Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes.

Significance Statement

After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.

Advancements in immunotherapy in the perioperative setting have revolutionised the treatment of resectable nonsmall cell lung cancer (NSCLC). Here we present the methodology and results of the clinical trial CheckMate 816 demonstrating the benefit of neoadjuvant therapy with nivolumab plus chemotherapy compared with chemotherapy alone. Furthermore, this article discusses the implications for future practice in resectable NSCLC and the need for future research.

The City of Vancouver council has reneged on a previous commitment to a living wage for its employees.

The post City of Vancouver to lowest paid workers: Let them eat cuts! appeared first on rabble.ca.

The plane is hailed as 'one of the most advanced aircraft available on the market'

Republican vice presidential candidate JD Vance boldly said “no,” Donald Trump did not lose the 2020 election, when pressed on the issue at a campaign event Wednesday in Williamsport, Pennsylvania.

The Ohio senator has avoided directly denying the results over the past few weeks.

When quizzed by The New York Times about the results over the weekend, for example, he refused multiple times to answer the question, on one occasion claiming he was “focused on the future”—echoing an answer he gave to Democratic opponent Tim Walz at the vice presidential debate.

Read more at The Daily Beast.

Ronnie O'Sullivan has agreed to compete in new snooker events.

There has been another shock at the Grand Slam of Darts.

The identification of a new hominin group called Denisovans was one of the most exciting discoveries in human evolution in the last decade.

The post Several Denisovan Populations Introgressed into Modern Humans Multiple Times: Study appeared first on Sci.News: Breaking Science News.

The Associated Press has declared a winner in Colorado's 8th Congressional District which has been one of the most closely watched races in the country.

Speculator swapped pricey domain for OpenAI shares instead of taking cash payment.

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Hello gentle readers, and welcome to the SwitchArcade Round-Up for September 3rd, 2024. In today’s article, I have a few …

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The rare type of cloud, whose name is Latin for "roughness," was first observed in 2006 by an amateur cloudspotter in Iowa.

There are not many usable precedents for what J. D. Vance can do with a one-term vice presidency.

Voyez ce que l’ancien défenseur avait à dire sur son passage dans la Belle Province!

Following a mother and son during the the Blitz, Nazi Germany's bombing campaign on London during the Second World War, director Steve McQueen's new drama understands the war film — perhaps a bit too well.

James Van Der Beek s’est ouvert sur son combat contre le cancer.

Indian and multinational pharma companies are leading the charge by investing in digital transformation and aligning Indian operations with global standards. Essentially, pharmaceutical water systems are

PDUFA V commitments signal a strong commitment to tolerance of open debate in the face of uncertainty.

I can admit to a rather powerful lack of enthusiasm when reading about interpersonal squabbles. It’s even worse in the scientific world: when I read about debates getting mired in personal attacks I tend to simply stop reading and move on to something else.

However, the really interesting part of this week’s meeting of an FDA joint Advisory Committee to discuss the controversial diabetes drug Avandia – at least in the sense of likely long-term impact – is not the scientific question under discussion, but the surfacing and handling of the raging interpersonal battle going on right now inside the Division of Cardiovascular and Renal Products. So I'll have to swallow my distaste and follow along with the drama.

Two words that make us mistrust Duke:  Anil Potti Christian Laettner

Not that the scientific question at hand – does Avandia pose significant heart risks? – isn't interesting. It is. But if there’s one thing that everyone seems to agree on, it’s that we don’t have good data on the topic. Despite the re-adjudication of RECORD, no one trusts its design (and, ironically, the one trial with a design to rigorously answer the question was halted after intense pressure, despite an AdComm recommendation that it continue).  And no one seems particularly enthused about changing the current status of Avandia: in all likelihood it will continue to be permitted to be marketed under heavy restrictions. Rather than changing the future of diabetes, I suspect the committee will be content to let us slog along the same mucky trail.

The really interesting question, that will potentially impact CDER for years to come, is how it can function with frothing, open dissent among its staffers. As has been widely reported, FDA reviewer Tom Marciniak has written a rather wild and vitriolic assessment of the RECORD trial, excoriating most everyone involved. In a particularly stunning passage, Marciniak appears to claim that the entire output of anyone working at Duke University cannot be trusted because of the fraud committed by Duke cancer researcher Anil Potti:

I would have thought that the two words “Anil Potti” are sufficient for convincing anyone that Duke University is a poor choice for a contractor whose task it is to confirm the integrity of scientific research. 

(One wonders how far Marciniak is willing to take his guilt-by-association theme. Are the words “Cheng Yi Liang” sufficient to convince us that all FDA employees, including Marciniak, are poor choices for deciding matter relating to publicly-traded companies? Should I not comment on government activities because I’m a resident of Illinois (my two words: “Rod Blagojevich”)?)

Rather than censoring or reprimanding Marciniak, his supervisors have taken the extraordinary step of letting him publicly air his criticisms, and then they have in turn publicly criticized his methods and approach.

I have been unable to think of a similar situation at any regulatory agency. The tolerance for dissent being displayed by FDA is, I believe, completely unprecedented.

And that’s the cliffhanger for me: can the FDA’s commitment to transparency extend so far as to accommodate public disagreements about its own approval decisions? Can it do so even when the disagreements take an extremely nasty and inappropriate tone?

• Rather than considering that open debate is a good thing, will journalists jump on the drama and portray agency leadership as weak and indecisive?
• Will the usual suspects in Congress be able to exploit this disagreement for their own political gain? How many House subcommittees will be summoning Janet Woodcock in the coming weeks?

I think what Bob Temple and Norman Stockbridge are doing is a tremendous experiment in open government. If they can pull it off, it could force other agencies to radically rethink how they go about crafting and implementing regulations. However, I also worry that it is politically simply not a viable approach, and that the agency will ultimately be seriously hurt by attacks from the media and legislators.

Where is this coming from?

As part of its recent PDUFA V commitment, the FDA put out a fascinating draft document, Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making. It didn't get a lot of attention when first published back in February (few FDA documents do). However, it lays out a rather bold vision for how the FDA can acknowledge the existence of uncertainty in its evaluation of new drugs. Its proposed structure even envisions an open and honest accounting of divergent interpretations of data:

When they're frothing at the mouth, even Atticus doesn't let them publish a review

A framework for benefit-risk decision-making that summarizes the relevant facts, uncertainties, and key areas of judgment, and clearly explains how these factors influence a regulatory decision, can greatly inform and clarify the regulatory discussion. Such a framework can provide transparency regarding the basis of conflicting recommendations made by different parties using the same information.

(Emphasis mine.)

Of course, the structured framework here is designed to reflect rational disagreement. Marciniak’s scattershot insults are in many ways a terrible first case for trying out a new level of transparency.

The draft framework notes that safety issues, like Avandia, are some of the major areas of uncertainty in the regulatory process. Contrast this vision of coolly and systematically addressing uncertainties with the sad reality of Marciniak’s attack:

In contrast to the prospective and highly planned studies of effectiveness, safety findings emerge from a wide range of sources, including spontaneous adverse event reports, epidemiology studies, meta-analyses of controlled trials, or in some cases from randomized, controlled trials. However, even controlled trials, where the evidence of an effect is generally most persuasive, can sometimes provide contradictory and inconsistent findings on safety as the analyses are in many cases not planned and often reflect multiple testing. A systematic approach that specifies the sources of evidence, the strength of each piece of evidence, and draws conclusions that explain how the uncertainty weighed on the decision, can lead to more explicit communication of regulatory decisions. We anticipate that this work will continue beyond FY 2013.

I hope that work will continue beyond 2013. Thoughtful, open discussions of real uncertainties are one of the most worthwhile goals FDA can aspire to, even if it means having to learn how to do so without letting the Marciniaks of the world scuttle the whole endeavor.

Now is the time for health plans to step up and embrace the tools and strategies that will not only meet regulatory demands, but also drive innovation in care delivery. 

The post Where Medicare Advantage Goes From Here appeared first on MedCity News.

We’ve all seen Medicare Advantage (MA) plans become a significant player in the healthcare industry. Yet, with the […]

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Dec 15, 2023

Calder Walton writes that if proved, Victor Manuel Rocha's espionage would place him among the longest-serving spies in modern times. Allowing him to operate as a spy in the senior echelons of the U.S. government for so long would represent a staggering U.S. security failure.

Sep 10, 2015

"It is estimated that the spotted stem borer and the African stem borer reduce Kenya's maize crop by 13 per cent or 400,000 tonnes annually. Controlling the pest using biotechnology will not only reduce Kenya's food imports, it will also equip the country with new techniques that can be redeployed for other sectors such as drug and vaccine development."

Feb 22, 2024

Authors Narayanamurti and Tsao propose a new architecture for how technoscientific knowledge advances, which maps to the actual operational practice of research and development nurtured at the iconic Bell Labs.

Jun 28, 2024

Ensuring that space remains a domain for peaceful exploration and mutual benefit rather than a new frontier for conflict will significantly depend on the global community's ability to navigate the complex interplay of technological advancements, regulatory frameworks, economic opportunities, and geopolitical challenges. 

This paper was written for the final assignment of IGA-250, a Harvard Kennedy School course on emerging technology: security, strategy, and risk.

May 24, 2024

At first glance, the European Union’s Carbon Border Adjustment Mechanism may look like a potential source of international discord. But a closer look suggests that the EU’s strict carbon-pricing regime may be the best chance the world has to achieve the Paris climate agreement’s ambitious emissions-reduction goals.

Apr 17, 2024

Meghan O’Sullivan, Harvard University’s Belfer Center for Science and International Affairs director and former Deputy National Security Advisor, joins 'Squawk Box' to discuss the latest developments in the Middle East conflict, the potential impact of new sanctions on Iran, what a possible retaliatory strikes from Israel could look like, and more.

May 22, 2024

Joseph Nye posits that an open civil society that allows protest can be a soft power asset.

Jul 25, 2024

Stephen Walt argues that if Trump and Vance win in November, it will do enormous long-term damage to America's global position.

Mar 18, 2024

Harvard Kennedy School hosted Jahi Wise, Senior Adviser to the Administrator of the U.S. Environmental Protection Agency, to discuss the design and implementation of the Greenhouse Gas Reduction Fund, a historic investment in American clean energy technology finance.

May 6, 2024

International relations expert Meghan O'Sullivan, the Jeane Kirkpatrick Professor of the Practice of International Affairs at Harvard Kennedy School, expressed her hopes for achieving successful international climate policy solutions in the latest episode of “Environmental Insights: Discussions on Policy and Practice from the Harvard Environmental Economics Program.”

Vanilla Reload Swipe Load is a quick, safe and easy way to load cash on to your prepaid card.

See how easy it is to apply for a mortgage through Vanderbilt Mortgage and Finance, Inc.

Mitch Eitel discusses shareholder activism and post-financial crisis enforcement issues

Hotel Transylvania 2 Shop Goodwill Ad

XVIII Habanos Festival: Once Again Havana Hosts the Major Annual Event of the World's Finest Tobacco, the Habano

Carhartt. Sweating the details since 1889.

IBM Watson is bringing cognitive computing to education to bring personalized learning to kids around the world - transforming early childhood education to help kids grow smarter, stronger and kinder.

Kala Gibson, Head of Business Banking at Fifth Third Bank, discusses the importance of small businesses to our economy and communities

El avance de Habla Men

Rob Stevens presents groundbreaking AdlensFocuss� eyeglasses at New York�s CE Week.

Top Breast Cancer Surgeons Discuss Advanced Surgical Options

If we talk about the frequency, the TDS return may be revised multiple times, which allows taxpayers to make corrections as and when needed. However, it is advisable to avoid excessive revisions to prevent complexities in record-keeping.

Download CA Intermediate Advanced Accounting Question Papers New Course Sep 2024 in PDF. For other question papers of CA IPC May 2024, Nov 2023, May 2023, Nov 2022, May 2022, Dec 2021, Nov 2020, Nov 18, May 18, Nov 2017, May 2017, May 2016, CA IPC Nov 2015, CA IPC may 2015, CA IPC Nov 2014 check similar section. Previous years Advanced Accounting CA Intermediate IPC question papers can also be downloaded using Search. You can also search and download may 2015 Final question papers here. We are providing ca final question papers of may 2016 for Financial Reporting FR, Advanced Financial Management AFM, Advanced Auditing and Professional Ethics, Direct Tax Laws DT, Indirect Tax Laws IDT and Inter/IPC May 2024 question papers for Advanced Accounting, Corporate and Other Laws, Taxation, Advanced Accounting , Auditing & Assurance, Information Technology & Strategic Management ITSM.

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