Date:
August 6, 2018

Source:
University of California – San Diego

Summary:
Researchers report that they have successfully created spinal cord neural stem cells (NSCs) from human pluripotent stem cells (hPSCs) that differentiate into a diverse population of cells capable of dispersing throughout the spinal cord and can be maintained for long periods of time.

Scanning electron micrograph of cultured human neuron from induced pluripotent stem cell.
Credit: Mark Ellisman and Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego

 

 

Researchers at University of California San Diego School of Medicine report that they have successfully created spinal cord neural stem cells (NSCs) from human pluripotent stem cells (hPSCs) that differentiate into a diverse population of cells capable of dispersing throughout the spinal cord and can be maintained for long periods of time.

The achievement, described in the August 6 online issue of Nature Methods, advances not only basic research like biomedical applications of in vitro disease modeling, but may constitute an improved, clinically translatable cell source for replacement strategies in spinal cord injuries and disorders.

In recent years, much work has been done exploring the potential of using hPSC-derived stem cells to create new spinal cord cells needed to repair damaged or diseased spinal cords. Progress has been steady but slow and limited.

In their new paper, first author and postdoctoral scholar Hiromi Kumamaru, MD, PhD, and senior author Mark Tuszynski, MD, PhD, professor of neuroscience and director of the UC San Diego Translational Neuroscience Institute, and colleagues describe creating a cell line that appears to significantly advance the cause.

After grafting cultured hPSC-derived NSCs into injured spinal cords of rats, they noted that the grafts were rich in excitatory neurons, extended large numbers of axons over long distances, innervated their target structures and enabled robust corticospinal regeneration.

“We established a scalable source of human spinal cord NSCs that includes all spinal cord neuronal progenitor cell types,” said Kumamaru. “In grafts, these cells could be found throughout the spinal cord, dorsal to ventral. They promoted regeneration after spinal cord injury in adult rats, including corticospinal axons, which are extremely important in human voluntary motor function. In rats, they supported functional recovery.”

Tuszynski said that, although more work needs to be done, these newly generated cells will constitute source cells for advancement to human clinical trials on a time frame of three to five years. It still needs to be determined that the cells are safe over long time periods in rodent and non-human primate studies, and that their efficacy can be replicated.

He noted that the work presents potential benefits beyond spinal cord injury therapies since the NSCs can be used in modeling and drug screening for disorders that also involve spinal cord dysfunction, such as amyotrophic lateral sclerosis, progressive muscular atrophy, hereditary spastic paraplegia and spinocerebellar ataxia, a group of genetic disorders characterized by progressive discoordination of gait, hands and eye movement.

Co-authors include: Ken Kadoya, Andrew F. Adler, Yoshio Takashima, and Lori Graham, all at UC San Diego, and Giovanni Coppola, UCLA.

Story Source:

Materials provided by University of California – San Diego. Original written by Scott LaFee. Note: Content may be edited for style and length.


Journal Reference:

  1. Hiromi Kumamaru, Ken Kadoya, Andrew F. Adler, Yoshio Takashima, Lori Graham, Giovanni Coppola, Mark H. Tuszynski. Generation and post-injury integration of human spinal cord neural stem cellsNature Methods, 2018; DOI: 10.1038/s41592-018-0074-3

 

Source: University of California – San Diego. “Created line of spinal cord neural stem cells shows diverse promise.” ScienceDaily. ScienceDaily, 6 August 2018. <www.sciencedaily.com/releases/2018/08/180806162716.htm>.

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Our learning capabilities are limited during slow wave sleep

Date:
August 6, 2018

Source:
Université libre de Bruxelles

Summary:
Using magnetoencephalography, researchers showed that while the human brain is still able to perceive sounds during sleep, it is unable to group these sounds according to their organization in a sequence.

 
Led by Philippe Peigneux, ULB Neuroscience Institute, a group of researchers found that our learning capabilities are limited during slow wave sleep. Using magnetoencephalography (MEG), they showed that while our brain is still able to perceive sounds during sleep, it is unable to group these sounds according to their organisation in a sequence.

 

 

Hypnopedia, or the ability to learn during sleep, was popularized in the ’60s, with for example the dystopia Brave New World by Aldous Huxley, in which individuals are conditioned to their future tasks during sleep. This concept has been progressively abandoned due to a lack of reliable scientific evidence supporting in-sleep learning abilities.

Recently however, few studies showed that the acquisition of elementary associations such as stimulus-reflex response is possible during sleep, both in humans and in animals. Nevertheless, it is not clear if sleep allows for more sophisticated forms of learning.

A study published this August 6 in the journal Scientific Reportsby researchers from the ULB Neuroscience Institute (UNI) shows that while our brain is able to continue perceiving sounds during sleep like at wake, the ability to group these sounds according to their organization in a sequence is only present at wakefulness, and completely disappears during sleep.

Juliane Farthouat, while a Research Fellow of the FNRS under the direction of Philippe Peigneux, professor at the Faculty of Psychological Science and Education at Université libre de Bruxelles, ULB, used magnetoencephalography (MEG) to record the cerebral activity mirroring the statistical learning of series of sounds, both during slow wave sleep (a part of sleep during which brain activity is highly synchronized) and during wakefulness.

During sleep, participants were exposed to fast flows of pure sounds, either randomly organized or structured in such a way that the auditory stream could be statistically grouped into sets of 3 elements.

During sleep, brain MEG responses demonstrated preserved detection of isolated sounds, but no response reflecting statistical clustering.

During wakefulness, however, all participants presented brain MEG responses reflecting the grouping of sounds into sets of 3 elements.

The results of this study suggest intrinsic limitations in de novo learning during slow wave sleep, that might confine the sleeping brain’s learning capabilities to simple, elementary associations.

Story Source:

Materials provided by Université libre de BruxellesNote: Content may be edited for style and length.


Journal Reference:

  1. Juliane Farthouat, Anne Atas, Vincent Wens, Xavier De Tiege, Philippe Peigneux. Lack of frequency-tagged magnetic responses suggests statistical regularities remain undetected during NREM sleepScientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-30105-5

 

Source: Université libre de Bruxelles. “Learning while sleeping? Our learning capabilities are limited during slow wave sleep.” ScienceDaily. ScienceDaily, 6 August 2018. <www.sciencedaily.com/releases/2018/08/180806104242.htm>.

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Date:
August 2, 2018

Source:
University of Oxford

Summary:
Despite over a century of intense study, we still know very little about the people buried at Stonehenge or how they came to be there. Now, archeologists suggest that a number of the people that were buried at the Wessex site had moved with and likely transported the bluestones used in the early stages of the monument’s construction, sourced from the Preseli Mountains of west Wales.

 

Stonehenge. The excavation crew around Aubrey Hole 7 following excavations in 2008.
Credit: Adam Stanford, Aerial-Cam Ltd

 

 

Despite over a century of intense study, we still know very little about the people buried at Stonehenge or how they came to be there. Now, a new University of Oxford research collaboration, published in Scientific Reports suggests that a number of the people that were buried at the Wessex site had moved with and likely transported the bluestones used in the early stages of the monument’s construction, sourced from the Preseli Mountains of west Wales.

Conducted in partnership with colleagues at the UCL, Université Libre de Bruxelles & Vrije Universiteit Brussel), and the Muséum National d’Histoire Naturelle de Paris, France, the research combined radiocarbon-dating with new developments in archaeological analysis, pioneered by lead author Christophe Snoeck during his doctoral research in the School of Archaeology at Oxford.

While there has been much speculation as to how and why Stonehenge was built, the question of ‘who’ built it has received far less attention. Part of the reason for this neglect is that many of the human remains were cremated, and so it was difficult to extract much useful information from them. Snoeck demonstrated that that cremated bone faithfully retains its strontium isotope composition, opening the way to use this technique to investigate where these people had lived during the last decade or so of their lives.

With permission from Historic England and English Heritage, the team analysed skull bones from 25 individuals to better understand the lives of those buried at the iconic monument. These remains were originally excavated from a network of 56 pits in the 1920s, placed around the inner circumference and ditch of Stonehenge, known as ‘Aubrey Holes’.

Analysis of small fragments of cremated human bone from an early phase of the site’s history around 3000 BC, when it was mainly used as a cemetery, showed that at least 10 of the 25 people did not live near Stonehenge prior to their death. Instead, they found the highest strontium isotope ratios in the remains were consistent with living in western Britain, a region that includes west Wales — the known source of Stonehenge’s bluestones. Although strontium isotope ratios alone cannot distinguish between places with similar values, this connection suggests west Wales as the most likely origin of at least some of these people.

While the Welsh connection was known for the stones, the study shows that people were also moving between west Wales and Wessex in the Late Neolithic, and that some of their remains were buried at Stonehenge. The results emphasise the importance of inter-regional connections involving the movement of both materials and people in the construction and use of Stonehenge, providing rare insight into the large scale of contacts and exchanges in the Neolithic, as early as 5000 years ago.

Lead author Christophe Snoeck said: ‘The recent discovery that some biological information survives the high temperatures reached during cremation (up to 1000 degrees Celsius) offered us the exciting possibility to finally study the origin of those buried at Stonehenge.’

John Pouncett, a lead author on the paper and Spatial Technology Officer at Oxford’s School of Archaeology, said: ‘The powerful combination of stable isotopes and spatial technology gives us a new insight into the communities who built Stonehenge. The cremated remains from the enigmatic Aubrey Holes and updated mapping of the biosphere suggest that people from the Preseli Mountains not only supplied the bluestones used to build the stone circle, but moved with the stones and were buried there too.’

Rick Schulting, a lead author on the research and Associate Professor in Scientific and Prehistoric Archaeology at Oxford, explained: ‘To me the really remarkable thing about our study is the ability of new developments in archaeological science to extract so much new information ¬from such small and unpromising fragments of burnt bone.

‘Some of the people’s remains showed strontium isotope signals consistent with west Wales, the source of the bluestones that are now being seen as marking the earliest monumental phase of the site.’

Commenting on how they came to develop the innovative technique, Prof Julia Lee-Thorp, Head of Oxford’s School of Archaeology and an author on the paper, said: ‘This new development has come about as the serendipitous result of Dr Snoeck’s interest in the effects of intense heat on bones, and our realization that that heating effectively “sealed in” some isotopic signatures.’

The technique could be used to improve our understanding of the past using previously excavated ancient collections, Dr Schulting said: ‘Our results highlight the importance of revisiting old collections. The cremated remains from Stonehenge were first excavated by Colonel William Hawley in the 1920s, and while they were not put into a museum, Col Hawley did have the foresight to rebury them in a known location on the site, so that it was possible for Mike Parker Pearson (UCL Institute of Archaeology) and his team to re-excavate them, allowing various analytical methods to be applied.’

Story Source:

Materials provided by University of OxfordNote: Content may be edited for style and length.


Journal Reference:

  1. Christophe Snoeck, John Pouncett, Philippe Claeys, Steven Goderis, Nadine Mattielli, Mike Parker Pearson, Christie Willis, Antoine Zazzo, Julia A. Lee-Thorp, Rick J. Schulting. Strontium isotope analysis on cremated human remains from Stonehenge support links with west WalesScientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-28969-8

 

Source: University of Oxford. “New light shed on the people who built Stonehenge.” ScienceDaily. ScienceDaily, 2 August 2018. <www.sciencedaily.com/releases/2018/08/180802102414.htm>.

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Date:
August 1, 2018

Source:
Monash University

Summary:
If people cannot adapt to future climate temperatures, deaths caused by severe heatwaves will increase dramatically in tropical and subtropical regions, followed closely by Australia, Europe and the United States, a global new study shows.

 

Future heatwaves are expected to become more frequent, more intense and longer-lasting.
Credit: © nnudoo / Fotolia

 

 

If people cannot adapt to future climate temperatures, deaths caused by severe heatwaves will increase dramatically in tropical and subtropical regions, followed closely by Australia, Europe and the United States, a global new Monash-led study shows.

Published today in PLOS Medicine, it is the first global study to predict future heatwave-related deaths and aims to help decision makers in planning adaptation and mitigation strategies for climate change.

Researchers developed a model to estimate the number of deaths related to heatwaves in 412 communities across 20 countries for the period of 2031 to 2080.

The study projected excess mortality in relation to heatwaves in the future under different scenarios characterised by levels of greenhouse gas emissions, preparedness and adaption strategies and population density across these regions.

Study lead and Monash Associate Professor Yuming Guo said the recent media reports detailing deadly heatwaves around the world highlight the importance of the heatwave study.

“Future heatwaves in particular will be more frequent, more intense and will last much longer,” Associate Professor Guo said.

“If we cannot find a way to mitigate the climate change (reduce the heatwave days) and help people adapt to heatwaves, there will be a big increase of heatwave-related deaths in the future, particularly in the poor countries located around the equator.”

A key finding of the study shows that under the extreme scenario, there will be a 471 per cent increase in deaths caused by heatwaves in three Australian cities (Brisbane, Sydney and Melbourne) in comparison with the period 1971-2010.

“If the Australia government cannot put effort into reducing the impacts of heatwaves, more people will die because of heatwaves in the future,” Associate Professor Guo said.

The study comes as many countries around the world have been affected by severe heatwaves, leaving thousands dead and tens of thousands more suffering from heatstroke-related illnesses. The collective death toll across India, Greece, Japan and Canada continues to rise as the regions swelter through record temperatures, humidity, and wildfires. Associate Professor Antonio Gasparrini, from the London School of Hygiene & Tropical Medicine and study co-author, said since the turn of the century, it’s thought heatwaves have been responsible for tens of thousands of deaths, including regions of Europe and Russia.

“Worryingly, research shows that is it highly likely that there will be an increase in their frequency and severity under a changing climate, however, evidence about the impacts on mortality at a global scale is limited,” Associate Professor Gasparrini said.

“This research, the largest epidemiological study on the projected impacts of heatwaves under global warming, suggests it could dramatically increase heatwave-related mortality, especially in highly-populated tropical and sub-tropical countries. The good news is that if we mitigate greenhouse gas emissions under scenarios that comply with the Paris Agreement, then the projected impact will be much reduced.”

Associate Professor Gasparrini said he hoped the study’s projections would support decision makes in planning crucial adaptation and mitigation strategies for climate change.

In order to prevent mass population death due to increasingly severe heatwaves, the study recommends the following six adaption interventions, particularly significant for developing countries and tropical and subtropical regions:

  • Individual: information provision, adverting
  • Interpersonal: Information sharing; communication; persuasive arguments; counselling; peer education
  • Community: Strengthening community infrastructure; encouraging community engagement; developing vulnerable people group; livelihoods; neighbourhood watch
  • Institutional: Institutional policies; quality standards; formal procedures and regulations; partnership working
  • Environmental: Urban planning and management; built environment; planting trees; public available drink water; house quality
  • Public policy: Improvement of health services; poverty reduction; redistribution of resources; education; heatwave-warning system.

Story Source:

Materials provided by Monash UniversityNote: Content may be edited for style and length.


Journal Reference:

  1. Yuming Guo, Antonio Gasparrini, Shanshan Li, Francesco Sera, Ana Maria Vicedo-Cabrera, Micheline de Sousa Zanotti Stagliorio Coelho, Paulo Hilario Nascimento Saldiva, Eric Lavigne, Benjawan Tawatsupa, Kornwipa Punnasiri, Ala Overcenco, Patricia Matus Correa, Nicolas Valdes Ortega, Haidong Kan, Samuel Osorio, Jouni J. K. Jaakkola, Niilo R. I. Ryti, Patrick G. Goodman, Ariana Zeka, Paola Michelozzi, Matteo Scortichini, Masahiro Hashizume, Yasushi Honda, Xerxes Seposo, Ho Kim, Aurelio Tobias, Carmen Íñiguez, Bertil Forsberg, Daniel Oudin Åström, Yue Leon Guo, Bing-Yu Chen, Antonella Zanobetti, Joel Schwartz, Tran Ngoc Dang, Dung Do Van, Michelle L. Bell, Ben Armstrong, Kristie L. Ebi, Shilu Tong. Quantifying excess deaths related to heatwaves under climate change scenarios: A multicountry time series modelling studyPLOS Medicine, 2018; 15 (7): e1002629 DOI: 10.1371/journal.pmed.1002629

 

Source: Monash University. “Heatwave deaths will rise steadily by 2080 as globe warms up.” ScienceDaily. ScienceDaily, 1 August 2018. <www.sciencedaily.com/releases/2018/08/180801093636.htm>.

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The research advances search for compounds that may someday accelerate wound healing and reverse balding

Date:
July 30, 2018

Source:
Johns Hopkins Medicine

Summary:
In a series of experiments with mice, investigators have used an experimental compound to successfully reverse hair loss, hair whitening and skin inflammation linked by previous studies to human diets heavy in fat and cholesterol.

 

Balding man.
Credit: © Aisylu / Fotolia

 

 

In a series of experiments with mice, Johns Hopkins investigators have used an experimental compound to successfully reverse hair loss, hair whitening and skin inflammation linked by previous studies to human diets heavy in fat and cholesterol.

The investigators say the compound halts the production of certain fats called glycosphingolipids, or GSLs, that are major components of skin and other cell membranes. Current research shows that mice fed a diet high in fat and cholesterol are more likely to have hair discoloration from black to gray to white, extensive hair loss and inflammation of skin exhibited by multiple wounds. Feeding these animals the compound, however, appears to reverse such symptoms.

The Hopkins investigators caution that such results in mice do not mean that the same effects would occur in people, and there is no evidence at this time that the compounds they used would be safe in people. But the findings, they say, do shed light on possible pathways for addressing hair loss and skin wounds in humans with oral or topical medications.

A report on the findings was published July 30 in Scientific Reports.

“Further research is needed, but our findings show promise for someday using the drug we developed for skin diseases such as psoriasis, and wounds resulting from diabetes or plastic surgery,” says Subroto Chatterjee, Ph.D., M.S., M.Sc., professor of pediatrics and medicine at the Johns Hopkins University School of Medicine. Chatterjee conducts research as part of Johns Hopkins Children’s Center.

More specifically, previous studies showed that GSLs are prevalent in the cells that make up the uppermost layer of the skin, as well as in cells called keratinocytes that help regulate pigmentation of the eyes, skin and hair.

To determine how disrupting GSLs might affect skin appearance and color, and whether treatment with D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) — a human-made compound that halts GSL production — would reverse any negative effects, Chatterjee and his colleagues first genetically modified a group of mice to have atherosclerosis, a disease in which arteries are clogged by fat deposits.

The researchers then fed one group of these mice a Western diet high in fat and cholesterol, and a second group standard chow. All mice were fed their assigned diets from 12 weeks of age to 20 weeks.

Compared to those fed standard chow, the mice that ate a Western diet lost hair, formed skin lesions and suffered from hair whitening. These results became more severe when the mice continued eating a Western diet for 36 weeks, with 75 percent of the mice having skin, hair loss and multiple skin lesions.

From 20 to 36 weeks of age, mice in both groups were given varying amounts of D-PDMP, either in a capsule or as a liquid, while they ate the same diet. Mice that received 1 milligram and 10 milligrams of D-PDMP in a capsule per kilogram of body weight from 20 to 36 weeks while eating a Western diet started regaining hair and hair color, and their skin inflammation lessened. Treatment with 1 milligram of D-PDMP in a capsule per kilogram of body weight was as effective as 10 milligrams per kilogram as a liquid. This suggests that an encapsulated form of D-PDMP is a better method of drug delivery.

The research team then looked at the skin of the mice’s under a microscope and found that mice eating the Western diet experienced an infiltration of neutrophils, a type of white blood cell implicated in inflammation, in various skin areas. Treatment with D-PDMP in a capsule significantly reduced the number of neutrophils, implying reduced skin inflammation and wounding.

Next, the researchers used mass spectrometry analysis, a method of identifying and quantifying the chemical composition of a mixture, to determine ceramide, glucosylceramide and lactosylceramide levels in the mice. Ceramides are a type of lipid, or fat, that helps protect the skin’s moisture, and glucosylceramide is the first derivative of ceramide, whereas lactosylceramide, a later derivative of ceramide, activates inflammation.

Compared to mice fed normal chow, those fed a Western diet had decreased total ceramide levels, decreased glucosylceramide and nearly three times more lactosylceramide. Treatment with 1 milligram of D-PDMP in a capsule per kilogram of body weight or 10 milligrams of D-PDMP as a liquid per kilogram of body weight, however, noticeably increased ceramide levels to normal.

“Our findings show that a Western diet causes hair loss, hair whitening and skin inflammation in mice, and we believe a similar process occurs in men who lose hair and experience hair whitening when they eat a diet high in fat and cholesterol,” says Chatterjee.

More animal research needs to be done to confirm and expand on the findings, and to determine how well and what amount of D-PDMP might heal wounds and activate hair growth.

“Hopefully someday in the future this can mean faster, more effective recovery from baldness, hair whitening in aging populations and wound healing,” says Chatterjee.

Other authors on this paper include Djahida Bedja, Wenwen Yan, Dominica Iocca, Veera Ratnam Bandaru and Nickesh Ramakrishnan of the Johns Hopkins University School of Medicine, and Wenwen Yan of Tongji University.

This study was funded by the National Institutes of Health (PO1HL10715301).

Story Source:

Materials provided by Johns Hopkins MedicineNote: Content may be edited for style and length.


Journal Reference:

  1. Djahida Bedja, Wenwen Yan, Viren Lad, Domenica Iocco, Nickash Sivakumar, Veera Venkata Ratnam Bandaru, Subroto Chatterjee. Inhibition of glycosphingolipid synthesis reverses skin inflammation and hair loss in ApoE−/− mice fed western dietScientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-28663-9

 

Source: Johns Hopkins Medicine. “Experimental drug reverses hair loss and skin damage linked to fatty diet, shows new study in mice: The research advances search for compounds that may someday accelerate wound healing and reverse balding.” ScienceDaily. ScienceDaily, 30 July 2018. <www.sciencedaily.com/releases/2018/07/180730090152.htm>.

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Date:
July 30, 2018

Source:
University of Cologne

Summary:
Observations made with ESO’s Very Large Telescope have for the first time clearly revealed the effects of Einstein’s general relativity on the motion of a star passing through the extreme gravitational field very close to the supermassive black hole in the center of the Milky Way. This long-sought result represents the climax of a 26-year-long observation campaign using ESO’s telescopes in Chile.

 

Observations made with ESO’s Very Large Telescope have for the first time revealed the effects predicted by Einstein’s general relativity on the motion of a star passing through the extreme gravitational field near the supermassive black hole in the center of the Milky Way. This long-sought result represents the climax of a 26-year-long observation campaign using ESO’s telescopes in Chile.
Credit: European Space Observatory

 

 

Obscured by thick clouds of absorbing dust, the closest supermassive black hole to the Earth lies 26,000 light years away at the centre of the Milky Way. This gravity monster, which has a mass four million times that of the Sun, is surrounded by a small group of stars orbiting at high speed. This extreme environment — the strongest gravitational field in our galaxy — makes it the perfect place to test gravitational physics, particularly Einstein’s general theory of relativity.

New infrared observations from the exquisitely sensitive GRAVITY, NACO and SINFONI instruments on ESO’s Very Large Telescope (VLT) have now allowed astronomers to follow one of these stars, called S2, as it passed very close to the black hole during May 2018 at a speed in excess of 25 million kilometres per hour — three percent of the speed of light — and at a distance of less than 20 billion kilometres.

These extremely delicate measurements were made by an international team led by Reinhard Genzel of the Max Planck Institute for extraterrestrial physics (MPE) in Garching, Germany, in conjunction with collaborators around the world. The observations form the culmination of a 26-year series of ever more precise observations of the centre of the Milky Way using ESO instruments. ‘This is the second time that we have observed the close passage of S2 around the black hole in our galactic centre. But this time, because of much improved instrumentation, we were able to observe the star with unprecedented resolution’, explains Genzel. ‘We have been preparing intensely for this event over several years, as we wanted to make the most of this unique opportunity to observe general relativistic effects.’

The new measurements clearly reveal an effect called gravitational redshift. Light from the star is stretched to longer wavelengths by the very strong gravitational field of the black hole. And the stretch in wavelength of light from S2 agrees precisely with that predicted by Einstein’s theory of general relativity. This is the first time that this deviation from the predictions of simpler Newtonian gravity has been observed in the motion of a star around a supermassive black hole. The team used SINFONI to measure the motion of S2 towards and away from Earth and the GRAVITY interferometric instrument to make extraordinarily precise measurements of the position of S2 in order to define the shape of its orbit. GRAVITY creates such sharp images that it can reveal the motion of the star from night to night as it passes close to the black hole — 26,000 light years from Earth.

‘Our first observations of S2, about two years ago, already showed that we would have the ideal black hole laboratory’, adds Frank Eisenhauer (MPE), Co-Principal Investigator of the GRAVITY instrument. ‘During the close passage, we managed not only to precisely follow the star on its orbit, we could even detect the faint glow around the black hole on most of the images.’ By combining the position and velocity measurements from SINFONI and GRAVITY, as well as previous observations using other instruments, the team could compare them to the predictions of Newtonian gravity, general relativity and other theories of gravity. As expected, the new results are inconsistent with Newtonian predictions and in excellent agreement with the predictions of general relativity. More than one hundred years after he published his paper setting out the equations of general relativity, Einstein has been proved right once more.

The hardware contribution of the Institute of Physics I of the University of Cologne was the development and construction of the two spectrometers of GRAVITY. The spectrometers analyse the wavelength of the observed stellar light and convert the received photons into electronic signals. ‘GRAVITY is a technological challenge. However, after more than two decades of astrophysical research on the high velocity stars in the Galactic Centre and on the development of astronomical instrumentation, the effort has been rewarded with an excellent result in experimental physics’, says Andreas Eckhart from the University of Cologne.

Continuing observations are expected to reveal another relativistic effect later in the year — a small rotation of the star’s orbit, known as Schwarzschild precession — as S2 moves away from the black hole.

Story Source:

Materials provided by University of CologneNote: Content may be edited for style and length.


Journal Reference:

  1. R. Abuter, A. Amorim, N. Anugu, M. Bauböck, M. Benisty, J. P. Berger, N. Blind, H. Bonnet, W. Brandner, A. Buron, C. Collin, F. Chapron, Y. Clénet, V. Coudé du Foresto, P. T. de Zeeuw, C. Deen, F. Delplancke-Ströbele, R. Dembet, J. Dexter, G. Duvert, A. Eckart, F. Eisenhauer, G. Finger, N. M. Förster Schreiber, P. Fédou, P. Garcia, R. Garcia Lopez, F. Gao, E. Gendron, R. Genzel, S. Gillessen, P. Gordo, M. Habibi, X. Haubois, M. Haug, F. Haußmann, Th. Henning, S. Hippler, M. Horrobin, Z. Hubert, N. Hubin, A. Jimenez Rosales, L. Jochum, L. Jocou, A. Kaufer, S. Kellner, S. Kendrew, P. Kervella, Y. Kok, M. Kulas, S. Lacour, V. Lapeyrère, B. Lazareff, J.-B. Le Bouquin, P. Léna, M. Lippa, R. Lenzen, A. Mérand, E. Müler, U. Neumann, T. Ott, L. Palanca, T. Paumard, L. Pasquini, K. Perraut, G. Perrin, O. Pfuhl, P. M. Plewa, S. Rabien, A. Ramírez, J. Ramos, C. Rau, G. Rodríguez-Coira, R.-R. Rohloff, G. Rousset, J. Sanchez-Bermudez, S. Scheithauer, M. Schöller, N. Schuler, J. Spyromilio, O. Straub, C. Straubmeier, E. Sturm, L. J. Tacconi, K. R. W. Tristram, F. Vincent, S. von Fellenberg, I. Wank, I. Waisberg, F. Widmann, E. Wieprecht, M. Wiest, E. Wiezorrek, J. Woillez, S. Yazici, D. Ziegler, G. Zins. Detection of the gravitational redshift in the orbit of the star S2 near the Galactic centre massive black holeAstronomy & Astrophysics, 2018; 615: L15 DOI: 10.1051/0004-6361/201833718

 

Source: University of Cologne. “Einstein’s general relativity confirmed near black hole.” ScienceDaily. ScienceDaily, 30 July 2018. <www.sciencedaily.com/releases/2018/07/180730090158.htm>.

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Target Health’s Mary Shatzoff on FDA Panel

 

At the invitation of Office of Antimicrobial Products (CDER), Mary Shatzoff, Senior Director of Regulatory Affairs at Target Health, will be a speaker at the FDA workshop entitled: “Development of Non-Traditional Therapies for Bacterial Infections.” The purpose of this public workshop is to discuss the general development considerations of non-traditional therapies, including pre-clinical development, early clinical studies, and the design and evaluation of safety and efficacy in phase 3 clinical trials. This workshop will be held on August 21, 2018 from 8:30 to 4:30, and on August 22, 2018 from 8:30 to 12. This public workshop will also be available via a webcast.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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Circadian Rhythms

Overview of biological circadian clock in humans. Biological clock affects the daily rhythm of many physiological processes. This diagram depicts the circadian patterns typical of someone who rises early in morning, eats lunch around noon, and sleeps at night (10 p.m.). Although circadian rhythms tend to be synchronized with cycles of light and dark, other factors – such as ambient temperature, meal times, stress and exercise – can influence the timing as well.

 

Graphic credit: NoNameGYassineMrabetTalk fixed by Addicted04 – The work was done with Inkscape by YassineMrabet. Informations were provided from “The Body Clock Guide to Better Health“ by Michael Smolensky and Lynne Lamberg; Henry Holt and Company, Publishers (2000). Landscape was sampled from Open Clip Art Library (Ryan, Public domain). Vitruvian Man and the clock were sampled from Image:P human body.svg (GNU licence) and Image:Nuvola apps clock.png, respectively., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3017148

 

 

A circadian rhythm is any biological process that displays an endogenous, entrainable oscillation of about 24 1) ___. These 24-hour rhythms are driven by a circadian clock, and they have been widely observed in plants, animals, fungi, and cyanobacteria. The term circadian comes from the Latin circa, meaning “around“ (or “approximately“), and diem, meaning 2) ___. The formal study of biological temporal rhythms, such as daily, tidal, weekly, seasonal, and annual rhythms, is called chronobiology. Processes with 24-hour oscillations are more generally called diurnal rhythms; strictly speaking, they should not be called circadian rhythms unless their endogenous nature is confirmed. Although circadian rhythms are endogenous (“built-in“, self-sustained), they are adjusted (entrained) to the local environment by external cues called zeitgebers (from German, “time giver“), which include light, temperature and redox cycles. In medical science, an abnormal circadian rhythm in humans is known as circadian3) ___ disorder.

 

To produce the near 24 h rhythm in mammals requires a complex mechanism involving clock genes, clock proteins, phosphorylation of proteins, dimerization of proteins and subsequent degradation, and nuclear receptors. An internal 4) ___ also allows the multiple biochemical and physiological rhythms within the body to be aligned appropriately to each other. The activity of organs such as the stomach, liver, small intestine and pancreas and the blood supply to these organs need internal synchronization, and a clock can provide this co-ordination. To date, up to 20 genes and their protein products have been linked to the generation of circadian rhythms. At the heart of the molecular clock is a negative feedback loop, which in a very simplified description consists of the following sequence of events: clock genes are transcribed and their mRNAs are translated into proteins; the 5) ___ interact to form complexes, which move from the cytoplasm into the nucleus, where the transcription of the clock genes is inhibited; the inhibitory clock protein complexes are then degraded, and the core clock genes are once more free to make their mRNA and hence fresh protein, and so the cycle continues. This negative feedback loop generates a near 24 h rhythm of protein production and degradation, which encodes the biological day.

 

Although chronobiologists commonly study rhythms in constant conditions, organisms live in the cycling world of day and night. The two chief entraining stimuli that synchronize the endogenous clock with the exogenous temporal environment are 6) ___ and temperature. With the cloning of the Drosophila per gene, which encodes a novel protein of unknown function, the central question in clock research immediately became, “how can this gene product generate a circadian rhythm?“ Negative feedback loops had been suspected to underlie the circadian clock, and several observations on per suggested that it might fit into such a loop. per mRNA abundance showed a circadian oscillation that was followed, with a lag of ~4 h, by oscillations in PER protein. As PER protein accumulated, per mRNA declined in abundance. This suggested a simple autoregulatory negative feedback 7) ___: the clock gene is transcribed and the transcript is translated into a protein that accumulates in the nucleus to inhibit further transcription. Degradation of both mRNA and protein relieves this inhibition, and the cycle renews. This simple model has largely withstood the test of time, although it has increased in complexity.

 

There are at least two interlocked feedback loops that include both positive and negative feedback. Positive components promote the transcription of negative components, and negative components play a dual role, blocking their own expression as well as increasing the expression of positive components, which interlocks the loops to create a robust sustained oscillation. This paradigm of interlocked transcriptional/translational feedback loops underpins the molecular mechanisms of the circadian clock in all eukaryotes studied to date. However, the combination of components recruited to form the clock varies among organisms; the fungal clock is quite distinct from the animal clock, although fly and mouse clocks are fairly similar. It is also clear that cyanobacteria provide a stunning exception to the essential ubiquity of transcriptional regulation in clock function, as a temperature-compensated circadian rhythm can be reconstituted in vitro with three Synechococcus proteins and ATP. Although we can safely conclude that the paradigm of interlocked feedback loops constituting a circadian oscillator is conserved in plants, not all the components have yet been identified, and the mechanistic details of almost every step are only incompletely understood. After so much effort and progress, almost all questions remain only incompletely answered and, effectively, all questions remain! Moreover, the field is now expanding its view from the purely reductionist goal of identifying the oscillator itself to a consideration of the evolutionary and ecological consequences of variation in clock function, so a host of new questions are being considered. It is exhilarating to consider what a retrospective view a decade from now will reveal.

 

Oxidative stress seems to have a circadian rhythm connection. The toxic effects of oxygen were first appreciated in 1954 with Gershman’s free-radical theory, suggesting that oxygen toxicity may happen due to partially reduced forms of oxygen. Commoner et al., in the same year, suggested the presence of free radicals in a variety of biological materials. These new ideas triggered a surge of scientific research into the idea that although a necessary part of life, oxygen may not always be beneficial. The cell has evolved an intricate web of energy synthesis and signaling mechanisms that are dependent on oxygen and its more reactive forms, reactive oxygen species (ROS). Intense research has been done on ROS, their beneficial and detrimental effects on the organism, as well as the efforts mounted by the cell to counteract them. Interestingly, many of these efforts, including the production of antioxidants and protective enzymes, have been reported to be regulated by a biological clock or expressed in rhythmic fashions. The circadian clock system confers daily anticipatory physiological processes with the ability to be reset by environmental cues. This “circadian adaptation system“ (CAS), driven by cell-autonomous molecular clocks, orchestrates various rhythmic physiological processes in the entire 8) ___. Hence, the dysfunction of these clocks exacerbates various diseases, which may partially be due to the impairment of protective pathways. If this is the case, how does the CAS respond to cell injury stresses that are critical in maintaining health and life by evoking protective pathways?

 

A short nap during the day does not affect circadian rhythms. Timing of medical treatment in coordination with the body clock, chronotherapeutics, may significantly increase efficacy and reduce drug toxicity or adverse reactions. A number of studies have concluded that a short period of sleep during the day, a power-nap, does not have any measurable effect on normal circadian rhythms but can decrease stress and improve productivity.

 

Health problems can result from a disturbance to the circadian rhythm. 9) ___ rhythms also play a part in the reticular activating system, which is crucial for maintaining a state of consciousness. A reversal in the sleep – wake cycle may be a sign or complication of uremia, azotemia or acute renal failure. Studies have shown that light has a direct effect on human health because of the way it influences the circadian rhythms. A great deal more research is needed to determine the interactions between biological clocks, human health and disease.

 

In 2017, the Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm“ in fruit 10) ___.

 

ANSWERS: 1) hours; 2) “day”; 3) rhythm; 4) clock; 5) proteins; 6) light; 7) loop; 8) body; 9) Circadian; 10) flies

 

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The Biological Clock

A mosaic of Hippocrates on the floor of the Asclepieion of Kos, with Asklepius in the middle, 2nd-3rd century.Photo credit: This file is licensed under the Creative Commons Attribution-Share Alike 2.5 Generic license. Wikipedia Commons

 

 

Hippocratic medicine was humble and passive. The therapeutic approach was based on the healing power of nature. “If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health”. Hippocrates, 460 BCE.

 

The earth rotates on its axis every 24 hours, with the result that any position on the earth’s surface alternately faces toward or away from the sun -day and night. That the metabolism, physiology, and behavior of most organisms changes profoundly between day and night is obvious to even the most casual observer. These biological oscillations are apparent as diurnal rhythms. It is less obvious that most organisms have the innate ability to measure time. Indeed, most organisms do not simply respond to sunrise but, rather, anticipate the dawn and adjust their biology accordingly. When deprived of exogenous time cues, many of these diurnal rhythms persist, indicating their generation by an endogenous biological circadian clock. Until recently, the molecular mechanisms by which organisms functioned in this fourth dimension, time, remained mysterious. However, over the last 30 or so years, the powerful approaches of molecular genetics have revealed the molecular underpinnings of a cellular circadian clockwork as complicated and as beautiful as the wonderful chronometers developed in the 18th century.

 

CHARACTERISTICS OF CIRCADIAN RHYTHMS

 

Circadian rhythms are the subset of biological rhythms with period, defined as the time to complete one cycle of~24 hours. This defining characteristic inspired Franz Halberg in 1959 to coin the term circadian, from the Latin words “circa“ (about) and “dies“ (day). A second defining attribute of circadian rhythms is that they are endogenously generated and self-sustaining, so they persist under constant environmental conditions, typically constant light (or dark) and constant temperature. Under these controlled conditions, the organism is deprived of external time cues, and the free-running period of ~24 h is observed. A third characteristic of all circadian rhythms is temperature compensation; the period remains relatively constant over a range of ambient temperatures. This is thought to be one facet of a general mechanism that buffers the clock against changes in cellular metabolism.

 

The first writings, at least in the western canon, to recognize diurnal rhythms come from the fourth century BCE. Androsthenes described the observation of daily leaf movements of the tamarind tree, Tamarindus indicus, that were observed on the island of Tylos (now Bahrein) in the Persian Gulf during the marches of Alexander the Great. There was no suggestion that the endogenous origin of these rhythms was suspected at the time, and it took more than two millennia for this to be experimentally tested. The scientific literature on circadian rhythms began in 1729 when the French astronomer de Mairan reported that the daily leaf movements of the sensitive heliotrope plant (probably Mimosa pudica) persisted in constant darkness, demonstrating their endogenous origin. Presciently, de Mairan suggested that these rhythms were related to the sleep rhythms of bedridden humans. It took 30 years before de Mairan’s observations were independently repeated. These studies excluded temperature variation as a possible zeitgeber driving the leaf movement rhythms.

 

The observation of a circadian or diurnal process in humans is mentioned in Chinese medical texts dated to around the 13th century, including the Noon and Midnight Manual and the Mnemonic Rhyme to Aid in the Selection of Acu-points According to the Diurnal Cycle, the Day of the Month and the Season of the Year. As early as 1880, Charles and Francis Darwin suggested the heritability of circadian rhythms, as opposed to the imprinting of a 24-hour period by exposure to diurnal cycles during development. This was initially explored in the 1930s by two strategies. In one, plants or animals were raised in constant conditions for multiple generations. One of the most grueling among such studies demonstrated the retention of stable rhythms among fruit flies reared in constant conditions for 700 generations. In a second strategy, seedlings or animals were exposed to cycles that differed from 24 hour in an effort to imprint novel periods; such studies could sometimes impose the novel period length during the novel cycles, but upon release into continuous conditions, the endogenous circadian period was restored. The inheritance of period length among progeny from crosses of parents with distinct period lengths was first reported in Phaseolus; hybrids had period length intermediates between those of the parents. In 1896, Patrick and Gilbert observed that during a prolonged period of sleep deprivation, sleepiness increases and decreases with a period of approximately 24 hours. In 1918, J.S. Szymanski showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature. In the early 20th century, circadian rhythms were noticed in the rhythmic feeding times of bees. Extensive experiments were done by Auguste Forel, Ingeborg Beling, and Oskar Wahl to see whether this rhythm was due to an endogenous clock. The existence of circadian rhythm was independently discovered in the fruit fly Drosophila melanogaster in 1935 by two German zoologists, Hans Kalmus and Erwin Bunning.In 1954, an important experiment was reported by Colin Pittendrigh who showed that eclosion (the process of pupa turning into adult) in D. pseudoobscura was a circadian behavior. He demonstrated that temperature played a vital role in eclosion rhythm, the period of eclosion was delayed but not stopped when temperature was decreased. It was an indication that circadian rhythm was controlled by an internal biological clock. The term circadian was coined by Franz Halberg in 1959. Genetic analysis identifying components of circadian clocks began in the 1970s. Although now it seems axiomatic that circadian clocks are composed of the products of genes, just how this might be so was the source of considerable controversy. It was argued that forward genetic efforts would be fruitless because clocks were sufficiently complex to reasonably be expected to exhibit polygenic inheritance and would not yield easily to standard genetic approaches. However, mutations conferring altered period length were identified and characterized in the fruit fly Drosophila melanogaster, the green alga Chlamydomonas reinhardtii, and the filamentous fungus N. crassa. It took more than a decade to clone the first clock gene, the Drosophila period (per) gene, and another 5 years to clone the second, the Neurospora frequency gene. However, the decade of the 1990s saw rapid progress toward the identification of clock components and the elucidation of oscillator mechanisms central to the circadian clock in a number of organisms, most notably Drosophila, Neurospora, and mice.

 

Ron Konopka and Seymour Benzer identified the first clock mutant in Drosophila in 1971 and called it “period“ (per) gene, the first discovered genetic determinant of behavioral rhythmicity per gene was isolated in 1984 by two teams of researchers. In 1977, the International Committee on Nomenclature of the International Society for Chronobiology formally adopted the definition, which states:

 

Circadian: relating to biologic variations or rhythms with a frequency of 1 cycle in 24 + 4 h; circa (about, approximately) and dies (day or 24 h). Note: term describes rhythms with an about 24-h cycle length, whether they are frequency-synchronized with (acceptable) or are desynchronized or free-running from the local environmental time scale, with periods of slightly yet consistently different from 24-h.

 

Joseph Takahashi discovered the first mammalian circadian clock mutation using mice in 1994. However, recent studies show that deletion of clock does not lead to a behavioral phenotype (the animals still have normal circadian rhythms), which questions its importance in rhythm generation. Konopka, Jeffrey Hall, Michael Roshbash and their team showed that per locus is the center of the circadian rhythm, and that loss of per stops circadian activity. At the same time, Michael W. Young’s team reported similar effects of per, and that the gene covers 7.1-kilobase (kb) interval on the X chromosome and encodes a 4.5-kb poly(A)+ RNA. They went on to discover the key genes and neurones in Drosophila circadian system, for which Hall, Rosbash and Young received the Nobel Prize in Physiology or Medicine 2017. Sources: nih.gov; Wikipedia

 

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Protein Affected By Rare Parkinson’s Mutation May Lurk Behind Many Cases

 

Parkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopamine-producing (“dopaminergic“) neurons in a specific area of the brain called substantia nigra. Symptoms generally develop slowly over years. The progression of symptoms is often a bit different from one person to another due to the diversity of the disease. People with PD may experience: tremor (mainly at rest and described as pill rolling tremor in hands), bradykinesia (slowness of movement), limb rigidity, and gait/balance problems.

 

Mutations in the gene LRRK2 have been linked to about 3% of PD cases. Now, according to an article published in Science Translational Medicine (25 July 2018), evidence has been found that the activity of LRRK2 protein might be affected in many more patients with PD, even when the LRRK2 gene itself is not mutated. More than 10 years ago, researchers linked mutations in the LRRK2 gene with an increased risk for developing PD. The observed mutations produce a version of LRRK2 protein that behaves abnormally and is much more active than it would be normally. Despite its importance in PD, the very small amount of normal LRRK2 protein in nerve cells made it difficult to study. In the current study, the authors developed a new method for observing LRRK2 cells that made them glow fluorescently only when LRRK2 was in its activated state. The authors also used detection of fluorescent signals to demonstrate loss of binding of an inhibitor protein to LRRK2 when LRRK2 was activated.

 

For the study, the authors looked first at postmortem brain tissue from PD patients who did not have mutations in LRRK2. Compared to healthy individuals of similar ages, there was a striking increase in LRRK2 activity in the dopamine-containing neurons of the substantia nigra, the area of the brain most affected in PD. This suggested that increased LRRK2 activity could be a common feature of the disease. To get a closer look at how LRRK2 activity is related to Parkinson’s disease. The authors next turned to rodent models of the disorder. The sensitivity of their new technique allowed for the direct study of LRRK2 activity, which until now could not be done. By injecting rodents with the environmental toxin rotenone and studying the effect on LRRK2, the authors linked increased LRRK2 activity with the accumulation of alpha-synuclein, a process that leads to the formation of Lewy bodies in the brain, a hallmark of Parkinson’s disease. In another model of the disease, where synuclein was present in much higher amounts than normal, LRRK2 activity was increased. In contrast, when the animals were treated with a drug that blocks LRRK2 activity, the accumulation of alpha-synuclein and Lewy body formation were both prevented. Finally, additional links were found between LRRK2 activity and the potentially damaging consequences of PD. The authors also observed that reactive oxygen species (ROS), compounds that can interact and affect other components within cells, were increased in the brains of both rodent models. ROS were seen to increase the activity of LRRK2, and when ROS production was blocked, LRRK2 activation was not observed.

 

According to the authors, the findings suggest that both genetic and environmental causes of PD can be tied back to the activity of LRRK2 protein. The authors added that this is important, because it suggests that the drugs being developed for patients with the LRRK2 mutation, which represent a very small percentage of the affected population, could benefit a much greater number of people with the disease.

 

More Information:

 

PD Information Page

Patient and Caregiver Information

NINDS NIH

 

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