Feeds:
Posts
Comments

Lesson 7 of Cell Signaling 7 Motility: Tubulin and Tutorial Quizes for #TUBiol3373

Stephen J. Williams, Ph.D.

This lesson (lesson 7) will discuss the last type of cytoskeletal structure: microtubules and tubulin.  In addition I want to go over the last quiz answers and also introduce some new poll quizes.

I had given the lecture 7 over Canvas and each of you can download and go over the lecture but I will highlight a few slides in the lecture.

Let’s first review:

Remember that microtubules are the largest of the three cytoskeletal structures:

actin microfilaments < intermediate filaments < microtubules

This is very important to understand as the microtubules, as shown later, shuttle organelles and cellular structures like synaptic vesicles, as well as forming the centrisome and spindle fibers of mitosis.

 

 

 

 

 

 

 

 

 

 

 

 

 

Now remember the quiz question from last time

Remember that actin monomers (the G actin binds ATP)  while tubulin, the protein which makes up the microtubules binds GTP {although it is a little more complex than that as the following diagram shows}

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

See how the growth at the plus end is dependent on tubulin heterodimer GTP while when GDP is only bound to tubulin (both forms) you get a destabilization of the plus end and removal of tubulin dimers (catastrophe) if there is no source of tubulin GTP dimers (alpha tubulin GTP with beta tubulin GTP).

 

 

 

 

Also remember that like actin microfilaments you can have treadmilling (the plus end  continues growing while minus end undergoes catasrophe).  The VIDEO below describes these processes:

 

 

 

Certain SNPs and mutants of tubulin are found and can result in drastic phenotypic changes in microtubule stability and structure. Below is an article where a mutation in tubulin can result in microtubule catastrophe or destabilization of microtubule structures.

 

From: A mutation uncouples the tubulin conformational and GTPase cycles, revealing allosteric control of microtubule dynamics;, E.A. Geyer et al..; elife 2015;4:e10113

Abstract

Microtubule dynamic instability depends on the GTPase activity of the polymerizing αβ-tubulin subunits, which cycle through at least three distinct conformations as they move into and out of microtubules. How this conformational cycle contributes to microtubule growing, shrinking, and switching remains unknown. Here, we report that a buried mutation in αβ-tubulin yields microtubules with dramatically reduced shrinking rate and catastrophe frequency. The mutation causes these effects by suppressing a conformational change that normally occurs in response to GTP hydrolysis in the lattice, without detectably changing the conformation of unpolymerized αβ-tubulin. Thus, the mutation weakens the coupling between the conformational and GTPase cycles of αβ-tubulin. By showing that the mutation predominantly affects post-GTPase conformational and dynamic properties of microtubules, our data reveal that the strength of the allosteric response to GDP in the lattice dictates the frequency of catastrophe and the severity of rapid shrinking.

https://doi.org/10.7554/eLife.10113.001

 

Remember the term allosterism: change in the affinity for binding of a ligand or substrate that is caused by the binding of another ligand away from the active site (for example like 2,3 DPG effect on oxygen binding to hemoglobin

 

Cellular transport of organelles and vesicles: a function of microtubules

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Now the above figure (figure 9 in your Powerpoint) shows the movement of organelles and vesicles in two different types of cells along microtubules.

Note the magenta arrow which goes from the nucleus toward the plus end of the microtubule (at cell membrane) is referred to as anterograde transport and is movement away from center of cell to the periphery.  Retrograde transport is movement of organelles and vesicles from periphery of cell to the center of the cell.

Note that kinesin is involved in anterograde transport while dyenin is involved in retrograde transport

Also refer to the Wiki page which shows a nice cartoon of this walking down a microtubule on the right hand side of the page

https://en.wikipedia.org/wiki/Axonal_transport

 

 

 

 

 

 

 

Cilia; a cellular structure of microtubules (we will talk about cilia later)

for more information on structure of Cillia please see https://www.ncbi.nlm.nih.gov/books/NBK21698/

This is from a posting by Dr. Larry Bernstein of Yale University at https://pharmaceuticalintelligence.com/2015/11/04/cilia-and-tubulin/

 

RESEARCHERS VIDEO AND MEASURE TUBULIN TRANSPORT IN CILIA FOR THE FIRST TIME.

http://health-innovations.org/2015/01/27/researchers-image-and-measure-tubulin-transport-in-cilia/

 

 

https://michellepetersen76.files.wordpress.com/2015/01/uga-researchers-image-and-measure-tubulin-transport-in-cilia-healthinnovations1.png

 

Defective cilia can lead to a host of diseases and conditions in the human body, from rare, inherited bone malformations to blindness, male infertility, kidney disease and obesity. It is known that these tiny cell organelles become deformed and cause these diseases because of a problem related to their assembly, which requires the translocation of vast quantities of the vital cell protein tubulin. What they didn’t know was how tubulin and another cell organelle known as flagella fit into the process.

Now, a new study from University of Georgia shows the mechanism behind tubulin transport and its assembly into cilia, including the first video imagery of the process. The study was published in the Journal of Cell Biology.

Cilia are found throughout the body, so defects in cilia formation affect cells that line airways, brain ventricles or the reproductive track.  One of the main causes of male infertility is the cilia won’t function properly.

The team used total internal reflection fluorescence microscopy to analyze moving protein particles inside the cilia of Chlamydomonas reinhardtii, a green alga widely used as a model for cilia analysis.

The team exploited the natural behaviour of the organism, which is to attach by its cilia to a smooth surface, such as a microscope glass cover. This positions the cilia within the 200-nanometer reach of the total internal reflection fluorescence microscope allowing for the imaging of individual proteins as they move inside the cilia.  A video explaining the process was published along with the study.

Tubulin is transported by this process called intraflagellar transport, or IFT.  Though it has long been suspected in the field and there was indirect evidence to support the theory, this is the first time it has been shown directly, through live imaging, that IFT does function as a tubulin pump.  The team observed that about 400,000 tubulin dimers need to be transported within 60 minutes to assemble a single cilium. Being able to see tubulin moving into cilia allowed for first insights into how this transport is regulated to make sure cilia will have the correct size.

The new findings are expected to have wide implications for a variety of diseases and conditions related to cilia defects in the body.  The team state that they are on the very basic side of this research.  But because more and more diseases are being connected to cilia-related conditions, including obesity and even diabetes, the number of people working on cilia has greatly expanded over the last few years.

 

So here are the answer to last weeks polls

  1. Actin filaments are the SMALLEST of the cytoskeletal structures.  As shown in this lecture it is tubulin that binds GTP.  Actin binds ATP.
  2.  ARP2/3 or actin related proteins 2 and 3 are nucleating proteins that assist in initiating growth of branched chain micofiliment networks.  Formins are associated with unbranched actin formations.
  3.  The answer is GAPs or GTPase activating proteins.  Remember RAS in active state when GTP is bound and when you hydrolyze the GTP to GDP Ras is inactive state

 

 

 

 

 

4.  Okay so I did a type here but the best answer was acetylcholinesterase (AchE) degrading acetylcholine.  Acetylcholinesterase degrades the neurotransmitter acetylcholine into choline and acetate not as I accidentally put into acetylCoA.  The freed choline can then be taken back up into the presynaptic neuron and then, with a new acetyl group (with Coenzyme A) will form acetylcholine.

 

Synthesis of the neurotransmitter acetylcholine

 

 

 

The neuromuscular junction

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Thanks to all who took the quiz.  Remember it is for your benefit.

 

 

 

 


Economic Implications Of The Coronavirus

“From: Washington Post (March 19, 2020), The Atlantic (March 19, 2020), American Progress (3/6/2020), Morningstar (March 10, 2020)

1. THE CONCEPT OF A PANDEMIC

Pandemics are particularly dangerous because the general population does not have immunity to the disease. Interestingly, flu pandemics have decreased in severity with time, perhaps partly due to viral preference for diseases that are very transmissible but not lethal. Despite some similarities between seasonal and pandemic flu, there are also key differences. While seasonal flu is every year, pandemics can have multiple waves; Spanish flu came in three waves, and the 2009 swine flu had two waves.

Past pandemics have varied substantially in their lethality. For example, the 1957 Asian flu, considered a moderate pandemic, emerged in China in February 1957, reached the U.S. by June, and spread very rapidly in the fall in the U.S. and Europe, with the return to school seen as a significant driver for starting new community epidemics during that pandemic. The corresponding vaccine was developed too late and was not more than 60% effective. Most schools remained open and no travel restrictions or restrictions on social gatherings were undertaken; 25% of the U.S. population was infected. The 1968 Hong Kong flu was milder but more widespread (estimated at almost 40% of the U.S. population infected). The death rate may have been significantly lower than Asian flu because patients had some pre-existing immunity.

Coronavirus 101: A New Virus Related to SARS and MERS

On Jan. 7, a new coronavirus was identified as the cause of several cases of pneumonia in Wuhan, China. COVID-19 is the disease caused by SARS-CoV-2, one of a family of coronaviruses, and this particular strain was new to humans. Most coronaviruses spread between animals, although the common cold is often caused by a coronavirus. Like more serious coronaviruses SARS and MERS, SARS-CoV-2 is believed to have jumped to humans by first moving from one species known to carry these diseases to another species capable of transmitting the disease to humans. Like SARS-CoV and MERS, it is believed to be mostly spread through respiratory droplets, often from a patient’s cough.

A comparison with other outbreaks is one of the easiest ways to think about the potential spread of coronavirus, although every disease has slightly different characteristics that limit the accuracy of this analysis. The intersection of the fatality rate (the percentage of infected patients who succumb to the disease) and how contagious it is, if left unchecked, is a simple way to begin to outline the potential impact versus past pandemics. Epidemiologists measure how contagious a disease is using a reproduction number, termed R0, reflecting how many people an infected person can typically infect. Generally speaking, an R0 of greater than 1 is a threshold for a disease being able to expand into an epidemic, and a virus with an R0 above 1.9 is considered highly transmissible. In addition, a higher R0 means a sharper rise and fall of infection rates with a shorter duration of the outbreak. An R0 of 1.9 could imply an outbreak of months, with a two-month peak in infections, as seen with the 1957 and 1968 pandemics.

Diseases are generally the most dangerous if they are both very deadly and very contagious (high R0), but most diseases tend to be more one than the other, as the self-interest of viruses would favor evolution toward diseases that don’t kill their victims. For example, Ebola and rabies have very high fatality rates but are tougher to transmit. At the opposite end of the spectrum is the common cold, which is fairly easy to transmit but almost never fatal. Smallpox was one of the most destructive diseases, as it was both very contagious and very deadly. Also, the Spanish flu of 1918-19 caused more than 50 million deaths worldwide and killed nearly 3% of the population. However, the spread of a disease is more than these numbers–significant efforts to contain SARS have eradicated the disease, even though it is more easily transmissible than the standard flu (which is very widespread every year).

Even though death rates have been falling gradually for flu pandemics since the 1918 pandemic, coronavirus pandemics are a newer phenomenon and don’t have an established trend. Fatality rates are already being estimated, but this is very difficult to do accurately at the start of any pandemic.

One interesting observation on the lethality of the 1918 flu pandemic is that the high mortality rate of soldiers on the front lines of Western Europe exerted an evolutionary pressure on the flu virus. From the virus’ viewpoint, it makes no sense to preserve the life of your victim if the victim is going to die anyway from non-flu causes. Therefore, natural selection favored the emergence of flu mutation that both infected and killed rapidly.

2. WHAT IS TO BE DONE?

International Monetary Fund says the outbreak is the world’s “most pressing uncertainty.” The economic disruptions caused by the virus and the increased uncertainty are being reflected in lower valuations and increased volatility in the financial markets. While the exact effect of the coronavirus on the U.S. economy is unknown and unknowable, it is clear that it poses tremendous risks.

Policymakers should therefore immediately undertake a number of steps to address any economic fallout from the virus. The burden of meeting this challenge falls squarely on Congress and the Trump administration. The guiding principles need to be:

• Do no harm
• Put more, not fewer, resources in public health efforts
• Assure businesses that things will be fine if the virus hits their sector and remediate harm when necessary
• Calm financial markets
• Ease the risks for households and vulnerable populations

3. THE CHINA SYNDROME – 2020 VERSION

Economists have been using the SARS epidemic to put the coronavirus outbreak in context. The 2003 SARS epidemic is estimated to have shaved 0.5 percent to 1 percent off of China’s growth that year and cost the global economy about $40 billion (or 0.1 percent of global GDP).The coronavirus epidemic, which like SARS originated in China, differs in a few key ways.

China’s economy accounted for roughly 4 percent of the world’s GDP in 2003; it now commands 16.3 percent. If the coronavirus has a similar effect on China as SARS, the impact on global growth will be worse. Moreover, China’s growth is weaker than it was in 2003—after years of rapid economic development, China’s growth stands at 6 percent, the lowest it’s been since 1990. The dual effects of general economic deceleration and the U.S.-China trade war escalation has shaken its confidence. Even before the epidemic, China’s Purchasing Managers’ Index was already showing signs of contraction. The February reading slowed from 50 to 35.7, a level in line with that of November 2008 during the global financial crisis. The economic fallout from the coronavirus could rattle China’s economy further and dampen global growth.

Outside China, the outbreak has also affected global supply chains, as other governments have also taken immediate steps to slow the spread of the virus. The Harvard Business Review predicts that the peak of the impact will occur in late-March, “forcing thousands of companies to throttle down or temporarily shut assembly and manufacturing plants in the U.S. and Europe.” This again will disrupt global supply chains as well as demand for goods and services in the affected economies. These disruptions make it more difficult for companies in the U.S. and elsewhere to bring their goods to customers, and these companies will reduce exports from the U.S. to the rest of the world in the coming months.

Furthermore, households, companies, and governments alike are deeper in debt now than they were when SARS hit. For example, the U.S. nonfinancial corporate debt of large companies is currently around $10 trillion, up from around $4.8 trillion in 2003. Deutsche Bank released analysis showing the world’s major economies harboring the highest debt levels of the past 150 years, with World War II as an exception. They all still need to continue repaying that debt, even if jobs, customers, and tax revenues decline in a weakening economy. These fixed costs then will leave less money to spend on other things. Large amounts of debt often exacerbate an economic slowdown, especially if central banks can do little to ease that burden by cutting interest rates.

The world looks different from the last global virus outbreak in 2003. Global growth is already slow, and financial markets already have very low interest rates, which means that central banks in almost every major country have little ammunition with which to mitigate any potential economic fallout. This puts greater pressure on governments to use the power of their purse to counter the economic fallout from the coronavirus. While the fallout from the coronavirus will disrupt supply chains and global demand that could also affect the U.S. economy, the current situation also creates a lot of uncertainty over the longer term. Congress and the Trump administration can do a lot to counter the risks associated with the spread of the virus by engaging in fiscal policies (deficit spending) that will provide relief to affected populations and mitigate disruptions to U.S firms.

4. OUR FRAGILE SUPPLY CHAIN….CHEAP, BUT AT A PRICE

When Trump invoked the Defense Production Act, it was telling in two respects. First, it showed that the full force of the federal government will be brought to bear in the manufacturing of vital medical supplies. Second, it underlined what has already become clear: The way our modern supply chain is built is incredibly fragile.

We’ve built a global supply chain that runs on outsourcing and thin margins, and the coronavirus has exposed just how delicate it is.

We need to realize that there’s almost no industry sector—manufacturing and non-manufacturing—that isn’t reliant on China in the United States.
Chinese materials and manufacturing are so pervasive that the average customer has no idea how many of their everyday products contain Chinese components, or how reliant on Chinese components most companies have become. If you don’t have a first-tier supplier who’s sourcing from China, then your supplier’s supplier is.

To understand why the modern supply chain is uniquely vulnerable to a threat like the coronavirus, you have to realize how quickly it has changed. China joined the World Trade Organization in 2001, and surpassed the U.S. as an industrial powerhouse in 2010. During the SARS epidemic of 2002 and 2003, China represented 4.31 percent of worldwide GDP – today, it’s 16 percent.

Western companies find it cheaper to manufacture goods in China, and elsewhere in Asia, than to do so closer to home. Car parts, technology, fashion, medical gear, and drug components are particularly vulnerable to disruptions in Asian markets. In 2012, after the Japanese tsunami, you couldn’t buy a red Toyota for months, because the one factory that made red pigment for Toyota was offline. Apple, Fiat Chrysler, and Hyundai have already warned investors of potential supply constraints due to the coronavirus pandemic.

In addition to offshoring, companies have emphasized “just in time” delivery, keeping only 15 to 30 days of products on hand. That has made global companies more profitable but has also “significantly increased supply-chain risk.”


The worst of the supply-chain disruptions would begin now. Fewer Chinese ships are on the water, and major ports around the world, such as Rotterdam and Le Havre, are already feeling the effects. Those 15 to 30 days of inventory (even if a company stocked up prior to the Chinese Lunar New Year holiday) are likely running low now. We are going to see a slowdown, disruption, less variety, less options to the customers.

As the COVID-19 pandemic ripples throughout the world economy, it’s possible that it may begin to change the way global supply chains work. Companies will come under pressure to diversify where they make their products, which will prove easier for some than for others. While the blood thinner heparin may still be made in China, it’s not as difficult to move the infrastructure for, say, the kind of fashion sold at H&M and Zara to other Asian countries. “You can still emphasize low labor costs by moving into Vietnam, Malaysia, and Cambodia,” he said. More electronic and car-part production could shift to factories in Mexico and Brazil.

5. THE NEW NORMAL

Taking the above into account (plus numerous other factors): how bad will this all be?

We have essentially made a collective decision to have ourselves a recession. We’ve shut down a significant portion of our economy, knowing that the result will be businesses going bankrupt, huge job losses and people losing their homes.

How bad it gets depends on decisions the federal government makes in coming days.

JP Morgan forecast that the second quarter contraction would be a stunning 14 percent — worse than the depth of the Great Recession. If they’re right, this would translate to 7.5 million jobs lost by the summer. In the Great Recession, about 8 million jobs disappeared. Now some are predicting that the drop in payrolls for April alone could be as high as 5 million.

Recessions are often set off by some kind of shock, but it’s usually preceded by a period of slowdown or uncertainty. Now we’ve gone from 60 to zero in days. You can now go to restaurants that are shuttered that were doing a booming business a few weeks ago.

We’re already seeing a dramatic jump in unemployment claims, but current data almost certainly underestimate how bad the situation has already gotten. Those who have filed so far were people who were laid off last week, and also got their act together to file unemployment claims.

If we know that we’re plunging off a cliff, the next question is how quickly we might begin to recover. Forecasts from Goldman Sachs, JPMorgan and Bank of America all assume the economy will bounce back in the third and fourth quarters of this year, but that might not be the case even if we get the virus under control: there are a lot of people losing their livelihoods.

As part of the federal solution, we have to make it possible for businesses not to lay people off even if they aren’t working, through some combination of grants and low-interest loans, to get a “quick bounce-back” by keeping people connected to their employers.

All these economists said we must do everything: Give support to state governments that are particularly vulnerable because they’re required by law to balance budgets; help employers not go out of business; shore up the safety net, including unemployment insurance, Medicaid and food stamps; and give support directly to people.

During the Great Recession, we turned to austerity way too fast and lengthened the pain way longer than we should have. The danger is not in building up debt that eventually will have to be repaid, but in holding back because the numbers look too large. The risk is not in doing too much, but in doing too little. All this is pretty frightening — and it doesn’t even take into account how long it might take to control the coronavirus.

Sources: Washington Post (March 19, 2020) , The Atlantic (March 19, 2020), American Progress (3/6/2020), Morningstar (March 10, 2020)


Reporter: Gail S. Thornton, M.A.

The following article is reprinted from the Anchorage Daily News.

https://www.adn.com/alaska-news/2020/03/18/one-of-alaskas-first-confirmed-coronavirus-patients-tells-his-story/

One of Alaska’s first confirmed coronavirus patients tells his story

March 19, 2020

A Ketchikan man who contracted the illness caused by the new coronavirus is speaking out about his experience.

In a social media post and an interview with the Ketchikan Daily News, he described his symptoms, how he was tested and his experience communicating with Alaska public health officials.

As of Wednesday morning, Glenn Brown, the attorney for the Ketchikan Gateway Borough, is one of nine people statewide who have confirmed cases of the virus. Officials have not said any of the people with confirmed cases have been hospitalized.

Brown said in a Facebook post that he was feeling better and was notified by public health officials that he’d tested positive for COVID-19 on Tuesday afternoon.

“I became sick Saturday morning with fever, headache, general achiness and chills,” Brown wrote.

Brown said he has “no idea” how he contracted the illness.

“I interacted with no one in recent weeks who was exhibiting obvious symptoms,” he wrote.

According to a statement Tuesday from the Ketchikan Emergency Operations Center saying one of its employees tested positive for the virus, the employee had a history of travel to the Lower 48. The Ketchikan Emergency Operations Center on Wednesday confirmed Brown is the employee.

The Ketchikan Daily News reported that Brown had recently traveled to Oregon and Juneau before returning to Ketchikan on March 9.

After public health officials told Brown his diagnosis, he said that he went through more than an hour of questions with them, he told the Ketchikan Daily News.

“I used everything from cellphone records to work calendars to debit card bills, to recall everybody that I may have had contact with,” Brown told the Ketchikan Daily News. “I wanted to provide that information to public health, (so) that they could alert those people and really hope to kind of arrest this thing.”

Brown told the paper that public health officials focused on two days before he developed symptoms of the illness. Brown had been “working closely with borough staff and upper management” in those days as part of his job, the paper reported.

“I apologize for causing undue concern for anyone, especially my co-workers at the Borough,” Brown said in the Facebook post.

Ketchikan Gateway Borough employees in direct contact with Brown were instructed to self-quarantine for two weeks, according to the Ketchikan Emergency Operations Center statement.

The statement also said that the borough had hired a service to disinfect the now-closed White Cliff Building, which houses the Ketchikan Borough offices.

According to the Ketchikan Daily News, the last time Brown was at the borough’s White Cliff Building was Friday.

The paper reported that as of Tuesday night, there were no plans to test people who had been in direct contact with Brown.

A public information officer for Ketchikan’s Emergency Operations Center told the Ketchikan Daily News that she understood that to be tested, people would need to have “several” symptoms of the virus.

“I would also ask that you join me and all of Ketchikan to actively minimize community transmission so that we can protect our seniors or other medically vulnerable folks in Ketchikan,” Brown wrote. “I pray that we all make it through this largely unharmed, and together.”

The first person in Alaska to test positive for COVID-19 was an air cargo pilot who arrived at Ted Stevens Anchorage International Airport on March 11, officials announced last week. He went through the airport’s North Terminal, which is separate from the domestic terminal.

Alaska’s chief medical officer, Dr. Anne Zink, said last week the man had self-isolated and was “stable.”

On Monday, officials said two older men in Fairbanks were diagnosed with the illness. Both had recently traveled to the Lower 48, Zink said, but were not traveling together.

In addition to the Anchorage case, the case in Ketchikan and the two in Fairbanks, officials on Tuesday announced that two more people had become sick with the virus — one in Fairbanks and one in Anchorage — bringing the total number of confirmed cases as of Wednesday morning to six.

Zink said that both of those cases were also travel-related. None of the three people who tested positive for COVID-19 on Tuesday were hospitalized, Zink said.

Fairbanks Memorial Hospital released a statement Tuesday saying a woman with a history of recent travel had tested positive for COVID-19.

“She self-isolated prior to testing,” the statement said. “This patient has been notified and is in stable condition and does not require hospitalization.”

A University of Alaska Fairbanks employee was one of the people who had recently tested positive for the virus in Alaska, university officials said Tuesday.

An internal email advised anyone who had used the O’Neill Building, which houses the College of Fisheries and Ocean Sciences, to stay home and monitor themselves for two weeks.

State and local officials have taken a series of steps to stem the spread of COVID-19 in Alaska, including closing schools, calling on hospitals to halt elective surgeries and shutting down dine-in service at all restaurants, bars, breweries, cafes and similar businesses.

About this Author

Morgan Krakow

Morgan Krakow is a general assignment reporter for the Anchorage Daily News. She is a 2019 graduate of the University of Oregon and spent the past summer as a reporting intern on the general assignment desk of The Washington Post. Contact her at mkrakow@adn.com.

###


Responses to the #COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

Curator: Stephen J. Williams, Ph.D.

UPDATED 3/20/2020

Among the people who are identified at risk of coronovirus 2019 infection and complications of the virus include cancer patients undergoing chemotherapy, who in general, can be immunosuppressed, especially while patients are undergoing their treatment.  This has created anxiety among many cancer patients as well as their care givers and prompted many oncologist professional groups, cancer societies, and cancer centers to formulate some sort of guidelines for both the cancer patients and the oncology professional with respect to limiting the risk of infection to coronavirus (COVID19). 

 

This information will be periodically updated and we are working to get a Live Twitter Feed to bring oncologist and cancer patient advocacy groups together so up to date information can be communicated rapidly.  Please see this page regularly for updates as new information is curated.

IN ADDITION, I will curate a listing of drugs with adverse events of immunosuppression for people who might wonder if the medications they are taking are raising their risk of infections.

Please also see @pharma_BI for updates as well.

Please also see our Coronavirus Portal at https://pharmaceuticalintelligence.com/coronavirus-portal/

For ease of reading information for patients are BOLDED and in RED

ASCO’s Response to COVID-19

From the Cancer Letter: The following is a guest editorial by American Society of Clinical Oncology (ASCO) Executive Vice President and Chief Medical Officer Richard L. Schilsky MD, FACP, FSCT, FASCO. This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.

 

The worldwide spread of the coronavirus (COVID-19) presents unprecedented challenges to the cancer care delivery system.

Our patients are already dealing with a life-threatening illness and are particularly vulnerable to this viral infection, which can be even more deadly for them. Further, as restrictions in daily movement and social distancing take hold, vulnerable patients may be disconnected from friends, family or other support they need as they manage their cancer.

As providers, we rely on evidence and experience when treating patients but now we face uncertainty. There are limited data to guide us in the specific management of cancer patients confronting COVID-19 and, at present, we have no population-level guidance regarding acceptable or appropriate adjustments of treatment and practice operations that both ensure the best outcome for our patients and protect the safety of our colleagues and staff.

As normal life is dramatically changed, we are all feeling anxious about the extreme economic challenges we face, but these issues are perhaps even more difficult for our patients, many of whom are now facing interruption

As we confront this extraordinary situation, the health and safety of members, staff, and individuals with cancer—in fact, the entire cancer community—is ASCO’s highest priority.

ASCO has been actively monitoring and responding to the pandemic to ensure that accurate information is readily available to clinicians and their patients. Recognizing that this is a rapidly evolving situation and that limited oncology-specific, evidence-based information is available, we are committed to sharing what is known and acknowledging what is unknown so that the most informed decisions can be made.

To help guide oncology professionals as they deal with the impact of coronavirus on both their patients and staff, ASCO has collated questions from its members, posted responses at asco.org and assembled a compendium of additional resources we hope will be helpful as the virus spreads and the disease unfolds. We continue to receive additional questions regarding clinical care and we are updating our FAQs on a regular basis.

We hope this information is helpful even when it merely confirms that there are no certain answers to many questions. Our answers are based on the best available information we identify in the literature, guidance from public health authorities, and input received from oncology and infectious disease experts.

For patients, we have posted a blog by Dr. Merry Jennifer Markham, chair of ASCO’s Cancer Communications Committee. This can be found on Cancer.Net, ASCO’s patient information website, and it provides practical guidance to help patients reduce their risk of exposure, better understand COVID-19 symptoms, and locate additional information.

This blog is available both in English and Spanish. Additional blog posts addressing patient questions will be posted as new questions are received and new information becomes available.

Find below a Tweet from Dr.Markham which includes links to her article on COVID-19 for cancer patients

https://twitter.com/DrMarkham/status/1237797251038220289?s=20

NCCN’s Response to COVID-19 and COVID-19 Resources

JNCCN: How to Manage Cancer Care during COVID-19 Pandemic

Experts from the Seattle Cancer Care Alliance (SCCA)—a Member Institution of the National Comprehensive Cancer Network® (NCCN®)—are sharing insights and advice on how to continue providing optimal cancer care during the novel coronavirus (COVID-19) pandemic. SCCA includes the Fred Hutchinson Cancer Research Center and the University of Washington, which are located in the epicenter of the COVID-19 outbreak in the United States. The peer-reviewed article sharing best practices is available for free online-ahead-of-print via open access at JNCCN.org.

Coronavirus disease 2019 (COVID-19) Resources for the Cancer Care Community

NCCN recognizes the rapidly changing medical information relating to COVID-19 in the oncology ecosystem, but understands that a forum for sharing best practices and specific institutional responses may be helpful to others.  Therefore, we are expeditiously providing documents and recommendations developed by NCCN Member Institutions or Guideline Panels as resources for oncology care providers. These resources have not been developed or reviewed by the standard NCCN processes, and are provided for information purposes only. We will post more resources as they become available so check back for additional updates.

Documents

Links

National Cancer Institute Response to COVID-19

More information at https://www.cancer.gov/contact/emergency-preparedness/coronavirus

What people with cancer should know: https://www.cancer.gov/coronavirus

Get the latest public health information from CDC: https://www.coronavirus.gov

Get the latest research information from NIH: https://www.nih.gov/coronavirus

 

Coronavirus: What People with Cancer Should Know

ON THIS PAGE

Both the resources at cancer.gov (NCI) as well as the resources from ASCO are updated as new information is evaluated and more guidelines are formulated by members of the oncologist and cancer care community and are excellent resources for those living with cancer, and also those who either care for cancer patients or their family and relatives.

Related Resources for Patients (please click on links)

 

 

 

Some resources and information for cancer patients from Twitter

Twitter feeds which may be useful sources of discussion and for cancer patients include:

 

@OncLive OncLive.com includes healthcare information for patients and includes videos and newsletters

 

 

@DrMarkham Dr. Markham is Chief of Heme-Onc & gyn med onc @UF | AD Med Affairs @UFHealthCancer and has collected very good information for patients concerning #Covid19 

 

 

@DrMaurieMarkman Dr. Maurie Markman is President of Medicine and Science (Cancer Centers of America, Philadelphia) @CancerCenter #TreatThePerson #Oncology #Genomics #PrecisionMedicine and hosts a great online live Tweet feed discussing current topics in cancer treatment and care for patients called #TreatThePerson Chat

UPDATED 3/20/2020 INFORMATION FROM NCI DESIGNATED CANCER CENTERS FOR PATIENTS/PROVIDERS

The following is a listing with links of NCI Designated Comprehensive Cancer Centers and some select designated Cancer Centers* which have information on infectious risk guidance for cancer patients as well as their physicians and caregivers.   There are 51 NCI Comprehensive Cancer Centers and as more cancer centers formulate guidance this list will be updated. 

 

Cancer Center State Link to COVID19 guidance
City of Hope CA Advice for cancer patients, survivors and caregivers
Jonsson Cancer Center at UCLA CA Cancer and COVID19
UCSF Hellen Diller Family Comprehensive Cancer CA COVID-19 Links for Patients and Providers
Lee Moffit FL Protecting against Coronavirus 19
University of Kansas Cancer Center* KS COVID19 Info for patients
Barbara & Karmanos Cancer Institute (Wayne State) MI COVID19 Resources
Rogel Cancer Center (Univ of Michigan) MI COVID19 Patient Specific Guidelines
Alvin J. Siteman Cancer Center (MO) Coronavirus
Fred & Pamela Buffet CC* NE Resources for Patients and Providers
Rutgers Cancer Institute of NJ NJ What patients should know about COVID19
Memorial Sloan Kettering NY What COVID19 means for cancer patients
Herbert Irving CC (Columbia University) NY Coronavirus Resource Center
MD Anderson Cancer  TX Planning for Patients, Providers
Hunstman Cancer Center UT COVID19 What you need to know
Fred Hutchinson WA COVID19 What patients need to know

 

 

Please also see related information on Coronavirus 2019 and Cancer and Immunotherapy at the following links on the Open Access Online Journal:

Volume Two: Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery 

at

https://pharmaceuticalintelligence.com/biomed-e-books/series-c-e-books-on-cancer-oncology/volume-two-immunotherapy-in-cancer-radiation-oncology/

AND

Coronavirus Portal

 

 

 

 


Will the Coronavirus Permanently Change Our Way of Working?

Reporter: Joel Shertok, PhD

 

FROM “THE ECONOMIST”

DATE: XXXX

What happens if after 2 – 3 months of industry personnel working from home, senior management finds that workers productivity is just as good as in an office environment, and the workers are happier??
————————-
In February 2014 a strike on the London Underground offered management theorists a lesson in resilience and adaptation. Because the shutdown closed some but not all Tube lines, frustrated Londoners were forced to rethink their commutes to and from work. Researchers at Oxford and Cambridge universities subsequently found that around 5% of passengers stuck to their new itineraries even after normal service resumed. The long-term economic gains of one in 20 travellers adopting new and improved ways to get to work turned out to be greater than the short-term costs of the disruption.

The global covid-19 outbreak presents a far greater challenge to the corporate world than striking transport workers. Profit warnings are spreading nearly as fast as the disease. Analysts at Goldman Sachs, a bank, estimate that earnings growth for firms in the s&p 500 index could grind to a halt. Gauges of business activity, such as purchasing managers’ indices, have cratered in Asia and are expected to weaken elsewhere as the coronavirus crosses more borders. Consumers are spending money on little except sanitary wipes, face masks and tins of Campbell’s Soup. Fears of a pandemic have wiped $7trn off the market value of listed firms worldwide in the past fortnight (see article).

Some companies will, like most of London’s commuters, revert to autopilot once the threat recedes. But for others the interruption will have a lasting effect, accelerating trends in business organisation that were already under way. Two are particularly important. The next few months are set to be a giant experiment in whether new technologies can allow successful mass remote working for employees, speeding up the reinvention of the office. And for firms already worried about rickety supply chains amid a trade war, the virus gives another reason to reconfigure them.

Take employees first. Companies have had to ask themselves whether to let employees travel, attend conferences or even come into the office. In all three cases the answer is increasingly “no”. Many big firms, including Amazon and JPMorgan Chase, have banned all non-essential excursions. Airlines and hotels are reporting steep falls in bookings. Corporate Travel Management, a listed Australian firm that organizes business jaunts, has warned the impact could last up to six months. It has slashed its earnings forecast for the year by up to 16.5%. A survey by the Global Business Travel Association, an industry body, found that business travel, which costs companies over $1trn a year (and emits roughly as much carbon as Ukraine in flights alone), could fall by over a third while the epidemic rages.

Large corporate events are being called off. The oil industry’s biggest annual jamboree in Houston and the Geneva motor show will not take place this month. Google and Facebook have given the term “teleconferencing” a whole new meaning by moving a few of their big shindigs partly or wholly online. With Milan and Paris fashion weeks curtailed, Armani streamed its autumn/winter show from behind closed doors. This is bad news for events firms such as Informa, whose share price is down by a fifth since the start of February, especially at a time when many high-profile industry powwows are already losing their lustre.

At the same time more companies are learning to love telecommuting. On March 3rd JPMorgan Chase told thousands of its bankers in America to work from home as it tests its contingency plans. Twitter has asked its 5,000 employees to do likewise. Sony went so far as to shut some of its European offices altogether, just in case. The affected workers are nonetheless expected to toil remotely.

As well as highlighting how bloated some travel budgets are, virus contingency plans may also reveal how inefficiently office space is used. Big British and American firms pay on average $5,000 per employee in annual rental costs. Just 40-50% of desks are actually used during working hours—often not very well. Last year two in five respondents to a survey of 600,000 desk-jockeys by Leesman, a data provider, said their office prevented them from working productively. If their managers now find that productivity does indeed rise—or at least doesn’t dip—as staff self-isolate at home, the case for teleworking may look irresistible. Investors are betting it will. In the past month the share prices of Slack, a corporate-messaging platform, and Zoom, which makes videoconferencing software, have shot up by 18% and 35%, respectively.

The second way in which companies are rethinking their business has to do with supply chains. Since the 1980s these have become more complex and global, with large firms now dependent on thousands of suppliers. The embrace of lean manufacturing and just-in-time delivery of components, pioneered by Toyota in the 1970s, has made production more efficient but more vulnerable to disruption, as companies stockpile fewer and fewer necessary materials. The median firm in the s&p 500 carries only 66 days of inventory, and some have far smaller buffers than even that—Apple has just nine days, according to data from Bloomberg.

When natural disasters strike big companies usually get by, shifting production temporarily from afflicted areas to those that are not. But unlike a flood, an earthquake or even the Sino-American trade war, all of which companies have some experience in planning for, covid-19 could affect all of a firm’s actual and potential subcontractors simultaneously. In such a scenario carrying bigger inventories and having suppliers at home may no longer look wasteful. It may come to be seen as necessary.

Immune response
The coronavirus will not make business travel or lean global supply chains disappear. Chinese factories are cranking up again and high-flyers will, in all likelihood, be back in airport lounges soon enough. But the crisis offers a chance to experiment with new ways of doing things—and to question the wisdom of old habits. Chief executives should not be immune to the opportunity.

SOURCE


Lesson 6 of Cell Signaling & Motility – Cytoskeleton II: #TUBiol3373

Stephen J. Williams, Ph.D.

In this lesson we will go over the biochemical makeup and formation of various actin containing cellular structures involved in cellular motility, structure, as well as the dynamics of muscular contraction.  The lesson had been put on your Canvas and I am emailing you the Google Docs version.  If you are having problems downloading you can download here (I believe maybe the Canvas version had problems with embedding videos properly so that is why I am sending you also by email)

Download Below

cell signaling 6 lesson 2020

After opening the powerpoint (or Google Doc) please review with the following notes which highlight some concepts as well as some reviews and reminders of past lectures.  It may be handy to also have lecture 5 handy if you need to refer to it.  In between some sections there will be polls (really multiple choice quizzes DON’T WORRY you will not be graded on them but they are for your benefit.  There will also be a section under Comments all the way at the end and at the last quiz where you can also ask questions.

Remember you can always email me or Tweet me any questions @StephenJWillia2 using the hashtag #TUBiol3373.

In addition you can also leave comments at the very bottom which can be answered.

Slide 2 of lesson 6 is a refresher of the end of our last lecture, talking about Actin Binding Regulatory Proteins.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The picture above shows a brief review of some of the structures and actin binding proteins involved in helping to form these actin filament structures (like filamin in cross linked structures, profilin which binds the actin monomers [G-actin] and helps with addition of these monomers to the leading plus end.

*** Remember G-actin (Globular Actin) is the monomer and F-actin (filamentious actin) is the polymerized actin strand [filament]

Also remember from the last lecture that G-Actin as monomer has affinity for ATP {Adenosine triphosphate} and these G-Actin-ATP will be able to polymerize to form the F-Actin form.  Also F-actin can then hydrolyze the ATP to ADP and inorganic phosphate.  At this point the actin-ADP unit looses affinity for the remaining F-Actin chain and depolymerization can occur

 

An event referred to as TREADMILLING or when the G actin units are removed from minus end and added to the plus (or growing barbed) end

Also remember that there is a critical concentration of G-Actin-ATP needed for bypassing the lag phase of nucleation before the elongation phase and the rate of addition to the plus end is faster than addition to minus end and greater than the rate of depolymerization at the minus end

Cell Structures That Involve Actin (see links for more information)

  1. filopodia
  2. parallel actin bundles
  3. actin cortex
  4. lamellipodia
  5. stress fibers
  6. microvilli
  7. contractile ring in cytokinesis

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Nucleating proteins Arp (actin related protein and Formins

Arp ====> formation of lamellipodia

Formins ====> formation of stress fibers

Process involving formins starts with a signaling event by activation of a G-protein, the GTP binding protein Rho

Rho is a subfamily member of the Ras superfamily.  The Rho family consists of cdc42, rac1, and RhoA (we will discuss at a later date).  Rho acts like G proteins, as a molecular switch.

Note that just like the Ras member of G-proteins and the Ras GTP/GDP cycle, the Rho activation, deactivation cycle also depends on GEFs [Guanine nucleotide exchange factors] and GAPs [GTPase activating proteins] and also GDIs [guanine nucleotide dissociation inhibitors which we will discuss later but involved in preventing Rho diffusion in the cell, acting as a tether].

Myosin and Motor (muscle) Function; Neuromuscular junctions, the sarcoplasmic reticulum and Ohhh the plethora of signaling events

In this section, from slides 29 to 54, we talk about myosin and the interactions between myosin and actin in formation of the contractile unit of the muscle (skeletal).

We also talk about some familiar signaling events, in particular the neuromuscular junction.

At this junction is a special type of acetylcholine receptor

Remember we talked about two types of acetylcholine receptors:

  1. muscarinic receptors – typical GPCRs that tranduce the signal via Gi or Gq depending on the muscarinic subtype
  2. nicotinic receptors – these are ligand {receptor} operated channels and when activated opens a Na+ channel which leads to depolarization

 

Now the depolarization activates another set of channels, the voltage operated calcium channels so we have two types of ion channels: Receptor {ligand} operated channels and Voltage operated channels.  These are sometimes abbreviated as ROCs and VOCs.

The unit of the myofibril on the contactile unit of the skeletal muscle is the sarcomere and upon the calcium transient, the sarcomere shortens with the two z-disks moving closer to each other as shown in the video in the lecture.

Also briefly review the introduction part on microtubules. We will finish that next week. Note that the microtubule is comprised of the protein tubulin, which is another GTP binding protein.

For other articles and more information please see

Lesson 5 Cell Signaling And Motility: Cytoskeleton & Actin: Curations and Articles of reference as supplemental information: #TUBiol3373

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Identification of Biomarkers that are Related to the Actin Cytoskeleton

 

 

 

 

 

 

 

 

 


Ethics Behind Genetic Testing in Breast Cancer: A Webinar by Laura Carfang of survivingbreastcancer.org

Reporter: Stephen J. Williams, PhD

The following are Notes from a Webinar sponsored by survivingbreastcancer.org  on March 12,2020.

The webinar started with a brief introduction of attendees , most who are breast cancer survivors.  Survivingbreastcancer.org is an organization committed to supplying women affected with breast cancer up to date information, including podcasts, webinars, and information for treatment, care, and finding support and support groups.

Some of the comments of survivors:

  • being strong
  • making sure to not feel overwhelmed on initial diagnosis
  • get good information
  • sometimes patients have to know to ask for genetic testing as physicians may not offer it

Laura Carfang discussed her study results presented at  a bioethics conference in Clearwater, FL   on issues driving breast cancer patient’s  as well as at-risk women’s decision making process for genetic testing.  The study was a phenomenological study in order to determine, through personal lived experiences, what are pivotal choices to make genetic testing decisions in order to improve clinical practice.

The research involved in depth interviews with 6 breast cancer patients (all women) who had undergone breast cancer genetic testing.

Main themes coming from the interviews

  • information informing decisions before diagnosis:  they did not have an in depth knowledge of cancer or genetics or their inherent risk before the diagnosis.
  • these are my genes and I should own it: another common theme among women who were just diagnosed and contemplating whether or not to have genetic testing
  • information contributing to decision making after diagnosis: women wanted the option, and they wanted to know if they carry certain genetic mutations and how it would guide their own personal decision to choose the therapy they are most comfortable with and gives them the best chance to treat their cancer (the decision and choice is very personal)
  • communicating to family members and children was difficult for the individual affected;  women found that there were so many ramifications about talking with family members (how do I tell children, do family members really empathize with what I am going through).  Once women were tested they felt a great strain because they now were more concerned with who in their family (daughters) were at risk versus when they first get the diagnosis the bigger concern was obtaining information.
  • Decision making to undergo genetic testing not always linear but a nonlinear process where women went from wanting to get tested for the information to not wanting to get tested for reasons surrounding negative concerns surrounding knowing results (discrimination based on results, fear of telling family members)
  • Complex decision making involves a shift or alteration in emotion
  • The Mayo Clinic has come out with full support of genetic testing and offer to any patient.

Additional resources discussed was a book by Leslie Ferris Yerger “Probably Benign” which discusses misdiagnoses especially when a test comes back as “probably benign” and how she found it was not.

 

for more information on further Podcasts and to sign up for newsletters please go to https://www.survivingbreastcancer.org/

and @SBC_org

More articles on this Online Open Access Journal on Cancer and Bioethics Include:

Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Tweets and Re-Tweets by @Pharma_BI ‏and @AVIVA1950 at 2019 Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies, Friday, May 17, 2019 from 8:00 AM to 5:00 PM EDT @Harvard_Law

Genomics & Ethics: DNA Fragments are Products of Nature or Patentable Genes?

Study Finds that Both Women and their Primary Care Physicians Confusion over Ovarian Cancer Symptoms May Lead to Misdiagnosis