Tech

Nixing bone cancer fuel supply offers new treatment approach, mouse study suggests

image: A new study from Washington University School of Medicine in St. Louis suggests that a two-drug combination targeting a tumor's energy sources could be as effective and less toxic than methotrexate, a long-used chemotherapy drug often given in high doses to treat osteosarcoma, a bone cancer. Shown is a cross section of osteosarcoma.

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RICHA RATHORE

An innovative approach to treating bone tumors - starving cancer cells of the energy they need to grow - could one day provide an alternative to a commonly used chemotherapy drug without the risk of severe side effects, suggests a new study from Washington University School of Medicine in St. Louis. Studying human cancer cells and mice, the researchers said that a two-drug combination targeting a tumor's energy sources could be as effective and less toxic than methotrexate, a long-used chemotherapy drug often given in high doses to treat osteosarcoma, a bone cancer.

The study appears Jan. 26 in the journal Cell Reports.

Osteosarcoma is the most common tumor of the bone in adults and children. It accounts for about 4% of all pediatric cancers and more than half of all pediatric bone cancers. Standard treatment for osteosarcoma includes surgery, radiation and a cocktail of chemotherapy drugs including high-dose methotrexate, which can cause liver and kidney damage.

"We are interested in developing therapies that kill cancer cells without harming healthy cells, potentially avoiding the sometimes severe side effects of traditional chemotherapy," said senior author Brian Van Tine, MD, PhD, an associate professor of medicine. "In high doses, methotrexate can lead to liver failure and the need for kidney dialysis. We would like to get rid of the methotrexate in this regimen and replace it with a targeted metabolic therapy that would shorten the treatment, reduce the side effects and potentially eliminate the need for multiple hospitalizations."

The researchers studied an investigational drug called NCT-503, a member of a relatively new class of drugs called PHGDH inhibitors that have gained interest as potential metabolic therapies for cancer. Metabolic therapies target the chemical reactions that cancer cells perform to sustain life. This investigational drug prevents cancer cells from manufacturing the amino acid serine, a source of energy that fuels cancer growth. Losing serine production stops cell division but doesn't kill cancer cells.

Unfortunately, osteosarcoma cells can then quickly adapt and turn to another energy source, said Van Tine, an oncologist who treats patients at the Adolescent and Young Adult Sarcoma program at Siteman Cancer Center at Barnes-Jewish Hospital and Siteman Kids at St. Louis Children's Hospital, both at Washington University School of Medicine.

Studying the cells that adapt to being treated with this drug, the researchers revealed a way that the cells' metabolism shifts to try to burn another type of fuel. Without serine, the osteosarcoma cell can't move through its typical metabolic cycle, so parts of that cycle build up. The buildup of these cellular components - which includes fats, other amino acids, and waste products - then activates a central metabolic signaling molecule called mTORC1. Triggering mTORC1 tells the cell to start burning all the built-up products.

So, the researchers added a second drug that blocks mTORC1. Now deprived of both serine and the secondary fuel source, the cancer cells were starved of energy and died.

"When we added an mTORC1 inhibitor, suddenly we could control tumor growth in mice for a prolonged period of time, well past when the cells would adapt to treatment with either drug alone," said first author Richa Rathore, PhD, who just completed her doctoral studies in Van Tine's lab.

The mTORC1 inhibitor is called perhexiline and has been used since the 1970s to treat angina, or chest pain. More recently, it has been investigated as a treatment for certain types of heart failure.

The researchers studied mice implanted with human osteosarcoma tumors. In mice receiving either drug alone or a control treatment, the tumors increased in volume by almost 800% over less than 30 days. In contrast, in the mice receiving the two-drug combination, the tumors increased in volume by only 75% over 30 days.

"We are still working to optimize these drug treatments, but we hope to be able to take these findings into a clinical trial," Van Tine said. "In the future, we would like to add more metabolic therapies so that one day we might be able to eliminate the remaining chemotherapy drugs that these patients will still receive. The ultimate goal is to transform therapy by going after the metabolic properties that are inherent to osteosarcoma and move away from the classic drugs that damage the whole body."

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Washington University School of Medicine

Crunch! Underwater acoustics expose 'shell-crushing' sounds in a large marine predator

video: Turn up the sound! Using the whitespotted eagle ray and underwater acoustic recorders, a study is the first to characterize how they consume hard-shelled mollusk prey like clams in a controlled environment. Scientists could tell what a predator was eating based on how it sounds, and with this process it's audible above ambient noise in coastal lagoons out to 100 meters. The team hopes this technology will be useful in monitoring how many clams are being eaten by large predators like rays as restoration efforts ramp up in Florida.

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Florida Atlantic University's Harbor Branch Oceanographic Institute

"Shell-crushing" - exactly what it sounds like - is a predatory mode used by numerous marine life from crabs to octopuses to large fishes and mammals when they eat hard-shelled mollusks like clams, oysters and conchs. These predators have to break apart the shell using robust claws or fortified jaws to access the prey's soft tissues.

Despite its prevalence in the marine environment, this feeding behavior has remained elusive to study remotely, particularly for larger marine animals that destroy shells almost completely, leaving behind little trace. Moreover, because they are highly mobile, scientists have difficulty in directly observing their foraging habits, which is why the ecology of shell-crushing (durophagy) remains poorly understood in larger marine predators and the ecosystems with which they interact. So, there is little understanding of where or when this happens.

Using the whitespotted eagle ray (Aetobatus narinari) as a model, a team of scientists led by Florida Atlantic University's Harbor Branch Oceanographic Institute in collaboration with FAU's College of Engineering and Computer Science; Mote Marine Laboratory & Aquarium; and the Florida Institute of Technology, are the first to use passive acoustics to characterize how they consume hard-shelled mollusk prey in a controlled environment.

Scientists both quantified and classified shell-crushing by monitoring underwater sounds using acoustic recorders. Results, published in the Journal of Experimental Marine Biology and Ecology, reveal that using this technology, prey types could be distinguished based on acoustic features. Researchers were able to determine what a predator is eating based on how it sounds. In addition, shell-crushing simulation tests in the natural environment suggest the process is audible above ambient noise in coastal lagoons out to 100 meters.

"Interactions between molluscan predators and shellfish often occur in low-visibility estuarine waters. Scientists need alternative non-visual based methods to continuously monitor, gather and document critical data that may have serious conservation ramifications," said Matt Ajemian, Ph.D., lead author, an assistant research professor at FAU's Harbor Branch and head of the Fisheries Ecology and Conservation (FEC) Lab, who worked with FAU Harbor Branch co-authors Laurent Chérubin, Ph.D., an associate research professor; and Breanna DeGroot, M.S., research coordinator. "Passive acoustics-based documentation of shell-crushing behavior has not been seriously considered as a tool to identify the ecological role of large, mobile molluscivores before this study. We knew from previous experience with these animals that the cracks they made during feeding were loud, almost like an explosion, but there were no data to support it at the time. That's what led us to conduct this initial study."

Whitespotted eagle rays consume a wide variety of mollusk species, including both bivalves and gastropods. For the study, scientists recorded a total of 434 prey items being eaten by rays, spanning eight species of hard-shelled mollusks. On the menu: hard clams, banded tulip, crown conch, lettered olive, Florida fighting conch, lightning whelk, pear whelk and horse conch.

"Mollusks vary in texture, thickness and strength. The differences we observed in consumption signals and behavior associated with the two primary prey types analyzed are likely due to variations in these shell shapes," said Kim Bassos-Hull, M.Sc., co-author and senior biologist with Mote Marine Lab's Sharks & Rays Conservation Research Program. "It was clear that hard clams took a considerably longer time to process than banded tulip shells and all other gastropods. This was likely driven by the greater number of fractures rays needed to implement during processing and winnowing of hard clams presumably to access the prey's soft tissues."

Signal characteristics of simulated crushing of hard clams in the field, which the researchers conducted by crushing clams by hand using modified heavy-duty pliers, also were similar to those recorded in the large, circular saltwater habitat.

"It's obviously hard to get a ray to eat on command in a particular time and place, so we had to get somewhat creative with the field testing," said Ajemian.

Data from this study are critically important with respect to molluscan shellfish, which provide high-quality and high-value seafood to humans, and beneficial ecosystem services, yet sources of natural mortality from large predators are largely unknown for both natural and restored populations.

"The passive acoustics approach demonstrated in our study provides a unique, less-intrusive platform to remotely and directly observe predation events like shell fracture in the aquatic environment and support surveillance techniques to quantify predator-induced losses to these valuable resources, even in challenging environmental conditions," said Chérubin.

The team is hoping this technology will be of utility in monitoring how many clams are being eaten by large predators like rays as restoration efforts ramp up around the state of Florida.

"We still have a lot of work to do on the automated detection-classification side of things, but this work brings us closer to remotely capturing predation in these elusive species," said Ajemian.

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Florida Atlantic University

Beauty in imperfection: How crystal defects can help convert waste heat into electricity

image: Examples of applications of power generation using thermoelectric conversion. It involves conversion of exhaust heat from automobile engines into electricity for reuse, or using the difference in temperature between the human body and ambient air to generate electricity that can power IoT sensors.

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Photo courtesy: Hidetoshi Miyazaki from Nagoya Institute of Technology

If we are to prevent the impending environmental crisis, it is imperative that we find efficient and sustainable ways to avoid being wasteful. One area with much room for improvement is the recycling of waste heat from industrial processes and technological devices into electricity. Thermoelectric materials are at the core of research in this field because they allow for clean power generation at little cost.

For thermoelectric materials to be used in vastly different fields such as steel works and transportation, they need to be able to operate in both high and low temperature regimes. In this regard, "half-Heusler Ni-based alloys" are currently under the spotlight thanks to their attractive thermoelectric efficiency, mechanical strength, and durability. Though much effort has been devoted to understanding and improving upon these peculiar alloys, scientists have found it difficult to clarify why half-Heusler Ni-based alloys have such a high conversion efficiency. Some have theorized that defects in the material's crystal structure increase its thermal conductivity and, in turn, its conversion efficiency. However, the crystal structure around the defects is unknown and so are their specific contributions.

In a recent study published in Scientific Reports, a team of scientists from Japan and Turkey, led by Associate Professor Hidetoshi Miyazaki from Nagoya Institute of Technology, Japan, have now attempted to make this issue crystal clear! Their research combined theoretical and experimental analyses in the form of large-scale crystal structure simulations and X?ray absorption fine structure (XAFS) spectra on NiZrSn alloys.

Using these techniques, the team first calculated the structural effects that an additional Ni atom (defect) would have in the arrangement of NiZrSn crystals. Then, they verified the theoretical predictions through different types of XAFS measurements, as Dr. Miyazaki explains, "In our theoretical framework, we assumed crystal lattice distortions to be a consequence of atomic defects to perform first-principles band structure calculations. XAFS made it possible to obtain detailed information on the local crystal structure around atomic defects by comparing the experimental and theoretical spectra of the crystal structure." These observations allowed the scientists to accurately quantify the strain that Ni defects cause in nearby atoms. They also analyzed the mechanisms by which these alterations give rise to a higher thermal conductivity (and conversion efficiency).

The results of this study will be crucial in advancing thermoelectric technology, as Dr. Miyazaki remarks: "We expect that our results will contribute to the development of a strategy centered around controlling the strain around defective atoms, which in turn will allow us to engineer new and better thermoelectric materials." Hopefully, this will lead to a leap in thermoelectric conversion technology and hasten the transition to a less wasteful, decarbonized society--one in which excess heat is not simply discarded but instead recovered as an energy source.

On a final note, Dr. Miyazaki highlights that the techniques used to observe fine changes in strain in crystalline structures can be readily adapted to other types of material, such as those intended for spintronic applications and catalysts.

There is certainly much to gain from going after the fine details in materials science, and we can rest assured that this study marks a step in the right direction toward a better future!

Credit: 
Nagoya Institute of Technology

New neural network enables easy screening of sleep apnoea in patients with cerebrovascular disease

image: A new neural network enables an easy and accurate assessment of sleep apnoea severity in patients with cerebrovascular disease.

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UEF / Raija Törrönen

A new neural network developed by researchers at the University of Eastern Finland and Kuopio University Hospital enables an easy and accurate assessment of sleep apnoea severity in patients with cerebrovascular disease. The assessment is automated and based on a simple nocturnal pulse oximetry, making it possible to easily screen for sleep apnoea in stroke units.

Up to 90% of patients experiencing a stroke have sleep apnoea, according to earlier studies conducted at Kuopio University Hospital. If left untreated, sleep apnoea can reduce the quality of life and rehabilitation of patients with stroke and increase the risk for recurrent cerebrovascular events.

"Although screening of sleep apnoea is recommended for patients with cerebrovascular disease, it is rarely done in stroke units due to complicated measurement devices, time-consuming manual analysis, and high costs," Researcher Akseli Leino from the University of Eastern Finland says.

In the new study, researchers developed a neural network to assess the severity of sleep apnoea in patients with acute stroke and transient ischaemic attack (TIA) by using a simple nocturnal oxygen saturation signal. The apnoea-hypopnea index, which represents the number of apnoea and hypopnea events per hour, is commonly used in the diagnostics of sleep apnoea. When the researchers compared the results of manual scoring and those obtained using the new neural network, the median difference was only 1.45 events per hour. The neural network was also 78% accurate in classifying patients into four different categories on the basis of sleep apnoea severity (no sleep apnoea, mild, moderate, severe). The neural network was able to identify moderate and severe sleep apnoea, both of which require treatment, in patients with acute stroke or TIA with a 96% specificity and a 92% sensitivity.

"The neural network developed in the study enables an easy and cost-effective screening of sleep apnoea in patients with cerebrovascular disease in hospital wards and stroke units. The nocturnal oxygen saturation signal can be recorded with a simple finger pulse oximetry measurement, with no time-consuming manual analysis required," Medical Physicist Katja Myllymaa from Kuopio University Hospital points out.

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University of Eastern Finland

New research: Monitoring online posts by consumers could help improve food safety

An estimated 48 million cases of foodborne illness are contracted in the United States every year, causing about 128,000 hospitalizations and 3,000 deaths, according to the Centers for Disease Control (CDC). In some instances, the source is well known, such as a batch of tainted ground beef that infected 209 people with E. Coli in 2019. But 80 percent of food poisoning cases are of unknown origin, making it impossible to inform consumers of hazardous food items.

David Goldberg, assistant professor of management information systems at San Diego State University, wants to improve the traceability and communication of risky food products. In a new study published by the journal Risk Analysis, his research team proposes a new Food Safety Monitoring System (FSMS) that utilizes consumer comments posted on websites to identify products associated with food-related illnesses.

The researchers utilized an AI technology called text mining to analyze comments and reviews from two websites: Amazon.com, the world's largest e-commerce retailer, and IWasPoisoned.com, a site where consumers alert others to cases of food poisoning. The database consisted of 11,190 randomly selected Amazon reviews of "grocery and canned food" items purchased between 2000 and 2018, along with 8,596 reviews of food products posted on IWasPoisoned.com. These two datasets allowed the researchers to test the text mining tools before analyzing 4.4 million more Amazon reviews.

The computers were programmed to recognize words associated with foodborne illness such as "sick," "vomiting," "diarrhea," "fever," and "nausea." This resulted in a list of flagged products that included specific brands of protein bars, herbal teas, and protein powder. Two of the products flagged by the computers had already been recalled.

An important final step in the monitoring system was a manual review by a panel of 21 food safety experts. Their job was to verify the risk level of a product and suggest a remediation strategy for the manufacturer. For example, in the case of an allergic reaction, experts would recommend investigating alternative ingredients or revising product packaging to include a consumer warning.

In future work, Goldberg hopes to create a way of alerting consumers to food product risks when they are shopping online. Amazon reviewers can give products a star rating and post comments, but it is difficult and time consuming to sort through those reviews looking for health risks. "If there were a panel that popped up on their screen, it would make them more informed as a consumer and allow them to make a purchasing decision that may ultimately make them feel safer," says Goldberg.

Credit: 
Society for Risk Analysis

Development of rapid method for extraction of natural blue chromophore from cyanobacteria

image: A highly efficient and rapid extraction method of PCB from cyanobacterial cells

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COPYRIGHT (C) TOYOHASHI UNIVERSITY OF TECHNOLOGY. ALL RIGHTS RESERVED.

Overview:

Phycocyanobilin (PCB) is a natural blue chromophore found in cyanobacteria. PCB is expected to be applied as food colorants and pharmaceuticals with anti-inflammatory and antioxidant properties. PCB also functions as the chromophore of photoswitches that control biological functions in synthetic biology. PCB is covalently bound to phycocyanin, a component of photosynthetic antenna protein, and its extraction requires specialized expertise, time-consuming procedures, and/or expensive reagents. A research group led by Assistant Professor Yuu Hirose at Toyohashi University of Technology succeeded in developing a highly efficient and rapid extraction method for PCB by treating cyanobacterial cells with alcohol under high-temperature and high-pressure conditions. They also demonstrated that this method can be applied to the isotopic labeling of PCB and its reconstitution with photoswitch protein. This technique is expected to lead to the development of new functional foods and medicines and the structural elucidation of various PCB-binding photoswitches.

Details:

Cyanobacteria are prokaryotes that perform oxygen-evolving photosynthesis and utilize phycobilisomes as light-harvesting antenna complexes for photosynthesis. Phycocyanin is a pigment protein that constitutes phycobilisome and has been used as a natural blue colorant in foods such as ice cream. Phycocyanin consists of a blue PCB chromophore and a colorless protein matrix that covalently bounds PCB. The protein matrix of phycocyanin is easily denatured under acidic and high-temperature conditions, which limits the application of phycocyanin as a food colorant. However, PCB is resistant to high temperature and acidic conditions and has the potential to complement the limitations of phycocyanin. However, conventional methods for the extraction of PCB from phycocyanin require a time-consuming purification step for phycocyanin and/or inefficient chemical reaction over 10 h for the cleavage of PCB.

A group comprising Takanari Kamo, Toshihiko Eki, and Yuu Hirose at the Department of Applied Chemistry and Biotechnology, Toyohashi University of Technology, established a simple and rapid method for extracting PCB from cyanobacterial cells. In the method, cyanobacterial cells were washed with alcohol at ambient temperature and atmospheric pressure to remove non-covalently bound chromophores, such as chlorophyll (Fig. 1). PCB was then separated from the protein matrix and extracted in ethanol via three 5-minute treatments under high temperature (125°C) and high pressure (100 bar) conditions (Fig. 1). The extraction efficiency of PCB is comparable to that of conventional methods. The extracted PCB can be used as a food colorant because it uses ethanol as the extraction solvent.

It has been reported in animal experiments that PCB has pharmacological effects, such as anti-inflammatory and anti-oxidant effects. It is expected to be consumed by humans as powder of dried cyanobacteria cells or purified phycocyanin through oral intake. The extraction of PCB would enable a 143- and 25-fold enrichment of PCB concentration in relation to the dried cell powder and purified phycocyanin, respectively, and could facilitate consumption by humans. Therefore, the use of this technology is expected to lead to the development of foods and pharmaceuticals containing higher concentrations of PCB.

PCB is also important in synthetic biology because it functions as a chromophore for photoswitch proteins that control biological functions. In this study, we demonstrated that PCB labeled with isotopic elements (13C and 15N) can be extracted from cyanobacteria cells grown in an isotopic medium. Isotopically labeled PCBs are useful in investigating the detailed structure of the photoswitch by vibrational spectroscopy and nuclear magnetic resonance spectroscopy. We also confirmed that the extracted PCB was incorporated into the photoswitch protein, sensing green and red light, and showing normal spectral sensitivities. Therefore, our technique will contribute to the elucidation of the structure of various PCB-binding photoswitches and the modification of their performance.

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Toyohashi University of Technology (TUT)

First direct band gap measurements of wide-gap hydrogen using inelastic X-ray scattering

image: IXS spectra of hydrogen under compression and the inset shows the band gap energy narrowing as a function of density.

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Bing Li

Utilizing a newly developed state-of-the-art synchrotron technique, a group of scientists led by Dr. Ho-kwang Mao, Director of HPSTAR, conducted the first-ever high-pressure study of the electronic band and gap information of solid hydrogen up to 90 GPa. Their innovative high pressure inelastic X-ray scattering result serves as a test for direct measurement of the process of hydrogen metallization and opens a possibility to resolve the electronic dispersions of dense hydrogen. This work is published in the recent issue of Physical Review Letters.

The pressure-induced evolution of hydrogen's electronic band from a wide gap insulator to a closed gap metal, or metallic hydrogen, has been a longstanding problem in modern physics. However, hydrogen's remarkably high energy has prevented the electronic band gap from being directly observed under pressure before. Existing probes, such as electrical conductivity, optical absorption, or reflection spectroscopy measurements, are limited and provide little information on a wide-gap insulator. "All previous studies of the band gap in insulating hydrogen under compression were based on an indirect scheme using optical measurements," explains Dr. Mao.

The team used high-brilliance, high-energy synchrotron radiation to develop an inelastic x-ray (IXS) probe, yielding electronic band information of hydrogen in situ under high pressure in a diamond anvil cell (DAC). "The development of our DAC-IXS technique for this project took an international team of many experts in synchrotron inelastic X-ray spectroscopy, instrumentation, and ultra-high-pressure techniques over five years to complete," said Dr. Bing Li, the first author.

"Actually, the real beginning of this project can be traced back more than 20 years, and these results are the culmination of all that preparation and experimentation. A true testament to the enormous efforts and talents of the team involved," said Dr. Mao. The novel IXS probe technique enabled an inaccessible and extensive UV energy range of 45 eV to be measured, showing how dense hydrogen's electronic joint density of states and band gap evolve with pressure. The electronic band gap decreased linearly from 10.9 eV to 6.57 eV, with an 8.6 times densification from zero pressure up to 90 GPa.

These developments in state-of-the-art synchrotron capabilities with submicron to nanometer-scaled X-ray probes will only extend future experimental possibilities. Advances of IXS to higher pressure could place the semiconducting region of phases II-V within reach and enable the study of hydrogen metallization through direct and quantitative electronic band gap measurements.

This work overcomes formidable technical challenges, achieving direct experimental measurements of hydrogen's electronic band and its gap for the first time.

Credit: 
Center for High Pressure Science & Technology Advanced Research

Wirelessly rechargeable soft brain implant controls brain cells

image: Optical image of a wirelessly rechargeable, soft optoelectronic system held with fingers. The device is emitting blue light from its bilateral probes.

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KAIST

A group of KAIST researchers and collaborators have engineered a tiny brain implant that can be wirelessly recharged from outside the body to control brain circuits for long periods of time without battery replacement. The device is constructed of ultra-soft and bio-compliant polymers to help provide long-term compatibility with tissue. Geared with micrometer-sized LEDs (equivalent to the size of a grain of salt) mounted on ultrathin probes (the thickness of a human hair), it can wirelessly manipulate target neurons in the deep brain using light.

This study, led by Professor Jae-Woong Jeong, is a step forward from the wireless head-mounted implant neural device he developed in 2019. That previous version could indefinitely deliver multiple drugs and light stimulation treatment wirelessly by using a smartphone.

For the new upgraded version, the research team came up with a fully implantable, soft optoelectronic system that can be remotely and selectively controlled by a smartphone. This research was published on January 22, 2021 in Nature Communications.

The new wireless charging technology addresses the limitations of current brain implants. Wireless implantable device technologies have recently become popular as alternatives to conventional tethered implants, because they help minimize stress and inflammation in freely-moving animals during brain studies, which in turn enhance the lifetime of the devices. However, such devices require either intermittent surgeries to replace discharged batteries, or special and bulky wireless power setups, which limit experimental options as well as the scalability of animal experiments.

"This powerful device eliminates the need for additional painful surgeries to replace an exhausted battery in the implant, allowing seamless chronic neuromodulation," said Professor Jeong. "We believe that the same basic technology can be applied to various types of implants, including deep brain stimulators, and cardiac and gastric pacemakers, to reduce the burden on patients for long-term use within the body."

To enable wireless battery charging and controls, researchers developed a tiny circuit that integrates a wireless energy harvester with a coil antenna and a Bluetooth low-energy chip. An alternating magnetic field can harmlessly penetrate through tissue, and generate electricity inside the device to charge the battery. Then the battery-powered Bluetooth implant delivers programmable patterns of light to brain cells using an "easy-to-use" smartphone app for real-time brain control.

"This device can be operated anywhere and anytime to manipulate neural circuits, which makes it a highly versatile tool for investigating brain functions," said lead author Choong Yeon Kim, a researcher at KAIST.

Neuroscientists successfully tested these implants in rats and demonstrated their ability to suppress cocaine-induced behaviour after the rats were injected with cocaine. This was achieved by precise light stimulation of relevant target neurons in their brains using the smartphone-controlled LEDs. Furthermore, the battery in the implants could be repeatedly recharged while the rats were behaving freely, thus minimizing any physical interruption to the experiments.

"Wireless battery re-charging makes experimental procedures much less complicated," said the co-lead author Min Jeong Ku, a researcher at Yonsei University's College of Medicine.

"The fact that we can control a specific behaviour of animals, by delivering light stimulation into the brain just with a simple manipulation of smartphone app, watching freely moving animals nearby, is very interesting and stimulates a lot of imagination," said Jeong-Hoon Kim, a professor of physiology at Yonsei University's College of Medicine. "This technology will facilitate various avenues of brain research."

The researchers believe this brain implant technology may lead to new opportunities for brain research and therapeutic intervention to treat diseases in the brain and other organs.

Credit: 
The Korea Advanced Institute of Science and Technology (KAIST)

Scientists developed energy saving ceramic phosphors for high power LED systems

image: The microstructure of a composite ceramic phosphor, and the appearance of an LED device based on

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Denis Kosyanov, FEFU

Materials scientists of Far Eastern Federal University (FEFU), in collaboration with an international research team, have advanced the design of composite ceramic materials (Ce3+:YAG-Al2O3), i.e. solid-state light converters (phosphors) that can be applied in-ground and aerospace technologies. The LED systems based on the developed materials to save 20-30 percent more energy compared to commercial analogues. A related article was published in Materials Characterization.

Over 15% of the total global electricity production or about $ 450 billion annually spent on lighting. According to the photonics development roadmap run in Russia, the development of LED technology with an efficiency of more than 150 lm/W will allow to release up to 30% of electricity by 2025.

Based on the developed ceramic light converters, it is possible to produce both compact energy-efficient white light-emitting diodes (wLEDs) and high-power (high brightness) systems. The new material is in demand for many photonic applications from portable projectors and endoscopes to laser TVs with a diagonal of more than 100 inches, lighting devices for auto and aircraft construction, megastructures, etc.

"The consumption of white LEDs is more than half of the total consumption of high brightness LEDs. Some peculiarities of the technology for the production of organic phosphors for modern commercial white LEDs lead to the quick aging of the light-emitting diode that loses brightness and quality of color rendering. We get around the problem by creating completely inorganic light converters in the form of composite ceramics based on yttrium aluminum garnet, activated by cerium ions Ce3+:YAG, and a thermally stable phase of aluminum oxide Al2O3", says Anastasia Vornovskikh, a Junior Researcher at the REC for "Advanced Ceramic Materials" of the FEFU Polytechnic Institute (school, PI).

The new materials are characterized by high values of thermal strength and thermal conductivity, endure high pumping power, and generate bright white light without obvious thermal quenching of the photoluminescence intensity. This makes it possible to reduce the operating temperature of the LED device down to 120-70°C, more than 2 times in comparison with commercial samples of Ce3+:YAG.

"We synthesized materials by vacuum reactive sintering of initial oxide powders of aluminum, yttrium, cerium, and gadolinium. Particular attention we paid to the identification of the quantitative relationship between the main scattering centers that are residual pores and Al2O3 crystallites and the spectroscopic properties of ceramic phosphors. Our light converters meet all the requirements for new generation wLEDs. They have a long lifespan, high luminous efficacy and color rendering index while maintaining the requirements for the environmental friendliness and material dimensions", says project manager Denis Kosyanov, Director of the REC for "Advanced Ceramic Materials", of the Industrial Safety Department of FEFU PI.

In the study took part researchers from Far Eastern Federal University (FEFU); Shanghai Institute of Ceramics, the Shanghai Technological Institute, the University of the Chinese Academy of Sciences; Institute of Chemistry of the Far Eastern Branch of the Russian Academy of Sciences; Institute of Solid State Chemistry and Mechanochemistry of the Siberian Branch of the Russian Academy of Sciences.

Credit: 
Far Eastern Federal University

Biodegradable displays for sustainable electronics

image: Thanks to its flexibility and adhesion, the biodegradable display can be worn directly on the hand.

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Manuel Pietsch, KIT

In the next years, increasing use of electronic devices in consumables and new technologies for the internet of things will increase the amount of electronic scrap. To save resources and minimize waste volumes, an eco-friendlier production and more sustainable lifecycle will be needed. Scientists of Karlsruhe Institute of Technology (KIT) have now been the first to produce displays, whose biodegradability has been checked and certified by an independent office. The results are reported in the Journal of Materials Chemistry. (DOI: 10.1039/d0tc04627b)

"For the first time, we have demonstrated that it is possible to produce sustainable displays that are largely based on natural materials with the help of industrially relevant production methods. After use, these displays are no electronic scrap, but can be composted. In combination with recycling and reuse, this might help minimize or completely prevent some of the environmental impacts of electronic scrap," says Manuel Pietsch, first author of the publication and researcher of KIT's Light Technology Institute (LTI), who is working at the Heidelberg InnovationLab.

Low Energy Consumption, Simple Component Architecture

Functioning of the display is based on the so-called electrochromic effect of the initial organic material. When voltage is applied, light absorption is modified and the material changes its color. Electrochromic displays have a low energy consumption and simple component architecture compared to commercially available displays, such as LED, LCD, and E-paper. Another advantage is that these displays can be produced by inkjet printing in a customized, inexpensive, and material-efficient way. Moreover, this process is suited for scaling with a high throughput. The materials used mainly are of natural origin or biocompatible. Sealing with gelatine makes the display adhesive and flexible, such that it can be worn directly on the skin.

Use in Medical Diagnostics and Food Packagings

The display is generally suited for short-lifecycle applications in various sectors. In medical diagnostics, for instance, where hygiene plays an important role, sensors and their indicators have to be cleaned or disposed of after use. The newly developed display will not be dumped as electronic scrap, but is compostable. It can also be used for quality monitoring in food packagings, where reuse is not permitted. Digital printing allows the displays to be adapted to persons or complex shapes without any expensive modification of the process. This reduces the consumption of resources.

"As far as we know, this is the first demonstration of a biodegradable display produced by inkjet printing. It will pave the way to sustainable innovations for other electronic components and to the production of eco-friendlier electronics," says Gerardo Hernandez-Sosa, Head of LTI's Printed Electronics Group at the Heidelberg InnovationLab.

Credit: 
Karlsruher Institut für Technologie (KIT)

Study finds water quality improvements in Maryland's Choptank River

CAMBRIDGE, MD (January 26, 2021)--The Chesapeake Bay has a long history of nutrient pollution resulting in degraded water quality. However, scientists from the University of Maryland Center for Environmental Science are reporting some improvements in the Choptank River on Maryland's Eastern Shore.

The Choptank is a tributary of Chesapeake Bay, and its watershed lies primarily in the state of Maryland, with a portion in Delaware. There are strong similarities between the Choptank basin and the Chesapeake as a whole, which enables the Choptank to be used as a model for progress in the Bay.

The Chesapeake Bay is an estuary which has undergone considerable water quality degradation from human impacts and nitrogen and phosphorus pollutants from the air and land that have impaired use of receiving waters for drinking and recreation, and result in algal blooms and hypoxia. Algae blooms occur downstream in the Choptank and Chesapeake, blocking sunlight and reducing oxygen after the algae settle to the bottom, making it difficult for fish and oysters to survive.

"The eutrophication of the Choptank estuary is a microcosm of the Chesapeake Bay as a whole," said University of Maryland Center for Environmental Science Professor Emeritus Tom Fisher. "The data presented here indicate that public and industrial investments in reductions of atmospheric emissions and upgrades to wastewater treatment plants have improved estuarine water quality in the Choptank."

For the last 20 years, scientists have worked with farmers, wastewater treatment plant operators, government agencies, and water quality groups to encourage conservation efforts and to discern trends in water quality in the Choptank basin. In this study, scientists evaluated whether the total maximum daily load (TMDL) for the Chesapeake--established by the U.S. Environmental Protection Agency to address degraded water quality-- and other management practices to curb atmospheric deposition, clean up point sources for pollution such as waste water treatment plants, and reduce runoff from agriculture have led to improved water quality in streams and in the Choptank estuary.

Fisher and fellow researchers evaluated progress towards water quality goals between 1998 and 2017. They found that both atmospheric deposition and wastewater treatment inputs declined due to these management actions, whereas overall inputs increased due to higher agricultural inputs, despite conservation efforts.

Out of three monitoring stations on the Choptank River, the one nearest a wastewater treatment plant outfall, a few miles downstream from Cambridge, Maryland, showed improvement, indicating that public and industrial investments in reductions of atmospheric emissions and upgrades to wastewater treatment plants have improved estuarine water quality. In surface waters, water clarity increased and the amount of algae decreased. In bottom waters, dissolved oxygen increased.

"An interesting question is why there is improving water quality at the monitoring station near the wastewater treatment plant despite an overall increase in nitrogen and pollution inputs to the estuary as a whole," said Fisher. "This response suggests that local actions matter; in this case greatly reducing local inputs from the largest wastewater treatment plant in the area improved adjacent estuarine water quality, even when the overall estuary was receiving more nutrient pollution."

The agricultural sector, the dominant source of nitrogen and phosphorus pollution, appeared to provide little contribution to improved water quality during this period, despite efforts to encourage best management practices such as fertilizer management, drainage control structures, or winter cover crops to reduce losses of nitrogen and phosphorus from fertilizers applied to fields. The watershed contains numerous concentrated animal feeding operations, particularly poultry, which produce manure that is applied as organic fertilizer on crop fields. Fertilizer applied to crops such as corn, wheat and soybeans may also enter the watershed through surface runoff or groundwater.

"If reductions in agricultural nitrogen and phosphorus inputs over broad areas do occur in the future, improvements in estuarine water quality larger than those reported here, and more consistently throughout the entire estuary, could be expected. For this reason, it is important to continue monitoring agricultural areas with enhanced management practices," said Fisher.

Credit: 
University of Maryland Center for Environmental Science

Anonymous cell phone data can quantify behavioral changes for flu-like illnesses

Cell phone data that is routinely collected by telecommunications providers can reveal changes of behavior in people who are diagnosed with a flu-like illness, while also protecting their anonymity, a new study finds. The Proceedings of the National Academy of Sciences (PNAS) published the research, led by computer scientists at Emory University and based on data drawn from a 2009 outbreak of H1N1 flu in Iceland.

"To our knowledge, our project is the first major, rigorous study to individually link passively-collected cell phone metadata with actual public health data," says Ymir Vigfusson, assistant professor in Emory University's Department of Computer Science and a first author of the study. "We've shown that it's possible to do so without comprising privacy and that our method could potentially provide a useful tool to help monitor and control infectious disease outbreaks."

The researchers collaborated with a major cell phone service provider in Iceland, along with public health officials of the island nation. They analyzed data for more than 90,000 encrypted cell phone numbers, which represents about a quarter of Iceland's population. They were permitted to link the encrypted cell phone metadata to 1,400 anonymous individuals who received a clinical diagnosis of a flu-like illness during the H1N1 outbreak.

"The individual linkage is key," Vigfusson says. "Many public-health applications for smartphone data have emerged during the COVID-19 pandemic but tend to be based around correlations. In contrast, we can definitively measure the differences in routine behavior between the diagnosed group and the rest of the population."

The results showed, on average, those who received a flu-like diagnosis changed their cell phone usage behavior a day before their diagnosis and the two-to-four days afterward: They made fewer calls, from fewer unique locations. On average, they also spent longer time than usual on the calls that they made on the day following their diagnosis.

The study, which began long before the COVID-19 pandemic, took 10 years to complete. "We were going into new territory and we wanted to make sure we were doing good science, not just fast science," Vigfusson says. "We worked hard and carefully to develop protocols to protect privacy and conducted rigorous analyses of the data."

Vignusson is an expert on data security and developing software and programming algorithms that work at scale.

He shares first authorship of the study with two of his former students: Thorgeir Karlsson, a graduate student at Reykjavik University who spent a year at Emory working on the project, and Derek Onken, a Ph.D. student in the Computer Science department. Senior author Leon Danon -- from the University of Bristol, and the Alan Turing Institute of the British Library -- conceived of the study.

While only about 40 percent of humanity has access to the Internet, cell phone ownership is ubiquitous, even in lower and middle-income countries, Vigfusson notes. And cell phone service providers routinely collect billing data that provide insights into the routine behaviors of a population, he adds.

"The COVID pandemic has raised awareness of the importance of monitoring and measuring the progression of an infectious disease outbreak, and how it is essentially a race against time," Vigfusson says. "More people also realize that there will likely be more pandemics during our lifetimes. It is vital to have the right tools to give us the best possible information quickly about the state of an epidemic outbreak."

Privacy concerns are a major reason why cell phone data has not been linked to public health data in the past. For the PNAS paper, the researchers developed a painstaking protocol to minimize these concerns.

The cell phone numbers were encrypted, and their owners were not identified by name, but by a unique numerical identifier not revealed to the researchers. These unique identifiers were used to link the cell phone data to de-identified health records.

"We were able to maintain anonymity for individuals throughout the process," Vigfusson says. "The cell phone provider did not learn about any individual's health diagnosis and the health department did not learn about any individual's phone behaviors."

The study encompassed 1.5 billion call record data points including calls made, the dates of the calls, the cell tower location where the calls originated and the duration of the calls. The researchers linked this data to clinical diagnoses of a flu-like illness made by a health providers in a central database. Laboratory confirmation of influenza was not required.

The analyses of the data focused on 29 days surrounding each clinical diagnosis, and looked at changes in mobility, the number of calls made and the duration of the calls. They measured these same factors during the same time period for location-matched controls.

"Even though individual cell phones generated only a few data points per day, we were able to see a pattern where the population was behaving differently near the time they were diagnosed with a flu-like illness," Vigfusson says.

While the findings are significant, they represent only a first step for the possible broader use of the method, Vigfusson adds. The current work was limited to the unique environment of Iceland: An island with only one port of entry and a fairly homogenous, affluent and small population. It was also limited to a single infectious disease, H1N1, and those who received a clinical diagnosis for a flu-like illness.

"Our work contributes to the discussion of what kinds of anonymous data lineages might be useful for public health monitoring purposes," Vigfusson says. "We hope that others will build on our efforts and study whether our method can be adapted for use in other places and for other infectious diseases."

Credit: 
Emory Health Sciences

Genetically-modified mosquitoes key to stopping Zika virus spread

image: Dr. Alexander Franz is an associate professor in the MU College of Veterinary Medicine.

Image: 
MU College of Veterinary Medicine

COLUMBIA, Mo. - In 2016, the World Health Organization called the Zika virus epidemic a "public health emergency of international concern" due to the virus causing birth defects for pregnant women in addition to neurological problems. Since then, researchers have wrestled with different strategies for controlling the spread of Zika virus, which gets transmitted to humans from female mosquito bites.

One approach, which was approved by the Environmental Protection Agency in May, will release more than 750 million genetically modified mosquitos into the Florida Keys in 2021 and 2022. These "suicide mosquitos" are genetically-altered to produce offspring that die before emerging into adults and therefore cannot bite humans and spread disease.

However, wiping out future generations of mosquitoes may cause environmental complications, such as potentially disrupting food chains. A new research study at the University of Missouri offers another option: genetically modifying mosquitoes to be resistant to Zika virus altogether.

Alexander Franz, an associate professor in the MU College of Veterinary Medicine, collaborated with researchers at Colorado State University by using CRISPR gene-editing technology to produce mosquitoes that are unable to replicate Zika virus and therefore cannot infect a human through biting.

"We genetically manipulated these mosquitoes by inserting an artificial gene into their genome that triggers one of the immune pathways in the midgut to recognize and destroy the RNA genome of Zika virus," Franz said. "By developing these mosquitoes that are resistant to the virus, the disease cycle is interrupted so transmission to humans can no longer take place."

Franz added that the genetic modification is inheritable, so future generations of the altered mosquitoes would be resistant to Zika virus as well.

"We are interested in strategies for controlling insect vectors like mosquitoes that transmit various viruses affecting human health," Franz said. "Public health experts suggest having a toolbox with different approaches available to tackle a virus such as Zika, and unfortunately right now there are limited options. There is no vaccine for the Zika virus widely available and spraying insecticides has become ineffective since the mosquitoes can develop resistance, so we are simply trying to expand the toolbox and provide a solution by genetically modifying the mosquitoes to become Zika-resistant while keeping them alive at the same time."

Franz' research is designed to help prevent another outbreak of Zika virus disease from occurring.

"If you can ever find a way to block the transmission of a pathogen that negatively affects humans, that is good news," Franz said. "We have shown this is a viable option for genetically modifying mosquitos in a lab setting. There would need to be thorough discussions about regulatory compliance to see if this can be a solution out in the field down the road, and who knows when another Zika outbreak might happen in the future, which is why this research is so important."

Credit: 
University of Missouri-Columbia

Compelling evidence of neutrino process opens physics possibilities

image: SCGSR Awardee Jacob Zettlemoyer, Indiana University Bloomington, led data analysis and worked with ORNL's Mike Febbraro on coatings, shown under blue light, to shift argon light to visible wavelengths to boost detection.

Image: 
Rex Tayloe/Indiana University

The COHERENT particle physics experiment at the Department of Energy's Oak Ridge National Laboratory has firmly established the existence of a new kind of neutrino interaction. Because neutrinos are electrically neutral and interact only weakly with matter, the quest to observe this interaction drove advances in detector technology and has added new information to theories aiming to explain mysteries of the cosmos.

"The neutrino is thought to be at the heart of many open questions about the nature of the universe," said Indiana University physics professor Rex Tayloe. He led the installation, operation and data analysis of a cryogenic liquid argon detector for neutrinos at the Spallation Neutron Source, or SNS, a DOE Office of Science User Facility at ORNL.

The study, published in Physical Review Letters, observed that low-energy neutrinos interact with an argon nucleus through the weak nuclear force in a process called coherent elastic neutrino-nucleus scattering, or CEvNS, which is pronounced "sevens." Like a ping-pong ball bombarding a softball, a neutrino that hits a nucleus transfers only a small amount of energy to the much larger nucleus, which recoils almost imperceptibly in response to the tiny assault.

Laying the groundwork for the discovery made with the argon nucleus was a 2017 study published in Science in which COHERENT collaborators used the world's smallest neutrino detector to provide the first evidence of the CEvNS process as neutrinos interacted with larger and heavier cesium and iodine nuclei. Their recoils were even tinier, like bowling balls reacting to ping-pong balls.

"The Standard Model of Particle Physics predicts coherent elastic scattering of neutrinos off nuclei," said Duke University physicist Kate Scholberg, spokesperson and organizer of science and technology goals for COHERENT. The collaboration has 80 participants from 19 institutions and four countries. "Seeing the neutrino interaction with argon, the lightest nucleus for which it has been measured, confirms the earlier observation from heavier nuclei. Measuring the process precisely establishes constraints on alternative theoretical models."

Yuri Efremenko, a physicist at the University of Tennessee, Knoxville, and ORNL who led development of more sensitive photodetectors, said, "Argon provides a 'door' of sorts. The CEvNS process is like a building that we know should exist. The first measurement on cesium and iodine was one door that let us in to explore the building. We've now opened this other argon door." The argon data is consistent with the Standard Model within error bars. However, increased precision enabled by bigger detectors may let scientists see something new. "Seeing something unexpected would be like opening the door and seeing fantastic treasures," Efremenko added.

"We're looking for ways to break the Standard Model. We love the Standard Model; it's been really successful. But there are things it just doesn't explain," said physicist Jason Newby, ORNL's lead for COHERENT. "We suspect that in these small places where the model might break down, answers to big questions about the nature of the universe, antimatter and dark matter, for instance, could lie in wait."

The COHERENT team uses the world's brightest pulsed neutron source at SNS to help find the answers. The neutrons SNS produces for research create neutrinos as a byproduct. A service corridor beneath the SNS mercury target has been converted into a dedicated neutrino laboratory, dubbed Neutrino Alley, under the leadership of Newby and Efremenko. A 53-pound, or 24-kilogram, detector called CENNS-10 sits 90 feet, or 27.5 meters, from a low-energy neutrino source that optimizes opportunities to spot interactions that are coherent. This means approaching neutrinos see the weak force of the nucleus as a whole, leading to a bigger effect as compared to non-coherent interactions.

Bigger detectors are better at making high-precision measurements, and the CENNS-10 detector technology is easy to scale up by merely adding more liquid argon.

The CENNS-10 detector was originally built at Fermilab by COHERENT collaborator Jonghee Yoo. He and Tayloe brought it to IU and reworked it there before it was installed at SNS in 2016. Newby and Efremenko had prepared the SNS site with shielding of layered lead, copper and water to eliminate neutron backgrounds.

After initial measurements indicated the experiment would not be dominated by background, wavelength-shifting coatings were applied to the photodetectors and inner reflectors that significantly improved light collection. The detector was calibrated by injecting krypton-83m into the liquid argon to allow calculation of the number of photons present.

The published results used 18 months of data collected from CENNS-10. Analysis of the data revealed 159 CEvNS events, consistent with the Standard Model prediction.

COHERENT's data will help researchers worldwide interpret their neutrino measurements and test their theories of possible new physics. The calculable fingerprint of neutrino-nucleus interactions predicted by the Standard Model and seen by COHERENT has practical applications, too. "This is a way to measure the distribution of neutrons inside nuclei and the density of neutron stars," Efremenko said. "It's a contribution to nuclear physics and astrophysics because the processes are very similar."

Different types of detectors are necessary for comprehensive neutrino studies. To further the goal of observing CEvNS on a variety of nuclei, a 16-kilogram detector based on germanium nuclei, which are bigger than argon but smaller than cesium and iodine, will be installed in Neutrino Alley next year. An array of sodium iodide detectors has been installed to augment the cesium iodide detector in operation there since 2017.

Meanwhile, data collection continues 24/7 despite COVID-19 because COHERENT collaborators monitor their liquid argon detector remotely. They aspire to enlarge it to ton-scale to see 25 times as many events annually and enable observation of detailed energy spectra that could reveal signatures of the new physics, including the existence of sterile neutrinos that have no weak interaction and, therefore, would not demonstrate a coherent interaction.

Eventually, they would like to add an even bigger 10-ton, liquid-argon detector at SNS's Second Target Station. "We're pushing on the technology so that, in the future, we will be able to answer questions that require greater precision," Newby said.

Credit: 
DOE/Oak Ridge National Laboratory

Study helps understand why kids of obese mothers may be susceptible to metabolic diseases

image: Image of a mitofusin-2 deficient egg shows mitochondria [stained green] to be fewer, more aggregated, and swollen than in controls

Image: 
Marcos Chiaratti

A Brazilian study published in the journal Molecular Human Reproduction helps understand why obese mothers tend to have children with a propensity to develop metabolic disease during their lifetime, as suggested by previous research.

According to the authors, "transgenerational transmission of metabolic diseases" may be associated with Mfn2 deficiency in the mother's oocytes (immature eggs). Mfn2 refers to mitofusin-2, a protein involved in the regulation of vascular smooth muscle cell proliferation. It is normally found in the outer membrane of mitochondria, the organelles that supply cells with energy. A deficiency leads to mitochondrial swelling and dysfunction, as well as altering the expression of almost 1,000 genes in female gametes.

"A number of studies have found mitofusin-2 to be an important metabolic regulator. There's evidence that weight gain leads to a reduction in levels of the protein in muscle and liver cells, both of which play a key role in regulating blood sugar levels. In the case of diabetics, its expression is reduced in these cells," Marcos Chiaratti, a professor at the Federal University of São Carlos (UFSCar) and principal investigator for the study, which was supported by São Paulo Research Foundation - FAPESP, told.

In the recent publication, Chiaratti and his group report the results of experiments with mice genetically modified so as not to express Mfn2 only in oocytes. The Mfn2 deficiency was expected to affect their fertility, but this was not the case. However, their offspring gained more weight than the offspring of control animals and had become diabetic by the age of 9 months, despite being fed a standard diet.

To investigate the molecular mechanisms associated with this abnormal phenomenon, Chiaratti established a collaboration with researchers at the Center for Research on Redox Processes in Biomedicine (Redoxome) and the Obesity and Comorbidities Research Center (OCRC), both of which are Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP. Part of the study was conducted during the master's research of Bruna Garcia at UFSCar's Center for Biological and Health Sciences (CCBS), with Chiaratti supervising.

The first step was the identification of the type of dysfunction displayed by Mfn2-deficient oocytes on reaching the stage at which they are ready to be fertilized. The analysis showed a reduced number of mitochondria in these cells and a lower level of ATP (adenosine triphosphate), the molecule that serves as cell fuel.

The researchers also observed that oocyte mitochondria were more aggregated than normal, enlarged to twice the expected size, and further away from the endoplasmic reticulum, an organelle with which they need to interact to import calcium and other substances crucial to their functioning.

According to Chiaratti, one of the known roles of Mfn2 is ensuring that mitochondria stay in contact with the endoplasmic reticulum, a structure that participates in the synthesis and transport of several substances in cells. The results of the study suggest Mfn2 deficiency compromises interaction between the two organelles, impairing the functions of both in oocytes.

"There's evidence that transgenerational transmission of diseases such as diabetes is associated with mitochondrial dysfunction and endoplasmic reticulum stress in oocytes. Our findings corroborate this hypothesis," Chiaratti said. "Mfn2 deficiency appears to affect mitochondrial biogenesis [reducing the number of mitochondria] and the capacity of mitochondria to move about in the cytoplasm in order to meet cellular demand for energy."

The next step consisted of characterizing the Mfn2-deficient oocyte's transcriptome (the full range of messenger RNA molecules expressed) and comparing it with controls. Using RNA sequencing, the researchers found 517 genes that were less expressed in the genetically modified animals' oocytes than in controls and 426 genes that were more expressed.

"We then set out to identify the signaling pathways that belonged to these differentially expressed genes. We found pathways associated with the functioning of the endoplasmic reticulum and mitochondria, as well as pathways associated with endocrine processes such as regulation of blood sugar," Chiaratti said.

Alterations in offspring

Analysis of the offspring of genetically modified females focused on skeletal muscle and liver cells. The aim was to understand why these animals became diabetic even when fed a balanced diet.

Neither muscle cells nor liver cells were found to be in endoplasmic reticulum stress, a condition characterized by an accumulation of proteins that impairs the organelle's functioning, and no mitochondrial alterations were found in muscle cells. Liver cell mitochondria were moderately dysfunctional.

Because this alteration was not sufficient to explain the hyperglycemic phenotype of the offspring, the group decided to study insulin signaling in these animals, as insulin produced by the pancreas enables glucose to enter cells and thereby lowers the level of blood sugar.

Their analysis of pancreas cells showed that insulin production was normal, but the level of insulin in the bloodstream was reduced and the signal it normally sends to muscle and liver cells was weak.

"In these two tissues, insulin causes a biochemical change in the protein Akt [protein kinase B]. The signal sent by insulin makes this molecule become phosphorylated [via addition of phosphate to the protein chain] and this triggers a cascade of biochemical reactions in the cell," Chiaratti explained.

The results of these analyses, therefore, suggested that the offspring's muscle and liver tissue received a small amount of insulin, even though the level of insulin production by the pancreas was normal. This raised the hypothesis, to be confirmed in future studies, that insulin was being broken down faster in the organism of these animals.

Next steps

To deepen their understanding of the molecular mechanisms that led to augmented weight gain and hyperglycemia in Mfn2-deficient pups, the researchers plan to repeat the experiment with some modifications. Mfn2-deficient females will be fed a high-calorie diet to exacerbate the effects of the deficiency in their offspring.

"We also plan to investigate, in animals without any genetic modification, whether a high-calorie diet alone is sufficient to reduce Mfn2 expression and change the way mitochondria function and interact with the reticulum," Chiaratti said.

The knowledge created by these studies, he added, is expected to permit the development of strategies to manipulate Mfn2 expression in the context of obesity and help prevent transgenerational transmission of metabolic diseases.

For Alicia Kowaltowski, a professor at the University of São Paulo's Chemistry Institute (IQ-USP), a member of Redoxome and a co-author of the study, the results obtained so far show that a person's diet and nutritional status influence mitochondrial shape, one of the factors that affect cellular physiology. Proteins that regulate mitochondrial morphology are therefore potential therapeutic targets and should be explored in future research.

"It should be stressed that we didn't find significant alterations to the mitochondria in liver tissue even though the animals were diabetic. This accords with other studies showing that mitochondrial function in the liver is highly resilient," Kowaltowski said. "In our view, there must be protection mechanisms in the liver, given its importance to the metabolism. When mitochondrial dysfunction appears in the liver, the reason is that metabolic syndrome has reached an advanced stage of development."

Infertility and maternal inheritance

Funded by FAPESP via several projects 09/54035-4, 12/50231-6, 17/05899-2, 17/04372-0, 16/11935-9, 16/11942-5, 16/07868-4, 18/06119-3, and 10/51906-1, the study reported in the latest publication is part of a research line that aims to understand how mitochondrial alterations, including DNA mutations, are associated with infertility and transgenerational disease transmission.

"Previous research has shown that mitochondrial dysfunction can compromise egg fertility. We created two animal models with which to investigate this mechanism in more detail: in one we inhibited expression of mitofusin-1 in oocytes, and in the other, we inhibited expression of mitofusin-2," Chiaratti said.

Mfn1 deficiency made females infertile, as reported in an article published in The Faseb Journal.

"In this earlier study we showed that oocyte-specific Mfn1 deletion altered the expression of 161 genes and affected several processes in oocytes, above all communication with ovarian cells," Chiaratti said. "In the case of the Mfn2-deficient animals, we observed other alterations in oocytes and offspring, but fertility was not affected. Curiously, the effects of Mfn1 deletion were attenuated in oocytes when Mfn2 was simultaneously inhibited, suggesting that the action of Mfn1 occurs after that of Mfn2."

Credit: 
Fundação de Amparo à Pesquisa do Estado de São Paulo