How Cancers Hurt Themselves to Hurt Immune Cells More (Medicine)

A study of melanoma cells explains a puzzling response they exhibit to ward off T cell attacks.

Cancers like melanoma are hard to treat, not least because they have a varied bag of tricks for defeating or evading treatments. A combined research effort by scientists at the Weizmann Institute of Science and researchers in the Netherlands Cancer Institute in Amsterdam and the University of Oslo, Norway, shows exactly how tumors, in their battles to survive, will go so far as to starve themselves in order to keep the immune cells that would eradicate them from functioning.

Checkpoint inhibitors like this one are not always effective against cancers like melanoma. Image: Getty Images

The immunotherapies currently administered for melanomas work by removing obstacles that keep immune cells called T cells from identifying and killing tumor cells. Recent research suggested that in melanoma, another blocker could assist the T cells – this one to stop an enzyme called IDO1 that is overproduced by the cancer cells. IDO1 breaks down an essential amino acid, tryptophan, which is needed to make proteins, in the process leaving behind tryptophan breakdown byproducts that suppress the immune response. But IDO1 blockers did not fare well in clinical trials, suggesting more knowledge was needed – including how the cancer cells, which also require tryptophan, can function after they have destroyed this resource.

The research team, including the group of Prof. Yardena Samuels of Weizmann’s Molecular Cell Biology Department, members of the lab of Prof. Reuven Agami of the Netherlands Cancer Institute; Dr. Noam Stern-Ginossar of the Weizmann Institute’s Molecular Genetics Department; Dr. Yishai Levin and his group at the Nancy and Stephen Grand Israel National Center for Personalized Medicine on the Institute campus; and the group of Prof. Johanna Olweus of the University of Oslo, investigated the mystery of the missing tryptophan in melanoma cells.

Agami and his team had, in previous research shown that in normal cells, when an amino acid like tryptophan is missing, this causes a sort of logjam in the protein production process. The ribosomes – protein production units – make their way down a strand of messenger RNA (mRNA), translating three-letter “words” known as codons into amino acids, which they grab and add to the expanding protein chain. When an amino acid is missing, the ribosomes stop working until one can be found, causing a pile-up in the ribosomes coming up the mRNA strand from behind.

Ribosomes (large, dark circles) working their way down a strand of mRNA. Proteins are forming to the top and bottom. Amino acid scarcity results in ribosome logjams

But that is not what happens in melanoma cells. The group found that some ribosomes manage to keep going, past the codons encoding the missing tryptophan. What was going on?

It turned out that the melanoma ribosomes were engaging in a ruse known as “frameshifting.” That is, they simply moved up or down one letter in the RNA strand. In the economical gene code – based on just four letters – the next three spelled the name of a different amino acid and the ribosomes continued down the mRNA strand, assembling protein chains. Of course, the frames of subsequent codon triplets shifted as well, so that the resultant proteins were quite abnormal. The cancer cells then displayed them on their outer membranes, where immune cells could pick up on the aberrant protein structures.

When things get stressful in the tumor’s microenvironment, it can affect protein production.

Such frameshifting had been seen before in viruses and bacteria, but not in human cells. Previous studies have missed these proteins because they do not arise from genetic mutations (of which there are hundreds in melanoma), but from a sort of calculated blip in the production process. Agami, whose lab is now investigating exactly how this frameshifting is initiated and whether it occurs in other cancers, says: “This flexibility in mRNA translation might stimulate tumor growth and aggressive behavior by using an emergency program for scarcity.”

Image: Getty Images

Dr. Osnat Bartok, in Samuels’s group: “When things get stressful in the tumor’s microenvironment, it can affect protein production, harming immune cells but also adding to the immune cells’ clues for identifying cancer.” Samuels adds: “These findings add to our knowledge of immune system interactions with cancer as well as the landscape immune cells encounter in a tumor. They suggest exciting ways we might regulate and therapeutically target the presentation of defective immune-reactive peptides on the cell surface.”

Reference: Bartok, O., Pataskar, A., Nagel, R. et al. Anti-tumour immunity induces aberrant peptide presentation in melanoma. Nature (2020).

Provided by Weizmann Institute of Science

Three In A Row – Hat Trick For Brain Electrodes (Neuroscience)

In order to study how the brain functions and to develop new technologies for treating neurological diseases, researchers at Lund University in Sweden have developed tissue-friendly and flexible microelectrodes that are roughly one tenth as thick as a strand of hair. Three of the doctoral students in the research team have just defended their theses.

Mohsin Mohammed, Jens Schoenborg, Johan Agorelius and Alexander Dontsios Holmkvist. © Lund University

The brain is the most complicated structure we know of and is behind our intelligence, creativity, thoughts, memories, feelings and senses. It has been likened to a computer, but this comparison falters given the fact we are not even close to understanding how the brain functions. A vital missing piece of the puzzle is tissue-friendly electrodes to listen to, and interact with, individual nerve cells connected to networks over a long period. It is this kind of electrode that Jens Schouenborg’s research team at Lund University have researched and developed over many years.

“We have taken decisive steps towards our goal of producing entirely biocompatible electrodes that do not disrupt the normal signalling between nerve cells in the brain tissue”, explains Jens Shouenborg, the professor leading research activities at the Neuronano Research Centre at Lund University.

To evaluate the new electrodes they use models for Parkinson’s – a disease that leads to the disintegration of nerve cells in a specific area of the brain. When this occurs, stimulation via implanted electrodes, often referred to as Deep Brain Stimulation (DBS), can be used as a treatment to reduce the motor symptoms that afflict patients.

There are challenges, however. It is often difficult to achieve a therapeutic result without side effects using the electrodes available today, in part because they are so large in relation to the areas of tissue being stimulated that it makes it difficult to avoid spreading electric currents to unintended areas of the brain. As inflammation and scar tissue (known as “foreign body reaction”) regularly form around such electrodes, stronger currents must also be used in order to have an effect.

It is this problem that the research team at Lund University have wanted to solve. Their concept is based on using many tiny microelectrodes that spread out as a cluster in the target tissue, before selecting the microelectrodes that offer a therapeutic result without visible side effects upon stimulation.

Electrode construction developed by the group – next to an English penny © Lund University

Thanks to these electrodes, the researchers can get extremely close to the nerve cells, which means the current used does not need to be as strong, thus also reducing the risk of undesirable effects. But does it have a therapeutic effect?

“We are seeing an effect, to put it mildly. Particularly if we combine 4-8 microelectrodes in the cluster, and perhaps most importantly: we can avoid side effects. In the future this may mean it will be possible to tailor the treatment to each patient by testing different combinations in line with the target and symptoms; something we are now assessing in large animal models together with Neuronan AB and Jens Christian Hedemann Sörensen’s research team at Århus University Hospital.”

“As the electrodes are so flexible, they need to have support when being implanted. The research team has developed a technology whereby the electrodes are embedded in hard gelatine that dissolves after implantation and is then broken down by the enzymes in the brain. Gelatine is a very difficult and complicated material to manipulate, however,” sighs Schouenborg.

For example, it is easy for the electrode to become warped if there is even the slightest asymmetry during the drying process. But it has been worth the hard work – in the end we now have a solution that has a considerably smaller impact on the tissue than previous electrodes.”

Provided by Lund University

Eating Fish, But Not Meat, Offers Key Health Benefits (Food)

Compared with meat eaters, fish eaters have a lower risk of several adverse heart diseases, including stroke.

These findings, which were part of new research looking at the diets and risk of developing or dying from heart diseases of more than 420,000 people in the UK, also concluded that vegetarianism was associated with a lower risk of developing heart disease.

© University of Glasgow

The study, led by researchers from the University of Glasgow and published today in the European Heart Journal, suggests that a pescatarian diet should be promoted and encouraged as a healthy option.

The study, which set out to find whether vegetarians, fish, poultry or meat eaters had a higher risk of developing or dying from heart diseases, used data from the UK Biobank to link diets with health in the British population.

Researchers found that meat-eaters, who comprised 94.7% of the cohort, were more likely to be obese than other diet groups. After a median follow-up of 8.5 years, fish eaters, compared with meat-eaters, had lower risks of cardiovascular outcomes such as stroke, heart disease and heart failure.

Vegetarians had lower risk of developing heart diseases. However, the researchers noted that, as a group, vegetarians consumed more unhealthy foods, such as crisps, than meat-eaters and that therefore vegetarians should not be considered a homogeneous group. They concluded that the avoidance of meat does not appear sufficient to reduce health risks if a person’s overall diet is not healthy.

Overall, meat-eaters consumed the least fibre, polyunsaturated fat, water, and fruit and vegetables. However, vegetarians reported consuming more crisps, slices of pizza and smoothie drinks than meat-eaters. Fish eaters were more likely to drink more sugary drinks and ready meals compared with the other groups, but also reported eating the least amount of takeaways. Fish & poultry eaters were more likely to eat home-cooked meals, followed by vegetarians.

In comparison to meat-eaters, vegetarian, fish, and fish & poultry eaters were younger, more likely to be women, south Asian and to have a lower body weight. Meat-eaters, in turn, were more likely to have more than one multimorbidity, and to be current smokers.

Professor Jill Pell, senior author on the study from the University of Glasgow, said: “Our findings showed that people who follow a pescatarian diet are less likely to suffer from heart disease, stroke, and heart failure, than people who eat meat. Reducing consumption of meat, especially red and processed meat, could improve health as well as being more environmentally sustainble.”

Fanny Petermann-Rocha, led author from the University of Glasgow said: “It is likely that fish eaters have a higher intake of cardio-protective nutrients such as polyunsaturated fats and, which could explain the lower risk association between fish eaters and heart diseases in our study. In particular, the polyunsaturated fat N-3 has been shown to be cardio-protective, and oily fish is one of its rich sources.”

Finally, Dr Carlos Celis highlighted: “Cardiovascular diseases remains one of the top ten causes of death worldwide. Although there are several behavioural risk factors, a poor diet accounts for around 11 million of these deaths worldwide. Of these, 3.8 million deaths have been attributable to a diet low in fruit and vegetables, 1.4 million to a diet low in seafood intake and 150,000 to high red and processed meat intake”.

References: Fanny Petermann-Rocha, Solange Parra-Soto, Stuart Gray, Jana Anderson, Paul Welsh, Jason Gill, Naveed Sattar, Frederick K Ho, Carlos Celis-Morales, Jill P Pell, Vegetarians, fish, poultry, and meat-eaters: who has higher risk of cardiovascular disease incidence and mortality? A prospective study from UK Biobank, European Heart Journal, , ehaa939,

Provided by University of Glasgow

A Rare Celestial Treat On the Winter Solstice (Planetary Science)

Four tips and takeaways from astronomer Cullen Blake on the upcoming alignment of Jupiter and Saturn and how to best catch a glimpse of the ‘great conjunction.’

During the past several weeks, Jupiter and Saturn’s orbits have been slowly approaching one another in the early evening sky. On the night of the winter solstice, the two gas giants will appear closer to one another than they have been for the past 400 years. Known as the “great conjunction,” this bright planetary alignment will be easily visible just after sunset.

Saturn (top) and Jupiter visible just after sunset at Shenandoah National Park on December 13th. On the winter solstice, December 21st, the two gas giants will appear a tenth of a degree apart from one another. (Image: NASA/Bill Ingalls)

To learn more about this rare event and how to best catch a glimpse of the great conjunction, Penn Today spoke with astronomer Cullen Blake, who shares four tips and takeaways for making the most of this end-of-the-year celestial spectacle.

What is a planetary conjunction?

A conjunction happens when two planets in the same solar system appear to pass extremely close to one another in the sky. “From our perspective, we’re closer to the sun than Jupiter and Saturn. That means when we look out at the night sky every few hundred years, these two planets align and will be located in the same part of the sky,” says Blake.

The orbits of the planets can be thought of as a racetrack, he says, with Earth circling the Sun more quickly on an inside lane while Jupiter and Saturn move more slowly in the outer lanes. A conjunction happens as Jupiter begins to “pass” Saturn on the inside and overtakes the slower-moving planet, which happens on the night of the solstice.

Because each planet in the solar system has its own orbital period—the time it takes to complete its rotation around the sun—the orbits of individual planets don’t coincide with each other very often. “Our moon comes back to the same position every 28 to 29 days, while Jupiter is going around the sun within a period of 12 years and Saturn of 29.5 years,” Blake says. “If you have two things going in orbit at that period, they only line up quite rarely.”

On the night of the winter solstice, Jupiter and Saturn can be found low in the southwestern section of the horizon in the hour just after sunset. (Image: NASA/JPL-Caltech)

According to NASA, it has been nearly 400 years since Jupiter and Saturn were this close to one another, but that event, in 1623, wasn’t visible in the night sky, so it’s now been nearly 800 years, in 1226, since the great conjunction has been as visible as it is this year.

How close is ‘close’?

For stargazers on Earth, the angle in the sky will be incredibly small—about 0.1 of a degree. “If you hold up your little finger at arm’s length, it will cover both planets,” says Blake of the level of closeness as perceived here on Earth.

In terms of actual distance, on the night of the solstice Jupiter and Saturn will be around 4 astronomical units (AUs) apart. That’s four times the distance between Earth and the sun, or around 400 million miles. When Jupiter and Saturn are on opposite sides of the solar system from one another, they are around 14 AUs apart.

No fancy telescope needed, just good timing, clear weather, and a pair of binoculars

To get the best glimpse of the great conjunction, Blake suggests finding a place with a clear line of sight towards the southwestern sky right at sunset. “During the hour after the sun goes down, it will be easy to see and very bright; you might even think it’s a plane,” he says. “It’s surprising how quickly after sunset you can start to see it.”

A clear evening makes for the best viewing, but even under thin clouds the conjunction should still be visible. There might also be a long enough break in the clouds to catch a glimpse—colloquially referred to by astronomers as a “sucker hole”—but, if not, Blake suggests trying again after the solstice on a clearer night. “It should be amazing for the next few days,” he says. “You will be able to see them separating after the solstice, so it will still look neat.”

There’s also no advanced astronomical equipment needed. Because of how large and bright the two plants are, a standard pair of binoculars will do just fine, says Blake. “Even with the kind of binoculars you have at home, looking at Jupiter and Saturn is awe-inspiring in terms of how much detail and color you can see,” he says.

Be sure to take advantage of this rare celestial opportunity

Blake hopes that people take the time to get out, while staying warm and socially distanced, to see this rare event. “It’s a great opportunity, especially when it’s easy to catch a glimpse of something neat in sky, and I hope that it makes people excited about astronomy,” he says.

Cullen Blake is an associate professor in the Department of Physics & Astronomy in the School of Arts & Sciences at the University of Pennsylvania.

Provided by Penn Today

New, Ultrastable Tetrahedral “Chiral Zinc” Added to Synthetic Chemistry Toolbox (Chemistry)

Catalyst with chirality at the zinc center could be useful for drug, electronic manufacturing.

Researchers have designed and built a new chemical tool inspired by natural metal-containing enzymes in living organisms. The product, a tetrahedral “chiral zinc”, maintains its shape for years, providing a new structure with exciting possibilities for manufacturing pharmaceuticals and optical electronics. Experts add quotation marks around “chiral zinc” to emphasize that a chiral bond is attached to the zinc, rather than another atom in a molecule that happens to contain zinc.

© Stock

“We expect that the results of this study will add a new page to the chemistry textbooks and will have a great impact on many industries involved in substance synthesis,” said Professor Mitsuhiko Shionoya, leader of the lab that conducted the research at the University of Tokyo. The team’s results are published in Nature Communications.

An essential feature of the compound is its chirality at the atom of zinc in the center of the molecule. A chiral molecule comes in two versions, called enantiomers. The enantiomers are made of the same elements, but differ in the 3D orientation of how the atoms are bonded, like left and right hands.

Chirality can give chemicals unique optical properties, which can be useful in electronics. Some chiral drug molecules are therapeutic in one orientation and toxic in the opposite, so isolating the desired enantiomer is often essential for drug manufacturers and methods to force chemical reactions to produce only the desired enantiomer could save time and reduce waste.

Left: Molecular structure of tetrahedral “chiral zinc” complex. The chiral tetrahedral compound has a zinc ion at the center (gray ball), surrounded by a tridentate ligand (connecting atoms are highlighted by red, green and yellow) and a monodentate ligand (blue). Right: Illustration of selective construction of tetrahedral “chiral zinc.” Four different arms bound to the zinc atom form one mirror image of the paired enantiomers. © Mitsuhiko Shionoya, CC-BY

Chemists have developed many efficient ways to build chiral compounds with carbon and other nonmetals at the chiral center. Additionally, the design of chiral catalysts that contain metal – but whose chirality is not centered at the metal atom – earned the 2001 Nobel Prize in chemistry for their useful ability to induce carbon-centered chirality. However, making metal-centered chiral molecules remains an open challenge. Metals are more difficult to use as chiral centers because the bonds they make are often less stable.

“My dream was a little bigger. I would like every element of the periodic table to become the center of chirality,” Shionoya remarked. Single atoms of zinc surrounded by four arms in a triangular pyramid, or tetrahedral, shape are common in nature – many types of tetrahedral zinc compounds, such as zinc fingers, bind to DNA and others manage carbon dioxide in mammalian cells.

Synthetic chemists have made 3D five and six-armed zinc compounds, but the synthetic tetrahedral zinc compounds made to date have been stable for mere minutes before their bonds disassembled.

Shionoya’s research team hypothesized that if each of the four arms attached to the zinc is given a different role, the final chiral molecule could remain stable and serve as a useful tool to speed up other chemical reactions. The team’s first step was to design a three-armed structure, or unsymmetric tridentate ligand, and attach those arms to the central zinc atom.

“This was the most difficult part. There were no successful examples of stabilizing the tetrahedral metal-centered chirality before the start of this study, so we had to design the tridentate ligand from scratch,” said Shionoya.

This first step produced equal amounts of each enantiomer of a chiral zinc attached to the tridentate ligand.

Then, researchers attached an intermediate fourth arm called the auxiliary chiral ligand. This chiral ligand gave the whole tetrahedron two points of chirality – one in the fourth arm and one at the central zinc. Heating the solution coaxed almost all of the molecules to reconfigure into the one more stable enantiomer.

The last step was to replace the chiral auxiliary with an achiral fourth arm. The final product was obtained as 100% pure single enantiomer crystals. The purity of this enantiomer remained greater than 99% over time and even after dissolving the crystal in a solvent.

One exchangeable arm remains on the “chiral zinc,” which can then be used to speed up chemical reactions to produce useful products. Moreover, using a pure solution of one enantiomer of a chiral catalyst can often push a chemical reaction to produce a final product that is also a single enantiomer.

“We hope many chemists will start using tetrahedral metal complexes as catalysts to make useful products for society,” said Shionoya.

References: Kenichi Endo, Yuanfei Liu, Hitoshi Ube, Koichi Nagata, and Mitsuhiko Shionoya, “Asymmetric construction of tetrahedral chiral zinc with high configurational stability and catalytic activity,” Nature Communications: December 9, 2020, doi:10.1038/s41467-020-20074-7.

Provided by University of Tokyo

AI-supported Test Predicts Eye Disease Three Years Before Symptoms (Ophthalmology / Medicine)

A pioneering new eye test, developed by scientists at UCL in collaboration with the Western Eye Hospital, London, may predict wet AMD, a leading cause of severe sight loss, three years before symptoms develop.

Researchers hope their test could be used to identify the disease early enough so that treatment can effectively prevent any vision loss.

DARC image (top) with corresponding OCT scan below © UCL

The findings of the study, funded by Wellcome, are published today in Expert Review of Molecular Diagnostics.

Wet age-related macular degeneration (AMD), also known as macular disease, is the most common cause of permanent and severe sight loss in the UK.

Currently the diagnosis of wet AMD relies on a person developing symptoms, which then leads them to seek advice from a clinician. Initially, someone with wet AMD would notice distortion in their vision, normally interfering with their reading. Very quickly, this can progress to complete central vision loss, which may be extremely troubling to elderly patients who will fear blindness and loss of independence.

Wet AMD involves abnormal growth of blood vessels, which leak fluid into the retina. The introduction of new treatments has led to much improved results for patients, for a disease that over 20 years ago was regarded as untreatable. However, patient outcomes could be even better if treatment was started in the very earliest stages of the disease.

The test, called DARC (Detection of Apoptosing Retinal Cells), involves injecting into the bloodstream (via the arm) a fluorescent dye that attaches to retinal cells, and illuminates those that are undergoing stress or in the process of apoptosis, a form of programmed cell death. The damaged cells appear bright white when viewed in eye examinations – the more damaged cells detected, the higher the DARC count.

One challenge with evaluating eye diseases is that specialists often disagree when viewing the same scans, so the researchers have incorporated an AI algorithm into their method.

Using the same technology (test) the researchers had previously found that they can detect the earliest signs of glaucoma progression.* This new study, which forms part of the same ongoing clinical trial of DARC, assessed 19 of the study participants who had already shown signs of AMD, but not necessarily in both eyes. The AI was newly trained to detect the formation of leaking and new blood vessels, which corresponded with the spots that DARC picked up.

The new analysis found that DARC can uniquely highlight endothelial cells (which line our blood vessels) under stress in the retina. These stressed cells then predict future wet AMD activity with the formation of leaking and new blood vessels seen in patients three years later, using conventional eye scans with Optical Coherence Tomography (OCT).

The researchers say their test could be valuable in detecting new lesions in someone affected by AMD, often in the opposite, unaffected eye, and may eventually be useful for screening people over a certain age or with known risk factors.

Lead researcher Professor Francesca Cordeiro (UCL Institute of Ophthalmology, Imperial College London, and Western Eye Hospital Imperial College Healthcare NHS Trust) said: “Our results are very promising as they show DARC could be used as a biomarker for wet AMD when combined with the AI-aided algorithm.

“Our new test was able to predict new wet AMD lesions up to 36 months in advance of them occurring and that is huge – it means that DARC activity can guide a clinician into treating more intensively those patients who are at high risk of new lesions of wet AMD and also be used as a screening tool.”

The study team hope to continue their research with a clinical trial with more participants, and hope to investigate the test in other eye diseases as well.

Chief Executive of eye research charity Fight for Sight, Sherine Krause said: “Our Time to Focus report on the social and economic impact of sight loss stressed the importance of early detection for prevention of sight loss, and so this is a very encouraging development in tackling the leading cause of blindness.”

DARC is being commercialised by Novai, a newly formed company of which Professor Cordeiro is Chief Scientific Officer.

Provided by UCL

Making Smart Thermostats More Efficient (Engineering)

A smart thermostat quickly learns to optimize building microclimates for both energy consumption and user preference.

Buildings account for about 40 percent of U.S. energy consumption, and are responsible for one-third of global carbon dioxide emissions. Making buildings more energy-efficient is not only a cost-saving measure, but a crucial climate change mitigation strategy. Hence the rise of “smart” buildings, which are increasingly becoming the norm around the world.

A diagram from a new paper detailing a smart thermostat shows the interaction of weather conditions, control systems, sensors, and learning algorithms to optimize microclimates in buildings. Credits: Image courtesy of the researchers.

Smart buildings automate systems like heating, ventilation, and air conditioning (HVAC); lighting; electricity; and security. Automation requires sensory data, such as indoor and outdoor temperature and humidity, carbon dioxide concentration, and occupancy status. Smart buildings leverage data in a combination of technologies that can make them more energy-efficient.

Since HVAC systems account for nearly half of a building’s energy use, smart buildings use smart thermostats, which automate HVAC controls and can learn the temperature preferences of a building’s occupants.

In a paper published in the journal Applied Energy, researchers from the MIT Laboratory for Information and Decision Systems (LIDS), in collaboration with Skoltech scientists, have designed a new smart thermostat which uses data-efficient algorithms that can learn optimal temperature thresholds within a week.

“Despite recent advances in internet-of-things technology and data analytics, implementation of smart buildings is impeded by the time-consuming process of data acquisition in buildings,” says co-author Munther Dahleh, professor of electrical engineering and computer science and director of the Institute for Data, Systems, and Society (IDSS). Smart thermostat algorithms use building data to learn how to operate optimally, but the data can take months to collect.

To speed up the learning process, the researchers used a method called manifold learning, where complex and “high-dimensional” functions are represented by simpler and lower-dimensional functions called “manifolds.” By leveraging manifold learning and knowledge of building thermodynamics, the researchers replaced a generic control method, which can have many parameters, with a set of “threshold” policies that each have fewer, more interpretable parameters. Algorithms developed to learn optimal manifolds require fewer data, so they are more data-efficient.

The algorithms developed for the thermostat employ a methodology called reinforcement learning (RL), a data-driven sequential decision-making and control approach that has gained much attention in recent years for mastering games like backgammon and Go.

“We have efficient simulation engines for computer games that can generate abundant data for the RL algorithms to learn a good playing strategy,” says Ashkan Haji Hosseinloo, a postdoc at LIDS and the lead author of the paper. “However, we do not have the luxury of big data for microclimate control in buildings.”

With a background in mechanical engineering and training in methods like RL, Hosseinloo can apply insights from statistics and state-of-the-art computing to real-world physical systems. “My main motivation is to slow down, and even prevent, an energy and environmental crisis by improving the efficiency of these systems,” he says.

The smart thermostat’s new RL algorithms are “event-triggered,” meaning they make decisions only when certain events occur, rather than on a predetermined schedule. These “events” are defined by certain conditions reaching a threshold — such as the temperature in a room dropping out of optimal range. “This enables less-frequent learning updates and makes our algorithms computationally less expensive,” Hosseinloo says.

Computational power is a potential constraint for learning algorithms, and computational resources depend on whether algorithms run in the cloud or on a device itself — such as a smart thermostat. “We need learning algorithms that are both computationally efficient and data-efficient,” says Hosseinloo.

Energy-efficient buildings offer additional advantages beyond reducing emissions and cutting costs. A building’s “microclimate” and air quality can directly affect the productivity and decision-making performance of building occupants. Considering the many large-scale economic, environmental, and societal impacts, microclimate control has become an important issue for governments, building managers, and even homeowners.

“The new generation of smart buildings aims to learn from data how to operate autonomously and with minimum user interventions,” says co-author Henni Ouerdane, a professor on the Skoltech side of the collaboration. “A learning thermostat can potentially learn how to adjust its set-point temperatures in coordination with other HVAC devices, or based on its prediction of electricity tariffs in order to save energy and cost.”

Hosseinloo also believes their methodology and algorithms apply to a diverse range of other physics-based control problems in areas including robotics, autonomous vehicles, and transportation, where data- and computational efficiency are of paramount importance.

This research was a Skoltech-MIT Joint Project conducted as part of the MIT Skoltech Next Generation Program.

References: Ashkan Haji Hosseinloo, Alexander Ryzhov, Aldo Bischi, Henni Ouerdane, Konstantin Turitsyn, Munther A. Dahleh, “Data-driven control of micro-climate in buildings: An event-triggered reinforcement learning approach”, Applied Energy, Volume 277, 2020, 115451, ISSN 0306-2619,

Provided by MIT

How Could Be The Neutron Star Made Up of The Mixture of Ordinary and Dark Matter? (Astronomy)

Neutron Stars (NSs) are compact stellar objects that are stable solutions in General Relativity. Their internal structure is usually described using an equation of state that involves the presence of ordinary matter and its interactions. However there is now a large consensus that an elusive sector of matter in the Universe, described as dark matter, remains as yet undiscovered. Now, Perez and Silk proposed that, in such a case, NSs should contain both, baryonic and dark matter (cold).

Artwork by Mark Garlick/gettyimages

In their paper, they argue that depending on the nature of the dark matter and in certain circumstances, the two matter components would form a mixture inside NSs that could trigger further changes, some of them observable.

For instance, the interior of the star reaches a temperature kBT ∼ 50 MeV immediately after the supernova collapse and the presence of an additional component of light DM with a weak cross-section could facilitate heat and energy conduction from the central part of the star to the outer regions. This effect could be observable at later times as a plateau of hotter stars than expected for the NS ages, since heat is conducted more efficiently due to the extra steady flux of incoming, accreting DM.

Besides, they claimed that there are several indirect signals that could be linked to DM existence in NS scenarios. One such observational consequence would be the generation of a very short Gamma Ray Burst (GRB) with a hard spike spectrum and few ms duration when the NS transition to a more compact quark star takes place.

They also suggested that the luminous and apparently young stars detected within 0.1 pc of the galactic centre, where the DM density is likely to be elevated by the presence of the central supermassive black hole (BH), are the possible candidates for such objects.

References: M. Angeles Perez-Garcia, Joseph Silk, “Neutron stars as probes of dark matter”, ArXiv, pp. 1-5, 2020.

Copyright of this article totally belongs to our author S. Aman. One is allowed to re-use it only by giving proper credit either to him or to us i.e. uncover reality.

How Fear of the Unknown Influences Decision-making (Psychology)

Fear of unknown is a risk factor for addiction.

The dictionary definition of uncertainty is experiencing an unknown, unpredictability, and unfamiliarity. We live in a world filled with uncertainty. It is hard to predict what will happen to us in the future.


The capacity to tolerate unknowns fuel the experience of anxiety and worry. Individuals with high intolerance of uncertainty (IU) are vulnerable to increased worry and distress in the face of uncertainty. Experiencing “what if” questions are common among those who experience severe anxiety, which is a source of impairments in their lives (Carleton, 2016).

Anxiety is an emotion caused by unpredictable potential threats that may occur in the future. Anxiety is potential harm rather than certain harm. Uncertainty impairs our ability to prepare for future events. Anxiety felt in the face of uncertainty can result in maladaptive behaviors such as impulsive decision making and unhealthy behaviors.

Intolerance of uncertainty is a cognitive bias that affects how a person perceives, interprets, and responds to uncertain situations. For example, if you have social anxiety, you are uncertain how you may look asking a question. The negative experience of uncertainty could lead you to exaggerate the threat (e.g., I am going to look stupid and will be humiliated). People who are the most intolerant of uncertainty are more likely to take efforts to try to control the situation or avoid uncertainty (McEvoy & Mahoney, 2012). This explains why a shy student may not volunteer to ask questions.  

Higher IU is associated with a tendency to make hasty decisions to alleviate distress in stressful situations. Waiting in uncertain situations tends to be perceived as highly unpleasant, leading to poor choices (Luhmann et al., 2011). Not surprisingly, IU has been linked to indecisiveness.

Higher IU is a risk factor for developing an addiction if substance abuse is used as a way of coping in the face of unavoidable uncertainty. For example, drinking alcohol is used as an avoidance strategy to cope with worry and distress (Gorka, et al., 2016). Those who have the tendency to find uncertain outcomes distressing and unpleasant are likely to find alcohol use to be highly motivating which sets the stage for continued and escalated drinking (Kraemer et al., 2015).

IU can also lead to an eating disorder in attempts to control the anxiety (Kesby et al., 2109). For instance, women with Anorexia Nervosa (AN) experience significantly higher degrees of IU compared to women with other types of eating disorders. Food restriction in AN may, in part, represent an attempt to avoid the fear of gaining weight and/or obsession with thinness. Thus, the fear of the unknown in individuals with AN represents a vulnerability factor for the inflexible mindset.

The capacity to tolerate unknowns is likely to be determined and maintained by a complex interplay of many factors, such as genes, temperament, and self-efficacy (McEvoy and Mahoney, 2012). Intolerance to uncertainty is a personality trait that runs in the family. A meta-analysis found that 40% of individual differences in personality traits have genetic origins. It is possible that genetic factors predispose one to develop IU. These genes may also interact with environmental factors such as stressful life events, parental neglect, and abusive parenting styles.  

The intolerance of uncertainty also varies with control (or self-efficacy). Control can be thought of as the belief that one has at one’s disposal a response that can influence the aversiveness of an event. People with a high level of fear of unknowns will likely have limited perceptions of self-efficacy, and a greater need for predictability.

In sum, the presence of uncertainty is often unpleasant, and individuals’ reactions vary along a continuum in terms of the extent to which they are comfortable with uncertainty. Research shows that treatments designed to increase acceptance of uncertainty and exposure to uncertainty are successful in increasing tolerance for uncertainty (Olatunji, 2019).

References: (1) Carleton RN (2016). Into the unknown: a review and synthesis of contemporary models involving uncertainty, Journal of Anxiety Disorders, vol. 39, pp. 30–43. (2) Gorka SM, Hee D, Lieberman L, Mittal VA, Phan KL, Shankman SA (2016) Reactivity to uncertain threat as a familial vulnerability factor for alcohol use disorder. Psychol Med 46:3349–3358. (3) Kesby, A., Maguire, S., Vartanian, L.R., Grisham, J.R (2018), Intolerance of uncertainty and eating disorder behaviour: Piloting a consumption task in a non-clinical sample. Journal of Behavior Therapy and Experimental Psychiatry; 65:101492. (4) Kraemer KM, McLeish AC, O’Bryan EM (2105). The role of intolerance of uncertainty in terms of alcohol use motives among college students. Addict. Behav. 42:162–166. (5) Luhmann C, Ishida K, Hajcak G (2011). Intolerance of uncertainty and decisions about delayed, probabilistic rewards. Behav Ther. 42(3):378. (6) McEvoy PM, Mahoney AEJ (2012). To be sure, to be sure: Intolerance of uncertainty mediates symptoms of various anxiety disorders and depression. Behav Ther.;43(3):533–45. (7) Olatunji BO (2019). The Cambridge Handbook of Anxiety and Related Disorders. Cambridge University Press.

This article is originally written by Shahram Heshmat, who is an associate professor emeritus of health economics of addiction at the University of Illinois at Springfield. This article is republished here from psychology today under common creative licenses