Acne, bronchitis, pink eye, ear infections, and sexually transmitted diseases are just a few of the illnesses treatable by antibiotics — assuming that the bacteria that cause these illnesses are not resistant to antibiotics.
Antibiotic resistance, one of the most urgent threats to public health, occurs when antibiotics are unable to kill the bacteria causing an infection. According to the Centers for Disease Control, each year in the United States at least 2 million people become infected with bacteria that are resistant to antibiotics and at least 23,000 people die as a direct result of these infections.
Understanding antibiotic resistance starts with understanding bacteria. Bacteria are tiny single-celled organisms found nearly everywhere on Earth. Most bacteria are harmless to humans. Some are helpful. Some cause disease. Over millennia, bacteria have evolved ways to keep out harmful foreign substances. Many so-called Gram-negative bacteria, which have two cellular membranes, have evolved protein structures called efflux pumps that are lodged between the membranes and expel toxins out of the cell.
But what happens when the bacteria in question are the dangerous, disease-causing kind? Doctors try to kill them with antibiotics. But the dangerous bacteria often use efflux pumps to flush out antibiotics before the drugs get a chance to work.
One type of efflux pump, which until recently had only been studied piecemeal, was modeled in its entirety and simulated using supercomputers at Los Alamos National Laboratory. The work harnessed the Laboratory’s extensive modeling and supercomputing simulation capabilities developed in support of its national security mission.
By understanding how the pump moves and behaves, my colleagues and I at the Laboratory, the University of Oklahoma, and Goethe University in Frankfurt, Germany, can potentially find a way to deactivate the pump — which might make antibiotics that haven’t worked in a long time useful again.
For this study, we focused on an efflux pump inside the Gram-negative bacteria Pseudomonas aeruginosa, which causes serious illnesses such as pneumonia and sepsis. Approximately a million-and-a-half atoms in size, the P. aeruginosa pump stretches between the cell’s inner and outer membranes and connects the cell’s interior and periplasm (the compartment between the membranes) to the cell’s exterior. That connection creates a path for drug molecules to exit the cell.
The Laboratory’s supercomputers were able to perform the first atomistic simulations of the entire pump on a microsecond time scale. We then used the simulations to investigate how the pump works.
By applying this kind of computer simulation to the variety of efflux pumps found in different Gram-negative pathogens, we hope to find out whether the different pumps share the same general mechanisms or each pump has its own way of working.
Knowing that could help researchers develop effective drug therapies aimed at the efflux pumps. For example, perhaps a drug could target and counteract the amino acid interactions that stabilize the pump, allowing currently defunct antibiotics to linger inside the bacteria cell and kill it. Then these antibiotics could once again effectively cure people with dangerous diseases.
Restoring effectiveness to currently obsolete antibiotics is one of the key goals of this research. By allowing us to explore models of the efflux pumps in a controlled way, the supercomputer simulations speed up research that might otherwise involve months or even years of laborious lab work — and, hopefully, speed up the return of once-effective antibiotics to the medical community’s medicine cabinet.
Sandrasegaram “Gnana” Gnanakaran is a theoretical biologist at Los Alamos National Laboratory, where his research is aimed at developing and applying computational methodologies to understand the structural characteristics and thermodynamics of peptides, carbohydrates and proteins — and, most recently, efflux pumps.
The Aftermath of Michael Jackson’s Antigravity Lean
The infamous lean.
In Michael Jackson’s 1987 music video “Smooth Criminal,” the legendary performer leans forward 45 degrees from a straight-up position — and comes back. It’s a feat that seemingly defies both physics and physiology, and the move has become another element of MJ’s aura of mystery.
Some type of cinematic or mechanical trick must be responsible, since most people can manage only a 20-degree forward tilt before toppling headlong. Yet Jackson performed the move live on tours around the world for years.
In a study published this week in the Journal of Neurosurgery, three scientists examine the so-called Antigravity Lean, not from a physics but from a physiological perspective. The three neurosurgeons, all at the Postgraduate Institute of Medical Education and Research in Chandigarh, India, combine in the article their knowledge of Jackson with data on spine biomechanics.
It’s been known for years how Jackson defied gravity. His shoes had a slot that slid onto a bolt in the floor, allowing him to perform the dramatic lean.
Bending forward is limited by the erector spinae muscles, which act like cables to support forward bends up to 20 degrees, though some dancers can achieve 30 degrees, the paper says. When near the max of a bend, you can feel the strain on the Achilles’ heel as the ankles become the fulcrum for balance. People soon return to vertical or catch themselves from falling headlong.
Though Jackson’s 45-degree bend is not physically possible without trickery, the King of Pop still needed incredible core strength and leg muscles to pull it off, the authors write. Not just anyone can lock their shoes into the floor and become Michael Jackson, it seems.
“Several MJ fans, including the authors, have tried to copy this move and failed, often injuring themselves in their endeavors,” the researchers write.
Figure A shows the Antigravity Tilt (a 45-degree forward bend) and the normal limit that most people can bend forward. Jackson used shoes with a slot that slid onto a bolt in the floor. Figure B shows the shift when the body’s fulcrum is the hip and when it’s the Achilles’ tendon. (Illustration courtesy of Manjul Tripathi)
Tough Act to Follow
Jackson’s sleight of foot inspired generations of dancers who push the limits physically. This has resulted in spinal stresses not previously seen by neurosurgeons.
This is not to point the finger at Jackson. But it does suggest the reality that injuries can occur that might require implant spinal surgery, the article says, something potentially devastating to a dancer.
But it’s not all bad news — neurosurgeons have gained a lot of new information on how to treat spinal cord injuries in recent years, something that could be in part thanks to MJ’s envelope-pushing dance moves.
“The King of Pop has not only been an inspiration but a challenge to the medical fraternity,” Tripathi says.
Your Emergency Contact Does More Than You Think
You know when you’re filling out your medical paperwork and it asks for your emergency contact? Sure, the process might be annoying, but that emergency contact could actually be put to good use by researchers.
Since many of us use a family member, those contacts can help scientists create family trees. And they can also be used for genetics and disease research, according to a study released Thursday in Cell. Discovering what diseases are inheritable can be a laborious and expensive process — patients must be recruited and researchers must clearly determine patients’ phenotypes (physical traits that include eye color, height, and overall health and are often influenced by your genes).
To make that process easier researchers from three major New York medical centers generated family trees from millions of electronic medical records to create a database.This is the first time electronic health records have been used to trace ancestry and it’s the largest study of heritability using such records.
The More You Know
The researchers identified 7.4 million relatives with an algorithm that matched names, addresses and phone numbers from three medical centers. They found 500 inheritable phenotypes in the data just by looking at test results and observations in health records. The traits included diseases affecting skin, blood and mental health.
The data can help determine the heritability level of many common diseases. For example, researchers found that having an increase of HDL (good) cholesterol is 50 percent heritable, while LDL (bad) cholesterol is only 25 percent heritable. The study’s findings were consistent across the participating medical centers and published studies.
Previous heritability research primarily documented Caucasians of northern European descent, according to the study’s first author Fernanda Polubriaginof, but this research is much broader.
“This dataset will allow us for the first time to compute whether there are differences in other races and ethnicities,” said Polubriaginof in a news release.
Future studies could look at medical records for the hereditary contribution of any trait. Due to privacy issues, patient identifiers were removed for the data, which can only be used for research at the moment. Though, with patient consent, emergency contacts could be put to important use in the future.
Mosquito Bites Leave A Lasting Impression On Our Immune System
Mosquito bites are like a gross form of French kissing — the insects swap your blood with their saliva, and leave a trail of salivary secretions behind like mosquito cooties. Some of those compounds prevent clotting as the insects slurp up your blood. Now researchers find mosquito spit aggravates your immune system for days afterward. The findings could help scientists develop vaccines for mosquito-born diseases like Zika.
Rebecca Rico-Hesse, a virologist at Baylor College of Medicine in Houston, Texas, wanted to know how mosquitoes exploit our immune systems with their drool. So, she and her team exposed mice with human-like immune systems to live mosquitoes. Then, they sized up the mice’s immune response as it reacted to the mosquito spittle.
The bug’s saliva toyed with their immune systems in both bone marrow and skin cells with effects that lasted up to seven days after biting, the team reports today in PLoS: Neglected Tropical Diseases. The researchers say their discovery could explain how these tissues might act as virus incubators and help spread disease.
In 2012, Rico-Hesse was looking to untangle how Dengue virus causes Dengue hemorrhagic fever — an illness that affects 400 million people each year and can lead to death — when she came across a strange occurrence. Mice infected with the virus from mosquito bites fared far worse than mice that had received an injection of the virus but hadn’t been served as a mosquito meal. The result made Rico-Hesse take a step back.
It seems that mosquito bites caused the immune system to behave differently, and in ways that could potentially give infectious diseases a leg up.
To find out, Rico-Hesse and her team set starving Aedes aegypti mosquitoes on mice that had received a dose of human stem cells to make their immune systems look more like a human’s. Each mouse endured eight mosquito bites total. Then the team checked out different parts of the immune system — blood, bone marrow, spleen, and skin cells — six and 24 hours after biting, as well as seven days later. By then, the immune system should have returned to normal.
Instead, the team discovered immune cells that had disappeared from the skin at least six hours post-bite came back seven days later after maturing in bone marrow, something that shouldn’t have happened. If those cells harbored a virus, they could then pass it on to new mosquitoes, who could infect others.
The research is pointing out new ways in which mosquito bites affect our immune systems, and it goes beyond simple itching and scratching.
“Mosquito saliva has evolved to modify our immune system,” Rico-Hesse said. And as their new research shows, viruses and parasites could be hijacking that activity to get to the cells they reproduce in, like bone marrow cells, faster, according to her.
Essentially, viruses might be taking advantage of the immune system’s response to travel from their point of entry — the skin — to a place they can multiply in that’s away from attacks by the immune system.
“It’s mind-blowing,” Rico-Hesse said. “No one has ever seen this before.”
Ultimately, the work could lead to infection-blocking vaccines, said Duane Gubler, an international health expert who was not involved in the research.
That’s what Rico-Hesse hopes, too. “If we can make a vaccine that would protect us against the effects of the [mosquito] saliva, or blocking our immune reaction … then we could stop global vector-born diseases,” she said.
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