Category Archives: Physiology

Physiology

A wet Amazon may be more resilient to a drying climate than thought: Study – Mongabay.com

In some of the wettest parts of the Amazon rainforest, dry air may increase plant photosynthesis rates a response that contradicts the assumptions of many climate models, according to a recent study published in Science Advances.

When conditions are dry, plants attempt to retain water by closing the tiny pores on their leaves called stomata. But this also reduces the rate of photosynthesis, with knock-on effects for forest growth, carbon absorption, and large-scale weather patterns. Thats the theory, but data on how these dynamics play out at the scale of whole tropical forests is limited.

An international team of researchers led by Julia Green, a postdoctoral researcher at Laboratoire des Sciences du Climat et de lEnvironnement (LSCE) in France, used machine learning to cluster data from nine years of monthly satellite images of South and Central America into areas with similar climate, and modeled the relationship between air moisture and photosynthesis in each cluster. They found that dry tropical forests and savannas showed the expected pattern: photosynthesis slowed in dryer air. However, wetter areas of the Amazon basin displayed a reverse trend, with photosynthesis actually increasing as the air dried, an effect that became even more pronounced in the wet season.

The researchers used sun-induced fluorescence (SIF), a measure of excess light energy released by photosynthesizing leaves, to estimate the rate of photosynthesis using satellite imagery. Experts say there is still scientific debate over the reliability of SIF as a measure of a forests photosynthetic output, known as gross primary production (GPP). Green acknowledged that SIF may be an unreliable measure of GPP at the scale of individual leaves, but said that SIF tracks GPP quite well at the ecosystem scale, and that this relationship has been widely exploited in other studies.

David Lapola, an Earth system modeler at the University of Campinas (UNICAMP) in Brazil, who was not involved in the study, said he is skeptical about the results, but that this article opens up a hypothesis that deserves further investigation.

To photosynthesize, plants face a trade-off. Opening their stomata allows them to absorb CO2, a crucial ingredient for photosynthesis, but in doing so they also lose water through the process of transpiration. At the same time, plants need to maintain a continuous column of water from root to leaf. If there isnt enough water available in the soil to match water loss from the stomata, the water column will become strained and eventually break. To avoid these potentially fatal breaks, plants can partly or fully close their stomata.

The team analyzed four years of hourly data collected at three established monitoring towers in the states of Amazonas, Para, and Tocantins in Brazil, which allowed them to explain the remote sensing findings and try to link the large scale to the small scale, Green said. When the air was dry, plants absorbed less CO2, suggesting that their stomata were fully or partially closed, yet their leaves were releasing the same amount of heat, indicating high rates of photosynthesis.

The authors say this can be explained, at least in part, by leaf ageing. At the beginning of the dry season, trees in wet tropical forests drop the leaves at the top of the canopy, allowing more light through and stimulating growth of plants in the understory. By the time the wet season arrives, the shed leaves have been replaced by young leaves that are able to photosynthesize far more efficiently. Even in the Amazon, the stomata will partially close when the air gets drier, but because of the higher photosynthetic capacity of the young leaves its more than compensated for, Green said.

Marielle Smith, a postdoctoral researcher at Michigan State University in the U.S., who was not involved in the study, says that plentiful soil moisture may explain why plants in wet regions are able to continue photosynthesizing even when the air is very dry.

In a separate study published in Nature Plants in October , Smith and colleagues compared photosynthesis rates with changing air temperature and humidity in a climate-controlled experimental tropical forest biome in Arizona, with data collected at monitoring towers in the Brazilian Amazon, and found declining photosynthesis rates as the air dried, indicating that plants were closing their stomata when they experienced water stress. But if the potential for hydraulic stress is alleviated by sufficient soil water, the response of stomata to air dryness may be reduced or eliminated. This would mean that forests in wet places could take full advantage of the high light availability that tends to accompany dry air, Smith said.

Smith also expressed doubts that dry air was the causal factor behind higher rates of photosynthesis in wet regions. This conclusion is opposite to what we found at the particular sites used in our analyses, she said, despite using data from two of the same monitoring towers.

The source of this disparity, Smith says, is light. If light availability, which tends to be higher when the air is dryer, is controlled for statistically, the rate of photosynthesis at the monitoring towers declines as air dryness increases. The tower analyses they use to validate the artificial neural network analysis of SIF show the opposite: [air dryness] has a negative impact on GPP when GPPs response to light is accounted for, she said. Therefore, some independent validation is required in order for this interesting hypothesis to be convincing.

Experts say controlled experiments are needed to validate and investigate these complex interactions between water availability, climate, and plant physiology in tropical forests. Im leading the effort trying to establish a FACE [free-air carbon dioxide enrichment] experiment near Manaus and it might be that we can also change moisture conditions in the air, Lapola said. This is a very good suggestion that the authors give and is something we will definitely think about.

The researchers applied the same clustering analysis to the outputs from 10 different climate models and found that they failed to replicate the regional differences in photosynthesis found in the satellite data. Models are overestimating water stress in the Amazon rainforest, Green said.

Climate models must accurately represent photosynthetic processes in the Amazon if they are to produce meaningful results, because changes in gas and water exchange between these vast forests and the atmosphere can have widespread impact on climate and weather patterns. This region is bigger than just itself, Green said.

The Amazon rainforest represents a huge stock of carbon and flux of moisture to the atmosphere, Lapola said. This misrepresentation in vegetation models might significantly change the [predicted] carbon cycle and water cycle in the region.

Green says the good news is that this data suggest Amazon forests are potentially more resilient than we thought, but cautioned that if air dryness exceeds levels currently experienced by Amazon forests, the plant physiological responses observed in this study may change.

The team found that the relationship can reverse during extreme weather events, which are also expected to become more frequent and severe as the climate warms. Their analysis included the El Nio event that caused severe and widespread droughts in the Amazon in 2015 and 2016; for that period, we see that this positive response of photosynthesis to air dryness either diminished or reversed, Green said.

Citation:

Green, J. K., Berry, J., Ciais, P., Zhang, Y., & Gentine, P. (2020). Amazon rainforest photosynthesis increases in response to atmospheric dryness. Science advances, 6(47), eabb7232.https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abb7232

Banner Image: Plants are expected to photosynthesize less in response to dry air, but a machine-learning analysis of satellite data found that the wettest parts of the Amazon basin actually photosynthesize more when the air is dry. Image by CIFOR via Visualhunt (CC BY-NC-ND).

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A wet Amazon may be more resilient to a drying climate than thought: Study - Mongabay.com

Physiology

11 MSU employees found in violation of OIE policy are still affiliated, LSJ reports – The State News

Content warning: This story contains descriptions of sexual abuse and sexual harassment.

Out of 49 Michigan State faculty and staff in violation of university sexual misconduct policy since 2015, at least 11 are still affiliated with the university in some way, according to an 18-month Lansing State Journal investigation.

At least 14 people had multiple people accuse them of sexual harassment or sexual assault, five of which remain employed: marketing Professor Tomas Hult, criminal justice Professor David Foran, anatomic pathology Professor Matti Kiupel, communications Professor William Donohue and physiology Professor Robert Wiseman.

Despite being found responsible for sexual harassment of a coworker and being accused of sexual misconduct two other times, Hult was a member of the presidential search committee that brought in current MSU President Samuel L. Stanley Jr.

The former Osteopathic Medicine Dean William Strampel as well as political science professor William Jacoby, were allowed to retire prior to the completion of the investigation or any punishment. According to the report, this allowed them to keep some retirement benefits, such as health and life insurance.

Strampel was arrested and jailed in 2019 for his willful neglect of the ongoing abuse committed by former MSU doctor Larry Nassar, as well as 11 months of misconduct in office.

Two retired professors lost their emeritus title, two are under review and while four others were allowed to keep them, according to the report.

Much work has been done to change the culture of Michigan State University," Deputy Spokesperson Dan Olsen said. "To foster culture change, we continue to make broad-based systemic improvements to our handling of any behavioral issues of our faculty and staff. We have strengthened compliance through our changes to the Discipline and Dismissal of Tenured Faculty for Cause Policy, Consensual Amorous or Sexual Relationships with Students Policy, Travel Policy and Emeritus Policy. Communication and collaboration have increased with Human Resources and the accountable administrators at all levels to address any and all behavioral issues. We review and investigate all reports of misconduct. Notice and transparency has strengthened the universitys ability to address behaviors, apply interim measures, and improve the quality of the working environment for the students, faculty, and staff. Culture change does not happen with one individual, it takes the whole system to work collectively to achieve the same goal ofpreventinginappropriate behaviorand creating a culture where the behavior is not tolerated. Theres no mistake we have more work to do and the university is committed to that work.

Olsen also confirmed that the contents of the report are accurate.

University administrators sent a preemptive response to MSU faculty, staff and students Friday, Jan. 15, outlining policy and procedure changes surrounding relationship violence and sexual misconduct three years after 204 women provided nine days of impact statements in Ingham and Eaton Counties in the wake of Nassar's abuse.

"Their powerful testimonies continue to remind us that MSU failed survivors and our community," the email said. "Their stories and voices challenge us to create culture change at MSU, and we know we have more work still to do."

Lansing State Journal made 25 public records requests to Michigan State University over the course of the investigation, spending nearly $2,000 for public documents.

Stanley, along with Provost Teresa Woodruff, Executive Vice President for Administration and Chief Information Officer Melissa Woo and Executive Vice President for Health Sciences Norman Beauchamp, signed the message.

"We are sharing this with you not to excuse past decisions; rather, we want you to know the actions we have taken the past few years and continue to take will improve our consistency and accountability," the email said. "Changes have been made, and more work will be completed soon to address inequities in the disciplinary outcomes and further strengthen our disciplinary actions."

Wendy Guzman contributed to the reporting in this article.

Editor's note: This article was updated to properly aggregate reporting by The Lansing State Journal.

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Physiology

Taking temperature is not a reliable way of detecting Covid-19 – The Star Online

Making people stand in front of a scanner to have their body temperature read can result in a large number of false negatives, allowing people with Covid-19 to pass through airports and hospitals undetected.

Leading experts in physiology have suggested that taking temperature readings of a persons fingertip and eye instead would give a significantly better and more reliable reading, and help identify those with fever.

The study, co-led by human physiologist and expert in temperature regulation Professor Mike Tipton, was published in the journal Experimental Physiology.

Prof Tipton from the University of Portsmouth in the United Kingdom says: If scanners are not giving an accurate reading, we run the risk of falsely excluding people from places they may want or need to go, and we also risk allowing people with the virus to spread the undetected infection they have.

The study found four key factors:

Prof Tipton says: Using a surface temperature scanner to obtain a single surface temperature, usually the forehead, is an unreliable method to detect the fever associated with Covid-19.

Too many factors make the measurement of a skin temperature a poor surrogate for deep body temperature skin temperature can change independently of deep body temperature for lots of reasons.

Even if such a single measure did reflect deep body temperature reliably, other things, such as exercise, can raise deep body temperature.

The pandemic has had a devastating global effect on all aspects of our lives, and unfortunately, its unlikely to be the last pandemic we face.

Its critical we develop a method of gauging if an individual has a fever thats accurate and fast.

A change in deep body temperature is a critical factor in diagnosing disease with as little as a one degree increase indicating a potential disease.

The most common symptom of 55,924 confirmed cases of Covid-19 reported in China up to Feb 22, 2020, was fever, followed by other symptoms, including dry cough, sputum production, shortness of breath, muscle or joint pain, sore throat, headache, chills, nausea or vomiting, nasal congestion, and diarrhoea.

However, the researchers say a significant proportion (at least 11%) of those with Covid-19 do not have a fever, and that fewer than half of those admitted to hospital with suspected Covid-19 had a fever.

Although the majority of positive cases go on to develop a high temperature after being admitted to hospital, they were infectious before their temperature soared.

Prof Tipton says: We think we can improve the identification of the presence of fever using the same kit, but looking at the difference between eye and finger temperature its not perfect, but it is potentially better and more reliable.

He adds: During the SARS (severe acute respiratory syndrome) epidemic in 2003, there was a need for a fast and effective mass-screening method and infrared thermography became, and remains, the cornerstone measurement, despite concerns over its reliability.

A 2005 study of 1,000 people comparing forehead temperature with three different infrared thermometers gave different temperatures, ranging from 31C to 35.6 C.

The same infrared thermometer alone varied by as much as 2C.

In another study, more than 80% of the 500 people tested using infra-red thermometers, gave a false negative result.

Such differences in skin temperature could be due to a range of reasons, including whether the individual has recently exercised, has an infection, sunburn or recently drunk alcohol, how close they stand to the scanner, the air temperature, how much fat they have, and even their blood pressure.

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Taking temperature is not a reliable way of detecting Covid-19 - The Star Online

Physiology

Women temporarily synchronize their menstrual cycles with the luminance and gravimetric cycles of the Moon – Science Advances

Many species synchronize reproductive behavior with a particular phase of the lunar cycle to increase reproductive success. In humans, a lunar influence on reproductive behavior remains controversial, although the human menstrual cycle has a period close to that of the lunar cycle. Here, we analyzed long-term menstrual recordings of individual women with distinct methods for biological rhythm analysis. We show that womens menstrual cycles with a period longer than 27 days were intermittently synchronous with the Moons luminance and/or gravimetric cycles. With age and upon exposure to artificial nocturnal light, menstrual cycles shortened and lost this synchrony. We hypothesize that in ancient times, human reproductive behavior was synchronous with the Moon but that our modern lifestyles have changed reproductive physiology and behavior.

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Women temporarily synchronize their menstrual cycles with the luminance and gravimetric cycles of the Moon - Science Advances

Physiology

The Physiology of the Finishing Kick | Outside Online – Outside

I used to see my finishing kick as a sign of toughness. Nobody passed me in the closing stages of a race, Id tell myself, because nobody wanted it more than me.

But as time went on, I began to see it from a different perspective. No matter how a race played out, whether it was fast or slow and whether I was way ahead or way behind, I would always manage to sprint the last quarter-mile or so. Why did I always have energy left for a sprint, even if Id been dropped by the leaders? Shouldnt I have used that energy to avoid being dropped in the first place? Eventually, my kick became a source of frustration. I tried to race hard enough that Id have nothing left for a kick, but I almost never managed it.

As a result, Ive always been fascinated by attempts to unravel the physiology and psychology of the finishing kick. The most recent addition: a study in Medicine & Science in Sports & Exercise, led by graduate student Rafael Azevedo at the University of Calgary under the direction of Juan Murias and Guillaume Millet, using an interesting new methodology to tease out levels of fatigue in the brain and body before and after the finishing kick.

Some important background: I always come back to a 2006 study by University Cape Town researchers Ross Tucker, Michael Lambert, and Tim Noakes that analyzed pacing patterns in a centurys worth of mens world record performances over distances between 800 and 10,000 meters. As I discussed in more detail here, they observed a remarkably consistentU-shaped pacing template for races longer than 800 meters, featuring a fast start, even-paced middle, and fast finish, as shown in this graph:

(Illustration: International Journal of Sports Physiology and Performance)

The presence of a finishing kick even in elite athletes running at world-record pace, they argued, reflected a hardwired tendency to maintain a physiological reserve during intense exercise. In other words, it was evolution rather than cowardice that made me hold back energy for a sprint.

This big-picture explanation makes intuitive sense, but actually unraveling whats going in your body at different stages in a race has turned out to be more complicated than expected. To that end, Azevedos new study involved 12 male volunteers performing a series of 4K cycling time trials. The trials lasted a little over six minutes on average, and as expected they followed a U-shaped pacing profile with a fast start, even-paced middle, and finishing sprint. On average, according to a mathematical analysis, the fast start lasted 827 meters, and the finishing kick started with 410 meters left.

After a couple of familiarization trials, the subjects completed three experimental trials in randomized order: one in which they were stopped after the fast start, a second in which they were stopped after the even-paced section, and a third in which they continued to the finish. As soon as they stopped, they underwent a battery of tests to assess fatigue in various ways. The measurements used force sensors mounted in the pedals of the bikea crucial detail, since fatigue starts dissipating within a few seconds. Previous experiments have involved getting subjects off the bike and then strapping them into a separate apparatus to measure fatigue, so this is a key technical innovation.

The simplest way of measuring muscle fatigue is with a maximal voluntary contraction: you ask the subject to contract the relevant muscle (in this case the quads) as hard as possible. Using more sophisticated techniques, you can also break it down into two subcomponents. Central fatigue is how much the signal from the brain to the muscles has decreased; peripheral fatigue is how much weaker the muscle fibers themselves are when you stimulate them with electricity. The researchers performed all three of these measurements.

The results showed a rapid increase in fatigue during the initial fast start: the max voluntary contraction dropped by 23 percent, central fatigue was 8 percent, and peripheral fatigue was 40 percent. Then things stabilized: by the end of the even-paced phase, which accounts for about 70 percent of the overall race, all three of the fatigue markers were essentially unchanged compared to just after the fast start. But after the finishing sprint, fatigue ramped up again, for example to 34 percent for max voluntary contraction.

In other words, muscle fatigue doesnt accumulate in a nice straight line. After the initial excitement of the start, we settle into a sustainable pace that seems to have very little impact on muscle function. The sensation that your jellied legs couldnt take another step after a race is produced almost entirely by the finishing sprint, not by the miles that preceded it. One way to understand this is in terms of critical speed (or, equivalently, critical power), a concept Ive written about in detail a few times recently. Your critical speed is essentially the threshold of whats metabolically sustainable. You can run above critical speed for a while, but youre using up your finite reserves of anaerobic capacityand once theyre done, youre cooked.

If you were to run a race at a perfectly even pace, youd use up your anaerobic capacity gradually, hitting zero as you cross the finish line if you judge it right. In contrast, what most of us tend to do is use up a chunk of anaerobic capacity at the start. (There may be good physiological reasons for that, since a fast start ramps up your oxygen-processing capacities more quickly.) Then we settle into a pace relatively close to critical power, where were only nibbling away very slowly at anaerobic capacity. Then, as we approach the finish, we use it all up with a glorious sprint.

Sure enough, in Azevedos data, the cyclists settled into a pace barely above critical power for the middle portion of the race, meaning that they used most of their anaerobic capacity at the beginning and end. The big question is whether this approach is suboptimal. Thats certainly my intuition. When Joshua Cheptegei broke the 5,000-meter world record last summer, I argued that the Wavelight pacing lights flashing around the perimeter of the track at a perfectly even pace helped Cheptegei by enabling him to run the most evenly paced world record ever. It must be more efficient, right?

But its perhaps not as obvious as I thought. Back in 2013, a study from Andy Joness lab at the University of Exeter compared different pacing strategies in three-minute cycling trials: the typical self-paced U-shape, an all-out-from-the-start effort, and an even-paced trial. Heres what those pacing patterns looked like, with the amount of work done above critical power (i.e. the anaerobic capacity) shaded in grey. Panel A is an incremental test to exhaustion, B is all-out from the start, C is even pacing, and D is self-paced.

(Illustration: Medicine & Science in Sports & Exercise)

The numbers indicate the total anaerobic capacity shown by the shaded areas, and there are no significant differences between them. Even pacing produced an anaerobic capacity of 12.9 kJ; self-pacing with a finishing kick produced 12.8 kJ. Theres a big difference in how these different strategies feel, though. The closer you are to emptying your anaerobic capacity, the worse you feel. My interpretation/hunch, Jones told me by email, is that athletes have learnt, or know intuitively, that a pacing strategy involving an end spurt results in the same performance outcome as other strategies, BUT that this same performance can be achieved with less pain for most of the race! The athletes will be just as knackered at the end but that middle section wont be quite so excruciatingly intolerable if they implement an end spurt strategy.

Its an interesting idea. And it would explain why U-shaped pacing patterns are so ubiquitous even among the greatest runners in the world. It has always puzzled me that a seemingly suboptimal pacing strategy could produce so many world records. Even if were wired to pace ourselves cautiously, youd still expect that world records would happen when athletes accidentally started too fast if having a finishing kick was really so bad for performance.

On the other hand, as Ross Tucker has noted, the pacing in world records does seem to be getting more and more even. The gains from smoothing out your pacing may be marginal, but at that level you have to look for every possible edge. Personally, though, I find Andy Joness argument very temptingbecause if U-shaped pacing doesnt cost you anything, then I can start thinking of my finishing kick as a badge of pride again, rather than a mark of shame.

For more Sweat Science, join me on Twitter and Facebook, sign up for the email newsletter, and check out my book Endure: Mind, Body, and the Curiously Elastic Limits of Human Performance.

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Physiology

The Need for New Biological Targets for Therapeutic Intervention in COPD – Pulmonology Advisor

Chronic obstructive pulmonary disease (COPD) continues to be a major cause of disability and is one of the leading causes of mortality worldwide. While there are numerous treatment options for the lung disease, the available treatments focus on symptoms secondary to inflammation, and are not curative. In a review published in the American Journal of Physiology Lung Cellular and Molecular Physiology, experts focus on potential disease-relevant pathways and emphasize the important of developing new treatments for patients with COPD.1

The objective of the review was to summarize COPD pathology, available treatment options and additional potential pathways and targets for new therapeutic development.

Cigarette smoke contains thousands of injurious agents and is the key cause of COPD worldwide as these induce tissue damage and inflammatory process leading to destruction of alveolar tissue, loss of extracellular matrix and alveolar cells, along with airway remodeling.2 As COPD may progress in patients despite smoking cessation it was suggested that persistent airway inflammation in these patients is related to repair of smoke-induced tissue damage in the airways.3 Failure to achieve normal lung function in early adulthood followed by age-appropriate rates of decline causes up to half of COPD cases.4

The 2020 Global Initiative for Chronic Obstructive Lung Disease guidelines recommend that the management strategy of COPD should be based on the assessment of symptoms and future risk of exacerbations and the main goals of pharmacological therapy for COPD are to reduce symptoms and frequency and severity of exacerbations, as well as to improve exercise tolerance and health status. However, at this point there is no evidence that any of the available medications can modify the long-term decline in lung function.5

The commonly used maintenance medications in COPD are short- and long-acting beta-2 agonists and anti-cholinergics, methylxanthines, inhaled or systemic corticosteroids, phosphodiesterase (PDE)-4 inhibitors and mucolytic agents.5 As these medications are mainly focused on relieving symptoms and reducing the risk for exacerbations, more effective treatment strategies are needed. COPD is a complex disease and precision medicine strategy, that considers biologic and psychosocial factors, may improve disease outcomes.4

New Treatment Targets

There is a real need to uncover new biology in order to advance more precision-based therapeutic strategies for patients with COPD. New disease-specific strategies in development are focusing on inflammatory pathways, hoping this will help to address disease onset. Early reports suggest there are several promising targets that can address inflammatory complications, including oxidative stress, kinase-mediates pathways, phosphodiesterase inhibitors, interleukins and chemokines.

Oxidative Stress a common denominator for aging and cellular senescence, resulting in macromolecular damage and DNA damage.2 With cigarette smoke exposure there is an increased oxidative stress, associated with an increase in Nrf2 activity which declines with the progression of COPD.6 As several studies have implicated Nrf2 in COPD pathology, this pathway is a potential important therapeutic target. Several agents may change Nrf2 expression and activity in airway cell, including aspirin-triggered resolvin D1, crocin, sulforaphane, and schisandrin B.1,6

Kinase-mediated Pathways as various kinases, including MAPK, receptor-tyrosine kinases, phosphoinositide-3-kinases, JAK, and NF-B, may induce chronic inflammation, they may serve as new targets for COPD treatment. There are several drugs that target different kinases but these are not approved for clinical use. Drugs with a more specific action, such as RV568 that inhibits p38, was well tolerated in a 14-day clinical trial and showed promising results with potent anti-inflammatory effects on cell and animal models relevant to COPD, with evidence for improvement in lung function and anti-inflammatory effects on sputum biomarkers.7

Phosphodiesterase Inhibitors inhibiting PDE leads to an increase in intracellular cAMP levels that may have anti-inflammatory effects. Roflumilast is an oral PDE-4 inhibitor already in use for more severe cases of COPD, but more potent medications are being developed, including several inhaled formulations, such as CHF6001, which was reported to have significant anti-inflammatory properties in the lungs of patients with COPD already receiving triple inhaled therapy (8). Ensifentrine is a PDE3/PDE4 inhibitor with anti-inflammatory and bronchodilator properties and when combined with short-acting bronchodilators or tiotropium caused additional improvement in lung function, reduced gas trapping, and improved airway conductance.9

Inflammatory Mediators exposure to inhaled irritants and tobacco smoke results in an increase in various interleukins (IL) that increase the number of immune cells and induce inflammatory responses. Hence, treatment directed against these mediators may reduce inflammation.1 Mepolizumab, reslizumab, and benralizumab are antibodies directed against IL-5 and its receptor and reduced eosinophil-related inflammation. These medications are approved for use for asthma, and were not effective in COPD, but may be valuable for patients with COPD with eosinophilia. Dupilumab, a monoclonal antibody directed against IL-4 and IL-13 receptor, is another potential candidate for future use. microRNAs are also involved in inflammation regulation, and miR-155 expression was shown to be increased in COPD, but at this point there are no available miRNA-based therapeutics for COPD.10

Additional Potential Treatment Targets

While multiple medications under development for COPD are focusing on the inflammatory pathways, they are not expected to reverse the lung damage. For this reason, it is important to study the upstream pathways that may help to identify strategies to reverse exiting lung damage, including targets that can lead to lung repair and regeneration.

These potential breakthrough targets may include treatments directed against mitochondrial dysfunction; structural integrity of airway epithelium such as proteins that comprise tight junctions or the extracellular matrix; various ion channels that are responsible for airway hydration; and pro-regenerative strategies, including stem cell and tissue-engineering treatments to repair lung damage.1

Animal models and 3D human-based disease models have an important role in the efforts to better understand disease process and identify specific therapeutic targets and pathways.11,12 These models improve our knowledge about the basic mechanisms underlying COPD physiology, pathophysiology and treatment. Although they can only mimic some of the features of the disease, they are valuable for further investigation of mechanisms involved in human COPD.11

Several different types of 3D cell culture models have been developed in recent years, and these have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data. Ex vivo modeling using primary human material can improve translational research activities by fostering the mechanistic understanding of human lung diseases while reducing animal usage. It is believed that using new model organisms may allow exploring new avenues and treatments approached for human disease, and these are especially promising.12

COPD is a major public health concern, and as it continues to be a global burden, the importance of developing new treatments is apparent. Current treatments are not curative, and while new strategies and drugs are in the pipeline, they still address mostly secondary inflammatory pathways of the disease. An additional major complication in COPD drug development likely comes from the essential dependency on surrogate endpoints like FEV1 to assess the impact of a therapeutic strategy. Thus, any new therapeutic strategy will ultimately require long-term studies to confirm that the surrogate endpoints accurately reflect efficacy on disease outcome, concluded the researchers.

References

1.Nguyen JMK, Robinson DN, Sidhaye VK. Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2021;320(1):L1-L11. doi:10.1152/ajplung.00367.2020

2.Tuder RM, Petrache I. Pathogenesis of chronic obstructive pulmonary disease. J Clin Invest. 2012;122(8):2749-55. doi:10.1172/JCI60324

3.Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26(5):835-45. doi:10.1183/09031936.05.00108904

4.Sidhaye VK, Nishida K, Martinez FJ. Precision medicine in COPD: where are we and where do we need to go? Eur Respir Rev. 2018;27(149):180022. doi:10.1183/16000617.0022-2018

5.Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2020 report [Online]. Global Initiative for Chronic Obstructive Lung Disease. https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.1wms.pdf. Accessed January 25, 2021.

6.Cuadrado A, Rojo AI, Wells G, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18(4):295-317. doi:10.1038/s41573-018-0008-x

7.Charron CE, Russell P, Ito K, et al. RV568, a narrow-spectrum kinase inhibitor with p38 MAPK- and - selectivity, suppresses COPD inflammation. Eur Respir J. 2017;50(4):1700188. doi:10.1183/13993003.00188-2017

8.Singh D, Beeh KM, Colgan B, et al. Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD. Respir Res. 2019;20(1):180. doi:10.1186/s12931-019-1142-7

9.Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018;52(5):1801074. doi:10.1183/13993003.01074-2018

10.Barnes PJ. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2018;18(7):454-466. doi:10.1038/s41577-018-0006-6

11.Ghorani V, Boskabady MH, Khazdair MR, Kianmeher M. Experimental animal models for COPD: a methodological review. Tob Induc Dis. 2017;15:25. doi:10.1186/s12971-017-0130-2

12.Zscheppang K, Berg J, Hedtrich S, et al. Human pulmonary 3D models For translational research. Biotechnol J. 2018;13(1):1700341. doi:10.1002/biot.201700341

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The Need for New Biological Targets for Therapeutic Intervention in COPD - Pulmonology Advisor

Physiology

Males and females are evolutionarily programmed differently in terms of sex – Tech Explorist

Regardless of sharing a very similar genome and nervous system, males and females vary significantly in reproductive investments. They require different behavioral, morphological, and physiological adaptions, suggests a new study from Oxford, which found sex-specific signals affect behavior.

As the study suggested, Males and females behave differently in terms of sex, but the reality is both are evolutionarily programmed to do so. They both have evolved profoundly different adaptations to suit their own reproductive needs.

In their study, scientists uncovered a novel circuit architecture principle that permits deployment of entirely behavioral repertoires in males and females, with minimal circuit changes.

Scientists found that the nervous system of vinegar flies, Drosophila melanogaster, produced differences in behavior by delivering different information to the sexes.

In the vinegar fly, males compete for a mate through courtship displays; thus, the ability to chase other flies is adaptive to males but of little use. A females investment is focused on the success of their offspring; thus, choosing the best sites to lay eggs is adaptive to females.

While discovering the different roles of only four neurons clustered in pairs in each hemisphere of the central brain of both male and female flies, scientists detected sex differences in their neuronal connectivity. This neuronal connectivity reconfigures circuit logic in a sex-specific manner.

In essence, males received visual inputs and females received primarily olfactory (odor) inputs. Notably, the team demonstrated that this dimorphism leads to sex-specific behavioral roles for these neurons: visually guided courtship pursuit in males and communal egg-laying in females.

Scientists noted, Ultimately, these circuit reconfigurations lead to the same resultan increase in reproductive success.

Our findings suggest a flexible strategy used to structure the nervous system, where relatively minor modifications in neuronal networks allow each sex to react to their surroundings in a sex-appropriate manner.

Professor Stephen Goodwin from the Department of Physiology, Anatomy, and Genetics said, Previous high-profile papers in the field have suggested that sex-specific differences in higher-order processing of sensory information could lead to sex-specific behaviors; however, those experiments remained exclusively at the level of differences in neuroanatomy and physiology without any demonstrable link to behavior. I think we have gone further as we have linked higher-order sexually dimorphic anatomical inputs, with sex-specific physiology and sex-specific behavioral roles.

Scientists noted, In this study, we have shown how a sex-specific switch between visual and olfactory inputs underlies adaptive sex differences in behavior and provides insight on how similar mechanisms may be implemented in the brains of other sexually-dimorphic species.

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Males and females are evolutionarily programmed differently in terms of sex - Tech Explorist

Physiology

Subadditivity begins to explain the mysteries of the circadian system’s response to light (MAGAZINE) – LEDs Magazine

FIG. 1. Example of how the biological clock perceives light signals differently than the visual system. (Image credits: All illustrations and tables courtesy of Allison Thayer, Lighting Research Center, except where expressly indicated.)

As discussed in the previous article of the circadian light series, Industry must move beyond CCT to articulate circadian metrics, a wide range of photopic illuminance levels at the eye may be required to reach a specific circadian stimulus (CS), even for light sources of the same correlated color temperature (CCT). Since we know the circadian system to be a blue-sky detector, it may be generally true that cooler light-source spectra (>4000K) require a lower illuminance at the eye than warm light-source spectra (

Consider a blue LED (max = 486 nm) that produces 17 lx at the eye this gives a CS = 0.3. If one were to add 100 lx of low-pressure sodium (LPS) to make the combined light appear white (CCT = 3241K), the total illuminance at the eye would obviously be 117 lx, but counterintuitively, the circadian effectiveness of the combined light would drop to CS = 0.27 (Fig. 1). This is known as subadditivity in other words, 1 + 1

For humans, color vision has three dimensions (Fig. 2), each defined by a different neural channel. The first channel is the achromatic (black-and-white) channel that simply adds all the flux incident on the retina the more flux on the retina, the brighter the light will be, if it has no apparent hue. Hue is handled by two chromatic channels one that responds to light as blue or yellow (or nothing if it is black or white), and one that responds to light as red or green (or nothing if it is black or white).

FIG. 2. Schematic of the achromatic and chromatic channels in the retina that enable color vision and brightness perception in humans.

The two chromatic channels blue versus yellow (b-y) and red versus green (r-g) are spectrally opponent, meaning that a greenish red or a bluish yellow cannot exist. All hues we see are combinations of these two spectrally-opponent channel outputs so we can see a greenish blue (turquoise) or a bluish red (purple), for example.

Brightness perception is determined by these two chromatic channels as well as an achromatic, black-and-white channel. When more light is added to the retina, the achromatic channel increases its response. If that light has a hue, it will appear brighter than a white light that produces the same response in the achromatic channel. For example, a red light of 100 lx will look brighter than a white light of 100 lx because its red hue contributes to brightness perception. Because the color channels are spectrally opponent, adding a green light to the red light can make the red light appear less bright even though the achromatic channel increases.

As a specific example, 100 lx of light emitted by a red LED will appear equally as bright as 150 lx from a green LED (Fig. 3). If these two lights are combined, the achromatic illuminance at the eye will be 250 lx and its hue will appear yellow. Remarkably, the resulting yellow light of 250 lx will actually appear less bright than either the red light alone at 100 lx or the green light alone at 150 lx. This is a clear example of subadditivity. The reason behind this surprising outcome is that perceived brightness of a light depends not only on its achromatic light level but also on its apparent hue. Red and green lights are more hueful than a yellow (or white) light. The same basic physiology contributes to circadian light.

FIG. 3. The accompanying chart is the 1931 CIE chromaticity chart with contour lines of chromaticities of equal perceived brightness (Guth et al., 1980). The chromaticities of a red and a green LED are plotted along with a specific combination of light from these two LEDs seen as yellow. For this example, the red LED provides an illuminance of 100 lx, delivering a perceived brightness of B(r) = 100 2.93 = 293; and the green LED provides an illuminance of 150 lx, delivering a brightness of B(g) = 150 2.15 = 322. The combined yellow light has a brightness of B(y) = 1.07 250 = 268. Image adapted from J. Optical Soc. of America, 70, 2, Vector model for normal and dichromatic color vision, by S. Lee Guth, Robert W. Massof, and Terry Benzschawel, 1980; http://bit.ly/3nXBEXr.

The intrinsically photosensitive retinal ganglion cells (ipRGCs) represent the lynchpin between the retina and the biological clock, linking the external 24-hour light dark cycle to our internal rhythms of behavior and physiology. As the name implies, ipRGCs contain the photopigment melanopsin that absorbs light and generates a neural signal for the biological clock. Without ipRGCs, our physiology and behavior would no longer be synchronized with sunrise and sunset. Experiments have shown that as long as the ipRGCs are intact, even without the photopigment melanopsin, light can still synchronize our biological clock to the daily light-dark cycle by neural signals from the rods and cones (photoreceptors responsible for vision). There is no direct connection between these photoreceptors and the ipRGCs rather, their signals are processed by a variety of neural circuits before reaching the ipRGCs. One of these neural circuits is a spectrally-opponent chromatic channel that also affects brightness perception. Specifically, the spectrally-opponent blue-yellow channel processes cone signals before reaching the ipRGC. This is why the blue LED delivering 17 lx at the eye becomes less effective for the circadian system when 100 lx of LPS is added the effectiveness of the blue LED for stimulating the ipRGC is reduced by adding yellow LPS.

As for creating metrics to quantify circadian response, the Lighting Research Center (LRC) uses circadian light (CLA) and circadian stimulus (CS; see the first installment in this series, which defines the terminology). Subsequently, the research team has developed a computational model that includes subadditivity. The spectral sensitivity of the modeled circadian circuit in the eye for one achromatic light level can be graphed with two curves (Fig. 4). It is a two-state model one for white light sources where the b-y channel balance tilts to signal blue or for another light source where it tilts to signal yellow. These white sources would appear cool or warm, respectively, but again the CCT designation will not necessarily be related to the actual appearance of the light.

FIG. 4. Warm and cool spectral response curves.

Recalling the summary from the previous article, the photopic illuminance level at the eye needs to reach a target CS of 0.3 for light sources categorized by their CCTs of 3000K, 4000K, and 5000K (Fig. 5, top).

The corresponding table in Fig. 5 indicates on which side of the b-y channel warm or cool a given light source falls. One 3000K light source has a cool spectral response unlike the others, and one 4000K light source has a warm spectral response. With regard to all warm sources, the spectral sensitivity of the circadian system (yellow dashed line in Fig. 4) is governed almost exclusively by melanopsin in the ipRGCs. For cool sources, however, subadditivity will come into play as illustrated by the positive and negative lobes of the solid blue line in Fig. 4. Again, adding a yellow light in the negative region to a blue light in the positive region will reduce the circadian effectiveness of the combined light relative to the blue light alone.

FIG. 5. Relating the previously-discussed chart of vertical illuminance values needed to reach 0.3 CS to which spectral response of the circadian system it falls on.

In Fig. 6, the spectral power distributions (SPDs) of a blue LED, a 3000K LED (Maximum), and a 5000K LED (Minimum) are indicated by the black curves, accompanied by the respective modeled spectral sensitivity responses indicated by the blue or yellow curves. Different combinations of spectra and vertical illuminance are required to reach the target CS of 0.3.

FIG. 6. Examples of illuminance at the eye required to achieve a CS of 0.3 using different light spectra.

This is fairly complicated! But the concepts are important to advancing the science behind applying circadian lighting principles. However, now that these complexities have been established, it should be relieving to know that a lighting manufacturer or designer does not need to know all of the intricacies of retinal neurophysiology to provide circadian light to building occupants. The final article of the series will go more into depth on the adaptation of the new language into application.

ALLISON THAYER, MS, BA, is a research specialist at the Lighting Research Center (LRC), formerly part of Rensselaer Polytechnic Institute. She holds a bachelors in architecture, and a masters of science with a concentration in lighting from Rensselaer. Thayer has played a main role in the development of the structure and content of the Healthy Living website.

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Subadditivity begins to explain the mysteries of the circadian system's response to light (MAGAZINE) - LEDs Magazine

Physiology

When Is Dead Really Dead? Results From the Largest International Study of Its Kind – SciTechDaily

A new international study, led by Dr. Sonny Dhanani of the CHEO Research Institute, and published in the January 28, 2021, issue of the New England Journal of Medicine, documents the physiology of the dying process. Working closely with the Canadian Donation and Transplantation Research Program, the research team asked over 600 families to allow their loved ones in the ICU to have their vital signs monitored during the dying process. This is the largest international study of its kind.

For families to choose organ donation when a loved one has died, they must be able to trust that death has really happened and that it is irreversible. Trust allows people to decide to donate at a time of grief and allows the medical community to feel comfortable opening a dialogue about donation. For donation after circulatory-determined death to be medically possible, death must be declared within a window of time after life sustaining measures are withdrawn. Yet, stories persist about people coming back to life following a declaration of death, and there was little evidence to inform the medical understanding of dying.

To do this, we had to go into ICUs and monitor people as they were dying. This is a very personal experience. And here we were collecting data, sending it to a server, downloading it and having people review the vital signs how things stopped and if they restarted. People were worried. Some physicians didnt want to do it. Some researchers felt uncomfortable. But we knew we should keep going when we met Heather.

Dr. Sonny Dhanani, MDDePPaRT Study LeadInvestigator, CHEO Research InstituteChief Critical Care, Childrens Hospital of Eastern OntarioAssociate Professor, University of Ottawa

Dr. Dhanani and his team found that the classic flatline of death is not so straightforward. The study showed that cardiac activity often stops and re-starts several times during the dying process before it finally stops completely but no one regained sustained circulation or consciousness. The study provides evidence to support the current standard to wait for 5 minutes after the heart stops before determining death and proceeding to organ donation.

How do you ask a family whose loved one is dying in the ICU to participate in a research study on organ donation? DePPaRT was empowered by the support and perspectives of a family partner, Ms. Heather Talbot, a woman whose son became a donor after dying in a car accident. The Canadian Donation and Transplantation Research Programs Patient, Family and Donor Partnership Platform connected Heather with the DePPaRT team in 2015, and she took on the emotional challenges of joining as a consultant. Heather provided feedback from a familys perspective, contributing ideas on how to appropriately approach families of dying patients. Her ability to reflect on her experiences and apply them to the study was pivotal for the projects success. Her contributions helped achieve a family consent rate of 93% and dampened the teams fears of overstepping boundaries. Her sons gift of organ donation saved at least four lives and her involvement in DePPaRT is multiplying those gifts.

This is an outstanding example of the powerful impact that a national framework for collaborative team science can achieve. Through the Canadian Donation and Transplantation Research Program, we have brought together different research communities, patient, family and donor partners, stakeholder organizations, and health care professionals who take non-traditional paths to doing research. This has created new synergies and new knowledge that will help more Canadians become donors and more patients receive transplants.

Dr. Lori West, MD, DPhilCanada Research Chair in Cardiac Transplantation, University of AlbertaDirector, Canadian Donation and Transplantation Research ProgramOfficer of the Order of Canada (2020)

Families and health care teams can trust that when death is determined, it is safe to begin the organ donation process. DePPaRT study data can now be used to inform policy and guidelines for determining death for organ donation both nationally and internationally. Further work using the study data will allow donation and transplant teams to predict how long it will take patients to die after removing life-sustaining measures. Predicting a time of death would be immensely useful to coordinate a donation and improve how organs are allocated.

On behalf of the Canadian Institutes of Health Research (CIHR), I would like to congratulate CDTRP and the DePPaRT team on the publication of this important study. CIHR is very pleased to be supporting a national network like CDTRP that has been able to bring together multiple stakeholders in the transplant area. This study is an example of the impactful work collaborations such as this one can achieve that will lead to improved outcomes for Canadians waiting for transplants.

Dr. Charu Kaushic, MSc, PhDScientific Director, CIHR Institute of Infection and Immunity

Reference: Resumption of Cardiac Activity after Withdrawal of Life-Sustaining Measures by Sonny Dhanani, M.D., Laura Hornby, M.Sc., Amanda van Beinum, M.Sc., Nathan B. Scales, Ph.D., Melanie Hogue, M.Sc., Andrew Baker, M.D., Stephen Beed, M.D., J. Gordon Boyd, M.D., Ph.D., Jennifer A. Chandler, L.L.B., L.L.M., Michal Chass, M.D., Ph.D., Frederick DAragon, M.D., Ph.D., Cameron Dezfulian, M.D., Christopher J. Doig, M.D., Frantisek Duska, M.D., Ph.D., Jan O. Friedrich, M.D., D.Phil., Dale Gardiner, M.D., Teneille Gofton, M.D., Dan Harvey, M.D., Christophe Herry, Ph.D., George Isac, M.D., Andreas H. Kramer, M.D., Demetrios J. Kutsogiannis, M.D., David M. Maslove, M.D., Maureen Meade, M.D., Sangeeta Mehta, M.D., Laveena Munshi, M.D., Loretta Norton, Ph.D., Giuseppe Pagliarello, M.D., Tim Ramsay, Ph.D., Katerina Rusinova, M.D., Ph.D., Damon Scales, M.D., Ph.D., Matous Schmidt, M.D., Andrew Seely, M.D., Ph.D., Jason Shahin, M.D., C.M., Marat Slessarev, M.D., Derek So, M.D., Heather Talbot, B.Ed., Walther N.K.A. van Mook, M.D., Ph.D., Petr Waldauf, M.D., Matthew Weiss, M.D., Jentina T. Wind, R.N., Ph.D. and Sam D. Shemie, M.D. for the Canadian Critical Care Trials Group and the Canadian Donation and Transplantation Research Program, 27 January 2021, New England Journal of Medicine.DOI: 10.1056/NEJMoa2022713

This research was supported by the Canadian Institutes of Health Research as part of the Canadian Donation and Transplantation Research Program, the CHEO Research Institute, and Karel Pavlk Foundation.

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When Is Dead Really Dead? Results From the Largest International Study of Its Kind - SciTechDaily

Physiology

Impact of Obesity and Its Associated Comorbid Conditions on COVID-19 P | DMSO – Dove Medical Press

Osama Mehanna,1,2 Ahmad El Askary,3,4 Ebtesam Ali,5 Basem El Esawy,3,6 Tamer FathAlla,7 Amal F Gharib3,8

1Department of Medical Physiology, College of Medicine, Taif University, Taif 21944, Saudi Arabia; 2Department of Medical Physiology, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 3Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia; 4Department of Medical Biochemistry, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 5Directorate of Health Affairs, Gharbia Governorate, Ministry of Health and Population, Cairo, Egypt; 6Department of Pathology, Faculty of Medicine, Mansoura University, Al Mansurah, Egypt; 7Department of Anaesthesia and ICU, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt; 8Department of Medical Biochemistry, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence: Osama Mehanna Email dr587@yahoo.com

Background: There is great variability in clinical presentation of COVID-19 worldwide. The current study evaluated the impact of obesity and its related complications on the course of COVID-19 in Egyptian patients.Methods: We included 230 COVID-19 Egyptian patients from Tanta City. According to their body-mass index (BMI), patient were divided into three groups: normal weight (BMI < 25 kg/m2), overweight (BMI > 25< 30 kg/m2), and obese (BMI 30 kg/m2). Patients glycemic status, lipid profile, and serum levels of acute-phase reactants were assessed. The number of patients receiving intensive care and the number of deaths in each group were counted.Results: Mean values of random blood sugar, serum cholesterol, triglycerides, serum ferritin, erythrocyte-sedimentation rate, LDH, CRP, D-dimer levels, and blood pressure were significantly higher in obese patients (165.6, 129.5, 105, 1,873, 26, 403, 56.45, 977.16 and 142/87, respectively) than in normal-weight (97.2, 103.5, 70.4, 479, 17.4, 252, 23.2, 612.4, and 118.6/76.8, respectively) and overweight patients (111.4, 106.3, 78.13, 491.3, 19.8, 269.27, 25.42, 618.4, and 120.3/79.3, respectively). Lymphopenia was also significantly predominant in the obese group. Multivariate logistic regression analysis revealed that elevated serum triglycerides, total cholesterol, low densitylipoprotein cholesterol, blood pressure, ferritin, CRP, and low relative lymphocyte count were significant risk factors in obese COVID-19 patients.Conclusion: Obesity and its related complications increase the risk of presenting a more severe form of COVID-19 in Egyptian patients.

Keywords: obesity, COVID-19, Egyptian

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Impact of Obesity and Its Associated Comorbid Conditions on COVID-19 P | DMSO - Dove Medical Press