Connect with us

International

Drilling down on treatment-resistant fungi with molecular machines

Fungal infections can be among the hardest to treat, and since the pandemic began they’ve become only more common. To prevent future antifungal resistance,…

Newly developed molecular drills may be able to fight treatment-resistant fungal infections like *Candida auris*. Dr_Microbe/iStock via Getty Images

Fungi are present on the skin of around 70% of the population, without causing harm or benefit. Some fungal infections, like athlete’s foot, are minor. Others, like Candida albicans, can be deadly – especially for individuals with weakened immune systems.

Fungal infections are on the rise because of an aging population and an increased prevalence of chronic diseases. At the same time, fungi are becoming more resistant to treatment. As a result, fungal infections could soon become a serious public health threat.

In 2022, the World Health Organization released its first-ever “Fungal Priority Pathogen List,” calling for improved surveillance, public health interventions and the development of new antifungal drugs.

We are an interdisciplinary team of chemists and biologists charting a new path to tackle drug-resistant infections. We are using tiny nanoscale drills that combat harmful pathogens at the molecular level. As the traditional antimicrobial research pipeline struggles, our approach has the potential to rejuvenate the fight against these stubborn infections.

Molecular machines as alternative antifungals

While doctors urgently need new antifungal drugs, developing them is challenging. First, it is difficult to develop drugs that selectively kill fungi without harming human cells because of their many similarities.

Second, fungi can rapidly develop resistance to multiple antifungal drugs at once when medications are misused or overused. As such, developing antifungal drugs is much less rewarding for drug companies than developing medications for chronic conditions like diabetes and hypertension that require long-term use.

One solution to this problem could lie in a Nobel Prize-winning technology: molecular machines.

Molecular machines are synthetic compounds that rapidly rotate their components at about 3 million times per second when exposed to light. Doctors can use a light-tipped probe to activate these molecular machines to treat internal infections, or a lamp for skin infections. The light starts the machines spinning, and that rotational motion pushes them to drill through and puncture the cell’s membranes and organelles, which results in cell death.

Our group first used this technology to kill cancer cells in 2017. To target the right cells, molecular machines can be linked to specific peptides that bind only to the desired cells, allowing, for instance, the targeting of specific cancer types. Since then, we have used these molecules to kill bacteria, destroy tissue and stimulate muscle contraction. These properties make molecular machines an enticing candidate technology to address the growing fungal threat.

A diagram showing the structure of a molecular machine as gray lines connected in the shape of several hexagons
The 3D structure of a molecular machine. The molecular machine consists of rotor (top) and stator (bottom) portions connected by a central axle. Following light activation, molecular machines rotate rapidly, drilling into fungal cells. Tour Lab, Rice University

Testing antifungal molecular machines

Researchers first tested the ability of light-activated molecular machines to kill fungi in Candida albicans. This yeastlike fungus can cause life-threatening infections in immunocompromised people. Compared with conventional drugs, molecular machines killed C. albicans much faster.

Subsequent studies found that molecular machines could also kill other fungi, including molds like Aspergillus fumigatus and species of dermatophytes, the types of fungi that cause skin, scalp and nail infections. Molecular machines even eliminated fungal biofilms, which are slimy, antimicrobial-resistant communities of microorganisms that stick together on surfaces and commonly cause medical device-associated infections.

Unlike conventional antifungals, which target the fungal cell membrane or cell wall, molecular machines localize to the fungal mitochondria. Often referred to as the “powerhouses of the cell,” mitochondria produce energy to power other cellular activities. When activated with visible light, molecular machines destroy the fungal mitochondria. Once the fungal cell’s mitochondria stop working, the cell loses its energy supply and dies.

Two black-and-white electron microscopy images of a fungal cell. The left image shows a large, round, healthy cell, while the cell on the right is shrunken following treatment with light-activated molecular machines.
Candida albicans before and after being exposed to light-activated molecular machines. Molecular machines puncture C. albicans‘ cell wall and intracellular organelles, eventually killing the fungal cell. Matthew Meyer/Rice University.

At the same time, molecular machines also disrupt the tiny pumps that remove antifungal agents from the cell, thus preventing the cell from fighting back. Because these molecular machines act by a mechanical instead of a chemical mechanism, fungi are unlikely to develop defenses against this treatment.

In lab experiments, combining light-activated molecular machines with conventional antifungal drugs also reduced the amount of fungi in C. albicans-infected worms and in pig nails infected with Trichophyton rubrum, the most common cause of athlete’s foot.

New frontiers for fighting fungal infections

These results suggest that combining molecular machines with conventional antifungals can improve existing therapies and provide new options for treating resistant fungal strains. This strategy could also help reduce the side effects of traditional antifungals, such as gastrointestinal upset and skin reactions.

Fungal infection rates will likely continue to rise. As such, the need for new treatments will only become more urgent. Climate change is already causing new human pathogenic fungi to emerge and spread, including Candida auris. C. auris is often resistant to treatment and spread rapidly in health care facilities during the COVID-19 pandemic. According to the Centers for Disease Control and Prevention, strained health care systems, overuse of immunosuppressants and misuse of antibiotics have all been implicated in outbreaks of C. auris.

In the future, researchers could use artificial intelligence to create better antifungal molecular machines. By using AI to predict how different molecular machines will interact with fungi and human cells, we can develop safer and more effective antifungal molecules that specifically kill fungi without harming healthy cells.

Antifungal molecular machines are still in the early stages of development and are not yet available for routine clinical use. However, continuing research gives hope that these machines could one day provide better treatments for fungal infections and other infectious diseases.

Ana L. Santos receives funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 843116.

Jacob Beckham receives funding from the National Science Foundation Graduate Research Fellowship Program.

James M. Tour receives funding from the Discovery Institute and the Robert A. Welch Foundation (C-2017-20190330). Rice University owns intellectual property on the use of electromagnetic (light) activation of molecular machines for the killing of cells. This intellectual property has been licensed to a company in which James M. Tour is a stockholder, although he is not an officer or director of that company.

Read More

Continue Reading

International

China Auto Sales Jump 55% Year Over Year As Price Cuts Continue To Move NEV Metal

China Auto Sales Jump 55% Year Over Year As Price Cuts Continue To Move NEV Metal

Retail sales of passenger vehicles scorched higher in May,…

Published

on

China Auto Sales Jump 55% Year Over Year As Price Cuts Continue To Move NEV Metal

Retail sales of passenger vehicles scorched higher in May, with 1.76 million units sold, according to preliminary data from the China Passenger Car Association released this week. 

The sales figure represents 8% growth from the month prior. As has been the case over the last several years, new energy vehicles continue to grow disproportionately to the rest of the sector, driving sales higher.

Last month 557,000 NEVs were sold, growth of 55% year over year and 6% sequentially, according to a Bloomberg wrap up of the data. 

The sales boost comes as the country slashed prices to move metal throughout the first 5 months of the year. In late May we noted that China's auto industry association was urging automakers to "cool" the hype behind price cuts that were sweeping across the country. 

The price cuts were getting so egregious that the China Association of Automobile Manufacturers went so far as to put out a message on its official WeChat account, stating that "a price war is not a long-term solution". Instead "automakers should work harder on technology and branding," it said at the time.

Recall we wrote in May that most major automakers were slashing prices in China. The move is coming after lifting pandemic controls failed to spur significant demand in China, the Wall Street Journal reported last month. Ford and GM will be joined by BMW and Volkswagen in offering the discounts and promotions on EVs, the report says. 

At the time, Ford was offering $6,000 off its Mustang Mach-E, putting the standard version of its EV at just $31,000. In April, prior to the discounts, only 84 of the vehicles were sold, compared to 1,500 sales in December. There was some pulling forward of demand due to the phasing out of subsidies heading into the new year, and Ford had also cut prices by about 9% in December. 

A spokesperson for Ford called it a "stock clearance" at the time. 

Discounts at Volkswagen ranged from around $2,200 to $7,300 a car. Its electric ID series is seeing price cuts of almost $6,000. The company called the cuts "temporary promotions due to general reluctance among car buyers, the new emissions rule and discounts offered by competitors."

China followed suit, and thus, now we have the sales numbers to prove it...

Tyler Durden Wed, 06/07/2023 - 20:00

Read More

Continue Reading

International

World Bank: Global Economic Growth Expected To Slow To 2008 Levels

World Bank: Global Economic Growth Expected To Slow To 2008 Levels

Authored by Michael Maharrey via SchiffGold.com,

Most people in the mainstream…

Published

on

World Bank: Global Economic Growth Expected To Slow To 2008 Levels

Authored by Michael Maharrey via SchiffGold.com,

Most people in the mainstream concede that the economy is heading for a recession, but the consensus seems to be that downturn will be short and shallow. Projections by the World Bank undercut that optimism.

According to the World Bank, global growth in 2023 will slow to the lowest level since the 2008 financial crisis.

In other words, the World Bank is predicting the beginning of Great Recession 2.0.

You might recall that the Great Recession was neither short nor shallow.

In fact, World Bank Group chief economist and senior vice president Indermit Gill said, “The world economy is in a precarious position.”

According to the World Bank’s new Global Economic Prospects report, global growth is projected to decelerate to 2.1% this year, falling from 3.1% in 2022. The bank forecasts a significant slowdown during the last half of this year.

That would match the global growth rate during the 2008 financial crisis.

According to the World Bank, higher interest rates, inflation, and more restrictive credit conditions will drive the economic downturn.

The report forecasts that growth in advanced economies will slow from 2.6% in 2022 to 0.7% this year and remain weak in 2024.

Emerging market economies will feel significant pain from the economic slowdown. Yahoo Finance reported, “Higher interest rates are a problem for emerging markets, which already were reeling from the overlapping shocks of the pandemic and the Russian invasion of Ukraine. They make it harder for those economies to service debt loans denominated in US dollars.”

The World Bank report paints a bleak picture.

The world economy remains hobbled. Besieged by high inflation, tight global financial markets, and record debt levels, many countries are simply growing poorer.”

Absent from the World Bank analysis is any mention of how more than a decade of artificially low interest rates and trillions of dollars in quantitative easing by central banks created the wave of inflation that continues to sweep the globe, along with massive levels of debt and all kinds of economic bubbles.

If you listen to the mainstream narrative, you would think inflation just came out of nowhere, and central banks are innocent victims nobly struggling to save the day by raising interest rates. Pundits fret about rising rates but never mention that rates were only so low for so long because of the actions of central banks. And they seem oblivious to the consequences of those policies.

But being oblivious doesn’t shield you from the impact of those consequences.

In reality, central banks and governments implemented policies intended to incentivize the accumulation of debt. They created trillions of dollars out of thin air and showered the world with stimulus, unleashing the inflation monster. And now they’re trying to battle the dragon they set loose by raising interest rates. This will inevitably pop the bubble they intentionally blew up. That’s why the World Bank is forecasting Great Recession-era growth. All of this was entirely predictable.

After all, artificially low interest rates are the mother’s milk of a global economy built on easy money and debt. When you take away the milk, the baby gets hungry. That’s what’s happening today. With interest rates rising, the bubbles are starting to pop.

And it’s probably going to be much worse than most people realize. There are more malinvestments, more debt, and more bubbles in the global economy today than there were in 2008. There is every reason to believe the bust will be much worse today than it was then.

In other words, you can strike “short” and “shallow” from your recession vocabulary.

Even the World Bank is hinting at this.

Tyler Durden Wed, 06/07/2023 - 15:20

Read More

Continue Reading

International

DNAmFitAge: Biological age indicator incorporating physical fitness

“We expect DNAmFitAge will be a useful biomarker for quantifying fitness benefits at an epigenetic level and can be used to evaluate exercise-based interventions.”…

Published

on

“We expect DNAmFitAge will be a useful biomarker for quantifying fitness benefits at an epigenetic level and can be used to evaluate exercise-based interventions.”

Credit: 2023 McGreevy et al.

“We expect DNAmFitAge will be a useful biomarker for quantifying fitness benefits at an epigenetic level and can be used to evaluate exercise-based interventions.”

BUFFALO, NY- June 7, 2023 – A new research paper was published in Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 15, Issue 10, entitled, “DNAmFitAge: biological age indicator incorporating physical fitness.”

Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. 

In this new study, researchers Kristen M. McGreevy, Zsolt Radak, Ferenc Torma, Matyas Jokai, Ake T. Lu, Daniel W. Belsky, Alexandra Binder, Riccardo E. Marioni, Luigi Ferrucci, Ewelina Pośpiech, Wojciech Branicki, Andrzej Ossowski, Aneta Sitek, Magdalena Spólnicka, Laura M. Raffield, Alex P. Reiner, Simon Cox, Michael Kobor, David L. Corcoran, and Steve Horvath from the University of California Los Angeles, University of Physical Education, Altos Labs, Columbia University Mailman School of Public Health, University of Hawaii, University of Edinburgh, National Institute on Aging, Jagiellonian University, Pomeranian Medical University in Szczecin, University of Łódź, Central Forensic Laboratory of the Police in Warsaw, Poland, University of North Carolina at Chapel Hill, University of Washington, and University of British Columbia develop blood-based DNAm biomarkers for fitness parameters including gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets (average r between 0.16–0.48). 

“These parameters were chosen because handgrip strength and VO2max provide insight into the two main categories of fitness: strength and endurance [23], and gait speed and FEV1 provide insight into fitness-related organ function: mobility and lung function [8, 24].”

The researchers then used these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge was associated with low-intermediate physical activity levels across validation datasets (p = 6.4E-13), and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. 

DNAmFitAge was lower (p = 0.046) and DNAmVO2max is higher (p = 0.023) in male body builders compared to controls. Physically fit people had a younger DNAmFitAge and experienced better age-related outcomes: lower mortality risk (p = 7.2E-51), coronary heart disease risk (p = 2.6E-8), and increased disease-free status (p = 1.1E-7). These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.

“Our newly constructed DNAm biomarkers and DNAmFitAge provide researchers and physicians a new method to incorporate physical fitness into epigenetic clocks and emphasizes the effect lifestyle has on the aging methylome.”
 

Read the full study: DOI: https://doi.org/10.18632/aging.204538 

Corresponding Authors: Kristen M. McGreevy, Zsolt Radak, Steve Horvath

Corresponding Emails: kristenmae@ucla.edu, radak.zsolt@tf.hu, shorvath@mednet.ucla.edu 

Keywords: epigenetics, aging, physical fitness, biological age, DNA methylation

Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204538

 

About Aging-US:

Launched in 2009, Aging publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at www.Aging-US.com​​ and connect with us:

  • SoundCloud
  • Facebook
  • Twitter
  • Instagram
  • YouTube
  • LabTube
  • LinkedIn
  • Reddit
  • Pinterest

 

Click here to subscribe to Aging publication updates.

For media inquiries, please contact media@impactjournals.com.

 

Aging (Aging-US) Journal Office

6666 E. Quaker Str., Suite 1B

Orchard Park, NY 14127

Phone: 1-800-922-0957, option 1

###


Read More

Continue Reading

Trending