Nature
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Blood-Based Multiplexed Diagnostic Sensor Helps to Accurately Detect Alzheimer’s Disease
A research team at KAIST reported clinically accurate multiplexed electrical biosensor for detecting Alzheimer’s disease by measuring its core biomarkers using densely aligned carbon nanotubes.
Alzheimer’s disease is the most prevalent neurodegenerative disorder, affecting one in ten aged over 65 years. Early diagnosis can reduce the risk of suffering the disease by one-third, according to recent reports. However, its early diagnosis remains challenging due to the low accuracy but high cost of diagnosis.
Research team led by Professors Chan Beum Park and Steve Park described an ultrasensitive detection of multiple Alzheimer's disease core biomarker in human plasma. The team have designed the sensor array by employing a densely aligned single-walled carbon nanotube thin films as a transducer.
The representative biomarkers of Alzheimer's disease are beta-amyloid42, beta-amyloid40, total tau protein, phosphorylated tau protein and the concentrations of these biomarkers in human plasma are directly correlated with the pathology of Alzheimer’s disease.
The research team developed a highly sensitive resistive biosensor based on densely aligned carbon nanotubes fabricated by Langmuir-Blodgett method with a low manufacturing cost.
Aligned carbon nanotubes with high density minimizes the tube-to-tube junction resistance compared with randomly distributed carbon nanotubes, which leads to the improvement of sensor sensitivity. To be more specific, this resistive sensor with densely aligned carbon nanotubes exhibits a sensitivity over 100 times higher than that of conventional carbon nanotube-based biosensors.
By measuring the concentrations of four Alzheimer’s disease biomarkers simultaneously Alzheimer patients can be discriminated from health controls with an average sensitivity of 90.0%, a selectivity of 90.0% and an average accuracy of 88.6%.
This work, titled “Clinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma”, were published in Nature Communications on January 8th 2020. The authors include PhD candidate Kayoung Kim and MS candidate Min-Ji Kim.
Professor Steve Park said, “This study was conducted on patients who are already confirmed with Alzheimer’s Disease. For further use in practical setting, it is necessary to test the patients with mild cognitive impairment.” He also emphasized that, “It is essential to establish a nationwide infrastructure, such as mild cognitive impairment cohort study and a dementia cohort study. This would enable the establishment of world-wide research network, and will help various private and public institutions.”
This research was supported by the Ministry of Science and ICT, Human Resource Bank of Chungnam National University Hospital and Chungbuk National University Hospital.
< A schematic diagram of a high-density aligned carbon nanotube-based resistive sensor that distinguishes patients with Alzheimer’s Disease by measuring the concentration of four biomarkers in the blood. >
Profile:
Professor Steve Park
stevepark@kaist.ac.kr
Department of Materials Science and Engineering
http://steveparklab.kaist.ac.kr/
KAIST
Profile:
Professor Chan Beum Park
parkcb at kaist.ac.kr
Department of Materials Science and Engineering
http://biomaterials.kaist.ac.kr/
KAIST
2020.02.07 View 8942 -
Scientists Discover the Mechanism of DNA High-Order Structure Formation
(Molecular structures of Abo1 in different energy states (left), Demonstration of an Abo1-assisted histone loading onto DNA by the DNA curtain assay. )
The genetic material of our cells—DNA—exists in a high-order structure called “chromatin”. Chromatin consists of DNA wrapped around histone proteins and efficiently packs DNA into a small volume. Moreover, using a spool and thread analogy, chromatin allows DNA to be locally wound or unwound, thus enabling genes to be enclosed or exposed. The misregulation of chromatin structures results in aberrant gene expression and can ultimately lead to developmental disorders or cancers. Despite the importance of DNA high-order structures, the complexity of the underlying machinery has circumvented molecular dissection.
For the first time, molecular biologists have uncovered how one particular mechanism uses energy to ensure proper histone placement onto DNA to form chromatin. They published their results on Dec. 17 in Nature Communications.
The study focused on proteins called histone chaperones. Histone chaperones are responsible for adding and removing specific histones at specific times during the DNA packaging process. The wrong histone at the wrong time and place could result in the misregulation of gene expression or aberrant DNA replication. Thus, histone chaperones are key players in the assembly and disassembly of chromatin.
“In order to carefully control the assembly and disassembly of chromatin units, histone chaperones act as molecular escorts that prevent histone aggregation and undesired interactions,” said Professor Ji-Joon Song in the Department of Biological Sciences at KAIST. “We set out to understand how a unique histone chaperone uses chemical energy to assemble or disassemble chromatin.”
Song and his team looked to Abo1, the only known histone chaperone that utilizes cellular energy (ATP). While Abo1 is found in yeast, it has an analogous partner in other organisms, including humans, called ATAD2. Both use ATP, which is produced through a cellular process where enzymes break down a molecule’s phosphate bond. ATP energy is typically used to power other cellular processes, but it is a rare partner for histone chaperones.
“This was an interesting problem in the field because all other histone chaperones studied to date do not use ATP,” Song said.
By imaging Abo1 with a single-molecule fluorescence imaging technique known as the DNA curtain assay, the researchers could examine the protein interactions at the single-molecule level. The technique allows scientists to arrange the DNA molecules and proteins on a single layer of a microfluidic chamber and examine the layer with fluorescence microscopy.
The researchers found through real-time observation that Abo1 is ring-shaped and changes its structure to accommodate a specific histone and deposit it on DNA. Moreover, they found that the accommodating structural changes are powered by ADP.
“We discovered a mechanism by which Abo1 accommodates histone substrates, ultimately allowing it to function as a unique energy-dependent histone chaperone,” Song said. “We also found that despite looking like a protein disassembly machine, Abo1 actually loads histone substrates onto DNA to facilitate chromatin assembly.”
The researchers plan to continue exploring how energy-dependent histone chaperones bind and release histones, with the ultimate goal of developing therapeutics that can target cancer-causing misbehavior by Abo1’s analogous human counterpart, ATAD2.
-Profile
Professor Ji-Joon Song
Department of Biological Sciences KI for the BioCentury (https://kis.kaist.ac.kr/index.php?mid=KIB_O) KAIST
2020.01.07 View 8736 -
‘Carrier-Resolved Photo-Hall’ to Push Semiconductor Advances
(Professor Shin and Dr. Gunawan (left))
An IBM-KAIST research team described a breakthrough in a 140-year-old mystery in physics. The research reported in Nature last month unlocks the physical characteristics of semiconductors in much greater detail and aids in the development of new and improved semiconductor materials.
Research team under Professor Byungha Shin at the Department of Material Sciences and Engineering and Dr. Oki Gunawan at IBM discovered a new formula and technique that enables the simultaneous extraction of both majority and minority carrier information such as their density and mobility, as well as gain additional insights about carrier lifetimes, diffusion lengths, and the recombination process. This new discovery and technology will help push semiconductor advances in both existing and emerging technologies.
Semiconductors are the basic building blocks of today’s digital electronics age, providing us with a multitude of devices that benefit our modern life. To truly appreciate the physics of semiconductors, it is very important to understand the fundamental properties of the charge carriers inside the materials, whether those particles are positive or negative, their speed under an applied electric field, and how densely they are packed into the material.
Physicist Edwin Hall found a way to determine those properties in 1879, when he discovered that a magnetic field will deflect the movement of electronic charges inside a conductor and that the amount of deflection can be measured as a voltage perpendicular to the flow of the charge. Decades after Hall’s discovery, researchers also recognized that they can measure the Hall effect with light via “photo-Hall experiments”. During such experiments, the light generates multiple carriers or electron–hole pairs in the semiconductors.
Unfortunately, the basic Hall effect only provided insights into the dominant charge carrier (or majority carrier). Researchers were unable to extract the properties of both carriers (the majority and minority carriers) simultaneously. The property information of both carriers is crucial for many applications that involve light such as solar cells and other optoelectronic devices.
In the photo-Hall experiment by the KAIST-IBM team, both carriers contribute to changes in conductivity and the Hall coefficient. The key insight comes from measuring the conductivity and Hall coefficient as a function of light intensity. Hidden in the trajectory of the conductivity, the Hall coefficient curve reveals crucial new information: the difference in the mobility of both carriers. As discussed in the paper, this relationship can be expressed elegantly as: Δµ = d (σ²H)/dσ
The research team solved for both majority and minority carrier mobility and density as a function of light intensity, naming the new technique Carrier-Resolved Photo Hall (CRPH) measurement. With known light illumination intensity, the carrier lifetime can be established in a similar way.
Beyond advances in theoretical understanding, advances in experimental techniques were also critical for enabling this breakthrough. The technique requires a clean Hall signal measurement, which can be challenging for materials where the Hall signal is weak due to low mobility or when extra unwanted signals are present, such as under strong light illumination.
The newly developed photo-Hall technique allows the extraction of an astonishing amount of information from semiconductors. In contrast to only three parameters obtained in the classic Hall measurements, this new technique yields up to seven parameters at every tested level of light intensity. These include the mobility of both the electron and hole; their carrier density under light; the recombination lifetime; and the diffusion lengths for electrons, holes, and ambipolar types. All of these can be repeated N times (i.e. the number of light intensity settings used in the experiment).
Professor Shin said, “This novel technology sheds new light on understanding the physical characteristics of semiconductor materials in great detail.” Dr. Gunawan added, “This will will help accelerate the development of next-generation semiconductor technology such as better solar cells, better optoelectronics devices, and new materials and devices for artificial intelligence technology.”
Profile:
Professor Byungha Shin
Department of Materials Science and Engineering
KAIST
byungha@kaist.ac.kr
http://energymatlab.kaist.ac.kr/
2019.11.18 View 12481 -
Ultrafast Quantum Motion in a Nanoscale Trap Detected
< Professor Heung-Sun Sim (left) and Co-author Dr. Sungguen Ryu (right) >
KAIST researchers have reported the detection of a picosecond electron motion in a silicon transistor. This study has presented a new protocol for measuring ultrafast electronic dynamics in an effective time-resolved fashion of picosecond resolution. The detection was made in collaboration with Nippon Telegraph and Telephone Corp. (NTT) in Japan and National Physical Laboratory (NPL) in the UK and is the first report to the best of our knowledge.
When an electron is captured in a nanoscale trap in solids, its quantum mechanical wave function can exhibit spatial oscillation at sub-terahertz frequencies. Time-resolved detection of such picosecond dynamics of quantum waves is important, as the detection provides a way of understanding the quantum behavior of electrons in nano-electronics. It also applies to quantum information technologies such as the ultrafast quantum-bit operation of quantum computing and high-sensitivity electromagnetic-field sensing. However, detecting picosecond dynamics has been a challenge since the sub-terahertz scale is far beyond the latest bandwidth measurement tools.
A KAIST team led by Professor Heung-Sun Sim developed a theory of ultrafast electron dynamics in a nanoscale trap, and proposed a scheme for detecting the dynamics, which utilizes a quantum-mechanical resonant state formed beside the trap. The coupling between the electron dynamics and the resonant state is switched on and off at a picosecond so that information on the dynamics is read out on the electric current being generated when the coupling is switched on.
NTT realized, together with NPL, the detection scheme and applied it to electron motions in a nanoscale trap formed in a silicon transistor. A single electron was captured in the trap by controlling electrostatic gates, and a resonant state was formed in the potential barrier of the trap.
The switching on and off of the coupling between the electron and the resonant state was achieved by aligning the resonance energy with the energy of the electron within a picosecond. An electric current from the trap through the resonant state to an electrode was measured at only a few Kelvin degrees, unveiling the spatial quantum-coherent oscillation of the electron with 250 GHz frequency inside the trap.
Professor Sim said, “This work suggests a scheme of detecting picosecond electron motions in submicron scales by utilizing quantum resonance. It will be useful in dynamical control of quantum mechanical electron waves for various purposes in nano-electronics, quantum sensing, and quantum information”.
This work was published online at Nature Nanotechnology on November 4. It was partly supported by the Korea National Research Foundation through the SRC Center for Quantum Coherence in Condensed Matter. For more on the NTT news release this article, please visit https://www.ntt.co.jp/news2019/1911e/191105a.html
-ProfileProfessor Heung-Sun Sim
Department of PhysicsDirector, SRC Center for Quantum Coherence in Condensed Matterhttps://qet.kaist.ac.kr KAIST
-Publication:Gento Yamahata, Sungguen Ryu, Nathan Johnson, H.-S. Sim, Akira Fujiwara, and Masaya Kataoka. 2019. Picosecond coherent electron motion in a silicon single-electron source. Nature Nanotechnology (Online Publication). 6 pages. https://doi.org/10.1038/s41565-019-0563-2
2019.11.05 View 15677 -
A Single, Master Switch for Sugar Levels?
When a fly eats sugar, a single brain cell sends simultaneous messages to stimulate one hormone and inhibit another to control glucose levels in the body. Further research into this control system with remarkable precision could shed light on the neural mechanisms of diabetes and obesity in humans .
A single neuron appears to monitor and control sugar levels in the fly body, according to research published this week in Nature. This new insight into the mechanisms in the fly brain that maintain a balance of two key hormones controlling glucose levels, insulin and glucagon, can provide a framework for understanding diabetes and obesity in humans.
Neurons that sense and respond to glucose were identified more than 50 years ago, but what they do in our body has remained unclear. Researchers at the Korea Advanced Institute of Science and Technology (KAIST) and New York University School of Medicine have now found a single “glucose-sensing neuron” that appears to be the master controller in Drosophila, the vinegar fly, for maintaining an ideal glucose balance, called homeostasis.
Professor Greg Seong-Bae Suh, Dr. Yangkyun Oh and colleagues identified a key neuron that is excited by glucose, which they called CN neuron. This CN neuron has a unique shape – it has an axon (which is used to transmit information to downstream cells) that is bifurcated. One branch projects to insulin-producing cells, and sends a signal triggering the secretion of the insulin equivalent in flies. The other branch projects to glucagon-producing cells and sends a signal inhibiting the secretion of the glucagon equivalent.
When flies consume food, the levels of glucose in their body increase; this excites the CN neuron, which fires the simultaneous signals to stimulate insulin and inhibit glucagon secretion, thereby maintaining the appropriate balance between the hormones and sugar in the blood. The researchers were able to see this happening in the brain in real time by using a combination of cutting-edge fluorescent calcium imaging technology, as well as measuring hormone and sugar levels and applying highly sophisticated molecular genetic techniques.
When flies were not fed, however, the researchers observed a reduction in the activity of CN neuron, a reduction in insulin secretion and an increase in glucagon secretion. These findings indicate that these key hormones are under the direct control of the glucose-sensing neuron. Furthermore, when they silenced the CN neuron rendering dysfunctional CN neuron in flies, these animals experienced an imbalance, resulting in hyperglycemia – high levels of sugars in the blood, similar to what is observed in diabetes in humans. This further suggests that the CN neuron is critical to maintaining glucose homeostasis in animals.
While further research is required to investigate this process in humans, Suh notes this is a significant step forward in the fields of both neurobiology and endocrinology.
“This work lays the foundation for translational research to better understand how this delicate regulatory process is affected by diabetes, obesity, excessive nutrition and diets high in sugar,” Suh said.
Profile: Greg Seong-Bae Suh
seongbaesuh@kaist.ac.kr
Professor Department of Biological Sciences
KAIST
(Figure: A single glucose-excited CN neuron extends bifurcated axonal branches,
one of which innervates insulin producing cells and stimulates their activity an the other axonal branch projects to glucagon producing cells and inhibits their activity.)
2019.10.24 View 16198 -
A Mathematical Model Reveals Long-Distance Cell Communication Mechanism
How can tens of thousands of people in a large football stadium all clap together with the same beat even though they can only hear the people near them clapping?
A combination of a partial differential equation and a synthetic circuit in microbes answers this question. An interdisciplinary collaborative team of Professor Jae Kyoung Kim at KAIST, Professor Krešimir Josić at the University of Houston, and Professor Matt Bennett at Rice University has identified how a large community can communicate with each other almost simultaneously even with very short distance signaling. The research was reported at Nature Chemical Biology.
Cells often communicate using signaling molecules, which can travel only a short distance. Nevertheless, the cells can also communicate over large distances to spur collective action. The team revealed a cell communication mechanism that quickly forms a network of local interactions to spur collective action, even in large communities.
The research team used an engineered transcriptional circuit of combined positive and negative feedback loops in E. coli, which can periodically release two types of signaling molecules: activator and repressor. As the signaling molecules travel over a short distance, cells can only talk to their nearest neighbors. However, cell communities synchronize oscillatory gene expression in spatially extended systems as long as the transcriptional circuit contains a positive feedback loop for the activator.
Professor Kim said that analyzing and understanding such high-dimensional dynamics was extremely difficult. He explained, “That’s why we used high-dimensional partial differential equation to describe the system based on the interactions among various types of molecules.” Surprisingly, the mathematical model accurately simulates the synthesis of the signaling molecules in the cell and their spatial diffusion throughout the chamber and their effect on neighboring cells.
The team simplified the high-dimensional system into a one-dimensional orbit, noting that the system repeats periodically. This allowed them to discover that cells can make one voice when they lowered their own voice and listened to the others. “It turns out the positive feedback loop reduces the distance between moving points and finally makes them move all together. That’s why you clap louder when you hear applause from nearby neighbors and everyone eventually claps together at almost the same time,” said Professor Kim.
Professor Kim added, “Math is a powerful as it simplifies complex thing so that we can find an essential underlying property. This finding would not have been possible without the simplification of complex systems using mathematics."
The National Institutes of Health, the National Science Foundation, the Robert A. Welch Foundation, the Hamill Foundation, the National Research Foundation of Korea, and the T.J. Park Science Fellowship of POSCO supported the research.
(Figure: Complex molecular interactions among microbial consortia is simplified as interactions among points on a limit cycle (right).)
2019.10.15 View 24065 -
Algorithm Identifies Optimal Pairs for Composing Metal-Organic Frameworks
The integration of metal-organic frameworks (MOFs) and other metal nanoparticles has increasingly led to the creation of new multifunctional materials. Many researchers have integrated MOFs with other classes of materials to produce new structures with synergetic properties.
Despite there being over 70,000 collections of synthesized MOFs that can be used as building blocks, the precise nature of the interaction and the bonding at the interface between the two materials still remains unknown. The question is how to sort out the right matching pairs out of 70,000 MOFs.
An algorithmic study published in Nature Communications by a KAIST research team presents a clue for finding the perfect pairs. The team, led by Professor Ji-Han Kim from the Department of Chemical and Biomolecular Engineering, developed a joint computational and experimental approach to rationally design MOF@MOFs, a composite of MOFs where an MOF is grown on a different MOF.
Professor Kim’s team, in collaboration with UNIST, noted that the metal node of one MOF can coordinately bond with the linker of a different MOF and the precisely matched interface configurations at atomic and molecular levels can enhance the likelihood of synthesizing MOF@MOFs.
They screened thousands of MOFs and identified optimal MOF pairs that can seamlessly connect to one another by taking advantage of the fact that the metal node of one MOF can form coordination bonds with the linkers of the second MOF. Six pairs predicted from the computational algorithm successfully grew into single crystals.
This computational workflow can readily extend into other classes of materials and can lead to the rapid exploration of the composite MOFs arena for accelerated materials development. Even more, the workflow can enhance the likelihood of synthesizing MOF@MOFs in the form of large single crystals, and thereby demonstrated the utility of rationally designing the MOF@MOFs.
This study is the first algorithm for predicting the synthesis of composite MOFs, to the best of their knowledge. Professor Kim said, “The number of predicted pairs can increase even more with the more general 2D lattice matching, and it is worth investigating in the future.”
This study was supported by Samsung Research Funding & Incubation Center of Samsung Electronics.
(Figure: An example of a rationally synthesized MOF@MOFs (cubic HKUST-1@MOF-5 ))
2019.08.30 View 15042 -
Enhanced Natural Gas Storage to Help Reduce Global Warming
< Professor Atilhan (left) and Professor Yavuz (right) >
Researchers have designed plastic-based materials that can store natural gas more effectively. These new materials can not only make large-scale, cost-effective, and safe natural gas storage possible, but further hold a strong promise for combating global warming.
Natural gas (predominantly methane) is a clean energy alternative. It is stored by compression, liquefaction, or adsorption. Among these, adsorbed natural gas (ANG) storage is a more efficient, cheaper, and safer alternative to conventional compressed natural gas (CNG) and liquefied natural gas (LNG) storage approaches that have drawbacks such as low storage efficiency, high costs, and safety concerns. However, developing adsorptive materials that can more fully exploit the advantages of ANG storage has remained a challenging task.
A KAIST research team led by Professor Cafer T. Yavuz from the Graduate School of Energy, Environment, Water, and Sustainability (EEWS), in collaboration with Professor Mert Atilhan’s group from Texas A&M University, synthesized 29 unique porous polymeric structures with inherent flexibility, and tested their methane gas uptake capacity at high pressures. These porous polymers had varying synthetic complexities, porosities, and morphologies, and the researchers subjected each porous polymer to pure methane gas under various conditions to study the ANG performances.
Of these 29 distinct chemical structures, COP-150 was particularly noteworthy as it achieved a high deliverable gravimetric methane working capacity when cycled between 5 and 100 bar at 273 K, which is 98% of the total uptake capacity. This result surpassed the target set by the United States Department of Energy (US DOE).
COP-150 is the first ever structure to fulfil both the gravimetric and volumetric requirements of the US DOE for successful vehicular use, and the total cost to produce the COP-150 adsorbent was only 1 USD per kilogram.
COP-150 can be produced using freely available and easily accessible plastic materials, and moreover, its synthesis takes place at room temperature, open to the air, and no previous purification of the chemicals is required. The pressure-triggered flexible structure of COP-150 is also advantageous in terms of the total working capacity of deliverable methane for real applications.
The research team believed that the increased pressure flexes the network structure of COP-150 showing “swelling” behavior, and suggested that the flexibility provides rapid desorption and thermal management, while the hydrophobicity and the nature of the covalently bonded framework allow these promising materials to tolerate harsh conditions.
This swelling mechanism of expansion-contraction solves two other major issues, the team noted. Firstly, when using adsorbents based on such a mechanism, unsafe pressure spikes that may occur due to temperature swings can be eliminated. In addition, contamination can also be minimized, since the adsorbent remains contracted when no gas is stored.
Professor Yavuz said, “We envision a whole host of new designs and mechanisms to be developed based on our concept. Since natural gas is a much cleaner fuel than coal and petroleum, new developments in this realm will help switching to the use of less polluting fuels.”
Professor Atilhan agreed the most important impact of their research is on the environment. “Using natural gas more than coal and petroleum will significantly reduce greenhouse gas emissions. We believe, one day, we might see vehicles equipped with our materials that are run by a cleaner natural gas fuel,” he added.
This study, reported in Nature Energy on July 8, was supported by National Research Foundation of Korea (NRF) grants ( NRF-2016R1A2B4011027, NRF-2017M3A7B4042140, and NRF-2017M3A7B4042235).
< Suggested chemical structure of COP-150 >
< Initial ingredients (left) and final product (right) of COP-150 synthesis >
< Comparison of highest reported volumetric working capacities >
(END)
2019.08.09 View 25553 -
Newly Identified Meningeal Lymphatic Vessels Answers the Key Questions on Brain Clearance
(Figure: Schematic images of location and features of meningeal lymphatic vessels and their changes associated with ageing.)
Just see what happens when your neighborhood’s waste disposal system is out of service. Not only do the piles of trash stink but they can indeed hinder the area’s normal functioning. That is also the case when the brain’s waste management is on the blink.
The buildup of toxic proteins in the brain causes a massive damage to the nerves, leading to cognitive dysfunction and increased probability of developing neurodegenerative disorders such as Alzheimer's disease. Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism.
Medical scientists led by Professor Gou Young Koh at the Graduate School of Medical Science and Engineering have reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage.
They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging. Their findings have been reported in the journal Nature on July 24.
Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question — where is the main exit for the CSF? Though mLVs in the upper part of the skull (dorsal meningeal lymphatic vessels) were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section.
“As a hidden exit for CSF, we looked into the mLVs trapped within complex structures at the base of the skull,” says Dr. Ji Hoon Ahn, the first author of this study. The researchers used several techniques to characterize the basal mLVs in detail. They used a genetically engineered lymphatic-reporter mouse model to visualize mLVs under a fluorescence microscope. By performing a careful examination of the mice skull, they found distinctive features of basal mLVs that make them suitable for CSF uptake and drainage. Just like typical functional lymphatic vessels, basal mLVs are found to have abundant lymphatic vessel branches with finger-like protrusions. Additionally, valves inside the basal mLVs allow the flow to go in one direction. In particular, they found that the basal mLVs are closely located to the CSF. Dr. Hyunsoo Cho, the first author of this study explains, “All up, it seemed a solid case that basal mLVs are the brain’s main clearance pathways.
The researchers verified such specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs. Jun-Hee Kim, the first author of this study notes, “We literally saw that the brain clearance mechanism utilizing basal outflow route to exit the skull.
It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. The corresponding author of this study, Dr. Koh says, “By characterizing the precise route for fluids leaving the brain, this study improves our understanding on how waste is cleared from the brain. Our findings also provide further insights into the role of impaired CSF clearance in the development of age-related neurodegenerative diseases.”
Many current therapies for Alzheimer’s disease target abnormally accumulated proteins, such as beta-amyloid. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function. Such breakthrough might become quite a sensational strategy for eliminating the buildup of aging-related toxic proteins. “It definitely warrants more extensive investigation of mLVs in patients with age-related neurodegenerative disease such as Alzheimer’s disease prior to clinical investigation,” adds Professor Koh.
2019.07.25 View 31046 -
Deciphering Brain Somatic Mutations Associated with Alzheimer's Disease
Researchers have found a potential link between non-inherited somatic mutations in the brain and the progression of Alzheimer’s disease
Researchers have identified somatic mutations in the brain that could contribute to the development of Alzheimer’s disease (AD). Their findings were published in the journal Nature Communications last week.
Decades worth of research has identified inherited mutations that lead to early-onset familial AD. Inherited mutations, however, are behind at most half the cases of late onset sporadic AD, in which there is no family history of the disease. But the genetic factors causing the other half of these sporadic cases have been unclear.
Professor Jeong Ho Lee at the Graduate School of Medical Science and Engineering and colleagues analysed the DNA present in post-mortem hippocampal formations and in blood samples from people aged 70 to 96 with AD and age-matched controls. They specifically looked for non-inherited somatic mutations in their brains using high-depth whole exome sequencing.
The team developed a bioinformatics pipeline that enabled them to detect low-level brain somatic single nucleotide variations (SNVs) – mutations that involve the substitution of a single nucleotide with another nucleotide. Brain somatic SNVs have been reported on and accumulate throughout our lives and can sometimes be associated with a range of neurological diseases.
The number of somatic SNVs did not differ between individuals with AD and non-demented controls. Interestingly, somatic SNVs in AD brains arise about 4.8 times more slowly than in blood. When the team performed gene-set enrichment tests, 26.9 percent of the AD brain samples had pathogenic brain somatic SNVs known to be linked to hyperphosphorylation of tau proteins, which is one of major hallmarks of AD.
Then, they pinpointed a pathogenic SNV in the PIN1 gene, a cis/trans isomerase that balances phosphorylation in tau proteins, found in one AD patient’s brain. They found the mutation was 4.9 time more abundant in AT8-positive – a marker for hyper-phosphorylated tau proteins– neurons in the entorhinal cortex than the bulk hippocampal tissue. Furthermore, in a series of functional assays, they observed the mutation causing a loss of function in PIN1 and such haploinsufficiency increased the phosphorylation and aggregation of tau proteins.
“Our study provides new insights into the molecular genetic factors behind Alzheimer’s disease and other neurodegenerative diseases potentially linked to somatic mutations in the brain,” said Professor Lee.
The team is planning to expand their study to a larger cohort in order to establish stronger links between these brain somatic mutations and the pathogenesis of Alzheimer’s disease.
(Figure 1. Bioinformatic pipeline for detecting low-level brain somatic mutations in AD and non-AD.)
(Figure 2. Pathogenic brain somatic mutations associated with tau phosphorylation are significantly enriched in AD brains.)
(Figure 3. A pathogenic brain somatic mutation in PIN1 (c. 477 C>T) is a loss-of-function and related functional assays show its haploinsufficiency increases phosphorylation and aggregation of tau.)
2019.07.19 View 34139 -
Efficiently Producing Fatty Acids and Biofuels from Glucose
Researchers have presented a new strategy for efficiently producing fatty acids and biofuels that can transform glucose and oleaginous microorganisms into microbial diesel fuel, with one-step direct fermentative production.
The newly developed strain, created by Distinguished Professor Sang Yup Lee and his team, showed the highest efficiency in producing fatty acids and biodiesels ever reported. It will be expected to serve as a new platform to sustainably produce a wide array of fatty acid-based products from glucose and other carbon substrates.
Fossil fuels, which have long been energy resources for our daily lives, are now facing serious challenges: depletion of their reserves and their role in global warming. The production of sustainable bio-based renewable energy has emerged as an essential alternative and many studies to replace fossil fuels are underway. One of the representative examples is biodiesel. Currently, it is mainly being produced through the transesterification of vegetable oils or animal fats.
The research team engineered oleaginous microorganisms, Rhodococcus opacus, to produce fatty acids and their derivatives that can be used as biodiesel from glucose, one of the most abundant and cheap sugars derived from non-edible biomass.
Professor Lee’s team has already engineered Escherichia coli to produce short-chain hydrocarbons, which can be used as gasoline (published in Nature as the cover paper in 2013). However, the production efficiency of the short-chain hydrocarbons using E. coli (0.58 g/L) fell short of the levels required for commercialization.
To overcome these issues, the team employed oil-accumulating Rhodococcus opacus as a host strain in this study. First, the team optimized the cultivation conditions of Rhodococcus opacus to maximize the accumulation of oil (triacylglycerol), which serves as a precursor for the biosynthesis of fatty acids and their derivatives. Then, they systematically analyzed the metabolism of the strain and redesigned it to enable higher levels of fatty acids and two kinds of fatty acid-derived biodiesels (fatty acid ethyl esters and long-chain hydrocarbons) to be produced.
They found that the resulting strains produced 50.2, 21.3, and 5.2 g/L of fatty acids, fatty acid ethyl esters, and long-chain hydrocarbons, respectively. These are all the highest concentrations ever reported by microbial fermentations. It is expected that these strains can contribute to the future industrialization of microbial-based biodiesel production.
“This technology creates fatty acids and biodiesel with high efficiency by utilizing lignocellulose, one of the most abundant resources on the Earth, without depending on fossil fuels and vegetable or animal oils. This will provide new opportunities for oil and petroleum industries, which have long relied on fossil fuels, to turn to sustainable and eco-friendly biotechnologies,” said Professor Lee.
This paper titled “Engineering of an oleaginous bacterium for the production of fatty acids and fuels” was published in Nature Chemical Biology on June 17.
This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries from the Ministry of Science and ICT through the National Research Foundation (NRF) of Korea (NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557).
(Figure: Metabolic engineering for the production of free fatty acids (FFAs), fatty acid ethyl esters (FAEEs), and long-chain hydrocarbons (LCHCs) in Rhodococcus opacus PD630. Researchers have presented a new strategy for efficiently producing fatty acids and biofuels that can transform glucose and oleaginous microorganisms into microbial diesel fuel, with one-step direct fermentative production.)
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Source:
Hye Mi Kim, Tong Un Chae, So Young Choi, Won Jun Kim and Sang Yup Lee. Engineering of an oleaginous bacterium for the production of fatty acids and fuels. Nature Chemical Biology ( https://www.nature.com/nchembio/ ) DOI: 10.1038/s41589-019-0295-5
Profile
Dr. Sang Yup Lee
leesy@kaist.ac.kr
Distinguished Professor at the Department of Chemical and Biomolecular Engineering
KAIST
2019.06.19 View 46344 -
Real-Time Analysis of MOF Adsorption Behavior
Researchers have developed a technology to analyze the adsorption behavior of molecules in each individual pore of a metal organic framework (MOF). This system has large specific surface areas, allowing for the real-time observation of the adsorption process of an MOF, a new material effective for sorting carbon dioxide, hydrogen, and methane.
Accurate measurements and assessments of gas adsorption isotherms are important for characterizing porous materials and developing their applications. The existing technology is only able to measure the amount of gas molecules adsorbed to the material, without directly observing the adsorption behavior.
The research team led by Professor Jeung Ku Kang from the Graduate School of Energy, Environment, Water and Sustainability (EEWS) prescribed a real time gas adsorption crystallography system by integrating an existing X-ray diffraction (XRD) measurement device that can provide structural information and a gas adsorption measurement device.
Specifically, the system allowed the observation of a mesoporous MOF that has multiple pores rather than a single pore structure. The research team categorized the adsorption behaviors of MOF molecules by pore type, followed by observations and measurements, resulting in the identification of a stepwise adsorption process that was previously not possible to analyze.
Further, the team systematically and quantitatively analyzed how the pore structure and the type of adsorption molecule affect the adsorption behavior to suggest what type of MOF structure is appropriate as a storage material for each type of adsorption behavior.
Professor Kang said, “We quantitatively analyzed each pore molecule in real time to identify the effects of chemical and structural properties of pores on adsorption behavior.” He continued, “By understanding the real-time adsorption behavior of molecules at the level of the pores that form the material, rather than the whole material, we will be able to apply this technology to develop a new high-capacity storage material.”
This research was published in Nature Chemistry online on May 13, 2019 under the title ‘Isotherms of Individual Pores by Gas Adsorption Crystallography’.
(Figure. Schematic illustration of molecules adsorbed on metal organic frameworks with different pores of various structures, where the In-situ X-ray crystallography has been developed to classify each pore structure and analyze the position of the molecule to determine the amount of molecules adsorbed to each pore.)
2019.06.18 View 38125