Culture

New York, NY--May 11, 2021--Widely used to monitor and map biological signals, to support and enhance physiological functions, and to treat diseases, implantable medical devices are transforming healthcare and improving the quality of life for millions of people. Researchers are increasingly interested in designing wireless, miniaturized implantable medical devices for in vivo and in situ physiological monitoring. These devices could be used to monitor physiological conditions, such as temperature, blood pressure, glucose, and respiration for both diagnostic and therapeutic procedures.

To date, conventional implanted electronics have been highly volume-inefficient--they generally require multiple chips, packaging, wires, and external transducers, and batteries are often needed for energy storage. A constant trend in electronics has been tighter integration of electronic components, often moving more and more functions onto the integrated circuit itself.

Researchers at Columbia Engineering report that they have built what they say is the world's smallest single-chip system, consuming a total volume of less than 0.1 mm3. The system is as small as a dust mite and visible only under a microscope. In order to achieve this, the team used ultrasound to both power and communicate with the device wirelessly. The study was published online May 7 in Science Advances.

"We wanted to see how far we could push the limits on how small a functioning chip we could make," said the study's leader Ken Shepard, Lau Family professor of electrical engineering and professor of biomedical engineering. "This is a new idea of 'chip as system'--this is a chip that alone, with nothing else, is a complete functioning electronic system. This should be revolutionary for developing wireless, miniaturized implantable medical devices that can sense different things, be used in clinical applications, and eventually approved for human use."

The team also included Elisa Konofagou, Robert and Margaret Hariri Professor of Biomedical engineering and professor of radiology, as well as Stephen A. Lee, PhD student in the Konofagou lab who assisted in the animal studies.

The design was done by doctoral student Chen Shi, who is the first author of the study. Shi's design is unique in its volumetric efficiency, the amount of function that is contained in a given amount of volume. Traditional RF communications links are not possible for a device this small because the wavelength of the electromagnetic wave is too large relative to the size of the device. Because the wavelengths for ultrasound are much smaller at a given frequency because the speed of sound is so much less than the speed of light, the team used ultrasound to both power and communicate with the device wirelessly. They fabricated the "antenna" for communicating and powering with ultrasound directly on top of the chip.

The chip, which is the entire implantable/injectable mote with no additional packaging, was fabricated at the Taiwan Semiconductor Manufacturing Company with additional process modifications performed in the Columbia Nano Initiative cleanroom and the City University of New York Advanced Science Research Center (ASRC) Nanofabrication Facility.

Shepard commented, "This is a nice example of 'more than Moore' technology--we introduced new materials onto standard complementary metal-oxide-semiconductor to provide new function. In this case, we added piezoelectric materials directly onto the integrated circuit to transducer acoustic energy to electrical energy."

Konofagou added, "Ultrasound is continuing to grow in clinical importance as new tools and techniques become available. This work continues this trend."

The team's goal is to develop chips that can be injected into the body with a hypodermic needle and then communicate back out of the body using ultrasound, providing information about something they measure locally. The current devices measure body temperature, but there are many more possibilities the team is working on.

2003 was a big year for virologists. The first giant virus was discovered in this year, which shook the virology scene, revising what was thought to be an established understanding of this elusive group and expanding the virus world from simple, small agents to forms that are as complex as some bacteria. Because of their link to disease and the difficulties in defining them--they are biological entities but do not fit comfortably in the existing tree of life--viruses incite the curiosity of many people.

Scientists have long been interested in how viruses evolved, especially when it comes to giant viruses that can produce new viruses with very little help from the host--in contrast to most small viruses, which utilize the host's machinery to replicate.

Even though giant viruses are not what most people would think of when it comes to viruses, they are actually very common in oceans and other water bodies. They infect single-celled aquatic organisms and have major effects on the latter's population. In fact, Dr. Kiran Kondabagil, molecular virologist at the Indian Institute of Technology (IIT) Bombay, suggests, "Because these single-celled organisms greatly influence the carbon turnover in the ocean, the viruses have an important role in our world's ecology. So, it is just as important to study them and their evolution, as it is to study the disease-causing viruses."

In a recent study, the findings of which have been published in Molecular Biology and Evolution, Dr. Kondabagil and co-researcher Dr. Supriya Patil performed a series of analyses on major genes and proteins involved in the DNA replication machinery of Mimivirus, the first group of giant viruses to be identified. They aimed to determine which of two major suggestions regarding Mimivirus evolution--the reduction and the virus-first hypotheses--were more supported by their results. The reduction hypothesis suggests that the giant viruses emerged from unicellular organisms and shed genes over time; the virus-first hypothesis suggests that they were around before single-celled organisms and gained genes, instead.

Dr. Kondabagil and Dr. Patil created phylogenetic trees with replication proteins and found that those from Mimivirus were more closely related to eukaryotes than to bacteria or small viruses. Additionally, they used a technique called multidimensional scaling to determine how similar the Mimiviral proteins are. A greater similarity would indicate that the proteins co-evolved, which means that they are linked together in a larger protein complex with coordinated function. And indeed, their findings showed greater similarity. Finally, the researchers showed that genes related to DNA replication are similar to and fall under purifying selection, which is natural selection that removes harmful gene variants, constraining the genes and preventing their sequences from varying. Such a phenomenon typically occurs when the genes are involved in essential functions (like DNA replication) in an organism.

Taken together, these results imply that Mimiviral DNA replication machinery is ancient and evolved over a long period of time. This narrows us down to the reduction hypothesis, which suggests that the DNA replication machinery already existed in a unicellular ancestor, and the giant viruses were formed after getting rid of other structures in the ancestor, leaving only replication-related parts of the genome.

"Our findings are very exciting because they inform how life on earth has evolved," Dr. Kondabagil says. "Because these giant viruses probably predate the diversification of the unicellular ancestor into bacteria, archaea, and eukaryotes, they should have had major influence on the subsequent evolutionary trajectory of eukaryotes, which are their hosts."

In terms of applications beyond this contribution to basic scientific knowledge, Dr. Kondabagil feels that their work could lay the groundwork for translational research into technology like genetic engineering and nanotechnology. He says, "An increased understanding of the mechanisms by which viruses copy themselves and self-assemble means we could potentially modify these viruses to replicate genes we want or create nanobots based on how the viruses function. The possibilities are far-reaching!"

An international team of researchers at Great Ormond Street Hospital (GOSH), and University of California, Los Angeles (UCLA) have developed a gene therapy that successfully treated 48 out of 50 children with a form of severe combined immunodeficiency that leaves them without an immune system.

Severe combined immunodeficiency due to adenosine deaminase deficiency, also known as ADA-SCID, is a rare, life-threatening disease that prevents children from living a normal life. It is caused by mutations in the gene that creates the enzyme adenosine deaminase, which is essential to a functioning immune system.

Children with ADA-SCID have no immune system and, if left untreated, the condition can be fatal within the first two years of life. Day-to-day activities like going to school or playing with friends can lead to a dangerous infection. Recently, new-born screening for SCID has been implemented in some countries to help diagnose the condition early in life.

In a new study published in the New England Journal of Medicine, co-lead authors Professor Donald Kohn (UCLA) and Dr Claire Booth (GOSH) reported the two- to three-year outcomes of 50 children who were treated in clinical trials with an experimental stem cell gene therapy for ADA-SCID between 2012 and 2017.

The standard treatment for ADA-SCID involves once or twice weekly injections of the ADA enzyme until a matched bone marrow donor - usually a close family member - can be found. If a matched bone marrow donor is not available, patients require lifelong ADA injections along with preventative medicines. These treatments are expensive and therefore out of reach for patients in many countries.

If approved, gene therapy would be a welcome new treatment option for ADA-SCID as it is a one-time procedure that has the potential to provide life-long results.

Two to three years after the treatment, all of the 50 children treated with the new gene therapy at Great Ormond Street Hospital, UCLA Mattel Children's Hospital and the National Institutes of Health (NIH) are alive and well. Of these, 48 are no longer showing symptoms of ADA-SCID, although they will have lifelong monitoring. In the two cases in which treatment wasn't successful, both children were able to return to current standard treatments, with one eventually receiving a bone marrow transplant. No serious side effects have so far been reported, with generally mild or moderate complications experienced from the necessary preparation for the gene therapy.

One of the patients treated was four-year-old Sarah from South Yorkshire. She was less than ten days old when her mum Maria became concerned about her daughter's weight loss and sore, bleeding nappy rash that wouldn't heal. Tests revealed Sarah had ADA-SCID:

"I remember the exact time I saw the paper that had the blood test results on and the diagnosis. I saw it was SCID and I was incredibly upset... I wasn't allowed to kiss my daughter or sleep next to her. Everything had to be highly sterilised to keep her safe. It was horrible to not be able to do normal things with my own daughter."

Sarah was referred to GOSH for gene therapy and several years after her treatment is doing very well:

"Before, her nappy rash was always bleeding and sore, she was being sick and losing weight. Six months after she was given the gene therapy her skin was clean and healthy and the other symptoms got a lot better. She's doing so well now and can do everything a normal child her age would do."

Sarah's treatment has had a huge impact on the whole family, but it also inspired Maria to go back to studying and train to become a nurse.

"I now know how it feels to have your child as a patient and to be so sick, and I want to use my experience to help others in a similar position."

In earlier trials of gamma-retroviral gene therapy for other similar diseases, serious side effects including leukaemia have been seen in some patients. Now, lentiviral gene therapy technology has advanced significantly and offers the potential to improve the safety and efficacy profile of this treatment option for patients.

The gene therapy approach described in the paper involves first removing some of the patient's blood-forming stem cells, which create all types of blood and immune cells. Next, a viral vector is used to deliver a new copy of the ADA gene into the DNA of the patient's cells.

These corrected stem cells are then returned to the patient where, once engrafted, they go on to produce a seemingly continual supply of healthy immune cells capable of fighting infection.

Dr Claire Booth, co-lead author, Mahboubian Associate Professor in Gene Therapy and GOSH consultant in Paediatric Immunology and Gene Therapy: "If approved in the future, this treatment could be standard for ADA-SCID, and potentially many other genetic conditions, removing the need to find a matched-donor for bone marrow transplant and the toxic side effects often associated with that treatment. We need and want guidelines to change so we can start offering this potential cure to children and provide it as a first-choice treatment - this research could set those wheels in motion."

Prof Adrian Thrasher, Professor of Paediatric Immunology at GOSH and Wellcome Principal Research Fellow, said "We started gene therapy at GOSH around 20 years ago and now have refined the process to offer a potential cure for children born with this debilitating condition. Over 200 patients with various genetic conditions across the world have now been treated with this type of gene therapy - this is another very significant breakthrough."

Ten of the children in the study were treated at UCLA using a frozen preparation of corrected stem cells. These children experienced similar outcomes to the children treated with cells that were not frozen. This approach using frozen preparation may allow children to have their stem cells collected locally, have them transported and processed at a manufacturing facility elsewhere, and then shipped back to a local specialised hospital, possibly removing the need to travel long distances to specialist centres.

A trial of the cryopreserved treatment is now underway at the Zayed Centre for Research into Rare Diseases in Children in partnership with Great Ormond Street Hospital, London, UK. The investigational lentiviral vector treatment is licensed to Orchard Therapeutics. Professors Thrasher and Kohn serve on Orchard Therapeutics' scientific advisory board.

Positive results from this trial could support gene therapy to become a possible first-line treatment for this devastating disease.

Saw-toothed grain beetles live in a symbiotic association with bacteria. Their bacterial partners provide important building blocks for the formation of the insect's exoskeleton, which protects the beetles from their enemies as well as from desiccation. In a new study, a team of scientists from the Johannes Gutenberg University in Mainz, the Max Planck Institute for Chemical Ecology in Jena, and the National Institute of Advanced Industrial Science and Technology in Japan demonstrates that glyphosate inhibits the symbiotic bacteria of the grain beetle. Beetles exposed to the weedkiller no longer receive the building blocks they need from the bacteria. The study shows that glyphosate has the potential to harm insects indirectly by targeting their bacterial partners and thus to contribute to their decline (Communications Biology, doi: 10.1038/s42003-021-02057-6, May 2021).

Insects need microbial partners to survive

Organisms exist not in isolation but in an intricate network of ecological interactions. These interactions must be kept in mind when judging the impact of human activities. Insects in particular benefit in diverse ways from microbial symbionts, mostly via supplemented nutrients and chemical defenses. However, the benefits derived from such symbiotic associations may also make the insect more vulnerable. Insect hosts often become so reliant on their microbial partners that they can hardly survive alone. Without symbiosis, insects' development may be delayed or prevented, their susceptibility to natural enemies may be increased, their reproductive potential and competitiveness with conspecifics may be impaired, or they may die.

Glyphosate prevents symbiotic bacteria from providing the building blocks for the insect exoskeleton

Glyphosate is currently one of the most widely used pesticides in agriculture, despite increasing controversy about its potentially harmful side-effects. It is supposed to selectively suppress the growth of plants by inhibiting the biosynthesis of aromatic amino acids via the so-called shikimate pathway, a metabolic pathway occurring in plants and many microorganisms. Animals, on the other hand, do not encode the shikimate pathway, and thus are thought to be unharmed by glyphosate. However, many animals engage in mutualistic interactions with symbiotic microbes that rely on the shikimate pathway to produce amino acids required by these animals. "An impact of glyphosate on animals via their essential bacterial partners that use or even specialize in the shikimate metabolic pathway seems obvious, once the interaction of both partners is understood," explains Tobias Engl, one of the lead authors of the study. Glyphosate has already been shown to negatively affect microorganisms in the gut of honeybees, making the bees more susceptible to various stress factors. Furthermore, mutualistic bacteria across several herbivorous insect taxa provide a core benefit: the aromatic amino acid tyrosine needed for the biosynthesis of the insect exoskeleton (cuticle). This dependence on the symbiosis, in turn, may render insect herbivores particularly vulnerable to glyphosate in agriculture: The herbicide inhibits the shikimate pathway in their symbiotic bacteria and, as a result, important amino acids needed for cuticle formation are missing.

Is dependence on their symbiotic partners the Achilles heel of insects?

In the current study, the scientists show that glyphosate negatively influences the mutualistic bacteria harbored by the saw-toothed grain beetle Oryzaephilus surinamensis, an economically important pest of stored grain products. Exposure to the herbicide completely abolished the mutualistic benefit that symbiotic bacteria provide for the formation of the cuticle, an insect's primary protection against stresses, such as drought or predator attack.

The researchers sequenced the genome of the symbiont associated with O. surinamensis. The tiny symbiont genome (300 kbp) contains the genetic instruction for a metabolism specialized on the synthesis of aromatic amino acids via the shikimate pathway. Interestingly, the genome strongly resembles that of the bacterial partners of the palm weevil, which are also involved in cuticle formation, although these symbionts belong to a different group of bacteria.

"Finding a functionally equivalent symbiotic relationship that arose independently in two different bacteria phyla and distantly related beetle families highlights the importance of cuticle-supporting symbioses in beetles," says Julian Kiefer, the study's first author. The scientists tested the functional benefits for the host experimentally by supplementing the beetles' diet with aromatic amino acids, thus compensating for the elimination of their symbionts. Conversely, glyphosate exposure inhibited the establishment of the symbiotic bacteria throughout the beetle's development and abolished completely the mutualistic benefit for cuticle synthesis.

"When we observed the detrimental impact of glyphosate exposure on this symbiotic association, we wondered whether glyphosate poses a general threat to insects that depend on their microbial partners," explains Engl. By using phylogenetic analyses, the authors demonstrate that many obligate mutualistic bacteria associated with various different insect hosts indeed encode a glyphosate-sensitive enzyme in the shikimate pathway, suggesting that the susceptibility of its microbial symbionts to glyphosate represents an Achilles heel for an insect.

We are currently experiencing insect decline on a massive scale. Insect abundance is decreasing, as is insect diversity, not to mention the impact of the disappearance of bees, beetles and other insects at higher levels in the food chain. The new findings highlight the fact that the use of the herbicide glyphosate in agriculture endangers vital symbiotic relationships between insects and microorganisms and thus poses a serious threat to our ecosystems.

Inks containing metal nanoparticles are among the most commonly-used conductive materials for printed electronics. Ink-jetting layers of MNP materials allows for unpreceded design flexibility, rapid processing and 3D printing of functional electronic devices such as sensors, solar panels, LED displays, transistors and smart textiles.

Inkjet 3D printing of metals typically form a solid printed object via a two-step process: solvent evaporation upon printing (pinning) and subsequent low-temperature consolidation of nanoparticles (sintering). The low temperature is important as in many applications the nanoparticles are co-printed with other functional/structural organic materials that are sensitive to higher temperatures.

However, layers produced by inkjet printing of metal nanoparticles have different electrical conductivity between horizontal and vertical directions. This effect is known as functional anisotropy and is a long-standing problem for the 3D printing of functional electronic devices, preventing its use for advanced applications.

It was previously thought that reduced vertical conductivity through a printed device is mainly caused by shape and physical continuity problems at the interfaces of the constituent nanoparticles (at the very small micro and nanoscale). However, Nottingham researchers used silver nanoparticles to show, for the first time, that it is caused by organic chemical residues in the inks.

These residues, which are added to the inks to help stabilise the nanomaterials, lead to the formation of low-conducting, very thin nanoscale layers which interfere with the electrical conductivity of the printed sample in the vertical direction.

With a clearer understanding of the distribution of residual organic additives within printed layers, the researchers hope to go on to define new techniques and develop new ink formulations to overcome functional anisotropy of inkjet-based 3D printed electronics.

Lead author, CfAM Research Fellow Dr Gustavo Trindade, said, "The conductivity of inkjet-printed metal nanoparticles is known to be dependent on processing temperature and have been previously attributed to changes in the shape and porosity of clustered nanoparticles, with the role of organic residues being only speculated."

"This new insight enables the development of routes to overcome functional anisotropy in inkjet-based nanoparticles, and will therefore improve uptake of this potentially transformational technology, making it competitive with conventional manufacturing. Our approach is transferable to other nanomaterial-based inks including those containing graphene and functionalised nanocrystals, and will enable the development and exploitation of both 2D and 3D printed electronics like flexible and wearable sensors, solar panels, LED displays, transistors and smart textiles."

The study was carried out by the Centre for Additive Manufacturing (CfAM), under the £5.85m EPSRC-funded Programme Grant, Enabling Next Generation Additive Manufacturing. Their findings are published in a new paper 'Residual polymer stabiliser causes anisotropic electrical conductivity during inkjet printing of metal nanoparticles' in the Nature journal Communications Materials.

The researchers used the unique chemical sensitivity of a state-of-the-art 3D orbiSIMS instrument owned by the University of Nottingham. The Nottingham orbiSIMS - the only one at a UK university - allows label-free 3D chemical imaging of materials with very high resolution, revealing insights that have informed this study.

Researchers at the University of Bristol have discovered how microbes responsible for human African sleeping sickness produce sex cells.

In these single-celled parasites, known as trypanosomes, each reproductive cell splits off in turn from the parental germline cell, which is responsible for passing on genes. Conventional germline cells divide twice to produce all four sex cells - or gametes - simultaneously. In humans four sperms are produced from a single germline cell. So, these strange parasite cells are doing their own thing rather than sticking to the biology rulebook.

Trypanosome cell biology has already revealed several curious features. They have two unique intracellular structures - the kinetoplast, a network of circular DNA and the glycosome, a membrane-enclosed organelle that contains the glycolytic enzymes. They don't follow the central dogma that DNA is faithfully transcribed into RNA, but will go back and edit some of the RNA transcripts after they've been made.

Professor Wendy Gibson of the University of Bristol's School of Biological Sciences led the study. She said "We've got used to trypanosomes doing things their own way, but of course what we think of as normal cell biology is based on very few so-called model organisms like yeast and mice. There's a whole world of weird and wonderful single-celled organisms - protozoa - out there that we don't know much about! Trypanosomes have got more attention because they're such important pathogens - both of humans and their livestock."

Biologists think that sexual reproduction evolved very early on, after the first complex cells appeared a couple of billion years ago. The sex cells are produced by a special form of cell division called meiosis that reduces the number of chromosomes by half, so that gametes have only one complete set of chromosomes instead of two. The chromosome sets from two gametes combine during sexual reproduction, producing new combinations of genes in the offspring. In the case of disease-causing microbes like the trypanosome, sex can potentially lead to a lot of harmful genes being combined in one strain. Thus, research on sexual reproduction helps scientists understand how new strains of disease-causing microbes arise and how characteristics such as drug resistance get spread between different strains.

Every high-school physics student learns that sound and light travel at very different speeds. If the brain did not account for this difference, it would be much harder for us to tell where sounds came from, and how they are related to what we see.

Instead, the brain allows us to make better sense of our world by playing tricks, so that a visual and a sound created at the same time are perceived as synchronous, even though they reach the brain and are processed by neural circuits at different speeds.

One of the brain's tricks is temporal recalibration: altering our sense of time to synchronize our joint perception of sound and vision. A new study finds that recalibration depends on brain signals constantly adapting to our environment to sample, order and associate competing sensory inputs together.

Scientists at The Neuro (Montreal Neurological Institute-Hospital) of McGill university recruited volunteers to view short flashes of light paired with sounds with a variety of delays and asked them to report whether they thought both happened at the same time. The participants performed this task inside a magnetoencephalography (MEG) machine, which recorded and imaged their brain waves with millisecond precision. The audio-visual pairs of stimuli changed each time, with sounds and visual objects presented closer or farther apart in time, and with random orders of presentation.

The researchers found that the volunteers' perception of simultaneity between the audio and visual stimuli in a pair was strongly affected by the perceived simultaneity of the stimulus pair before it. For example, if presented with a sound followed by a visual milliseconds apart and perceived as asynchronous, one is much more likely to report the next audio-visual stimulus pair as synchronous, even when it's not. This form of active temporal recalibration is one of the tools used by the brain to avoid a distorted or disconnected perception of reality, and help establish causal relations between the images and sounds we perceive, despite different physical velocities and neural processing speeds.

The MEG signals revealed that this brain feat was enabled by a unique interaction between fast and slow brain waves in auditory and visual brain regions. Slower brain rhythms pace the temporal fluctuations of excitability in brain circuits. The higher the excitability, the easier an external input is registered and processed by receiving neural networks.

Based on this, the researchers propose a new model for understanding recalibration, whereby faster oscillations riding on top of slower fluctuations create discrete and ordered time slots to register the order of sensory inputs. For example, when an audio signal reaches the first available time slot in the auditory cortex and so does a visual input, the pair is perceived as simultaneous. For this to happen, the brain needs to position the visual time slots a bit later than the auditory ones to account for the slower physiological transduction of visual signals. The researchers found that this relative delay between neural auditory and visual time slots is a dynamic process that constantly adapts to each participant's recent exposure to audiovisual perception.

Their data confirmed the new dynamic integration model by showing how these subtle tens-of-millisecond delays of fast brain oscillations can be measured in every individual and explain their respective judgments of perceived simultaneity.

In autism and speech disorders, the processing of the senses, especially hearing, is altered. In schizophrenia as well, patients can be affected by perceived distortions of sensory inputs. The neurophysiological mechanisms of temporal recalibration described in this study may be altered in these disorders, and their discovery may reveal new research goals to improve these deficits.

"Overall, this study emphasizes that our brains constantly absorb and adapt to the bombardment of sensory information from diverse sources," says Sylvain Baillet, a researcher at The Neuro and the study's senior author. "To make sense of our complex environments, including social interactions, brain circuits actively make adjustments of subtle physiological mechanisms to better anticipate and predict the nature and timing of external stimulations. That helps us build a resilient and adaptive mental map of their representation."

Like many around the world, the lab of Professor Mriganka Sur in The Picower Institute for Learning and Memory at MIT has embraced the young technology of cerebral organoids, or "minibrains," for studying human brain development in health and disease. By making a surprising finding about a common practice in the process of growing the complex tissue cultures, the lab has produced both new guidance that can make the technology better, and also new insight into the important roles a prevalent enzyme takes in natural brain development.

To make organoids, scientists take skin cells from a donor, induce them to become stem cells and then culture those in a bioreactor, guiding their development with the addition of growth factors and other chemicals. Over the course of weeks, the stem cells become progenitor cells that multiply and then go on to become, or "differentiate" into, neurons or other brain cell types. Along the way the cells also migrate within the growing blob to take their places forming basic brain structures and circuits.

A beauty of organoids, therefore, is that as the cells in the culture grow and develop together, they simulate many of the basic processes that occur when real brains take shape. When cell donors have genes that cause disease, the organoid grown from their cells will reproduce underlying disease characteristics. The Sur lab uses organoids to study the abnormal brain development in Rett Syndrome, a devastating autism-like condition with a genetic underpinning.

A common practice among labs growing organoids is to improve the viability of the cells by adding a small molecule chemical called CHIR 99021 to inhibit the activity of a ubiquitous natural enzyme called GSK3-beta. In the new study in PLOS ONE the team led by Picower Fellow Chloé Delépine, confirmed that while different doses of CHIR 99021 can indeed keep cells alive, they have opposite effects on organoid growth - low doses promote growth but high doses constrain it and very high doses will stop it altogether. That information alone has obvious implications for labs using varying doses of CHIR 99021, but because Delépine's team investigated how these growth effects occur, it also helps to clarify what GSK3-beta activity affects during brain development.

It's an important question. Other research groups, for instance, have shown that perturbations in a signaling pathway involving GSK3-beta in the brain are associated with schizophrenia and autism. The new findings model how varying levels of inhibition may affect development.

"It's is not just increasing the viability of the cells, it is also changing other cellular processes such as division, differentiation and migration," Delépine said. "Our idea was to test the effects of different doses and to better understand these mechanisms we observed."

Eight organoids are shown in three columns. They appear as irregularly shaped white blobs. A scale marker suggests they are about 3mm in width.

Organoids showed different degrees of growth based on the dose of CHIR 99021. Controls are on the left. The ones in the middle received a low dose. The ones on the right received a high dose.

Different doses, opposite effects

To conduct the study, Delépine's team cultured organoids and, from day 15 through 35 of their development, treated them with doses of either an inert control, or 1, 10 or 50 micromolar of CHIR 99021. They then tracked various properties of cells by staining for different molecular markers of those properties.

Straight away, she noticed major differences in organoid size depending on the dose received. Low dose (1 micromolar) organoids were 1.6 times bigger than controls, but high dose (10 micromolar) organoids were 1.8 times smaller and very high dose (50 micromolar) organoids simply stopped growing at all early into treatment.

The growth differences were not because of cell death. As expected given that labs use CHIR 99021 to improve cell survival, adding CHIR 99021 enhanced cell viability and the effect was stronger for high dose than low dose treatments. But when the lab stained for markers of proliferation, or cell division, they found that high-dose organoids exhibited less while low-dose organoids exhibited more than controls.

When the team looked at another cellular activity that could affect growth they found a similar pattern. In high-dose organoids fewer cells differentiated into neural progenitor cells needed to produce new neurons while in low-dose organoids proliferation increased. As a result, high-dose organoids had fewer neurons.

Additionally, the low dose of CHIR 99021 resulted in more migration of newborn neurons to places needed for structural development of the organoid than control treatment did, suggesting that slight inhibition of GSK3 beta contributes to increased migration.

Delépine noted that the growth-promoting effects of low doses or the growth-limiting effects of high doses are not "good" or "bad." They are just levels of control of the culture. The new study provides more insight into how to use CHIR 99021 to achieve the desired end.

"It really depends on the goal of the organoid research that you are doing," she said. "Depending on what you want, different doses of this molecule can help you achieve a different phenotype."

And in natural brains, the study suggests, GSK3-beta likely plays a key role in the proliferation of progenitor cells, their differentiation into mature brain cells, and the propensity of those cells to migrate.

In addition to Delépine and Sur, the paper's other authors are Vincent Pham and Hayley Tsang.

The National Institutes of Health, The Simons Foundation Autism Research Initiative and the JPB Foundation supported the research.

Duluth, Minnesota - A new paper in the May issue of Nature Communications demonstrates why keeping local lakes and other waterbodies clean produces cost-effective benefits locally and globally.

A single season of a lake or water body with a harmful algal bloom that results in public do-not-drink orders, damages to fishing activity, lost recreational opportunities, decreased property values and increased likelihood of low birth weight among infants born to mothers exposed to polluted water bodies are but just a handful of reasons why clean water is important.

Most everyone wants their local lake or stream to be clean and useable for drinking, fishing, swimming and recreation. But previous cost-benefit studies showed the costs of protecting local water sources often exceeded the benefits.

Not so fast say the authors. One of the reasons past studies showed costs exceeding benefits is that not all benefits, especially global ones, were analyzed by economists.

New research, led by University of Minnesota Sea Grant Director John A. Downing, found that adding up global financial benefits of clean water shows that keeping water clean can help slow climate change, saving trillions of dollars. Using one Lake Erie case study as an example, the authors also found that the global climate change value of protecting and preventing this Great Lake from algae blooms was ten times greater than the value of beach use or sport fishing.

"Surface water is one of the Earth's most important resources," said Downing, who is also a lake scientist at the University of Minnesota Duluth Large Lake Observatory. "Yet people have mistakenly assumed that it costs more to protect our water than it is worth. Our research demonstrates that there is significant local and global value to protecting local water quality."

One reason for this, said the authors, is that scientists and economists have previously considered only a narrow range of local benefits when calculating the outcomes of good water quality. Downing and co-authors sought to calculate the potential global benefits.

Locally, cleaning or keeping a local lake or waterbody free of unwanted nutrients- what scientists call eutrophication - is obviously good for people who use or want to access that particular water body. Globally, it's also good for reducing the amount of the greenhouse gas methane that is released into the atmosphere from that eutrophic water body.

Methane is a stronger greenhouse gas than carbon dioxide because it has a much higher heat-trapping ability and has about 21 times the global warming potential of carbon dioxide. Less methane in the atmosphere can help slow global warming.

The authors sought to answer the question: is keeping a local water body clean worth the cost?

The cost of climate change comes from health-care costs, damages to urban infrastructure, agricultural damages, catastrophic storm damage, negative impacts on recreation, forestry, fisheries, energy systems, water systems, construction, and coastal infrastructure. 

"We calculated the global climate damages from methane emissions from eutrophic lakes and calculated the damages that would be avoided damages by preventing increased emissions from 2015 to 2050," said Downing. "If we could hold methane emissions at current levels rather than the expected 20-100% increase by 2050, the value of avoiding the resulting damages could be as much as $24 trillion." The authors estimated the costs of global climate change due to eutrophication from 2015 to 2050 to be as much as $81 trillion.

The authors' analysis shows that local water quality protection has global economic implications. The substantial emissions they document from lakes and reservoirs and the potential for increased emissions suggest that there is considerable value to be gained by improving water quality in lakes and reservoirs and in preventing further deterioration.

"It's not possible to avoid all emissions from lakes and reservoirs, but with concerted effort it may be possible to prevent increased emissions or even reverse it," said Downing.

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

Majority of COVID-19 patients receiving home-based hospital care did not require care escalation to traditional hospital setting
Free full text: https://www.acpjournals.org/doi/10.7326/M21-0409

A retrospective, single-center study found that the majority of COVID-19 patients receiving home-based hospital care did not require care escalation to a traditional hospital setting, even if the patients were older or obese. The findings are published in Annals of Internal Medicine.

The COVID-19 pandemic has challenged health care systems to rapidly transform care to address resource demands. Early in the pandemic, a large integrated health system implemented a hospital-at-home program to deliver home-based, hospital-level care to patients with COVID-19 and increase the health system's bed capacity.

Researchers from Atrium Health studied 391 adults 18 or older who met evidence-informed inclusion criteria and received treatment for COVID-19 in their program between March and November 2020 to determine which hospital-at-home patients were at increased risk for care escalation to traditional brick-and-mortar facilities. The researchers found that most patients did not require care escalation, with approximately 1 in 5 admitted within 14 days. More severe respiratory involvement was observed among transferred patients, particularly those requiring immediate care escalation. In addition, overall comorbidity burden was associated with transfer. The researchers expressed surprise that they did not observe independent associations between older age or obesity and transfer and speculate that this could be due to physician hesitation to enroll such patients with additional risk factors into the program.

According to the authors, this study is important because it provides practical initial evidence to help inform patient selection guidelines for hospital-at-home care as it becomes a standard care delivery option.

One of the most basic structural aspects of relativistic spacetime is the description of how time and distances are altered by motion. The theory of special relativity describes a spacetime framework for linear constant motion in which time dilates and lengths contract in response to motion. This framework is described by the Lorentz transformation, which encompasses mathematical formulas that describe how time and distance are altered between moving reference frames. The Lorentz transformation also describes how a stationary observer views time in the moving frame to be offset with distance. The offsetting of time with distance between reference frames generates differential simultaneity, in which events that are simultaneous for one observer will not be simultaneous for a second observer moving relative to the first observer.

The nature of spacetime in rotating frames has not been established at the most fundamental level of defining the transformation that accurately describes the relativistic effects and the simultaneity framework. There are four distinct rotational relativistic transformations in the literature: the Langevin metric; Post transformation; Franklin transformation; and the absolute Lorentz transformation (ALT) in its rotational form. Determining which transformation accurately describes experimental data would indicate the spacetime framework that is present in real-world rotating frames. Understanding this fundamental information has wide applicability because the majority of visible matter in the Universe is in rotational motion, including the rotating Earth.

The most widely-cited rotational transformation is the Langevin metric, which was first described in 1921. Over the decades, the Langevin metric has been used to describe relativity in rotating frames in hundreds of textbooks and research papers. However, the Langevin metric has never been assessed with experimental data that has sufficient resolution to distinguish it from the other major rotational transformations.

A transformation's combination of relativistic effects and simultaneity framework affects how light propagates. The four transformations have different predictions for the rotating-frame one-way speeds of light, two-way speed of light, and the Sagnac effect. This study derives the optical predictions for each transformation directly from their transformation equations, with several of the predictions not previously reported in the literature. The predictions are then compared to recent high-resolution optical experimental data.

Optical resonator data on the two-way speed of light is among the highest resolution scientific measurements, with resolutions of 10-18. This high resolution is required to distinguish between the predictions of the transformations. The study reveals that ALT and the Franklin transformation prediction of the constant two-way speed of light, c, matches the optical resonator data, while the Langevin metric and Post transformation predictions are invalidated by the data. The failure of the Langevin metric and Post transformation to match optical resonator data is shown to be due to their exhibiting no (or no net) length contraction in the rotating frame. In contrast, the ALT and Franklin transformations exhibit length contraction, which allows their accurate predictions for the two-way speed of light.

Data on the Sagnac effect, which has lower resolutions of 10-8, is compatible with the Sagnac effect predictions of the Langevin metric, Post, and ALT transformations, but is incompatible with the Franklin transformation, which predicts no Sagnac effect. The failure of the Franklin transformation to generate an overt Sagnac effect is shown to be due to its incorporation of differential simultaneity. In contrast, the other three transformations incorporate absolute simultaneity in which time is not offset with distance, which allows overt Sagnac effects. Thus, ALT is the only transformation that accurately describes the full range of relativistic optical data.

Multiple publications have proposed mechanisms to incorporate differential simultaneity into rotating frames to allow the generation of an overt Sagnac effect. However, these mechanisms generate alternate Sagnac effect equations. The study shows that these alternate Sagnac effect equations imply two-way speeds of light that are invalidated by the high-resolution optical resonator data. In contrast, ALT predicts the conventional Sagnac effect, which implies the constant two-way speed of light, c.

The study demonstrates that the ALT rotational transformation accurately predicts both high-resolution optical data and non-optical rotating-frame relativistic observations. This analysis implies that the ALT rotational transformation describes the basic framework of spacetime in rotating frames. This clarifies that rotating-frame spacetime is characterized by the relativistic effects of time dilation and length contraction within an absolute simultaneity framework in which time is not offset with distance.

A new study from the University of Portsmouth calls for further government oversight to curb potential illegal activity through these zones.

This study demonstrates the attractive trading advantages offered by freeports to enable enterprise and innovation. Eight new freeports in England are due to enter operation in late 2021, which are hoped to drive investment, economic opportunities and growth to those regions.

However, researchers also advise that stronger regulation is needed to prevent Freeports being abused for money-laundering and tax-evasion purposes. The study, published today in the Journal of Money Laundering Control, raises justifiable concerns over the misuse of Freeports.

In early 2020, and with Brexit looming on the horizon, the UK government published a consultation into proposals to create Freeports across the country. The idea was to stimulate the economy following the departure from the EU.

Report lead author Paul Gilmour, from the University's Institute of Criminal Justice Studies, explains the role of freeports. He says: "In their basic form they are warehouses located within free-trade zones that lie within a country's geographical border but are designated by that country's government to be outside its normal customs regime.

"The companies based within these zones enjoy several concessions, such as cheaper import duties, suspended custom obligations, and reduced bureaucratic checks intended to streamline cross-border trade. They effectively act as offshore jurisdictions that offer attractive trading advantages which enable enterprise and innovation."

The research examined existing freeports around the world and found they are often used as tactical depots: intended as spaces to temporarily house valuable assets, such as artwork, precious metals and gems, wine collections and antiques.

Researchers say that many art dealers now commonly exploit the beneficial goods-in-transit position of freeports, to house assets on a more permanent basis. This means, as long as the dealers' goods remain within the freeports storage facility, those dealers are unaccountable for any duties (such as value-added taxes [VAT] or capital gains taxes) which would normally be applied upon export.

Gilmour explains: "The growth in freeports may have originally evolved from a desire to stimulate global investment by deregulating financial markets. However, there is an argument that permanent storage spaces within freeports only act to stifle capital mobility. Nonetheless, freeports do seem to provide innovative trading advantages to enable businesses to thrive in today's competitive global market."

The study warns that freeports can be abused for money-laundering and tax-evasion purposes because of a lack of transparency. It says they can help to obscure the true beneficial owners of assets through secretive corporate practices that thwart efforts by authorities to trace illicit profits and recoup government taxes.

"There is also evidence that these zones enable trade-based money laundering by the falsifying of trade invoices to deceive authorities," says Gilmour. "The many international transactions occurring through freeports, coupled with a lack of regulatory supervision, poses notable challenges for government officials."

The study suggests that banks that facilitate numerous international trade transactions need to be more alert to illicit trading and should be responsible for carrying out proper due diligence around freeport trade. It says that although governments have recognised the threat that freeports present by ensuring they fall within the scope of anti-money laundering control, there is still opportunity for freeports to operate without transparency.

In recent decades, Spain has undergone rapid social changes in terms of gender equality, despite, as a result of the Franco dictatorship, starting from a more backward position than most European countries. This process is hampered by the economic downturn that began in 2008, underlining the importance of the economic context in the development of gender inequality levels. Little attention has been paid in academia to how this gender revolution is associated with factors related to individual wellbeing.

A study by Jordi Gumà, a researcher at the Department of Political and Social Sciences and member of the UPF Sociodemography Research Group (DEMOSOC), together with Bruno Arpino, a researcher at the University of Florence (Italy), explores the association between the subjective level of satisfaction with life and the degree of relative participation by women and men in terms of providing financial resources to the household and performing domestic chores among the partnered adult Spanish population.

"When no financial difficulties are reported, it seems that gender behaviour in the home environment has less influence on individuals' levels of life satisfaction, whether men or women, than in homes with financial problems".

Following their research, published in Revista Internacional de Sociología, the researchers (who separate the analysis of the public and the private spheres to capture the effects differentially) conclude that the level of satisfaction with life is marked largely by household financial capacity: "When no financial difficulties are reported, it seems that gender behaviour in the home environment has less influence on individuals' levels of life satisfaction, whether men or women, than in homes with financial problems", the researchers assert.

Furthermore, the results reveal that there would be a situation of tension between the social context and inherited values (with an imbalance between gender values, far more egalitarian, and the end practices observed) would affect the levels of individual wellbeing.

The research methodology analyses Spanish samples from the European Social Survey (ESS) of 2004 and 2010 together, in which questions about family, work and wellbeing were introduced. The various analyses have been carried out independently according to sex, in order to identify possible differences between men and women. The sample was restricted to partnered individuals, within the 25-59 years age bracket.

The researchers state that the relative contribution to household income and the performance of household chores "has a significant effect on life satisfaction in the specific case of people with financial difficulties". This effect shows that the gender profile in households that report having financial difficulties is far closer to the traditional one. However, significant differences were found between men and women.

The overall situation of the household determines women's satisfaction

With regard to women, the researchers found that "their satisfaction with life is defined mainly by the overall situation of the household, beyond their own situation in terms of their relative contribution to income and relative time spent on household tasks". That is, it is their position within the private sphere that has the greatest impact on the values of life satisfaction in respect of women in Spain.

The position of women within the private sphere has the greatest impact on the values of life satisfaction in respect of women in Spain.

Among women who report not having financial difficulties (reaching the end of the month adequately or comfortably), the authors observe a positive relationship between their levels of satisfaction and time spent on household tasks: the greater their dedication, the higher their level of satisfaction. This pattern is exactly the opposite in the case of women who report having financial difficulties, whereby the greater their dedication to household tasks, the lower their satisfaction.

According to the researchers, one possible explanation is that more solvent households would be more able to hire paid services to perform household chores, so that although these women spend more time on household tasks than their partners, the actual number of hours allocated may be less than those who report having financial difficulties, and neither does this mean that there is parity with men. In fact, if we look at the average number of hours spent on such tasks, the figure is significantly lower among women with greater economic power.

Men's satisfaction with life is marked by their individual situation

In the case of men, the authors found significant differences in the level of satisfaction with regard to their relative contribution to the family budget. In the context of households with financial difficulties, men who report contributing more to total family income display higher levels of satisfaction than those who report contributing less than their partners.

According to the researchers, "being the main provider of material resources to the household is associated with values of satisfaction in the group of men in households with financial difficulties, while among men who report not having financial difficulties, being the main contributor does not seem to give them an extra boost to their levels of satisfaction".

In the context of households with financial difficulties, men who report contributing more to total family income display higher levels of satisfaction than those who report contributing less than their partners.

The same applies in the case of participation in household tasks, where significant differences were only observed, again, in men with financial difficulties, who reveal that devoting less time than their partners to household tasks is a situation associated with higher levels of satisfaction.

In consequence, according to the researchers, unlike the case of women, Spanish men's life satisfaction is determined to a greater extent by their individual situation, beyond the characteristics of the household as a whole. This suggests that, in this particular group of men, their position within the public sphere continues to set their perception of satisfaction with life.

It was commonly assumed that wildlife products are exported from low-income countries to meet the demand of consumers in wealthy economies, and therefore, a widening wealth gap may drive up the volume of global trade and endanger wildlife.

Recently, a research team co-led by Research Division for Ecology and Biodiversity (E&B), Faculty of Science, the University of Hong Kong (HKU) and the Science Unit (SU) of Lingnan University (LU) corroborated this premise by analysing global wildlife trade databases. The research team includes Dr Jia Huan LIEW, Research Assistant Professor of SU, and Emeritus Professor David DUDGEON from E&B, HKU. Their findings are published in Science Advances.

Wealthier countries take the vast part of the responsibility

A major take-home message of the study was that wealthy countries are responsible for most of the world's wildlife trade. The top three importers of wild animals were the United States, France, and Italy, while in Asia, wealthier nations including China, Singapore, and Japan were all net importers of wildlife products. On the supply-end of the trade, countries with better logistics capabilities (e.g., Indonesia) also exported more wildlife products.

Hong Kong has long been a global hub of the legal wildlife trade, importing approximately 13 million individual animals between 1998 and 2018. In particular, the city was a major destination for fishes, sharks, and rays.

The researchers looked at 20 years of legal wildlife trade data, ranging from live corals for hobbyist, to wild-caught sturgeons for aquaculture, and seahorses for traditional remedies. During this period, an estimated 421 million individual animals were traded globally, and the market was more extensive when there was greater wealth inequality between countries.

The study's findings may have important implications in a post-pandemic world, where issues surrounding the wildlife trade is once again in the spotlight. The COVID-19 virus is believed to have spread to humans via the wildlife trade, leading notably, to a ban on the consumption of wild terrestrial animals in China. While increased regulation may suppress trade in the short term, the pandemic's impact on the global economy will likely exacerbate wealth inequality between nations by disproportionately impacting some parts of the world. This, according to research findings that show a positive correlation between wealth inequality and the extent of the global wildlife market, could encourage more international trade in wildlife products.

There were marked inequalities between exporters and importers of wildlife products, and importers were generally better off in all measures of socioeconomic well-being. For example, the largest trade partnership the study recorded was between the USA (importer) and Indonesia (exporter), where the per capita GDP of the US was 20 times that of Indonesia. Other prominent trade flows include exports from Jamaica to France (importer per capita GDP 8 times higher) and exports from Indonesia to Singapore (importer per capita GDP 17 times higher).

Urge for reduction of demands for animal products

Inequalities in the wildlife market and the dominant role of wealthy countries highlights the importance of efforts to reduce the demand for wildlife products via awareness campaigns or product substitution, among others. "One message is that it is evidently demand from richer countries that is fueling the capture and trade of wildlife from poor/low-income countries. That means that it is the responsibility of affluent consumers in rich countries to do something to limit their demands and greed for animal products," says Emeritus Professor Dudgeon.

This may also be a more socially equitable approach than blanket bans on wildlife harvesting that could impact vulnerable communities reliant on the trade. "Globally, we need to manage the trade in wildlife in a way which does not endanger their populations and the communities that rely on it for a source of protein or important source of livelihood," says Dr Janice LEE, Assistant Professor at the Asian School of the Environment.

YouTube channels run by zoos focus on entertainment over education, according to a new study.

The videos also focus disproportionately on mammals, rather than reflecting the diversity of zoos' animals.

Conservation was the focus of just 3% of zoo videos in the study - but it found that conservation content in videos is gradually increasing.

The study evaluated the most recent and most-viewed videos, so the findings partly reflect the public's preference for certain species and content.

Of the animals that appeared in zoos' most-viewed videos, the top nine were mammals - with giant pandas top of the list - and the only non-mammals were penguins in tenth place.

"They key question is: what are zoos using YouTube for?" said Dr Paul Rose, of the University of Exeter.

"If the aim is to get people to visit the zoo, then a focus on entertainment and popular species might make sense.

"This way, education about wildlife and conservation can be done once people get to the zoo, where they will spend much more time than they would watching a YouTube video.

"However, some zoos have large YouTube audiences, so they should carefully consider how they represent different classes of animal, and how they can create educational material in interesting and accessible forms.

"If an animal is in a zoo's collection, there should be a way for it to be promoted."

Dr Rose said he was encouraged to see an increased focus on conservation in zoo videos.

For example, videos about animals of conservation concern on the IUCN Red List have featured more often in recent years.

Lead author Thomas Llewellyn, a graduate from UWE's Science Communication Unit, said: "It is important that zoos produce a variety of conservation-focused content for a range of different animals.

"Whilst it is reassuring to see YouTube channels upload more conservation-focused videos in recent times, this research is especially important to the conservation projects associated with those 'favoured animals'.

"There is no doubt that YouTube has the potential to become an effective and efficient tool for global conservation education, but more research is needed to be done."

The study's information was gathered before the COVID pandemic, and the content posted on many zoo YouTube channels has changed dramatically since then.

"I've seen a lot more zoos doing live videos during lockdown to explain the significance of their animal collections," Dr Rose said.

"With zoo admissions essentially being non-existent this year, the pandemic has only emphasised the importance of social media for this type of online outreach", added Llewellyn.

The researchers evaluated the content of 1,000 videos from 20 zoological organisations (50 most-viewed videos from each channel) from 2006 to 2019. More than 75% of these videos focussed on mammals.

Separately, educational content in a subsample of 300 of the most viewed and most recent videos from three zoo YouTube channels was catalogued and evaluated for the period 2016 to 2019.