonor of 25 additional study hours each week, which meant I was at school at 5 a.m. and every weekend. This is how the Nuclear Navy builds the appropriate level of knowledge and right temperament to deal with shipboard reactor operations.

I finally sat down for a formal psychological evaluation a few months before my first deployment. I was ushered into a room no bigger than a broom closet and instructed to click through a computer-based questionnaire with multiple-choice questions about my emotions. I never did  learn the results, so I assume my responses didn’t raise too many red flags.

During my first year onboard, I spent all my waking hours either supervising reactor operations or learning the intricacies of every inch of the 350-foot tube and the science behind how it all worked. The electrolysis machine that split water molecules to generate oxygen was almost always out of commission, so instead we burned chlorate candles that produced breathable air. Seawater was distilled each day for drinking and shower water. Our satellite communications link had less bandwidth than my dial-up modem in the 1990s and we were permitted to send text-only emails to friends and family at certain times and in certain locations so as not to risk being detected. I took tests every month to demonstrate proficiency in nuclear engineering, navigation, and the battle capabilities of the ship. When I earned my submarine warfare qualification, the Captain pinned the gold dolphins insignia on my uniform and gave me the proverbial keys to the $4 billion warship. At that point, I was responsible for coordinating missions and navigating the ship as the Officer of the Deck.

Modern submarines are hydrodynamically shaped to have the most efficient laminar flow underwater, so that’s where we operated 99 percent of the time. The rare exception to being submerged is when we’d go in and out of port. The most unfortunate times were long transits tossing about in heavy swells, which made for a particularly nauseated cruise. To this day, conjuring the memory of some such sails causes a reflux flashback. A submariner’s true comfort zone is beneath the waves so as soon as we broke ties with the pier we navigated toward water that was deep enough for us to dive.

It’s unnatural to stuff humans, torpedoes, and a nuclear reactor into a steel boat that’s intentionally meant to sink. This engineering marvel ranks among the most complex, and before we’d proceed below and subject the ship and its inhabitants to extreme sea pressures, the officers would visually inspect thousands of valves to verify the proper lineup of systems that would propel us to the surface if we started flooding uncontrollably and sinking—a no-mistakes procedure called rigging for dive. Once we’d slip beneath the waves, the entire crew would walk around to check for leaks before we’d settle into a rotation of standing watch, practicing our casualty drills, engineering training, eating, showering (sometimes), and sleeping (rarely). The full cycle was 18 hours, which meant the timing of our circadian cycles were constantly changing. Regardless of the amount of government-issued Folger’s coffee I’d pour down my throat, I’d pass out upon immediate contact with my rack (the colloquialism for a submarine bunk in which your modicum of privacy was symbolized by a cloth curtain).

As an officer, I lived luxuriously with only two other grown men in a stateroom no bigger than a walk-in closet. Most of the crew slept stacked like lumber in an 18-person bunk room and they all took turns in the rack. This alternative lifestyle is known as hot-racking, because of the sensation you get when you crawl into bedding that’s been recently occupied. The bunk rooms are sanctuaries where silence is observed with monastic intensity. Slamming the door or setting an alarm clock was a cardinal sin so wakeups were conducted by a junior sailor who gently coaxed you awake when it was time to stand watch. Lieutenant Weiner, it’s time to wake up. You’ve got the midnight watch, sir. Words that haunt my dreams.

The electrolysis machine was out of commission, so we burned chlorate candles that produced breathable air.

I maintained some semblance of sanity and physical fitness by sneaking a workout on a rowing erg in the engine room or a stationary bike squeezed between electronics cabinets. The rhythmic beating of footsteps on a treadmill was a noise offender—the sound could be detected on sonar from miles away—so we shut it off unless we were in friendly waters where we weren’t concerned with counter-detection.

Like a heavily watered-down version of a Buddhist monk taking solitary retreat in a cave, my extended submarine confinements opened something up in my psyche and I gave myself permission to let go of my anxieties. Transiting underneath a vast ocean in a vessel with a few inches of steel preventing us from drowning helps put things into perspective. Now that I’m out of the Navy, I have more appreciation for the freedoms of personal choice, a fresh piece of fruit, and 24 hours in a day. My only regrets are not keeping a journal or having the wherewithal to discover the practice of meditation under the sea.

Today, I’m learning Turkish so I can understand more about what’s happening around me. I’m doing Kundalini yoga (a moving meditation that focuses on breathwork) and running on the treadmill (since I’m no longer concerned about my footsteps being detected on sonar). On my submarine, I looked at photos to stay connected to the world I left behind, knowing that I’d return soon enough. Now our friend who is isolating in our apartment in San Francisco sends us pictures of our cat and gives us reports about how the neighborhood has changed.

It’s hard to imagine that we’ll resume our lifestyles exactly as they were. But the submariner in me is optimistic that we have it in us to adapt to whatever conditions are waiting for us when it’s safe to ascend from the depths and return to the surface.

Steve Weiner is the founder of Very Scarce, a business design studio. He used to lead portfolio companies at Expa and drive nuclear submarines in the U.S. Navy. He has an MBA from The Wharton School and a BS from the U.S. Naval Academy. Instagram: @steve Twitter: @weenpeace

Lead image: Mike H. / Shutterstock

The debate over nuclear technology is a controversial one, yet many leaders in the field believe it's time for an open and calm discussion about the energy alternative.

The Justice Department today announced that a scientist and his wife, who both previously worked as contractors at the Los Alamos National Laboratory in New Mexico, have been indicted on charges of communicating classified nuclear weapons data to a person they believed to be a Venezuelan government official and conspiring to participate in the development of an atomic weapon for Venezuela, among other violations.

The Department of Justice today announced that it will not challenge a proposal by seven nuclear power plant operators to share resources and coordinate best practices and other operational activities through a proposed venture to be named the STARS Alliance LLC.

Peter Picone, 40, of Methuen, Mass., has been charged with importing counterfeit semiconductors from China for sale in the United States.

The Justice Department announced today that General Electric Hitachi Nuclear Energy Americas LLC (GE Hitachi) has agreed to pay $2.7 million to resolve allegations under the False Claims Act that it made false statements and claims to the Department of Energy and the Nuclear Regulatory Commission (NRC) concerning an advanced nuclear reactor design.

Guns N' Roses frontman Axl Rose criticized Steven Mnuchin and Trump's coronavirus response, which irked the Treasury secretary and started a Twitter spat.

The pair announced their first investment on Tuesday into edtech startup Eduka System.

The post Bukalapak co-founders Zaky, Xinuc set up early-stage VC fund Init 6 appeared first on DealStreetAsia.

siRNNs could enable RNAi knockdown of therapeutic targets in a broader range of cells and tissue types than siRNA.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Dec 15, 2019

• Russians View Terrorists as Third Most Probable Source of Nuclear Attack
• U.S. Adopts New Strategy for Countering of WMD Terrorism
• Elbe Group Calls for U.S.-Russian Cooperation against Terrorism
• Belfer Center Experts on Combatting Complacency about Nuclear Terrorism
• Can Threat Emanating from Jihadists of Central Asia Have a WMD Dimension?
• NTI and CENESS on Radiological Risks in Central Asia
• Hecker Assesses Probability of Radiological and Nuclear Terrorism
• Luxembourg Forum: It’s Vital for US and Russia to Intensify Cooperation to Combat Nuclear Terrorism

Dec 17, 2019

Julius Weitzdörfer’s earliest childhood memories are the major global events of 1986—the Space Shuttle Challenger explosion and the Chernobyl disaster. Looking back, he realizes that these events must have contributed to shaping his later research interests in managing technological risks. 

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Jan 28, 2020

In the unintuitive world of nuclear weapons strategy, it’s often difficult to identify which decisions can serve to decrease the risk of a devastating nuclear conflict and which might instead increase it. Such complexity stems from the very foundation of the field: Nuclear weapons are widely seen as bombs built never to be used. Historically, granular—even seemingly mundane—decisions about force structure, research efforts, or communicated strategy have confounded planners, sometimes causing the opposite of the intended effect.

Feb 10, 2020

Realistic, creative vulnerability assessment and testing are critical to finding and fixing nuclear security weaknesses and avoiding over-confidence. Both vulnerability assessment and realistic testing are needed to ensure that nuclear security systems are providing the level of protection required. Systems must be challenged by experts thinking like adversaries, trying to find ways to overcome them. Effective vulnerability assessment and realistic testing are more difficult in the case of insider threats, and special attention is needed. Organizations need to find ways to give people the mission and the incentives to find nuclear security weaknesses and suggest ways they might be fixed. With the right approaches and incentives in place, effective vulnerability assessment and testing can be a key part of achieving and sustaining high levels of nuclear security.

Feb 10, 2020

Nuclear security is never finished. Nuclear security measures for protecting all nuclear weapons, weapons-usable nuclear materials, and facilities whose sabotage could cause disastrous consequences should protect against the full range of plausible threats. It is an ongoing endeavor that requires constant assessment of physical protection operations and reevaluation of potential threats. One of the most challenging areas of nuclear security is how to account for the impact–positive and negative—of non-nuclear emerging technologies. The amended Convention on the Physical Protection of Nuclear Material (amended CPPNM) states it should be reviewed in light of the prevailing situation, and a key part of the prevailing situation is technological evolution. Therefore, the upcoming review conference in 2021, as well as any future review conferences, should examine the security threats and benefits posed by emerging technologies.

Feb 10, 2020

Civil society has played a very important role in nuclear security over the years, and its role could be strengthened in the future. Some nuclear organizations react against the very idea of civil society involvement, thinking of only one societal role—protesting. In fact, however, civil society has played quite a number of critical roles in nuclear security over the years, including highlighting the dangers of nuclear terrorism; providing research and ideas; nudging governments to act; tracking progress and holding governments and operators accountable; educating the public and other stakeholders; promoting dialogue and partnerships; helping with nuclear security implementation; funding initial steps; and more. Funding organizations (both government and non-government) should consider ways to support civil society work and expertise focused on nuclear security in additional countries. Rather than simply protesting and opposing, civil society organizations can help build more effective nuclear security practices around the world.

Feb 10, 2020

Participants at the final Nuclear Security Summit in 2016 agreed on “action plans” for initiatives they would support by five international organizations and groups—the International Atomic Energy Agency, the Global Initiative to Combat Nuclear Terrorism, INTERPOL, the United Nations, and the Global Partnership Against the Spread of Weapons and Materials of Destruction. These institutions were supposed to play key roles in bolstering ongoing nuclear security cooperation after the summit process ended. The action plans were modest documents, largely endorsing activities already underway, and there have been mixed results in implementing them. To date, these organizations have not filled any substantial part of the role once played by the nuclear security summits.

Feb 23, 2020

With the Russia investigation and impeachment behind him, President Trump finally may feel empowered to engage with Russian President Vladimir Putin and pursue an arms control deal.  

Mar 5, 2020

The opening of the British archives has seen historians uncover the secrets of the UK's nuclear weapons programme since the 1990s. While a growing number have sought to expose these former secrets, there has been less effort to consider government secrecy itself. What was kept a secret, when and why? And how and why, notably from the 1980s, did the British government decide to officially disclose greater information about the British nuclear weapons programme to Members of Parliament, journalists, defence academics and the tax-paying general public. 

Mar 31, 2020

A nuclear explosion detonated anywhere by a terrorist group would be a global humanitarian, economic, and political catastrophe. The current COVID-19 pandemic reminds us not to ignore prevention of and preparation for low-probability, high-consequence disasters. For nuclear terrorism, while preparation is important, prevention must be the top priority. The most effective strategy for keeping nuclear weapons out of the hands of terrorists is to ensure that nuclear materials and facilities around the world have strong and sustainable security. Every president for more than two decades has made strengthening nuclear security around the globe a priority. This includes the Trump administration, whose 2018 Nuclear Posture Review states: “[n]uclear terrorism remains among the most significant threats to the security of the United States, allies, and partners.”

Apr 11, 2020

A simplified nuclear exchange model demonstrates that China’s ability to launch a successful nuclear retaliatory strike in response to an adversary’s nuclear first strike has been and remains far from assured. This study suggests that China’s criterion for effective nuclear deterrence is very low.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.

Apr 27, 2020

The authors conducted a study which highlights how the U.S. public as a whole and various demographic groups view President Donald Trump's positions on nuclear weapons.