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Love in the time of thermo




An 81-year-old medical doctor has fallen off a ladder in his house. His pet bird hopped out of his reach, from branch to branch of a tree on the patio. The doctor followed via ladder and slipped. His servants cluster around him, the clamor grows, and he longs for his wife to join him before he dies. She arrives at last. He gazes at her face; utters, “Only God knows how much I loved you”; and expires.

I set the book down on my lap and looked up. I was nestled in a wicker chair outside the Huntington Art Gallery in San Marino, California. Busts of long-dead Romans kept me company. The lawn in front of me unfurled below a sky that—unusually for San Marino—was partially obscured by clouds. My final summer at Caltech was unfurling. I’d walked to the Huntington, one weekend afternoon, with a novel from Caltech’s English library.1

What a novel.

You may have encountered the phrase “love in the time of corona.” Several times. Per week. Throughout the past six months. Love in the Time of Cholera predates the meme by 35 years. Nobel laureate Gabriel García Márquez captured the inhabitants, beliefs, architecture, mores, and spirit of a Colombian city around the turn of the 20th century. His work transcends its setting, spanning love, death, life, obsession, integrity, redemption, and eternity. A thermodynamicist couldn’t ask for more-fitting reading.

Love in the Time of Cholera centers on a love triangle. Fermina Daza, the only child of a wealthy man, excels in her studies. She holds herself with poise and self-assurance, and she spits fire whenever others try to control her. The girl dazzles Florentino Ariza, a poet, who restructures his life around his desire for her. Fermina Daza’s pride impresses Dr. Juvenal Urbino, a doctor renowned for exterminating a cholera epidemic. After rejecting both men, Fermina Daza marries Dr. Juvenal Urbino. The two personalities clash, and one betrays the other, but they cling together across the decades. Florentino Ariza retains his obsession with Fermina Daza, despite having countless affairs. Dr. Juvenal Urbino dies by ladder, whereupon Florentino Ariza swoops in to win Fermina Daza over. Throughout the book, characters mistake symptoms of love for symptoms of cholera; and lovers block out the world by claiming to have cholera and self-quarantining.

As a thermodynamicist, I see the second law of thermodynamics in every chapter. The second law implies that time marches only forward, order decays, and randomness scatters information to the wind. García Márquez depicts his characters aging, aging more, and aging more. Many characters die. Florentino Ariza’s mother loses her memory to dementia or Alzheimer’s disease. A pawnbroker, she buys jewels from the elite whose fortunes have eroded. Forgetting the jewels’ value one day, she mistakes them for candies and distributes them to children.

The second law bites most, to me, in the doctor’s final words, “Only God knows how much I loved you.” Later, the widow Fermina Daza sighs, “It is incredible how one can be happy for so many years in the midst of so many squabbles, so many problems, damn it, and not really know if it was love or not.” She doesn’t know how much her husband loved her, especially in light of the betrayal that rocked the couple and a rumor of another betrayal. Her husband could have affirmed his love with his dying breath, but he refused: He might have loved her with all his heart, and he might not have loved her; he kept the truth a secret to all but God. No one can retrieve the information after he dies.2 

Love in the Time of Cholera—and thermodynamics—must sound like a mouthful of horseradish. But each offers nourishment, an appetizer and an entrée. According to the first law of thermodynamics, the amount of energy in every closed, isolated system remains constant: Physics preserves something. Florentino Ariza preserves his love for decades, despite Fermina Daza’s marrying another man, despite her aging.

The latter preservation can last only so long in the story: Florentino Ariza, being mortal, will die. He claims that his love will last “forever,” but he won’t last forever. At the end of the novel, he sails between two harbors—back and forth, back and forth—refusing to finish crossing a River Styx. I see this sailing as prethermalization: A few quantum systems resist thermalizing, or flowing to the physics analogue of death, for a while. But they succumb later. Florentino Ariza can’t evade the far bank forever, just as the second law of thermodynamics forbids his boat from functioning as a perpetuum mobile.

Though mortal within his story, Florentino Ariza survives as a book character. The book survives. García Márquez wrote about a country I’d never visited, and an era decades before my birth, 33 years before I checked his book out of the library. But the book dazzled me. It pulsed with the vibrancy, color, emotion, and intellect—with the fullness—of life. The book gained another life when the coronavius hit. Thermodynamics dictates that people age and die, but the laws of thermodynamics remain.3 I hope and trust—with the caveat about humanity’s not destroying itself—that Love in the Time of Cholera will pulse in 350 years. 

What’s not to love?

1Yes, Caltech has an English library. I found gems in it, and the librarians ordered more when I inquired about books they didn’t have. I commend it to everyone who has access.

2I googled “Only God knows how much I loved you” and was startled to see the line depicted as a hallmark of romance. Please tell your romantic partners how much you love them; don’t make them guess till the ends of their lives.

3Lee Smolin has proposed that the laws of physics change. If they do, the change seems to have to obey metalaws that remain constant.



CAR-T cells turned into molecular computers destroy tumours more effectively




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One of the biggest challenges in cancer therapy is to develop drugs that are as selective as possible, so as to target cancer cells while leaving healthy surrounding tissues intact. Over the last decade, the development of chimeric antigen receptor (CAR) T cell-based immunotherapies has brought us significantly closer to solving this challenge. These therapies involve collecting from a patient’s blood the immune system T cells responsible for identifying and killing cancer cells, and engineering them to produce new surface proteins (CAR) that recognise specific markers – antigens – on the tumours. Once reinjected into the patient’s bloodstream, these CAR-T cells can identify and attack cancer cells more effectively.

While CAR-T cells have proved efficient for treating blood cancers such as leukaemia and lymphoma, solid tumours, such as found in the breast, liver or lung, have been more difficult to vanquish. Many of the markers characteristic to those tumours are also found in normal tissues, causing the destruction of both, as CAR-T cells do not distinguish between healthy and diseased cells. The challenge has hence shifted from “how do we target cancer cells” to “how do we do this while ensuring healthy tissues are left unharmed”.

A possible approach has recently been presented in two complementary articles by Wendell Lim’s research group at University of California San Francisco and Olga Troyanskaya’s group at Princeton and the Flatiron Institute of the Simons Foundation. The researchers combine machine learning and cell engineering techniques to create CAR-T cells that, instead of recognising just one antigen, use Boolean logic (AND, OR and NOT operators) to target combinations of up to three antigens. For example, if antigens A and B are mostly found in tumours but can also be present in healthy cells, while C is only found in normal tissues, the combination “A” OR “B” AND NOT “C” would help differentiate the tumour from normal tissues.

“Currently, most cancer treatments, including cell therapies, are told ‘block this’ or ‘kill this’,” explains Lim. “We want to increase the nuance and sophistication of the decisions that a therapeutic cell makes.”

Preventing off-target killing of healthy cells

In the first article, published in Cell Systems, the researchers investigated the efficiency of antigen combinations to distinguish normal and cancerous tissues in a database of the human genome containing 2358 antigens. A clustering-based score sorted over 2.5 million antigen pairs and approximately 60 million triple antigens. Pairing antigens using either AND or NOT logic gates significantly improved tumour recognition, outperforming well-established single antigens already investigated clinically, in 33 tumours and 34 normal samples.

These Boolean instructions can be programmed into CAR-T cells via synthetic Notch receptors (synNotch), one of the latest developments in cell engineering. Briefly, when a protein binds the Notch receptor, a portion of the receptor breaks off and heads for the cell nucleus, where it acts as a switch to turn on other genes. This allows cells to behave like molecular computers that can sense their environment and then integrate that information to make decisions.

To prove the accuracy of the method, the researchers programmed synNotch receptors to recognise two markers found in kidney tumours, CD70 and AXL, using an AND gate. Targeted separately, CAR-T cells would result in off-target damage, as CD70 is also widely present in healthy blood cells and AXL can be found in healthy lung tissues. But targeting both using an AND gate not only suppressed their expression in tumours in vitro, it also ensured that normal tissue containing just one of these antigens were left unharmed. For example, Raji B cells, which are found in the blood and express CD70, had a survival rate close to 100% with the two antigens, while only around 20% survived when only CD70 was targeted.

Adding a third antigen in the combination helped improve the overall performance across several types of tumour. It also revealed the importance of NOT gates, with 92 of the top-100 combinations of gates for each cancer having at least one such gate. This further highlights the importance of NOT gates in preventing toxic cross reactions, while also significantly improving the correct identification of challenging tumours, such as cholangiocarcinoma, a type of cancer that forms in bile ducts.

New killing strategies

In a second study, published in Science, Lim’s research team expanded on their initial work and daisy-chained multiple synNotch receptors to create a host of complex cancer recognition circuits. The “plug-and-play” nature of synNotch enabled them to customize circuits with diverse Boolean functions, allowing for precise recognition of diseased cells and a range of responses when those cells are identified.

Such circuits can be used in complex scenarios. For example, an antigen localized on the surface of a cell can be targeted, and the decision whether or not to launch the killing process would then be tied to the presence of a second cancer antigen inside the cell. Since CAR-T cells are usually restricted to recognising extracellular antigens, which only represent about 25% of a cell proteome, resorting to this Boolean logic enables targeting of new cancer antigens. As the researchers demonstrated in vitro with melanoma cells, this dual intracellular–extracellular targeting approach both improved specificity and reduced off-target killing.

In vivo experiments also showed promising results. The researchers injected a mouse presenting different tumours in each flank – one with two antigens, one with the same two antigens plus an additional third – with a three-antigen-AND-gate T cell composed of three sequentially linked receptors. Allowed to autonomously explore and act on both tumours, the T cells rapidly cleared the three-antigen tumours while ignoring the two-antigen tumours on the opposing flank, similarly to the results observed in vitro.

The possibilities are endless as these smart cells can be designed to fight all kind of tumours. Lim’s group is now exploring how these circuits could be used in CAR-T cells to treat glioblastoma, an aggressive form of brain cancer that is nearly always fatal, using conventional therapies.

“You’re not just looking for one magic-bullet target. You’re trying to use all the data,” Lim says. “We need to comb through all of the available cancer data to find unambiguous combinatorial signatures of cancer. If we can do this, then it could launch the use of these smarter cells that really harness the computational sophistication of biology and have real impact on fighting cancer.”


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Gas flows follow conventional theory even at the nanoscale




gas flow through nanoscale pores
Atomic aperture of WS2. Courtesy: R Boya

Gases flow through a porous membrane at ultrahigh speeds even when the pores’ diameter approaches the atomic scale. This finding by researchers at the University of Manchester in the UK and the University of Pennsylvania in the US shows that the century-old Knudsen description of gas flow remains valid down to the nanoscale – a discovery that could have applications in water purification, gas separation and air-quality monitoring.

Gas permeation through nano-sized pores is both ubiquitous in nature and technologically important, explains Manchester’s Radha Boya, who led the research effort along with Marija Drndić at Pennsylvania. Because the diameter of these narrow pores is much smaller than the mean free diffusion path of gas molecules, the molecules’ flow can be described using a model developed by the Danish physicist Martin Knudsen in the early decades of the 20th century. During so-called Knudsen flow, the diffusing molecules randomly scatter from the pore walls rather than colliding with each other.

Until now, however, researchers didn’t know whether Knudsen flow might break down if the pores became small enough. Boya, Drndić and colleagues have now shown that the model holds even at the ultimate atomic-scale limit.

Measuring gas flow through atomic-sized holes

The Manchester-Pennsylvania team performed their experiments on 0.3 nm-wide holes drilled in a monolayer of tungsten disulphide (WS2), a two-dimensional material. Until recently, the only way to check that such holes were present and of the right size was to inspect finished samples using high-resolution aberration-corrected scanning transmission microscopy (AC-STEM). While this “manual inspection” method is accurate, it is also painstaking, says team member Ashok Keerthi. As an alternative, Drndić and colleagues developed a technique for making hole-filled samples using focused ion beam (FIB) irradiation, which they demonstrated last year.

In the present work, the researchers created a system for measuring gas flow through atomic-sized holes and used their flow measurements to quantify the density of holes in a sample. To do this, they mounted their samples on silicon chips and placed them between two vacuum chambers: one at variable pressure and the other held at high vacuum and connected to a mass spectrometer. The samples were sealed in with O-rings, so that the holes in the WSmembrane were the only connecting path between the two chambers through which gas molecules (helium, in this case) can flow, Boya explains.

Close to values predicted by Knudsen theory

The researchers found that the WS2 monolayers containing atomic-sized pores are mechanically robust and that helium gas flows through them rapidly. The flow values they measured are within an order of magnitude of the values predicted by Knudsen theory and, surprisingly, there is no (or only a minimal) energy barrier to the flow through the pores.

“Our work has enabled a robust method for confirming the formation of atomic apertures over large areas using gas flows,” Boya says. This method is, she adds, “an essential step for pursuing their prospective applications in various domains, including molecular separation, sensing and monitoring of gases at ultra-low concentrations”.

Members of the teams say they now plan to further investigate the pores’ stability over time. “We also plan to look into gas separation through these tiny structures,” Drndić tells Physics World.

The present research is detailed in Science Advances.


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Entangled electron pairs created using heat




Electron entangler
Heating up: a false-colour electron microscope image of the device, which creates entangled pairs of electrons. The green layers are graphene on top of the grey superconductor. The two quantum dots can be seen protruding into the superconductor channel in the centre of the image. The blue metal electrodes are on the top layer and are used to extract the entangled electrons. (Courtesy: Aalto University)

A new device that produces entangled pairs of electrons by the application of heat has been unveiled by international team of researchers led by Pertti Hakonen at Aalto University in Finland. The device works by splitting up Cooper pairs of electrons in a superconductor — and then collecting the entangled electrons. This ability to produce entangled, tuneable electrical signals could be an important step towards creating new electron-based quantum technologies and research applications.

Entanglement is a purely quantum-mechanical phenomenon that allows two or more particles, such as electrons, to have a much closer relationship than is predicted by classical physics. Once considered an exotic consequence of quantum physics, entanglement now has very practical applications in quantum computing and quantum sensing. As a result, physicists are very keen on developing new and better ways of creating entangled particles.

Temperature gradient

When a temperature gradient is applied across a conducting material, its electrons will diffuse from the hot side to the cold side, generating a voltage. Known as the Seebeck effect, this phenomenon is widely exploited in modern technologies, including thermoelectric power generators and temperature sensors.

A Cooper pair comprises two entangled electrons that are bound together within a superconductor. Because Cooper pairs are bosons, they can condense at very low temperatures and flow with zero electrical resistance. The interaction that binds the electrons is long range and therefore the electrons in Cooper pairs do not necessarily have to be very close together.

In their study, Hakonen’s team created a tiny section of aluminium superconductor that is sandwiched between two tiny graphene electrodes that functioned as quantum dots – these are semiconductors that behave like artificial atoms with electron energy levels that can be tuned separately.

Nonlocal Seebeck effect

When the researchers applied a temperature gradient across their device, Cooper pairs within the superconductor split up. Thanks to the nonlocal Seebeck effect, electrons could then leave the superconductor by tunnelling through different quantum dots – which is encouraged by setting different energy levels on the two quantum dots. These electrons can then be extracted from the device by separate metal electrodes, one connected to each quantum dot. Because the two electrons were quantum-mechanically entangled in a Cooper pair, they maintain this special relationship when separated.

By tuning the quantum dots, the team could vary relative contributions to the currents of electrons from Cooper pair splitting and another process called elastic co-tunnelling. This gave the team control over the two output signals of their device.

The new device could have a wealth of potential applications in electron-based quantum technologies. Furthermore, the tuneability of the device could soon facilitate fundamental tests of theoretical concepts in entanglement and thermodynamics.

The device is described in Nature Communications.


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X-ray images determine MRI safety of embedded bullet fragments




MRI of nonferromagnetic bulletsSmall Arms Survey, 40% of firearms in the world are owned by Americans. In 2017, a survey by the Pew Research Centre found that 44% of Americans know someone that has been shot, either accidentally or intentionally, with 3% of adults saying they have been shot.

Being shot can have important implications for medical diagnostics, even years later, as people with gunshot wounds are frequently denied MRI scans. This is because the composition of embedded bullet fragments cannot be identified to determine whether they are nonferromagnetic, or not.

Ferromagnetic materials are not safe in MRI scanners because the high-powered magnets that the machines use can heat or move them. This could burn the patient. And if the material is near a critical structure, such as the spinal cord, even small movements could cause significant damage.

Jason Allen, a neuroradiologist at Emory University in Atlanta, says that issues arise more frequently with patients that have been shot in the past. “They survive that injury and then they come along later, and they have a new problem,” he explains. “It is particularly problematic at that point because there is really zero chance of us knowing what kind of bullet they were shot with.”

MRI is important, Allen says, because there are clinical questions that doctors are unable to answer with other imaging techniques, particularly for issues related to the brain and spinal cord. “In terms of traumas, if we need to look for damage to those tissues, or someone may have had a stroke or a suspected stroke, these are things that we really need to define with MRI,” he explains.

Allen and his colleagues wondered whether bullets made from ferromagnetic and nonferromagnetic metals deformed and broke up in different ways on impact, leaving identifiable differences in the debris embedded in those who had been shot. This could allow the composition of the bullets to be determined from images taken using non-magnetic radiological techniques, to check MRI safety.

To test this, the researchers fired handgun and shotgun ammunition commercially available in the US into blocks of ballistic gelatin – a material that is an analogue for human tissue and is used to simulate the effect of bullet impact. They then took CT and X-ray images of the gelatin blocks.

The team were able to distinguish between ferromagnetic and nonferromagnetic fired bullets, they report in the American Journal of Roentgenology. They found that a bullet that leaves a metallic debris trail from entry to final position or has been appreciably deformed is of copper, copper-alloy or lead composition, or represents lead shotgun shot. These nonferromagnetic materials deform more because they are softer than ferromagnetic metals. Based on this, the researchers created a simple triage algorithm for patients with retained ballistic fragments that doctors can follow to determine MRI safety. “This can be done by any radiologist of any background,” Allen says.

American Journal of Roentgenology)”>American Journal of Roentgenology)”>

Allen and his colleagues also took MRI scans of unfired bullets suspended in ballistic gelatin blocks, and assessed magnetic attractive force, rotational torque and heating effects. Although ferromagnetic bullets showed evidence of having moved or rotated during the scans, nonferromagnetic bullets did not. None of the bullets tested showed heating above the US Food and Drug Administration limit of 2°C. This shows that nonferromagnetic bullets do not pose a significant risk for MRI scans, regardless of when the injury occurred, the researchers say.

“We’ve scanned hundreds of these patients over the years, we’ve not had any cases where the patient has gone into the scanner based on this algorithm and had an injury of some sort, had a heating of the bullet or had a movement of the bullet,” Allen tells Physics World.


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