Culture

An international collaboration between researchers at Queen Mary University of London and the Chinese Academy of Science in Nanjing has led to the discovery of world's oldest animal sperm inside a tiny crustacean trapped in amber around 100 million years ago in Myanmar.

The research team, led by Dr He Wang of the Chinese Academy of Science in Nanjing, found the sperm in a new species of crustacean they named Myanmarcypris hui. They predict that the animals had sex just before their entrapment in the piece of amber (tree resin), which formed in the Cretaceous period.

Fossilised sperm are exceptionally rare; previously the oldest known examples were only 17 million years old. Myanmarcypris hui is an ostracod, a kind of crustacean that has existed for 500 million years and lives in all kinds of aquatic environments from deep oceans to lakes and rivers. Their fossil shells are common and abundant but finding specimens preserved in ancient amber with their appendages and internal organs intact provides a rare and exciting opportunity to learn more about their evolution.

Professor Dave Horne, Professor of Micropalaeontology at Queen Mary University of London said: "Analyses of fossil ostracod shells are hugely informative about past environments and climates, as well as shedding light on evolutionary puzzles, but exceptional occurrences of fossilised soft parts like this result in remarkable advances in our understanding."

During the Cretaceous period in what is now Myanmar, the ostracods were probably living in a coastal lagoon fringed by trees where they became trapped in a blob of tree resin. The Kachin amber of Myanmar has previously yielded outstanding finds including frogs, snakes and a feathered dinosaur tail. Bo Wang, also of the Chinese Academy of Science in Nanjing added: "Hundreds of new species have been described in the past five years, and many of them have made evolutionary biologists re-consider long-standing hypotheses on how certain lineages developed and how ecological relationships evolved."

The study, published in Royal Society Proceedings B, also has implications for understanding the evolutionary history of an unusual mode of sexual reproduction involving "giant sperm".

The new ostracod finds may be extremely small but in one sense they are giants. Males of most animals (including humans) typically produce tens of millions of really small sperm in very large quantities, but there are exceptions. Some tiny fruit flies (insects) and ostracods (crustaceans) are famous for investing in quality rather than quantity: relatively small numbers of "giant" sperm that are many times longer than the animal itself, a by-product of evolutionary competition for reproductive success. The new discovery is not only by far the oldest example of fossil sperm ever found but also shows that these ostracods had already evolved giant sperm, and specially-adapted organs to transfer them from male to female, 100 million years ago.

Each ostracod is less than a millimetre long. Using X-ray microscopy the team made computer-aided 3-D reconstructions of the ostracods embedded in the amber, revealing incredible detail. "The results were amazing - not only did we find their tiny appendages to be preserved inside their shells, we could also see their reproductive organs," added He Wang. "But when we identified the sperm inside the female, and knowing the age of the amber, it was one of those special Eureka-moments in a researcher's life".

Wang's team found adult males and females but it was a female specimen that contained the sperm, indicating that it must have had sex shortly before becoming trapped in the amber. The reconstructions also revealed the distinctive muscular sperm pumps and penises (two of each) that male ostracods use to inseminate the females, who store them in bag-like receptacles until eggs are ready to be fertilised.

Such extensive adaptation raises the question of whether reproduction with giant sperms can be an evolutionarily-stable character. "To show that using giant sperms in reproduction is not an extinction-doomed extravagance of evolution, but a serious long-term advantage for the survival of a species, we need to know when they first appeared" says co-author Dr Renate Matzke-Karasz of Ludwig-Maximilians-University in Munich.

This new evidence of the persistence of reproduction with giant sperm for a hundred million years shows it to be a highly successful reproductive strategy that evolved only once in this group - quite impressive for a trait that demands such a substantial investment from both males and females, especially when you consider that many ostracods can reproduce asexually, without needing males at all. "Sexual reproduction with giant sperm must be very advantageous" says Matzke-Karasz.

Tortoises are born with a natural preference for faces, according to new research from scientists at Queen Mary University of London, the University of Trento and the Fondazione Museo Civico Rovereto.

The study provides the first evidence of the tendency for solitary animals to approach face-like shapes at the beginning of life, a preference only previously observed in social species such as human babies, chicks and monkeys.

The researchers tested the reactions of hatchlings from five different species of tortoise to different patterned stimuli, made up of a series of blobs. They found that the tortoises consistently moved to areas with the 'face-like' configuration - containing three blobs arranged in an upside-down triangle shape.

The findings suggest that this early behaviour likely evolved in the common ancestors of mammals, reptiles and birds more than 300 million years ago.

Dr Elisabetta Versace, lead author of the study from Queen Mary University of London, said: "Researchers have previously observed this spontaneous attraction to faces in social animals such as humans, monkeys and chicks. Because all these species require parental care, it was thought this early adaptation was important for helping young animals respond to their parents or other members of the same species. However, now we have shown that this behaviour is also found in solitary tortoise hatchlings, suggesting it may have evolved for another reason."

Tortoises were hatched and kept away from any animal or human faces from birth until the start of the test. Each animal was then placed in the middle of a rectangular space divided into four areas containing either a face-like or control stimuli. The researchers analysed the preference of hatchlings for face-like stimuli by recording the first area the animal entered during the experimental period.

Unlike birds and mammals, tortoises are solitary species - they have no post-hatching parental care and do not form social groups as adults. Previous research has even shown that tortoise hatchlings ignore or avoid members of the same species in early life.

Silvia Damini from the University of Trento, said: "It is possible that this preference for face-like stimuli enhances learning from living animals in both social and solitary species from the early stages of life. In fact, other animals can provide information on important environmental factors, such as the availability of resources".

Gionata Stancher, Head of the Tortoise Sanctuary Sperimentarea (Fondazione Museo Civico Rovereto, Italy) where the experiments were conducted, said: "Being able to recognise and respond to cues associated with other living animals could help young animals acquire information vital for their survival."

Artificial intelligence researchers at North Carolina State University have improved the performance of deep neural networks by combining feature normalization and feature attention modules into a single module that they call attentive normalization (AN). The hybrid module improves the accuracy of the system significantly, while using negligible extra computational power.

"Feature normalization is a crucial element of training deep neural networks, and feature attention is equally important for helping networks highlight which features learned from raw data are most important for accomplishing a given task," says Tianfu Wu, corresponding author of a paper on the work and an assistant professor of electrical and computer engineering at NC State. "But they have mostly been treated separately. We found that combining them made them more efficient and effective."

To test their AN module, the researchers plugged it into four of the most widely used neural network architectures: ResNets, DenseNets, MobileNetsV2 and AOGNets. They then tested the networks against two industry standard benchmarks: the ImageNet-1000 classification benchmark and the MS-COCO 2017 object detection and instance segmentation benchmark.

"We found that AN improved performance for all four architectures on both benchmarks," Wu says. "For example, top-1 accuracy in the ImageNet-1000 improved by between 0.5% and 2.7%. And Average Precision (AP) accuracy increased by up to 1.8% for bounding box and 2.2% for semantic mask in MS-COCO.

"Another advantage of AN is that it facilitates better transfer learning between different domains," Wu says. "For example, from image classification in ImageNet to object detection and semantic segmentation in MS-COCO. This is illustrated by the performance improvement in the MS-COCO benchmark, which was obtained by fine-tuning ImageNet-pretrained deep neural networks in MS-COCO, a common workflow in state-of-the-art computer vision.

"We have released the source code and hope our AN will lead to better integrative design of deep neural networks."

In the first research of its kind, a new University of California, Davis, study suggests that for the most part, people formulate goals consistent with their personality traits -- and an individual's goals are related to how their personality subsequently changes over time.

The study surveyed more than 500 students when they started college, each year during college, and 20 years later on their goals related to being creative, having a successful career, having a family, being wealthy, or being active in religion or politics. The goals of these UC Berkeley students -- about half were still responding after two decades -- remained relatively stable over time, though there were some notable changes.

"This study was a unique opportunity to examine how individuals' personalities and major life goals were related to each other across two decades of life," said Olivia E. Atherton, the lead author of the study and former doctoral student in psychology at UC Davis. "We found that, in many ways, one's personality shapes the types of life goals that are valued, and as a result of pursuing those goals, personality changes."

Successful people stress goals

Various enormously successful people, such as Albert Einstein, have noted the importance of goals, researchers said. Einstein once said, for example: "If you want to live a happy life, tie it to a goal, not to people or things." The personality characteristics he possessed were likely the driving force behind the types of goals he aimed to achieve, researchers said.

"Einstein's tendency to be creative, curious, and intellectual likely fueled his scientific goals, as well as his more aesthetic goals, such as his passion for playing the violin," the study authors wrote.

The study, "Stability and Change in Personality Traits and Major Life Goals from College to Midlife," was published in late August in the Personality and Social Psychology Bulletin.

Besides Atherton, co-authors include Richard Robins, a professor of psychology who is director of the UC Davis Personality, Self and Emotion Lab; as well as Emily Grijalva, University of Buffalo; and Brent W. Roberts, University of Illinois, Urbana-Champaign.

The personality traits examined in the present study are termed the "Big Five" in psychology. They are neuroticism, extraversion, openness to experience, agreeableness and conscientiousness. These five traits broadly capture most of the ways in which people differ from one another, and they are related to a wide range of important life outcomes.

Researchers examined these traits, along with aesthetic goals (wanting to be creative and artistic); economic goals (wanting to have a successful career and be wealthy); family/relationship goals (wanting to be married and have children); hedonistic goals (wanting to have fun and experience pleasure); political goals (wanting to have influence in public affairs); religious goals (wanting to participate in religious institutions); and social goals (wanting to help others in need).

"... We found that, on average, individuals increased in agreeableness and conscientiousness, decreased in neuroticism, and showed little change in openness to experience and extraversion from age 18 to 40," researchers said.

Some goals become less relevant

They also found that people place less importance on all goals over time, suggesting that individuals winnow the goals they value with age, presumably because they are achieving milestones associated with those goals and thus, the goals become less important as a result.

"By identifying their own personal strengths and limitations, middle-aged adults may place less importance on certain major life goals because some goals may no longer be viewed as self-relevant," researchers said.

The authors did find that personality traits are related to major life goal development over time. For example, individuals who become more agreeable, kind and compassionate, also tend to place more emphasis on social and family/relationship goals over time. And, individuals who become more responsible, organized and self-controlled tend to value more economic and family goals.

Researchers at Helmholtz Zentrum München and the Technical University of Munich (TUM) have developed the world's smallest ultrasound detector. It is based on miniaturized photonic circuits on top of a silicon chip. With a size 100 times smaller than an average human hair, the new detector can visualize features that are much smaller than previously possible, leading to what is known as super-resolution imaging.

Since the development of medical ultrasound imaging in the 1950s, the core detection technology of ultrasound waves has primarily focused on using piezoelectric detectors, which convert the pressure from ultrasound waves into electric voltage. The imaging resolution achieved with ultrasound depends on the size of the piezoelectric detector employed. Reducing this size leads to higher resolution and can offer smaller, densely packed one or two dimensional ultrasound arrays with improved ability to discriminate features in the imaged tissue or material. However, further reducing the size of piezoelectric detectors impairs their sensitivity dramatically, making them unusable for practical application.

Using computer chip technology to create an optical ultrasound detector

Silicon photonics technology is widely used to miniaturize optical components and densely pack them on the small surface of a silicon chip. While silicon does not exhibit any piezoelectricity, its ability to confine light in dimensions smaller than the optical wavelength has already been widely exploited for the development of miniaturized photonic circuits.

Researchers at Helmholtz Zentrum Mu?nchen and TUM capitalized on the advantages of those miniaturized photonic circuits and built the world's smallest ultrasound detector: the silicon waveguide-etalon detector, or SWED. Instead of recording voltage from piezoelectric crystals, SWED monitors changes in light intensity propagating through the miniaturized photonic circuits.

"This is the first time that a detector smaller than the size of a blood cell is used to detect ultrasound using the silicon photonics technology", says Rami Shnaiderman, developer of SWED. "If a piezoelectric detector was miniaturized to the scale of SWED, it would be 100 million times less sensitive."

Super-resolution imaging

"The degree to which we were we able to miniaturize the new detector while retaining high sensitivity due to the use of silicon photonics was breathtaking", says Prof. Vasilis Ntziachristos, lead of the research team. The SWED size is about half a micron (=0,0005 millimeters). This size corresponds to an area that is at least 10,000 times smaller than the smallest piezoelectric detectors employed in clinical imaging applications. The SWED is also up to 200 times smaller than the ultrasound wavelength employed, which means that it can be used to visualize features that are smaller than one micrometer, leading to what is called super-resolution imaging.

Inexpensive and powerful

As the technology capitalizes on the robustness and easy manufacturability of the silicon platform, large numbers of detectors can be produced at a small fraction of the cost of piezoelectric detectors, making mass production feasible. This is important for developing a number of different detection applications based on ultrasound waves. "We will continue to optimize every parameter of this technology - the sensitivity, the integration of SWED in large arrays, and its implementation in hand-held devices and endoscopes", adds Shnaiderman.

Future development and applications

"The detector was originally developed to propel the performance of optoacoustic imaging, which is a major focus of our research at Helmholtz Zentrum München and TUM. However, we now foresee applications in a broader field of sensing and imaging", says Ntziachristos.

While the researchers are primarily aiming for applications in clinical diagnostics and basic biomedical research, industrial applications may also benefit from the new technology. The increased imaging resolution may lead to studying ultra-fine details in tissues and materials. A first line of investigation involves super-resolution optoacoustic (photoacoustic) imaging of cells and micro-vasculature in tissues, but the SWED could be also used to study fundamental properties of ultrasonic waves and their interactions with matter on a scale that was not possible before.

Tropical Storm Karina was making night moves like the old Bob Seger song. NASA-NOAA's Suomi NPP satellite provided an infrared image of Tropical Storm Karina's nighttime movement as it moved away from the Baja California peninsula of Mexico. Infrared data showed the storm was weakening.

NASA's Night-Time View of Karina's Weakening

The Visible Infrared Imaging Radiometer Suite (VIIRS) instrument aboard Suomi NPP was used to capture a nighttime image of Karina. NASA-NOAA's Suomi NPP satellite passed over the Eastern Pacific Ocean during the early morning of Sept. 16 at 3 a.m. PDT/6 a.m. EDT (1000 UTC) and captured a nighttime image of Tropical Storm Karina moving farther away from Baja California, Mexico.

The infrared imagery revealed that there was very little deep convection (and building thunderstorms). Cloud top temperatures were near minus 40 degrees Celsius, which indicates they are warming and cloud heights are dropping. It is an indication that the uplift in the storm is weakening, and thunderstorm development drops off. The coldest cloud tops were found well to the west-northwest of the center of circulation.

The image was created using the NASA Worldview application at NASA's Goddard Space Flight Center in Greenbelt, Md.

Karina's Status on Sept. 16

At 11 a.m. EDT (1500 UTC), the center of Tropical Storm Karina was located near latitude 22.6 degrees north and longitude 123.9 degrees west.  Karina is moving toward the northwest near 8 mph (13 kph), and a turn back toward the west-northwest is forecast today.  A slower westward motion is expected toward the end of the week. Maximum sustained winds are near 40 mph (65 kph) with higher gusts. Continued weakening is forecast, and Karina is expected to become a remnant low by tonight. The estimated minimum central pressure is 1004 millibars.

Karina's Forecast

"Karina is expected to continue traversing cooler waters while moving farther into an inhibiting thermodynamic environment and unfavorable upper-level winds," noted U.S. Navy Hurricane Specialist Dave Roberts of NOAA's National Hurricane Center in Miami, Fla. "Therefore, weakening is forecast and Karina should degenerate to a remnant low [pressure area] tonight."

Diversity in many biological communities is a sign of an ecosystem in balance. When one species dominates, the entire system can go haywire. For example, the uncontrolled overgrowth of certain oceanic algae species causes toxic red tides that kill fish and other sea life, and sicken humans. On a more individual level, the human gut hosts a large community of different bacteria that is crucial for proper digestion and absorption of nutrients. Disruption of or imbalances in this bacterial community can cause a bloom in the growth of a toxic species, causing nausea, diarrhea and other illnesses. Plainly, there's an urgent need to understand how microbial community diversity is developed and maintained, especially as human activities change our external and internal environments.

Like all life, microbes require certain nutrients, such as sunlight, sugars or nitrogen sources, to survive and reproduce. Many microbe species' nutrient requirements overlap, putting them in competition with each other. Much effort has been devoted to understanding how this competition influences microbial diversity when nutrients are steadily supplied. However, in nature, it's quite common for the resources to be available only seasonally so that their supply is severely limited at least some of the time. For example, bacteria in the gut that live on sugars might find these abundant right after the human's had a meal, and scarcer the rest of the time. Because each bacterial species is genetically unique, it will have its own particular strategy for using a given nutrient. Species with the most efficient strategies for using the available nutrients experience the best growth.

"A long-standing question about microbes concerns how so many different microbial species manage to coexist when competing for limited resources," said Ned Wingreen, a professor in Princeton's Department of Molecular Biology and the senior author on a paper in the Sept. 11 issue of the journal eLife.

Researchers can recreate seasonal nutrient supply in a laboratory by placing bacteria in a container with nutrients, letting them grow, then taking a small sample and moving it to a new container of nutrients -- a process called "serial dilution." Over time, the relative abundance of different species in the culture will change according to the nutrients available and the species' nutrient use strategies. By performing repeated rounds of serial dilution, scientists can observe the effects of seasonally supplied nutrients on community diversity.

Of course, it would be impractical to examine all possible combinations of bacteria, nutrients and nutrient utilization strategies using this method. Instead, associate research scholar Amir Erez and graduate student Jaime Lopez, co-authors on the paper and members of Wingreen's lab, and their collaborators investigated this question by mathematically modeling serial dilution.

"In our paper, we develop a general theory of microbial resource competition in a seasonal ecosystem by modeling recurrent nutrient addition and depletion," explained Wingreen.

When nutrients are only seasonally available, the modeling uncovered a surprising relationship between species diversity and the amount of nutrients supplied. First, species diversity is high when all nutrients are supplied in very high amounts because growth of all species is equally unlimited at high nutrient levels. Diversity is also high at very low nutrient amounts because growth of all species is restricted under such conditions and no species can gain an advantage.

"Nutrient-consumption trade-offs in seasonal ecosystems can lead to stable ecosystems that support diversity beyond what is predicted by simpler mathematical models," observed Wingreen.

At intermediate nutrient levels, however, species diversity nose-dives because there will always be one species whose ability to use the most abundant nutrient present outstrips that of others. This species, which the authors call the "early bird," gains an early growth advantage the others can never make up for.

"The early bird species use their earlier access to nutrients to exclude their not-so-early competitors," explains Wingreen. "The early bird is efficient at consuming easily accessible nutrients and uses its early advantage to out-compete competitors for nutrients that are not as easily accessible."

The early bird effect crops up even in more elaborate versions of the model that allow species to feed off others' metabolic byproducts, or for members of a dwindling species to be replenished by in-migration of new individuals. But the identity of the early bird, or whether there will even be one, shifts according to the inputs of the model: what nutrients are present and in what amounts; how often nutrients are supplied; and which species are present and what their strategies are. Whenever it appears, the early bird influences how the ecosystem responds to nutrient changes.

"Ecologists have long sought a universal relationship between biodiversity and the amount of nutrient supplied to a community. The existence of this universal relationship is not supported by our model," says Wingreen.

"This is an important paper," says Alvaro Sanchez, a professor in ecology and evolutionary biology at Yale University and an editor at eLife. "It provides an elegant modeling framework to understand how nutrient supply and competition can structure coexistence and diversity in microbial communities, and it will motivate new experiments."

A medical robotic hand could allow doctors to more accurately diagnose and treat people from halfway around the world, but currently available technologies aren't good enough to match the in-person experience.

Researchers report in Science Advances that they have designed and produced a smart electronic skin and a medical robotic hand capable of assessing vital diagnostic data by using a newly invented rubbery semiconductor with high carrier mobility.

Cunjiang Yu, Bill D. Cook Associate Professor of Mechanical Engineering at the University of Houston and corresponding author for the work, said the rubbery semiconductor material also can be easily scaled for manufacturing, based upon assembly at the interface of air and water.

That interfacial assembly and the rubbery electronic devices described in the paper suggest a pathway toward soft, stretchy rubbery electronics and integrated systems that mimic the mechanical softness of biological tissues, suitable for a variety of emerging applications, said Yu, who also is a principal investigator at the Texas Center for Superconductivity at UH.

The smart skin and medical robotic hand are just two potential applications, created by the researchers to illustrate the discovery's utility.

In addition to Yu, authors on the paper include Ying-Shi Guan, Anish Thukral, Kyoseung Sim, Xu Wang, Yongcao Zhang, Faheem Ershad, Zhoulyu Rao, Fengjiao Pan and Peng Wang, all of whom are affiliated with UH. Co-authors Jianliang Xiao and Shun Zhang are affiliated with the University of Colorado.

Traditional semiconductors are brittle, and using them in otherwise stretchable electronics has required special mechanical accommodations. Previous stretchable semiconductors have had drawbacks of their own, including low carrier mobility - the speed at which charge carriers can move through a material - and complicated fabrication requirements.

Yu and collaborators last year reported that adding minute amounts of metallic carbon nanotubes to the rubbery semiconductor of P3HT - polydimethylsiloxane composite - improves carrier mobility, which governs the performances of semiconductor transistors.

Yu said the new scalable manufacturing method for these high performance stretchable semiconducting nanofilms and the development of fully rubbery transistors represent a significant step forward.

The production is simple, he said. A commercially available semiconductor material is dissolved in a solution and dropped on water, where it spreads; the chemical solvent evaporates from the solution, resulting in improved semiconductor properties.

It is a new way to create the high quality composite films, he said, allowing for consistent production of fully rubbery semiconductors.

Electrical performance is retained even when the semiconductor is stretched by 50%, the researchers reported. Yu said the ability to stretch the rubbery electronics by 50% without degrading the performance is a notable advance. Human skin, he said, can be stretched only about 30% without tearing.

JUPITER, FL -- Failures in a quality control system that protects protein-building fidelity in cells can lead to motor neuron degeneration and related diseases, according to a new study from an international team co-directed by Scripps Research molecular biologist Claudio Joazeiro, PhD.

Motor neurons control movement, breathing, swallowing and speaking. Their death is a hallmark of progressive diseases such as spinal muscular atrophy and ALS, also known as Lou Gehrig's disease. Understanding what can cause motor neurons to die is a key to developing precision treatments. Scientists are finding that the causes of motor neuron diseases are many.

The study, appearing Sept. 15, 2020 in the journal Nature Communications, singles out several variants of a gene called NEMF as a new driver of motor neuron diseases. NEMF, short for "nuclear export mediator factor," is known for its role in helping clear glitches that inevitably occur during protein production by cellular organelles called ribosomes.

Healthy NEMF helps the cell recycle garbled protein fragments produced in error. But several mutant forms of NEMF in mice interfered with the system and resulted in neuromuscular, neurodegenerative or other disease, the scientists found.

The research was led by both Joazeiro, who has joint appointments at Scripps Research in Jupiter, Florida and the Center for Molecular Biology of Heidelberg University in Germany, and Gregory Cox, PhD, of the Jackson Laboratory of Mammalian Genetics in Bar Harbor, Maine.

A decade ago, Joazeiro discovered an enzyme, the E3 ubiquitin ligase listerin/Ltn1, that works in a specialized quality control process now known as RQC, or ribosome-associated quality control. He and his team also found that inactivation of the enzyme causes motor neuron degeneration in mice. However, whether neurodegeneration resulted from defective ribosome-associated quality control or some other function of listerin remained unclear. At the Jackson Laboratory, Cox had been studying mice with mutations in another quality control factor, NEMF. They exhibited movement difficulties including walking and gripping. The labs teamed up to investigate whether those defects resulted from a neurodegenerative process. They wanted to find the molecular mechanisms at work.

"The results provide strong evidence that dysfunction of ribosomal quality control causes neurodegeneration," Joazeiro says.

Within cells, millions of ribosomes transform genetic code into proteins by stringing together one amino acid at a time. Mistakes occasionally happen, some of which lead to the production of potentially toxic protein fragments. When that happens, manufacturing may be suspended, and the cell's ribosome protein quality control system chops up the garbled pieces for recycling.

But whether defective ribosome quality control contributed to human disease had remained unknown. Human data backed up the team's mouse and yeast-based investigations.

Working through GeneMatcher, a tool for patients developed at the Baylor-Hopkins Center for Mendelian Genomics in Texas, the team identified nine patients from seven unrelated families who had likely pathogenic NEMF variants and displayed neuromuscular disease, along with a variety of developmental issues including speech delay and intellectual disability.

"It was amazing to see how our early and new mouse data, together with the knowledge acquired on molecular mechanisms, were so predictive of these findings in human patients," Joazeiro says. "We're hopeful these advances will one day prove helpful to families affected by these difficult diseases."

The team is now investigating the role of ribosome-associated quality control in other related diseases, he adds.

Another fascinating takeaway from this research is that this pathway of protein quality control appears to be necessary across species, he adds.

"Last year we reported that it is also present in bacteria, and is likely to have already been active in the last universal common ancestor, the organism that gave rise to all domains of life," Joazeiro says.

Together with the findings that disabling the system results in neurodegeneration, this evolutionary conservation highlights the importance of aberrant protein disposal, and also suggests the system's development may have played a critical role enabling the evolution of complex organisms, Joazeiro says.

"This research shows that failure of ribosome-associated quality control is a cause of motor neuron disease that should be explored in greater detail," he says.

Research led by Dr. Wonmuk Hwang has led to better understanding on how components of the body's immune system find intruding or damaged cells, which could lead to novel approaches to viral and cancer treatments.

Hwang, associate professor in the Department of Biomedical Engineering at Texas A&M University, has written about this in an article recently published in the journal Proceedings of the National Academy of Sciences.

When viruses enter the body, the immune system kicks into gear to seek out and destroy the intruder. T-cells are one component of the immune system, and they seek out viruses hiding in host cells, acting as an ultimate line of defense against antigens, or foreign bodies. T-cells probe the surface of other cells, examining materials scooped from inside the cell and presented by the major histocompatibility complex (MHC) molecules on the surface of the cells.

"The problem is there are hundreds of thousands of MHC molecules displaying peptides, and only a few are from invading cells, if at all," Hwang said. "The rest of them are normal products of cellular metabolism, which means the T-cell needs to be able to see that needle in the haystack."

Researchers have discovered recently that T-cells increase their detection power mechanically: when T-cells probe the surface of other cells, there is a natural contact force created. If the cell is infected by an antigen, the applied force results in a "catch bond" between the T-cell receptors (TCRs) and MHC molecules, which strengthens the contact. This bond does not occur between TCRs and MCH molecules that do not carry specific antigens.

However, it is almost impossible to see this interaction in atomic details experimentally, so Hwang developed a computer simulation that could realistically demonstrate and analyze the interaction between TCRs and MHC molecules when force is applied.

"Only the simulation can see and analyze molecular motion under load. A lab experiment doesn't have the resolution," Hwang said. "Experimentally determined atomic structures of proteins are static snapshots, but when the molecule moves, you have basically no way to see the motion."

What Hwang discovered was how the motion between the parts of the TCR controls their interaction with the MHC molecules. When force is applied, the motion is suppressed only when the MHC molecule has the matching antigen, thereby stabilizing the entire complex. Other cases will refuse to interlock with the TCR, and the constant motion between the two eventually leads to them disconnecting. It is like a lock-and-key system where the lock and key constantly change shape, and only with a perfect match and under an adequate level of force, can the molecules interlock.

Hwang said the knowledge of which parts of the molecule respond to force can help tailor T-cells for certain applications. Other than fighting infections, TCRs are also the rising stars of cancer therapy.

"If you can train the T-cell to see those cancerous antigens, it'll be really specific therapy," Hwang said. "Chemotherapy kills all the cells. But T-cells you can train to recognize cancer cells with extreme accuracy."

Hwang said the next step for him is to investigate what is general and what pertains to specific T-cell receptor systems.

"To see how this principle applies to different T-cell receptors, I'm going to expand this initial finding," Hwang said. "This is the very first work that has found the operation mechanism of T-cell receptors under force."

LA JOLLA, CA--Ever since SARS-CoV-2 first appeared, researchers have been trying to understand whether sometimes the immune system does more harm than good during the acute phase of COVID-19. The latest study by researchers at La Jolla Institute for Immunology clearly argues in favor of the immune system.

Their work, published in the Sept. 16, 2020, online issue of Cell, confirms that a multi-layered, virus-specific immune response is important for controlling the virus during the acute phase of the infection and reducing COVID-19 disease severity, with the bulk of the evidence pointing to a much bigger role for T cells than antibodies. A weak or uncoordinated immune response, on the other hand, predicts a poor disease outcome. The findings suggest that vaccine candidates should aim to elicit a broad immune response that include antibodies, helper and killer T cells to ensure protective immunity.

"Our observations could also explain why older COVID-19 patients are much more vulnerable to the disease," says senior author Shane Crotty, Ph.D., who co-led the study with Alessandro Sette, Dr. Biol.Sci., both professors in LJI's Center for Infectious Disease and Vaccine Research. "With increasing age, the reservoir of T cells that can be activated against a specific virus declines and the body's immune response becomes less coordinated, which looks to be one factor making older people drastically more susceptible to severe or fatal COVID-19."

Adds Sette, "What we didn't see was any evidence that T cells contribute to a cytokine storm, which is more likely mediated by the innate immune system."

When SARS-CoV-2 (or any other virus) infiltrates the body, the innate immune system is first on the scene and launches a broad and unspecific attack against the intruder. It releases waves of signaling molecules that incite inflammation and alert the immune system's precision forces to the presence of a pathogen.

Within days, the so-called adaptive immune system tools up and moves with pinpoint precision against the virus, intercepting viral particles and killing infected cells.

The adaptive immune system consists of three branches: antibodies; helper T cells (Th), which assist B cell to make protective antibodies; and killer T cells (CTL), which seek out virus-infected cells and eliminate them.

For their latest study, the researchers collected blood samples from 50 COVID-19 patients and analyzed all three branches of the adaptive immune system--SARS-CoV-2 specific antibodies, helper and killer T cells--in great detail.

"It was particularly important to us to capture the whole range of disease manifestation from mild to critically ill so we could identify differentiating immunological factors," says co-first author and infectious disease specialist Sydney Ramirez, M.D., Ph.D., who spearheaded the sample collection.

What the team found was that similar to their previous study all fully recovered individuals had measurable antibody, helper and killer T cell responses, while the adaptive immune response in acute COVID-19 patients varied more widely with some lacking neutralizing antibodies, others helper or killer T cells or any combination thereof.

"When we looked at a combination of all of our data across all 111 measured parameters we found that in general, people who mounted a broader and well-coordinated adaptive response tended to do better. A strong SARS-CoV-2 specific T cell response, in particular, was predictive of milder disease," says co-first author and postdoctoral research Carolyn Moderbacher, Ph.D. "Individuals whose immune response was less coordinated tended to have poorer outcomes."

The effect was magnified when the researchers broke down the dataset by age. "People over the age of 65 were much more likely to have poor T cell responses, and a poorly coordinated immune response, and thus have much more severe or fatal COVID-19," says Crotty. "Thus, part of the massive susceptibility of the elderly to COVID-19 appears to be a weak adaptive immune response, which may be because of fewer naïve T cells in the elderly."

Naïve T cells are inexperienced T cells that have not met their viral match yet and are waiting to be called up. As we age, the immune system's supply of deployable naïve T cells dwindles and fewer cells are available to be activated to respond to a new virus. "This could either lead to a delayed adaptive immune response that is unable to control a virus until it is too late to limit disease severity or the magnitude of the response is insufficient," says Moderbacher.

In line with what other research teams had found before, antibodies don't seem to play an important role in controlling acute COVID-19. Instead, T cells and helper T cells in particular are associated with protective immune responses. "This was perplexing to many people," says Crotty, "but controlling a primary infection is not the same as vaccine-induced immunity, where the adaptive immune system is ready to pounce at time zero."

If a vaccination is successful, vaccine-induced antibodies are ready to intercept the virus when it shows up at the doorstep. In contrast, in a normal infection the virus gets a head start because the immune system has never seen anything like it. By the time the adaptive immune system is ready to go during a primary infection, the virus has already replicated inside cells and antibodies can't get to it.

"Thus, these findings indicate it is plausible T cells are more important in natural SARS-CoV-2 infection, and antibodies more important in a COVID-19 vaccine," says Crotty, "although it is also plausible that T cell responses against this virus are important in both cases."

WASHINGTON -- Researchers have developed an automated 3D printing method that can produce multicolor 3D microstructures using different materials. The new method could be used to make a variety of optical components including optical sensors and light-driven actuators as well as multimaterial structures for applications such as soft robotics and medical applications.

"Combining multiple kinds of materials can be used to create a function that cannot be realized with a single material," said research team leader Shoji Maruo from Yokohama National University in Japan. "Methods like ours that allow single-step fabrication of multimaterial structures eliminates assembling processes, allowing the production of devices with high precision and low cost."

In The Optical Society (OSA) journal Optical Materials Express, Maruo and colleagues describe their new 3D printing method and demonstrate it by creating various multicolor 3D structures. Their technique is based on stereolithography, a 3D printing method that is ideal for making microdevices because it uses a tightly focused laser beam to make intricately detailed features.

"The ability to make multimaterial microscale optical elements using 3D printing could aid in the miniaturization of optical devices used for medical treatments and diagnoses," said Maruo. "This could improve the ability to use these devices in or on the body while also enabling them to be disposable, which would help provide an advanced and safe medical diagnosis."

Optimizing color stereolithography

Stereolithography builds up a high-precision 3D structure by using a laser to harden light-activated materials known as photocurable resins in a layer by layer fashion. Microfluidics are often used to hold the liquid resins, but it is challenging to keep the different resins from contaminating each other when switching materials without creating large amounts of waste or forming air bubbles in the printed object.

In the new work, the researchers developed a way to hold the various materials in a droplet state, which allows them to be more easily exchanged in a closed space such as a microchannel without creating waste. To suppress air bubbles, the 3D-printed structure is moved around inside the resin each time a resin is replaced. They also integrated a two-step process for cleaning the 3D printed structure when the resins are changed to completely prevent cross-contamination.

To implement this optimized approach, the researchers created a palette to hold multiple resins and placed it, two cleaning tanks and an air blow nozzle on a motorized stage. "All the processes, including 3D printing, resin replacement, bubble removal and cleaning are sequentially carried out using software we developed," said Maruo. "This allows multicolor 3D microstructures to be created automatically."

Creating multicolor 3D structures

The researchers tested the approach by placing various types of photocurable resins in a palette and using them to create 3D microstructures. For one of these demonstration structures, a tiny multicolor cube just 1.5 millimeters across, the 3D printing system exchanged five colors of resin 250 times during a 6-hour fabrication process. The researchers also showed that adjusting the number of layers of multicolor resins made it possible to adjust absorbance of each part of the structure, allowing them to create microstructures with colors such as black by combining layers of red, blue, green and yellow.

"This method can be applied not only to multicolor resins but also to a wider variety of materials," said Maruo. "For example, mixing various ceramic micro- or nanoparticles with a photocurable resin can be used to 3D print various types of glass. It could also be used with biocompatible ceramic materials to create scaffolds for regenerating bones and teeth."

The researchers are now working to shorten the time required for processes such as resin replacement and bubble removal to allow for even faster fabrication. They also plan to use technology they previously demonstrated to build a multiscale fabrication system in which the fabrication resolution can be changed from less than a micrometer to several tens of micrometers by modifying the focusing lens and laser exposure conditions.

New Rochelle, NY, September 16, 2020—A novel taxonomic approach to obesity prevention using existing U.S. obesity prevention studies is highlighted in a special supplement of the peer-reviewed journal Childhood Obesity. The studies demonstrate an approach to breaking down and reaggregating study specifics to enable a determination of which obesity intervention strategies work and under what circumstances. Click here to read the supplement now. 

The work is a collaborative effort between the National Collaborative on Childhood Obesity Research (NCCOR) and Mission Measurement. NCCOR is a partnership between The Centers for Disease Control and Prevention (CDC); National Institutes of Health (NIH); Robert Wood Johnson Foundation (RWJF); and the United States Department of Agriculture (USDA).

“The Childhood Obesity Evidence Base Project” is guest edited by Deborah Young-Hyman, PhD, National Institutes of Health, and Laura Kettel Khan, PhD, Centers for Disease Control and Prevention.

The issue includes these studies:

A Rationale for Taxonomic Versus Conventional Meta-Analysis 
Methods for Taxonomy Development for Application in Taxonomic Meta-Analysis
A Systematic Review and Meta-Analysis of a New Taxonomy of Intervention Components to Improve Weight Status in Children 2-5 Years of Age, 2005-2019
Building Translational Capacity Through Meta-Analytic Methods

Shiriki Kumanyika, PhD, MPH, Drexel University, presents a Commentary entitled "Learning More from What We Already Know About Childhood Obesity Prevention."  Christina Economos, PhD, Tufts University, and Debra Haire-Joshu, PhD, Brown School at Washington University, St. Louis, present their perspective in a Commentary entitled "Preventing Obesity in 2-5-Year Olds: A Pathway to Advancing Intervention Research.”

The research reported in this supplement was supported by the Office of Behavioral and Social Sciences Research of the NIH under contract number GS-00F-0007M. The findings and conclusions in these articles are those of the authors and do not necessarily represent the official position of the NIH or the CDC

About the Journal
Childhood Obesity is a bimonthly peer-reviewed journal, published in print and online, and the journal of record for all aspects of communication on the broad spectrum of issues and strategies related to weight management and obesity prevention in children and adolescents. Led by Editor-in-Chief Tom Baranowski, PhD, Baylor College of Medicine, and Editor Elsie M. Taveras, MD, MPH, Massachusetts General Hospital for Children & Harvard Medical School, the Journal provides authoritative coverage of new weight management initiatives, early intervention strategies, nutrition, clinical studies, comorbid conditions, health disparities and cultural sensitivity issues, community, and public health measures, and more. Complete tables of content and a sample issue may be viewed on the Childhood Obesity website.

About the Publisher
Mary Ann Liebert, Inc., publishers is known for establishing authoritative medical and biomedical peer-reviewed journals. A complete list of the firm’s 90 journals, newsmagazines, and books is available on the Mary Ann Liebert, Inc., publishers website.

Journal

Childhood Obesity

DOI

10.1089/chi.2020.0137

The cover for issue 37 of Oncotarget features Figure 7, "The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL," by Scotto, et al. which reported that the antiproliferative effect induced by histone deactylase inhibitors is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug.

HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated activity.

The Oncotarget authors explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor.

KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase.

Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor.

Dr. Owen A. O'Connor from The Columbia University Medical Center said, "HDAC inhibitors (HDACi) have emerged as valuable drugs in the treatment of select lymphomas and synergize with a diverse range of pharmacological and biological agents."

The observation leads to the following hypothesis: if induction of p21 compromises the efficacy of HDAC inhibitors, then strategies to mitigate HDAC inhibitor induced p21 expression could lead to promising synergistic combinations.

Induction of p21 by HDAC inhibitors is compromised in A-T cells given that ATM activity is essential for HDAC inhibitor-induced p21 expression.

Collectively, these observations have led to the following hypothesis: If ATM activity is necessary for HDAC inhibitor mediated p21 induction, then selective ATM inhibitors could mitigate the HDAC induced p21 expression and potentiate its cytotoxic effect.

The ATM inhibitor nullifies HDAC induction of p21 expression resulting in a synergistic interaction.

KU60019 reduces p21 expression at the transcriptional level and antagonizes romidepsin transcriptional induction of p21. In both instances, the result is a markedly down-regulation of p21 expression at the protein level.

The O'Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival.

Strategies directed toward understanding how to mitigate the unfavorable influences of the class can lead to improved efficacy in rational combinations.

Many examples of drug synergy with HDAC inhibitors have been driven by random efforts in mixing and matching in order to identify possible complementary partners.

Obviously, a clear understanding of the molecular pharmacologic features of pleotropic drug classes like HDAC inhibitors can afford unique opportunities to think about logical combinations.

Ultimately, these approaches need to be translated to the clinic in order to establish therapeutic merit in the clinic.

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DOI - https://doi.org/10.18632/oncotarget.27723

Full text - https://www.oncotarget.com/article/27723/text/

Correspondence to - Owen A. O'Connor - owenaoconnor@gmail.com

Keywords -
lymphoma,
HDAC inhibitor,
ATM inhibitor,
p21,
cell cycle

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Journal

Oncotarget

DOI

10.18632/oncotarget.27723

In another fascinating snapshot from deep time, an international team of paleontologists has reported the discovery of specimens of a minuscule crustacean that dates back to the Cretaceous (about 100 million years ago), conserved in samples of amber from Myanmar. The most spectacular find is a single female, which turns out on closer examination to contain giant sperm cells in its reproductive tract. In fact, this is the oldest fossil in which sperm cells have been conclusively identified. Moreover, the specimen represents a previously unknown species of crustacean, which has been named Myanmarcypris hui. M. hui was an ostracod, as clearly indicated by the paired calcareous valves that form the carapace, whose form recalls that of a mussel shell. Ostracods have been around for 500 million years, and thousands of modern species have been described. They are found in the oceans and in freshwater lakes and rivers. Fossilized shells of these crustaceans are by no means rare, but the specimens preserved in Burmese amber reveal details of their internal organs, including those involved in reproduction. "The finds gave us an extremely rare opportunity to learn more about the evolution of these organs," says Ludwig-Maximilians-Universitaet (LMU) in Munich geobiologist Renate Matzke-Karasz, who played a major role in the morphological analysis of the fossils. 

During the Cretaceous period, ostracods must have lived in the coastal and inland waters of what is now Myanmar, which were fringed by forests dominated by trees that produced huge quantities of resin. The newly described specimens are among the many organisms that were trapped in the oozing blobs of the gooey substance. In recent years, the amber found in the province of Kachin has yielded a spectacular trove of fossils, including frogs and snakes, as well as part of a putative dinosaur (according to new evidence, that specimen may actually represent an unusual lizard). Over the past 5 years, hundreds of previously unknown species have been described based on these inclusions. Indeed, many of them have forced evolutionary biologists to reconsider conventional hypotheses concerning phylogenetic and ecological relationships. 

The new ostracod specimens were analyzed with the aid of computer-assisted 3D X-ray reconstructions. The images revealed astonishing details of the anatomy of these animals, ranging from their tiny limbs to their reproductive organs. - And in one female specimen, Matzke-Karasz and her colleagues discovered ripe sperm. The cells were discovered in the paired sperm receptacles in which they were stored after copulation, ready for release when the female's eggs matured. "This female must have mated shortly before being encased in the resin," says He Wang of the Chinese Academy of Sciences in Nanjing. The X-ray images also revealed the sperm pumps and the pair of penises that male ostracods insert into the twin gonopores of the females.

The finds in Burmese amber provide unprecedented insights into an unexpectedly ancient and advanced instance of evolutionary specialization. "The complexity of the reproductive system in these specimens raises the question of whether the investment in giant sperm cells might represent an evolutionarily stable strategy, says Matzke-Karasz. The males of most animal species (including humans) produce very large numbers of very small sperm. Comparatively few animals, including some fruit flies - and of course, ostracods - have opted for a different approach. They make a relatively small numbers of oversized sperm, whose motile tails are several times longer than the animal itself. 

"In order to prove that the use of giant sperm is not an extravagant whim on the part of evolution, but a viable strategy that can confer an enduring advantage that enables species to survive for long periods of time, we must establish when this mode of reproduction first appeared," says Matzke-Karasz. Examples of fossilized sperm cells are extremely rare. The oldest known ostracod sperm (prior to the new discovery) are 17 million years old, and the previous record age, 50 Myr, was held by a species of worm. The new evidence extends that age by a factor of at least two. The fact that animals had already developed giant sperm 100 million years ago implies that this reproductive strategy can indeed be successful in the (very) long term, Matzke-Karasz points out. "That's a pretty impressive record for a trait that requires a considerable investment from both the males and females of the species. From an evolutionary point of view, sexual reproduction with the aid of giant sperm must therefore be a thoroughly profitable strategy."