KurzweilAI » News – Page 54

April 6, 2016April 8, 2016

A stem-cell repair system that can regenerate any kind of human tissue

UNSW researchers say the therapy has enormous potential for treating spinal disc injury and joint and muscle degeneration and could also speed up recovery following complex surgeries where bones and joints need to integrate with the body (credit: UNSW TV)

A stem cell therapy system capable of regenerating any human tissue damaged by injury, disease, or aging could be available within a few years, say University of New South Wales (UNSW Australia) researchers.

Their new repair system*, similar to the method used by salamanders to regenerate limbs, could be used to repair everything from spinal discs to bone fractures, and could transform current treatment approaches to regenerative medicine.

The UNSW-led research was published this week in the Proceedings of the National Academy of Sciences journal.

Reprogramming bone and fat cells

The system reprograms bone and fat cells into induced multipotent stem cells (iMS), which can regenerate multiple tissue types and has been successfully demonstrated in mice, according to study lead author, haematologist, and UNSW Associate Professor John Pimanda.

“This technique is a significant advance on many of the current unproven stem cell therapies, which have shown little or no objective evidence they contribute directly to new tissue formation,” Pimanda said. “We have taken bone and fat cells, switched off their memory and converted them into stem cells so they can repair different cell types once they are put back inside the body.”

“We are currently assessing whether adult human fat cells reprogrammed into iMS cells can safely repair damaged tissue in mice, with human trials expected to begin in late 2017.”

(credit: UNSW Media/Michael Whitehead)

Advantages over stem-cell types

There are different types of stem cells including embryonic stem (ES) cells, which during embryonic development generate every type of cell in the human body, and adult stem cells, which are tissue-specific, but don’t regenerate multiple tissue types. Embryonic stem cells cannot be used to treat damaged tissues because of their tumor forming capacity. The other problem when generating stem cells is the requirement to use viruses to transform cells into stem cells, which is clinically unacceptable, the researchers note.

Research shows that up to 20% of spinal implants either don’t heal or there is delayed healing. The rates are higher for smokers, older people and patients with diseases such diabetes or kidney disease.

Human trials are planned next year once the safety and effectiveness of the technique using human cells in mice has been demonstrated.

* The technique involves extracting adult human fat cells and treating them with the compound 5-Azacytidine (AZA), along with platelet-derived growth factor-AB (PDGF-AB) for about two days. The cells are then treated with the growth factor alone for a further two-three weeks.

AZA is known to induce cell plasticity, which is crucial for reprogramming cells. The AZA compound relaxes the hard-wiring of the cell, which is expanded by the growth factor, transforming the bone and fat cells into iMS cells. When the stem cells are inserted into the damaged tissue site, they multiply, promoting growth and healing.

The new technique is similar to salamander limb regeneration, which is also dependent on the plasticity of differentiated cells, which can repair multiple tissue types, depending on which body part needs replacing.

Along with confirming that human adult fat cells reprogrammed into iMS stem cells can safely repair damaged tissue in mice, the researchers said further work is required to establish whether iMS cells remain dormant at the sites of transplantation and retain their capacity to proliferate on demand.

UNSW Australia | Breakthrough for stem cell therapies

Abstract of PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs. 5-Azacytidine (AZA) is a nucleoside analog that is used to treat preleukemic and leukemic blood disorders. AZA is also known to induce cell plasticity. We hypothesized that AZA-induced cell plasticity occurs via a transient multipotent cell state and that concomitant exposure to a receptive growth factor might result in the expansion of a plastic and proliferative population of cells. To this end, we treated lineage-committed cells with AZA and screened a number of different growth factors with known activity in mesenchyme-derived tissues. Here, we report that transient treatment with AZA in combination with platelet-derived growth factor–AB converts primary somatic cells into tissue-regenerative multipotent stem (iMS) cells. iMS cells possess a distinct transcriptome, are immunosuppressive, and demonstrate long-term self-renewal, serial clonogenicity, and multigerm layer differentiation potential. Importantly, unlike mesenchymal stem cells, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner and, unlike embryonic or pluripotent stem cells, do not form teratomas. Taken together, this vector-free method of generating iMS cells from primary terminally differentiated cells has significant scope for application in tissue regeneration.

April 6, 2016April 7, 2016

Electrical stimulation of brain pleasure center reduces chronic pain

A brain slice showing electrode tip location (credit: Ai‑Ling Li et al./ Experimental Brain Research)

Are you in pain, but your doc won’t increase your hydrocodone dosage (or you don’t want to overdose)?

University of Texas at Arlington researchers may have a (future) drug-free fix: electrical stimulation of a deep middle-brain structure that blocks pain signals at the spinal cord level while triggering release of pleasure-associated dopamine to reduce the associated emotional distress.

“This is the first study to use a wireless electrical device to alleviate pain by directly stimulating the ventral tegmental area of the brain,” said Yuan Bo Peng, UTA psychology professor and co-author of a paper in the journal Experimental Brain Research.

Ventral tegmental area (VTA) of the brain, a pleasure center that generates dopamine (credit: Bruno Dubuc)

“While still under laboratory testing [in rats], this new method does provide hope that in the future we will be able to alleviate chronic pain without the side effects of medications,” said Peng.

Nearly two million Americans were dependent on or abused opioid medicines in 2014, and 165,000 died between 1999 and 2014 from overdoses related to opioid prescriptions, according to the Centers for Disease Control.

The project was supported partly by grants from the Texas Norman Hackerman Advanced Research Program, Intel Corporation, and the Texas Medical Research Collaborative.

Abstract of Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague–Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

April 5, 2016April 7, 2016

World’s smallest electronic diode made from single DNA molecule

By inserting a small “coralyne” molecule into DNA, scientists were able to create a single-molecule diode (connected here by two gold electrodes), which can be used as an active element in future nanoscale circuits. The diode circuit symbol is shown on the left. (credit: University of Georgia and Ben-Gurion University)

Nanoscale electronic components can be made from single DNA molecules, as researchers at the University of Georgia and at Ben-Gurion University in Israel have demonstrated, using a single molecule of DNA to create the world’s smallest diode.

DNA double helix with base pairs (credit: National Human Genome Research Institute)

A diode is a component vital to electronic devices that allows current to flow in one direction but prevents its flow in the other direction. The development could help stimulate development of DNA components for molecular electronics.

As noted in an open-access Nature Chemistry paper published this week, the researchers designed a 11-base-pair (bp) DNA molecule and inserted a small molecule named coralyne into the DNA.*

They found, surprisingly, that this caused the current flowing through the DNA to be 15 times stronger for negative voltages than for positive voltages, a necessary feature of a diode.

Electronic elements 1,00o times smaller than current components

“Our discovery can lead to progress in the design and construction of nanoscale electronic elements that are at least 1,000 times smaller than current components,” says the study’s lead author, Bingqian Xu an associate professor in the UGA College of Engineering and an adjunct professor in chemistry and physics.

The research team plans to enhance the performance of the molecular diode and construct additional molecular devices, which may include a transistor (similar to a two-layer diode, but with one additional layer).

A theoretical model developed by Yanantan Dubi of Ben-Gurion University indicated the diode-like behavior of DNA originates from the bias voltage-induced breaking of spatial symmetry inside the DNA molecule after the coralyne is inserted.

The research is supported by the National Science Foundation.

*“We prepared the DNA–coralyne complex by specifically intercalating two coralyne molecules into a custom-designed 11-base-pair (bp) DNA molecule (5′-CGCGAAACGCG-3′) containing three mismatched A–A base pairs at the centre,” according to the authors.

UPDATE April 6, 2016 to clarify the coralyne intercalation (insertion) into the DNA molecule.

Abstract of Molecular rectifier composed of DNA with high rectification ratio enabled by intercalation

The predictability, diversity and programmability of DNA make it a leading candidate for the design of functional electronic devices that use single molecules, yet its electron transport properties have not been fully elucidated. This is primarily because of a poor understanding of how the structure of DNA determines its electron transport. Here, we demonstrate a DNA-based molecular rectifier constructed by site-specific intercalation of small molecules (coralyne) into a custom-designed 11-base-pair DNA duplex. Measured current–voltage curves of the DNA–coralyne molecular junction show unexpectedly large rectification with a rectification ratio of about 15 at 1.1 V, a counter-intuitive finding considering the seemingly symmetrical molecular structure of the junction. A non-equilibrium Green’s function-based model—parameterized by density functional theory calculations—revealed that the coralyne-induced spatial asymmetry in the electron state distribution caused the observed rectification. This inherent asymmetry leads to changes in the coupling of the molecular HOMO−1 level to the electrodes when an external voltage is applied, resulting in an asymmetric change in transmission.

April 5, 2016April 6, 2016

Hacking life: how to program new functions for living bacteria and yeast

MIT biological engineers have devised a programming language that can be used to add new functions to E. coli bacteria (credit: Janet Iwasa)

MIT biological engineers have created a programming language for bacteria. It allows anyone to rapidly design complex, DNA-encoded circuits that add new functions to living cells — no genetic engineering knowledge required.

For example: design bacterial cells that can produce a cancer drug when they detect a tumor or create yeast cells that can halt their own fermentation process if too many toxic byproducts build up.

Repurposing a computer-chip programming language

The language is based on Verilog, a text-based language commonly used to program computer chips. To create a version of the language that would work for cells, the researchers designed computing elements such as logic gates and sensors that can be encoded in a bacterial cell’s DNA.

The sensors can detect different compounds, such as oxygen or glucose, and environmental conditions like light, temperature, and acidity. You can also add your own sensors, and you can compile a program for different organisms to get the right DNA sequence for each one.

You also specify the sensors, actuators, and a user constraints file (UCF), which defines the organism, gate technology, and valid operating conditions.

Cello (think of it as a compiler), a website, then uses this information to automatically design a DNA sequence encoding the desired circuit, using a set of algorithms that parse the Verilog text, create the circuit diagram, assign gates, balance constraints to build the DNA, and simulate performance, drawing on a library of Boolean logic gates.

Overview of Cello. Cello users write Verilog code and select or upload sensors and a UCF. On the basis of the Verilog design, a truth table is constructed, from which a circuit diagram is synthesized. Regulators are assigned from a library to each gate (each color is a different repressor). Combinatorial design is then used to concatenate parts into a linear DNA sequence. (credit: Alec A. K. Nielsen et al./Science)

In the current Verilog version, the genetic parts are optimized for E. coli, but the researchers are working on expanding the language for other strains of bacteria, including Bacteroides, commonly found in the human gut; Pseudomonas,which often lives in plant roots; and the yeast Saccharomyces cerevisiae.

Christopher Voigt, an MIT professor of biological engineering, and colleagues at Boston University and the National Institute of Standards and Technology have used this language, which they describe in the April 1 issue of Science.

No experience needed

Over the past 15 years, biologists and engineers have designed many genetic parts, such as sensors, memory switches, and biological clocks, that can be combined to modify existing cell functions and add new ones. However, designing each circuit is a laborious process that requires great expertise and often a lot of trial and error. “You have to have this really intimate knowledge of how those pieces are going to work and how they’re going to come together,” Voigt says.

Users of the new programming language, however, need no special knowledge of genetic engineering.

“You could be completely naive as to how any of it works. That’s what’s really different about this,” Voigt says. “You could be a student in high school and go onto the Web-based server and type out the program you want, and it spits back the DNA sequence.”

Using this language, the MIT researchers programmed 60 circuits with different functions, and 45 of them worked correctly the first time they were tested. Many of the circuits were designed to measure one or more environmental conditions, such as oxygen level or glucose concentration, and respond accordingly. Another circuit was designed to rank three different inputs and then respond based on the priority of each one.

One of the new circuits is the largest biological circuit ever built, containing seven logic gates and about 12,000 base pairs of DNA.

Another advantage of this technique is its speed. Until now, “it would take years to build these types of circuits. Now you just hit the button and immediately get a DNA sequence to test,” Voigt says.

His team plans to work on several different applications using this approach: bacteria that can be swallowed to aid in digestion of lactose; bacteria that can live on plant roots and produce insecticide if they sense the plant is under attack; and yeast that can be engineered to shut off when they are producing too many toxic byproducts in a fermentation reactor.

Abstract of Genetic circuit design automation

Computation can be performed in living cells by DNA-encoded circuits that process sensory information and control biological functions. Their construction is time-intensive, requiring manual part assembly and balancing of regulator expression. We describe a design environment, Cello, in which a user writes Verilog code that is automatically transformed into a DNA sequence. Algorithms build a circuit diagram, assign and connect gates, and simulate performance. Reliable circuit design requires the insulation of gates from genetic context, so that they function identically when used in different circuits. We used Cello to design 60 circuits for Escherichia coli (880,000 base pairs of DNA), for which each DNA sequence was built as predicted by the software with no additional tuning. Of these, 45 circuits performed correctly in every output state (up to 10 regulators and 55 parts), and across all circuits 92% of the output states functioned as predicted. Design automation simplifies the incorporation of genetic circuits into biotechnology projects that require decision-making, control, sensing, or spatial organization.

April 4, 2016April 5, 2016

3D-printing a structure with active chemistry

A Filabot Wee Extruder (left) extruded standard ABS filament containing titanium dioxide nanoparticles. The filament was used in a Flashforge Creator Pro 3D Printer (right) to 3D-print a small sponge-like material for mitigating pollution. (credit: Filabot and Zhejiang Flashforge 3D Technology Co., Ltd.)

Researchers at American University have demonstrated the first use of commercial 3D printers to create a structure with active chemistry — in this case, a structure that acts to mitigate pollution.

The researchers added titanium dioxide nanoparticles to standard ABS filament material (used in 3D printers) and extruded a filament that they then used to print a small, sponge-like plastic object on a low-cost Flashforge Creator Pro 3D Printer.

To test whether or not the nanoparticles would remain active after printing, they placed the object in water and added an organic molecule (a pollutant), which was then destroyed. In another test, the titanium dioxide nanoparticles photocatalyzed the degradation of rhodamine 6G (a flourescent tracer dye) in solution.

The researchers next plan to 3D-print a variety of different geometries to determine an optimal printed shape for applications that involve photocatalytic removal of environmental pollutants.

The study, led by chemistry professor Matthew Hartings, was described in an online, open-access paper April 1 in Science and Technology of Advanced Materials.

Abstract of The chemical, mechanical, and physical properties of 3D printed materials composed of TiO₂-ABS nanocomposites

To expand the chemical capabilities of 3D printed structures generated from commercial thermoplastic printers, we have produced and printed polymer filaments that contain inorganic nanoparticles. TiO₂ was dispersed into acrylonitrile butadiene styrene (ABS) and extruded into filaments with 1.75 mm diameters. We produced filaments with TiO₂compositions of 1, 5, and 10% (kg/kg) and printed structures using a commercial 3D printer. Our experiments suggest that ABS undergoes minor degradation in the presence of TiO₂ during the different processing steps. The measured mechanical properties (strain and Young’s modulus) for all of the composites are similar to those of structures printed from the pure polymer. TiO₂ incorporation at 1% negatively affects the stress at breaking point and the flexural stress. Structures produced from the 5 and 10% nanocomposites display a higher breaking point stress than those printed from the pure polymer. TiO₂within the printed matrix was able to quench the intrinsic fluorescence of the polymer. TiO₂ was also able to photocatalyze the degradation of a rhodamine 6G in solution. These experiments display chemical reactivity in nanocomposites that are printed using commercial 3D printers, and we expect that our methodology will help to inform others who seek to incorporate catalytic nanoparticles in 3D printed structures.

April 2, 2016April 5, 2016

Largest network of cortical neurons mapped from ~100 terabytes data set

Neuroscientists have constructed a network map of connections between cortical neurons, traced from a ~100 terabytes 3D data set. The data were created by an electron microscope in nanoscopic detail, allowing every one of the “wires” to be seen, along with their connections. Some of the neurons are color-coded according to their activity patterns in the living brain. (credit: Clay Reid, Allen Institute; Wei-Chung Lee, Harvard Medical School; Sam Ingersoll, graphic artist)

The largest network of the connections between neurons in the cortex to date has been published by an international team of researchers from the Allen Institute for Brain Science, Harvard Medical School, and Neuro-Electronics Research Flanders (NERF).

In the process of their study*, the researchers developed new tools that will be useful for “reverse engineering the brain by discovering relationships between circuit wiring and neuronal and network computations,” says Wei-Chung Lee, Ph.D., Instructor in Neurobiology at Harvard Medicine School and lead author of a paper published this week in the journal Nature.

The study is part of a “functional connectomics” research program started almost ten years ago that aims at bridging a longstanding gap between two areas of neuroscience study: brain activity (using fMRI imaging) and brain wiring (using detailed electron microscopy).

The research began by identifying neurons in the mouse visual cortex that responded to particular visual stimuli (pyramidal cells in V1, the rodent primary visual cortex), such as vertical or horizontal bars on a screen. The scientists then made ultra-thin slices of brain and captured millions of detailed images of those targeted cells and synapses, which were then reconstructed in three dimensions. Teams of annotators simultaneously traced individual neurons through the 3D stacks of images and located connections between individual neurons.

Analyzing this wealth of data yielded several results, including the first direct structural evidence to support the hypothesis that neurons that do similar tasks are more likely to be connected to each other than to nearby neurons that carry out different tasks.

New tools for reverse engineering the brain

The researchers said these new research tools will also be employed in an $18.7 million IARPA project announced March 12 with the Allen Institute for Brain Science, Baylor College of Medicine, and Princeton University, which seeks to scale these methods to a larger segment of brain tissue. That project is part of the Machine Intelligence from Cortical Networks (MICrONS) program (see CMU announces research project to reverse-engineer brain algorithms, funded by IARPA), which seeks to revolutionize machine learning by reverse-engineering the algorithms of the brain.

The 3D image data from the Allen Institute-Baylor study will be sent to Princeton University, under Sebastian Seung, Ph.D., Professor of Computer Science and the Princeton Neuroscience Institute, where it will be painstakingly reconstructed in three dimensions by human annotators aided by powerful machine vision and machine learning algorithms, and each individual neuron with all its myriad processes will be traced and analyzed.

The end goal of that functional connectomics project is to create a reconstruction of a cubic millimeter of brain tissue, the size of a grain of sand, yet containing the largest section of brain ever to be studied in this way to date.

Improving artificial neural networks algorithms

Beyond that, the ultimate goal of MICrONS is to implement the algorithms and learning rules that scientists decipher from the brain to advance the field of artificial intelligence by improving artificial neural networks algorithms — for speech recognition, recognizing faces, and helping analyze big data for biomedical research, for example.

“In many ways, these artificial neural networks are still primitive compared to biological networks of neurons and do not learn the way real brains do,” says Andreas Tolias, Ph.D., Associate Professor in the Department of Neuroscience at Baylor College of Medicine. “Our goal is to fill this gap and apply the algorithms of the brain to engineer novel artificial network architectures.”

* This work was supported by the Harvard Medical School Vision Core Grant, the Bertarelli Foundation, the Edward R. and Anne G. Lefler Center,the Stanley and Theodora Feldberg Fund, Neuro-Electronics Research Flanders (NERF), the Allen Institute for Brain Science, and the National Institutes of Health, through resources provided by the National Resource for Biomedical Supercomputing at the Pittsburgh Supercomputing Center and the National Center for Multiscale Modeling of Biological Systems.

Abstract of Anatomy and function of an excitatory network in the visual cortex

Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (<5 μm) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.

April 1, 2016April 5, 2016

Creating custom drugs on a portable refrigerator-size device

This device built by MIT researchers can be reconfigured to manufacture several different types of pharmaceuticals (credit: courtesy of the researchers)

MIT researchers have developed a compact, portable pharmaceutical manufacturing system that can be reconfigured to produce a variety of drugs on demand — if you have the right chemicals.

The device could be rapidly deployed to produce drugs needed to handle an unexpected disease outbreak, to prevent a drug shortage caused by a manufacturing plant shutdown, or produce small quantities of drugs needed for clinical trials or to treat rare diseases, the researchers say.

Traditional “batch processing” drug manufacturing can take weeks or months. Active pharmaceutical ingredients are synthesized in chemical manufacturing plants and then shipped to other sites to be converted into a form that can be given to patients, such as tablets, drug solutions, or suspensions.

With research funded by DARPA’s Make-It program, the new system prototype can produce four drugs formulated as solutions or suspensions: Benadryl, Lidocaine, Valium, and Prozac. Using this apparatus, the researchers can manufacture about 1,000 doses of a given drug in 24 hours.

The key to the new system: chemical reactions that can take place as the reactants flow through relatively small tubes as opposed to the huge vats in which most pharmaceutical reactions now take place. Traditional batch processing is limited by the difficulty of cooling these vats, but the flow system allows reactions that produce a great deal of heat to be run safely.*

Personalized “orphan drugs”

One of the advantages of this small-scale system is that it could be used to make small amounts of drugs that would be prohibitively expensive to make in a large-scale plant. This would be useful for “orphan drugs” — drugs needed by a small number of patients. “Sometimes it’s very difficult to get those drugs, because economically it makes no sense to have a huge production operation for those,” says Klavs Jensen, the Warren K. Lewis Professor of Chemical Engineering at MIT and a senior author of a paper describing the new system in the March 31 online edition of Science.

The researchers are now working on the second phase of the project, which includes making the system about 40 percent smaller and producing drugs whose chemical syntheses are more complex. They are also working on producing tablets, which are more complicated to manufacture than liquid drugs.

*The chemical reactions required to synthesize each drug take place in the first of two modules. The reactions were designed so that they can take place at temperatures up to 250 degrees Celsius and pressures up to 17 atmospheres. By swapping in different module components, the researchers can easily reconfigure the system to produce different drugs. “Within a few hours we could change from one compound to the other,” Jensen says.

In the second module, the crude drug solution is purified by crystallization, filtered, and dried to remove solvent, then dissolved or suspended in water as the final dosage form. The researchers also incorporated an ultrasound monitoring system that ensures the formulated drug solution is at the correct concentration.

Abstract of On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system

Pharmaceutical manufacturing typically uses batch processing at multiple locations. Disadvantages of this approach include long production times and the potential for supply chain disruptions. As a preliminary demonstration of an alternative approach, we report here the continuous-flow synthesis and formulation of active pharmaceutical ingredients in a compact, reconfigurable manufacturing platform. Continuous end-to-end synthesis in the refrigerator-sized [1.0 meter (width) × 0.7 meter (length) × 1.8 meter (height)] system produces sufficient quantities per day to supply hundreds to thousands of oral or topical liquid doses of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride that meet U.S. Pharmacopeia standards. Underlying this flexible plug-and-play approach are substantial enabling advances in continuous-flow synthesis, complex multistep sequence telescoping, reaction engineering equipment, and real-time formulation.

April 1, 2016April 4, 2016

How to use laser cloaking to hide Earth from remote detection by aliens

A 22W laser used for adaptive optics on the Very Large Telescope in Chile. A suite of similar lasers could be used to cloak our planet’s transit around the Sun. (credit: ESO/G. Hüdepohl)

We could use lasers to conceal the Earth from observation by an advanced extraterrestrial civilization by shining massive laser beams aimed at a specific star where aliens might be located — thus masking our planet during its transit of the Sun, suggest two astronomers at Columbia University in an open-access paper in Monthly Notices of the Royal Astronomical Society.

The idea comes from the NASA Kepler mission’s search method for exoplanets (planets around other stars), which looks for transits (a planet crossing in front a star) — identified by a tiny decrease in the star’s brightness.*

To detect exoplanets, NASA’s Kepler measures the light from a star. When a planet crosses in front of a star, the event is called a transit. The planet is usually too small to see, but it can produce a small change in a star’s brightness of about 1/10,000 (100 parts per million), lasting for 2 to 16 hours. (credit: NASA Ames)

Kepler has confirmed the existence of more than 1,000 planets using this technique, with tens of these worlds similar in size to the Earth. Kipping and Teachey speculate that alien scientists could use this approach to locate Earth, since it’s in the “habitable zone” of our Sun (a distance where the temperature is right for liquid water, so it may be a promising place for life), and may be of interest to aliens.*

How to cloak our Earth from aliens

Columbia Professor David Kipping and graduate student Alex Teachey suggest that transits could be masked by controlled laser emission, with the beam directed at the star where the suspected aliens might be located. When the planet’s transit takes place, the laser would be switched on to compensate for the dip in light.**

Illustration (not to scale) of the transit cloaking device. To cloak the Earth, a laser beam (orange) is fired from the night side of the Earth (blue circle) toward a target star (“receiver”) during the transit. (credit: David M. Kipping and Alex Teachey/MNRAS)

According to the authors, emitting a continuous 30 MW laser for about 10 hours, once a year, would be enough to eliminate the transit signal, at least in the visible-light range. The energy needed is comparable to that collected by the International Space Station solar array in a year. A chromatic (multi-wavelength) cloak, effective at all solar wavelengths, is more challenging, and would need a large array of tuneable lasers with a total power of 250 MW.***

“Alternatively, we could cloak only the atmospheric signatures associated with biological activity, such as oxygen, which is achievable with a peak laser power of just 160 kW per transit. To another civilization, this should make the Earth appear as if life never took hold on our world”, said Teachey.

Cool Worlds Lab/Columbia University | A Cloaking Device for Planets

Broadcasting our existence: the METI (message SETI) approach

The lasers could also be used to broadcast our existence by modifying the light from the Sun during a transit to make it obviously artificial, such as modifying the normal “U” transit light curve (the intensity vs. time pattern during transit). The authors suggest that we could even transmit information by modulating the laser beams at the same time, providing a way to send messages to aliens.

However, several prominent scientists, including Stephen Hawking, have cautioned against humanity broadcasting our presence to intelligent life on other planets. Hawking and others are concerned that extraterrestrials might wish to take advantage of the Earth’s resources, and that their visit, rather than being benign, could be as devastating as when Europeans first traveled to the Americas. (See Are you ready for contact with extraterrestrial intelligence? and METI: should we be shouting at the cosmos?)

Perhaps aliens have had the same thought. The two astronomers propose that the Search for Extraterrestrial Intelligence (SETI), which currently looks mailing for alien radio signals, could be broadened to search for artificial star transits. Such signatures could also be readily searched in the NASA archival data of Kepler transit surveys.

* Once detected, the planet’s orbital size can be calculated from the period (how long it takes the planet to orbit once around the star) and the mass of the star using Kepler’s Third Law of planetary motion. The size of the planet is found from the depth of the transit (how much the brightness of the star drops) and the size of the star. From the orbital size and the temperature of the star, the planet’s characteristic temperature can be calculated. From this, the question of whether or not the planet is habitable (not necessarily inhabited) can be answered. — Kepler and K2, NASA Mission Overview

** It’s not clear what indicators might lead to such a suspicion, aside from a confirmed SETI transmission detection. It would be interesting to calculate the required number and locations of lasers, their operational schedule, and their power requirements for a worst-case scenario — assuming potential threats from certain types of stars, or all stars — considering laser beam divergence angle, beam flux gradients, and maximum star distance within about one degree of a planet’s ecliptic plane can see it transit in the ecliptic plane, based on assumed maximum alien telescope resolving power.

[UPDATE 1/3/2016: Kipping correction: "within about one degree" and added "based on assumed maximum alien telescope resolving power"]

[UPDATE 1/3/2016: from Kipping regarding beam divergence angle, flux gradients, and primary focus of the paper]: “Beam shaping, through the use of multiple beams, can produce effectively isotropic radiation within the beam width. Unless the target is very close, the beam width typically encompasses the entire alien solar system by the time it reaches, due to beam divergence. So we don’t even really need to know the position of the target planet that well (although we likely do anyway thanks to our detection methods). A common misunderstanding of our paper is to erroneously assume that we are advocating that humanity should build this for the Earth, but actually we are pointing out that if even our current technology can pull off a pretty effective cloak then other more advanced civilizations may be able to hide from us perfectly.”]

*** For example, a chromatic cloak for the NIRSpec instrument planned for James Webb Space Telescope covering from 0.6 to 5 µm would require approximately 6000 monochromatic lasers in the array.

Abstract of A Cloaking Device for Transiting Planets

The transit method is presently the most successful planet discovery and characterization tool at our disposal. Other advanced civilizations would surely be aware of this technique and appreciate that their home planet’s existence and habitability is essentially broadcast to all stars lying along their ecliptic plane. We suggest that advanced civilizations could cloak their presence, or deliberately broadcast it, through controlled laser emission. Such emission could distort the apparent shape of their transit light curves with relatively little energy, due to the collimated beam and relatively infrequent nature of transits. We estimate that humanity could cloak the Earth from Kepler-like broadband surveys using an optical monochromatic laser array emitting a peak power of ∼30 MW for ∼10 hours per year. A chromatic cloak, effective at all wavelengths, is more challenging requiring a large array of tunable lasers with a total power of ∼250 MW. Alternatively, a civilization could cloak only the atmospheric signatures associated with biological activity on their world, such as oxygen, which is achievable with a peak laser power of just ∼160 kW per transit. Finally, we suggest that the time of transit for optical SETI is analogous to the water-hole in radio SETI, providing a clear window in which observers may expect to communicate. Accordingly, we propose that a civilization may deliberately broadcast their technological capabilities by distorting their transit to an artificial shape, which serves as both a SETI beacon and a medium for data transmission. Such signatures could be readily searched in the archival data of transit surveys.

March 31, 2016April 5, 2016

An astounding nanoscale magnified view of bacterial ‘motors’

Two bacterial micro machines in a bacterial cell extend and retract fibers (called pili) that pull cells forward. ATP hydrolysis in the cytoplasm generates the energy to cause an assembler-mechanism adapter protein in the inner membrane (detail shown in white rectangle) to rotate, facilitating the transfer of pilin subunits (small green balls) onto the growing pilus. The process is reversed during retraction. (credit: Yi-Wei Chang et al./Science)

Caltech researchers have used a state-of-the-art imaging technique to capture detailed 3D views of the complex mobile nanomachinery in bacteria for the first time.

Grant Jensen, a professor of biophysics and biology at Caltech and an investigator with the Howard Hughes Medical Institute (HHMI), and his colleagues used a technique called electron cryotomography to capture 3D images of intact cells with a resolution that ranges from 2 to 5 nanometers (for comparison, a whole cell can be several thousand nanometers in diameter).

(credit: Sony Pictures/Marvel Studios/HD Wallpapers)

In a paper published in the March 11 issue of the journal Science, the researchers explain they used an advanced technique to analyze bacteria-cell motility machinery — a structure called the type IVa pilus machine (T4PM). This machine enables a bacterium to move through its environment in a manner similar to how Spider-Man travels between skyscrapers.

The T4PM assembles a long fiber (the pilus) that attaches to a surface like a grappling hook and subsequently retracts, thus pulling the cell forward.

Science Magazine | How the bacterium Myxococcus xanthus makes a grappling hook for propulsion

The making of the bacteria mobility movie

First, the researchers froze the bacteria cells instantaneously to prevent water molecules from rearranging to form ice crystals. That locked the cells in place without damaging their structure. Then, using a transmission electron microscope, the researchers imaged the cells from different angles, producing a series of 2-D images. They then digitally reconstructed these images into a 3-D picture of the cell’s structures (like creating a CT scan). Jensen’s laboratory is one of only a few in the entire world that can do this type of imaging.

The researchers found that the bacteria structure is made up of several parts, including a pore on the outer membrane of the cell, four interconnected ring structures, and a stemlike structure. By systematically imaging mutants, each of which lacked one of the 10 T4PM core components, and comparing these mutants with normal M. xanthus cells, they mapped the locations of all 10 T4PM core components, providing insights into pilus assembly, structure, and function.

Strongest motor known in nature — how it works

“The machine lets M. xanthus, a predatory bacterium, move across a field to form a ‘wolf pack’ with other M. xanthus cells, and hunt together for other bacteria on which to prey,” Jensen says. “T4PMs … generate forces as high as 150 pN to pull the cell forward, making T4PMs the strongest molecular motors known,” the authors note.

Another way that bacteria move about their environment is by employing a flagellum — a long whiplike structure that extends outward from the cell. The flagellum is spun by cellular machinery, creating a sort of propeller that motors the bacterium through a substrate (see Tiny swimming ‘biobots’ propelled by heart cells or magnetic fields).

However, cells that must push through the thick mucus of the intestine, for example, need more powerful versions of these motors, compared to cells that only need enough propeller power to travel through a pool of water.

Heavy-duty vs. light-duty bacterial propellers

In a second work, published in an open-access paper in the online early edition of the Proceedings of the National Academy of Sciences (PNAS) on March 14, Jensen and his colleagues used electron cryotomography to study the differences between heavy-duty and light-duty versions of the bacterial propeller. The 3-D images they captured showed that the varying levels of propeller power among several different species of bacteria can be explained by structural differences in these tiny motors.

In order for the flagellum to act as a propeller, structures in the cell’s motor must apply torque — the force needed to cause an object to rotate—to the flagellum. The researchers found that the high-power motors have additional torque-generating protein complexes that are found at a relatively wide radius from the flagellum. This extra distance provides greater leverage to rotate the flagellum, thus generating greater torque. The strength of the cell’s motor was directly correlated with the number of these torque-generating complexes in the cell.

“These two studies establish a technique for solving the complete structures of large macromolecular complexes in situ, or inside intact cells,” Jensen says. “Other structure determination methods, such as X-ray crystallography, require complexes to be purified out of cells, resulting in loss of components and possible contamination. On the other hand, traditional 2-D imaging alone doesn’t let you see where individual protein pieces fit in the complete structure. Our electron cryotomography technique is a good solution because it can be used to look at the whole cell, providing a complete picture of the architecture and location of these structures.”

The work involving the type IVa pilus machinery was published in a Science paper by research scientists at Caltech, the Max Planck Institute for Terrestrial Microbiology, and the University of Utah. The study was funded by the National Institutes of Health (NIH), HHMI, the Max Planck Society, and the Deutsche Forschungsgemeinschaft.

Work involving the flagellum machinery in the second study was published in a PNAS paper. Additional coauthors include collaborators from Imperial College London; the University of Texas Southwestern Medical Center; and the University of Wisconsin–Madison. The study was supported by funding from the UK’s Biotechnology and Biological Sciences Research Council and from HHMI and NIH.

UPDATE April 1, 2016: Added quote from Science paper regarding forces generated by the type IVa pilus machine.

Abstract of Architecture of the type IVa pilus machine

Many bacteria, including important pathogens, move by projecting grappling-hook–like extensions called type IV pili from their cell bodies. After these pili attach to other cells or objects in their environment, the bacteria retract the pili to pull themselves forward. Chang et al. used electron cryotomography of intact cells to image the protein machines that extend and retract the pili, revealing where each protein component resides. Putting the known structures of the individual proteins in place like pieces of a three-dimensional puzzle revealed insights into how the machine works, including evidence that ATP hydrolysis by cytoplasmic motors rotates a membrane-embedded adaptor that slips pilin subunits back and forth from the membrane onto the pilus.

Abstract of Diverse high-torque bacterial flagellar motors assemble wider stator rings using a conserved protein scaffold

Although it is known that diverse bacterial flagellar motors produce different torques, the mechanism underlying torque variation is unknown. To understand this difference better, we combined genetic analyses with electron cryo-tomography subtomogram averaging to determine in situ structures of flagellar motors that produce different torques, from Campylobacter and Vibrio species. For the first time, to our knowledge, our results unambiguously locate the torque-generating stator complexes and show that diverse high-torque motors use variants of an ancestrally related family of structures to scaffold incorporation of additional stator complexes at wider radii from the axial driveshaft than in the model enteric motor. We identify the protein components of these additional scaffold structures and elucidate their sequential assembly, demonstrating that they are required for stator-complex incorporation. These proteins are widespread, suggesting that different bacteria have tailored torques to specific environments by scaffolding alternative stator placement and number. Our results quantitatively account for different motor torques, complete the assignment of the locations of the major flagellar components, and provide crucial constraints for understanding mechanisms of torque generation and the evolution of multiprotein complexes.

Abstract of Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Abstract of The chemical, mechanical, and physical properties of 3D printed materials composed of TiO2-ABS nanocomposites

Abstract of Anatomy and function of an excitatory network in the visual cortex

Abstract of The chemical, mechanical, and physical properties of 3D printed materials composed of TiO₂-ABS nanocomposites