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Comment by Dr. Krishna Kumari Challa on January 24, 2024 at 6:42am

Cells' electric fields keep nanoparticles at bay, scientists confirm

The humble membranes that enclose our cells have a surprising superpower: They can push away nano-sized molecules that happen to approach them. A team including scientists at the National Institute of Standards and Technology (NIST) has figured out why, by using artificial membranes that mimic the behavior of natural ones. Their discovery could make a difference in how we design the many drug treatments that target our cells.

The team's findings, which appear in the Journal of the American Chemical Society, confirm that the powerful electrical fields that cell membranes generate are largely responsible for repelling nanoscale particles from the surface of the cell.
This repulsion notably affects neutral, uncharged nanoparticles, in part because the smaller, charged molecules the electric field attracts crowd the membrane and push away the larger particles. Since many drug treatments are built around proteins and other nanoscale particles that target the membrane, the repulsion could play a role in the treatments' effectiveness.

The findings provide the first direct evidence that the electric fields are responsible for the repulsion.

This repulsion, along with the related crowding that the smaller molecules exert, is likely to play a significant role in how molecules with a weak charge interact with biological membranes and other charged surfaces.

This has implications for drug design and delivery, and for the behavior of particles in crowded environments at the nanometer scale.

Part 1

Comment by Dr. Krishna Kumari Challa on January 24, 2024 at 6:37am

Chemists tie a knot using only 54 atoms

A trio of chemists  has tied the smallest knot ever, using just 54 atoms. In their study, published in the journal Nature Communications, the researchers accidentally tied the knot while trying to create metal acetylides in their lab.

The researchers were attempting to create types of alkynes called metal acetylides as a means to conduct other types of organic reactions. More specifically, they were attempting to connect carbon structures to gold acetylides—typically, such work results in the creation of simple chains of gold known as caternames.
But, unexpectedly, the result of one reaction created a chain that knotted itself into a trefoil knot with no loose ends. Trefoil knots are used in making pretzels and play a major role in knot theory. The researchers noted that the knot had a backbone crossing ratio (BCR) of 23. Knot BCRs are a measure of the strength of the knot. Most organic knots, the team notes, have a BCR somewhere between 27 and 33.

The knot represents a record—its three-leaf clover shape beats out a previous record held by a different team in China that created a 69-atom knot back in 2020. The prior record holder was created on purpose by that team using techniques developed to entwine strands into knots. The new record holder self-assembled, and the team behind it still does not understand how it happened. It is not yet known if it is possible to make a knot any smaller.

The creation of such tiny knots, the research team points out, is not just an interesting lab trick—microscopic knots are formed in many natural settings, such as in RNA and DNA and several other proteins. By creating tiny knots, chemists are learning more about how and why they come about in nature. It also could help in the discovery of new types of polymers and/or plastics.

More information: Zhiwen Li et al, Self-assembly of the smallest and tightest molecular trefoil knot, Nature Communications (2024). DOI: 10.1038/s41467-023-44302-y

Comment by Dr. Krishna Kumari Challa on January 23, 2024 at 12:07pm

Developmental biologist Sarah Hadyniak, who co-authored the study while at Johns Hopkins University, says their findings have implications for figuring out exactly how retinoic acid is acting on genes.

To get a sense of how much this could be affecting human vision, the researchers studied the retinas of 738 male adults with no signs of color vision deficiency.

The researchers were astonished at the natural variation in red/green cone ratio across this group.

"Seeing how the green and red cone proportions changed in humans was one of the most surprising findings of the new research", Hadyniak says.

It's unclear how this much variation could occur without affecting changes in vision. As Johnston put it, "if these types of cells determined the length of a human arm, the different ratios would produce amazingly different arm lengths."

This research was published in PLOS Biology.
Part 3
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Comment by Dr. Krishna Kumari Challa on January 23, 2024 at 12:07pm

Now, new research offers some clarity as to what those key vision-defining ingredients – making up just a 4 percent difference between the genes that code for these proteins – actually are.
We previously thought cone determination was basically random, though more recent studies have pointed to thyroid levels playing a role.

But a team from Johns Hopkins University and the University of Washington has discovered that levels of a molecule derived from vitamin A called retinoic acid make or break red-green cone ratios, at least in the case of their lab-grown retinas.

"These retinal organoids allowed us for the first time to study this very human-specific trait," says developmental biologist Robert Johnston from Johns Hopkins University. "It's a huge question about what makes us human, what makes us different."

In the lab, retinas exposed to more retinoic acid during early development (the first 60 days) resulted in higher ratios of green cones across the organoid after 200 days, while immature cones exposed to low levels of the acid developed into red cones later on.

The timing matters, too. If the retinoic acid was introduced at 130 days onwards, the effect was the same as if none had been added at all. This suggests the acid determines cone type early, and can't cause red cones to 'switch' into green cones that have already matured.

All the lab-grown retinas had similar cone densities, which allowed the team to rule out cone cell death as affecting the ratio of red to green.
part 2

Comment by Dr. Krishna Kumari Challa on January 23, 2024 at 12:06pm

Just One Molecule Allows Us to See Millions More Colors Than Our Pets

It's pretty hard to imagine the world through someone else's eyes, especially different animals. But a new study using lab-grown human retinas reveals that even between different humans, our vision is extremely diverse. And it might be to do with how the red and green cones form in our retinas. Cones are light-sensing cells in vertebrates' eyes; their combined responses to different wavelengths enable color vision.

Humans and some closely related primates are some of the only mammals known that can see the color red, as well as green and blue.

Other animals can also see red, like many birds and some insects. The kind of vision an animal has is closely related to its evolution alongside plants that produce fruits and flowers. This ability has been pretty useful, for instance, for spotting a ripe red apple among a dense canopy of green.

Another mammal outlier with the ability to see red is the honey possum (Tarsipes rostratus). This Australian marsupial pollinator has a bird-like ability to probe the nectar from a blushing banksia, in a fascinating example of convergent evolution.

Our red and green cones are basically identical, with slightly different chemistry to determine which color they'll detect. A protein called opsin comes in two different 'flavors', red-sensitive or green-sensitive, and their genetic 'recipes' sit side-by-side on the X chromosome.

So it's very easy for them to get mixed up in recombination, resulting in variations of congenital red-green color blindness.
Part 1

Comment by Dr. Krishna Kumari Challa on January 23, 2024 at 9:49am

Scientists spin naturalistic silk from artificial spider gland

Researchers have succeeded in creating a device that spins artificial spider silk that closely matches what spiders naturally produce. The artificial silk gland was able to re-create the complex molecular structure of silk by mimicking the various chemical and physical changes that naturally occur in a spider's silk gland.

This eco-friendly innovation is a big step towards sustainability and could impact several industries.

Famous for its strength, flexibility, and light weight, spider silk has a tensile strength that is comparable to steel of the same diameter, and a strength-to-weight ratio that is unparalleled. Added to that, it's biocompatible, meaning that it can be used in medical applications, as well as biodegradable. So why isn't everything made from spider silk? Large-scale harvesting of silk from spiders has proven impractical for several reasons, leaving it up to scientists to develop a way to produce it in the laboratory.

Spider silk is a biopolymer fiber made from large proteins with highly repetitive sequences, called spidroins. Within the silk fibers are molecular substructures called beta sheets, which must be aligned properly for the silk fibers to have their unique mechanical properties. Re-creating this complex molecular architecture has confounded scientists for years. Rather than trying to devise the process from scratch, scientists now took a biomimicry approach.

They  attempted to mimic natural spider silk production using microfluidics, which involves the flow and manipulation of small amounts of fluids through narrow channels. Indeed, one could say that the spider's silk gland functions as a sort of natural microfluidic device.

The device developed by the researchers looks like a small rectangular box with tiny channels grooved into it. Precursor spidroin solution is placed at one end and then pulled towards the other end by means of negative pressure. As the spidroins flow through the microfluidic channels, they are exposed to precise changes in the chemical and physical environment, which are made possible by the design of the microfluidic system. Under the correct conditions, the proteins self-assembled into silk fibers with their characteristic complex structure.

The researchers experimented to find these correct conditions, and eventually were able to optimize the interactions among the different regions of the microfluidic system. Among other things, they discovered that using force to push the proteins through did not work; only when they used negative pressure to pull the spidroin solution could continuous silk fibers with the correct telltale alignment of beta sheets be assembled.

The ability to artificially produce silk fibers using this method could provide numerous benefits. Not only could it help reduce the negative impact that current textile manufacturing has on the environment, but the biodegradable and biocompatible nature of spider silk makes it ideal for biomedical applications, such as sutures and artificial ligaments.

Jianming Chen et al, Replicating shear-mediated self-assembly of spider silk through microfluidics, Nature Communications (2024). DOI: 10.1038/s41467-024-44733-1

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:59am

A synthetic space for the growth of bacterial therapies 

This is an example of how two different engineered systems can be complementary and synergize their function.

 Beyond remodeling the tumor environment to boost CAR T efficacy, researchers are exploring how engineered bacteria can enhance positron emission tomography (PET)/magnetic resonance imaging (MRI), focus ultrasounds, and even deliver drug-loaded nanoparticles

https://www.the-scientist.com/news/bugs-as-drugs-to-boost-cancer-th...

Part 5

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Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:58am

To increase CAR T cell proliferation and persistence, patients must first undergo lymphodepletion to kill circulating T cells. However, a long-term goal of immunotherapies is to administer the treatment to an intact immune system. 

To test their system on a functioning immune system, the researchers implanted mouse-derived tumors on both hind flanks of immune-competent mice and then administered the engineered bacteria directly to one of the tumor sites, followed a few days later by two rounds of CAR T treatment. (They introduced an extra dose of CAR T cells to combat T cell exhaustion.) The researchers hoped that their system could generate enough inflammation to stimulate the host immune system to recognize the additional tumor, so they were excited to find a reduction in tumor growth in not only the treated tumor but also the untreated site.

The subcutaneous experiments prepared for the big experiment: intravenous administration of the probiotic CAR system. For this, they implanted human cancer cells into the mammary fat pads of mice with weakened immune systems and then administered the probiotic CAR regimen with one small tweak to the system. In order to further coax the CAR T cells to the tumor site, the researchers engineered the bacteria to corelease the immune cell attractant human chemokine ligand 16 (CXCL16).¹³ This paved a concentration gradient for the CAR T cells to drive along towards the tumor. The added chemokine cargo added a boost to the system, outperforming the standard probiotic CAR regimen with respect to tumor growth inhibition. Additionally, analyses of other organs showed that bacteria and GFP expression was restricted to the tumor site.

Before transitioning these experiments to humans, the researchers will first need to genetically attenuate their engineered bacteria. In this study, they used a wild type strain of E coli, but mice are less sensitive than humans to Gram-negative bacteria toxicity. The major focus of the lab now is trying to make a translational strain of bacteria.

Part 4

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:56am

This time researchers designed their CAR to target their synthetic GFP antigen.

When they tested their probiotic CAR system in vitro using different human cancer cell lines, the researchers observed increased specificity and cytotoxicity relative to systems lacking either the GFP tag or receptor. Following the in vitro inspections, their system was ready to leave the garage and hit the road.

For the first in vivo test of their probiotic CAR platform, the researchers turned to immunodeficient mice bearing subcutaneous tumors derived from human cancer cells. After injecting the engineered bacteria directly into the tumor, they waited 48 hours to allow for quorum-regulated release of the GFP tags before similarly delivering the engineered CAR.¹¹ The engineered probiotic CAR system inhibited tumor growth, and subsequent flow cytometry analyses of the tumors provided evidence of increased T cell activation. 

The researchers also found that a partial system produced a partial response: empty bacteria administered alongside the engineered CAR still triggered some T cell activation at the tumor site. The best part of the system is the fact that the T cells respond really strongly to bacteria.

Part 3

Comment by Dr. Krishna Kumari Challa on January 21, 2024 at 9:54am

The tumour microenvironment is an inhospitable ecosystem. “For bacteria, they kind of don't care about all of that. They are really, at a very general level, looking for a place where they can survive in the body that's away from the immune system.

The hypoxic, minimally surveilled core of a solid tumor is the perfect bacterial bungalow. However, some bacterial strains can still inhabit healthy organs, so researchers need to explore ways to modify the bacterial genome to reduce virulence and toxicity. Although attenuated bacteria proved safer in both mice and humans, researchers observed poor tumor colonization and no tumor regression. Now, to improve tumor targeting and specificity, researchers are searching for synthetic biology solutions.

Bacteria already have a proclivity for the tumor microenvironment.

So researchers engineered the probiotic strain Escherichia coli Nissle 1917, which was equipped with Danino’s quorum sensing lysis circuit. Once the bacteria reached quorum, they released synthetic antigens that stuck to the tumor. Specifically, the researchers fused a green fluorescent protein (GFP) to the heparin binding domain (HBD) of a placental growth factor protein.¹⁰ The sticky HBD anchored to collagens and polysaccharides, ubiquitous components in the tumor environment, thus planting GFP flags on the tumor. Although these molecules are found in healthy tissue, they are highly abundant in the tumour.

Part 2

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