Artificial intelligence applied to the genome identifies an unknown human ancestor

By combining deep learning algorithms and statistical methods, investigators from the Institute of Evolutionary Biology (IBE), the Centro Nacional de Análisis Genómico (CNAG-CRG) of the Centre for Genomic Regulation (CRG) and the Institute of Genomics at the University of Tartu have identified, in the genome of Asian individuals, the footprint of a new hominid who cross bred with its ancestors tens of thousands of years ago.

Modern human DNA computational analysis suggests that the extinct species was a hybrid of Neanderthals and Denisovans and cross bred with Out of Africa modern humans in Asia. This finding would explain that the hybrid found this summer in the caves of Denisova -- the offspring of a Neanderthal mother and a Denisovan father -- was not an isolated case, but rather was part of a more general introgression process.
The study, published in Nature Communications, uses deep learning for the first time ever to account for human evolution, paving the way for the application of this technology in other questions in biology, genomics and evolution.
Humans had descendants with an species that is unknown to us
One of the ways of distinguishing between two species is that while both of them may cross breed, they do not generally produce fertile descendants. However, this concept is much more complex when extinct species are involved. In fact, the story told by current human DNA blurs the lines of these limits, preserving fragments of hominids from other species, such as the Neanderthals and the Denisovans, who coexisted with modern humans more than 40,000 years ago in Eurasia.
Now, investigators of the Institute of Evolutionary Biology (IBE), the Centro Nacional de Análisis Genómico (CNAG-CRG) of the Centre for Genomic Regulation (CRG), and the University of Tartu have used deep learning algorithms to identify a new and hitherto-unknown ancestor of humans that would have interbred with modern humans tens of thousands of years ago. "About 80,000 years ago, the so-called Out of Africa occurred, when part of the human population, which already consisted of modern humans, abandoned the African continent and migrated to other continents, giving rise to all the current populations," explained Jaume Bertranpetit, principal investigator at the IBE and head of Department at the UPF. "We know that from that time onwards, modern humans cross bred with Neanderthals in all the continents, except Africa, and with the Denisovans in Oceania and probably in South-East Asia, although the evidence of cross-breeding with a third extinct species had not been confirmed with any certainty."
Deep learning: deciphering the keys to human evolution in ancient DNA
Hitherto, the existence of the third ancestor was only a theory that would explain the origin of some fragments of the current human genome (part of the team involved in this study had already posed the existence of the extinct hominid in a previous study). However, deep learning has made it possible to make the transition from DNA to the demographics of ancestral populations.
The problem the investigators had to contend with is that the demographic models they have analysed are much more complex than anything else considered to date and there were no statistic tools available to analyse them. Deep learning "is an algorithm that imitates the way in which the nervous system of mammals works, with different artificial neurons that specialise and learn to detect, in data, patterns that are important for performing a given task," stated Òscar Lao, principal investigator at the CNAG-CRG and an expert in this type of simulations. "We have used this property to get the algorithm to learn to predict human demographics using genomes obtained through hundreds of thousands of simulations. Whenever we run a simulation we are travelling along a possible path in the history of humankind. Of all simulations, deep learning allows us to observe what makes the ancestral puzzle fit together."
It is the first time that deep learning has been used successfully to explain human history, paving the way for this technology to be applied in other questions in biology, genomics and evolution.
An extinct hominid could explain the history of humankind
The deep learning analysis has revealed that the extinct hominid is probably a descendant of the Neanderthal and Denisovan populations. The discovery of a fossil with these characteristics this summer would seem to endorse the study finding, consolidating the hypothesis of this third species or population that coexisted with modern human beings and mated with them. "Our theory coincides with the hybrid specimen discovered recently in Denisova, although as yet we cannot rule out other possibilities," said Mayukh Mondal, an investigator of the University of Tartu and former investigator at the IBE.
 

Journal Reference:

1. Mayukh Mondal, Jaume Bertranpetit, Oscar Lao. Approximate Bayesian computation with deep learning supports a third archaic introgression in Asia and Oceania. Nature Communications, 2019; 10 (1) DOI: 10.1038/s41467-018-08089-7 

Courtesy: ScienceDaily
 

It may be possible to restore memory function in Alzheimer's, preclinical study finds

Yan and her team used an epigenetic approach to restore memory function in an animal model of Alzheimer's Disease.

Credit: Douglas Levere/University at Buffalo

Research published today (Jan. 22) in the journal Brain reveals a new approach to Alzheimer's disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.

The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences -- called epigenetics -- it was possible to reverse memory decline in an animal model of AD.

"In this paper, we have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of AD," said senior author Zhen Yan, PhD, a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB.

The research was conducted on mouse models carrying gene mutations for familial AD -- where more than one member of a family has the disease -- and on post-mortem brain tissues from AD patients.

AD is linked to epigenetic abnormality

AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.

The epigenetic changes in AD happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan said. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.

"We found that in Alzheimer's disease, many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory," Yan said.

The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.

Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell's transcriptional machinery.

"This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits," Yan said.

Potential drug targets

Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.

"Our study not only reveals the correlation between epigenetic changes and AD, we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors," Yan said.

The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.

"When we gave the AD animals this enzyme inhibitor, we saw the rescue of cognitive function confirmed through evaluations of recognition memory, spatial memory and working memory. We were quite surprised to see such dramatic cognitive improvement," Yan said.

"At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex."

The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.

Epigenetic advantage

Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.

"An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function," she explained.

"We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer's disease," Yan concluded. "If many of the dysregulated genes in AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior."

The study was funded by a $2 million National Institutes of Health grant focused on novel treatment strategies for AD.

Other UB co-authors are Yan Zheng; Aiyi Liu; Zi-Jun Wang, PhD; Qing Cao, PhD; Lin Lin; Kaijie Ma; Freddy Zhang; Jing Wei, PhD; Emmanuel Matas, PhD and Jia Cheng, PhD. Additional co-authors are Guo-Jun Chen of Chongqing Medical University, PhD, and Xiaomin Wang, MD, PhD., of the Beijing Institute for Brain Disorders, Capital Medical University.

Journal Reference:

1. Yan Zheng Aiyi Liu Zi-Jun Wang Qing Cao Wei Wang Lin Lin Kaijie Ma Freddy Zhang Jing Wei Emmanuel Matas Jia Cheng Guo-Jun Chen Xiaomin Wang Zhen Yan. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease. Brain, 2019 DOI: 10.1093/brain/awy354 

Courtesy: ScienceDaily

Genes reveal clues about people's potential life expectancy

Longevity concept (stock illustration).

Credit: © iQoncept / Fotolia

The team has analysed the combined effect of genetic variations that influence lifespan to produce a scoring system.

People who score in the top ten per cent of the population might expect to live up to five years longer than those who score in the lowest ten per cent, they say.

The findings also revealed fresh insights into diseases and the biological mechanisms involved in ageing, the researchers say.

Experts at the University of Edinburgh's Usher Institute looked at genetic data from more than half a million people alongside records of their parents' lifespan.

Some 12 areas of the human genome were pinpointed as having a significant impact on lifespan, including five sites that have not been reported before.

The DNA sites with the greatest impact on overall lifespan were those that have previously been linked to fatal illnesses, including heart disease and smoking-related conditions.

Genes that have been linked to other cancers, not directly associated with smoking, did not show up in this study, however.

This suggests that susceptibility to death caused by these cancers is either a result of rarer genetic differences in affected people, or social and environmental factors.

The researchers had hoped to discover genes that directly influence how quickly people age. They say that if such genes exist, their effects were too small to be detected in this study.

The research, published in the journal eLife, was funded by the UK Medical Research Council and the AXA Research Fund.

Dr Peter Joshi, an AXA Fellow at the University of Edinburgh's Usher Institute, said: "If we take 100 people at birth, or later, and use our lifespan score to divide them into ten groups, the top group will live five years longer than the bottom on average."

Paul Timmers, PhD student at the Usher Institute, said "We found genes that affect the brain and the heart are responsible for most of the variation in lifespan."

Journal Reference:

1. Paul RHJ Timmers, Ninon Mounier, Kristi Lall, Krista Fischer, Zheng Ning, Xiao Feng, Andrew D Bretherick, David W Clark, M Agbessi, H Ahsan, I Alves, A Andiappan, P Awadalla, A Battle, MJ Bonder, D Boomsma, M Christiansen, A Claringbould, P Deelen, J van Dongen, T Esko, M Favé, L Franke, T Frayling, SA Gharib, G Gibson, G Hemani, R Jansen, A Kalnapenkis, S Kasela, J Kettunen, Y Kim, H Kirsten, P Kovacs, K Krohn, J Kronberg-Guzman, V Kukushkina, Z Kutalik, M Kähönen, B Lee, T Lehtimäki, M Loeffler, U Marigorta, A Metspalu, J van Meurs, L Milani, M Müller-Nurasyid, M Nauck, M Nivard, B Penninx, M Perola, N Pervjakova, B Pierce, J Powell, H Prokisch, BM Psaty, O Raitakari, S Ring, S Ripatti, O Rotzschke, S Ruëger, A Saha, M Scholz, K Schramm, I Seppälä, M Stumvoll, P Sullivan, A Teumer, J Thiery, L Tong, A Tönjes, J Verlouw, PM Visscher, U Võsa, U Völker, H Yaghootkar, J Yang, B Zeng, F Zhang, M Agbessi, H Ahsan, I Alves, A Andiappan, P Awadalla, A Battle, MJ Bonder, D Boomsma, M Christiansen, A Claringbould, P Deelen, J van Dongen, T Esko, M Favé, L Franke, T Frayling, SA Gharib, G Gibson, G Hemani, R Jansen, A Kalnapenkis, S Kasela, J Kettunen, Y Kim, H Kirsten, P Kovacs, K Krohn, J Kronberg-Guzman, V Kukushkina, Z Kutalik, M Kähönen, B Lee, T Lehtimäki, M Loeffler, U Marigorta, A Metspalu, J van Meurs, L Milani, M Müller-Nurasyid, M Nauck, M Nivard, B Penninx, M Perola, N Pervjakova, B Pierce, J Powell, H Prokisch, BM Psaty, O Raitakari, S Ring, S Ripatti, O Rotzschke, S Ruëger, A Saha, M Scholz, K Schramm, I Seppälä, M Stumvoll, P Sullivan, A Teumer, J Thiery, L Tong, A Tönjes, J Verlouw, PM Visscher, U Võsa, U Völker, H Yaghootkar, J Yang, B Zeng, F Zhang, Xia Shen, Tõnu Esko, Zoltán Kutalik, James F Wilson, Peter K Joshi. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. eLife, 2019; 8 DOI: 10.7554/eLife.39856 

Courtesy: ScienceDaily

How to rapidly image entire brains at nanoscale resolution

A forest of dendritic spines protrude from the branches of neurons in the mouse cortex.

Credit: Gao et al./ Science 2019

Two scientists, Ruixuan Gao and Shoh Asano, wanted to use his team's microscope on brain samples expanded to four times their usual size -- blown up like balloons. The duo, part of Howard Hughes Medical Institute (HHMI) Investigator Ed Boyden's lab at the Massachusetts Institute of Technology (MIT), uses a chemical technique to make small specimens bigger so scientists can more easily see molecular details.

Their technique, called expansion microscopy, worked well on single cells or thin tissue sections imaged in conventional light microscopes, but Boyden's team wanted to image vastly larger chunks of tissue. They wanted to see complete neural circuits spanning millimeters or more. The scientists needed a microscope that was high-speed, high resolution, and relatively gentle -- something that didn't destroy a sample before they could finish imaging it.

So, they turned to Betzig. His team at HHMI's Janelia Research Campus had used their lattice light-sheet microscope to image the rapid subcellular dynamics of sensitive living cells in 3-D. Combining the two microscopy techniques could potentially offer rapid, detailed images of wide swaths of brain tissue.

"I thought they were full of it," Betzig remembers. "The idea does sound a bit crude," Gao says. "We're stretching tissues apart." But Betzig invited Gao and Asano to try the lattice scope out.

"I was going to show them," Betzig laughs. Instead, he was blown away. "I couldn't believe the quality of the data I was seeing. You could have knocked me over with a feather."

Now, he and his Janelia colleagues have teamed up with Boyden's group and imaged the entire fruit fly brain and sections of mouse brain the thickness of the cortex. Their combined method offers high resolution with the ability to visualize any desired protein -- and it's fast, too. Imaging the fly brain in multiple colors took just 62.5 hours, compared to the years it would take using an electron microscope, Boyden, Betzig, and their colleagues report January 17, 2018, in the journal, Science.

"I can see us getting to the point of imaging at least 10 fly brains per day," says Betzig, now an HHMI investigator at the University of California, Berkeley. Such speed and resolution will let scientists ask new questions, he says, like how brains differ between males and females, or how brain circuits vary between flies of the same type.

Boyden's group dreams of making a map of the brain so detailed you can simulate it in a computer. "We've crossed a threshold in imaging performance," he says. "That's why we're so excited. We're not just scanning incrementally more brain tissue, we're scanning entire brains."

Expanding the brain

Making detailed maps of the brain requires charting its activity and wiring -- in humans, the thousands of connections made by each of more than 80 billion neurons. Such maps could help scientists spot where brain disease begins, build better artificial intelligence, or even explain behavior. "That's like the holy grail for neuroscience," Boyden says.

Years ago, his group had an idea to figure out how everything was organized: What if they could actually make the brain bigger -- big enough to look inside? By infusing samples with swellable gels -- like the stuff in baby diapers -- the team invented a way to expand tissues, making the molecules inside less crowded and easier to see under a microscope. Molecules lock into a gel scaffold, keeping the same relative positions even after expansion.

But it wasn't easy to image large tissue volumes. The thicker a specimen gets, the harder it is to illuminate only the parts you want to see. Shining too much light on samples can photobleach them, burning out the fluorescent "bulbs" scientists use to light up cells.

Expanding a sample just four-fold increases its volume 64-fold, so imaging speed also becomes paramount, Gao says. "We needed something that was fast and didn't have much photobleaching, and we knew there was a fantastic microscope at Janelia."

The lattice light-sheet microscope sweeps an ultrathin sheet of light through a specimen, illuminating only that part in the microscope's plane of focus. That helps out-of-focus areas stay dark, keeping a specimen's fluorescence from being extinguished.

When Gao and Asano first tested their expanded mouse tissues on the lattice scope, they saw a thicket of glowing nubs protruding from neurons' branches. These nubs, called dendritic spines, often look like mushrooms, with bulbous heads on skinny necks that can be hard to measure. But the scientists were able to see even "the smallest necks possible," Asano says, while simultaneously imaging synaptic proteins nearby.

"It was incredibly impressive," says Betzig. The team was convinced that they should explore the combined technique further. "And that's what we've been doing ever since," he says.

The brain and beyond

Over the last two years, Gao and Asano have spent months at Janelia, teaming up with biologists, microscopists, physicists, and computer scientists across the campus to capture and analyze images. "This is like an Avengers-level collaboration," Gao says, referring to the crew of comic book superheroes.

Yoshinori Aso and the FlyLight team provided high-quality fly brain specimens, which Gao and Asano expanded and used to collect some 50,000 cubes of data across each brain -- forming a kind of 3-D jigsaw puzzle. Those images required complicated computational stitching to put the pieces back together, work led by Stephan Saalfeld and Igor Pisarev. "Stephen and Igor saved our bacon," Betzig says. "They dealt with all the horrible little details of image processing and made it work on each multi-terabyte data set."

Next, Srigokul Upadhyayula from Harvard Medical School, a co-first author of the report, analyzed the combined 200 terabytes of data and created the stunning movies that showcase the brain's intricacies in vivid color. He and his coauthors investigated more than 1,500 dendritic spines, imaged fatty sheaths that insulate mouse nerve cells, highlighted all of the dopaminergic neurons, and counted all the synapses across the entire fly brain.

The nuances of Boyden's team expansion technique make it well suited for the lattice scope; the technique produces nearly transparent samples. For the microscope, it's almost like looking through water, rather than a turbid sea of molecular gunk. "The result is that we get crystal clear images at blazingly fast speeds over very large volumes compared to earlier microscopy techniques," Boyden says.

Still, challenges remain. As with any kind of super resolution fluorescence microscopy, Betzig says, it can be hard to decorate proteins with enough fluorescent bulbs to see them clearly at high resolution. And since expansion microscopy requires many processing steps, there's still the potential for artifacts to be introduced. Because of this, he says, "we worked very hard to validate what we've done, and others would be well advised to do the same."

Now, Gao and the Janelia team are building a new lattice light-sheet microscope, which they plan to move to Boyden's lab at MIT. "Our hope is to rapidly make maps of entire nervous systems," Boyden says.

Journal Reference:

1. Ruixuan Gao, Shoh M. Asano, Srigokul Upadhyayula, Igor Pisarev, Daniel E. Milkie, Tsung-Li Liu, Ved Singh, Austin Graves, Grace H. Huynh, Yongxin Zhao, John Bogovic, Jennifer Colonell, Carolyn M. Ott, Christopher Zugates, Susan Tappan, Alfredo Rodriguez, Kishore R. Mosaliganti, Shu-Hsien Sheu, H. Amalia Pasolli, Song Pang, C. Shan Xu, Sean G. Megason, Harald Hess, Jennifer Lippincott-Schwartz, Adam Hantman, Gerald M. Rubin, Tom Kirchhausen, Stephan Saalfeld, Yoshinori Aso, Edward S. Boyden, and Eric Betzig. Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution. Science, 2019 DOI: 10.1126/science.aau8302 

Courtesy: ScienceDaily

Scientists grow perfect human blood vessels in a petri dish

Diabetic blood vessel changes in patients and human vascular organoids. The basement membrane (green) around the blood vessels (red) is massively enlarged in diabetic patients (white arrows). The human vascular organoids that were made “diabetic” in the laboratory can now be used as diabetic model to identify new treatments.

Credit: IMBA

Scientists have managed to grow perfect human blood vessels as organoids in a petri dish for the first time.

The breakthrough engineering technology, outlined in a new study published today in Nature, dramatically advances research of vascular diseases like diabetes, identifying a key pathway to potentially prevent changes to blood vessels -- a major cause of death and morbidity among those with diabetes.

An organoid is a three-dimensional structure grown from stem cells that mimics an organ and can be used to study aspects of that organ in a petri dish.

"Being able to build human blood vessels as organoids from stem cells is a game changer," said the study's senior author Josef Penninger, the Canada 150 Research Chair in Functional Genetics, director of the Life Sciences Institute at UBC and founding director of the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA).

"Every single organ in our body is linked with the circulatory system. This could potentially allow researchers to unravel the causes and treatments for a variety of vascular diseases, from Alzheimer's disease, cardiovascular diseases, wound healing problems, stroke, cancer and, of course, diabetes."

Diabetes affects an estimated 420 million people worldwide. Many diabetic symptoms are the result of changes in blood vessels that result in impaired blood circulation and oxygen supply of tissues. Despite its prevalence, very little is known about the vascular changes arising from diabetes. This limitation has slowed the development of much-needed treatment.

To tackle this problem, Penninger and his colleagues developed a groundbreaking model: three-dimensional human blood vessel organoids grown in a petri dish. These so-called "vascular organoids" can be cultivated using stem cells in the lab, strikingly mimicking the structure and function of real human blood vessels.

When researchers transplanted the blood vessel organoids into mice, they found that they developed into perfectly functional human blood vessels including arteries and capillaries. The discovery illustrates that it is possible to not only engineer blood vessel organoids from human stem cells in a dish, but also to grow a functional human vascular system in another species.

"What is so exciting about our work is that we were successful in making real human blood vessels out of stem cells," said Reiner Wimmer, the study's first author and a postdoctoral research fellow at IMBA. "Our organoids resemble human capillaries to a great extent, even on a molecular level, and we can now use them to study blood vessel diseases directly on human tissue."

One feature of diabetes is that blood vessels show an abnormal thickening of the basement membrane. As a result, the delivery of oxygen and nutrients to cells and tissues is strongly impaired, causing a multitude of health problems, such as kidney failure, heart attacks, strokes, blindness and peripheral artery disease, leading to amputations.

The researchers then exposed the blood vessel organoids to a "diabetic" environment in a petri dish.

"Surprisingly, we could observe a massive expansion of the basement membrane in the vascular organoids," said Wimmer. "This typical thickening of the basement membrane is strikingly similar to the vascular damage seen in diabetic patients."

The researchers then searched for chemical compounds that could block thickening of the blood vessel walls. They found none of the current anti-diabetic medications had any positive effects on these blood vessel defects. However, they discovered that an inhibitor of ?-secretase, a type of enzyme in the body, prevented the thickening of the blood vessel walls, suggesting, at least in animal models, that blocking ?-secretase could be helpful in treating diabetes.

The researchers say the findings could allow them to identify underlying causes of vascular disease, and to potentially develop and test new treatments for patients with diabetes.

Journal Reference:

1. Reiner A. Wimmer, Alexandra Leopoldi, Martin Aichinger, Nikolaus Wick, Brigitte Hantusch, Maria Novatchkova, Jasmin Taubenschmid, Monika Hämmerle, Christopher Esk, Joshua A. Bagley, Dominik Lindenhofer, Guibin Chen, Manfred Boehm, Chukwuma A. Agu, Fengtang Yang, Beiyuan Fu, Johannes Zuber, Juergen A. Knoblich, Dontscho Kerjaschki & Josef M. Penninger. Human blood vessel organoids as a model of diabetic vasculopathy. Nature, 2019 DOI: 10.1038/s41586-018-0858-8 

Courtesy: ScienceDaily

Rice plants engineered to be better at photosynthesis make more rice

A new bioengineering approach for boosting photosynthesis in rice plants could increase grain yield by up to 27%, according to a study publishing January 10 in the journal Molecular Plant. The approach, called GOC bypass, enriches plant cells with CO₂ that would otherwise be lost through a metabolic process called photorespiration. The genetically engineered plants were greener and larger and showed increased photosynthetic efficiency and productivity under field conditions, with particular advantages in bright light.

This image compares rice spikelets from the engineered plants with the wild type control.

Credit: Shen and Wang et al./Molecular Plant

"Food shortage related to world population growth will be a serious problem our planet will have to face," says senior study author Xin-Xiang Peng of South China Agricultural University in Guangzhou, China. "Our study could have a major impact on this problem by significantly increasing rice yield, especially for areas with bright light."
Bioengineering improvement of rice, a staple food crop worldwide, has high practical importance, particularly in light of the need for increased crop productivity due to world population growth and the reduction of cultivable soils. But increases in yield for rice and several other major crops have been sparse in recent years, and crop yield seems to be reaching a ceiling of maximal potential.
The main genetic approach for increasing the yield potential of major crops focuses on photosynthesis, the biochemical process in which CO₂ and water are converted into O₂ and energy-rich sugar compounds that fuel plant growth. One way to increase photosynthesis is to bypass photorespiration, a light-dependent process in which O₂ is taken up and CO₂ released. The cost of photorespiration is massive. Abolishing photorespiration could result in up to a 55% increase in photosynthesis, placing photorespiration on center stage in attempts to improve photosynthetic efficiency and yield.
Over the past few years, three photorespiratory bypasses have been introduced into plants, and two of these led to observable increases in photosynthesis and biomass yield. But most of the experiments were carried out using the model organism Arabidopsis, and the increases have typically been observed under environment-controlled, low-light, and short-day conditions. "To the best of our knowledge, our study is the first that tested photorespiration bypass in rice," says co-author Zheng-Hui He of San Francisco State University.
In the new study, the researchers developed a strategy to essentially divert CO₂ from photorespiration to photosynthesis. They converted a molecule called glycolate, which is produced via photorespiration, to CO₂ using three rice enzymes: glycolate oxidase, oxalate oxidase, and catalase. To deploy GOC bypass, which was named for the three enzymes, the researchers introduced genes encoding the enzymes into rice chloroplasts -- organelles where photosynthesis takes place in plant cells.
As a result, the photorespiratory rate was suppressed by 18%-31% compared to normal, and the net photosynthetic rate increased by 15%-22%, primarily due to higher concentrations of cellular CO₂ used for photosynthesis. Compared to plants that were not genetically engineered, the GOC plants were consistently greener and larger, with an above-ground dry weight that was 14%-35% higher. Moreover, starch grains grew in size by 100% and increased in number per cell by 37%. In the spring seeding season, grain yield improved by 7% to 27%.
Moving forward, the researchers plan to optimize the performance of the engineered plants in the field by putting the same metabolic bypass in other rice varieties. They would also like to apply the same approach to other crop plants such potatoes.
"Our engineered plants could be deployed in fields at a larger scale after further evaluations by independent researchers and government agencies," Peng says. "Although we don't expect this approach would affect the taste of these plants, both the nutritional quality and taste are yet to be comprehensively evaluated by independent labs and governmental agencies."
This work was supported by the National Natural Science Foundation of China and Science and Technology Project of Guangzhou City.
 

Journal Reference:

1. Bo-Ran Shen, Li-Min Wang, Xiu-Ling Lin, Zhen Yao, Hua-Wei Xu, Cheng-Hua Zhu, Hai-Yan Teng, Li-Li Cui, E.-E. Liu, Jian-Jun Zhang, Zheng-Hui He, Xin-Xiang Peng. Engineering a New Chloroplastic Photorespiratory Bypass to Increase Photosynthetic Efficiency and Productivity in Rice. Molecular Plant, 2019; DOI: 10.1016/j.molp.2018.11.013 

Courtesy: ScienceDaily
 

New materials could 'drive wound healing' by harnessing natural healing methods

Materials are widely used to help heal wounds: Collagen sponges help treat burns and pressure sores, and scaffold-like implants are used to repair bones. However, the process of tissue repair changes over time, so scientists are developing biomaterials that interact with tissues as healing takes place.

Nurse bandages hands (stock image).

Credit: © ctpaep / Fotolia

 

Now, Dr Ben Almquist and his team at Imperial College London have created a new molecule that could change the way traditional materials work with the body. Known as traction force-activated payloads (TrAPs), their method lets materials talk to the body's natural repair systems to drive healing.

The researchers say incorporating TrAPs into existing medical materials could revolutionise the way injuries are treated. Dr Almquist, from Imperial's Department of Bioengineering, said: "Our technology could help launch a new generation of materials that actively work with tissues to drive healing."

The findings are published today in Advanced Materials.

Cellular call to action

After an injury, cells 'crawl' through the collagen 'scaffolds' found in wounds, like spiders navigating webs. As they move, they pull on the scaffold, which activates hidden healing proteins that begin to repair injured tissue.

The researchers designed TrAPs as a way to recreate this natural healing method. They folded the DNA segments into three-dimensional shapes known as aptamers that cling tightly to proteins. Then, they attached a customisable 'handle' that cells can grab onto on one end, before attaching the opposite end to a scaffold such as collagen.

During laboratory testing of their technique, they found that cells pulled on the TrAPs as they crawled through the collagen scaffolds. The pulling made the TrAPs unravel like shoelaces to reveal and activate the healing proteins. These proteins instruct the healing cells to grow and multiply.

The researchers also found that by changing the cellular 'handle', they can change which type of cell can grab hold and pull, letting them tailor TrAPs to release specific therapeutic proteins based on which cells are present at a given point in time. In doing so, the TrAPs produce materials that can smartly interact with the correct type of cell at the correct time during wound repair.

This is the first time scientists have activated healing proteins using different types of cells in human-made materials. The technique mimics healing methods found in nature. Dr Almquist said: "Using cell movement to activate healing is found in creatures ranging from sea sponges to humans. Our approach mimics them and actively works with the different varieties of cells that arrive in our damaged tissue over time to promote healing."

From lab to humans

This approach is adaptable to different cell types, so could be used in a variety of injuries such as fractured bones, scar tissue after heart attacks, and damaged nerves. New techniques are also desperately needed for patients whose wounds won't heal despite current interventions, like diabetic foot ulcers, which are the leading cause of non-traumatic lower leg amputations.

TrAPs are relatively straightforward to create and are fully human-made, meaning they are easily recreated in different labs and can be scaled up to industrial quantities. Their adaptability also means they could help scientists create new methods for laboratory studies of diseases, stem cells, and tissue development.

Aptamers are currently used as drugs, meaning they are already proven safe and optimised for clinical use. Because TrAPs take advantage of aptamers that are currently optimised for use in humans, they may be able to take a shorter path to the clinic than methods that start from ground zero.

Dr Almquist said: "The TrAP technology provides a flexible method to create materials that actively communicate with the wound and provide key instructions when and where they are needed. This sort of intelligent, dynamic healing is useful during every phase of the healing process, has the potential to increase the body's chance to recover, and has far-reaching uses on many different types of wounds. This technology has the potential to serve as a conductor of wound repair, orchestrating different cells over time to work together to heal damaged tissues."

The research was funded by the Engineering and Physical Sciences Research Council and Wellcome Trust.

Journal Reference:

1. Anna Stejskalová, Nuria Oliva, Frances J. England, Benjamin D. Almquist. Biologically Inspired, Cell‐Selective Release of Aptamer‐Trapped Growth Factors by Traction Forces. Advanced Materials, 2018 DOI: 10.1002/adma.201806380 

Courtesy: ScienceDaily

New study of MRSA spread provides framework for community-based infection surveillance

The identification of the recent spread of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) in a Brooklyn religious enclave is helping medical experts better understand how certain high-risk populations can drive the evolution of antimicrobial resistance and identify steps that can be taken to curtail its spread, according to a new study.

Publishing Monday, January 7, 2019, in the journal PNAS (Proceedings of the National Academy of Sciences), a team of researchers led by NYU School of Medicine noted that, in 2016, they began to see a growing number of CA-MRSA related skin infections in infants and young children from Brooklyn's Orthodox Jewish communities. A preliminary investigation showed that a unique strain of CA-MRSA was spreading -- similar to what would happen in a hospital outbreak.

Their findings also suggested transmission was occurring via the gastrointestinal tract -- and, perhaps even more alarmingly, that this specific strain of CA-MRSA accumulated genes that both increased virulence and conferred resistance to the two most common topical treatments used for decolonization and infection prevention: mupiricin and chlorhexidine. The resulting strains and consequential DNA elements potentially threaten larger human populations, including vulnerable populations in hospitals.

Because of the study team's initial surveillance and rapid response, the outbreak in Brooklyn is well characterized. They further conclude that the use of genomic surveillance, which helped identify this bacterial cluster and which continues to enhance infection-control methods in hospital settings, should be applied more vigilantly to community-based pathogen surveillance.

"Our experience in Brooklyn suggests that hospital-based genomic surveillance data can be applied to bridge the divide between hospital and community epidemiology, and therefore make it easier to identify and respond to community-based disease clusters," says Bo Shopsin, MD, PhD, The Saul J. Farber Assistant Professor of Medicine at NYU School of Medicine, NYU Langone Health's Director of Epidemiology, and senior author on the study. "Follow-up infection control strategies could help prevent further spread of antimicrobial-resistant pathogens such as CA-MRSA."

Journal Reference:

1. Richard Copin, William E. Sause, Yi Fulmer, Divya Balasubramanian, Sophie Dyzenhaus, Jamil M. Ahmed, Krishan Kumar, John Lees, Anna Stachel, Jason C. Fisher, Karl Drlica, Michael Phillips, Jeffrey N. Weiser, Paul J. Planet, Anne-Catrin Uhlemann, Deena R. Altman, Robert Sebra, Harm van Bakel, Jennifer Lighter, Victor J. Torres, Bo Shopsin. Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus. Proceedings of the National Academy of Sciences, 2019; 201814265 DOI: 10.1073/pnas.1814265116.

Courtesy: ScienceDaily

New houseplant can clean your home's air

We like to keep the air in our homes as clean as possible, and sometimes we use HEPA air filters to keep offending allergens and dust particles at bay.

But some hazardous compounds are too small to be trapped in these filters. Small molecules like chloroform, which is present in small amounts in chlorinated water, or benzene, which is a component of gasoline, build up in our homes when we shower or boil water, or when we store cars or lawn mowers in attached garages. Both benzene and chloroform exposure have been linked to cancer.
Now researchers at the University of Washington have genetically modified a common houseplant -- pothos ivy -- to remove chloroform and benzene from the air around it. The modified plants express a protein, called 2E1, that transforms these compounds into molecules that the plants can then use to support their own growth. The team will publish its findings Wednesday, Dec. 19 in Environmental Science & Technology.
"People haven't really been talking about these hazardous organic compounds in homes, and I think that's because we couldn't do anything about them," said senior author Stuart Strand, who is a research professor in the UW's civil and environmental engineering department. "Now we've engineered houseplants to remove these pollutants for us."
The team decided to use a protein called cytochrome P450 2E1, or 2E1 for short, which is present in all mammals, including humans. In our bodies, 2E1 turns benzene into a chemical called phenol and chloroform into carbon dioxide and chloride ions. But 2E1 is located in our livers and is turned on when we drink alcohol. So it's not available to help us process pollutants in our air.
"We decided we should have this reaction occur outside of the body in a plant, an example of the 'green liver' concept," Strand said. "And 2E1 can be beneficial for the plant, too. Plants use carbon dioxide and chloride ions to make their food, and they use phenol to help make components of their cell walls."
The researchers made a synthetic version of the gene that serves as instructions for making the rabbit form of 2E1. Then they introduced it into pothos ivy so that each cell in the plant expressed the protein. Pothos ivy doesn't flower in temperate climates so the genetically modified plants won't be able to spread via pollen.
"This whole process took more than two years," said lead author Long Zhang, who is a research scientist in the civil and environmental engineering department. "That is a long time, compared to other lab plants, which might only take a few months. But we wanted to do this in pothos because it's a robust houseplant that grows well under all sort of conditions."
The researchers then tested how well their modified plants could remove the pollutants from air compared to normal pothos ivy. They put both types of plants in glass tubes and then added either benzene or chloroform gas into each tube. Over 11 days, the team tracked how the concentration of each pollutant changed in each tube.
For the unmodified plants, the concentration of either gas didn't change over time. But for the modified plants, the concentration of chloroform dropped by 82 percent after three days, and it was almost undetectable by day six. The concentration of benzene also decreased in the modified plant vials, but more slowly: By day eight, the benzene concentration had dropped by about 75 percent.
In order to detect these changes in pollutant levels, the researchers used much higher pollutant concentrations than are typically found in homes. But the team expects that the home levels would drop similarly, if not faster, over the same time frame.
Plants in the home would also need to be inside an enclosure with something to move air past their leaves, like a fan, Strand said.
"If you had a plant growing in the corner of a room, it will have some effect in that room," he said. "But without air flow, it will take a long time for a molecule on the other end of the house to reach the plant."
The team is currently working to increase the plants' capabilities by adding a protein that can break down another hazardous molecule found in home air: formaldehyde, which is present in some wood products, such as laminate flooring and cabinets, and tobacco smoke.
"These are all stable compounds, so it's really hard to get rid of them," Strand said. "Without proteins to break down these molecules, we'd have to use high-energy processes to do it. It's so much simpler and more sustainable to put these proteins all together in a houseplant."
Civil and environmental engineering research technician Ryan Routsong is also a co-author. This research was funded by the National Science Foundation, Amazon Catalyst at UW and the National Institute of Environmental Health Sciences.
 

Journal Reference:

1. Long Zhang, Ryan Routsong, Stuart E. Strand. Greatly Enhanced Removal of Volatile Organic Carcinogens by a Genetically Modified Houseplant, Pothos Ivy (Epipremnum aureum) Expressing the Mammalian Cytochrome P450 2e1 Gene. Environmental Science & Technology, 2018; DOI: 10.1021/acs.est.8b04811 

Courtesy: ScienceDaily
 

First 3-D structure of the enzymatic role of DNA

Structure of deoxyribozyme 9DB1, where we can see the synthetic strand of DNA (in green) once it has catalysed the ligation of two RNA strands (in orange), joined at the point which is represented by a sphere.

Credit: A. Ponce-Salvatierra / Max-Planck-Institut für biophysikalische Chemie

DNA does not always adopt the form of the double helix which is associated with the genetic code; it can also form intricate folds and act as an enzyme: a deoxyribozyme. A researcher from Spain and other scientists from the Max Planck Institute for Biophysical Chemistry (Germany) have solved the first three-dimensional structure of this biomolecule that has proved much more flexible than previously thought.

Chemists successfully isolated deoxyribozymes over 20 years ago -- a DNA with the ability to act as an enzyme. However, until now they had not been able to associate its catalytic activity with the three-dimensional structure that provides such function to this DNA.

Now, European scientists from the Max Planck Institute for Biophysical Chemistry in Göttingen (Germany) have succeeded after having bombarded this molecule with X-rays in the SLS synchrotron in Switzerland. The results, published in the journal 'Nature', have made it possible to build the crystal structure of this 'DNAzyme' using computers.

"We have uncovered the first structure of a deoxyribozyme, and for the first time we can see that this DNA is capable of taking on forms as complex as those of protein enzymes or ribozymes ‑an RNA capable of catalytic activity," points out the Spanish scientist Almudena Ponce-Salvatierra, a member of the European group responsible for accomplishing this breakthrough.

The researchers have broken the paradigm of the supposed stiffness of DNA -a sort of symbol that is popularly associated with the double helix of Watson and Crick-, by demonstrating that this molecule can also adopt complicated three-dimensional structures in addition to being much more flexible than what was previously thought.

Deoxyribozymes are single strands of DNA that are synthesised in the laboratory in order to exploit their catalytic activity. Specifically, the researchers have successfully visualised the structure of a deoxyribozyme named 9DB1, which catalyses the ligation of two RNA strands.

According to the authors of this study, the findings help us to better understand the molecular principles of the reactions in which this type of molecule plays a part.

"There are many applications for deoxyribozymes, from catalysing the ligation of two DNA or RNA fragments, to repairing any of its components, such as thymine," explains Ponce-Salvatierra, who announced that the clinical trials for its use in medicine are already underway.

Journal Reference:

1. Almudena Ponce-Salvatierra, Katarzyna Wawrzyniak-Turek, Ulrich Steuerwald, Claudia Höbartner, Vladimir Pena. Crystal structure of a DNA catalyst. Nature, 2016; 529 (7585): 231 DOI: 10.1038/nature16471 

Courtesy: ScienceDaily

Computers can be a real pain in the neck

Two San Francisco State University students show how people compress their neck at the computer.

Credit: San Francisco State University

It's a posture so common we almost don't notice it anymore: someone sitting at a computer jutting his or her head forward to look more closely at the screen. But this seemingly harmless position compresses the neck and can lead to fatigue, headaches, poor concentration, increased muscle tension and even injury to the vertebrae over time. It can even limit the ability to turn your head.

"When your posture is tall and erect, the muscles of your back can easily support the weight of your head and neck -- as much as 12 pounds," explains San Francisco State University Professor of Holistic Health Erik Peper. "But when your head juts forward at a 45 degree angle, your neck acts like a fulcrum, like a long lever lifting a heavy object. Now the muscle weight of your head and neck is the equivalent of about 45 pounds. It is not surprising people get stiff necks and shoulder and back pain."
Peper, Associate Professor of Health Education Richard Harvey and their colleagues, including two student researchers, tested the effects of head and neck position in a recent study published in the journal Biofeedback. First they asked 87 students to sit upright with their heads properly aligned on their necks and asked them to turn their heads. Then the students were asked to "scrunch" their necks and jut their heads forward. Ninety-two percent reported being able to turn their heads much farther when not scrunching. In the second test, 125 students scrunched their necks for 30 seconds. Afterwards, 98 percent reported some level of pain in their head, neck or eyes.
The researchers also monitored 12 students with electromyography equipment and found that trapezius muscle tension increased in the scrunched, head forward position.
So if you suffer from headaches or neck and backaches from computer work, check your posture and make sure your head is aligned on top of your neck, as if held by an invisible thread from the ceiling. "You can do something about this poor posture very quickly," said Peper. To increase body awareness, Peper advises purposefully replicating the head-forward/neck scrunched position. "You can exaggerate the position and experience the symptoms. Then when you find yourself doing it, you can become aware and stop."
Other solutions he offers include increasing the font on your computer screen, wearing computer reading glasses or placing your computer on a stand at eye level, all to make the screen easier to read without strain.
 

Story Source:
Materials provided by San Francisco State University. Original written by Lisa Owens Viani. Note: Content may be edited for style and length.
 

 

Courtesy: ScienceDaily

 

Engineers create an inhalable form of messenger RNA

MIT researchers have designed inhalable particles that can deliver messenger RNA. These lung epithelial cells have taken up particles (yellow) that carry mRNA encoding green fluorescent protein.

Credit: Asha Patel

Messenger RNA, which can induce cells to produce therapeutic proteins, holds great promise for treating a variety of diseases. The biggest obstacle to this approach so far has been finding safe and efficient ways to deliver mRNA molecules to the target cells.

In an advance that could lead to new treatments for lung disease, MIT researchers have now designed an inhalable form of mRNA. This aerosol could be administered directly to the lungs to help treat diseases such as cystic fibrosis, the researchers say.
"We think the ability to deliver mRNA via inhalation could allow us to treat a range of different disease of the lung," says Daniel Anderson, an associate professor in MIT's Department of Chemical Engineering, a member of MIT's Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study.
The researchers showed that they could induce lung cells in mice to produce a target protein -- in this case, a bioluminescent protein. If the same success rate can be achieved with therapeutic proteins, that could be high enough to treat many lung diseases, the researchers say.
Asha Patel, a former MIT postdoc who is now an assistant professor at Imperial College London, is the lead author of the paper, which appears in the Jan. 4 issue of the journal Advanced Materials. Other authors of the paper include James Kaczmarek and Kevin Kauffman, both recent MIT PhD recipients; Suman Bose, a research scientist at the Koch Institute; Faryal Mir, a former MIT technical assistant; Michael Heartlein, the chief technical officer at Translate Bio; Frank DeRosa, senior vice president of research and development at Translate Bio; and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.
Treatment by inhalation
Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins. Many researchers have been working on developing mRNA to treat genetic disorders or cancer, by essentially turning the patients' own cells into drug factories.
Because mRNA can be easily broken down in the body, it needs to transported within some kind of protective carrier. Anderson's lab has previously designed materials that can deliver mRNA and another type of RNA therapy called RNA interference (RNAi) to the liver and other organs, and some of these are being further developed for possible testing in patients.
In this study, the researchers wanted to create an inhalable form of mRNA, which would allow the molecules to be delivered directly to the lungs. Many existing drugs for asthma and other lung diseases are specially formulated so they can be inhaled via either an inhaler, which sprays powdered particles of medication, or a nebulizer, which releases an aerosol containing the medication.
The MIT team set out to develop a material that could stabilize RNA during the process of aerosol delivery. Some previous studies have explored a material called polyethylenimine (PEI) for delivering inhalable DNA to the lungs. However, PEI doesn't break down easily, so with the repeated dosing that would likely be required for mRNA therapies, the polymer could accumulate and cause side effects.
To avoid those potential side effects, the researchers turned to a type of positively charged polymers called hyperbranched poly (beta amino esters), which, unlike PEI, are biodegradable.
The particles the team created consist of spheres, approximately 150 nanometers in diameter, with a tangled mixture of the polymer and mRNA molecules that encode luciferase, a bioluminescent protein. The researchers suspended these particles in droplets and delivered them to mice as an inhalable mist, using a nebulizer.
"Breathing is used as a simple but effective delivery route to the lungs. Once the aerosol droplets are inhaled, the nanoparticles contained within each droplet enter the cells and instruct it to make a particular protein from mRNA," Patel says.
The researchers found that 24 hours after the mice inhaled the mRNA, lung cells were producing the bioluminescent protein. The amount of protein gradually fell over time as the mRNA was cleared. The researchers were able to maintain steady levels of the protein by giving the mice repeated doses, which may be necessary if adapted to treat chronic lung disease.
Broad distribution
Further analysis of the lungs revealed that mRNA was evenly distributed throughout the five lobes of the lungs and was taken up mainly by epithelial lung cells, which line the lung surfaces. These cells are implicated in cystic fibrosis, as well as other lung diseases such as respiratory distress syndrome, which is caused by a deficiency in surfactant protein. In her new lab at Imperial College London, Patel plans to further investigate mRNA-based therapeutics.
In this study, the researchers also demonstrated that the nanoparticles could be freeze-dried into a powder, suggesting that it may be possible to deliver them via an inhaler instead of nebulizer, which could make the medication more convenient for patients.
TranslateBio, a company developing mRNA therapeutics, partially funded this study and has also begun testing an inhalable form of mRNA in a Phase 1/2 clinical trial in patients with cystic fibrosis. Other sources of funding for this study include the United Kingdom Engineering and Physical Sciences Research Council and the Koch Institute Support (core) Grant from the National Cancer Institute.

Journal Reference:

1. Asha Kumari Patel, James C. Kaczmarek, Suman Bose, Kevin J. Kauffman, Faryal Mir, Michael W. Heartlein, Frank DeRosa, Robert Langer, Daniel G. Anderson. Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium. Advanced Materials, 2019; 1805116 DOI: 10.1002/adma.201805116

Courtesy: ScienceDaily