Safer Next-generation Nuclear Reactors

Computational researchers develop advanced model, the pebble bed reactor

From: Texas A&M College of Engineering

By Laura Simmons

May 20, 2021 -- When one of the largest modern earthquakes struck Japan on March 11, 2011, the nuclear reactors at Fukushima-Daiichi automatically shut down, as designed. The emergency systems, which would have helped maintain the necessary cooling of the core, were destroyed by the subsequent tsunami. Because the reactor could no longer cool itself, the core overheated, resulting in a severe nuclear meltdown, the likes of which haven’t been seen since the Chernobyl disaster in 1986.  

 Since then, reactors have improved exponentially in terms of safety, sustainability and efficiency. Unlike the light-water reactors at Fukushima, which had liquid coolant and uranium fuel, the current generation of reactors has a variety of coolant options, including molten-salt mixtures, supercritical water and even gases like helium.

Dr. Jean Ragusa and Dr. Mauricio Eduardo Tano Retamales from the Department of Nuclear Engineering at Texas A&M University have been studying a new fourth-generation reactor, pebble bed reactors. Pebble-bed reactors use spherical fuel elements (known as pebbles) and a fluid coolant (usually a gas).

“There are about 40,000 fuel pebbles in such a reactor,” said Ragusa. “Think of the reactor as a really big bucket with 40,000 tennis balls inside.”

During an accident, as the gas in the reactor core begins to heat up, the cold air from below begins to rise, a process known as natural convection cooling. Additionally, the fuel pebbles are made from pyrolytic carbon and tristructural-isotropic particles, making them resistant to temperatures as high as 3,000 degrees Fahrenheit. As a very-high-temperature reactor (VHTR), pebble-bed reactors can be cooled down by passive natural circulation, making it theoretically impossible for an accident like Fukushima to occur.

However, during normal operation, a high-speed flow cools the pebbles. This flow creates movement around and between the fuel pebbles, similar to the way a gust of wind changes the trajectory of a tennis ball. How do you account for the friction between the pebbles and the influence of that friction in the cooling process?

This is the question that Ragusa and Tano aimed to answer in their most recent publication  in the journal Nuclear Technology titled “Coupled Computational Fluid Dynamics–Discrete Element Method Study of Bypass Flows in a Pebble-Bed Reactor.”

“We solved for the location of these ‘tennis balls’ using the Discrete Element Method, where we account for the flow-induced motion and friction between all the tennis balls,” said Tano. “The coupled model is then tested against thermal measurements in the SANA experiment.” 

The SANA experiment was conducted in the early 1990s and measured how the mechanisms in a reactor interchange when transmitting heat from the center of the cylinder to the outer part. This experiment allowed Tano and Ragusa to have a standard to which they could validate their models.

As a result, their teams developed a coupled Computational Fluid Dynamics-Discrete Element Methods model for studying the flow over a pebble bed. This model can now be applied to all high-temperature pebble-bed reactors and is the first computational model of its kind to do so. It’s very-high-accuracy tools such as this that allow vendors to develop better reactors. 

“The computational models we create help us more accurately assess different physical phenomena in the reactor,” said Tano. “As a result, reactors can operate at a higher margin, theoretically producing more power while increasing the safety of the reactor. We do the same thing with our models for molten-salt reactors for the Department of Energy.” 

As artificial intelligence continues to advance, its applications to computational modeling and simulation grow. “We’re in a very exciting time for the field,” said Ragusa. “And we encourage any prospective students who are interested in computational modeling to reach out, because this field will hopefully be around for a long time.”

https://engineering.tamu.edu/news/2021/05/nuen-computational-researchers-develop-advanced-model-to-improve-safety-of-next-generation-reactors.html

Challenging the Standard Model of Cancer

New atavistic model shows role of ancient genes in the spread of cancer

From:  ARIZONA STATE UNIVERSITY

May 20, 2021 -- In spite of decades of research, cancer remains an enigma. Conventional wisdom holds that cancer is driven by random mutations that create aberrant cells that run amok in the body.

In a new paper published this week in the journal BioEssays, Arizona and Australian researchers challenge this model by proposing that cancer is a type of genetic throwback, that progresses via a series of reversions to ancestral forms of life. In contrast with the conventional model, the distinctive capabilities of cancer cells are not primarily generated by mutations, the researchers claim, but are pre-existent and latent in normal cells.

Regents' Professor Paul Davies, director of Arizona State University's Beyond Center for Fundamental Concepts in Science and Kimberly Bussey, cancer geneticist and bioinformatician from the Precision Medicine Program at Midwestern University, Glendale, Ariz., teamed up with Charles Lineweaver and Anneke Blackburn at the Australian National University (ANU) in Canberra to refine what they call the Serial Atavism Model (SAM) of cancer. This model suggests that cancer occurs through multiple steps that resurrect ancient cellular functions.

Such functions are retained by evolution for specific purposes such as embryo development and wound healing, and are usually turned off in the adult form of complex organisms. But they can be turned back on if something compromises the organism's regulatory controls. It is the resulting resurrection steps, or atavistic reversions, that are mostly responsible for the ability of cancer cells to survive, proliferate, resist therapy and metastasize, the researchers said.

Davies and Bussey are also members of ASU's Arizona Cancer Evolution Center (ACE) which seeks to understand cancer, not just in humans, but across all complex species, in the light of evolutionary processes.

"Cancer research has been transformed in recent years by comparing genetic sequences across thousands of species to determine gene ages," Davies said. Just as geologists can date rock strata, so geneticists can date genes, a technique known as phylostratigraphy.

"The atavistic model predicts that the genes needed for cancer's abilities are mostly ancient - in some cases little changed over billions of years," Davies added.

Lineweaver explained, "In biology, nothing makes sense except in the light of evolution, and in the case of cancer nothing makes sense except in the light of the deep evolutionary changes that occurred as we became multicellular organisms."

"The atavistic model of cancer has gained increasing traction around the world," added Bussey. "In part, this is because it makes many predictions that can be tested by phylostratigraphy, unlike the conventional somatic mutation theory."

Blackburn, a cancer biologist in ANU's John Curtin School of Medical Research, agreed.

"Appreciation of the importance of gene ages is growing among oncologists and cancer biologists," she said. "Now we need to use this insight to develop novel therapeutic strategies. A better understanding of cancer can lead to better therapeutic outcomes."

                  https://www.eurekalert.org/pub_releases/2021-05/asu-cts051921.php

Researchers Find New Form of Carbon

And that new arrangement is not graphene: researchers in Germany and Finland discover new type of atomically thin carbon material

From:  Aalto University

May 20, 2021 -- Carbon exists in various forms. In addition to diamond and graphite, there are recently discovered forms with astonishing properties. For example graphene, with a thickness of just one atomic layer, is the thinnest known material, and its unusual properties make it an extremely exciting candidate for applications like future electronics and high-tech engineering. In graphene, each carbon atom is linked to three neighbours, forming hexagons arranged in a honeycomb network. Theoretical studies have shown that carbon atoms can also arrange in other flat network patterns, while still binding to three neighbours, but none of these predicted networks had been realized until now.

Researchers at the University of Marburg in Germany and Aalto University in Finland have now discovered a new carbon network, which is atomically thin like graphene, but is made up of squares, hexagons, and octagons forming an ordered lattice. They confirmed the unique structure of the network using high-resolution scanning probe microscopy and interestingly found that its electronic properties are very different from those of graphene.

In contrast to graphene and other forms of carbon, the new Biphenylene network — as the new material is named —has metallic properties. Narrow stripes of the network, only 21 atoms wide, already behave like a metal, while graphene is a semiconductor at this size. “These stripes could be used as conducting wires in future carbon-based electronic devices.” said professor Michael Gottfried, at University of Marburg, who leads the team that developed the idea. The lead author of the study, Qitang Fan from Marburg continues, “This novel carbon network may also serve as a superior anode material in lithium-ion batteries, with a larger lithium storage capacity compared to that of the current graphene-based materials.”

The team at Aalto University helped image the material and decipher its properties. The group of Professor Peter Liljeroth carried out the high-resolution microscopy that showed the structure of the material, while researchers led by Professor Adam Foster used computer simulations and analysis to understand the exciting electrical properties of the material.

The new material is made by assembling carbon-containing molecules on an extremely smooth gold surface. These molecules first form chains, which consist of linked hexagons, and a subsequent reaction connects these chains together to form the squares and octagons. An important feature of the chains is that they are chiral, which means that they exist in two mirroring types, like left and right hands. Only chains of the same type aggregate on the gold surface, forming well-ordered assemblies, before they connect. This is critical for the formation of the new carbon material, because the reaction between two different types of chains leads only to graphene. “The new idea is to use molecular precursors that are tweaked to yield biphenylene instead of graphene” explains Linghao Yan, who carried out the high-resolution microscopy experiments at Aalto University.

For now, the teams work to produce larger sheets of the material, so that its application potential can be further explored. However, “We are confident that this new synthesis method will lead to the discovery of other novel carbon networks.” said Professor Liljeroth.

               https://www.aalto.fi/en/news/a-new-form-of-carbon

Disagreement About Forest Management

‘We can’t plant our way out of the climate crisis’

From: University of Michigan

May 20, 2021 -- Some climate activists advocate large-scale tree-planting campaigns in forests around the world to suck up heat-trapping carbon dioxide and help rein in climate change.

But in a Perspectives article scheduled for publication May 21 in the journal Science, a University of Michigan climate scientist and his University of Arizona colleague say the idea of planting trees as a substitute for the direct reduction of greenhouse gas emissions could be a pipe dream.

“We can’t plant our way out of the climate crisis,” said Arizona’s David Breshears, a top expert on tree mortality and forest die-off in the West. His co-author is Jonathan Overpeck, dean of the U-M School for Environment and Sustainability and an expert on paleoclimate and climate-vegetation interactions.

Instead of wasting money by planting lots of trees in a way that is destined to fail, it makes more sense to focus on keeping existing forests healthy so they can continue to act as carbon “sinks,” removing carbon from the atmosphere through photosynthesis and storing it in trees and soils, according to the researchers. At the same time, emissions must be reduced as much as possible, as quickly as possible.

Overpeck and Breshears say they hope the role of the world’s forests—and specifically the urgent need to protect existing forests and keep them intact—is thoroughly debated when the world’s climate action leaders gather at the COP26 climate change conference in Glasgow this November.

“Policymakers need to enable new science, policy and finance mechanisms optimized for the disturbance and vegetation change that is unstoppable, and also to ensure that the trees and forests we wish to plant or preserve for the carbon they sequester survive in the face of climate change and other human threats,” Overpeck and Breshears wrote.

“Failure to meet this challenge will mean that large terrestrial stores of carbon will be lost to the atmosphere, accelerating climate change and the impacts on vegetation that threaten many more of the ecosystem services on which humans depend.”

Keeping forests healthy will require a new approach to forest management, one that Overpeck and Breshears call managing for change. As a first step, policymakers and land managers need to acknowledge that additional large-scale vegetation changes are inevitable.

Climate change has been implicated in record-setting wildfires in the western United States, Australia and elsewhere, as well as extensive tree die-offs that are largely due to hotter, drier climate extremes. Those disturbing trends are expected to accelerate as the climate warms, according to Overpeck and Breshears.

“Even in a world where climate change is soon halted, global temperature rise will likely reach between 1.5 and 2 C above pre-industrial levels, with all the associated extreme heat waves that brings, and thus global vegetation will face up to double the climate change already experienced,” they wrote.

At the same time, deforestation continues to expand globally and is especially damaging in tropical forests, which hold vast amounts of biodiversity and sequestered carbon.

The next step toward a new managing-for-change paradigm is to manage forests proactively for the vegetation changes that can be anticipated—instead of trying to maintain forests as they were in the 20th century, Overpeck and Breshears say.

Managing for change means, for example, more aggressive thinning of forests to reduce the buildup of fuels that stoke massive wildfires. It also means selectively replacing some trees—after a wildfire, for example—that are no longer in optimal climate zones with new species that will thrive now and in coming decades.

Such activities, where needed, will inevitably increase the costs of forest management, according to the researchers. But such costs should be considered a prudent investment, one that helps preserve an underappreciated service that forests provide to humanity for free: carbon storage, also known as carbon sequestration.

Forests are already managed to preserve the natural resources and ecosystem services they provide. In addition to supplying timber, fuelwood, fiber and other products, forests clean the air, filter the water, and help control erosion and flooding. They preserve biodiversity and promote soil formation and nutrient cycling, while offering recreational opportunities such as hiking, camping, fishing and hunting.

Carbon sequestration should rank high on the list of invaluable services that forests provide, and efforts to preserve and enhance this vital function should be funded accordingly, Overpeck and Breshears say.

For example, there’s a big opportunity to improve the ability of forests to store carbon through increased use of biochar, a form of charcoal produced by exposing organic waste matter—such as wood chips, crop residue or manure—to heat in a low-oxygen environment. Large amounts of wood generated during forest thinning projects could be converted to biochar, then added to forest soils to improve their health and increase the amount of carbon that is locked away, Overpeck says.

“Thinning of forests, conversion of the removed wood to biochar and burial of the biochar in forest soils is a way to bring new jobs to forested rural areas while allowing forests to play a bigger role in keeping carbon out of the atmosphere and thus fighting climate change,” he said. “Forest carbon management could be a boon for rural areas in need of new economic engines.”

In the long run, such projects are likely to benefit forests and enhance their ability to store carbon far more than massive tree-planting campaigns conducted without appropriate management strategies, according to Overpeck and Breshears.

“Tree-planting has great appeal to some climate activists because it is easy and not that expensive,” Breshears said. “But it’s like bailing water with a big hole in the bucket: While adding more trees can help slow ongoing warming, we’re simultaneously losing trees because of that ongoing warming.”

In their Perspectives article, Overpeck and Breshears explore the implications of a new study by Ondřej Mottl et al., also scheduled for publication May 21 in Science, titled “Global acceleration in rates of vegetation change over the past 18,000 years.”

https://news.umich.edu/forests-and-climate-change-we-cant-plant-our-way-out-of-the-climate-crisis/

 

Spiking Immune System to Fight Cancer

A new study shows how engineered immune cells used in new cancer therapies can overcome physical barriers to allow a patient's own immune system to fight tumors.

From:  University of Minnesota

May 14, 2021 -- The research could improve cancer therapies in the future for millions of people worldwide.

The research is published in Nature Communications, a peer-reviewed, open access, scientific journal published by Nature Research.

Instead of using chemicals or radiation, immunotherapy is a type of cancer treatment that helps the patient's immune system fight cancer. T cells are a type of white blood cell that are of key importance to the immune system. Cytotoxic T cells are like soldiers who search out and destroy the targeted invader cells.

While there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, a T cell's job is much more difficult in solid tumors.

"The tumor is sort of like an obstacle course, and the T cell has to run the gauntlet to reach the cancer cells," said Paolo Provenzano, the senior author of the study and a biomedical engineering associate professor in the University of Minnesota College of Science and Engineering. "These T cells get into tumors, but they just can't move around well, and they can't go where they need to go before they run out of gas and are exhausted."

In this first-of-its-kind study, the researchers are working to engineer the T cells and develop engineering design criteria to mechanically optimize the cells or make them more "fit" to overcome the barriers. If these immune cells can recognize and get to the cancer cells, then they can destroy the tumor.

In a fibrous mass of a tumor, the stiffness of the tumor causes immune cells to slow down about two-fold -- almost like they are running in quicksand.

"This study is our first publication where we have identified some structural and signaling elements where we can tune these T cells to make them more effective cancer fighters," said Provenzano, a researcher in the University of Minnesota Masonic Cancer Center. "Every 'obstacle course' within a tumor is slightly different, but there are some similarities. After engineering these immune cells, we found that they moved through the tumor almost twice as fast no matter what obstacles were in their way."

To engineer cytotoxic T cells, the authors used advanced gene editing technologies (also called genome editing) to change the DNA of the T cells so they are better able to overcome the tumor's barriers. The ultimate goal is to slow down the cancer cells and speed up the engineered immune cells. The researchers are working to create cells that are good at overcoming different kinds of barriers. When these cells are mixed together, the goal is for groups of immune cells to overcome all the different types of barriers to reach the cancer cells.

Provenzano said the next steps are to continue studying the mechanical properties of the cells to better understand how the immune cells and cancer cells interact. The researchers are currently studying engineered immune cells in rodents and in the future are planning clinical trials in humans.

While initial research has been focused on pancreatic cancer, Provenzano said the techniques they are developing could be used on many types of cancers.

"Using a cell engineering approach to fight cancer is a relatively new field," Provenzano said. "It allows for a very personalized approach with applications for a wide array of cancers. We feel we are expanding a new line of research to look at how our own bodies can fight cancer. This could have a big impact in the future."

          https://www.sciencedaily.com/releases/2021/05/210514134222.htm

Certain Proteins Predict Future Dementia

LARGE STUDY OF PLASMA PROTEINS AND DEMENTIA ILLUMINATES THE BIOLOGY OF DEMENTIA AND ALZHEIMER’S AND MAY HELP LEAD TO TREATMENTS

May 17, 2021 -- The development of dementia, often from Alzheimer’s disease, late in life is associated with abnormal blood levels of dozens of proteins up to five years earlier, according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health. Most of these proteins were not known to be linked to dementia before, suggesting new targets for prevention therapies.

The findings are based on new analyses of blood samples of over ten thousand middle-aged and elderly people—samples that were taken and stored during large-scale studies decades ago as part of an ongoing study. The researchers linked abnormal blood levels of 38 proteins to higher risks of developing Alzheimers within five years. Of those 38 proteins, 16 appeared to predict Alzheimer’s risk two decades in advance.

Although most of these risk markers may be only incidental byproducts of the slow disease process that leads to Alzheimer’s, the analysis pointed to high levels of one protein, SVEP1, as a likely causal contributor to that disease process.

The study was published May 14 in Nature Aging

“This is the most comprehensive analysis of its kind to date, and it sheds light on multiple biological pathways that are connected to Alzheimer’s,” says study senior author Josef Coresh, MD, PhD, MHS, George W. Comstock Professor in the Department of Epidemiology at the Bloomberg School. “Some of these proteins we uncovered are just indicators that disease might occur, but a subset may be causally relevant, which is exciting because it raises the possibility of targeting these proteins with future treatments.”

More than six million Americans are estimated to have Alzheimer’s, the most common type of dementia, an irreversible fatal condition that leads to loss of cognitive and physical function. Despite decades of intensive study, there are no treatments that can slow the disease process, let alone stop or reverse it. Scientists widely assume that the best time to treat Alzheimer’s is before dementia symptoms develop.

Efforts to gauge people’s Alzheimer’s risk before dementia arises have focused mainly on the two most obvious features of Alzheimer’s brain pathology: clumps of amyloid beta protein known as plaques, and tangles of tau protein. Scientists have shown that brain imaging of plaques, and blood or cerebrospinal fluid levels of amyloid beta or tau, have some value in predicting Alzheimer’s years in advance.

But humans have tens of thousands of other distinct proteins in their cells and blood, and techniques for measuring many of these from a single, small blood sample have advanced in recent years. Would a more comprehensive analysis using such techniques reveal other harbingers of Alzheimer’s? That’s the question Coresh and colleagues sought to answer in this new study.

The researchers’ initial analysis covered blood samples taken during 2011–13 from more than 4,800 late-middle-aged participants in the Atherosclerosis Risk in Communities (ARIC) study, a large epidemiological study of heart disease-related risk factors and outcomes that has been running in four U.S. communities since 1985. Collaborating researchers at a laboratory technology company called SomaLogic used a technology they recently developed, SomaScan, to record levels of nearly 5,000 distinct proteins in the banked ARIC samples.

The researchers analyzed the results and found 38 proteins whose abnormal levels were significantly associated with a higher risk of developing Alzheimer’s in the five years following the blood draw.

They then used SomaScan to measure protein levels from more than 11,000 blood samples taken from much younger ARIC participants in 1993–95. They found that abnormal levels of 16 of the 38 previously identified proteins were associated with the development of Alzheimer’s in the nearly two decades between that blood draw and a follow-up clinical evaluation in 2011–13.

To verify these findings in a different patient population, the scientists reviewed the results of an earlier SomaScan of blood samples taken in 2002–06 during an Icelandic study. That study had assayed proteins including 13 of the 16 proteins identified in the ARIC analyses. Of those 13 proteins, six were again associated with Alzheimer’s risk over a roughly 10-year follow-up period.

In a further statistical analysis, the researchers compared the identified proteins with data from past studies of genetic links to Alzheimer’s. The comparison suggested strongly that one of the identified proteins, SVEP1, is not just an incidental marker of Alzheimer’s risk but is involved in triggering or driving the disease.

SVEP1 is a protein whose normal functions remain somewhat mysterious, although in a study published earlier this year it was linked to the thickened artery condition, atherosclerosis, which underlies heart attacks and strokes.

Other proteins associated with Alzheimer’s risk in the new study included several key immune proteins—which is consistent with decades of findings linking Alzheimer’s to abnormally intense immune activity in the brain.

The researchers plan to continue using techniques like SomaScan to analyze proteins in banked blood samples from long-term studies to identify potential Alzheimer’s-triggering pathways—a potential strategy to suggest new approaches for Alzheimer’s treatments.

The scientists have also been studying how protein levels in the ARIC samples are linked to other diseases such as vascular (blood vessel-related) disease in the brain, heart and the kidney.

First author Keenan Walker, PhD, worked on this analysis while on faculty at the Johns Hopkins University School of Medicine and the Bloomberg School’s Welch Center for Prevention, Epidemiology and Clinical Research. He is currently an investigator with the National Institute of Aging’s Intramural Research Program.

https://www.jhsph.edu/news/news-releases/2021/researchers-identify-proteins-that-predict-future-dementia-alzheimers-risk.html

Simple Surgery Prevents Some Strokes

Extends life for patients with heart arrhythmia

From: McMaster University in Canada

May 15, 2021 -- A simple surgery saves patients with heart arrhythmia from often-lethal strokes, says a large international study led by McMaster University.

Researchers found that removing the left atrial appendage— an unused, finger-like tissue that can trap blood in the heart chamber and increase the risk of clots— cuts the risk of strokes by more than one-third in patients with atrial fibrillation.

Even better, the reduced clotting risk comes on top of any other benefits conferred by blood-thinner medications patients with this condition are usually prescribed.

“If you have atrial fibrillation and are undergoing heart surgery, the surgeon should be removing your left atrial appendage, because it is a set-up for forming clots. Our trial has shown this to be both safe and effective for stroke prevention,” said Richard Whitlock, first author of the study.

“This is going to have a positive impact on tens of thousands of patients globally.”

Whitlock is a scientist at the Population Health Research Institute (PHRI), a joint institute of McMaster University and Hamilton Health Sciences (HHS); a professor of surgery at McMaster, the Canada Research Chair in cardiovascular surgical trials, a cardiac surgeon for HHS, and is supported by a Heart and Stroke Foundation career award.

The co-principal investigator of the study is Stuart Connolly who has also advanced this field by establishing the efficacy and safety of newer blood thinners. He is a professor emeritus of medicine at McMaster, a PHRI senior scientist and a HHS cardiologist.

“The results of this study will change practice right away because this procedure is simple, quick and safe for the 15 per cent of heart surgery patients who have atrial fibrillation. This will prevent a great burden of suffering due to stroke,” Connolly said.

The study results were fast tracked into publication by The New England Journal of Medicine and presented at the American College of Cardiology conference today.

The study tracked 4,811 people in 27 countries who are living with atrial fibrillation and taking blood thinners. Consenting patients undertaking cardiopulmonary bypass surgery were randomly selected for the additional left atrial appendage occlusion surgery; their outcomes compared with those who only took medicine. They were all followed for a median of four years.

Whitlock said it was suspected since the 1940s that blood clots can form in the left atrial appendage in patients with atrial fibrillation, and it made sense to cut this useless structure off if the heart was exposed for other surgery. This is now proven to be true.

Atrial fibrillation is common in elderly people and is responsible for about 25 per cent of ischemic strokes which are caused when blood clots block arteries supplying parts of the brain. The average age of patients in the study was 71.

“In the past all we had was medicine. Now we can treat atrial fibrillation with both medicines and surgery to ensure a much better outcome,” said Whitlock.

He said that the current study tested the procedure during cardiac surgery being undertaken for other reasons, but the procedure can also be done through less invasive methods for patients not having heart surgery. He added that future studies to examine that approach will be important.

Whitlock said the left atrial appendage is a leftover from how a person’s heart forms as an embryo and it has little function later in life.

“This is an inexpensive procedure that is safe, without any long-term adverse effects, and the impact is long-term.”

External funding for the study came from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.

    Simple surgery prevents strokes in heart patients – Brighter World (mcmaster.ca)