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Single-molecule level structural dynamics of DNA unwinding by human mitochondrial Twinkle helicase [Molecular Biophysics]

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.




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On the Brink of Demographic Crisis, Governments in East Asia Turn Slowly to Immigration

With many countries in East Asia facing unfavorable demographic shifts in the form of aging populations, low fertility, and shrinking workforces, governments in 2016 continued to explore immigration as a potential policy solution. However, a tradition of cultural homogeneity and wariness among publics about increased immigration is leading policymakers to test the waters with very small steps.




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Rethinking U.S. Immigration Policy: Building a Responsive, Effective Immigration System

This discussion marked the launch of MPI's Rethinking U.S. Immigration Policy Initiative, which aims to generate a big-picture, evidence-driven vision of the role immigration should play in America’s future, as well as to build a bipartisan center so needed reforms can be enacted. The initiative's leader, MPI Senior Fellow Doris Meissner, joins in conversation with former Bush administration Commerce Secretary Carlos Gutierrez and former Obama White House Domestic Policy Council Director Cecilia Muñoz about the prospects for action and what's needed.




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What math professors and k-12 teachers think of each other

By Michael Pershan, St. Ann’s School I. What do primary/secondary math educators think of the teaching that happens in colleges? And — the other way around — what do mathematics professors think of primary and secondary math teaching? I’m nearing … Continue reading




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Escaped emu found playing in sprinkler one day later

A Michigan family said their 6-foot-tall emu was found playing in another resident's sprinkler about a mile from home one day after escaping.




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3M inks $126M deal with DoD to increase N95 mask production in October

3M has signed a $126 million deal with the Pentagon to increase its production of N95 masks to 26 million per month beginning in October 2020.




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Brain model links herpes virus to development of Alzheimer's disease

Bio-engineered models of the human brain infected with herpes simplex virus-1 develop many of the same characteristics found in Alzheimer's disease, according to a new analysis published by Science Advances.




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Rethinking U.S. Immigration Policy: Building a Responsive, Effective Immigration System

This event marks the launch of a major new initiative—Rethinking U.S. Immigration Policy—that aims to generate a big-picture, evidence-driven vision of the role immigration can and should play in America’s future in order to leverage a comparative advantage for the nation.




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Ask Ariely: On Soiled Sinks, Busy Bathrooms, and Dainty Donations

Here’s my Q&A column from the WSJ this week — and if you have any questions for me, you can tweet them to @danariely with the hashtag #askariely, post a comment on my Ask Ariely Facebook page, or email them to AskAriely@wsj.com. ___________________________________________________ Dear Dan, People in my office drink a...




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Rethinking U.S. Immigration Policy: New Realities Call for New Answers

The U.S. immigration system is in desperate need of an overhaul. What has been missing is an alternate vision for a path forward that treats immigration as a strategic resource while also accounting for heightened security and rule-of-law imperatives, which together can further U.S. interests, values, and democratic principles as a society. This concept note outlines a new MPI initiative, Rethinking U.S. Immigration Policy, that seeks to fill this gap.




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[ Law & Ethics ] Open Question : Law and Ethics: Do you think gore should be illegal?

I certainly do, it doesn't make sense how someone crazy recording someone getting killed isn't illegal but CP is! That shouldn't be because, they should be either running away or trying to stop that super duper crazy person. Why can't both of them be illegal?




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A Game of Magical Thinking Leaves Reality on the Sidelines

The 58 fans sitting before the big-screen television were watching the Super Bowl. Psychologist Emily Pronin was watching the fans.




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Does Your Subconscious Think Obama Is Foreign?

A few years ago, psychologists Mahzarin Banaji and Thierry Devos showed the names of a number of celebrities to a group of volunteers and asked them to classify the well-known personalities as American or non-American. The list included television personality Connie Chung and tennis star Michael ...




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The Role of Think Tanks in Times of (Migration) Crisis: A Transatlantic Perspective

As European policymakers and publics continue to grapple with the migration crisis, this conversation offers an opportunity to reflect on the role and responsibility of experts in these politically sensitive debates.




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Legal Channels for Refugee Protection in Europe: A Pivotal Moment for Strategic Thinking

Following the release of the mid-term review of the European Agenda on Migration, this webinar offers insights from EU Member States on how existing, new, and untapped legal pathways interact with other humanitarian policies, and fit into a larger protection strategy.




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On the Brink: Prospects for UK Nationals in the EU-27 after a No-Deal Brexit

Six months on from the original March 2019 Brexit date and staring a new deadline in the face, many EU countries still had only skeletal plans for how to adjust the status of their resident UK nationals should a no-deal Brexit come to pass. This policy brief highlights critical gaps in these plans, the groups most likely to be affected by them, and strategies Member States and the United Kingdom could adopt to soften the impact.




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Glycated Hemoglobin, Prediabetes, and the Links to Cardiovascular Disease: Data From UK Biobank

OBJECTIVE

HbA1c levels are increasingly measured in screening for diabetes; we investigated whether HbA1c may simultaneously improve cardiovascular disease (CVD) risk assessment, using QRISK3, American College of Cardiology/American Heart Association (ACC/AHA), and Systematic COronary Risk Evaluation (SCORE) scoring systems.

RESEARCH DESIGN AND METHODS

UK Biobank participants without baseline CVD or known diabetes (n = 357,833) were included. Associations of HbA1c with CVD was assessed using Cox models adjusting for classical risk factors. Predictive utility was determined by the C-index and net reclassification index (NRI). A separate analysis was conducted in 16,596 participants with known baseline diabetes.

RESULTS

Incident fatal or nonfatal CVD, as defined in the QRISK3 prediction model, occurred in 12,877 participants over 8.9 years. Of participants, 3.3% (n = 11,665) had prediabetes (42.0–47.9 mmol/mol [6.0–6.4%]) and 0.7% (n = 2,573) had undiagnosed diabetes (≥48.0 mmol/mol [≥6.5%]). In unadjusted models, compared with the reference group (<42.0 mmol/mol [<6.0%]), those with prediabetes and undiagnosed diabetes were at higher CVD risk: hazard ratio (HR) 1.83 (95% CI 1.69–1.97) and 2.26 (95% CI 1.96–2.60), respectively. After adjustment for classical risk factors, these attenuated to HR 1.11 (95% CI 1.03–1.20) and 1.20 (1.04–1.38), respectively. Adding HbA1c to the QRISK3 CVD risk prediction model (C-index 0.7392) yielded a small improvement in discrimination (C-index increase of 0.0004 [95% CI 0.0001–0.0007]). The NRI showed no improvement. Results were similar for models based on the ACC/AHA and SCORE risk models.

CONCLUSIONS

The near twofold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors. While HbA1c adds minimally to cardiovascular risk prediction, those with prediabetes should have their conventional cardiovascular risk factors appropriately measured and managed.




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Epigenetic Link Between Statin Therapy and Type 2 Diabetes

OBJECTIVE

To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood.

RESEARCH DESIGN AND METHODS

Five cohort studies’ participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated.

RESULTS

Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 x 10–25 [DHCR24]), cg10177197 (3.94 x 10–08 [DHCR24]), cg06500161 (2.67 x 10–23 [ABCG1]), cg27243685 (6.01 x 10–09 [ABCG1]), and cg05119988 (7.26 x 10–12 [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression.

CONCLUSIONS

This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins’ effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.




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The Digital Transformation Playbook: Rethink Your Business for the Digital Age

Every business begun before the Internet now faces the same challenge: How to transform to compete in a digital economy? This is the leadership challenge examined by BRITE founder and Columbia Business School faculty member David Rogers in his newest book, The Digital Transformation Playbook (April 5, 2016; Columbia Business School Publishing). In the book, […]




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Can a Company be pro-regulation and pro-commerce? Gregg Renfrew from Beautycounter thinks so

It’s the middle of an election year and, according to the Pew Research Center, the country hasn’t been this polarized since the Civil War. In such a climate, it would seem to be an oxymoron for a company to push for both financial growth and tighter regulations. Gregg Renfrew, CEO & Founder of Beautycounter, wouldn’t […]




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Thinking with AND: Insights from KIND’s story

“I’m a confused Mexican Jew.” So says Daniel Lubetzky, Founder and CEO of KIND Snack, in his very personal interview with Columbia faculty member David Rogers at BRITE ’16. Their discussion touched on the many ideas behind KIND Snacks, from the beginnings of the company, to the strategic thinking that forces Lubetzky to stay away […]




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This Essential Mineral Linked To COVID-19 Recovery

An essential mineral in the body have been linked to recovery of COVID-19 patients.

Support PsyBlog for just $5 per month. Enables access to articles marked (M) and removes ads.

→ Explore PsyBlog's ebooks, all written by Dr Jeremy Dean:




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In uncertain times, think like a mother | Yifat Susskind

There's a simple and powerful way to confront the world's most pressing crises, says women's rights activist Yifat Susskind: think like a mother. As she puts it: "When you think like a mother, you prioritize the needs of the many, not the whims of the few." Follow along as she shares moving stories of people around the world who embody this mindset -- and shows how it can also help you see beyond suffering and act to build a better world.











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Talking Across Divides And Quashing Conspiracy Theories: The Week’s Best Psychology Links

Our weekly round-up of the best psychology coverage from elsewhere on the web




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Publication Bias And Lockdown Memories: The Week’s Best Psychology Links

Our weekly round-up of the best psychology coverage from elsewhere on the web




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Bettors don’t think Lamar Jackson will be running as much this year

Last year, Ravens quarterback Lamar Jackson rushed for 1,206 yards. This year, the betting public thinks he'll generate a lot fewer rushing yards than that. Via David Payne Purdum of ESPN.com, the initial over/under at Caesars of 999.5 already has dropped to 949.5. This means that the early money placed on the prop has tilted [more]




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Patchwork decisions throw wrinkle in college football plans

There are 130 major college football teams, spread across 41 states and competing in 10 conferences, save for a handful of independents. The goal is to have all those teams start the upcoming season at the same time - whether that's around Labor Day as scheduled or later - and play the same number of games. Despite the best intentions of conference leaders, the possibility exists of college football being played in SEC country before it begins in Pac-12 territory - or something else entirely.




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Drink Driving.




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Voyaging with ink - volume one : An anthology from contemporary Tokelau writers to the world.




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The China Defence Universities Tracker : exploring the military and security links of China's universities / Alex Joske.

The Chinese Communist Party (CCP) is building links between China’s civilian universities, military and security agencies. Those efforts, carried out under a policy of leveraging the civilian sector to maximise military power (known as ‘military–civil fusion’), have accelerated in the past decade. Research for the China Defence Universities Tracker has determined that greater numbers of Chinese universities are engaged in defence research, training defence scientists, collaborating with the military and cooperating with defence industry conglomerates and are involved in classified research.1 At least 15 civilian universities have been implicated in cyberattacks, illegal exports or espionage. China’s defence industry conglomerates are supervising agencies of nine universities and have sent thousands of their employees to train abroad.




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Nature's cache / Jayne Linke.




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The brink of being : talking about miscarriage / Julia Bueno.

Miscarriage.




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A manual for heartache / Cathy Rentzenbrink.

Rentzenbrink, Cathy -- Family.




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Sand talk : how Indigenous thinking can save the world / Tyson Yunkaporta.

Aboriginal Australians -- Attitudes.




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The big heat : Earth on the brink / Jeffrey St. Clair & Joshua Frank.

Climatic changes.




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The science of fate : why your future is more predictable than you think / Hannah Critchlow.

Neurosciences.




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Die multiple Fettgewebsnecrose : Klinische und experimentelle Studien / von Arthur Katz und Ferdinand Winkler ; mit einem Vorwort von Leopold Oser.

Berlin : S. Karger, 1899.




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Die Trinksitten, ihre hygienische und sociale Bedeutung : Ihre Beziehungen zur akademischen Jugend : eine Ansprache an die Enthaltsamkeits-Vereine der Studenten zu Christiania und Upsala ... / von August Forel.

Stuttgart : F. Enke, 1891.




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Die Verunreinigung der Gewässer, deren schädliche Folgen, sowie die Reinigung von Trink-und Schmutzwasser / von J. Konig.

Berlin : J. Springer, 1899.




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Directions for drinking the Cheltenham waters : with a selection of cases, illustrating their effects in a great variety of diseases / by James M'Cabe.

Cheltenham : printed for G.A. Williams, librarian, [1823]




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Drink restriction (thirst-cures), particularly in obesity / by Carl von Noorden and Hugo Salomon.

Bristol : Wright, 1905.




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Encyclopaedisches Woerterbuch der medicinischen Wissenschaften / Herausgegeben von den Professoren der Medicinischen Facultaet zu Berlin: C.F. v. Graefe, C.W. Hufeland, H.F. Link, K.A. Rudolphi, E. v. Siebold.

Berlin : J.W. Boike, 1828-49.




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A skull placed on some old books, a Venetian drinking glass, playing cards, a cigarette stub, and six coins. Watercolour.