People with schizophrenia have often problems in understanding some common figurative expressions, such as humour, irony, and spoken metaphors. They tend to take the metaphor at its literal meaning (for example, “a leap in the dark” may imply jumping and darkness for someone with schizophrenia): it may take some time for them to arrive at an understanding of what the metaphor is meant to imply. There has been little attempt to understand why this might be so at a neurological level.

A group of Polish and Czech researcher examined 30 patients who had been diagnosed with schizophrenia and 30 healthy controls. While undergoing a brain scan in a high-sensitivity MRI, they read 90 brief stories. 30 of the stories had a metaphorical ending, 30 had an absurd/nonsense ending, and 30 had a neutral ending (i.e. a literal ending). The scientists monitored brain activity while the subjects were reacting to the stories.

They found that compared to controls, the patient group showed increased brain activity in certain areas, but lower brain activity in others. For example, the healthy group showed brain activation in the prefrontal cortex (near the front of the brain) and left amygdala (at the centre of the brain, near the top of the brain stem), implying that these are the brain areas where metaphors are normally processed. Instead, schizophrenia patients showed a decreased activation in the temporal suculus (an area ascending from the low central brain towards the back of the head). Researcher Martin Jáni, from the Jagiellonian University, Krakow, Poland said:

“Previous researchers studied brain areas that are connected to impaired metaphor understanding in schizophrenia, so comparing metaphors with literal statements. However, by adding the absurd punchline, we were able to explore the stage at which the deficit occurs. We also used everyday metaphors, which would be easily understood.

We found that biggest changes in brain activity in schizophrenia patients occur during the basic stage of metaphor processing, that is when a person needs to recognize there is incongruity between the opening sentence and the punchline. These activated areas of the brain are very different to the brain areas activated in healthy patients, as if the brain is struggling to find a compensatory mechanism, to bypass the circuits normally used to understand metaphor”.

It’s likely that this inability to understand the sort of conventional metaphors we use in everyday life is socially isolating for people with schizophrenia. While this at the research stage, our hope is that we can develop practical skills in patients with schizophrenia – and indeed the people who know them – which will help them understand the speech the way it was intended”

Commenting, Dr Emilio Fernandez-Egea, University of Cambridge said;

“Understanding the neural basis of social cognition are of great relevance for people with schizophrenia. These deficits are often overlooked, despite the impact on the general functioning and in the ability to find and maintain social relationship and work. Expanding our knowledge of this often neglected domain will improve the recovery process in this population”.

This is an independent comment; Dr Fernandez-Egea was not involved in this work.

EXAMPLES:

The metaphors themselves were commonly used in everyday Polish speech. They were incorporated in brief stories, such as:

Metaphor

On the street, man on the bike accidentally hits a pedestrian “I am sorry, are you alright?” asked the cyclist, to which the pedestrian replied “No, I am sorry, I shouldn’t walk with my head in the clouds”.

Comment: People with schizophrenia had more difficulty in pulling the metaphorical meaning away from the literal “head in the clouds” meaning.

Neutral

A man comes back home after unusually long day at work. His partner asks “Why are you so late? The dinner is already cold” He replies “I am very sorry. I had to finish an important project”.

Comment: This is literal – there’s no hidden meaning here.

Absurd (nonsensical)

Two colleagues are talking at work. One says “I can’t believe that John is earning money than me for the same position!” The other says “The copy machine broke yesterday”.

Comment: In this case the reply is not relevant to the question.

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Type of study: Not peer reviewed/experimental study/people

Supine hypertension is present in about half of people with autonomic failure, a chronic degenerative disease that affects the part of the nervous system that regulates involuntary functions such as blood pressure and heart rate. Overnight increases in blood pressure are associated with damage to the heart and kidneys. It can also increase urine production, which can worsen a condition where a person’s blood pressure rapidly drops upon standing, such as when first getting out of bed in the morning.

Researchers studied 10 patients with autonomic failure and supine hypertension. The average age of the study participants was 76 years, with a systolic (upper number) blood pressure of 168 mm Hg measured in the lying position. During the two-night study, participants received heat at 100 degrees Fahrenheit from a medical grade heating pad placed under their torso on one night, and an unheated pad on the other. Supine blood pressure was monitored every two hours from 8 p.m. to 8 a.m., and heat therapy was applied from 10 p.m. to 6 a.m.

The researchers found that heat therapy applied during sleep decreased systolic blood pressure, with a maximum reduction of 30 mm Hg after four hours of heat. Despite lowering overnight systolic blood pressure, heat therapy did not decrease nighttime urine production or improve the sudden drop in morning blood pressure.

“In many patients with autonomic failure, heat exposure decreases blood pressure by shifting blood to skin vessels,” said Luis E. Okamoto, M.D., study author and research assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “The use of local, controlled heat therapy may be a novel and simple approach to treat supine hypertension in these patients without using medications; however, additional studies are needed to assess the long-term safety and efficacy of this approach.”

Among the study’s limitations are its small size and its focus on primary forms of autonomic failure, which is a rare condition. Although the study population was Caucasian, the researchers anticipate that the results may be applicable to other ethnic groups.

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Phosphorus is an essential mineral to grow food, but research suggests that this is being mined unsustainably. If reserves run low, food production will be constrained and starvation entirely possible.

Now, David Vaccari, an environmental engineer at Stevens Institute of Technology, and colleagues have developed a model to describe how phosphorus flows through the global food system. The model, reported in the Sept. 4 issue of Environmental Science & Technology, can predict how several different conservation approaches could reduce demand for a nonrenewable resource that is absolutely vital for feeding the world.

“Phosphate is spread across the planet but hardly recycled,” said Vaccari, a pioneer in phosphate research who led the work. “The model allows us to answer specific ‘what if’ questions to see how certain changes in human behavior could significantly improve the conservation of this resource and by extension, help sustain the world’s food production.”

In the past, the phosphorus cycle was practically closed: crops were eaten by humans and livestock while their feces were used as natural fertilizers to grow crops again. These days, the cycle is broken. Each year phosphate rocks are mined and turned into fertilizer. This is converted into crops which are transported to cities for food. Some phosphorus is lost at every step along the way and winds up in the environment. Runoff from farms goes into waterways, food waste goes to landfills, and the human waste goes to the sewage disposal, most of which ultimately ends up in the sea. A cycle has become a linear process.

Vaccari and colleagues model this cycle, with “knobs” that can be turned up or down to create different conservation scenarios. When a knob is turned — e.g. fraction of animal meat in diet, fraction of food that is wasted, fraction of human waste recycled — the model, which factors in leaks and losses from the food system, loops back to calculate the degree to which phosphate mining could be reduced.

The model shows several interesting results:

• Collective diet changes can reduce the demand for phosphate mining substantially. Since different animals have a different footprint on phosphate mining, these changes could include reducing total meat consumption or switching to meats that require less feed to produce; for example, it takes 32 pounds of feed to produce edible beef; 11 pounds to produce edible pork; and four to produce edible chicken and around one or two for milk and eggs. The fewer pounds of feed needed, the less demand for phosphate mining.
• Dietary changes would reduce demand for mining phosphorus only up to a point; then, surprisingly, demand would increase. That’s because eating less meat would necessarily lead to eating more crops and initially, crops could use phosphorus from non-mining resources such as natural mineral erosion in the soil. However, natural mineral erosion wouldn’t be enough to sustain the increased demand for crops, so phosphate mines would again need to be tapped.
• Calculations show that reducing the amount of food we waste is about 80 times more effective at conserving phosphorus than recycling that same waste.
• Even if 100 percent of the phosphorus in our human waste was recycled, mining of phosphorus would only be reduced about 16 percent; recycling 100 percent of food waste would reduce mining by 5 percent. Recycling has such a low effect on conservation because recycled phosphorus is subject to much of the same losses in the food system as is fertilizer. Thus, although recycling is still part of the solution, it is much better to reduce the amount of waste we produce in the first place.
• If the world had to depend entirely upon phosphorus other than from mining, it would only be able to support about one-third of the current world population, using current levels of usage and recycling efficiency.
• However, if we substantially increased our efficiency, it would be possible to support about twice the current world population.

The world, however, is not about to run out of phosphorus. At current usage rates, known phosphorus reserves could sustain agricultural production for several centuries, according to Vaccari. But unlike nitrogen, which makes up 78 percent of the atmosphere (and a main ingredient in fertilizer), phosphate is a finite resource — and “new sources of phosphorus will be hard to come by,” said Vaccari.

Reducing phosphate mining has other advantages. When phosphorus “leaks” from the agricultural, food production and waste disposal systems, it contributes to severe water pollution problems such as harmful algal blooms in lakes and in the coastal zone. Aside from the long known public health issues and economic impact of algal blooms in fishing communities, a deadly variety of algae has recently caused several dog deaths in the Southern United States.

“Phosphorus is essential for life,” said Vaccari. “So the plan is to keep it around for a long time by mining phosphate sustainably and responsibly — and this model helps us look at optimal ways on how to do that.”

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Now, a new technique called SWIFT (sacrificial writing into functional tissue) created by researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), overcomes that major hurdle by 3D printing vascular channels into living matrices composed of stem-cell-derived organ building blocks (OBBs), yielding viable, organ-specific tissues with high cell density and function. The research is reported in Science Advances.

“This is an entirely new paradigm for tissue fabrication,” said co-first author Mark Skylar-Scott, Ph.D., a Research Associate at the Wyss Institute. “Rather than trying to 3D-print an entire organ’s worth of cells, SWIFT focuses on only printing the vessels necessary to support a living tissue construct that contains large quantities of OBBs, which may ultimately be used therapeutically to repair and replace human organs with lab-grown versions containing patients’ own cells.”

SWIFT involves a two-step process that begins with forming hundreds of thousands of stem-cell-derived aggregates into a dense, living matrix of OBBs that contains about 200 million cells per milliliter. Next, a vascular network through which oxygen and other nutrients can be delivered to the cells is embedded within the matrix by writing and removing a sacrificial ink. “Forming a dense matrix from these OBBs kills two birds with one stone: not only does it achieve a high cellular density akin to that of human organs, but the matrix’s viscosity also enables printing of a pervasive network of perfusable channels within it to mimic the blood vessels that support human organs,” said co-first author Sébastien Uzel, PhD., a Research Associate at the Wyss Institute and SEAS.

The cellular aggregates used in the SWIFT method are derived from adult induced pluripotent stem cells, which are mixed with a tailored extracellular matrix (ECM) solution to make a living matrix that is compacted via centrifugation. At cold temperatures (0-4^oC), the dense matrix has the consistency of mayonnaise – soft enough to manipulate without damaging the cells, but thick enough to hold its shape – making it the perfect medium for sacrificial 3D printing. In this technique, a thin nozzle moves through this matrix depositing a strand of gelatin “ink” that pushes cells out of the way without damaging them.

When the cold matrix is heated to 37 ^oC, it stiffens to become more solid (like an omelet being cooked) while the gelatin ink melts and can be washed out, leaving behind a network of channels embedded within the tissue construct that can be perfused with oxygenated media to nourish the cells. The researchers were able to vary the diameter of the channels from 400 micrometers to 1 millimeter, and seamlessly connected them to form branching vascular networks within the tissues.

Organ-specific tissues that were printed with embedded vascular channels using SWIFT and perfused in this manner remained viable, while tissues grown without these channels experienced cell death in their cores within 12 hours. To see whether the tissues displayed organ-specific functions, the team printed, evacuated, and perfused a branching channel architecture into a matrix consisting of heart-derived cells and flowed media through the channels for over a week. During that time, the cardiac OBBs fused together to form a more solid cardiac tissue whose contractions became more synchronous and over 20 times stronger, mimicking key features of a human heart.

“Our SWIFT biomanufacturing method is highly effective at creating organ-specific tissues at scale from OBBs ranging from aggregates of primary cells to stem-cell-derived organoids,” said corresponding author Jennifer Lewis, Sc.D., who is a Core Faculty Member at the Wyss Institute as well as the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS. “By integrating recent advances from stem-cell researchers with the bioprinting methods developed by my lab, we believe SWIFT will greatly advance the field of organ engineering around the world.”

Collaborations are underway with Wyss Institute faculty members Chris Chen, M.D., Ph.D. at Boston University and Sangeeta Bhatia, M.D., Ph.D., at MIT to implant these tissues into animal models and explore their host integration, as part of the 3D Organ Engineering Initiative co-led by Lewis and Chris Chen.

“The ability to support living human tissues with vascular channels is a huge step toward the goal of creating functional human organs outside of the body,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS, the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at SEAS. “We continue to be impressed by the achievements in Jennifer’s lab including this research, which ultimately has the potential to dramatically improve both organ engineering and the lifespans of patients whose own organs are failing,”

UM biology Professor Winsor Lowe and his partners studied spring salamanders living in five New Hampshire streams. Like many streams around the globe, these waterways are experiencing greater fluctuations between low and high flows brought about by climate change.

The researchers revealed that streamflow variability can kill salamanders while they are metamorphosing from larvae to adults. The work was published recently in the Proceedings of the National Academy of Sciences in an article titled “Hydrologic variability contributes to reduced survival through metamorphosis in a stream salamander.”

“We feel this work is important because it expands our knowledge about the effects of climate change on a diverse group of species that are often overlooked because they spend most of their lives under rocks and logs in small, headwater streams,” Lowe said. “Increasing environmental variability may be especially challenging for species that undergo metamorphosis — like many insects and amphibians — because that’s a vulnerable period when they rely on stable environments for survival.”

He said the research suggests society shouldn’t focus on average conditions as it tries to understand and manage the effects of climate change. Scientists and managers also must pay attention to changes in environmental variability, which may increase with climate change.

“Small headwater streams are home to diverse species and the source of clean water to downstream communities, but these ecosystems are also easy to overlook and are losing protection under proposed Clean Water Act revisions,” Lowe said. “Our work underscores the vulnerability of headwater ecosystems in this era of climate change, the need for protection of vulnerable headwater species, and the value of long-term monitoring efforts.”

Using a 20-year dataset from Merrill Brook in New Hampshire, the researchers showed the abundance of spring salamander adults declined about 50% since 1999, but no trend was noted for larval abundance. Scientists then studied whether streamflow variability at Merrill Brook and streams in the nearby Hubbard Brook Experimental Forest affected the survival of salamanders metamorphosing from larvae to adults. They found that fewer salamanders survived metamorphosis during years when steamflow variability was high, leading to the decline in the adult population.

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The research team examined 33 healthy adult participants in their study. One group of 22 volunteers was studied during the 2014-2015 flu season, and the second group with 11 volunteers was studied during the 2015-2016 flu season. The group of 22 volunteers had high pre-existing immunity to the influenza virus strains contained in the 2014-2015 seasonal influenza vaccine. The group of 11 volunteers had low immunity to the 2015-2016 seasonal influenza vaccine’s virus strains.

All study participants received a seasonal influenza vaccine. Half the participants in each group also received a five-day course of a broad-spectrum antibiotic regimen (consisting of neomycin, vancomycin, and metronidazole) by mouth before receiving the vaccine. By analyzing stool and blood serum samples taken at various times up to one year after vaccination, the researchers tracked the participants’ immune response to the influenza vaccines, as well as the diversity and abundance of the organisms in their gut microbiomes.

As expected, most participants who received antibiotics experienced reduced levels of gut bacteria. In addition, among the 2015-2016 participants who had little prior immunity to the seasonal influenza virus vaccine strains, a course of antibiotics hindered their immune responses to one of the three influenza virus strains in the vaccine, an H1N1 A/California-specific virus. This likely indicates that should they be exposed to this H1N1 virus after vaccination, these participants would be less protected against infection with that strain than people who had not received antibiotics, according to the authors. This finding supports earlier research results in mice.

The researchers also found that people who took antibiotics experienced changes to their immune systems that promoted a pro-inflammatory state, similar to a condition seen in older adults who have received influenza vaccines. The investigators believe this pro-inflammatory state is related to the process by which the microbiome regulates the metabolism of bile acid — with fewer microorganisms, this process is disrupted. Humans’ microbiomes change naturally as they age, and the researchers suggest that further research on these pathways could provide insights into why older adults respond differently to influenza vaccination and why they have weaker immune systems overall.

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Researchers from the Salk Institute studying how plants evolved the abilities to make these natural chemicals have uncovered how an enzyme called chalcone isomerase evolved to enable plants to make products vital to their own survival. The researchers’ hope is that this knowledge will inform the manufacture of products that are beneficial to humans, including medications and improved crops. The study appeared in the print version of ACS Catalysis on September 6, 2019.

“Since land plants first appeared on earth approximately 450 million years ago, they have developed a sophisticated metabolic system to transform carbon dioxide from the atmosphere into a myriad of natural chemicals in their roots, shoots and seeds,” says Salk Professor Joseph Noel, the paper’s senior author. “This is the culmination of work we’ve been doing in my lab for the past 20 years, trying to understand plant chemical evolution. It gives us detailed knowledge about how plants have developed this unique ability to make some very unusual but important molecules.”

Previous research in the Noel lab looked at how these enzymes evolved from non-enzyme proteins, including studying more primitive versions of them that appear in organisms such as bacteria and fungi.

As an enzyme, chalcone isomerase acts as a catalyst to accelerate chemical reactions in plants. It also helps to ensure the chemicals that are made in the plant are the proper form, since molecules with the same chemical formula can take two different variations that are mirror images of each other (called isomers).

“In the pharmaceutical industry, it’s important that the drugs being made are the correct version, or isomer, because using the wrong one can lead to unintended side effects,” says Noel, who is director of Salk’s Jack H. Skirball Center for Chemical Biology and Proteomics and holds the Arthur and Julie Woodrow Chair. “By studying how chalcone isomerase works, we can learn more about how to accelerate the manufacture of the correct isomers of pharmaceuticals and other products that may be important to human health.”

In the current study, the investigators used several structural biology techniques to investigate the enzyme’s unique shape and how its shape changes as it interacts with other molecules. They pinpointed the part of chalcone isomerase’s structure that allowed it to catalyze reactions incredibly fast while also ensuring it makes the proper, biologically active isomer. These reactions lead to a host of activities in plants, including converting primary metabolites like phenylalanine and tyrosine into vital specialized molecules called flavonoids.

It turned out that one particular amino acid, arginine, that was one of many amino acids linked together in chalcone isomerase sat in a location, shaped by evolution, that allowed it to play the key role in how chalcone isomerase reactions were catalyzed.

“By doing structural studies and computer modeling, we could see the very precise positions of arginine within the enzyme’s active site as the reaction proceeded,” says first author Jason Burke, a former postdoctoral research in Noel’s lab who is now an assistant professor at California State University San Bernardino. “Without that arginine, it doesn’t work the same way.”

Burke adds that this type of catalyst has been long sought by organic chemists. “This is an example of nature already solving a problem that chemists have been looking at for a long time,” he adds.

“By understanding chalcone isomerase, we can create a new toolset that chemists will be able to use for the reactions they’re studying,” Noel says. “It’s absolutely vital to have this kind of foundational knowledge to be able to design molecular systems that can carry out a particular task even in the next generation of nutritionally dense crops capable of transforming the greenhouse gas carbon dioxide into molecules essential for life.”

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